Research ArticleDevelopment and Characterization ofNovel Floating-Mucoadhesive Tablets BearingVenlafaxine Hydrochloride

Raghvendra Misra1 and Peeyush Bhardwaj2

1Department of Pharmacy Vivek College of Technical Education Uttar Pradesh 246701 India2Institute of Pharmacy Bundelkhand University Jhansi Uttar Pradesh 284128 India

Correspondence should be addressed to Peeyush Bhardwaj meet2peeyushgmailcom

Received 31 December 2015 Revised 15 March 2016 Accepted 29 March 2016

Academic Editor Paul O Gubbins

Copyright copy 2016 R Misra and P Bhardwaj This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

The present investigation is concerned about the development of floating bioadhesive drug delivery system of venlafaxinehydrochloride which after oral administration exhibits a unique combination of floating and bioadhesion to prolong gastricresidence time and increase drug bioavailability within the stomach The floating bioadhesive tablets were prepared by the wetgranulationmethod using different ratios of hydroxypropyl methyl cellulose (HPMCK4MCR) and Carbopol 934PNF as polymersSodium bicarbonate (NaHCO

3) and citric acid were used as gas (CO

2) generating agents Tablets were characterized for floating

properties in vitro drug release detachment force and swelling index The concentration of hydroxypropyl methyl cellulose andCarbopol 934PNF significantly affects the in vitro drug release floating properties detachment force and swelling properties ofthe tablets The optimized formulation showed the floating lag time 72 plusmn 249 seconds and duration of floating 2450 plusmn 074 hrThe in vitro release studies and floating behavior were studied in simulated gastric fluid (SGF) at pH 12 Different drug releasekinetics models were also appliedThe in vitro drug release from tablets was sufficiently sustained (more than 18 hr) and the Fickiantransports of the drug from the tablets were confirmed The radiological evidence suggests that the tablets remained buoyant andaltered position in the stomach of albino rabbit and mean gastric residence time was prolonged (more than gt 6 hr)

1 Introduction

Depression is a chronic recurring and potentially life-threat-ening illness that affects up to 20 of the population acrossthe globe [1 2] This disease is one of the top ten causes ofmorbidity andmortalityworldwide and represents a high costto countryrsquos economy [2] Available therapy for depressiontreatment is often associated with several undesirable sideeffects and its effectiveness achieves only a certain portionof the population [3] Therefore the identification of thealternative therapeutic tools for the treatment of depressionis of high importance

Venlafaxine hydrochloride (plusmn)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride is ahighly water soluble and structurally novel antidepressant fororal administration It is a dual serotonin and norepinephrine

reuptake inhibitor (SNRI) It inhibits the serotonin trans-porter at 30-fold lower concentration than norepinephrinetransporter (Ki = 82 and 2480 nm) respectively [4] Itdisplays differential effects on norepinephrine reuptake inhealthy versus depressed patients [5] It is highly solublein 01 N HCl its solubility decreases with increasing pHover the physiological range Both venlafaxine and its activemetabolite ODV (O-desmethyl venlafaxine) have weakinhibitory effect on the reuptake of dopamine but unlike thetricyclics and similar to SSRIs (selective serotonin reuptakeinhibitors) they are not active in histaminergic muscarinicor alpha(1)-adrenergic receptors [6ndash9] The half-life of ven-lafaxine hydrochloride is 5 plusmn 2 hr necessitating the adminis-tration two or three times daily to maintain adequate plasmadrug concentration

Hindawi Publishing CorporationScientificaVolume 2016 Article ID 4282986 13 pageshttpdxdoiorg10115520164282986

2 Scientifica

Various attempts have been made to develop floatingsystem to control drug release among them is the socalled hydrodynamically balanced system (HBS) Floatingdrug delivery system (FDDS) or hydrodynamically balancedsystems (HBS) have a bulk density lower than the gastric fluidand thus remain buoyant in the stomach without affectingthe gastric emptying rate for a prolonged period of time[10] FDDS is suitable for those drugs which are havingan absorption window in the stomach or the upper smallintestine [11] for drugs which act locally in the stomach[12] and for drugs that are poorly soluble or unstable in theintestinal fluid [13] venlafaxine hydrochloride is one drugfrom the latter category

Floating dosage forms remain on the surface of gastricfluid because of its relatively lower density than that of gastricfluid Floating single unit dosage form also called hydro-dynamically balanced systems (HBS) has been extensivelystudied [14]

Mucoadhesive delivery systems were also proven to besuitable for reduction of transit time of the dosage formthrough the gastrointestinal tract Adhesiveness of the dosageform is based on the bioadhesive power of the polymerVarious synthetic as well as natural polymers have beenreported for this approach [15]

Venlafaxine hydrochloride is selected as a drug candidatefor this study as its bioavailability is low and half-life rangesin 5 plusmn 2 hr necessitating frequent administration to maintainthe adequate plasma level of drug

The present research endeavor involves development andcharacterization of newer floating-mucoadhesive tablets ofvenlafaxine hydrochloride using HPMC K4MCR and Car-bopol 934PNF and investigation of the combined effect ofthese polymers on the floating behavior and in vitro releasepattern of the drug Here the synergism effect of mucoad-hesion with floatation may increase the gastric retention ofdrug hence increasing its bioavailability

2 Materials and Methods

21 Materials Venlafaxine hydrochloride was a kind giftfromRanbaxy Research Lab Ltd (Gurgaon Haryana India)HPMCK4MCRwas obtained as a gift sample from ColorconAsia Pvt (Goa India) Carbopol 934PNF from ArihantTrading Co (Mumbai India) and lactose and magnesiumstearate were procured from Central Drug House (NewDelhi India) Sodium bicarbonate was obtained from SDFine-Chem Ltd (Mumbai India) All other reagents were ofanalytical grade which were used in preparation

22 Methodology Venlafaxine hydrochloride floating tabletswere prepared by the wet granulation method using hydrox-ypropyl methyl cellulose (HPMC K4MCR) Carbopol 934Plactose and sodium bicarbonate The compositions of differ-ent formulation codes of floating tablets are shown in Tables1ndash4

221 Preparation of Granules Granules were prepared bywet granulation method First of all the ingredients were

Table 1 Formulation for optimization of drug HPMC K4MCRratio

Ingredients (in mg) Formulation code (FC)FC1 FC2 FC3 FC4

Venlafaxine hydrochloride 4243 4243 4243 4243HPMC K4MCR 130 135 140 145Carbopol 934PNF 15 15 15 15Sodium bicarbonate 15 15 15 15Lactose 30 30 30 30Magnesium stearate 257 257 257 257Tablet Wt (mg) 235 240 245 250

Table 2 Formulation for optimization of drug Carbopol 934PNFratio

Ingredients (in mg) Formulation code (FC)FC3 FC5 FC6 FC7

Venlafaxine hydrochloride 4243 4243 4243 4243HPMC K4MCR 140 140 140 140Carbopol 934PNF 15 10 20 25Sodium bicarbonate 15 15 15 15Lactose 30 30 30 30Magnesium stearate 257 257 257 257Tablet Wt (mg) 245 240 250 255

Table 3 Formulation for optimization of drug sodium bicarbonateratio

Ingredients (in mg) Formulation code (FC)FC3 FC8 FC9 FC10

Venlafaxine hydrochloride 4243 4243 4243 4243HPMC K4MCR 140 140 140 140Carbopol 934PNF 15 15 15 15Sodium bicarbonate 15 20 25 30Lactose 30 30 30 30Magnesium stearate 257 257 257 257Tablet Wt (mg) 245 250 255 260

Table 4 Formulation for optimization of drug lactose ratio

Ingredients (in mg) Formulation code (FC)FC8 FC11 FC12 FC13

Venlafaxine hydrochloride 4243 4243 4243 4243HPMC K4MCR 140 140 140 140Carbopol 934PNF 15 15 15 15Sodium bicarbonate 20 20 20 20Lactose 30 20 40 50Magnesium stearate 257 257 257 257Tablet Wt (mg) 250 240 260 270

accurately weighed Then accurately weighed quantities ofvenlafaxine hydrochloride HPMC K4MCR lactose andsodium bicarbonate were mixed homogeneously using glass

Scientifica 3

Table 5 Comparative study of various granules characteristics

Formulation code Angle of repose (120579∘) Flow rate (gmsecond) Bulk density (gmcm3) Tapped density Carrrsquos indexFC1 2470 plusmn 182 118 plusmn 002 0672 plusmn 126 0826 plusmn 106 1864FC2 2598 plusmn 174 113 plusmn 017 0651 plusmn 028 0817 plusmn 102 2032FC3 2689 plusmn 102 098 plusmn 011 0681 plusmn 040 0887 plusmn 080 2322FC4 2812 plusmn 116 091 plusmn 013 0648 plusmn 016 0862 plusmn 050 2482FC5 3109 plusmn 082 110 plusmn 012 0624 plusmn 108 0801 plusmn 018 2210FC6 3147 plusmn 111 099 plusmn 009 0667 plusmn 030 0907 plusmn 120 2646FC7 3739 plusmn 173 095 plusmn 005 0662 plusmn 024 0901 plusmn 030 2653FC8 3215 plusmn 104 098 plusmn 003 0652 plusmn 101 0807 plusmn 108 1921FC9 2708 plusmn 132 107 plusmn 007 0664 plusmn 036 0823 plusmn 045 1932FC10 3007 plusmn 151 105 plusmn 019 0694 plusmn 050 0852 plusmn 016 1854FC11 3109 plusmn 086 121 plusmn 016 0701 plusmn 030 0905 plusmn 010 2254FC12 2606 plusmn 087 122 plusmn 010 0721 plusmn 018 0910 plusmn 123 2077FC13 2229 plusmn 085 120 plusmn 008 0736 plusmn 010 0899 plusmn 035 1813Mean plusmn SD 119899 = 3 FC formulation code

mortar and pestle The wet granulation was done withethanol (95) Wet mass was passed through a 40-meshscreen and dried in a hot air oven at 40∘C over night Thedried granules were sized through 4060 mesh and blendedwith Carbopol 934P and magnesium stearate (approximately1 ww) Lactose was used as filler and channeling agentSodium bicarbonate was used as a gas generating agent [16]

222 Evaluation of Granules Granules of different formula-tion codes are evaluated for angle of repose flow rate bulkdensity tapped density Carrrsquos index and so forth as per themethod described by Aulton [17] The angle of repose andflow rates were determined by the funnel method The bulkdensity and tapped density were obtained by the cylindermethod Consider

(angle of repose) 120579 = tanminus1 (ℎ119903) (1)

where 120579 is the angle of repose ℎ is height of the cone (or pileheight) and 119903 is radius of cone (or pile) or base radius

flow rate =weight of granulestime in seconds

bulk density (120588119887) =119908

119881119887

bulk density (120588119905) =119908

119881119905

(2)

where 119908 is weight of the sample in grams 119881119887is final bulk

volumes of granules in cm3 and 119881119905is final tapped volumes

of granules in cm3And Carrrsquos index of each formulation was calculated

according to the equation given below

Carrrsquos index ( compressibility) =120588119905minus 120588119887

120588119905

times 100 (3)

Experimental evaluations of granules are shown in Table 5

223 Preparation of Floating Tablet The homogeneouslylubricated granules with magnesium stearate (approximately1 ww) were then compressed into tablets using nine mmdiepunch set on a single punch tablet compression machine(Cadmach Machinery Ltd Ahmedabad India) Compres-sion force was adjusted to obtain tablets with hardness inthe range of 62ndash69 kgcm2 on a Monsanto tablet hardnesstester

224 Characterization of Floating Tablet Theprepared float-ing tablets were characterized for drug content uniformityof weight using 20 tablets hardness (a Monsanto hardnesstester) and friability (Roche type friabilator) The drug con-tent of the tablet was determined using 01 NHCl as a solventThe uniformity of drug content in each formulation wasdetermined by triturating 20 tablets and powder equivalentto average weight was added to 100mL of 01 N hydrochloricacid followed by stirring for 30 minutes [18] The solutionwas filtered through a Whatman filter paper number 41 anddiluted suitably and the absorbance of resultant solution wasmeasured using Double Beam UV spectrophotometer (Shi-madzu UV-1700 Japan) at 2250 nmusing 01 N hydrochloricacid as blank The average drug content is calculated

225 Floating Characteristics Floating characteristics of thetablets were studied at the temperature 37 plusmn 05∘C in 250mLof a 01 N HCl solution (pH = 12) (Figure 9) The timerequired for the tablet to rise to the surface of the solutionand to float was taken as the floating lag time The durationof time in which dosage form constantly remained on thesurface of the medium was considered as total floating time(Table 9)

226 In Vitro Dissolution Studies The in vitro dissolutionstudies of venlafaxine hydrochloride from floating tabletwere carried out using USP Dissolution Testing ApparatusII (Paddle Type) The dissolution test was performed using

4 Scientifica

900mL of 01 N HCl at 37 plusmn 05∘C at 75 rpm One mL ofthe aliquot was withdrawn from the dissolution apparatus atdifferent predetermined time intervals (1 2 3 4 5 6 8 1012 14 16 and 18 hours) and the samples were replaced withthe fresh dissolution medium Then the sample was filteredthrough the Whatman filter paper number 41 and analyzedat 225 nmusingUV Spectrophotometer (ShimadzuUV-1700Japan) Cumulative drug release was calculated using ldquoPCPDisso v208rdquo software

227 Mechanism of Drug Release The drug release mech-anism was determined by fitting the data to the variouskinetic equations such as zero-order first-order Higuchi andKorsmeyer-Peppas and finding the 119877 and 119899 values of therelease profile corresponding to each model

228 Swelling Properties (Hydration Behavior of MatrixTablets) The swelling of the polymer can be measured bytheir ability to absorb water and swell The swelling propertyof the formulation was determined by various techniqueshere the hydration behavior or swelling properties weredetermined as per the method described by Deshpande et al[19]

The swelling properties of HPMC and Carbopol polymermatrices containing the drug were determined by placing thetablet matrices in the USP dissolution test apparatus II Themedium used was 01 N HCl 900mL rotated at 75 rpm Themedium was maintained at 37 plusmn 05∘C throughout the studyThe tablets were removed periodically from the dissolutionmedium After draining free water these were measured forweight gain thickness and diameter Swelling characteristicswere expressed in terms of percentage water uptake (WU)according to the following equation

WU

=wt of swollen tablet minus initial wt of the tablet

initial wt of the tablet

times 100

(4)

229 Detachment Stress Pieces of sheep fundus tissues werebrought frommarket and stored frozen in saline solution andthawed to room temperature immediately before use At thetime of testing a section of tissue (I) was transferred keepingthe mucosal side out to the upper glass vial (G) using arubber band and an aluminum foil cap The diameter of eachexposed mucosal membrane was 11 cm The vials with thefundus tissue were stored at 37∘C for 10min Next one vialwith a section of tissue (I) was connected to the balance (B)and the other vial was fixed on a height-adjustable pan (P)A bioadhesive tablet (F) was applied to the lower vial withthe help of two pieces of adhesive tape The height of the vialwas adjusted so that the tablet could adhere to the mucosaltissues in the vial The mucoadhesive forces of the floatingtablets were determined by the measuring device shown inFigure 5

A constant weight (10 g) was placed on the upper vial andapplied for two minutes after which it was removed and the

upper vial was then connected to the balance Weights (W)were added at a constant rate to the pan on the other side ofthe modified balance of the device until the two vials wereseparated

The bioadhesive force expressed as the detachment stressin dynecm2 was determined from the minimum weightrequired to detach the two vials using the following equation

detachment stress (dynecm2) =119898119892

119860 (5)

where119898119892 is the weight required for detachment and 119860 is thesurface area of the tablet [20] The detachment stresses of thevarious formulation codes are given in Table 8

2210 Scanning Electron Microscopy (SEM) The surfacetopography of the floating tablet was examined using scan-ning electron microscopy (Philips FEI XL-30) at differentmagnification and the acceleration voltage of 149 KV Tabletsamples were mounted on a scanning electron microscopeholder (aluminum sample mount) using a double side adhe-sive tape and coated with gold palladium under vacuum andthen surface topography was investigated

2211 Stability Studies Stability studies were carried outaccording to ICH andWHOguidelines to assess the drug andformulation stability The prepared floating tablets of opti-mized formulation (FC8) containing hydroxypropyl methylcellulose (HPMC K4MCR) and Carbopol 934PNF (FC8)were selected for stability studies based on in vitro drugrelease floating lag time total floating time and their physicalproperties The selected tablets of venlafaxine hydrochloride(FC8) were sealed in aluminum foil packaging coated insidewith polyethylene and kept in a humidity chamber at 45∘Cand 75 RH for three months [21] At the end and during thestudy samples were analyzed for the drug content in vitrodissolution floating behavior and other physicochemicalparameters (Table 9)

2212 Tablet Preparation for In Vivo Studies The optimizedformulation FC8 had shown good in vitro buoyancy andsustained-release behavior and hence was finally selectedfor in vivo study (ie radiography) The tablets of ninemm diameter and 350mg in weight were prepared Tomake the tablet X-ray opaque incorporation of BaSO

4was

necessary Barium sulphate (BaSO4) has high relative density

(44777 gcm3) and poor floating properties The amount ofthe X-ray opaque material in these tablets was sufficient toensure visibility by X-rays but at the same time this amountof barium sulphate was low enough to enable tablets to floatFor this purpose the amount of venlafaxine hydrochloridein the formulation FC8 was replaced with 40mg of bariumsulphate and all other ingredients were kept constant Thesetablets were analyzed for hardness and floating propertiesThe analysis confirmed that these tablets were similar to thetablets for in vitro testing

2213 In Vivo Radiographic Studies Nowadays radio-graphic study is a very popular evaluation parameter for

Scientifica 5

floating dosage form It helps to locate dosage form in theGIT by which one can predict and correlate the gastricretention time floating behavior and passage of the dosageform in the GIT Here the inclusion of radio-opaque materialinto a solid dosage form enables it to be visualized by X-rays It is also important that dosage forms are nondisin-tegrating units and animal subjects are young and healthy[22]

The animal protocol to carry out in vivo radiographicstudies was reviewed and approved by the InstitutionalAnimals Ethical Committee of Bundelkhand UniversityIndia (registration number 71602aCPCSEA) The in vivoradiographic studies were conducted in young and healthymale albino rabbits weighing 20 to 22 kg The animals werekept under standard laboratory conditions (temperature 25plusmn 2∘C) Rabbits were kept for one week in the animal houseto acclimatize them and fed a fixed standard diet The 4healthy male albino rabbits were used to monitor the invivo transit behavior of the floating tablet None of themhad symptoms or history of gastrointestinal (GI) disease Inorder to standardize the conditions ofGImotility the animalswere fasted for 12 hours prior to the commencement of eachexperiment In each experiment the first radiograph of theanimal subjects was made to ensure the absence of radio-opaque material in the GIT One of the tablets preparedfor radiography was orally administered to rabbits with thesufficient amount of water During the study the rabbits werenot allowed to eat but water was available ad libitum

For radiographic imaging all four legs of the rabbit weretied over a piece of plywood (20 times 20 inch) and location ofthe formulation in the stomach was monitored by keepingthe subjects in front of X-ray machine (Allengers BharatElectricals India Model number E 080743) The distancebetween the source of X-rays and the object was the samefor all the imaging This allowed us to see the tablet in thebody of the stomach antrum andor pyloric part of thestomach so that observations of the tablet movements couldbe made Gastric radiography was done at 1 hr 3 hr and 6 hrIn between the radiographic imaging the animals were freedand allowed to move and carry out normal activities but werenot allowed to take any foodThemean gastric residence timeof the drug was calculated

3 Results and Discussion

The granules prepared for the compression of floating tabletswere evaluated for their flow properties (Table 5) Granulesof matrix tablets of different formulation codes showed theangle of repose from 2229∘ plusmn 085 to 3739∘ plusmn 173 andflow rates from 091 plusmn 013 to 122 plusmn 010 gmsec and Carrrsquosindex was found in the range of 1813 to 2653 These resultsindicate that as the concentration of the HPMC K4MCRand Carbopol 934PNF increased in the formulations theangle of repose and Carrrsquos index were found to be increasedwhile their flow rate was found to be decreased Thus theangle of repose and Carrrsquos index value of different batches ofgranules indicate satisfactory flow behavior Other granulesparameters were also determined and found to be withinacceptable limits

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20Time (hr)

Optimization of the HPMC K4MCR

FC1FC2

FC3FC4

Cum

ulat

ive

dru

g re

leas

e

Figure 1 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC1 FC2 FC3 and FC4

The floating tablets of venlafaxine hydrochloride wereprepared by wet granulation method using HPMC K4MCRCarbopol 934PNF sodium bicarbonate and lactose Themagnesium stearate was used as the lubricant

The optimization of the formulation was done based onadjusting the drug-polymer ratio floating lag time durationof floating gas generating agents in vitro drug release rate

Results indicated that the low-density polymers likeHPMC K4MCR and Carbopol 934PNF affects the floatingbehavior of the venlafaxine hydrochloride floating tabletHPMC K4MCR and Carbopol 934PNF are selected becauseof their high viscosities which are desired for the sustainedrelease For optimizing the concentration ratio of the drugpolymers and several formulations of the different batcheswere formulated randomly in which only drug to the poly-mer ratio varied and remaining ingredients of formulationremained constant Then floating behavior and release ratestudy of these formulations were determined in the 01 NHCl (pH 12) Then a certain ratio of drug to polymer givessatisfactory floating behavior and in vitro drug release in 01NHCl At this stage of optimization few batches of formulationcodes FC1 FC2 FC3 and FC4 were prepared for the opti-mizing concentration of the polymer for obtaining the bestfloatation behavior and in vitro drug release Floating lag timeand duration of floating was found to be 112 99 88 and 74seconds and approximately 17 18 23 and 27 hr respectivelyThe cumulative drug release was found to be 9734 97439443 and 9065 in 18 hr for the formulation codes FC1 FC2FC3 and FC4 (Figure 1) But the release pattern of the FC3showed better in vitro release of drug in the sustainedmannerin predetermined time intervals than formulations FC1 FC2and FC4 Formulation FC3 also showed better floatationbehavior (ie floating lag time 88 seconds and duration offloating approximately 23 hr) Therefore formulation FC3has been selected in order to obtain the optimum HPMCloading level because it has better in vitro release patternand floatation behavior Results also indicate that as theconcentration of theHPMC increased the cumulativedrug

6 Scientifica

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

Optimization of Carbopol 934PNF

FC3FC5

FC6FC7

Figure 2 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC3 FC5 FC6 and FC7

release behavior and floating lag time were also decreasedto a certain value After optimizing the concentration ofHPMC K4MCR next optimization was done for Carbopolconcentration As the concentration of the Carbopol in theFC5 formulation decreased then the in vitro drug releasepattern of the formulation (FC5) was increased compared tothat of the FC3 formulation for 18 hr dissolution study It wasfound that as the concentration of the Carbopol increased inthe formulation (ie FC6 (20mg) and FC7 (25mg)) thenin vitro drug release was also decreased compared to thatof FC3 (15mg) Because the release and floatation behaviorexhibited by the FC3 were much better than FC5 FC6 andFC7 (Figure 2) the formulation FC3 remained selected forthe further study

For the floating drug delivery system the ideal matrixshould be highly permeable for the dissolution media inorder to initiate rapid generation of the carbon dioxide gas(CO2) and also should be permeable for CO

2to promote

floating The buoyancy lag time of the tablets depends on theconcentration of the sodiumbicarbonate (NaHCO

3) involved

in the CO2formation In the trial study in vitro release of

drug from the different formulation batches was studied todetermine the optimum concentration of the gas generatingagent It was observed from the formulations FC8 FC9 andFC10 that as the concentration of the sodium bicarbonateincreased in these formulations the floating lag time wasfound to be decreased but their corresponding release ofdrug was increased (Figure 3) The trial study also showedthat at higher concentration of the sodium bicarbonate FC10(30mg) causes bursting and rapid disintegration of tabletHence it was desirable to use optimum concentration ofsodium bicarbonate to get the least floating lag time withminimum bursting effect and desired floating time with-out rapid disintegration So FC8 with sodium bicarbonate(20mg) was optimized and selected to achieve optimum invitro buoyancy with less bursting effectThe formulation FC8was preferred over the FC3 because the in vitro release of

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20Time (hr)

Optimization of sodium bicarbonate

FC3FC8

FC9FC10

Cum

ulat

ive

dru

g re

leas

e

Figure 3 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC3 FC8 FC9 and FC10

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

Optimization of lactose

FC8FC11

FC12FC13

Figure 4 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC8 FC11 FC12 and FC13

drug was increased in the more controlled manner than thatof FC3

Here the lactose acts as channeling agent which is solublein the dissolutionmedium therefore thematrix integrity getsbroken and showed faster in vitro drug dissolution Resultsindicate from the formulations (ie FC11 FC12 and FC13)that release rate of drug is directly proportional to the con-centration of the lactose (Figure 4) As the concentration ofthe lactose increased in vitro drug releases were also found tobe increased but if the concentration of the lactose increasedmore than 50mg then the tablet will start disintegration bythe erosion mechanism Therefore optimum concentrationof the lactose is required for getting the maximum in vitrodrug release without causing erosion From the above resultsFC8 was found to be the best formulation which showedbetter in vitro drug release and floatation behavior

Scientifica 7

Table 6 Physiochemical characterization of venlafaxine hydrochloride tablets

Code weight variation Hardness (kgcm2) friability drug contentuniformity

Floating lagtime (sec)

Total floatingtime (hr)

FC1 plusmn30 640 plusmn 016 0524 9921 plusmn 146 112 plusmn 287 1733 plusmn 205FC2 plusmn45 637 plusmn 045 0564 9847 plusmn 034 99 plusmn 249 1850 plusmn 187FC3 plusmn35 653 plusmn 057 0572 9886 plusmn 124 88 plusmn 287 2333 plusmn 062FC4 plusmn40 663 plusmn 058 0482 9720 plusmn 018 74 plusmn 327 2708 plusmn 095FC5 plusmn25 693 plusmn 052 0458 9853 plusmn 052 94 plusmn 327 1275 plusmn 208FC6 plusmn30 670 plusmn 070 0545 9908 plusmn 221 82 plusmn 294 2650 plusmn 102FC7 plusmn40 643 plusmn 033 0584 9740 plusmn 102 76 plusmn 245 2925 plusmn 074FC8 plusmn40 667 plusmn 098 0580 9891 plusmn 018 72 plusmn 249 2450 plusmn 074FC9 plusmn25 670 plusmn 049 0495 9800 plusmn 024 64 plusmn 294 2650 plusmn 154FC10 plusmn30 647 plusmn 090 0457 9756 plusmn 132 54 plusmn 245 2625 plusmn 187FC11 plusmn30 680 plusmn 043 0530 9843 plusmn 064 67 plusmn 374 2825 plusmn 069FC12 plusmn45 627 plusmn 041 0572 9902 plusmn 145 81 plusmn 287 2052 plusmn 092FC13 plusmn45 667 plusmn 066 0592 9874 plusmn 082 93 plusmn 327 1800 plusmn 082Mean plusmn SD 119899 = 3 FC formulation code

B

WF

G

I

T

PG998400

B modified balance W weights G and G998400 glass vialF bioadhesive tablet I fundus tissueT supportive adhesive tape P height-adjustable pan

Figure 5 Mucoadhesion measuring device for obtaining detach-ment stress

The diameter of the formulations FC1 to FC13 was foundin the range of 897 plusmn 001 to 899 plusmn 003 and thickness wasin the range of 396 plusmn 001 to 399 plusmn 002 The variationin the weight was found in the range of plusmn5 complyingwith pharmacopoeial specificationsThe hardness of differentformulation was found to be between 627 plusmn 041 and693 plusmn 052 kgcm2 indicating good mechanical strengthThe friability was below 1 for all formulations which isan indication of good mechanical resistance of tablet Thedrug content varied between 9800 and 9921 in differentformulation with low standard deviation (Table 6)

The swelling of the polymers used (ie HPMC K4MCRand Carbopol 934PNF) was determined by swelling indexof the tablet Hydrophilic matrices (ie HPMC K4MCRand Carbopol 934PNF) in contact with water swell andincrease their volume due to water diffusion through thematrix The polymer chains continue the hydration process

and the matrix gained more water Drug diffusion signif-icantly depends on the water content of the tablet Thismay be because the mobility of the polymer chains is verydependent on the water content of the system In case ofhigh-water content polymer chain relaxation takes placewith volume expansion resulting in marked swelling of thesystem Also higher water content could lead to greaterpenetration of the gastric fluid into the tablet leading toquicker carbon dioxide gas generation thereby reducing thefloating lag time Consequently quicker and greater swellingof the tablet would lead to an increase in the diffusionpathway and thus a reduction in diffusion rate So the drugrelease was found to be high initially and then graduallydecreased

The swelling index of all formulations from FC1 toFC10 at 24 hr was found to be between 13603 and 17099respectively The percentage water uptake was found to beimproved as the concentration of the HPMC K4MCR andCarbopol 934PNF increased in the formulation The resultindicates from Table 7 that swelling index was increasedmuch more in case of Carbopol compared to HPMC becauseCarbopol is bearing very goodwater sorption property It wasalso observed that as the concentration of the Carbopol in theformulation decreased the water uptake was also found tobe decreased (ie FC5)

Table 8 clearly indicates that the value of bioadhesiveforce was found to be increased significantly as the con-centration of the mucoadhesive polymer HPMC and Car-bopol increased All floating formulations showed mucoad-hesive forces in the range of 11042 to 16780 dynescm2Results indicate that as the concentration of HPMC K4MCRincreased in the formulations FC1 to FC4 then the valueof detachment forces also increased from 12345 to 15672dynescm2 respectively It was also observed that as theconcentration of Carbopol 934PNF increased the values ofdetachment forces were increased from the 15965 to 16700dynescm2 for formulations FC6 to FC7 respectively but as

8 Scientifica

Table7Sw

ellingbehavior

ofmatrix

tablets

Form

ulationcode

Initialweight(mg)

Initialthickn

ess(mm)

Initialdiam

eter

(mm)

Finalw

eight(mg)

Finalthickness(m

m)

Finald

iameter

(mm)

Swellin

gindex

FC1

23411plusmn305

397plusmn001

898plusmn001

55259plusmn311

442plusmn10

81816plusmn038

13603

FC2

24020plusmn435

398plusmn002

897plusmn002

57852plusmn13

2450plusmn074

1852plusmn12

014084

FC3

24418plusmn16

9397plusmn001

899plusmn001

60710plusmn506

456plusmn089

1873plusmn14

814867

FC4

25010plusmn17

1399plusmn002

897plusmn001

6372

2plusmn340

461plusmn12

11885plusmn092

15478

FC5

23958plusmn10

1398plusmn001

898plusmn002

57848plusmn225

453plusmn14

21862plusmn13

41414

5FC

625009plusmn18

9396plusmn001

899plusmn002

64886plusmn413

463plusmn12

71889plusmn088

1594

5FC

725558plusmn329

397plusmn002

897plusmn001

6816

8plusmn267

466plusmn054

1893plusmn15

316672

FC8

25017plusmn12

3399plusmn002

899plusmn001

65425plusmn328

462plusmn028

1899plusmn067

16152

FC9

25421plusmn353

398plusmn001

898plusmn001

67817plusmn14

4464plusmn078

1914plusmn025

16678

FC10

2596

7plusmn442

399plusmn002

897plusmn002

70367plusmn287

468plusmn038

1927plusmn14

417099

MeanplusmnSD

119899=3FC

form

ulationcode

Scientifica 9

Table 8 Detachment forces of different formulations

S numberFormulation code (FC) Detachment force (dynescm2)1 FC1 123452 FC2 131743 FC3 147534 FC4 156725 FC5 110426 FC6 159657 FC7 167808 FC8 142189 FC9 1402110 FC10 1362411 FC11 1437812 FC12 1452613 FC13 14065

the concentration of Carbopol decreased value of forces wasdecreased (ie FC5) Hence it was also concluded from theresults that the values of detachment forces were increasedmuchmore in case of Carbopol 934PNF compared to HPMCK4MCR because the Carbopol was highly bioadhesive ascompared to HPMC

Bioadhesion is a surface phenomenon inwhich amaterialof synthetic or natural origin adheres or sticks to a biologicalsurface usually mucus membrane Many hydrophilic poly-mers adhere to mucosal surfaces as they attract water fromthe mucus gel layer adhering to the epithelial surface This isthe simplest mechanism of adhesion and it has been definedas ldquoadhesion by hydrationrdquo The hydrogen bonding presentbetween the adherent polymer and mucus is involved inmucoadhesion at themolecular level As the concentration ofbioadhesive polymers increased then the hydrogen bondingbetween the mucus membrane and adherent polymer at themolecular level increased therefore detachment forces werealso found to be increased

Surface morphology of the optimized formulation FC8was examined by scanning electronmicroscopy (SEM) It wasobserved from the SEM photographs that the drug is releasedfrom the matrix tablet by the diffusion process The surfacemorphology of the matrix tablet after dissolution showedthat the solvent front enters the matrix and moves slowlytoward the center of the tablet The drug diffuses out of thematrix after it comes in contact with dissolution mediumThe images of the tablet showed a network in the swollenpolymer through which the drug diffused to the surroundingmedium Thus it was concluded that the drug was releasedfrom a matrix by diffusion mechanism (Figures 6 and7)

A comparative study was performed on the availablemarketed formulation of extended release tablet and capsulecontaining venlafaxine hydrochloride equivalent to venlafax-ine 375mgThe results obtained from the in vitro drug releasestudy showed that optimized formulations FC8 showedmore sustained-release action than that of tablet (marketed-1) and capsule (marketed-2) with respect to time of 18 hr(Figure 8)

Figure 6 Scanning electron microscopy of optimized formulationFC8 of tablet surface before dissolution

Figure 7 Scanning electron microscopy of optimized formulationFC8 of tablet surface after dissolution

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

FC8Marketed-1

Marketed-2

Figure 8 Comparison of drug release of optimized formulation(FC8) versus marketed formulations for 18 hr

The drug release was found to follow first-order kineticswith 119903 = 09935 and 09904 for marketed-1 (tablet) andmarketed-2 (capsule) respectively while optimized formula-tion FC8 followed the Peppasmodel with value of 119903 = 09962119899 = 04473 and 119896 = 252788 So the best-fit model was foundto be the Peppas model for optimized formulation FC8 Themarketed formulations of tablet and capsule showed morethan 90of drug release in 14 hrwhile optimized formulationFC8 showed only 8258 of drug release in 14 hr

The data obtained from in vitro dissolution studies werefitted to zero-order first-order Higuchi and Korsmeyer-Peppas equations All release kinetic models were applied

10 Scientifica

Table 9 Stability studies of venlafaxine hydrochloride floating tablets of optimized formulation (FC8)

Characteristic Initial 1st month 2nd month 3rd monthHardness (kgcm2) 667 plusmn 098 602 plusmn 056 642 plusmn 020 630 plusmn 088Drug content () 9891 plusmn 018 9834 plusmn 002 9812 plusmn 142 9800 plusmn 027Floating lag time (seconds) 72 plusmn 265 76 plusmn 126 84 plusmn 245 90 plusmn 326Total floating time (hours) 2450 plusmn 074 2416 plusmn 112 2418 plusmn 226 2408 plusmn 034Swelling index () 16152 16082 16064 16018Buoyancy on disturbing Float Float Float FloatMatrix integrity Very good Very good Very good Very good in vitro release 18 hours 9692 plusmn 083 9443 plusmn 138 9398 plusmn 042 9300 plusmn 156Mean plusmn SD 119899 = 3 FC formulation code

(a) (b)

Figure 9 In vitro floating studies of optimized formulation (FC8) (a) after 80 sec and (b) after 24 hr

on the formulation codes FC1 FC2 FC3 FC4 FC5 FC6FC7 FC8 FC9 FC10 FC11 FC12 and FC13 due to theirsatisfactory release behavior The best-fit model was found tobe the matrix for formulation codes FC1 FC2 and FC5 andPeppas for formulation codes FC3 FC4 FC6 FC7 FC8 FC9FC10 FC11 FC12 and FC13The selection criteria for the bestmodel were based on goodness of fit of the data and residualsum of squares The details of the best-fit model of differentformulation codes are given in Table 10

For confirming the diffusion mechanism of optimizedformulation FC8 the data was fitted to the Korsmeyerequation which showed the exponent value 119899 = 04473Because the optimized formulation FC8 had the exponentvalue (119899) less than 05 it was suggested that the releasemechanism of venlafaxine hydrochloride indicates swellingand diffusion mechanism of floating tablets which followedthe Fickian diffusion (Case I transport) This kinetic dataanalysis was done by using ldquoPCP Disso V208rdquo Software(Poona College of Pharmacy Pune India)

The optimized formulation FC8 was suggested for stabil-ity study based on in vitro floating lag time total floating timein vitro drug dissolution studies and its physical propertiesThe floating tablets were investigated at 400∘C75 RH in

aluminum foil packaging for three monthsThe increased lagtime indicates the possibility of reaction of sodium bicarbon-ate with moisture during the study period However therewas the very little effect on the duration of the floating andmatrix integrity of the tablets Some drug degradation wasfound but it was not statistically significant Decreased drugrelease was found from the formulation but drug releasedcompiled the official standard of release since more than80 of the drug was released (Table 9) Thus it was foundthat the floating tablets of venlafaxine hydrochloride werealmost stable under these storage conditions for at least threemonths

The in vitro studies with BaSO4-containing floating

tablets showed a floating lag time of 112plusmn200 seconds hard-ness of 660 plusmn 003 kgcm2 and thickness of 399 plusmn 001mmThe intragastric behavior of the BaSO

4-loaded tablet in the

albino rabbit was observed by using a radiographic imagingtechnique Radiographic images were taken after 1 3 and6 hr showing that the tablet had altered its position in thestomachThis provided evidence that the tablets were floatingon the gastric fluid After 4 hr of the tablet administrationthe swelling of the tablet is visualized very well together withthe white dry core and translucent swelling layer around it

Scientifica 11

Table 10 Drug release kinetics for floating-bioadhesive tablets

S number Formulation code (FC) Best-fit model 119877 value Parameters for Korsmeyer-Peppas equation

1 FC1 Matrix 09948 119899 = 04817

119896 = 242487

2 FC2 Matrix 09942 119899 = 05125

119896 = 213988

3 FC3 Peppas 09966 119899 = 04919

119896 = 210756

4 FC4 Peppas 09914 119899 = 05500

119896 = 169021

5 FC5 Matrix 09968 119899 = 04877

119896 = 229187

6 FC6 Peppas 09941 119899 = 05430

119896 = 171357

7 FC7 Peppas 09966 119899 = 06472

119896 = 130990

8 FC8 Peppas 09962 119899 = 04473

119896 = 252788

9 FC9 Peppas 09942 119899 = 03266

119896 = 374233

10 FC10 Peppas 09910 119899 = 03279

119896 = 396415

11 FC11 Peppas 09972 119899 = 04974

119896 = 213024

12 FC12 Peppas 09933 119899 = 03702

119896 = 332823

13 FC13 Peppas 09934 119899 = 03466

119896 = 366938

Note each sample was analyzed in triplicate (119899 = 3)119896 kinetic constant119899 exponent value

due to the swellable polymers HPMCK4MCR and Carbopol934PNF

Hence examination of the sequential radiographicimages of the GIT during the study clearly indicated that thetablet remained buoyant and altered its position in the gastriccontents for more than 6 hr So prolonged gastric retentiontime (GRT) of more than 6 hr is achieved (Figures 10(a)ndash10(c))

The objective of the in vivo studies was to provide theproof of concept that the floating capability of the floatingtablet was useful for the increasing the gastric residence timeof the dosage form For facilitating the trials on the rabbitsthe dosage form did not contain any drug and the scope waslimited to the observation of the behavior of the system in thestomach

4 Conclusion

The present study was carried out to develop the floating-bioadhesive drug delivery of venlafaxine hydrochloride using

HPMC K4MCR and Carbopol 934PNF polymers as the car-rier Optimized formulation FC8 gave satisfactory results forvarious physiochemical evaluations for tablets like hardnessweight variation floating lag time and uniformity of contentIn vitro dissolution studies of the optimized formulation FC8showed the sustained release for 18 hr followed by the Fickiandiffusion and an in vivo study indicated increased gastricresidence time by the floating principle and was considereddesirable for improving the bioavailability of the drug Allthese results also indicated that a low amount of floatingagent and high amount of hydrophilic polymer favored thesustained release of venlafaxine hydrochloride from the float-ing gastroretentive tablet formulations Developed sustained-release oral formulation for prolonged release would be asignificant advantage for the patient and may result in fewerside effects due to reduction of the blood concentrationfluctuations especially in long-term therapy Thus results ofthe current study clearly indicate a promising potential of thevenlafaxine hydrochloride floating system as an alternativeto the conventional dosage form However further clinical

12 Scientifica

(a)

(b)

(c)

Figure 10 Radiographic images showing the presence of BaSO4loaded floating tablet in the stomach at different time periods (the tablet is

indicated with an arrow) Images were taken after (a) 1 hr (b) 3 hr and (c) 6 hr after tablet administration

studies are needed to assess the utility of this system forpatients suffering from depression

Competing Interests

The authors declare that there are no competing interestsThe authors do not have a direct financial relation with thecommercial identities mentioned in the research paper thatmight lead to competing interests for any of the authors

Acknowledgments

The authors are thankful to Ranbaxy Research Lab Ltd Gur-gaon Haryana India for providing venlafaxine hydrochlo-ride as a gift sample and Arihant Trading CompanyMumbaiIndia and Colorcon Asia Pvt Ltd Goa India for providingthe polymer samples They also wish to thank Dr P KJain Radiologist VardhmanMedical Centre Jhansi India forextending radiography

Scientifica 13

References

[1] O Berton and E J Nestler ldquoNew approaches to antidepressantdrug discovery beyond monoaminesrdquo Nature Reviews Neuro-science vol 7 no 2 pp 137ndash151 2006

[2] E J Nestler M Barrot R J DiLeone A J Eisch S J Gold andLMMonteggia ldquoNeurobiology of depressionrdquoNeuron vol 34no 1 pp 13ndash25 2002

[3] E Richelson ldquoPharmacology of antidepressantsrdquo Mayo ClinicProceedings vol 76 no 5 pp 511ndash527 2001

[4] httpwwwdrugbankcadrugsDB00285[5] P Blier E Saint-Andre C Hebert C De Montigny N Lavoie

and G Debonnel ldquoEffects of different doses of venlafaxine onserotonin and norepinephrine reuptake in healthy volunteersrdquoInternational Journal of Neuropsychopharmacology vol 10 no1 pp 41ndash50 2007

[6] S M Holliday and P Benfield ldquoVenlafaxine a review of itspharmacology and therapeutic potential in depressionrdquo Drugsvol 49 no 2 pp 280ndash294 1995

[7] B Omprakash S Ajay G Santosh and P Amin ldquoFormulationdevelopment of venlafaxine hydrochloride extended releasetablet and invitro characterizationsrdquo International Journal ofPharmTech Research vol 4 no 4 pp 1777ndash1784 2012

[8] E AMuth J AMoyer J T Haskins T H Andree andG EMHusbands ldquoBiochemical neurophysiological and behavioraleffects of Wy-45233 and other identified metabolites of theantidepressant venlafaxinerdquo Drug Development Research vol23 no 2 pp 191ndash199 1991

[9] B Cusack A Nelson and E Richelson ldquoBinding of antide-pressants to human brain receptors focus on newer generationcompoundsrdquo Psychopharmacology vol 114 no 4 pp 559ndash5651994

[10] B N Singh and K H Kim ldquoFloating drug delivery systems anapproach to oral controlled drug delivery via gastric retentionrdquoJournal of Controlled Release vol 63 no 3 pp 235ndash259 2000

[11] P Bhardwaj R Singh and A Swarup ldquoStomach specific drugdelivery systemmdasha brief reviewrdquo Inventi Rapid NDDS no 3 pp1ndash9 2012

[12] R B Umamaheshwari S Jain D Bhadra and N K JainldquoFloating microspheres bearing acetohydroxamic acid for thetreatment of Helicobacter pylorirdquo Journal of Pharmacy andPharmacology vol 55 no 12 pp 1607ndash1613 2003

[13] S K Jain AMAwasthi N K Jain andG P Agrawal ldquoCalciumsilicate based microspheres of repaglinide for gastroretentivefloating drug delivery preparation and in vitro characteriza-tionrdquo Journal of Controlled Release vol 107 no 2 pp 300ndash3092005

[14] D Chaurasia K Kaushik P Bhardwaj H Chaurasia S K Jainand S Shobhna ldquoDevelopment and in vitro characterizationof floating microspheres bearing tramadol HClrdquo Acta PoloniaePharmaceuticamdashDrug Research vol 68 no 5 pp 795ndash801 2011

[15] P Bhardwaj H Chaurasia D Chaurasia S K Prajapati andS Singh ldquoFormulation and in-vitro evaluation of floatingmicroballoons of indomethacinrdquo Acta Poloniae Pharmaceuti-camdashDrug Research vol 67 no 3 pp 291ndash298 2010

[16] L Lachman H A Liberman and J L Kanig The Theoryand Practice of Industrial Pharmacy Varghese Publishin HouseBombay India 3rd edition 1991

[17] M E Aulton PharmaceuticsThe Science of Dosage formDesignElsevier Science Ltd Philadelphia Pa USA Churchill Living-stone London UK 2nd edition 2002

[18] M Jaimini A C Rana andY S Tanwar ldquoFormulation and eval-uation of famotidine floating tabletsrdquo Current Drug Deliveryvol 4 no 1 pp 51ndash55 2007

[19] A A Deshpande N H Shah C T Rhodes and W MalickldquoDevelopment of a novel controlled-release system for gastricretentionrdquo Pharmaceutical Research vol 14 no 6 pp 815ndash8191997

[20] G S Sonar D K Jain and D M More ldquoPreparation and invitro evaluation of bilayer and floating-bioadhesive tablets ofrosiglitazone maleaterdquo Asian Journal of Pharmaceutical Sciencevol 2 no 4 pp 161ndash169 2007

[21] B R Matthews ldquoRegulatory aspects of stability testing inEuroperdquo Drug Development and Industrial Pharmacy vol 25no 7 pp 831ndash856 1999

[22] R Gupta S K Prajapati S Pattnaik and P Bhardwaj ldquoFor-mulation and evaluation of novel stomach specific floatingmicrospheres bearing famotidine for treatment of gastric ulcerand their radiographic studyrdquo Asian Pacific Journal of TropicalBiomedicine vol 4 no 9 pp 729ndash735 2014

Submit your manuscripts athttpwwwhindawicom

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Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

2 Scientifica

Various attempts have been made to develop floatingsystem to control drug release among them is the socalled hydrodynamically balanced system (HBS) Floatingdrug delivery system (FDDS) or hydrodynamically balancedsystems (HBS) have a bulk density lower than the gastric fluidand thus remain buoyant in the stomach without affectingthe gastric emptying rate for a prolonged period of time[10] FDDS is suitable for those drugs which are havingan absorption window in the stomach or the upper smallintestine [11] for drugs which act locally in the stomach[12] and for drugs that are poorly soluble or unstable in theintestinal fluid [13] venlafaxine hydrochloride is one drugfrom the latter category

Floating dosage forms remain on the surface of gastricfluid because of its relatively lower density than that of gastricfluid Floating single unit dosage form also called hydro-dynamically balanced systems (HBS) has been extensivelystudied [14]

Mucoadhesive delivery systems were also proven to besuitable for reduction of transit time of the dosage formthrough the gastrointestinal tract Adhesiveness of the dosageform is based on the bioadhesive power of the polymerVarious synthetic as well as natural polymers have beenreported for this approach [15]

Venlafaxine hydrochloride is selected as a drug candidatefor this study as its bioavailability is low and half-life rangesin 5 plusmn 2 hr necessitating frequent administration to maintainthe adequate plasma level of drug

The present research endeavor involves development andcharacterization of newer floating-mucoadhesive tablets ofvenlafaxine hydrochloride using HPMC K4MCR and Car-bopol 934PNF and investigation of the combined effect ofthese polymers on the floating behavior and in vitro releasepattern of the drug Here the synergism effect of mucoad-hesion with floatation may increase the gastric retention ofdrug hence increasing its bioavailability

2 Materials and Methods

21 Materials Venlafaxine hydrochloride was a kind giftfromRanbaxy Research Lab Ltd (Gurgaon Haryana India)HPMCK4MCRwas obtained as a gift sample from ColorconAsia Pvt (Goa India) Carbopol 934PNF from ArihantTrading Co (Mumbai India) and lactose and magnesiumstearate were procured from Central Drug House (NewDelhi India) Sodium bicarbonate was obtained from SDFine-Chem Ltd (Mumbai India) All other reagents were ofanalytical grade which were used in preparation

22 Methodology Venlafaxine hydrochloride floating tabletswere prepared by the wet granulation method using hydrox-ypropyl methyl cellulose (HPMC K4MCR) Carbopol 934Plactose and sodium bicarbonate The compositions of differ-ent formulation codes of floating tablets are shown in Tables1ndash4

221 Preparation of Granules Granules were prepared bywet granulation method First of all the ingredients were

Table 1 Formulation for optimization of drug HPMC K4MCRratio

Ingredients (in mg) Formulation code (FC)FC1 FC2 FC3 FC4

Venlafaxine hydrochloride 4243 4243 4243 4243HPMC K4MCR 130 135 140 145Carbopol 934PNF 15 15 15 15Sodium bicarbonate 15 15 15 15Lactose 30 30 30 30Magnesium stearate 257 257 257 257Tablet Wt (mg) 235 240 245 250

Table 2 Formulation for optimization of drug Carbopol 934PNFratio

Ingredients (in mg) Formulation code (FC)FC3 FC5 FC6 FC7

Venlafaxine hydrochloride 4243 4243 4243 4243HPMC K4MCR 140 140 140 140Carbopol 934PNF 15 10 20 25Sodium bicarbonate 15 15 15 15Lactose 30 30 30 30Magnesium stearate 257 257 257 257Tablet Wt (mg) 245 240 250 255

Table 3 Formulation for optimization of drug sodium bicarbonateratio

Ingredients (in mg) Formulation code (FC)FC3 FC8 FC9 FC10

Venlafaxine hydrochloride 4243 4243 4243 4243HPMC K4MCR 140 140 140 140Carbopol 934PNF 15 15 15 15Sodium bicarbonate 15 20 25 30Lactose 30 30 30 30Magnesium stearate 257 257 257 257Tablet Wt (mg) 245 250 255 260

Table 4 Formulation for optimization of drug lactose ratio

Ingredients (in mg) Formulation code (FC)FC8 FC11 FC12 FC13

Venlafaxine hydrochloride 4243 4243 4243 4243HPMC K4MCR 140 140 140 140Carbopol 934PNF 15 15 15 15Sodium bicarbonate 20 20 20 20Lactose 30 20 40 50Magnesium stearate 257 257 257 257Tablet Wt (mg) 250 240 260 270

accurately weighed Then accurately weighed quantities ofvenlafaxine hydrochloride HPMC K4MCR lactose andsodium bicarbonate were mixed homogeneously using glass

Scientifica 3

Table 5 Comparative study of various granules characteristics

Formulation code Angle of repose (120579∘) Flow rate (gmsecond) Bulk density (gmcm3) Tapped density Carrrsquos indexFC1 2470 plusmn 182 118 plusmn 002 0672 plusmn 126 0826 plusmn 106 1864FC2 2598 plusmn 174 113 plusmn 017 0651 plusmn 028 0817 plusmn 102 2032FC3 2689 plusmn 102 098 plusmn 011 0681 plusmn 040 0887 plusmn 080 2322FC4 2812 plusmn 116 091 plusmn 013 0648 plusmn 016 0862 plusmn 050 2482FC5 3109 plusmn 082 110 plusmn 012 0624 plusmn 108 0801 plusmn 018 2210FC6 3147 plusmn 111 099 plusmn 009 0667 plusmn 030 0907 plusmn 120 2646FC7 3739 plusmn 173 095 plusmn 005 0662 plusmn 024 0901 plusmn 030 2653FC8 3215 plusmn 104 098 plusmn 003 0652 plusmn 101 0807 plusmn 108 1921FC9 2708 plusmn 132 107 plusmn 007 0664 plusmn 036 0823 plusmn 045 1932FC10 3007 plusmn 151 105 plusmn 019 0694 plusmn 050 0852 plusmn 016 1854FC11 3109 plusmn 086 121 plusmn 016 0701 plusmn 030 0905 plusmn 010 2254FC12 2606 plusmn 087 122 plusmn 010 0721 plusmn 018 0910 plusmn 123 2077FC13 2229 plusmn 085 120 plusmn 008 0736 plusmn 010 0899 plusmn 035 1813Mean plusmn SD 119899 = 3 FC formulation code

mortar and pestle The wet granulation was done withethanol (95) Wet mass was passed through a 40-meshscreen and dried in a hot air oven at 40∘C over night Thedried granules were sized through 4060 mesh and blendedwith Carbopol 934P and magnesium stearate (approximately1 ww) Lactose was used as filler and channeling agentSodium bicarbonate was used as a gas generating agent [16]

222 Evaluation of Granules Granules of different formula-tion codes are evaluated for angle of repose flow rate bulkdensity tapped density Carrrsquos index and so forth as per themethod described by Aulton [17] The angle of repose andflow rates were determined by the funnel method The bulkdensity and tapped density were obtained by the cylindermethod Consider

(angle of repose) 120579 = tanminus1 (ℎ119903) (1)

where 120579 is the angle of repose ℎ is height of the cone (or pileheight) and 119903 is radius of cone (or pile) or base radius

flow rate =weight of granulestime in seconds

bulk density (120588119887) =119908

119881119887

bulk density (120588119905) =119908

119881119905

(2)

where 119908 is weight of the sample in grams 119881119887is final bulk

volumes of granules in cm3 and 119881119905is final tapped volumes

of granules in cm3And Carrrsquos index of each formulation was calculated

according to the equation given below

Carrrsquos index ( compressibility) =120588119905minus 120588119887

120588119905

times 100 (3)

Experimental evaluations of granules are shown in Table 5

223 Preparation of Floating Tablet The homogeneouslylubricated granules with magnesium stearate (approximately1 ww) were then compressed into tablets using nine mmdiepunch set on a single punch tablet compression machine(Cadmach Machinery Ltd Ahmedabad India) Compres-sion force was adjusted to obtain tablets with hardness inthe range of 62ndash69 kgcm2 on a Monsanto tablet hardnesstester

224 Characterization of Floating Tablet Theprepared float-ing tablets were characterized for drug content uniformityof weight using 20 tablets hardness (a Monsanto hardnesstester) and friability (Roche type friabilator) The drug con-tent of the tablet was determined using 01 NHCl as a solventThe uniformity of drug content in each formulation wasdetermined by triturating 20 tablets and powder equivalentto average weight was added to 100mL of 01 N hydrochloricacid followed by stirring for 30 minutes [18] The solutionwas filtered through a Whatman filter paper number 41 anddiluted suitably and the absorbance of resultant solution wasmeasured using Double Beam UV spectrophotometer (Shi-madzu UV-1700 Japan) at 2250 nmusing 01 N hydrochloricacid as blank The average drug content is calculated

225 Floating Characteristics Floating characteristics of thetablets were studied at the temperature 37 plusmn 05∘C in 250mLof a 01 N HCl solution (pH = 12) (Figure 9) The timerequired for the tablet to rise to the surface of the solutionand to float was taken as the floating lag time The durationof time in which dosage form constantly remained on thesurface of the medium was considered as total floating time(Table 9)

226 In Vitro Dissolution Studies The in vitro dissolutionstudies of venlafaxine hydrochloride from floating tabletwere carried out using USP Dissolution Testing ApparatusII (Paddle Type) The dissolution test was performed using

4 Scientifica

900mL of 01 N HCl at 37 plusmn 05∘C at 75 rpm One mL ofthe aliquot was withdrawn from the dissolution apparatus atdifferent predetermined time intervals (1 2 3 4 5 6 8 1012 14 16 and 18 hours) and the samples were replaced withthe fresh dissolution medium Then the sample was filteredthrough the Whatman filter paper number 41 and analyzedat 225 nmusingUV Spectrophotometer (ShimadzuUV-1700Japan) Cumulative drug release was calculated using ldquoPCPDisso v208rdquo software

227 Mechanism of Drug Release The drug release mech-anism was determined by fitting the data to the variouskinetic equations such as zero-order first-order Higuchi andKorsmeyer-Peppas and finding the 119877 and 119899 values of therelease profile corresponding to each model

228 Swelling Properties (Hydration Behavior of MatrixTablets) The swelling of the polymer can be measured bytheir ability to absorb water and swell The swelling propertyof the formulation was determined by various techniqueshere the hydration behavior or swelling properties weredetermined as per the method described by Deshpande et al[19]

The swelling properties of HPMC and Carbopol polymermatrices containing the drug were determined by placing thetablet matrices in the USP dissolution test apparatus II Themedium used was 01 N HCl 900mL rotated at 75 rpm Themedium was maintained at 37 plusmn 05∘C throughout the studyThe tablets were removed periodically from the dissolutionmedium After draining free water these were measured forweight gain thickness and diameter Swelling characteristicswere expressed in terms of percentage water uptake (WU)according to the following equation

WU

=wt of swollen tablet minus initial wt of the tablet

initial wt of the tablet

times 100

(4)

229 Detachment Stress Pieces of sheep fundus tissues werebrought frommarket and stored frozen in saline solution andthawed to room temperature immediately before use At thetime of testing a section of tissue (I) was transferred keepingthe mucosal side out to the upper glass vial (G) using arubber band and an aluminum foil cap The diameter of eachexposed mucosal membrane was 11 cm The vials with thefundus tissue were stored at 37∘C for 10min Next one vialwith a section of tissue (I) was connected to the balance (B)and the other vial was fixed on a height-adjustable pan (P)A bioadhesive tablet (F) was applied to the lower vial withthe help of two pieces of adhesive tape The height of the vialwas adjusted so that the tablet could adhere to the mucosaltissues in the vial The mucoadhesive forces of the floatingtablets were determined by the measuring device shown inFigure 5

A constant weight (10 g) was placed on the upper vial andapplied for two minutes after which it was removed and the

upper vial was then connected to the balance Weights (W)were added at a constant rate to the pan on the other side ofthe modified balance of the device until the two vials wereseparated

The bioadhesive force expressed as the detachment stressin dynecm2 was determined from the minimum weightrequired to detach the two vials using the following equation

detachment stress (dynecm2) =119898119892

119860 (5)

where119898119892 is the weight required for detachment and 119860 is thesurface area of the tablet [20] The detachment stresses of thevarious formulation codes are given in Table 8

2210 Scanning Electron Microscopy (SEM) The surfacetopography of the floating tablet was examined using scan-ning electron microscopy (Philips FEI XL-30) at differentmagnification and the acceleration voltage of 149 KV Tabletsamples were mounted on a scanning electron microscopeholder (aluminum sample mount) using a double side adhe-sive tape and coated with gold palladium under vacuum andthen surface topography was investigated

2211 Stability Studies Stability studies were carried outaccording to ICH andWHOguidelines to assess the drug andformulation stability The prepared floating tablets of opti-mized formulation (FC8) containing hydroxypropyl methylcellulose (HPMC K4MCR) and Carbopol 934PNF (FC8)were selected for stability studies based on in vitro drugrelease floating lag time total floating time and their physicalproperties The selected tablets of venlafaxine hydrochloride(FC8) were sealed in aluminum foil packaging coated insidewith polyethylene and kept in a humidity chamber at 45∘Cand 75 RH for three months [21] At the end and during thestudy samples were analyzed for the drug content in vitrodissolution floating behavior and other physicochemicalparameters (Table 9)

2212 Tablet Preparation for In Vivo Studies The optimizedformulation FC8 had shown good in vitro buoyancy andsustained-release behavior and hence was finally selectedfor in vivo study (ie radiography) The tablets of ninemm diameter and 350mg in weight were prepared Tomake the tablet X-ray opaque incorporation of BaSO

4was

necessary Barium sulphate (BaSO4) has high relative density

(44777 gcm3) and poor floating properties The amount ofthe X-ray opaque material in these tablets was sufficient toensure visibility by X-rays but at the same time this amountof barium sulphate was low enough to enable tablets to floatFor this purpose the amount of venlafaxine hydrochloridein the formulation FC8 was replaced with 40mg of bariumsulphate and all other ingredients were kept constant Thesetablets were analyzed for hardness and floating propertiesThe analysis confirmed that these tablets were similar to thetablets for in vitro testing

2213 In Vivo Radiographic Studies Nowadays radio-graphic study is a very popular evaluation parameter for

Scientifica 5

floating dosage form It helps to locate dosage form in theGIT by which one can predict and correlate the gastricretention time floating behavior and passage of the dosageform in the GIT Here the inclusion of radio-opaque materialinto a solid dosage form enables it to be visualized by X-rays It is also important that dosage forms are nondisin-tegrating units and animal subjects are young and healthy[22]

The animal protocol to carry out in vivo radiographicstudies was reviewed and approved by the InstitutionalAnimals Ethical Committee of Bundelkhand UniversityIndia (registration number 71602aCPCSEA) The in vivoradiographic studies were conducted in young and healthymale albino rabbits weighing 20 to 22 kg The animals werekept under standard laboratory conditions (temperature 25plusmn 2∘C) Rabbits were kept for one week in the animal houseto acclimatize them and fed a fixed standard diet The 4healthy male albino rabbits were used to monitor the invivo transit behavior of the floating tablet None of themhad symptoms or history of gastrointestinal (GI) disease Inorder to standardize the conditions ofGImotility the animalswere fasted for 12 hours prior to the commencement of eachexperiment In each experiment the first radiograph of theanimal subjects was made to ensure the absence of radio-opaque material in the GIT One of the tablets preparedfor radiography was orally administered to rabbits with thesufficient amount of water During the study the rabbits werenot allowed to eat but water was available ad libitum

For radiographic imaging all four legs of the rabbit weretied over a piece of plywood (20 times 20 inch) and location ofthe formulation in the stomach was monitored by keepingthe subjects in front of X-ray machine (Allengers BharatElectricals India Model number E 080743) The distancebetween the source of X-rays and the object was the samefor all the imaging This allowed us to see the tablet in thebody of the stomach antrum andor pyloric part of thestomach so that observations of the tablet movements couldbe made Gastric radiography was done at 1 hr 3 hr and 6 hrIn between the radiographic imaging the animals were freedand allowed to move and carry out normal activities but werenot allowed to take any foodThemean gastric residence timeof the drug was calculated

3 Results and Discussion

The granules prepared for the compression of floating tabletswere evaluated for their flow properties (Table 5) Granulesof matrix tablets of different formulation codes showed theangle of repose from 2229∘ plusmn 085 to 3739∘ plusmn 173 andflow rates from 091 plusmn 013 to 122 plusmn 010 gmsec and Carrrsquosindex was found in the range of 1813 to 2653 These resultsindicate that as the concentration of the HPMC K4MCRand Carbopol 934PNF increased in the formulations theangle of repose and Carrrsquos index were found to be increasedwhile their flow rate was found to be decreased Thus theangle of repose and Carrrsquos index value of different batches ofgranules indicate satisfactory flow behavior Other granulesparameters were also determined and found to be withinacceptable limits

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20Time (hr)

Optimization of the HPMC K4MCR

FC1FC2

FC3FC4

Cum

ulat

ive

dru

g re

leas

e

Figure 1 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC1 FC2 FC3 and FC4

The floating tablets of venlafaxine hydrochloride wereprepared by wet granulation method using HPMC K4MCRCarbopol 934PNF sodium bicarbonate and lactose Themagnesium stearate was used as the lubricant

The optimization of the formulation was done based onadjusting the drug-polymer ratio floating lag time durationof floating gas generating agents in vitro drug release rate

Results indicated that the low-density polymers likeHPMC K4MCR and Carbopol 934PNF affects the floatingbehavior of the venlafaxine hydrochloride floating tabletHPMC K4MCR and Carbopol 934PNF are selected becauseof their high viscosities which are desired for the sustainedrelease For optimizing the concentration ratio of the drugpolymers and several formulations of the different batcheswere formulated randomly in which only drug to the poly-mer ratio varied and remaining ingredients of formulationremained constant Then floating behavior and release ratestudy of these formulations were determined in the 01 NHCl (pH 12) Then a certain ratio of drug to polymer givessatisfactory floating behavior and in vitro drug release in 01NHCl At this stage of optimization few batches of formulationcodes FC1 FC2 FC3 and FC4 were prepared for the opti-mizing concentration of the polymer for obtaining the bestfloatation behavior and in vitro drug release Floating lag timeand duration of floating was found to be 112 99 88 and 74seconds and approximately 17 18 23 and 27 hr respectivelyThe cumulative drug release was found to be 9734 97439443 and 9065 in 18 hr for the formulation codes FC1 FC2FC3 and FC4 (Figure 1) But the release pattern of the FC3showed better in vitro release of drug in the sustainedmannerin predetermined time intervals than formulations FC1 FC2and FC4 Formulation FC3 also showed better floatationbehavior (ie floating lag time 88 seconds and duration offloating approximately 23 hr) Therefore formulation FC3has been selected in order to obtain the optimum HPMCloading level because it has better in vitro release patternand floatation behavior Results also indicate that as theconcentration of theHPMC increased the cumulativedrug

6 Scientifica

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

Optimization of Carbopol 934PNF

FC3FC5

FC6FC7

Figure 2 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC3 FC5 FC6 and FC7

release behavior and floating lag time were also decreasedto a certain value After optimizing the concentration ofHPMC K4MCR next optimization was done for Carbopolconcentration As the concentration of the Carbopol in theFC5 formulation decreased then the in vitro drug releasepattern of the formulation (FC5) was increased compared tothat of the FC3 formulation for 18 hr dissolution study It wasfound that as the concentration of the Carbopol increased inthe formulation (ie FC6 (20mg) and FC7 (25mg)) thenin vitro drug release was also decreased compared to thatof FC3 (15mg) Because the release and floatation behaviorexhibited by the FC3 were much better than FC5 FC6 andFC7 (Figure 2) the formulation FC3 remained selected forthe further study

For the floating drug delivery system the ideal matrixshould be highly permeable for the dissolution media inorder to initiate rapid generation of the carbon dioxide gas(CO2) and also should be permeable for CO

2to promote

floating The buoyancy lag time of the tablets depends on theconcentration of the sodiumbicarbonate (NaHCO

3) involved

in the CO2formation In the trial study in vitro release of

drug from the different formulation batches was studied todetermine the optimum concentration of the gas generatingagent It was observed from the formulations FC8 FC9 andFC10 that as the concentration of the sodium bicarbonateincreased in these formulations the floating lag time wasfound to be decreased but their corresponding release ofdrug was increased (Figure 3) The trial study also showedthat at higher concentration of the sodium bicarbonate FC10(30mg) causes bursting and rapid disintegration of tabletHence it was desirable to use optimum concentration ofsodium bicarbonate to get the least floating lag time withminimum bursting effect and desired floating time with-out rapid disintegration So FC8 with sodium bicarbonate(20mg) was optimized and selected to achieve optimum invitro buoyancy with less bursting effectThe formulation FC8was preferred over the FC3 because the in vitro release of

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20Time (hr)

Optimization of sodium bicarbonate

FC3FC8

FC9FC10

Cum

ulat

ive

dru

g re

leas

e

Figure 3 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC3 FC8 FC9 and FC10

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

Optimization of lactose

FC8FC11

FC12FC13

Figure 4 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC8 FC11 FC12 and FC13

drug was increased in the more controlled manner than thatof FC3

Here the lactose acts as channeling agent which is solublein the dissolutionmedium therefore thematrix integrity getsbroken and showed faster in vitro drug dissolution Resultsindicate from the formulations (ie FC11 FC12 and FC13)that release rate of drug is directly proportional to the con-centration of the lactose (Figure 4) As the concentration ofthe lactose increased in vitro drug releases were also found tobe increased but if the concentration of the lactose increasedmore than 50mg then the tablet will start disintegration bythe erosion mechanism Therefore optimum concentrationof the lactose is required for getting the maximum in vitrodrug release without causing erosion From the above resultsFC8 was found to be the best formulation which showedbetter in vitro drug release and floatation behavior

Scientifica 7

Table 6 Physiochemical characterization of venlafaxine hydrochloride tablets

Code weight variation Hardness (kgcm2) friability drug contentuniformity

Floating lagtime (sec)

Total floatingtime (hr)

FC1 plusmn30 640 plusmn 016 0524 9921 plusmn 146 112 plusmn 287 1733 plusmn 205FC2 plusmn45 637 plusmn 045 0564 9847 plusmn 034 99 plusmn 249 1850 plusmn 187FC3 plusmn35 653 plusmn 057 0572 9886 plusmn 124 88 plusmn 287 2333 plusmn 062FC4 plusmn40 663 plusmn 058 0482 9720 plusmn 018 74 plusmn 327 2708 plusmn 095FC5 plusmn25 693 plusmn 052 0458 9853 plusmn 052 94 plusmn 327 1275 plusmn 208FC6 plusmn30 670 plusmn 070 0545 9908 plusmn 221 82 plusmn 294 2650 plusmn 102FC7 plusmn40 643 plusmn 033 0584 9740 plusmn 102 76 plusmn 245 2925 plusmn 074FC8 plusmn40 667 plusmn 098 0580 9891 plusmn 018 72 plusmn 249 2450 plusmn 074FC9 plusmn25 670 plusmn 049 0495 9800 plusmn 024 64 plusmn 294 2650 plusmn 154FC10 plusmn30 647 plusmn 090 0457 9756 plusmn 132 54 plusmn 245 2625 plusmn 187FC11 plusmn30 680 plusmn 043 0530 9843 plusmn 064 67 plusmn 374 2825 plusmn 069FC12 plusmn45 627 plusmn 041 0572 9902 plusmn 145 81 plusmn 287 2052 plusmn 092FC13 plusmn45 667 plusmn 066 0592 9874 plusmn 082 93 plusmn 327 1800 plusmn 082Mean plusmn SD 119899 = 3 FC formulation code

B

WF

G

I

T

PG998400

B modified balance W weights G and G998400 glass vialF bioadhesive tablet I fundus tissueT supportive adhesive tape P height-adjustable pan

Figure 5 Mucoadhesion measuring device for obtaining detach-ment stress

The diameter of the formulations FC1 to FC13 was foundin the range of 897 plusmn 001 to 899 plusmn 003 and thickness wasin the range of 396 plusmn 001 to 399 plusmn 002 The variationin the weight was found in the range of plusmn5 complyingwith pharmacopoeial specificationsThe hardness of differentformulation was found to be between 627 plusmn 041 and693 plusmn 052 kgcm2 indicating good mechanical strengthThe friability was below 1 for all formulations which isan indication of good mechanical resistance of tablet Thedrug content varied between 9800 and 9921 in differentformulation with low standard deviation (Table 6)

The swelling of the polymers used (ie HPMC K4MCRand Carbopol 934PNF) was determined by swelling indexof the tablet Hydrophilic matrices (ie HPMC K4MCRand Carbopol 934PNF) in contact with water swell andincrease their volume due to water diffusion through thematrix The polymer chains continue the hydration process

and the matrix gained more water Drug diffusion signif-icantly depends on the water content of the tablet Thismay be because the mobility of the polymer chains is verydependent on the water content of the system In case ofhigh-water content polymer chain relaxation takes placewith volume expansion resulting in marked swelling of thesystem Also higher water content could lead to greaterpenetration of the gastric fluid into the tablet leading toquicker carbon dioxide gas generation thereby reducing thefloating lag time Consequently quicker and greater swellingof the tablet would lead to an increase in the diffusionpathway and thus a reduction in diffusion rate So the drugrelease was found to be high initially and then graduallydecreased

The swelling index of all formulations from FC1 toFC10 at 24 hr was found to be between 13603 and 17099respectively The percentage water uptake was found to beimproved as the concentration of the HPMC K4MCR andCarbopol 934PNF increased in the formulation The resultindicates from Table 7 that swelling index was increasedmuch more in case of Carbopol compared to HPMC becauseCarbopol is bearing very goodwater sorption property It wasalso observed that as the concentration of the Carbopol in theformulation decreased the water uptake was also found tobe decreased (ie FC5)

Table 8 clearly indicates that the value of bioadhesiveforce was found to be increased significantly as the con-centration of the mucoadhesive polymer HPMC and Car-bopol increased All floating formulations showed mucoad-hesive forces in the range of 11042 to 16780 dynescm2Results indicate that as the concentration of HPMC K4MCRincreased in the formulations FC1 to FC4 then the valueof detachment forces also increased from 12345 to 15672dynescm2 respectively It was also observed that as theconcentration of Carbopol 934PNF increased the values ofdetachment forces were increased from the 15965 to 16700dynescm2 for formulations FC6 to FC7 respectively but as

8 Scientifica

Table7Sw

ellingbehavior

ofmatrix

tablets

Form

ulationcode

Initialweight(mg)

Initialthickn

ess(mm)

Initialdiam

eter

(mm)

Finalw

eight(mg)

Finalthickness(m

m)

Finald

iameter

(mm)

Swellin

gindex

FC1

23411plusmn305

397plusmn001

898plusmn001

55259plusmn311

442plusmn10

81816plusmn038

13603

FC2

24020plusmn435

398plusmn002

897plusmn002

57852plusmn13

2450plusmn074

1852plusmn12

014084

FC3

24418plusmn16

9397plusmn001

899plusmn001

60710plusmn506

456plusmn089

1873plusmn14

814867

FC4

25010plusmn17

1399plusmn002

897plusmn001

6372

2plusmn340

461plusmn12

11885plusmn092

15478

FC5

23958plusmn10

1398plusmn001

898plusmn002

57848plusmn225

453plusmn14

21862plusmn13

41414

5FC

625009plusmn18

9396plusmn001

899plusmn002

64886plusmn413

463plusmn12

71889plusmn088

1594

5FC

725558plusmn329

397plusmn002

897plusmn001

6816

8plusmn267

466plusmn054

1893plusmn15

316672

FC8

25017plusmn12

3399plusmn002

899plusmn001

65425plusmn328

462plusmn028

1899plusmn067

16152

FC9

25421plusmn353

398plusmn001

898plusmn001

67817plusmn14

4464plusmn078

1914plusmn025

16678

FC10

2596

7plusmn442

399plusmn002

897plusmn002

70367plusmn287

468plusmn038

1927plusmn14

417099

MeanplusmnSD

119899=3FC

form

ulationcode

Scientifica 9

Table 8 Detachment forces of different formulations

S numberFormulation code (FC) Detachment force (dynescm2)1 FC1 123452 FC2 131743 FC3 147534 FC4 156725 FC5 110426 FC6 159657 FC7 167808 FC8 142189 FC9 1402110 FC10 1362411 FC11 1437812 FC12 1452613 FC13 14065

the concentration of Carbopol decreased value of forces wasdecreased (ie FC5) Hence it was also concluded from theresults that the values of detachment forces were increasedmuchmore in case of Carbopol 934PNF compared to HPMCK4MCR because the Carbopol was highly bioadhesive ascompared to HPMC

Bioadhesion is a surface phenomenon inwhich amaterialof synthetic or natural origin adheres or sticks to a biologicalsurface usually mucus membrane Many hydrophilic poly-mers adhere to mucosal surfaces as they attract water fromthe mucus gel layer adhering to the epithelial surface This isthe simplest mechanism of adhesion and it has been definedas ldquoadhesion by hydrationrdquo The hydrogen bonding presentbetween the adherent polymer and mucus is involved inmucoadhesion at themolecular level As the concentration ofbioadhesive polymers increased then the hydrogen bondingbetween the mucus membrane and adherent polymer at themolecular level increased therefore detachment forces werealso found to be increased

Surface morphology of the optimized formulation FC8was examined by scanning electronmicroscopy (SEM) It wasobserved from the SEM photographs that the drug is releasedfrom the matrix tablet by the diffusion process The surfacemorphology of the matrix tablet after dissolution showedthat the solvent front enters the matrix and moves slowlytoward the center of the tablet The drug diffuses out of thematrix after it comes in contact with dissolution mediumThe images of the tablet showed a network in the swollenpolymer through which the drug diffused to the surroundingmedium Thus it was concluded that the drug was releasedfrom a matrix by diffusion mechanism (Figures 6 and7)

A comparative study was performed on the availablemarketed formulation of extended release tablet and capsulecontaining venlafaxine hydrochloride equivalent to venlafax-ine 375mgThe results obtained from the in vitro drug releasestudy showed that optimized formulations FC8 showedmore sustained-release action than that of tablet (marketed-1) and capsule (marketed-2) with respect to time of 18 hr(Figure 8)

Figure 6 Scanning electron microscopy of optimized formulationFC8 of tablet surface before dissolution

Figure 7 Scanning electron microscopy of optimized formulationFC8 of tablet surface after dissolution

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

FC8Marketed-1

Marketed-2

Figure 8 Comparison of drug release of optimized formulation(FC8) versus marketed formulations for 18 hr

The drug release was found to follow first-order kineticswith 119903 = 09935 and 09904 for marketed-1 (tablet) andmarketed-2 (capsule) respectively while optimized formula-tion FC8 followed the Peppasmodel with value of 119903 = 09962119899 = 04473 and 119896 = 252788 So the best-fit model was foundto be the Peppas model for optimized formulation FC8 Themarketed formulations of tablet and capsule showed morethan 90of drug release in 14 hrwhile optimized formulationFC8 showed only 8258 of drug release in 14 hr

The data obtained from in vitro dissolution studies werefitted to zero-order first-order Higuchi and Korsmeyer-Peppas equations All release kinetic models were applied

10 Scientifica

Table 9 Stability studies of venlafaxine hydrochloride floating tablets of optimized formulation (FC8)

Characteristic Initial 1st month 2nd month 3rd monthHardness (kgcm2) 667 plusmn 098 602 plusmn 056 642 plusmn 020 630 plusmn 088Drug content () 9891 plusmn 018 9834 plusmn 002 9812 plusmn 142 9800 plusmn 027Floating lag time (seconds) 72 plusmn 265 76 plusmn 126 84 plusmn 245 90 plusmn 326Total floating time (hours) 2450 plusmn 074 2416 plusmn 112 2418 plusmn 226 2408 plusmn 034Swelling index () 16152 16082 16064 16018Buoyancy on disturbing Float Float Float FloatMatrix integrity Very good Very good Very good Very good in vitro release 18 hours 9692 plusmn 083 9443 plusmn 138 9398 plusmn 042 9300 plusmn 156Mean plusmn SD 119899 = 3 FC formulation code

(a) (b)

Figure 9 In vitro floating studies of optimized formulation (FC8) (a) after 80 sec and (b) after 24 hr

on the formulation codes FC1 FC2 FC3 FC4 FC5 FC6FC7 FC8 FC9 FC10 FC11 FC12 and FC13 due to theirsatisfactory release behavior The best-fit model was found tobe the matrix for formulation codes FC1 FC2 and FC5 andPeppas for formulation codes FC3 FC4 FC6 FC7 FC8 FC9FC10 FC11 FC12 and FC13The selection criteria for the bestmodel were based on goodness of fit of the data and residualsum of squares The details of the best-fit model of differentformulation codes are given in Table 10

For confirming the diffusion mechanism of optimizedformulation FC8 the data was fitted to the Korsmeyerequation which showed the exponent value 119899 = 04473Because the optimized formulation FC8 had the exponentvalue (119899) less than 05 it was suggested that the releasemechanism of venlafaxine hydrochloride indicates swellingand diffusion mechanism of floating tablets which followedthe Fickian diffusion (Case I transport) This kinetic dataanalysis was done by using ldquoPCP Disso V208rdquo Software(Poona College of Pharmacy Pune India)

The optimized formulation FC8 was suggested for stabil-ity study based on in vitro floating lag time total floating timein vitro drug dissolution studies and its physical propertiesThe floating tablets were investigated at 400∘C75 RH in

aluminum foil packaging for three monthsThe increased lagtime indicates the possibility of reaction of sodium bicarbon-ate with moisture during the study period However therewas the very little effect on the duration of the floating andmatrix integrity of the tablets Some drug degradation wasfound but it was not statistically significant Decreased drugrelease was found from the formulation but drug releasedcompiled the official standard of release since more than80 of the drug was released (Table 9) Thus it was foundthat the floating tablets of venlafaxine hydrochloride werealmost stable under these storage conditions for at least threemonths

The in vitro studies with BaSO4-containing floating

tablets showed a floating lag time of 112plusmn200 seconds hard-ness of 660 plusmn 003 kgcm2 and thickness of 399 plusmn 001mmThe intragastric behavior of the BaSO

4-loaded tablet in the

albino rabbit was observed by using a radiographic imagingtechnique Radiographic images were taken after 1 3 and6 hr showing that the tablet had altered its position in thestomachThis provided evidence that the tablets were floatingon the gastric fluid After 4 hr of the tablet administrationthe swelling of the tablet is visualized very well together withthe white dry core and translucent swelling layer around it

Scientifica 11

Table 10 Drug release kinetics for floating-bioadhesive tablets

S number Formulation code (FC) Best-fit model 119877 value Parameters for Korsmeyer-Peppas equation

1 FC1 Matrix 09948 119899 = 04817

119896 = 242487

2 FC2 Matrix 09942 119899 = 05125

119896 = 213988

3 FC3 Peppas 09966 119899 = 04919

119896 = 210756

4 FC4 Peppas 09914 119899 = 05500

119896 = 169021

5 FC5 Matrix 09968 119899 = 04877

119896 = 229187

6 FC6 Peppas 09941 119899 = 05430

119896 = 171357

7 FC7 Peppas 09966 119899 = 06472

119896 = 130990

8 FC8 Peppas 09962 119899 = 04473

119896 = 252788

9 FC9 Peppas 09942 119899 = 03266

119896 = 374233

10 FC10 Peppas 09910 119899 = 03279

119896 = 396415

11 FC11 Peppas 09972 119899 = 04974

119896 = 213024

12 FC12 Peppas 09933 119899 = 03702

119896 = 332823

13 FC13 Peppas 09934 119899 = 03466

119896 = 366938

Note each sample was analyzed in triplicate (119899 = 3)119896 kinetic constant119899 exponent value

due to the swellable polymers HPMCK4MCR and Carbopol934PNF

Hence examination of the sequential radiographicimages of the GIT during the study clearly indicated that thetablet remained buoyant and altered its position in the gastriccontents for more than 6 hr So prolonged gastric retentiontime (GRT) of more than 6 hr is achieved (Figures 10(a)ndash10(c))

The objective of the in vivo studies was to provide theproof of concept that the floating capability of the floatingtablet was useful for the increasing the gastric residence timeof the dosage form For facilitating the trials on the rabbitsthe dosage form did not contain any drug and the scope waslimited to the observation of the behavior of the system in thestomach

4 Conclusion

The present study was carried out to develop the floating-bioadhesive drug delivery of venlafaxine hydrochloride using

HPMC K4MCR and Carbopol 934PNF polymers as the car-rier Optimized formulation FC8 gave satisfactory results forvarious physiochemical evaluations for tablets like hardnessweight variation floating lag time and uniformity of contentIn vitro dissolution studies of the optimized formulation FC8showed the sustained release for 18 hr followed by the Fickiandiffusion and an in vivo study indicated increased gastricresidence time by the floating principle and was considereddesirable for improving the bioavailability of the drug Allthese results also indicated that a low amount of floatingagent and high amount of hydrophilic polymer favored thesustained release of venlafaxine hydrochloride from the float-ing gastroretentive tablet formulations Developed sustained-release oral formulation for prolonged release would be asignificant advantage for the patient and may result in fewerside effects due to reduction of the blood concentrationfluctuations especially in long-term therapy Thus results ofthe current study clearly indicate a promising potential of thevenlafaxine hydrochloride floating system as an alternativeto the conventional dosage form However further clinical

12 Scientifica

(a)

(b)

(c)

Figure 10 Radiographic images showing the presence of BaSO4loaded floating tablet in the stomach at different time periods (the tablet is

indicated with an arrow) Images were taken after (a) 1 hr (b) 3 hr and (c) 6 hr after tablet administration

studies are needed to assess the utility of this system forpatients suffering from depression

Competing Interests

The authors declare that there are no competing interestsThe authors do not have a direct financial relation with thecommercial identities mentioned in the research paper thatmight lead to competing interests for any of the authors

Acknowledgments

The authors are thankful to Ranbaxy Research Lab Ltd Gur-gaon Haryana India for providing venlafaxine hydrochlo-ride as a gift sample and Arihant Trading CompanyMumbaiIndia and Colorcon Asia Pvt Ltd Goa India for providingthe polymer samples They also wish to thank Dr P KJain Radiologist VardhmanMedical Centre Jhansi India forextending radiography

Scientifica 13

References

[1] O Berton and E J Nestler ldquoNew approaches to antidepressantdrug discovery beyond monoaminesrdquo Nature Reviews Neuro-science vol 7 no 2 pp 137ndash151 2006

[2] E J Nestler M Barrot R J DiLeone A J Eisch S J Gold andLMMonteggia ldquoNeurobiology of depressionrdquoNeuron vol 34no 1 pp 13ndash25 2002

[3] E Richelson ldquoPharmacology of antidepressantsrdquo Mayo ClinicProceedings vol 76 no 5 pp 511ndash527 2001

[4] httpwwwdrugbankcadrugsDB00285[5] P Blier E Saint-Andre C Hebert C De Montigny N Lavoie

and G Debonnel ldquoEffects of different doses of venlafaxine onserotonin and norepinephrine reuptake in healthy volunteersrdquoInternational Journal of Neuropsychopharmacology vol 10 no1 pp 41ndash50 2007

[6] S M Holliday and P Benfield ldquoVenlafaxine a review of itspharmacology and therapeutic potential in depressionrdquo Drugsvol 49 no 2 pp 280ndash294 1995

[7] B Omprakash S Ajay G Santosh and P Amin ldquoFormulationdevelopment of venlafaxine hydrochloride extended releasetablet and invitro characterizationsrdquo International Journal ofPharmTech Research vol 4 no 4 pp 1777ndash1784 2012

[8] E AMuth J AMoyer J T Haskins T H Andree andG EMHusbands ldquoBiochemical neurophysiological and behavioraleffects of Wy-45233 and other identified metabolites of theantidepressant venlafaxinerdquo Drug Development Research vol23 no 2 pp 191ndash199 1991

[9] B Cusack A Nelson and E Richelson ldquoBinding of antide-pressants to human brain receptors focus on newer generationcompoundsrdquo Psychopharmacology vol 114 no 4 pp 559ndash5651994

[10] B N Singh and K H Kim ldquoFloating drug delivery systems anapproach to oral controlled drug delivery via gastric retentionrdquoJournal of Controlled Release vol 63 no 3 pp 235ndash259 2000

[11] P Bhardwaj R Singh and A Swarup ldquoStomach specific drugdelivery systemmdasha brief reviewrdquo Inventi Rapid NDDS no 3 pp1ndash9 2012

[12] R B Umamaheshwari S Jain D Bhadra and N K JainldquoFloating microspheres bearing acetohydroxamic acid for thetreatment of Helicobacter pylorirdquo Journal of Pharmacy andPharmacology vol 55 no 12 pp 1607ndash1613 2003

[13] S K Jain AMAwasthi N K Jain andG P Agrawal ldquoCalciumsilicate based microspheres of repaglinide for gastroretentivefloating drug delivery preparation and in vitro characteriza-tionrdquo Journal of Controlled Release vol 107 no 2 pp 300ndash3092005

[14] D Chaurasia K Kaushik P Bhardwaj H Chaurasia S K Jainand S Shobhna ldquoDevelopment and in vitro characterizationof floating microspheres bearing tramadol HClrdquo Acta PoloniaePharmaceuticamdashDrug Research vol 68 no 5 pp 795ndash801 2011

[15] P Bhardwaj H Chaurasia D Chaurasia S K Prajapati andS Singh ldquoFormulation and in-vitro evaluation of floatingmicroballoons of indomethacinrdquo Acta Poloniae Pharmaceuti-camdashDrug Research vol 67 no 3 pp 291ndash298 2010

[16] L Lachman H A Liberman and J L Kanig The Theoryand Practice of Industrial Pharmacy Varghese Publishin HouseBombay India 3rd edition 1991

[17] M E Aulton PharmaceuticsThe Science of Dosage formDesignElsevier Science Ltd Philadelphia Pa USA Churchill Living-stone London UK 2nd edition 2002

[18] M Jaimini A C Rana andY S Tanwar ldquoFormulation and eval-uation of famotidine floating tabletsrdquo Current Drug Deliveryvol 4 no 1 pp 51ndash55 2007

[19] A A Deshpande N H Shah C T Rhodes and W MalickldquoDevelopment of a novel controlled-release system for gastricretentionrdquo Pharmaceutical Research vol 14 no 6 pp 815ndash8191997

[20] G S Sonar D K Jain and D M More ldquoPreparation and invitro evaluation of bilayer and floating-bioadhesive tablets ofrosiglitazone maleaterdquo Asian Journal of Pharmaceutical Sciencevol 2 no 4 pp 161ndash169 2007

[21] B R Matthews ldquoRegulatory aspects of stability testing inEuroperdquo Drug Development and Industrial Pharmacy vol 25no 7 pp 831ndash856 1999

[22] R Gupta S K Prajapati S Pattnaik and P Bhardwaj ldquoFor-mulation and evaluation of novel stomach specific floatingmicrospheres bearing famotidine for treatment of gastric ulcerand their radiographic studyrdquo Asian Pacific Journal of TropicalBiomedicine vol 4 no 9 pp 729ndash735 2014

Submit your manuscripts athttpwwwhindawicom

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ToxinsJournal of

VaccinesJournal of

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AntibioticsInternational Journal of

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ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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MEDIATORSINFLAMMATION

of

Scientifica 3

Table 5 Comparative study of various granules characteristics

Formulation code Angle of repose (120579∘) Flow rate (gmsecond) Bulk density (gmcm3) Tapped density Carrrsquos indexFC1 2470 plusmn 182 118 plusmn 002 0672 plusmn 126 0826 plusmn 106 1864FC2 2598 plusmn 174 113 plusmn 017 0651 plusmn 028 0817 plusmn 102 2032FC3 2689 plusmn 102 098 plusmn 011 0681 plusmn 040 0887 plusmn 080 2322FC4 2812 plusmn 116 091 plusmn 013 0648 plusmn 016 0862 plusmn 050 2482FC5 3109 plusmn 082 110 plusmn 012 0624 plusmn 108 0801 plusmn 018 2210FC6 3147 plusmn 111 099 plusmn 009 0667 plusmn 030 0907 plusmn 120 2646FC7 3739 plusmn 173 095 plusmn 005 0662 plusmn 024 0901 plusmn 030 2653FC8 3215 plusmn 104 098 plusmn 003 0652 plusmn 101 0807 plusmn 108 1921FC9 2708 plusmn 132 107 plusmn 007 0664 plusmn 036 0823 plusmn 045 1932FC10 3007 plusmn 151 105 plusmn 019 0694 plusmn 050 0852 plusmn 016 1854FC11 3109 plusmn 086 121 plusmn 016 0701 plusmn 030 0905 plusmn 010 2254FC12 2606 plusmn 087 122 plusmn 010 0721 plusmn 018 0910 plusmn 123 2077FC13 2229 plusmn 085 120 plusmn 008 0736 plusmn 010 0899 plusmn 035 1813Mean plusmn SD 119899 = 3 FC formulation code

mortar and pestle The wet granulation was done withethanol (95) Wet mass was passed through a 40-meshscreen and dried in a hot air oven at 40∘C over night Thedried granules were sized through 4060 mesh and blendedwith Carbopol 934P and magnesium stearate (approximately1 ww) Lactose was used as filler and channeling agentSodium bicarbonate was used as a gas generating agent [16]

222 Evaluation of Granules Granules of different formula-tion codes are evaluated for angle of repose flow rate bulkdensity tapped density Carrrsquos index and so forth as per themethod described by Aulton [17] The angle of repose andflow rates were determined by the funnel method The bulkdensity and tapped density were obtained by the cylindermethod Consider

(angle of repose) 120579 = tanminus1 (ℎ119903) (1)

where 120579 is the angle of repose ℎ is height of the cone (or pileheight) and 119903 is radius of cone (or pile) or base radius

flow rate =weight of granulestime in seconds

bulk density (120588119887) =119908

119881119887

bulk density (120588119905) =119908

119881119905

(2)

where 119908 is weight of the sample in grams 119881119887is final bulk

volumes of granules in cm3 and 119881119905is final tapped volumes

of granules in cm3And Carrrsquos index of each formulation was calculated

according to the equation given below

Carrrsquos index ( compressibility) =120588119905minus 120588119887

120588119905

times 100 (3)

Experimental evaluations of granules are shown in Table 5

223 Preparation of Floating Tablet The homogeneouslylubricated granules with magnesium stearate (approximately1 ww) were then compressed into tablets using nine mmdiepunch set on a single punch tablet compression machine(Cadmach Machinery Ltd Ahmedabad India) Compres-sion force was adjusted to obtain tablets with hardness inthe range of 62ndash69 kgcm2 on a Monsanto tablet hardnesstester

224 Characterization of Floating Tablet Theprepared float-ing tablets were characterized for drug content uniformityof weight using 20 tablets hardness (a Monsanto hardnesstester) and friability (Roche type friabilator) The drug con-tent of the tablet was determined using 01 NHCl as a solventThe uniformity of drug content in each formulation wasdetermined by triturating 20 tablets and powder equivalentto average weight was added to 100mL of 01 N hydrochloricacid followed by stirring for 30 minutes [18] The solutionwas filtered through a Whatman filter paper number 41 anddiluted suitably and the absorbance of resultant solution wasmeasured using Double Beam UV spectrophotometer (Shi-madzu UV-1700 Japan) at 2250 nmusing 01 N hydrochloricacid as blank The average drug content is calculated

225 Floating Characteristics Floating characteristics of thetablets were studied at the temperature 37 plusmn 05∘C in 250mLof a 01 N HCl solution (pH = 12) (Figure 9) The timerequired for the tablet to rise to the surface of the solutionand to float was taken as the floating lag time The durationof time in which dosage form constantly remained on thesurface of the medium was considered as total floating time(Table 9)

226 In Vitro Dissolution Studies The in vitro dissolutionstudies of venlafaxine hydrochloride from floating tabletwere carried out using USP Dissolution Testing ApparatusII (Paddle Type) The dissolution test was performed using

4 Scientifica

900mL of 01 N HCl at 37 plusmn 05∘C at 75 rpm One mL ofthe aliquot was withdrawn from the dissolution apparatus atdifferent predetermined time intervals (1 2 3 4 5 6 8 1012 14 16 and 18 hours) and the samples were replaced withthe fresh dissolution medium Then the sample was filteredthrough the Whatman filter paper number 41 and analyzedat 225 nmusingUV Spectrophotometer (ShimadzuUV-1700Japan) Cumulative drug release was calculated using ldquoPCPDisso v208rdquo software

227 Mechanism of Drug Release The drug release mech-anism was determined by fitting the data to the variouskinetic equations such as zero-order first-order Higuchi andKorsmeyer-Peppas and finding the 119877 and 119899 values of therelease profile corresponding to each model

228 Swelling Properties (Hydration Behavior of MatrixTablets) The swelling of the polymer can be measured bytheir ability to absorb water and swell The swelling propertyof the formulation was determined by various techniqueshere the hydration behavior or swelling properties weredetermined as per the method described by Deshpande et al[19]

The swelling properties of HPMC and Carbopol polymermatrices containing the drug were determined by placing thetablet matrices in the USP dissolution test apparatus II Themedium used was 01 N HCl 900mL rotated at 75 rpm Themedium was maintained at 37 plusmn 05∘C throughout the studyThe tablets were removed periodically from the dissolutionmedium After draining free water these were measured forweight gain thickness and diameter Swelling characteristicswere expressed in terms of percentage water uptake (WU)according to the following equation

WU

=wt of swollen tablet minus initial wt of the tablet

initial wt of the tablet

times 100

(4)

229 Detachment Stress Pieces of sheep fundus tissues werebrought frommarket and stored frozen in saline solution andthawed to room temperature immediately before use At thetime of testing a section of tissue (I) was transferred keepingthe mucosal side out to the upper glass vial (G) using arubber band and an aluminum foil cap The diameter of eachexposed mucosal membrane was 11 cm The vials with thefundus tissue were stored at 37∘C for 10min Next one vialwith a section of tissue (I) was connected to the balance (B)and the other vial was fixed on a height-adjustable pan (P)A bioadhesive tablet (F) was applied to the lower vial withthe help of two pieces of adhesive tape The height of the vialwas adjusted so that the tablet could adhere to the mucosaltissues in the vial The mucoadhesive forces of the floatingtablets were determined by the measuring device shown inFigure 5

A constant weight (10 g) was placed on the upper vial andapplied for two minutes after which it was removed and the

upper vial was then connected to the balance Weights (W)were added at a constant rate to the pan on the other side ofthe modified balance of the device until the two vials wereseparated

The bioadhesive force expressed as the detachment stressin dynecm2 was determined from the minimum weightrequired to detach the two vials using the following equation

detachment stress (dynecm2) =119898119892

119860 (5)

where119898119892 is the weight required for detachment and 119860 is thesurface area of the tablet [20] The detachment stresses of thevarious formulation codes are given in Table 8

2210 Scanning Electron Microscopy (SEM) The surfacetopography of the floating tablet was examined using scan-ning electron microscopy (Philips FEI XL-30) at differentmagnification and the acceleration voltage of 149 KV Tabletsamples were mounted on a scanning electron microscopeholder (aluminum sample mount) using a double side adhe-sive tape and coated with gold palladium under vacuum andthen surface topography was investigated

2211 Stability Studies Stability studies were carried outaccording to ICH andWHOguidelines to assess the drug andformulation stability The prepared floating tablets of opti-mized formulation (FC8) containing hydroxypropyl methylcellulose (HPMC K4MCR) and Carbopol 934PNF (FC8)were selected for stability studies based on in vitro drugrelease floating lag time total floating time and their physicalproperties The selected tablets of venlafaxine hydrochloride(FC8) were sealed in aluminum foil packaging coated insidewith polyethylene and kept in a humidity chamber at 45∘Cand 75 RH for three months [21] At the end and during thestudy samples were analyzed for the drug content in vitrodissolution floating behavior and other physicochemicalparameters (Table 9)

2212 Tablet Preparation for In Vivo Studies The optimizedformulation FC8 had shown good in vitro buoyancy andsustained-release behavior and hence was finally selectedfor in vivo study (ie radiography) The tablets of ninemm diameter and 350mg in weight were prepared Tomake the tablet X-ray opaque incorporation of BaSO

4was

necessary Barium sulphate (BaSO4) has high relative density

(44777 gcm3) and poor floating properties The amount ofthe X-ray opaque material in these tablets was sufficient toensure visibility by X-rays but at the same time this amountof barium sulphate was low enough to enable tablets to floatFor this purpose the amount of venlafaxine hydrochloridein the formulation FC8 was replaced with 40mg of bariumsulphate and all other ingredients were kept constant Thesetablets were analyzed for hardness and floating propertiesThe analysis confirmed that these tablets were similar to thetablets for in vitro testing

2213 In Vivo Radiographic Studies Nowadays radio-graphic study is a very popular evaluation parameter for

Scientifica 5

floating dosage form It helps to locate dosage form in theGIT by which one can predict and correlate the gastricretention time floating behavior and passage of the dosageform in the GIT Here the inclusion of radio-opaque materialinto a solid dosage form enables it to be visualized by X-rays It is also important that dosage forms are nondisin-tegrating units and animal subjects are young and healthy[22]

The animal protocol to carry out in vivo radiographicstudies was reviewed and approved by the InstitutionalAnimals Ethical Committee of Bundelkhand UniversityIndia (registration number 71602aCPCSEA) The in vivoradiographic studies were conducted in young and healthymale albino rabbits weighing 20 to 22 kg The animals werekept under standard laboratory conditions (temperature 25plusmn 2∘C) Rabbits were kept for one week in the animal houseto acclimatize them and fed a fixed standard diet The 4healthy male albino rabbits were used to monitor the invivo transit behavior of the floating tablet None of themhad symptoms or history of gastrointestinal (GI) disease Inorder to standardize the conditions ofGImotility the animalswere fasted for 12 hours prior to the commencement of eachexperiment In each experiment the first radiograph of theanimal subjects was made to ensure the absence of radio-opaque material in the GIT One of the tablets preparedfor radiography was orally administered to rabbits with thesufficient amount of water During the study the rabbits werenot allowed to eat but water was available ad libitum

For radiographic imaging all four legs of the rabbit weretied over a piece of plywood (20 times 20 inch) and location ofthe formulation in the stomach was monitored by keepingthe subjects in front of X-ray machine (Allengers BharatElectricals India Model number E 080743) The distancebetween the source of X-rays and the object was the samefor all the imaging This allowed us to see the tablet in thebody of the stomach antrum andor pyloric part of thestomach so that observations of the tablet movements couldbe made Gastric radiography was done at 1 hr 3 hr and 6 hrIn between the radiographic imaging the animals were freedand allowed to move and carry out normal activities but werenot allowed to take any foodThemean gastric residence timeof the drug was calculated

3 Results and Discussion

The granules prepared for the compression of floating tabletswere evaluated for their flow properties (Table 5) Granulesof matrix tablets of different formulation codes showed theangle of repose from 2229∘ plusmn 085 to 3739∘ plusmn 173 andflow rates from 091 plusmn 013 to 122 plusmn 010 gmsec and Carrrsquosindex was found in the range of 1813 to 2653 These resultsindicate that as the concentration of the HPMC K4MCRand Carbopol 934PNF increased in the formulations theangle of repose and Carrrsquos index were found to be increasedwhile their flow rate was found to be decreased Thus theangle of repose and Carrrsquos index value of different batches ofgranules indicate satisfactory flow behavior Other granulesparameters were also determined and found to be withinacceptable limits

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20Time (hr)

Optimization of the HPMC K4MCR

FC1FC2

FC3FC4

Cum

ulat

ive

dru

g re

leas

e

Figure 1 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC1 FC2 FC3 and FC4

The floating tablets of venlafaxine hydrochloride wereprepared by wet granulation method using HPMC K4MCRCarbopol 934PNF sodium bicarbonate and lactose Themagnesium stearate was used as the lubricant

The optimization of the formulation was done based onadjusting the drug-polymer ratio floating lag time durationof floating gas generating agents in vitro drug release rate

Results indicated that the low-density polymers likeHPMC K4MCR and Carbopol 934PNF affects the floatingbehavior of the venlafaxine hydrochloride floating tabletHPMC K4MCR and Carbopol 934PNF are selected becauseof their high viscosities which are desired for the sustainedrelease For optimizing the concentration ratio of the drugpolymers and several formulations of the different batcheswere formulated randomly in which only drug to the poly-mer ratio varied and remaining ingredients of formulationremained constant Then floating behavior and release ratestudy of these formulations were determined in the 01 NHCl (pH 12) Then a certain ratio of drug to polymer givessatisfactory floating behavior and in vitro drug release in 01NHCl At this stage of optimization few batches of formulationcodes FC1 FC2 FC3 and FC4 were prepared for the opti-mizing concentration of the polymer for obtaining the bestfloatation behavior and in vitro drug release Floating lag timeand duration of floating was found to be 112 99 88 and 74seconds and approximately 17 18 23 and 27 hr respectivelyThe cumulative drug release was found to be 9734 97439443 and 9065 in 18 hr for the formulation codes FC1 FC2FC3 and FC4 (Figure 1) But the release pattern of the FC3showed better in vitro release of drug in the sustainedmannerin predetermined time intervals than formulations FC1 FC2and FC4 Formulation FC3 also showed better floatationbehavior (ie floating lag time 88 seconds and duration offloating approximately 23 hr) Therefore formulation FC3has been selected in order to obtain the optimum HPMCloading level because it has better in vitro release patternand floatation behavior Results also indicate that as theconcentration of theHPMC increased the cumulativedrug

6 Scientifica

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

Optimization of Carbopol 934PNF

FC3FC5

FC6FC7

Figure 2 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC3 FC5 FC6 and FC7

release behavior and floating lag time were also decreasedto a certain value After optimizing the concentration ofHPMC K4MCR next optimization was done for Carbopolconcentration As the concentration of the Carbopol in theFC5 formulation decreased then the in vitro drug releasepattern of the formulation (FC5) was increased compared tothat of the FC3 formulation for 18 hr dissolution study It wasfound that as the concentration of the Carbopol increased inthe formulation (ie FC6 (20mg) and FC7 (25mg)) thenin vitro drug release was also decreased compared to thatof FC3 (15mg) Because the release and floatation behaviorexhibited by the FC3 were much better than FC5 FC6 andFC7 (Figure 2) the formulation FC3 remained selected forthe further study

For the floating drug delivery system the ideal matrixshould be highly permeable for the dissolution media inorder to initiate rapid generation of the carbon dioxide gas(CO2) and also should be permeable for CO

2to promote

floating The buoyancy lag time of the tablets depends on theconcentration of the sodiumbicarbonate (NaHCO

3) involved

in the CO2formation In the trial study in vitro release of

drug from the different formulation batches was studied todetermine the optimum concentration of the gas generatingagent It was observed from the formulations FC8 FC9 andFC10 that as the concentration of the sodium bicarbonateincreased in these formulations the floating lag time wasfound to be decreased but their corresponding release ofdrug was increased (Figure 3) The trial study also showedthat at higher concentration of the sodium bicarbonate FC10(30mg) causes bursting and rapid disintegration of tabletHence it was desirable to use optimum concentration ofsodium bicarbonate to get the least floating lag time withminimum bursting effect and desired floating time with-out rapid disintegration So FC8 with sodium bicarbonate(20mg) was optimized and selected to achieve optimum invitro buoyancy with less bursting effectThe formulation FC8was preferred over the FC3 because the in vitro release of

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20Time (hr)

Optimization of sodium bicarbonate

FC3FC8

FC9FC10

Cum

ulat

ive

dru

g re

leas

e

Figure 3 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC3 FC8 FC9 and FC10

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

Optimization of lactose

FC8FC11

FC12FC13

Figure 4 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC8 FC11 FC12 and FC13

drug was increased in the more controlled manner than thatof FC3

Here the lactose acts as channeling agent which is solublein the dissolutionmedium therefore thematrix integrity getsbroken and showed faster in vitro drug dissolution Resultsindicate from the formulations (ie FC11 FC12 and FC13)that release rate of drug is directly proportional to the con-centration of the lactose (Figure 4) As the concentration ofthe lactose increased in vitro drug releases were also found tobe increased but if the concentration of the lactose increasedmore than 50mg then the tablet will start disintegration bythe erosion mechanism Therefore optimum concentrationof the lactose is required for getting the maximum in vitrodrug release without causing erosion From the above resultsFC8 was found to be the best formulation which showedbetter in vitro drug release and floatation behavior

Scientifica 7

Table 6 Physiochemical characterization of venlafaxine hydrochloride tablets

Code weight variation Hardness (kgcm2) friability drug contentuniformity

Floating lagtime (sec)

Total floatingtime (hr)

FC1 plusmn30 640 plusmn 016 0524 9921 plusmn 146 112 plusmn 287 1733 plusmn 205FC2 plusmn45 637 plusmn 045 0564 9847 plusmn 034 99 plusmn 249 1850 plusmn 187FC3 plusmn35 653 plusmn 057 0572 9886 plusmn 124 88 plusmn 287 2333 plusmn 062FC4 plusmn40 663 plusmn 058 0482 9720 plusmn 018 74 plusmn 327 2708 plusmn 095FC5 plusmn25 693 plusmn 052 0458 9853 plusmn 052 94 plusmn 327 1275 plusmn 208FC6 plusmn30 670 plusmn 070 0545 9908 plusmn 221 82 plusmn 294 2650 plusmn 102FC7 plusmn40 643 plusmn 033 0584 9740 plusmn 102 76 plusmn 245 2925 plusmn 074FC8 plusmn40 667 plusmn 098 0580 9891 plusmn 018 72 plusmn 249 2450 plusmn 074FC9 plusmn25 670 plusmn 049 0495 9800 plusmn 024 64 plusmn 294 2650 plusmn 154FC10 plusmn30 647 plusmn 090 0457 9756 plusmn 132 54 plusmn 245 2625 plusmn 187FC11 plusmn30 680 plusmn 043 0530 9843 plusmn 064 67 plusmn 374 2825 plusmn 069FC12 plusmn45 627 plusmn 041 0572 9902 plusmn 145 81 plusmn 287 2052 plusmn 092FC13 plusmn45 667 plusmn 066 0592 9874 plusmn 082 93 plusmn 327 1800 plusmn 082Mean plusmn SD 119899 = 3 FC formulation code

B

WF

G

I

T

PG998400

B modified balance W weights G and G998400 glass vialF bioadhesive tablet I fundus tissueT supportive adhesive tape P height-adjustable pan

Figure 5 Mucoadhesion measuring device for obtaining detach-ment stress

The diameter of the formulations FC1 to FC13 was foundin the range of 897 plusmn 001 to 899 plusmn 003 and thickness wasin the range of 396 plusmn 001 to 399 plusmn 002 The variationin the weight was found in the range of plusmn5 complyingwith pharmacopoeial specificationsThe hardness of differentformulation was found to be between 627 plusmn 041 and693 plusmn 052 kgcm2 indicating good mechanical strengthThe friability was below 1 for all formulations which isan indication of good mechanical resistance of tablet Thedrug content varied between 9800 and 9921 in differentformulation with low standard deviation (Table 6)

The swelling of the polymers used (ie HPMC K4MCRand Carbopol 934PNF) was determined by swelling indexof the tablet Hydrophilic matrices (ie HPMC K4MCRand Carbopol 934PNF) in contact with water swell andincrease their volume due to water diffusion through thematrix The polymer chains continue the hydration process

and the matrix gained more water Drug diffusion signif-icantly depends on the water content of the tablet Thismay be because the mobility of the polymer chains is verydependent on the water content of the system In case ofhigh-water content polymer chain relaxation takes placewith volume expansion resulting in marked swelling of thesystem Also higher water content could lead to greaterpenetration of the gastric fluid into the tablet leading toquicker carbon dioxide gas generation thereby reducing thefloating lag time Consequently quicker and greater swellingof the tablet would lead to an increase in the diffusionpathway and thus a reduction in diffusion rate So the drugrelease was found to be high initially and then graduallydecreased

The swelling index of all formulations from FC1 toFC10 at 24 hr was found to be between 13603 and 17099respectively The percentage water uptake was found to beimproved as the concentration of the HPMC K4MCR andCarbopol 934PNF increased in the formulation The resultindicates from Table 7 that swelling index was increasedmuch more in case of Carbopol compared to HPMC becauseCarbopol is bearing very goodwater sorption property It wasalso observed that as the concentration of the Carbopol in theformulation decreased the water uptake was also found tobe decreased (ie FC5)

Table 8 clearly indicates that the value of bioadhesiveforce was found to be increased significantly as the con-centration of the mucoadhesive polymer HPMC and Car-bopol increased All floating formulations showed mucoad-hesive forces in the range of 11042 to 16780 dynescm2Results indicate that as the concentration of HPMC K4MCRincreased in the formulations FC1 to FC4 then the valueof detachment forces also increased from 12345 to 15672dynescm2 respectively It was also observed that as theconcentration of Carbopol 934PNF increased the values ofdetachment forces were increased from the 15965 to 16700dynescm2 for formulations FC6 to FC7 respectively but as

8 Scientifica

Table7Sw

ellingbehavior

ofmatrix

tablets

Form

ulationcode

Initialweight(mg)

Initialthickn

ess(mm)

Initialdiam

eter

(mm)

Finalw

eight(mg)

Finalthickness(m

m)

Finald

iameter

(mm)

Swellin

gindex

FC1

23411plusmn305

397plusmn001

898plusmn001

55259plusmn311

442plusmn10

81816plusmn038

13603

FC2

24020plusmn435

398plusmn002

897plusmn002

57852plusmn13

2450plusmn074

1852plusmn12

014084

FC3

24418plusmn16

9397plusmn001

899plusmn001

60710plusmn506

456plusmn089

1873plusmn14

814867

FC4

25010plusmn17

1399plusmn002

897plusmn001

6372

2plusmn340

461plusmn12

11885plusmn092

15478

FC5

23958plusmn10

1398plusmn001

898plusmn002

57848plusmn225

453plusmn14

21862plusmn13

41414

5FC

625009plusmn18

9396plusmn001

899plusmn002

64886plusmn413

463plusmn12

71889plusmn088

1594

5FC

725558plusmn329

397plusmn002

897plusmn001

6816

8plusmn267

466plusmn054

1893plusmn15

316672

FC8

25017plusmn12

3399plusmn002

899plusmn001

65425plusmn328

462plusmn028

1899plusmn067

16152

FC9

25421plusmn353

398plusmn001

898plusmn001

67817plusmn14

4464plusmn078

1914plusmn025

16678

FC10

2596

7plusmn442

399plusmn002

897plusmn002

70367plusmn287

468plusmn038

1927plusmn14

417099

MeanplusmnSD

119899=3FC

form

ulationcode

Scientifica 9

Table 8 Detachment forces of different formulations

S numberFormulation code (FC) Detachment force (dynescm2)1 FC1 123452 FC2 131743 FC3 147534 FC4 156725 FC5 110426 FC6 159657 FC7 167808 FC8 142189 FC9 1402110 FC10 1362411 FC11 1437812 FC12 1452613 FC13 14065

the concentration of Carbopol decreased value of forces wasdecreased (ie FC5) Hence it was also concluded from theresults that the values of detachment forces were increasedmuchmore in case of Carbopol 934PNF compared to HPMCK4MCR because the Carbopol was highly bioadhesive ascompared to HPMC

Bioadhesion is a surface phenomenon inwhich amaterialof synthetic or natural origin adheres or sticks to a biologicalsurface usually mucus membrane Many hydrophilic poly-mers adhere to mucosal surfaces as they attract water fromthe mucus gel layer adhering to the epithelial surface This isthe simplest mechanism of adhesion and it has been definedas ldquoadhesion by hydrationrdquo The hydrogen bonding presentbetween the adherent polymer and mucus is involved inmucoadhesion at themolecular level As the concentration ofbioadhesive polymers increased then the hydrogen bondingbetween the mucus membrane and adherent polymer at themolecular level increased therefore detachment forces werealso found to be increased

Surface morphology of the optimized formulation FC8was examined by scanning electronmicroscopy (SEM) It wasobserved from the SEM photographs that the drug is releasedfrom the matrix tablet by the diffusion process The surfacemorphology of the matrix tablet after dissolution showedthat the solvent front enters the matrix and moves slowlytoward the center of the tablet The drug diffuses out of thematrix after it comes in contact with dissolution mediumThe images of the tablet showed a network in the swollenpolymer through which the drug diffused to the surroundingmedium Thus it was concluded that the drug was releasedfrom a matrix by diffusion mechanism (Figures 6 and7)

A comparative study was performed on the availablemarketed formulation of extended release tablet and capsulecontaining venlafaxine hydrochloride equivalent to venlafax-ine 375mgThe results obtained from the in vitro drug releasestudy showed that optimized formulations FC8 showedmore sustained-release action than that of tablet (marketed-1) and capsule (marketed-2) with respect to time of 18 hr(Figure 8)

Figure 6 Scanning electron microscopy of optimized formulationFC8 of tablet surface before dissolution

Figure 7 Scanning electron microscopy of optimized formulationFC8 of tablet surface after dissolution

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

FC8Marketed-1

Marketed-2

Figure 8 Comparison of drug release of optimized formulation(FC8) versus marketed formulations for 18 hr

The drug release was found to follow first-order kineticswith 119903 = 09935 and 09904 for marketed-1 (tablet) andmarketed-2 (capsule) respectively while optimized formula-tion FC8 followed the Peppasmodel with value of 119903 = 09962119899 = 04473 and 119896 = 252788 So the best-fit model was foundto be the Peppas model for optimized formulation FC8 Themarketed formulations of tablet and capsule showed morethan 90of drug release in 14 hrwhile optimized formulationFC8 showed only 8258 of drug release in 14 hr

The data obtained from in vitro dissolution studies werefitted to zero-order first-order Higuchi and Korsmeyer-Peppas equations All release kinetic models were applied

10 Scientifica

Table 9 Stability studies of venlafaxine hydrochloride floating tablets of optimized formulation (FC8)

Characteristic Initial 1st month 2nd month 3rd monthHardness (kgcm2) 667 plusmn 098 602 plusmn 056 642 plusmn 020 630 plusmn 088Drug content () 9891 plusmn 018 9834 plusmn 002 9812 plusmn 142 9800 plusmn 027Floating lag time (seconds) 72 plusmn 265 76 plusmn 126 84 plusmn 245 90 plusmn 326Total floating time (hours) 2450 plusmn 074 2416 plusmn 112 2418 plusmn 226 2408 plusmn 034Swelling index () 16152 16082 16064 16018Buoyancy on disturbing Float Float Float FloatMatrix integrity Very good Very good Very good Very good in vitro release 18 hours 9692 plusmn 083 9443 plusmn 138 9398 plusmn 042 9300 plusmn 156Mean plusmn SD 119899 = 3 FC formulation code

(a) (b)

Figure 9 In vitro floating studies of optimized formulation (FC8) (a) after 80 sec and (b) after 24 hr

on the formulation codes FC1 FC2 FC3 FC4 FC5 FC6FC7 FC8 FC9 FC10 FC11 FC12 and FC13 due to theirsatisfactory release behavior The best-fit model was found tobe the matrix for formulation codes FC1 FC2 and FC5 andPeppas for formulation codes FC3 FC4 FC6 FC7 FC8 FC9FC10 FC11 FC12 and FC13The selection criteria for the bestmodel were based on goodness of fit of the data and residualsum of squares The details of the best-fit model of differentformulation codes are given in Table 10

For confirming the diffusion mechanism of optimizedformulation FC8 the data was fitted to the Korsmeyerequation which showed the exponent value 119899 = 04473Because the optimized formulation FC8 had the exponentvalue (119899) less than 05 it was suggested that the releasemechanism of venlafaxine hydrochloride indicates swellingand diffusion mechanism of floating tablets which followedthe Fickian diffusion (Case I transport) This kinetic dataanalysis was done by using ldquoPCP Disso V208rdquo Software(Poona College of Pharmacy Pune India)

The optimized formulation FC8 was suggested for stabil-ity study based on in vitro floating lag time total floating timein vitro drug dissolution studies and its physical propertiesThe floating tablets were investigated at 400∘C75 RH in

aluminum foil packaging for three monthsThe increased lagtime indicates the possibility of reaction of sodium bicarbon-ate with moisture during the study period However therewas the very little effect on the duration of the floating andmatrix integrity of the tablets Some drug degradation wasfound but it was not statistically significant Decreased drugrelease was found from the formulation but drug releasedcompiled the official standard of release since more than80 of the drug was released (Table 9) Thus it was foundthat the floating tablets of venlafaxine hydrochloride werealmost stable under these storage conditions for at least threemonths

The in vitro studies with BaSO4-containing floating

tablets showed a floating lag time of 112plusmn200 seconds hard-ness of 660 plusmn 003 kgcm2 and thickness of 399 plusmn 001mmThe intragastric behavior of the BaSO

4-loaded tablet in the

albino rabbit was observed by using a radiographic imagingtechnique Radiographic images were taken after 1 3 and6 hr showing that the tablet had altered its position in thestomachThis provided evidence that the tablets were floatingon the gastric fluid After 4 hr of the tablet administrationthe swelling of the tablet is visualized very well together withthe white dry core and translucent swelling layer around it

Scientifica 11

Table 10 Drug release kinetics for floating-bioadhesive tablets

S number Formulation code (FC) Best-fit model 119877 value Parameters for Korsmeyer-Peppas equation

1 FC1 Matrix 09948 119899 = 04817

119896 = 242487

2 FC2 Matrix 09942 119899 = 05125

119896 = 213988

3 FC3 Peppas 09966 119899 = 04919

119896 = 210756

4 FC4 Peppas 09914 119899 = 05500

119896 = 169021

5 FC5 Matrix 09968 119899 = 04877

119896 = 229187

6 FC6 Peppas 09941 119899 = 05430

119896 = 171357

7 FC7 Peppas 09966 119899 = 06472

119896 = 130990

8 FC8 Peppas 09962 119899 = 04473

119896 = 252788

9 FC9 Peppas 09942 119899 = 03266

119896 = 374233

10 FC10 Peppas 09910 119899 = 03279

119896 = 396415

11 FC11 Peppas 09972 119899 = 04974

119896 = 213024

12 FC12 Peppas 09933 119899 = 03702

119896 = 332823

13 FC13 Peppas 09934 119899 = 03466

119896 = 366938

Note each sample was analyzed in triplicate (119899 = 3)119896 kinetic constant119899 exponent value

due to the swellable polymers HPMCK4MCR and Carbopol934PNF

Hence examination of the sequential radiographicimages of the GIT during the study clearly indicated that thetablet remained buoyant and altered its position in the gastriccontents for more than 6 hr So prolonged gastric retentiontime (GRT) of more than 6 hr is achieved (Figures 10(a)ndash10(c))

The objective of the in vivo studies was to provide theproof of concept that the floating capability of the floatingtablet was useful for the increasing the gastric residence timeof the dosage form For facilitating the trials on the rabbitsthe dosage form did not contain any drug and the scope waslimited to the observation of the behavior of the system in thestomach

4 Conclusion

The present study was carried out to develop the floating-bioadhesive drug delivery of venlafaxine hydrochloride using

HPMC K4MCR and Carbopol 934PNF polymers as the car-rier Optimized formulation FC8 gave satisfactory results forvarious physiochemical evaluations for tablets like hardnessweight variation floating lag time and uniformity of contentIn vitro dissolution studies of the optimized formulation FC8showed the sustained release for 18 hr followed by the Fickiandiffusion and an in vivo study indicated increased gastricresidence time by the floating principle and was considereddesirable for improving the bioavailability of the drug Allthese results also indicated that a low amount of floatingagent and high amount of hydrophilic polymer favored thesustained release of venlafaxine hydrochloride from the float-ing gastroretentive tablet formulations Developed sustained-release oral formulation for prolonged release would be asignificant advantage for the patient and may result in fewerside effects due to reduction of the blood concentrationfluctuations especially in long-term therapy Thus results ofthe current study clearly indicate a promising potential of thevenlafaxine hydrochloride floating system as an alternativeto the conventional dosage form However further clinical

12 Scientifica

(a)

(b)

(c)

Figure 10 Radiographic images showing the presence of BaSO4loaded floating tablet in the stomach at different time periods (the tablet is

indicated with an arrow) Images were taken after (a) 1 hr (b) 3 hr and (c) 6 hr after tablet administration

studies are needed to assess the utility of this system forpatients suffering from depression

Competing Interests

The authors declare that there are no competing interestsThe authors do not have a direct financial relation with thecommercial identities mentioned in the research paper thatmight lead to competing interests for any of the authors

Acknowledgments

The authors are thankful to Ranbaxy Research Lab Ltd Gur-gaon Haryana India for providing venlafaxine hydrochlo-ride as a gift sample and Arihant Trading CompanyMumbaiIndia and Colorcon Asia Pvt Ltd Goa India for providingthe polymer samples They also wish to thank Dr P KJain Radiologist VardhmanMedical Centre Jhansi India forextending radiography

Scientifica 13

References

[1] O Berton and E J Nestler ldquoNew approaches to antidepressantdrug discovery beyond monoaminesrdquo Nature Reviews Neuro-science vol 7 no 2 pp 137ndash151 2006

[2] E J Nestler M Barrot R J DiLeone A J Eisch S J Gold andLMMonteggia ldquoNeurobiology of depressionrdquoNeuron vol 34no 1 pp 13ndash25 2002

[3] E Richelson ldquoPharmacology of antidepressantsrdquo Mayo ClinicProceedings vol 76 no 5 pp 511ndash527 2001

[4] httpwwwdrugbankcadrugsDB00285[5] P Blier E Saint-Andre C Hebert C De Montigny N Lavoie

and G Debonnel ldquoEffects of different doses of venlafaxine onserotonin and norepinephrine reuptake in healthy volunteersrdquoInternational Journal of Neuropsychopharmacology vol 10 no1 pp 41ndash50 2007

[6] S M Holliday and P Benfield ldquoVenlafaxine a review of itspharmacology and therapeutic potential in depressionrdquo Drugsvol 49 no 2 pp 280ndash294 1995

[7] B Omprakash S Ajay G Santosh and P Amin ldquoFormulationdevelopment of venlafaxine hydrochloride extended releasetablet and invitro characterizationsrdquo International Journal ofPharmTech Research vol 4 no 4 pp 1777ndash1784 2012

[8] E AMuth J AMoyer J T Haskins T H Andree andG EMHusbands ldquoBiochemical neurophysiological and behavioraleffects of Wy-45233 and other identified metabolites of theantidepressant venlafaxinerdquo Drug Development Research vol23 no 2 pp 191ndash199 1991

[9] B Cusack A Nelson and E Richelson ldquoBinding of antide-pressants to human brain receptors focus on newer generationcompoundsrdquo Psychopharmacology vol 114 no 4 pp 559ndash5651994

[10] B N Singh and K H Kim ldquoFloating drug delivery systems anapproach to oral controlled drug delivery via gastric retentionrdquoJournal of Controlled Release vol 63 no 3 pp 235ndash259 2000

[11] P Bhardwaj R Singh and A Swarup ldquoStomach specific drugdelivery systemmdasha brief reviewrdquo Inventi Rapid NDDS no 3 pp1ndash9 2012

[12] R B Umamaheshwari S Jain D Bhadra and N K JainldquoFloating microspheres bearing acetohydroxamic acid for thetreatment of Helicobacter pylorirdquo Journal of Pharmacy andPharmacology vol 55 no 12 pp 1607ndash1613 2003

[13] S K Jain AMAwasthi N K Jain andG P Agrawal ldquoCalciumsilicate based microspheres of repaglinide for gastroretentivefloating drug delivery preparation and in vitro characteriza-tionrdquo Journal of Controlled Release vol 107 no 2 pp 300ndash3092005

[14] D Chaurasia K Kaushik P Bhardwaj H Chaurasia S K Jainand S Shobhna ldquoDevelopment and in vitro characterizationof floating microspheres bearing tramadol HClrdquo Acta PoloniaePharmaceuticamdashDrug Research vol 68 no 5 pp 795ndash801 2011

[15] P Bhardwaj H Chaurasia D Chaurasia S K Prajapati andS Singh ldquoFormulation and in-vitro evaluation of floatingmicroballoons of indomethacinrdquo Acta Poloniae Pharmaceuti-camdashDrug Research vol 67 no 3 pp 291ndash298 2010

[16] L Lachman H A Liberman and J L Kanig The Theoryand Practice of Industrial Pharmacy Varghese Publishin HouseBombay India 3rd edition 1991

[17] M E Aulton PharmaceuticsThe Science of Dosage formDesignElsevier Science Ltd Philadelphia Pa USA Churchill Living-stone London UK 2nd edition 2002

[18] M Jaimini A C Rana andY S Tanwar ldquoFormulation and eval-uation of famotidine floating tabletsrdquo Current Drug Deliveryvol 4 no 1 pp 51ndash55 2007

[19] A A Deshpande N H Shah C T Rhodes and W MalickldquoDevelopment of a novel controlled-release system for gastricretentionrdquo Pharmaceutical Research vol 14 no 6 pp 815ndash8191997

[20] G S Sonar D K Jain and D M More ldquoPreparation and invitro evaluation of bilayer and floating-bioadhesive tablets ofrosiglitazone maleaterdquo Asian Journal of Pharmaceutical Sciencevol 2 no 4 pp 161ndash169 2007

[21] B R Matthews ldquoRegulatory aspects of stability testing inEuroperdquo Drug Development and Industrial Pharmacy vol 25no 7 pp 831ndash856 1999

[22] R Gupta S K Prajapati S Pattnaik and P Bhardwaj ldquoFor-mulation and evaluation of novel stomach specific floatingmicrospheres bearing famotidine for treatment of gastric ulcerand their radiographic studyrdquo Asian Pacific Journal of TropicalBiomedicine vol 4 no 9 pp 729ndash735 2014

Submit your manuscripts athttpwwwhindawicom

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Volume 2014

ToxinsJournal of

VaccinesJournal of

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AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

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Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

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ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

4 Scientifica

900mL of 01 N HCl at 37 plusmn 05∘C at 75 rpm One mL ofthe aliquot was withdrawn from the dissolution apparatus atdifferent predetermined time intervals (1 2 3 4 5 6 8 1012 14 16 and 18 hours) and the samples were replaced withthe fresh dissolution medium Then the sample was filteredthrough the Whatman filter paper number 41 and analyzedat 225 nmusingUV Spectrophotometer (ShimadzuUV-1700Japan) Cumulative drug release was calculated using ldquoPCPDisso v208rdquo software

227 Mechanism of Drug Release The drug release mech-anism was determined by fitting the data to the variouskinetic equations such as zero-order first-order Higuchi andKorsmeyer-Peppas and finding the 119877 and 119899 values of therelease profile corresponding to each model

228 Swelling Properties (Hydration Behavior of MatrixTablets) The swelling of the polymer can be measured bytheir ability to absorb water and swell The swelling propertyof the formulation was determined by various techniqueshere the hydration behavior or swelling properties weredetermined as per the method described by Deshpande et al[19]

The swelling properties of HPMC and Carbopol polymermatrices containing the drug were determined by placing thetablet matrices in the USP dissolution test apparatus II Themedium used was 01 N HCl 900mL rotated at 75 rpm Themedium was maintained at 37 plusmn 05∘C throughout the studyThe tablets were removed periodically from the dissolutionmedium After draining free water these were measured forweight gain thickness and diameter Swelling characteristicswere expressed in terms of percentage water uptake (WU)according to the following equation

WU

=wt of swollen tablet minus initial wt of the tablet

initial wt of the tablet

times 100

(4)

229 Detachment Stress Pieces of sheep fundus tissues werebrought frommarket and stored frozen in saline solution andthawed to room temperature immediately before use At thetime of testing a section of tissue (I) was transferred keepingthe mucosal side out to the upper glass vial (G) using arubber band and an aluminum foil cap The diameter of eachexposed mucosal membrane was 11 cm The vials with thefundus tissue were stored at 37∘C for 10min Next one vialwith a section of tissue (I) was connected to the balance (B)and the other vial was fixed on a height-adjustable pan (P)A bioadhesive tablet (F) was applied to the lower vial withthe help of two pieces of adhesive tape The height of the vialwas adjusted so that the tablet could adhere to the mucosaltissues in the vial The mucoadhesive forces of the floatingtablets were determined by the measuring device shown inFigure 5

A constant weight (10 g) was placed on the upper vial andapplied for two minutes after which it was removed and the

upper vial was then connected to the balance Weights (W)were added at a constant rate to the pan on the other side ofthe modified balance of the device until the two vials wereseparated

The bioadhesive force expressed as the detachment stressin dynecm2 was determined from the minimum weightrequired to detach the two vials using the following equation

detachment stress (dynecm2) =119898119892

119860 (5)

where119898119892 is the weight required for detachment and 119860 is thesurface area of the tablet [20] The detachment stresses of thevarious formulation codes are given in Table 8

2210 Scanning Electron Microscopy (SEM) The surfacetopography of the floating tablet was examined using scan-ning electron microscopy (Philips FEI XL-30) at differentmagnification and the acceleration voltage of 149 KV Tabletsamples were mounted on a scanning electron microscopeholder (aluminum sample mount) using a double side adhe-sive tape and coated with gold palladium under vacuum andthen surface topography was investigated

2211 Stability Studies Stability studies were carried outaccording to ICH andWHOguidelines to assess the drug andformulation stability The prepared floating tablets of opti-mized formulation (FC8) containing hydroxypropyl methylcellulose (HPMC K4MCR) and Carbopol 934PNF (FC8)were selected for stability studies based on in vitro drugrelease floating lag time total floating time and their physicalproperties The selected tablets of venlafaxine hydrochloride(FC8) were sealed in aluminum foil packaging coated insidewith polyethylene and kept in a humidity chamber at 45∘Cand 75 RH for three months [21] At the end and during thestudy samples were analyzed for the drug content in vitrodissolution floating behavior and other physicochemicalparameters (Table 9)

2212 Tablet Preparation for In Vivo Studies The optimizedformulation FC8 had shown good in vitro buoyancy andsustained-release behavior and hence was finally selectedfor in vivo study (ie radiography) The tablets of ninemm diameter and 350mg in weight were prepared Tomake the tablet X-ray opaque incorporation of BaSO

4was

necessary Barium sulphate (BaSO4) has high relative density

(44777 gcm3) and poor floating properties The amount ofthe X-ray opaque material in these tablets was sufficient toensure visibility by X-rays but at the same time this amountof barium sulphate was low enough to enable tablets to floatFor this purpose the amount of venlafaxine hydrochloridein the formulation FC8 was replaced with 40mg of bariumsulphate and all other ingredients were kept constant Thesetablets were analyzed for hardness and floating propertiesThe analysis confirmed that these tablets were similar to thetablets for in vitro testing

2213 In Vivo Radiographic Studies Nowadays radio-graphic study is a very popular evaluation parameter for

Scientifica 5

floating dosage form It helps to locate dosage form in theGIT by which one can predict and correlate the gastricretention time floating behavior and passage of the dosageform in the GIT Here the inclusion of radio-opaque materialinto a solid dosage form enables it to be visualized by X-rays It is also important that dosage forms are nondisin-tegrating units and animal subjects are young and healthy[22]

The animal protocol to carry out in vivo radiographicstudies was reviewed and approved by the InstitutionalAnimals Ethical Committee of Bundelkhand UniversityIndia (registration number 71602aCPCSEA) The in vivoradiographic studies were conducted in young and healthymale albino rabbits weighing 20 to 22 kg The animals werekept under standard laboratory conditions (temperature 25plusmn 2∘C) Rabbits were kept for one week in the animal houseto acclimatize them and fed a fixed standard diet The 4healthy male albino rabbits were used to monitor the invivo transit behavior of the floating tablet None of themhad symptoms or history of gastrointestinal (GI) disease Inorder to standardize the conditions ofGImotility the animalswere fasted for 12 hours prior to the commencement of eachexperiment In each experiment the first radiograph of theanimal subjects was made to ensure the absence of radio-opaque material in the GIT One of the tablets preparedfor radiography was orally administered to rabbits with thesufficient amount of water During the study the rabbits werenot allowed to eat but water was available ad libitum

For radiographic imaging all four legs of the rabbit weretied over a piece of plywood (20 times 20 inch) and location ofthe formulation in the stomach was monitored by keepingthe subjects in front of X-ray machine (Allengers BharatElectricals India Model number E 080743) The distancebetween the source of X-rays and the object was the samefor all the imaging This allowed us to see the tablet in thebody of the stomach antrum andor pyloric part of thestomach so that observations of the tablet movements couldbe made Gastric radiography was done at 1 hr 3 hr and 6 hrIn between the radiographic imaging the animals were freedand allowed to move and carry out normal activities but werenot allowed to take any foodThemean gastric residence timeof the drug was calculated

3 Results and Discussion

The granules prepared for the compression of floating tabletswere evaluated for their flow properties (Table 5) Granulesof matrix tablets of different formulation codes showed theangle of repose from 2229∘ plusmn 085 to 3739∘ plusmn 173 andflow rates from 091 plusmn 013 to 122 plusmn 010 gmsec and Carrrsquosindex was found in the range of 1813 to 2653 These resultsindicate that as the concentration of the HPMC K4MCRand Carbopol 934PNF increased in the formulations theangle of repose and Carrrsquos index were found to be increasedwhile their flow rate was found to be decreased Thus theangle of repose and Carrrsquos index value of different batches ofgranules indicate satisfactory flow behavior Other granulesparameters were also determined and found to be withinacceptable limits

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20Time (hr)

Optimization of the HPMC K4MCR

FC1FC2

FC3FC4

Cum

ulat

ive

dru

g re

leas

e

Figure 1 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC1 FC2 FC3 and FC4

The floating tablets of venlafaxine hydrochloride wereprepared by wet granulation method using HPMC K4MCRCarbopol 934PNF sodium bicarbonate and lactose Themagnesium stearate was used as the lubricant

The optimization of the formulation was done based onadjusting the drug-polymer ratio floating lag time durationof floating gas generating agents in vitro drug release rate

Results indicated that the low-density polymers likeHPMC K4MCR and Carbopol 934PNF affects the floatingbehavior of the venlafaxine hydrochloride floating tabletHPMC K4MCR and Carbopol 934PNF are selected becauseof their high viscosities which are desired for the sustainedrelease For optimizing the concentration ratio of the drugpolymers and several formulations of the different batcheswere formulated randomly in which only drug to the poly-mer ratio varied and remaining ingredients of formulationremained constant Then floating behavior and release ratestudy of these formulations were determined in the 01 NHCl (pH 12) Then a certain ratio of drug to polymer givessatisfactory floating behavior and in vitro drug release in 01NHCl At this stage of optimization few batches of formulationcodes FC1 FC2 FC3 and FC4 were prepared for the opti-mizing concentration of the polymer for obtaining the bestfloatation behavior and in vitro drug release Floating lag timeand duration of floating was found to be 112 99 88 and 74seconds and approximately 17 18 23 and 27 hr respectivelyThe cumulative drug release was found to be 9734 97439443 and 9065 in 18 hr for the formulation codes FC1 FC2FC3 and FC4 (Figure 1) But the release pattern of the FC3showed better in vitro release of drug in the sustainedmannerin predetermined time intervals than formulations FC1 FC2and FC4 Formulation FC3 also showed better floatationbehavior (ie floating lag time 88 seconds and duration offloating approximately 23 hr) Therefore formulation FC3has been selected in order to obtain the optimum HPMCloading level because it has better in vitro release patternand floatation behavior Results also indicate that as theconcentration of theHPMC increased the cumulativedrug

6 Scientifica

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

Optimization of Carbopol 934PNF

FC3FC5

FC6FC7

Figure 2 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC3 FC5 FC6 and FC7

release behavior and floating lag time were also decreasedto a certain value After optimizing the concentration ofHPMC K4MCR next optimization was done for Carbopolconcentration As the concentration of the Carbopol in theFC5 formulation decreased then the in vitro drug releasepattern of the formulation (FC5) was increased compared tothat of the FC3 formulation for 18 hr dissolution study It wasfound that as the concentration of the Carbopol increased inthe formulation (ie FC6 (20mg) and FC7 (25mg)) thenin vitro drug release was also decreased compared to thatof FC3 (15mg) Because the release and floatation behaviorexhibited by the FC3 were much better than FC5 FC6 andFC7 (Figure 2) the formulation FC3 remained selected forthe further study

For the floating drug delivery system the ideal matrixshould be highly permeable for the dissolution media inorder to initiate rapid generation of the carbon dioxide gas(CO2) and also should be permeable for CO

2to promote

floating The buoyancy lag time of the tablets depends on theconcentration of the sodiumbicarbonate (NaHCO

3) involved

in the CO2formation In the trial study in vitro release of

drug from the different formulation batches was studied todetermine the optimum concentration of the gas generatingagent It was observed from the formulations FC8 FC9 andFC10 that as the concentration of the sodium bicarbonateincreased in these formulations the floating lag time wasfound to be decreased but their corresponding release ofdrug was increased (Figure 3) The trial study also showedthat at higher concentration of the sodium bicarbonate FC10(30mg) causes bursting and rapid disintegration of tabletHence it was desirable to use optimum concentration ofsodium bicarbonate to get the least floating lag time withminimum bursting effect and desired floating time with-out rapid disintegration So FC8 with sodium bicarbonate(20mg) was optimized and selected to achieve optimum invitro buoyancy with less bursting effectThe formulation FC8was preferred over the FC3 because the in vitro release of

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20Time (hr)

Optimization of sodium bicarbonate

FC3FC8

FC9FC10

Cum

ulat

ive

dru

g re

leas

e

Figure 3 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC3 FC8 FC9 and FC10

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

Optimization of lactose

FC8FC11

FC12FC13

Figure 4 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC8 FC11 FC12 and FC13

drug was increased in the more controlled manner than thatof FC3

Here the lactose acts as channeling agent which is solublein the dissolutionmedium therefore thematrix integrity getsbroken and showed faster in vitro drug dissolution Resultsindicate from the formulations (ie FC11 FC12 and FC13)that release rate of drug is directly proportional to the con-centration of the lactose (Figure 4) As the concentration ofthe lactose increased in vitro drug releases were also found tobe increased but if the concentration of the lactose increasedmore than 50mg then the tablet will start disintegration bythe erosion mechanism Therefore optimum concentrationof the lactose is required for getting the maximum in vitrodrug release without causing erosion From the above resultsFC8 was found to be the best formulation which showedbetter in vitro drug release and floatation behavior

Scientifica 7

Table 6 Physiochemical characterization of venlafaxine hydrochloride tablets

Code weight variation Hardness (kgcm2) friability drug contentuniformity

Floating lagtime (sec)

Total floatingtime (hr)

FC1 plusmn30 640 plusmn 016 0524 9921 plusmn 146 112 plusmn 287 1733 plusmn 205FC2 plusmn45 637 plusmn 045 0564 9847 plusmn 034 99 plusmn 249 1850 plusmn 187FC3 plusmn35 653 plusmn 057 0572 9886 plusmn 124 88 plusmn 287 2333 plusmn 062FC4 plusmn40 663 plusmn 058 0482 9720 plusmn 018 74 plusmn 327 2708 plusmn 095FC5 plusmn25 693 plusmn 052 0458 9853 plusmn 052 94 plusmn 327 1275 plusmn 208FC6 plusmn30 670 plusmn 070 0545 9908 plusmn 221 82 plusmn 294 2650 plusmn 102FC7 plusmn40 643 plusmn 033 0584 9740 plusmn 102 76 plusmn 245 2925 plusmn 074FC8 plusmn40 667 plusmn 098 0580 9891 plusmn 018 72 plusmn 249 2450 plusmn 074FC9 plusmn25 670 plusmn 049 0495 9800 plusmn 024 64 plusmn 294 2650 plusmn 154FC10 plusmn30 647 plusmn 090 0457 9756 plusmn 132 54 plusmn 245 2625 plusmn 187FC11 plusmn30 680 plusmn 043 0530 9843 plusmn 064 67 plusmn 374 2825 plusmn 069FC12 plusmn45 627 plusmn 041 0572 9902 plusmn 145 81 plusmn 287 2052 plusmn 092FC13 plusmn45 667 plusmn 066 0592 9874 plusmn 082 93 plusmn 327 1800 plusmn 082Mean plusmn SD 119899 = 3 FC formulation code

B

WF

G

I

T

PG998400

B modified balance W weights G and G998400 glass vialF bioadhesive tablet I fundus tissueT supportive adhesive tape P height-adjustable pan

Figure 5 Mucoadhesion measuring device for obtaining detach-ment stress

The diameter of the formulations FC1 to FC13 was foundin the range of 897 plusmn 001 to 899 plusmn 003 and thickness wasin the range of 396 plusmn 001 to 399 plusmn 002 The variationin the weight was found in the range of plusmn5 complyingwith pharmacopoeial specificationsThe hardness of differentformulation was found to be between 627 plusmn 041 and693 plusmn 052 kgcm2 indicating good mechanical strengthThe friability was below 1 for all formulations which isan indication of good mechanical resistance of tablet Thedrug content varied between 9800 and 9921 in differentformulation with low standard deviation (Table 6)

The swelling of the polymers used (ie HPMC K4MCRand Carbopol 934PNF) was determined by swelling indexof the tablet Hydrophilic matrices (ie HPMC K4MCRand Carbopol 934PNF) in contact with water swell andincrease their volume due to water diffusion through thematrix The polymer chains continue the hydration process

and the matrix gained more water Drug diffusion signif-icantly depends on the water content of the tablet Thismay be because the mobility of the polymer chains is verydependent on the water content of the system In case ofhigh-water content polymer chain relaxation takes placewith volume expansion resulting in marked swelling of thesystem Also higher water content could lead to greaterpenetration of the gastric fluid into the tablet leading toquicker carbon dioxide gas generation thereby reducing thefloating lag time Consequently quicker and greater swellingof the tablet would lead to an increase in the diffusionpathway and thus a reduction in diffusion rate So the drugrelease was found to be high initially and then graduallydecreased

The swelling index of all formulations from FC1 toFC10 at 24 hr was found to be between 13603 and 17099respectively The percentage water uptake was found to beimproved as the concentration of the HPMC K4MCR andCarbopol 934PNF increased in the formulation The resultindicates from Table 7 that swelling index was increasedmuch more in case of Carbopol compared to HPMC becauseCarbopol is bearing very goodwater sorption property It wasalso observed that as the concentration of the Carbopol in theformulation decreased the water uptake was also found tobe decreased (ie FC5)

Table 8 clearly indicates that the value of bioadhesiveforce was found to be increased significantly as the con-centration of the mucoadhesive polymer HPMC and Car-bopol increased All floating formulations showed mucoad-hesive forces in the range of 11042 to 16780 dynescm2Results indicate that as the concentration of HPMC K4MCRincreased in the formulations FC1 to FC4 then the valueof detachment forces also increased from 12345 to 15672dynescm2 respectively It was also observed that as theconcentration of Carbopol 934PNF increased the values ofdetachment forces were increased from the 15965 to 16700dynescm2 for formulations FC6 to FC7 respectively but as

8 Scientifica

Table7Sw

ellingbehavior

ofmatrix

tablets

Form

ulationcode

Initialweight(mg)

Initialthickn

ess(mm)

Initialdiam

eter

(mm)

Finalw

eight(mg)

Finalthickness(m

m)

Finald

iameter

(mm)

Swellin

gindex

FC1

23411plusmn305

397plusmn001

898plusmn001

55259plusmn311

442plusmn10

81816plusmn038

13603

FC2

24020plusmn435

398plusmn002

897plusmn002

57852plusmn13

2450plusmn074

1852plusmn12

014084

FC3

24418plusmn16

9397plusmn001

899plusmn001

60710plusmn506

456plusmn089

1873plusmn14

814867

FC4

25010plusmn17

1399plusmn002

897plusmn001

6372

2plusmn340

461plusmn12

11885plusmn092

15478

FC5

23958plusmn10

1398plusmn001

898plusmn002

57848plusmn225

453plusmn14

21862plusmn13

41414

5FC

625009plusmn18

9396plusmn001

899plusmn002

64886plusmn413

463plusmn12

71889plusmn088

1594

5FC

725558plusmn329

397plusmn002

897plusmn001

6816

8plusmn267

466plusmn054

1893plusmn15

316672

FC8

25017plusmn12

3399plusmn002

899plusmn001

65425plusmn328

462plusmn028

1899plusmn067

16152

FC9

25421plusmn353

398plusmn001

898plusmn001

67817plusmn14

4464plusmn078

1914plusmn025

16678

FC10

2596

7plusmn442

399plusmn002

897plusmn002

70367plusmn287

468plusmn038

1927plusmn14

417099

MeanplusmnSD

119899=3FC

form

ulationcode

Scientifica 9

Table 8 Detachment forces of different formulations

S numberFormulation code (FC) Detachment force (dynescm2)1 FC1 123452 FC2 131743 FC3 147534 FC4 156725 FC5 110426 FC6 159657 FC7 167808 FC8 142189 FC9 1402110 FC10 1362411 FC11 1437812 FC12 1452613 FC13 14065

the concentration of Carbopol decreased value of forces wasdecreased (ie FC5) Hence it was also concluded from theresults that the values of detachment forces were increasedmuchmore in case of Carbopol 934PNF compared to HPMCK4MCR because the Carbopol was highly bioadhesive ascompared to HPMC

Bioadhesion is a surface phenomenon inwhich amaterialof synthetic or natural origin adheres or sticks to a biologicalsurface usually mucus membrane Many hydrophilic poly-mers adhere to mucosal surfaces as they attract water fromthe mucus gel layer adhering to the epithelial surface This isthe simplest mechanism of adhesion and it has been definedas ldquoadhesion by hydrationrdquo The hydrogen bonding presentbetween the adherent polymer and mucus is involved inmucoadhesion at themolecular level As the concentration ofbioadhesive polymers increased then the hydrogen bondingbetween the mucus membrane and adherent polymer at themolecular level increased therefore detachment forces werealso found to be increased

Surface morphology of the optimized formulation FC8was examined by scanning electronmicroscopy (SEM) It wasobserved from the SEM photographs that the drug is releasedfrom the matrix tablet by the diffusion process The surfacemorphology of the matrix tablet after dissolution showedthat the solvent front enters the matrix and moves slowlytoward the center of the tablet The drug diffuses out of thematrix after it comes in contact with dissolution mediumThe images of the tablet showed a network in the swollenpolymer through which the drug diffused to the surroundingmedium Thus it was concluded that the drug was releasedfrom a matrix by diffusion mechanism (Figures 6 and7)

A comparative study was performed on the availablemarketed formulation of extended release tablet and capsulecontaining venlafaxine hydrochloride equivalent to venlafax-ine 375mgThe results obtained from the in vitro drug releasestudy showed that optimized formulations FC8 showedmore sustained-release action than that of tablet (marketed-1) and capsule (marketed-2) with respect to time of 18 hr(Figure 8)

Figure 6 Scanning electron microscopy of optimized formulationFC8 of tablet surface before dissolution

Figure 7 Scanning electron microscopy of optimized formulationFC8 of tablet surface after dissolution

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

FC8Marketed-1

Marketed-2

Figure 8 Comparison of drug release of optimized formulation(FC8) versus marketed formulations for 18 hr

The drug release was found to follow first-order kineticswith 119903 = 09935 and 09904 for marketed-1 (tablet) andmarketed-2 (capsule) respectively while optimized formula-tion FC8 followed the Peppasmodel with value of 119903 = 09962119899 = 04473 and 119896 = 252788 So the best-fit model was foundto be the Peppas model for optimized formulation FC8 Themarketed formulations of tablet and capsule showed morethan 90of drug release in 14 hrwhile optimized formulationFC8 showed only 8258 of drug release in 14 hr

The data obtained from in vitro dissolution studies werefitted to zero-order first-order Higuchi and Korsmeyer-Peppas equations All release kinetic models were applied

10 Scientifica

Table 9 Stability studies of venlafaxine hydrochloride floating tablets of optimized formulation (FC8)

Characteristic Initial 1st month 2nd month 3rd monthHardness (kgcm2) 667 plusmn 098 602 plusmn 056 642 plusmn 020 630 plusmn 088Drug content () 9891 plusmn 018 9834 plusmn 002 9812 plusmn 142 9800 plusmn 027Floating lag time (seconds) 72 plusmn 265 76 plusmn 126 84 plusmn 245 90 plusmn 326Total floating time (hours) 2450 plusmn 074 2416 plusmn 112 2418 plusmn 226 2408 plusmn 034Swelling index () 16152 16082 16064 16018Buoyancy on disturbing Float Float Float FloatMatrix integrity Very good Very good Very good Very good in vitro release 18 hours 9692 plusmn 083 9443 plusmn 138 9398 plusmn 042 9300 plusmn 156Mean plusmn SD 119899 = 3 FC formulation code

(a) (b)

Figure 9 In vitro floating studies of optimized formulation (FC8) (a) after 80 sec and (b) after 24 hr

on the formulation codes FC1 FC2 FC3 FC4 FC5 FC6FC7 FC8 FC9 FC10 FC11 FC12 and FC13 due to theirsatisfactory release behavior The best-fit model was found tobe the matrix for formulation codes FC1 FC2 and FC5 andPeppas for formulation codes FC3 FC4 FC6 FC7 FC8 FC9FC10 FC11 FC12 and FC13The selection criteria for the bestmodel were based on goodness of fit of the data and residualsum of squares The details of the best-fit model of differentformulation codes are given in Table 10

For confirming the diffusion mechanism of optimizedformulation FC8 the data was fitted to the Korsmeyerequation which showed the exponent value 119899 = 04473Because the optimized formulation FC8 had the exponentvalue (119899) less than 05 it was suggested that the releasemechanism of venlafaxine hydrochloride indicates swellingand diffusion mechanism of floating tablets which followedthe Fickian diffusion (Case I transport) This kinetic dataanalysis was done by using ldquoPCP Disso V208rdquo Software(Poona College of Pharmacy Pune India)

The optimized formulation FC8 was suggested for stabil-ity study based on in vitro floating lag time total floating timein vitro drug dissolution studies and its physical propertiesThe floating tablets were investigated at 400∘C75 RH in

aluminum foil packaging for three monthsThe increased lagtime indicates the possibility of reaction of sodium bicarbon-ate with moisture during the study period However therewas the very little effect on the duration of the floating andmatrix integrity of the tablets Some drug degradation wasfound but it was not statistically significant Decreased drugrelease was found from the formulation but drug releasedcompiled the official standard of release since more than80 of the drug was released (Table 9) Thus it was foundthat the floating tablets of venlafaxine hydrochloride werealmost stable under these storage conditions for at least threemonths

The in vitro studies with BaSO4-containing floating

tablets showed a floating lag time of 112plusmn200 seconds hard-ness of 660 plusmn 003 kgcm2 and thickness of 399 plusmn 001mmThe intragastric behavior of the BaSO

4-loaded tablet in the

albino rabbit was observed by using a radiographic imagingtechnique Radiographic images were taken after 1 3 and6 hr showing that the tablet had altered its position in thestomachThis provided evidence that the tablets were floatingon the gastric fluid After 4 hr of the tablet administrationthe swelling of the tablet is visualized very well together withthe white dry core and translucent swelling layer around it

Scientifica 11

Table 10 Drug release kinetics for floating-bioadhesive tablets

S number Formulation code (FC) Best-fit model 119877 value Parameters for Korsmeyer-Peppas equation

1 FC1 Matrix 09948 119899 = 04817

119896 = 242487

2 FC2 Matrix 09942 119899 = 05125

119896 = 213988

3 FC3 Peppas 09966 119899 = 04919

119896 = 210756

4 FC4 Peppas 09914 119899 = 05500

119896 = 169021

5 FC5 Matrix 09968 119899 = 04877

119896 = 229187

6 FC6 Peppas 09941 119899 = 05430

119896 = 171357

7 FC7 Peppas 09966 119899 = 06472

119896 = 130990

8 FC8 Peppas 09962 119899 = 04473

119896 = 252788

9 FC9 Peppas 09942 119899 = 03266

119896 = 374233

10 FC10 Peppas 09910 119899 = 03279

119896 = 396415

11 FC11 Peppas 09972 119899 = 04974

119896 = 213024

12 FC12 Peppas 09933 119899 = 03702

119896 = 332823

13 FC13 Peppas 09934 119899 = 03466

119896 = 366938

Note each sample was analyzed in triplicate (119899 = 3)119896 kinetic constant119899 exponent value

due to the swellable polymers HPMCK4MCR and Carbopol934PNF

Hence examination of the sequential radiographicimages of the GIT during the study clearly indicated that thetablet remained buoyant and altered its position in the gastriccontents for more than 6 hr So prolonged gastric retentiontime (GRT) of more than 6 hr is achieved (Figures 10(a)ndash10(c))

The objective of the in vivo studies was to provide theproof of concept that the floating capability of the floatingtablet was useful for the increasing the gastric residence timeof the dosage form For facilitating the trials on the rabbitsthe dosage form did not contain any drug and the scope waslimited to the observation of the behavior of the system in thestomach

4 Conclusion

The present study was carried out to develop the floating-bioadhesive drug delivery of venlafaxine hydrochloride using

HPMC K4MCR and Carbopol 934PNF polymers as the car-rier Optimized formulation FC8 gave satisfactory results forvarious physiochemical evaluations for tablets like hardnessweight variation floating lag time and uniformity of contentIn vitro dissolution studies of the optimized formulation FC8showed the sustained release for 18 hr followed by the Fickiandiffusion and an in vivo study indicated increased gastricresidence time by the floating principle and was considereddesirable for improving the bioavailability of the drug Allthese results also indicated that a low amount of floatingagent and high amount of hydrophilic polymer favored thesustained release of venlafaxine hydrochloride from the float-ing gastroretentive tablet formulations Developed sustained-release oral formulation for prolonged release would be asignificant advantage for the patient and may result in fewerside effects due to reduction of the blood concentrationfluctuations especially in long-term therapy Thus results ofthe current study clearly indicate a promising potential of thevenlafaxine hydrochloride floating system as an alternativeto the conventional dosage form However further clinical

12 Scientifica

(a)

(b)

(c)

Figure 10 Radiographic images showing the presence of BaSO4loaded floating tablet in the stomach at different time periods (the tablet is

indicated with an arrow) Images were taken after (a) 1 hr (b) 3 hr and (c) 6 hr after tablet administration

studies are needed to assess the utility of this system forpatients suffering from depression

Competing Interests

The authors declare that there are no competing interestsThe authors do not have a direct financial relation with thecommercial identities mentioned in the research paper thatmight lead to competing interests for any of the authors

Acknowledgments

The authors are thankful to Ranbaxy Research Lab Ltd Gur-gaon Haryana India for providing venlafaxine hydrochlo-ride as a gift sample and Arihant Trading CompanyMumbaiIndia and Colorcon Asia Pvt Ltd Goa India for providingthe polymer samples They also wish to thank Dr P KJain Radiologist VardhmanMedical Centre Jhansi India forextending radiography

Scientifica 13

References

[1] O Berton and E J Nestler ldquoNew approaches to antidepressantdrug discovery beyond monoaminesrdquo Nature Reviews Neuro-science vol 7 no 2 pp 137ndash151 2006

[2] E J Nestler M Barrot R J DiLeone A J Eisch S J Gold andLMMonteggia ldquoNeurobiology of depressionrdquoNeuron vol 34no 1 pp 13ndash25 2002

[3] E Richelson ldquoPharmacology of antidepressantsrdquo Mayo ClinicProceedings vol 76 no 5 pp 511ndash527 2001

[4] httpwwwdrugbankcadrugsDB00285[5] P Blier E Saint-Andre C Hebert C De Montigny N Lavoie

and G Debonnel ldquoEffects of different doses of venlafaxine onserotonin and norepinephrine reuptake in healthy volunteersrdquoInternational Journal of Neuropsychopharmacology vol 10 no1 pp 41ndash50 2007

[6] S M Holliday and P Benfield ldquoVenlafaxine a review of itspharmacology and therapeutic potential in depressionrdquo Drugsvol 49 no 2 pp 280ndash294 1995

[7] B Omprakash S Ajay G Santosh and P Amin ldquoFormulationdevelopment of venlafaxine hydrochloride extended releasetablet and invitro characterizationsrdquo International Journal ofPharmTech Research vol 4 no 4 pp 1777ndash1784 2012

[8] E AMuth J AMoyer J T Haskins T H Andree andG EMHusbands ldquoBiochemical neurophysiological and behavioraleffects of Wy-45233 and other identified metabolites of theantidepressant venlafaxinerdquo Drug Development Research vol23 no 2 pp 191ndash199 1991

[9] B Cusack A Nelson and E Richelson ldquoBinding of antide-pressants to human brain receptors focus on newer generationcompoundsrdquo Psychopharmacology vol 114 no 4 pp 559ndash5651994

[10] B N Singh and K H Kim ldquoFloating drug delivery systems anapproach to oral controlled drug delivery via gastric retentionrdquoJournal of Controlled Release vol 63 no 3 pp 235ndash259 2000

[11] P Bhardwaj R Singh and A Swarup ldquoStomach specific drugdelivery systemmdasha brief reviewrdquo Inventi Rapid NDDS no 3 pp1ndash9 2012

[12] R B Umamaheshwari S Jain D Bhadra and N K JainldquoFloating microspheres bearing acetohydroxamic acid for thetreatment of Helicobacter pylorirdquo Journal of Pharmacy andPharmacology vol 55 no 12 pp 1607ndash1613 2003

[13] S K Jain AMAwasthi N K Jain andG P Agrawal ldquoCalciumsilicate based microspheres of repaglinide for gastroretentivefloating drug delivery preparation and in vitro characteriza-tionrdquo Journal of Controlled Release vol 107 no 2 pp 300ndash3092005

[14] D Chaurasia K Kaushik P Bhardwaj H Chaurasia S K Jainand S Shobhna ldquoDevelopment and in vitro characterizationof floating microspheres bearing tramadol HClrdquo Acta PoloniaePharmaceuticamdashDrug Research vol 68 no 5 pp 795ndash801 2011

[15] P Bhardwaj H Chaurasia D Chaurasia S K Prajapati andS Singh ldquoFormulation and in-vitro evaluation of floatingmicroballoons of indomethacinrdquo Acta Poloniae Pharmaceuti-camdashDrug Research vol 67 no 3 pp 291ndash298 2010

[16] L Lachman H A Liberman and J L Kanig The Theoryand Practice of Industrial Pharmacy Varghese Publishin HouseBombay India 3rd edition 1991

[17] M E Aulton PharmaceuticsThe Science of Dosage formDesignElsevier Science Ltd Philadelphia Pa USA Churchill Living-stone London UK 2nd edition 2002

[18] M Jaimini A C Rana andY S Tanwar ldquoFormulation and eval-uation of famotidine floating tabletsrdquo Current Drug Deliveryvol 4 no 1 pp 51ndash55 2007

[19] A A Deshpande N H Shah C T Rhodes and W MalickldquoDevelopment of a novel controlled-release system for gastricretentionrdquo Pharmaceutical Research vol 14 no 6 pp 815ndash8191997

[20] G S Sonar D K Jain and D M More ldquoPreparation and invitro evaluation of bilayer and floating-bioadhesive tablets ofrosiglitazone maleaterdquo Asian Journal of Pharmaceutical Sciencevol 2 no 4 pp 161ndash169 2007

[21] B R Matthews ldquoRegulatory aspects of stability testing inEuroperdquo Drug Development and Industrial Pharmacy vol 25no 7 pp 831ndash856 1999

[22] R Gupta S K Prajapati S Pattnaik and P Bhardwaj ldquoFor-mulation and evaluation of novel stomach specific floatingmicrospheres bearing famotidine for treatment of gastric ulcerand their radiographic studyrdquo Asian Pacific Journal of TropicalBiomedicine vol 4 no 9 pp 729ndash735 2014

Submit your manuscripts athttpwwwhindawicom

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AntibioticsInternational Journal of

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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Advances in Pharmacological Sciences

Tropical MedicineJournal of

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Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

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Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Scientifica 5

floating dosage form It helps to locate dosage form in theGIT by which one can predict and correlate the gastricretention time floating behavior and passage of the dosageform in the GIT Here the inclusion of radio-opaque materialinto a solid dosage form enables it to be visualized by X-rays It is also important that dosage forms are nondisin-tegrating units and animal subjects are young and healthy[22]

The animal protocol to carry out in vivo radiographicstudies was reviewed and approved by the InstitutionalAnimals Ethical Committee of Bundelkhand UniversityIndia (registration number 71602aCPCSEA) The in vivoradiographic studies were conducted in young and healthymale albino rabbits weighing 20 to 22 kg The animals werekept under standard laboratory conditions (temperature 25plusmn 2∘C) Rabbits were kept for one week in the animal houseto acclimatize them and fed a fixed standard diet The 4healthy male albino rabbits were used to monitor the invivo transit behavior of the floating tablet None of themhad symptoms or history of gastrointestinal (GI) disease Inorder to standardize the conditions ofGImotility the animalswere fasted for 12 hours prior to the commencement of eachexperiment In each experiment the first radiograph of theanimal subjects was made to ensure the absence of radio-opaque material in the GIT One of the tablets preparedfor radiography was orally administered to rabbits with thesufficient amount of water During the study the rabbits werenot allowed to eat but water was available ad libitum

For radiographic imaging all four legs of the rabbit weretied over a piece of plywood (20 times 20 inch) and location ofthe formulation in the stomach was monitored by keepingthe subjects in front of X-ray machine (Allengers BharatElectricals India Model number E 080743) The distancebetween the source of X-rays and the object was the samefor all the imaging This allowed us to see the tablet in thebody of the stomach antrum andor pyloric part of thestomach so that observations of the tablet movements couldbe made Gastric radiography was done at 1 hr 3 hr and 6 hrIn between the radiographic imaging the animals were freedand allowed to move and carry out normal activities but werenot allowed to take any foodThemean gastric residence timeof the drug was calculated

3 Results and Discussion

The granules prepared for the compression of floating tabletswere evaluated for their flow properties (Table 5) Granulesof matrix tablets of different formulation codes showed theangle of repose from 2229∘ plusmn 085 to 3739∘ plusmn 173 andflow rates from 091 plusmn 013 to 122 plusmn 010 gmsec and Carrrsquosindex was found in the range of 1813 to 2653 These resultsindicate that as the concentration of the HPMC K4MCRand Carbopol 934PNF increased in the formulations theangle of repose and Carrrsquos index were found to be increasedwhile their flow rate was found to be decreased Thus theangle of repose and Carrrsquos index value of different batches ofgranules indicate satisfactory flow behavior Other granulesparameters were also determined and found to be withinacceptable limits

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20Time (hr)

Optimization of the HPMC K4MCR

FC1FC2

FC3FC4

Cum

ulat

ive

dru

g re

leas

e

Figure 1 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC1 FC2 FC3 and FC4

The floating tablets of venlafaxine hydrochloride wereprepared by wet granulation method using HPMC K4MCRCarbopol 934PNF sodium bicarbonate and lactose Themagnesium stearate was used as the lubricant

The optimization of the formulation was done based onadjusting the drug-polymer ratio floating lag time durationof floating gas generating agents in vitro drug release rate

Results indicated that the low-density polymers likeHPMC K4MCR and Carbopol 934PNF affects the floatingbehavior of the venlafaxine hydrochloride floating tabletHPMC K4MCR and Carbopol 934PNF are selected becauseof their high viscosities which are desired for the sustainedrelease For optimizing the concentration ratio of the drugpolymers and several formulations of the different batcheswere formulated randomly in which only drug to the poly-mer ratio varied and remaining ingredients of formulationremained constant Then floating behavior and release ratestudy of these formulations were determined in the 01 NHCl (pH 12) Then a certain ratio of drug to polymer givessatisfactory floating behavior and in vitro drug release in 01NHCl At this stage of optimization few batches of formulationcodes FC1 FC2 FC3 and FC4 were prepared for the opti-mizing concentration of the polymer for obtaining the bestfloatation behavior and in vitro drug release Floating lag timeand duration of floating was found to be 112 99 88 and 74seconds and approximately 17 18 23 and 27 hr respectivelyThe cumulative drug release was found to be 9734 97439443 and 9065 in 18 hr for the formulation codes FC1 FC2FC3 and FC4 (Figure 1) But the release pattern of the FC3showed better in vitro release of drug in the sustainedmannerin predetermined time intervals than formulations FC1 FC2and FC4 Formulation FC3 also showed better floatationbehavior (ie floating lag time 88 seconds and duration offloating approximately 23 hr) Therefore formulation FC3has been selected in order to obtain the optimum HPMCloading level because it has better in vitro release patternand floatation behavior Results also indicate that as theconcentration of theHPMC increased the cumulativedrug

6 Scientifica

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

Optimization of Carbopol 934PNF

FC3FC5

FC6FC7

Figure 2 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC3 FC5 FC6 and FC7

release behavior and floating lag time were also decreasedto a certain value After optimizing the concentration ofHPMC K4MCR next optimization was done for Carbopolconcentration As the concentration of the Carbopol in theFC5 formulation decreased then the in vitro drug releasepattern of the formulation (FC5) was increased compared tothat of the FC3 formulation for 18 hr dissolution study It wasfound that as the concentration of the Carbopol increased inthe formulation (ie FC6 (20mg) and FC7 (25mg)) thenin vitro drug release was also decreased compared to thatof FC3 (15mg) Because the release and floatation behaviorexhibited by the FC3 were much better than FC5 FC6 andFC7 (Figure 2) the formulation FC3 remained selected forthe further study

For the floating drug delivery system the ideal matrixshould be highly permeable for the dissolution media inorder to initiate rapid generation of the carbon dioxide gas(CO2) and also should be permeable for CO

2to promote

floating The buoyancy lag time of the tablets depends on theconcentration of the sodiumbicarbonate (NaHCO

3) involved

in the CO2formation In the trial study in vitro release of

drug from the different formulation batches was studied todetermine the optimum concentration of the gas generatingagent It was observed from the formulations FC8 FC9 andFC10 that as the concentration of the sodium bicarbonateincreased in these formulations the floating lag time wasfound to be decreased but their corresponding release ofdrug was increased (Figure 3) The trial study also showedthat at higher concentration of the sodium bicarbonate FC10(30mg) causes bursting and rapid disintegration of tabletHence it was desirable to use optimum concentration ofsodium bicarbonate to get the least floating lag time withminimum bursting effect and desired floating time with-out rapid disintegration So FC8 with sodium bicarbonate(20mg) was optimized and selected to achieve optimum invitro buoyancy with less bursting effectThe formulation FC8was preferred over the FC3 because the in vitro release of

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20Time (hr)

Optimization of sodium bicarbonate

FC3FC8

FC9FC10

Cum

ulat

ive

dru

g re

leas

e

Figure 3 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC3 FC8 FC9 and FC10

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

Optimization of lactose

FC8FC11

FC12FC13

Figure 4 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC8 FC11 FC12 and FC13

drug was increased in the more controlled manner than thatof FC3

Here the lactose acts as channeling agent which is solublein the dissolutionmedium therefore thematrix integrity getsbroken and showed faster in vitro drug dissolution Resultsindicate from the formulations (ie FC11 FC12 and FC13)that release rate of drug is directly proportional to the con-centration of the lactose (Figure 4) As the concentration ofthe lactose increased in vitro drug releases were also found tobe increased but if the concentration of the lactose increasedmore than 50mg then the tablet will start disintegration bythe erosion mechanism Therefore optimum concentrationof the lactose is required for getting the maximum in vitrodrug release without causing erosion From the above resultsFC8 was found to be the best formulation which showedbetter in vitro drug release and floatation behavior

Scientifica 7

Table 6 Physiochemical characterization of venlafaxine hydrochloride tablets

Code weight variation Hardness (kgcm2) friability drug contentuniformity

Floating lagtime (sec)

Total floatingtime (hr)

FC1 plusmn30 640 plusmn 016 0524 9921 plusmn 146 112 plusmn 287 1733 plusmn 205FC2 plusmn45 637 plusmn 045 0564 9847 plusmn 034 99 plusmn 249 1850 plusmn 187FC3 plusmn35 653 plusmn 057 0572 9886 plusmn 124 88 plusmn 287 2333 plusmn 062FC4 plusmn40 663 plusmn 058 0482 9720 plusmn 018 74 plusmn 327 2708 plusmn 095FC5 plusmn25 693 plusmn 052 0458 9853 plusmn 052 94 plusmn 327 1275 plusmn 208FC6 plusmn30 670 plusmn 070 0545 9908 plusmn 221 82 plusmn 294 2650 plusmn 102FC7 plusmn40 643 plusmn 033 0584 9740 plusmn 102 76 plusmn 245 2925 plusmn 074FC8 plusmn40 667 plusmn 098 0580 9891 plusmn 018 72 plusmn 249 2450 plusmn 074FC9 plusmn25 670 plusmn 049 0495 9800 plusmn 024 64 plusmn 294 2650 plusmn 154FC10 plusmn30 647 plusmn 090 0457 9756 plusmn 132 54 plusmn 245 2625 plusmn 187FC11 plusmn30 680 plusmn 043 0530 9843 plusmn 064 67 plusmn 374 2825 plusmn 069FC12 plusmn45 627 plusmn 041 0572 9902 plusmn 145 81 plusmn 287 2052 plusmn 092FC13 plusmn45 667 plusmn 066 0592 9874 plusmn 082 93 plusmn 327 1800 plusmn 082Mean plusmn SD 119899 = 3 FC formulation code

B

WF

G

I

T

PG998400

B modified balance W weights G and G998400 glass vialF bioadhesive tablet I fundus tissueT supportive adhesive tape P height-adjustable pan

Figure 5 Mucoadhesion measuring device for obtaining detach-ment stress

The diameter of the formulations FC1 to FC13 was foundin the range of 897 plusmn 001 to 899 plusmn 003 and thickness wasin the range of 396 plusmn 001 to 399 plusmn 002 The variationin the weight was found in the range of plusmn5 complyingwith pharmacopoeial specificationsThe hardness of differentformulation was found to be between 627 plusmn 041 and693 plusmn 052 kgcm2 indicating good mechanical strengthThe friability was below 1 for all formulations which isan indication of good mechanical resistance of tablet Thedrug content varied between 9800 and 9921 in differentformulation with low standard deviation (Table 6)

The swelling of the polymers used (ie HPMC K4MCRand Carbopol 934PNF) was determined by swelling indexof the tablet Hydrophilic matrices (ie HPMC K4MCRand Carbopol 934PNF) in contact with water swell andincrease their volume due to water diffusion through thematrix The polymer chains continue the hydration process

and the matrix gained more water Drug diffusion signif-icantly depends on the water content of the tablet Thismay be because the mobility of the polymer chains is verydependent on the water content of the system In case ofhigh-water content polymer chain relaxation takes placewith volume expansion resulting in marked swelling of thesystem Also higher water content could lead to greaterpenetration of the gastric fluid into the tablet leading toquicker carbon dioxide gas generation thereby reducing thefloating lag time Consequently quicker and greater swellingof the tablet would lead to an increase in the diffusionpathway and thus a reduction in diffusion rate So the drugrelease was found to be high initially and then graduallydecreased

The swelling index of all formulations from FC1 toFC10 at 24 hr was found to be between 13603 and 17099respectively The percentage water uptake was found to beimproved as the concentration of the HPMC K4MCR andCarbopol 934PNF increased in the formulation The resultindicates from Table 7 that swelling index was increasedmuch more in case of Carbopol compared to HPMC becauseCarbopol is bearing very goodwater sorption property It wasalso observed that as the concentration of the Carbopol in theformulation decreased the water uptake was also found tobe decreased (ie FC5)

Table 8 clearly indicates that the value of bioadhesiveforce was found to be increased significantly as the con-centration of the mucoadhesive polymer HPMC and Car-bopol increased All floating formulations showed mucoad-hesive forces in the range of 11042 to 16780 dynescm2Results indicate that as the concentration of HPMC K4MCRincreased in the formulations FC1 to FC4 then the valueof detachment forces also increased from 12345 to 15672dynescm2 respectively It was also observed that as theconcentration of Carbopol 934PNF increased the values ofdetachment forces were increased from the 15965 to 16700dynescm2 for formulations FC6 to FC7 respectively but as

8 Scientifica

Table7Sw

ellingbehavior

ofmatrix

tablets

Form

ulationcode

Initialweight(mg)

Initialthickn

ess(mm)

Initialdiam

eter

(mm)

Finalw

eight(mg)

Finalthickness(m

m)

Finald

iameter

(mm)

Swellin

gindex

FC1

23411plusmn305

397plusmn001

898plusmn001

55259plusmn311

442plusmn10

81816plusmn038

13603

FC2

24020plusmn435

398plusmn002

897plusmn002

57852plusmn13

2450plusmn074

1852plusmn12

014084

FC3

24418plusmn16

9397plusmn001

899plusmn001

60710plusmn506

456plusmn089

1873plusmn14

814867

FC4

25010plusmn17

1399plusmn002

897plusmn001

6372

2plusmn340

461plusmn12

11885plusmn092

15478

FC5

23958plusmn10

1398plusmn001

898plusmn002

57848plusmn225

453plusmn14

21862plusmn13

41414

5FC

625009plusmn18

9396plusmn001

899plusmn002

64886plusmn413

463plusmn12

71889plusmn088

1594

5FC

725558plusmn329

397plusmn002

897plusmn001

6816

8plusmn267

466plusmn054

1893plusmn15

316672

FC8

25017plusmn12

3399plusmn002

899plusmn001

65425plusmn328

462plusmn028

1899plusmn067

16152

FC9

25421plusmn353

398plusmn001

898plusmn001

67817plusmn14

4464plusmn078

1914plusmn025

16678

FC10

2596

7plusmn442

399plusmn002

897plusmn002

70367plusmn287

468plusmn038

1927plusmn14

417099

MeanplusmnSD

119899=3FC

form

ulationcode

Scientifica 9

Table 8 Detachment forces of different formulations

S numberFormulation code (FC) Detachment force (dynescm2)1 FC1 123452 FC2 131743 FC3 147534 FC4 156725 FC5 110426 FC6 159657 FC7 167808 FC8 142189 FC9 1402110 FC10 1362411 FC11 1437812 FC12 1452613 FC13 14065

the concentration of Carbopol decreased value of forces wasdecreased (ie FC5) Hence it was also concluded from theresults that the values of detachment forces were increasedmuchmore in case of Carbopol 934PNF compared to HPMCK4MCR because the Carbopol was highly bioadhesive ascompared to HPMC

Bioadhesion is a surface phenomenon inwhich amaterialof synthetic or natural origin adheres or sticks to a biologicalsurface usually mucus membrane Many hydrophilic poly-mers adhere to mucosal surfaces as they attract water fromthe mucus gel layer adhering to the epithelial surface This isthe simplest mechanism of adhesion and it has been definedas ldquoadhesion by hydrationrdquo The hydrogen bonding presentbetween the adherent polymer and mucus is involved inmucoadhesion at themolecular level As the concentration ofbioadhesive polymers increased then the hydrogen bondingbetween the mucus membrane and adherent polymer at themolecular level increased therefore detachment forces werealso found to be increased

Surface morphology of the optimized formulation FC8was examined by scanning electronmicroscopy (SEM) It wasobserved from the SEM photographs that the drug is releasedfrom the matrix tablet by the diffusion process The surfacemorphology of the matrix tablet after dissolution showedthat the solvent front enters the matrix and moves slowlytoward the center of the tablet The drug diffuses out of thematrix after it comes in contact with dissolution mediumThe images of the tablet showed a network in the swollenpolymer through which the drug diffused to the surroundingmedium Thus it was concluded that the drug was releasedfrom a matrix by diffusion mechanism (Figures 6 and7)

A comparative study was performed on the availablemarketed formulation of extended release tablet and capsulecontaining venlafaxine hydrochloride equivalent to venlafax-ine 375mgThe results obtained from the in vitro drug releasestudy showed that optimized formulations FC8 showedmore sustained-release action than that of tablet (marketed-1) and capsule (marketed-2) with respect to time of 18 hr(Figure 8)

Figure 6 Scanning electron microscopy of optimized formulationFC8 of tablet surface before dissolution

Figure 7 Scanning electron microscopy of optimized formulationFC8 of tablet surface after dissolution

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

FC8Marketed-1

Marketed-2

Figure 8 Comparison of drug release of optimized formulation(FC8) versus marketed formulations for 18 hr

The drug release was found to follow first-order kineticswith 119903 = 09935 and 09904 for marketed-1 (tablet) andmarketed-2 (capsule) respectively while optimized formula-tion FC8 followed the Peppasmodel with value of 119903 = 09962119899 = 04473 and 119896 = 252788 So the best-fit model was foundto be the Peppas model for optimized formulation FC8 Themarketed formulations of tablet and capsule showed morethan 90of drug release in 14 hrwhile optimized formulationFC8 showed only 8258 of drug release in 14 hr

The data obtained from in vitro dissolution studies werefitted to zero-order first-order Higuchi and Korsmeyer-Peppas equations All release kinetic models were applied

10 Scientifica

Table 9 Stability studies of venlafaxine hydrochloride floating tablets of optimized formulation (FC8)

Characteristic Initial 1st month 2nd month 3rd monthHardness (kgcm2) 667 plusmn 098 602 plusmn 056 642 plusmn 020 630 plusmn 088Drug content () 9891 plusmn 018 9834 plusmn 002 9812 plusmn 142 9800 plusmn 027Floating lag time (seconds) 72 plusmn 265 76 plusmn 126 84 plusmn 245 90 plusmn 326Total floating time (hours) 2450 plusmn 074 2416 plusmn 112 2418 plusmn 226 2408 plusmn 034Swelling index () 16152 16082 16064 16018Buoyancy on disturbing Float Float Float FloatMatrix integrity Very good Very good Very good Very good in vitro release 18 hours 9692 plusmn 083 9443 plusmn 138 9398 plusmn 042 9300 plusmn 156Mean plusmn SD 119899 = 3 FC formulation code

(a) (b)

Figure 9 In vitro floating studies of optimized formulation (FC8) (a) after 80 sec and (b) after 24 hr

on the formulation codes FC1 FC2 FC3 FC4 FC5 FC6FC7 FC8 FC9 FC10 FC11 FC12 and FC13 due to theirsatisfactory release behavior The best-fit model was found tobe the matrix for formulation codes FC1 FC2 and FC5 andPeppas for formulation codes FC3 FC4 FC6 FC7 FC8 FC9FC10 FC11 FC12 and FC13The selection criteria for the bestmodel were based on goodness of fit of the data and residualsum of squares The details of the best-fit model of differentformulation codes are given in Table 10

For confirming the diffusion mechanism of optimizedformulation FC8 the data was fitted to the Korsmeyerequation which showed the exponent value 119899 = 04473Because the optimized formulation FC8 had the exponentvalue (119899) less than 05 it was suggested that the releasemechanism of venlafaxine hydrochloride indicates swellingand diffusion mechanism of floating tablets which followedthe Fickian diffusion (Case I transport) This kinetic dataanalysis was done by using ldquoPCP Disso V208rdquo Software(Poona College of Pharmacy Pune India)

The optimized formulation FC8 was suggested for stabil-ity study based on in vitro floating lag time total floating timein vitro drug dissolution studies and its physical propertiesThe floating tablets were investigated at 400∘C75 RH in

aluminum foil packaging for three monthsThe increased lagtime indicates the possibility of reaction of sodium bicarbon-ate with moisture during the study period However therewas the very little effect on the duration of the floating andmatrix integrity of the tablets Some drug degradation wasfound but it was not statistically significant Decreased drugrelease was found from the formulation but drug releasedcompiled the official standard of release since more than80 of the drug was released (Table 9) Thus it was foundthat the floating tablets of venlafaxine hydrochloride werealmost stable under these storage conditions for at least threemonths

The in vitro studies with BaSO4-containing floating

tablets showed a floating lag time of 112plusmn200 seconds hard-ness of 660 plusmn 003 kgcm2 and thickness of 399 plusmn 001mmThe intragastric behavior of the BaSO

4-loaded tablet in the

albino rabbit was observed by using a radiographic imagingtechnique Radiographic images were taken after 1 3 and6 hr showing that the tablet had altered its position in thestomachThis provided evidence that the tablets were floatingon the gastric fluid After 4 hr of the tablet administrationthe swelling of the tablet is visualized very well together withthe white dry core and translucent swelling layer around it

Scientifica 11

Table 10 Drug release kinetics for floating-bioadhesive tablets

S number Formulation code (FC) Best-fit model 119877 value Parameters for Korsmeyer-Peppas equation

1 FC1 Matrix 09948 119899 = 04817

119896 = 242487

2 FC2 Matrix 09942 119899 = 05125

119896 = 213988

3 FC3 Peppas 09966 119899 = 04919

119896 = 210756

4 FC4 Peppas 09914 119899 = 05500

119896 = 169021

5 FC5 Matrix 09968 119899 = 04877

119896 = 229187

6 FC6 Peppas 09941 119899 = 05430

119896 = 171357

7 FC7 Peppas 09966 119899 = 06472

119896 = 130990

8 FC8 Peppas 09962 119899 = 04473

119896 = 252788

9 FC9 Peppas 09942 119899 = 03266

119896 = 374233

10 FC10 Peppas 09910 119899 = 03279

119896 = 396415

11 FC11 Peppas 09972 119899 = 04974

119896 = 213024

12 FC12 Peppas 09933 119899 = 03702

119896 = 332823

13 FC13 Peppas 09934 119899 = 03466

119896 = 366938

Note each sample was analyzed in triplicate (119899 = 3)119896 kinetic constant119899 exponent value

due to the swellable polymers HPMCK4MCR and Carbopol934PNF

Hence examination of the sequential radiographicimages of the GIT during the study clearly indicated that thetablet remained buoyant and altered its position in the gastriccontents for more than 6 hr So prolonged gastric retentiontime (GRT) of more than 6 hr is achieved (Figures 10(a)ndash10(c))

The objective of the in vivo studies was to provide theproof of concept that the floating capability of the floatingtablet was useful for the increasing the gastric residence timeof the dosage form For facilitating the trials on the rabbitsthe dosage form did not contain any drug and the scope waslimited to the observation of the behavior of the system in thestomach

4 Conclusion

The present study was carried out to develop the floating-bioadhesive drug delivery of venlafaxine hydrochloride using

HPMC K4MCR and Carbopol 934PNF polymers as the car-rier Optimized formulation FC8 gave satisfactory results forvarious physiochemical evaluations for tablets like hardnessweight variation floating lag time and uniformity of contentIn vitro dissolution studies of the optimized formulation FC8showed the sustained release for 18 hr followed by the Fickiandiffusion and an in vivo study indicated increased gastricresidence time by the floating principle and was considereddesirable for improving the bioavailability of the drug Allthese results also indicated that a low amount of floatingagent and high amount of hydrophilic polymer favored thesustained release of venlafaxine hydrochloride from the float-ing gastroretentive tablet formulations Developed sustained-release oral formulation for prolonged release would be asignificant advantage for the patient and may result in fewerside effects due to reduction of the blood concentrationfluctuations especially in long-term therapy Thus results ofthe current study clearly indicate a promising potential of thevenlafaxine hydrochloride floating system as an alternativeto the conventional dosage form However further clinical

12 Scientifica

(a)

(b)

(c)

Figure 10 Radiographic images showing the presence of BaSO4loaded floating tablet in the stomach at different time periods (the tablet is

indicated with an arrow) Images were taken after (a) 1 hr (b) 3 hr and (c) 6 hr after tablet administration

studies are needed to assess the utility of this system forpatients suffering from depression

Competing Interests

The authors declare that there are no competing interestsThe authors do not have a direct financial relation with thecommercial identities mentioned in the research paper thatmight lead to competing interests for any of the authors

Acknowledgments

The authors are thankful to Ranbaxy Research Lab Ltd Gur-gaon Haryana India for providing venlafaxine hydrochlo-ride as a gift sample and Arihant Trading CompanyMumbaiIndia and Colorcon Asia Pvt Ltd Goa India for providingthe polymer samples They also wish to thank Dr P KJain Radiologist VardhmanMedical Centre Jhansi India forextending radiography

Scientifica 13

References

[1] O Berton and E J Nestler ldquoNew approaches to antidepressantdrug discovery beyond monoaminesrdquo Nature Reviews Neuro-science vol 7 no 2 pp 137ndash151 2006

[2] E J Nestler M Barrot R J DiLeone A J Eisch S J Gold andLMMonteggia ldquoNeurobiology of depressionrdquoNeuron vol 34no 1 pp 13ndash25 2002

[3] E Richelson ldquoPharmacology of antidepressantsrdquo Mayo ClinicProceedings vol 76 no 5 pp 511ndash527 2001

[4] httpwwwdrugbankcadrugsDB00285[5] P Blier E Saint-Andre C Hebert C De Montigny N Lavoie

and G Debonnel ldquoEffects of different doses of venlafaxine onserotonin and norepinephrine reuptake in healthy volunteersrdquoInternational Journal of Neuropsychopharmacology vol 10 no1 pp 41ndash50 2007

[6] S M Holliday and P Benfield ldquoVenlafaxine a review of itspharmacology and therapeutic potential in depressionrdquo Drugsvol 49 no 2 pp 280ndash294 1995

[7] B Omprakash S Ajay G Santosh and P Amin ldquoFormulationdevelopment of venlafaxine hydrochloride extended releasetablet and invitro characterizationsrdquo International Journal ofPharmTech Research vol 4 no 4 pp 1777ndash1784 2012

[8] E AMuth J AMoyer J T Haskins T H Andree andG EMHusbands ldquoBiochemical neurophysiological and behavioraleffects of Wy-45233 and other identified metabolites of theantidepressant venlafaxinerdquo Drug Development Research vol23 no 2 pp 191ndash199 1991

[9] B Cusack A Nelson and E Richelson ldquoBinding of antide-pressants to human brain receptors focus on newer generationcompoundsrdquo Psychopharmacology vol 114 no 4 pp 559ndash5651994

[10] B N Singh and K H Kim ldquoFloating drug delivery systems anapproach to oral controlled drug delivery via gastric retentionrdquoJournal of Controlled Release vol 63 no 3 pp 235ndash259 2000

[11] P Bhardwaj R Singh and A Swarup ldquoStomach specific drugdelivery systemmdasha brief reviewrdquo Inventi Rapid NDDS no 3 pp1ndash9 2012

[12] R B Umamaheshwari S Jain D Bhadra and N K JainldquoFloating microspheres bearing acetohydroxamic acid for thetreatment of Helicobacter pylorirdquo Journal of Pharmacy andPharmacology vol 55 no 12 pp 1607ndash1613 2003

[13] S K Jain AMAwasthi N K Jain andG P Agrawal ldquoCalciumsilicate based microspheres of repaglinide for gastroretentivefloating drug delivery preparation and in vitro characteriza-tionrdquo Journal of Controlled Release vol 107 no 2 pp 300ndash3092005

[14] D Chaurasia K Kaushik P Bhardwaj H Chaurasia S K Jainand S Shobhna ldquoDevelopment and in vitro characterizationof floating microspheres bearing tramadol HClrdquo Acta PoloniaePharmaceuticamdashDrug Research vol 68 no 5 pp 795ndash801 2011

[15] P Bhardwaj H Chaurasia D Chaurasia S K Prajapati andS Singh ldquoFormulation and in-vitro evaluation of floatingmicroballoons of indomethacinrdquo Acta Poloniae Pharmaceuti-camdashDrug Research vol 67 no 3 pp 291ndash298 2010

[16] L Lachman H A Liberman and J L Kanig The Theoryand Practice of Industrial Pharmacy Varghese Publishin HouseBombay India 3rd edition 1991

[17] M E Aulton PharmaceuticsThe Science of Dosage formDesignElsevier Science Ltd Philadelphia Pa USA Churchill Living-stone London UK 2nd edition 2002

[18] M Jaimini A C Rana andY S Tanwar ldquoFormulation and eval-uation of famotidine floating tabletsrdquo Current Drug Deliveryvol 4 no 1 pp 51ndash55 2007

[19] A A Deshpande N H Shah C T Rhodes and W MalickldquoDevelopment of a novel controlled-release system for gastricretentionrdquo Pharmaceutical Research vol 14 no 6 pp 815ndash8191997

[20] G S Sonar D K Jain and D M More ldquoPreparation and invitro evaluation of bilayer and floating-bioadhesive tablets ofrosiglitazone maleaterdquo Asian Journal of Pharmaceutical Sciencevol 2 no 4 pp 161ndash169 2007

[21] B R Matthews ldquoRegulatory aspects of stability testing inEuroperdquo Drug Development and Industrial Pharmacy vol 25no 7 pp 831ndash856 1999

[22] R Gupta S K Prajapati S Pattnaik and P Bhardwaj ldquoFor-mulation and evaluation of novel stomach specific floatingmicrospheres bearing famotidine for treatment of gastric ulcerand their radiographic studyrdquo Asian Pacific Journal of TropicalBiomedicine vol 4 no 9 pp 729ndash735 2014

Submit your manuscripts athttpwwwhindawicom

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ToxinsJournal of

VaccinesJournal of

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ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

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Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

6 Scientifica

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

Optimization of Carbopol 934PNF

FC3FC5

FC6FC7

Figure 2 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC3 FC5 FC6 and FC7

release behavior and floating lag time were also decreasedto a certain value After optimizing the concentration ofHPMC K4MCR next optimization was done for Carbopolconcentration As the concentration of the Carbopol in theFC5 formulation decreased then the in vitro drug releasepattern of the formulation (FC5) was increased compared tothat of the FC3 formulation for 18 hr dissolution study It wasfound that as the concentration of the Carbopol increased inthe formulation (ie FC6 (20mg) and FC7 (25mg)) thenin vitro drug release was also decreased compared to thatof FC3 (15mg) Because the release and floatation behaviorexhibited by the FC3 were much better than FC5 FC6 andFC7 (Figure 2) the formulation FC3 remained selected forthe further study

For the floating drug delivery system the ideal matrixshould be highly permeable for the dissolution media inorder to initiate rapid generation of the carbon dioxide gas(CO2) and also should be permeable for CO

2to promote

floating The buoyancy lag time of the tablets depends on theconcentration of the sodiumbicarbonate (NaHCO

3) involved

in the CO2formation In the trial study in vitro release of

drug from the different formulation batches was studied todetermine the optimum concentration of the gas generatingagent It was observed from the formulations FC8 FC9 andFC10 that as the concentration of the sodium bicarbonateincreased in these formulations the floating lag time wasfound to be decreased but their corresponding release ofdrug was increased (Figure 3) The trial study also showedthat at higher concentration of the sodium bicarbonate FC10(30mg) causes bursting and rapid disintegration of tabletHence it was desirable to use optimum concentration ofsodium bicarbonate to get the least floating lag time withminimum bursting effect and desired floating time with-out rapid disintegration So FC8 with sodium bicarbonate(20mg) was optimized and selected to achieve optimum invitro buoyancy with less bursting effectThe formulation FC8was preferred over the FC3 because the in vitro release of

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20Time (hr)

Optimization of sodium bicarbonate

FC3FC8

FC9FC10

Cum

ulat

ive

dru

g re

leas

e

Figure 3 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC3 FC8 FC9 and FC10

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

Optimization of lactose

FC8FC11

FC12FC13

Figure 4 Release profile of venlafaxine hydrochloride in 01 N HCl(pH 12) for formulation codes FC8 FC11 FC12 and FC13

drug was increased in the more controlled manner than thatof FC3

Here the lactose acts as channeling agent which is solublein the dissolutionmedium therefore thematrix integrity getsbroken and showed faster in vitro drug dissolution Resultsindicate from the formulations (ie FC11 FC12 and FC13)that release rate of drug is directly proportional to the con-centration of the lactose (Figure 4) As the concentration ofthe lactose increased in vitro drug releases were also found tobe increased but if the concentration of the lactose increasedmore than 50mg then the tablet will start disintegration bythe erosion mechanism Therefore optimum concentrationof the lactose is required for getting the maximum in vitrodrug release without causing erosion From the above resultsFC8 was found to be the best formulation which showedbetter in vitro drug release and floatation behavior

Scientifica 7

Table 6 Physiochemical characterization of venlafaxine hydrochloride tablets

Code weight variation Hardness (kgcm2) friability drug contentuniformity

Floating lagtime (sec)

Total floatingtime (hr)

FC1 plusmn30 640 plusmn 016 0524 9921 plusmn 146 112 plusmn 287 1733 plusmn 205FC2 plusmn45 637 plusmn 045 0564 9847 plusmn 034 99 plusmn 249 1850 plusmn 187FC3 plusmn35 653 plusmn 057 0572 9886 plusmn 124 88 plusmn 287 2333 plusmn 062FC4 plusmn40 663 plusmn 058 0482 9720 plusmn 018 74 plusmn 327 2708 plusmn 095FC5 plusmn25 693 plusmn 052 0458 9853 plusmn 052 94 plusmn 327 1275 plusmn 208FC6 plusmn30 670 plusmn 070 0545 9908 plusmn 221 82 plusmn 294 2650 plusmn 102FC7 plusmn40 643 plusmn 033 0584 9740 plusmn 102 76 plusmn 245 2925 plusmn 074FC8 plusmn40 667 plusmn 098 0580 9891 plusmn 018 72 plusmn 249 2450 plusmn 074FC9 plusmn25 670 plusmn 049 0495 9800 plusmn 024 64 plusmn 294 2650 plusmn 154FC10 plusmn30 647 plusmn 090 0457 9756 plusmn 132 54 plusmn 245 2625 plusmn 187FC11 plusmn30 680 plusmn 043 0530 9843 plusmn 064 67 plusmn 374 2825 plusmn 069FC12 plusmn45 627 plusmn 041 0572 9902 plusmn 145 81 plusmn 287 2052 plusmn 092FC13 plusmn45 667 plusmn 066 0592 9874 plusmn 082 93 plusmn 327 1800 plusmn 082Mean plusmn SD 119899 = 3 FC formulation code

B

WF

G

I

T

PG998400

B modified balance W weights G and G998400 glass vialF bioadhesive tablet I fundus tissueT supportive adhesive tape P height-adjustable pan

Figure 5 Mucoadhesion measuring device for obtaining detach-ment stress

The diameter of the formulations FC1 to FC13 was foundin the range of 897 plusmn 001 to 899 plusmn 003 and thickness wasin the range of 396 plusmn 001 to 399 plusmn 002 The variationin the weight was found in the range of plusmn5 complyingwith pharmacopoeial specificationsThe hardness of differentformulation was found to be between 627 plusmn 041 and693 plusmn 052 kgcm2 indicating good mechanical strengthThe friability was below 1 for all formulations which isan indication of good mechanical resistance of tablet Thedrug content varied between 9800 and 9921 in differentformulation with low standard deviation (Table 6)

The swelling of the polymers used (ie HPMC K4MCRand Carbopol 934PNF) was determined by swelling indexof the tablet Hydrophilic matrices (ie HPMC K4MCRand Carbopol 934PNF) in contact with water swell andincrease their volume due to water diffusion through thematrix The polymer chains continue the hydration process

and the matrix gained more water Drug diffusion signif-icantly depends on the water content of the tablet Thismay be because the mobility of the polymer chains is verydependent on the water content of the system In case ofhigh-water content polymer chain relaxation takes placewith volume expansion resulting in marked swelling of thesystem Also higher water content could lead to greaterpenetration of the gastric fluid into the tablet leading toquicker carbon dioxide gas generation thereby reducing thefloating lag time Consequently quicker and greater swellingof the tablet would lead to an increase in the diffusionpathway and thus a reduction in diffusion rate So the drugrelease was found to be high initially and then graduallydecreased

The swelling index of all formulations from FC1 toFC10 at 24 hr was found to be between 13603 and 17099respectively The percentage water uptake was found to beimproved as the concentration of the HPMC K4MCR andCarbopol 934PNF increased in the formulation The resultindicates from Table 7 that swelling index was increasedmuch more in case of Carbopol compared to HPMC becauseCarbopol is bearing very goodwater sorption property It wasalso observed that as the concentration of the Carbopol in theformulation decreased the water uptake was also found tobe decreased (ie FC5)

Table 8 clearly indicates that the value of bioadhesiveforce was found to be increased significantly as the con-centration of the mucoadhesive polymer HPMC and Car-bopol increased All floating formulations showed mucoad-hesive forces in the range of 11042 to 16780 dynescm2Results indicate that as the concentration of HPMC K4MCRincreased in the formulations FC1 to FC4 then the valueof detachment forces also increased from 12345 to 15672dynescm2 respectively It was also observed that as theconcentration of Carbopol 934PNF increased the values ofdetachment forces were increased from the 15965 to 16700dynescm2 for formulations FC6 to FC7 respectively but as

8 Scientifica

Table7Sw

ellingbehavior

ofmatrix

tablets

Form

ulationcode

Initialweight(mg)

Initialthickn

ess(mm)

Initialdiam

eter

(mm)

Finalw

eight(mg)

Finalthickness(m

m)

Finald

iameter

(mm)

Swellin

gindex

FC1

23411plusmn305

397plusmn001

898plusmn001

55259plusmn311

442plusmn10

81816plusmn038

13603

FC2

24020plusmn435

398plusmn002

897plusmn002

57852plusmn13

2450plusmn074

1852plusmn12

014084

FC3

24418plusmn16

9397plusmn001

899plusmn001

60710plusmn506

456plusmn089

1873plusmn14

814867

FC4

25010plusmn17

1399plusmn002

897plusmn001

6372

2plusmn340

461plusmn12

11885plusmn092

15478

FC5

23958plusmn10

1398plusmn001

898plusmn002

57848plusmn225

453plusmn14

21862plusmn13

41414

5FC

625009plusmn18

9396plusmn001

899plusmn002

64886plusmn413

463plusmn12

71889plusmn088

1594

5FC

725558plusmn329

397plusmn002

897plusmn001

6816

8plusmn267

466plusmn054

1893plusmn15

316672

FC8

25017plusmn12

3399plusmn002

899plusmn001

65425plusmn328

462plusmn028

1899plusmn067

16152

FC9

25421plusmn353

398plusmn001

898plusmn001

67817plusmn14

4464plusmn078

1914plusmn025

16678

FC10

2596

7plusmn442

399plusmn002

897plusmn002

70367plusmn287

468plusmn038

1927plusmn14

417099

MeanplusmnSD

119899=3FC

form

ulationcode

Scientifica 9

Table 8 Detachment forces of different formulations

S numberFormulation code (FC) Detachment force (dynescm2)1 FC1 123452 FC2 131743 FC3 147534 FC4 156725 FC5 110426 FC6 159657 FC7 167808 FC8 142189 FC9 1402110 FC10 1362411 FC11 1437812 FC12 1452613 FC13 14065

the concentration of Carbopol decreased value of forces wasdecreased (ie FC5) Hence it was also concluded from theresults that the values of detachment forces were increasedmuchmore in case of Carbopol 934PNF compared to HPMCK4MCR because the Carbopol was highly bioadhesive ascompared to HPMC

Bioadhesion is a surface phenomenon inwhich amaterialof synthetic or natural origin adheres or sticks to a biologicalsurface usually mucus membrane Many hydrophilic poly-mers adhere to mucosal surfaces as they attract water fromthe mucus gel layer adhering to the epithelial surface This isthe simplest mechanism of adhesion and it has been definedas ldquoadhesion by hydrationrdquo The hydrogen bonding presentbetween the adherent polymer and mucus is involved inmucoadhesion at themolecular level As the concentration ofbioadhesive polymers increased then the hydrogen bondingbetween the mucus membrane and adherent polymer at themolecular level increased therefore detachment forces werealso found to be increased

Surface morphology of the optimized formulation FC8was examined by scanning electronmicroscopy (SEM) It wasobserved from the SEM photographs that the drug is releasedfrom the matrix tablet by the diffusion process The surfacemorphology of the matrix tablet after dissolution showedthat the solvent front enters the matrix and moves slowlytoward the center of the tablet The drug diffuses out of thematrix after it comes in contact with dissolution mediumThe images of the tablet showed a network in the swollenpolymer through which the drug diffused to the surroundingmedium Thus it was concluded that the drug was releasedfrom a matrix by diffusion mechanism (Figures 6 and7)

A comparative study was performed on the availablemarketed formulation of extended release tablet and capsulecontaining venlafaxine hydrochloride equivalent to venlafax-ine 375mgThe results obtained from the in vitro drug releasestudy showed that optimized formulations FC8 showedmore sustained-release action than that of tablet (marketed-1) and capsule (marketed-2) with respect to time of 18 hr(Figure 8)

Figure 6 Scanning electron microscopy of optimized formulationFC8 of tablet surface before dissolution

Figure 7 Scanning electron microscopy of optimized formulationFC8 of tablet surface after dissolution

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

FC8Marketed-1

Marketed-2

Figure 8 Comparison of drug release of optimized formulation(FC8) versus marketed formulations for 18 hr

The drug release was found to follow first-order kineticswith 119903 = 09935 and 09904 for marketed-1 (tablet) andmarketed-2 (capsule) respectively while optimized formula-tion FC8 followed the Peppasmodel with value of 119903 = 09962119899 = 04473 and 119896 = 252788 So the best-fit model was foundto be the Peppas model for optimized formulation FC8 Themarketed formulations of tablet and capsule showed morethan 90of drug release in 14 hrwhile optimized formulationFC8 showed only 8258 of drug release in 14 hr

The data obtained from in vitro dissolution studies werefitted to zero-order first-order Higuchi and Korsmeyer-Peppas equations All release kinetic models were applied

10 Scientifica

Table 9 Stability studies of venlafaxine hydrochloride floating tablets of optimized formulation (FC8)

Characteristic Initial 1st month 2nd month 3rd monthHardness (kgcm2) 667 plusmn 098 602 plusmn 056 642 plusmn 020 630 plusmn 088Drug content () 9891 plusmn 018 9834 plusmn 002 9812 plusmn 142 9800 plusmn 027Floating lag time (seconds) 72 plusmn 265 76 plusmn 126 84 plusmn 245 90 plusmn 326Total floating time (hours) 2450 plusmn 074 2416 plusmn 112 2418 plusmn 226 2408 plusmn 034Swelling index () 16152 16082 16064 16018Buoyancy on disturbing Float Float Float FloatMatrix integrity Very good Very good Very good Very good in vitro release 18 hours 9692 plusmn 083 9443 plusmn 138 9398 plusmn 042 9300 plusmn 156Mean plusmn SD 119899 = 3 FC formulation code

(a) (b)

Figure 9 In vitro floating studies of optimized formulation (FC8) (a) after 80 sec and (b) after 24 hr

on the formulation codes FC1 FC2 FC3 FC4 FC5 FC6FC7 FC8 FC9 FC10 FC11 FC12 and FC13 due to theirsatisfactory release behavior The best-fit model was found tobe the matrix for formulation codes FC1 FC2 and FC5 andPeppas for formulation codes FC3 FC4 FC6 FC7 FC8 FC9FC10 FC11 FC12 and FC13The selection criteria for the bestmodel were based on goodness of fit of the data and residualsum of squares The details of the best-fit model of differentformulation codes are given in Table 10

For confirming the diffusion mechanism of optimizedformulation FC8 the data was fitted to the Korsmeyerequation which showed the exponent value 119899 = 04473Because the optimized formulation FC8 had the exponentvalue (119899) less than 05 it was suggested that the releasemechanism of venlafaxine hydrochloride indicates swellingand diffusion mechanism of floating tablets which followedthe Fickian diffusion (Case I transport) This kinetic dataanalysis was done by using ldquoPCP Disso V208rdquo Software(Poona College of Pharmacy Pune India)

The optimized formulation FC8 was suggested for stabil-ity study based on in vitro floating lag time total floating timein vitro drug dissolution studies and its physical propertiesThe floating tablets were investigated at 400∘C75 RH in

aluminum foil packaging for three monthsThe increased lagtime indicates the possibility of reaction of sodium bicarbon-ate with moisture during the study period However therewas the very little effect on the duration of the floating andmatrix integrity of the tablets Some drug degradation wasfound but it was not statistically significant Decreased drugrelease was found from the formulation but drug releasedcompiled the official standard of release since more than80 of the drug was released (Table 9) Thus it was foundthat the floating tablets of venlafaxine hydrochloride werealmost stable under these storage conditions for at least threemonths

The in vitro studies with BaSO4-containing floating

tablets showed a floating lag time of 112plusmn200 seconds hard-ness of 660 plusmn 003 kgcm2 and thickness of 399 plusmn 001mmThe intragastric behavior of the BaSO

4-loaded tablet in the

albino rabbit was observed by using a radiographic imagingtechnique Radiographic images were taken after 1 3 and6 hr showing that the tablet had altered its position in thestomachThis provided evidence that the tablets were floatingon the gastric fluid After 4 hr of the tablet administrationthe swelling of the tablet is visualized very well together withthe white dry core and translucent swelling layer around it

Scientifica 11

Table 10 Drug release kinetics for floating-bioadhesive tablets

S number Formulation code (FC) Best-fit model 119877 value Parameters for Korsmeyer-Peppas equation

1 FC1 Matrix 09948 119899 = 04817

119896 = 242487

2 FC2 Matrix 09942 119899 = 05125

119896 = 213988

3 FC3 Peppas 09966 119899 = 04919

119896 = 210756

4 FC4 Peppas 09914 119899 = 05500

119896 = 169021

5 FC5 Matrix 09968 119899 = 04877

119896 = 229187

6 FC6 Peppas 09941 119899 = 05430

119896 = 171357

7 FC7 Peppas 09966 119899 = 06472

119896 = 130990

8 FC8 Peppas 09962 119899 = 04473

119896 = 252788

9 FC9 Peppas 09942 119899 = 03266

119896 = 374233

10 FC10 Peppas 09910 119899 = 03279

119896 = 396415

11 FC11 Peppas 09972 119899 = 04974

119896 = 213024

12 FC12 Peppas 09933 119899 = 03702

119896 = 332823

13 FC13 Peppas 09934 119899 = 03466

119896 = 366938

Note each sample was analyzed in triplicate (119899 = 3)119896 kinetic constant119899 exponent value

due to the swellable polymers HPMCK4MCR and Carbopol934PNF

Hence examination of the sequential radiographicimages of the GIT during the study clearly indicated that thetablet remained buoyant and altered its position in the gastriccontents for more than 6 hr So prolonged gastric retentiontime (GRT) of more than 6 hr is achieved (Figures 10(a)ndash10(c))

The objective of the in vivo studies was to provide theproof of concept that the floating capability of the floatingtablet was useful for the increasing the gastric residence timeof the dosage form For facilitating the trials on the rabbitsthe dosage form did not contain any drug and the scope waslimited to the observation of the behavior of the system in thestomach

4 Conclusion

The present study was carried out to develop the floating-bioadhesive drug delivery of venlafaxine hydrochloride using

HPMC K4MCR and Carbopol 934PNF polymers as the car-rier Optimized formulation FC8 gave satisfactory results forvarious physiochemical evaluations for tablets like hardnessweight variation floating lag time and uniformity of contentIn vitro dissolution studies of the optimized formulation FC8showed the sustained release for 18 hr followed by the Fickiandiffusion and an in vivo study indicated increased gastricresidence time by the floating principle and was considereddesirable for improving the bioavailability of the drug Allthese results also indicated that a low amount of floatingagent and high amount of hydrophilic polymer favored thesustained release of venlafaxine hydrochloride from the float-ing gastroretentive tablet formulations Developed sustained-release oral formulation for prolonged release would be asignificant advantage for the patient and may result in fewerside effects due to reduction of the blood concentrationfluctuations especially in long-term therapy Thus results ofthe current study clearly indicate a promising potential of thevenlafaxine hydrochloride floating system as an alternativeto the conventional dosage form However further clinical

12 Scientifica

(a)

(b)

(c)

Figure 10 Radiographic images showing the presence of BaSO4loaded floating tablet in the stomach at different time periods (the tablet is

indicated with an arrow) Images were taken after (a) 1 hr (b) 3 hr and (c) 6 hr after tablet administration

studies are needed to assess the utility of this system forpatients suffering from depression

Competing Interests

The authors declare that there are no competing interestsThe authors do not have a direct financial relation with thecommercial identities mentioned in the research paper thatmight lead to competing interests for any of the authors

Acknowledgments

The authors are thankful to Ranbaxy Research Lab Ltd Gur-gaon Haryana India for providing venlafaxine hydrochlo-ride as a gift sample and Arihant Trading CompanyMumbaiIndia and Colorcon Asia Pvt Ltd Goa India for providingthe polymer samples They also wish to thank Dr P KJain Radiologist VardhmanMedical Centre Jhansi India forextending radiography

Scientifica 13

References

[1] O Berton and E J Nestler ldquoNew approaches to antidepressantdrug discovery beyond monoaminesrdquo Nature Reviews Neuro-science vol 7 no 2 pp 137ndash151 2006

[2] E J Nestler M Barrot R J DiLeone A J Eisch S J Gold andLMMonteggia ldquoNeurobiology of depressionrdquoNeuron vol 34no 1 pp 13ndash25 2002

[3] E Richelson ldquoPharmacology of antidepressantsrdquo Mayo ClinicProceedings vol 76 no 5 pp 511ndash527 2001

[4] httpwwwdrugbankcadrugsDB00285[5] P Blier E Saint-Andre C Hebert C De Montigny N Lavoie

and G Debonnel ldquoEffects of different doses of venlafaxine onserotonin and norepinephrine reuptake in healthy volunteersrdquoInternational Journal of Neuropsychopharmacology vol 10 no1 pp 41ndash50 2007

[6] S M Holliday and P Benfield ldquoVenlafaxine a review of itspharmacology and therapeutic potential in depressionrdquo Drugsvol 49 no 2 pp 280ndash294 1995

[7] B Omprakash S Ajay G Santosh and P Amin ldquoFormulationdevelopment of venlafaxine hydrochloride extended releasetablet and invitro characterizationsrdquo International Journal ofPharmTech Research vol 4 no 4 pp 1777ndash1784 2012

[8] E AMuth J AMoyer J T Haskins T H Andree andG EMHusbands ldquoBiochemical neurophysiological and behavioraleffects of Wy-45233 and other identified metabolites of theantidepressant venlafaxinerdquo Drug Development Research vol23 no 2 pp 191ndash199 1991

[9] B Cusack A Nelson and E Richelson ldquoBinding of antide-pressants to human brain receptors focus on newer generationcompoundsrdquo Psychopharmacology vol 114 no 4 pp 559ndash5651994

[10] B N Singh and K H Kim ldquoFloating drug delivery systems anapproach to oral controlled drug delivery via gastric retentionrdquoJournal of Controlled Release vol 63 no 3 pp 235ndash259 2000

[11] P Bhardwaj R Singh and A Swarup ldquoStomach specific drugdelivery systemmdasha brief reviewrdquo Inventi Rapid NDDS no 3 pp1ndash9 2012

[12] R B Umamaheshwari S Jain D Bhadra and N K JainldquoFloating microspheres bearing acetohydroxamic acid for thetreatment of Helicobacter pylorirdquo Journal of Pharmacy andPharmacology vol 55 no 12 pp 1607ndash1613 2003

[13] S K Jain AMAwasthi N K Jain andG P Agrawal ldquoCalciumsilicate based microspheres of repaglinide for gastroretentivefloating drug delivery preparation and in vitro characteriza-tionrdquo Journal of Controlled Release vol 107 no 2 pp 300ndash3092005

[14] D Chaurasia K Kaushik P Bhardwaj H Chaurasia S K Jainand S Shobhna ldquoDevelopment and in vitro characterizationof floating microspheres bearing tramadol HClrdquo Acta PoloniaePharmaceuticamdashDrug Research vol 68 no 5 pp 795ndash801 2011

[15] P Bhardwaj H Chaurasia D Chaurasia S K Prajapati andS Singh ldquoFormulation and in-vitro evaluation of floatingmicroballoons of indomethacinrdquo Acta Poloniae Pharmaceuti-camdashDrug Research vol 67 no 3 pp 291ndash298 2010

[16] L Lachman H A Liberman and J L Kanig The Theoryand Practice of Industrial Pharmacy Varghese Publishin HouseBombay India 3rd edition 1991

[17] M E Aulton PharmaceuticsThe Science of Dosage formDesignElsevier Science Ltd Philadelphia Pa USA Churchill Living-stone London UK 2nd edition 2002

[18] M Jaimini A C Rana andY S Tanwar ldquoFormulation and eval-uation of famotidine floating tabletsrdquo Current Drug Deliveryvol 4 no 1 pp 51ndash55 2007

[19] A A Deshpande N H Shah C T Rhodes and W MalickldquoDevelopment of a novel controlled-release system for gastricretentionrdquo Pharmaceutical Research vol 14 no 6 pp 815ndash8191997

[20] G S Sonar D K Jain and D M More ldquoPreparation and invitro evaluation of bilayer and floating-bioadhesive tablets ofrosiglitazone maleaterdquo Asian Journal of Pharmaceutical Sciencevol 2 no 4 pp 161ndash169 2007

[21] B R Matthews ldquoRegulatory aspects of stability testing inEuroperdquo Drug Development and Industrial Pharmacy vol 25no 7 pp 831ndash856 1999

[22] R Gupta S K Prajapati S Pattnaik and P Bhardwaj ldquoFor-mulation and evaluation of novel stomach specific floatingmicrospheres bearing famotidine for treatment of gastric ulcerand their radiographic studyrdquo Asian Pacific Journal of TropicalBiomedicine vol 4 no 9 pp 729ndash735 2014

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Scientifica 7

Table 6 Physiochemical characterization of venlafaxine hydrochloride tablets

Code weight variation Hardness (kgcm2) friability drug contentuniformity

Floating lagtime (sec)

Total floatingtime (hr)

FC1 plusmn30 640 plusmn 016 0524 9921 plusmn 146 112 plusmn 287 1733 plusmn 205FC2 plusmn45 637 plusmn 045 0564 9847 plusmn 034 99 plusmn 249 1850 plusmn 187FC3 plusmn35 653 plusmn 057 0572 9886 plusmn 124 88 plusmn 287 2333 plusmn 062FC4 plusmn40 663 plusmn 058 0482 9720 plusmn 018 74 plusmn 327 2708 plusmn 095FC5 plusmn25 693 plusmn 052 0458 9853 plusmn 052 94 plusmn 327 1275 plusmn 208FC6 plusmn30 670 plusmn 070 0545 9908 plusmn 221 82 plusmn 294 2650 plusmn 102FC7 plusmn40 643 plusmn 033 0584 9740 plusmn 102 76 plusmn 245 2925 plusmn 074FC8 plusmn40 667 plusmn 098 0580 9891 plusmn 018 72 plusmn 249 2450 plusmn 074FC9 plusmn25 670 plusmn 049 0495 9800 plusmn 024 64 plusmn 294 2650 plusmn 154FC10 plusmn30 647 plusmn 090 0457 9756 plusmn 132 54 plusmn 245 2625 plusmn 187FC11 plusmn30 680 plusmn 043 0530 9843 plusmn 064 67 plusmn 374 2825 plusmn 069FC12 plusmn45 627 plusmn 041 0572 9902 plusmn 145 81 plusmn 287 2052 plusmn 092FC13 plusmn45 667 plusmn 066 0592 9874 plusmn 082 93 plusmn 327 1800 plusmn 082Mean plusmn SD 119899 = 3 FC formulation code

B

WF

G

I

T

PG998400

B modified balance W weights G and G998400 glass vialF bioadhesive tablet I fundus tissueT supportive adhesive tape P height-adjustable pan

Figure 5 Mucoadhesion measuring device for obtaining detach-ment stress

The diameter of the formulations FC1 to FC13 was foundin the range of 897 plusmn 001 to 899 plusmn 003 and thickness wasin the range of 396 plusmn 001 to 399 plusmn 002 The variationin the weight was found in the range of plusmn5 complyingwith pharmacopoeial specificationsThe hardness of differentformulation was found to be between 627 plusmn 041 and693 plusmn 052 kgcm2 indicating good mechanical strengthThe friability was below 1 for all formulations which isan indication of good mechanical resistance of tablet Thedrug content varied between 9800 and 9921 in differentformulation with low standard deviation (Table 6)

The swelling of the polymers used (ie HPMC K4MCRand Carbopol 934PNF) was determined by swelling indexof the tablet Hydrophilic matrices (ie HPMC K4MCRand Carbopol 934PNF) in contact with water swell andincrease their volume due to water diffusion through thematrix The polymer chains continue the hydration process

and the matrix gained more water Drug diffusion signif-icantly depends on the water content of the tablet Thismay be because the mobility of the polymer chains is verydependent on the water content of the system In case ofhigh-water content polymer chain relaxation takes placewith volume expansion resulting in marked swelling of thesystem Also higher water content could lead to greaterpenetration of the gastric fluid into the tablet leading toquicker carbon dioxide gas generation thereby reducing thefloating lag time Consequently quicker and greater swellingof the tablet would lead to an increase in the diffusionpathway and thus a reduction in diffusion rate So the drugrelease was found to be high initially and then graduallydecreased

The swelling index of all formulations from FC1 toFC10 at 24 hr was found to be between 13603 and 17099respectively The percentage water uptake was found to beimproved as the concentration of the HPMC K4MCR andCarbopol 934PNF increased in the formulation The resultindicates from Table 7 that swelling index was increasedmuch more in case of Carbopol compared to HPMC becauseCarbopol is bearing very goodwater sorption property It wasalso observed that as the concentration of the Carbopol in theformulation decreased the water uptake was also found tobe decreased (ie FC5)

Table 8 clearly indicates that the value of bioadhesiveforce was found to be increased significantly as the con-centration of the mucoadhesive polymer HPMC and Car-bopol increased All floating formulations showed mucoad-hesive forces in the range of 11042 to 16780 dynescm2Results indicate that as the concentration of HPMC K4MCRincreased in the formulations FC1 to FC4 then the valueof detachment forces also increased from 12345 to 15672dynescm2 respectively It was also observed that as theconcentration of Carbopol 934PNF increased the values ofdetachment forces were increased from the 15965 to 16700dynescm2 for formulations FC6 to FC7 respectively but as

8 Scientifica

Table7Sw

ellingbehavior

ofmatrix

tablets

Form

ulationcode

Initialweight(mg)

Initialthickn

ess(mm)

Initialdiam

eter

(mm)

Finalw

eight(mg)

Finalthickness(m

m)

Finald

iameter

(mm)

Swellin

gindex

FC1

23411plusmn305

397plusmn001

898plusmn001

55259plusmn311

442plusmn10

81816plusmn038

13603

FC2

24020plusmn435

398plusmn002

897plusmn002

57852plusmn13

2450plusmn074

1852plusmn12

014084

FC3

24418plusmn16

9397plusmn001

899plusmn001

60710plusmn506

456plusmn089

1873plusmn14

814867

FC4

25010plusmn17

1399plusmn002

897plusmn001

6372

2plusmn340

461plusmn12

11885plusmn092

15478

FC5

23958plusmn10

1398plusmn001

898plusmn002

57848plusmn225

453plusmn14

21862plusmn13

41414

5FC

625009plusmn18

9396plusmn001

899plusmn002

64886plusmn413

463plusmn12

71889plusmn088

1594

5FC

725558plusmn329

397plusmn002

897plusmn001

6816

8plusmn267

466plusmn054

1893plusmn15

316672

FC8

25017plusmn12

3399plusmn002

899plusmn001

65425plusmn328

462plusmn028

1899plusmn067

16152

FC9

25421plusmn353

398plusmn001

898plusmn001

67817plusmn14

4464plusmn078

1914plusmn025

16678

FC10

2596

7plusmn442

399plusmn002

897plusmn002

70367plusmn287

468plusmn038

1927plusmn14

417099

MeanplusmnSD

119899=3FC

form

ulationcode

Scientifica 9

Table 8 Detachment forces of different formulations

S numberFormulation code (FC) Detachment force (dynescm2)1 FC1 123452 FC2 131743 FC3 147534 FC4 156725 FC5 110426 FC6 159657 FC7 167808 FC8 142189 FC9 1402110 FC10 1362411 FC11 1437812 FC12 1452613 FC13 14065

the concentration of Carbopol decreased value of forces wasdecreased (ie FC5) Hence it was also concluded from theresults that the values of detachment forces were increasedmuchmore in case of Carbopol 934PNF compared to HPMCK4MCR because the Carbopol was highly bioadhesive ascompared to HPMC

Bioadhesion is a surface phenomenon inwhich amaterialof synthetic or natural origin adheres or sticks to a biologicalsurface usually mucus membrane Many hydrophilic poly-mers adhere to mucosal surfaces as they attract water fromthe mucus gel layer adhering to the epithelial surface This isthe simplest mechanism of adhesion and it has been definedas ldquoadhesion by hydrationrdquo The hydrogen bonding presentbetween the adherent polymer and mucus is involved inmucoadhesion at themolecular level As the concentration ofbioadhesive polymers increased then the hydrogen bondingbetween the mucus membrane and adherent polymer at themolecular level increased therefore detachment forces werealso found to be increased

Surface morphology of the optimized formulation FC8was examined by scanning electronmicroscopy (SEM) It wasobserved from the SEM photographs that the drug is releasedfrom the matrix tablet by the diffusion process The surfacemorphology of the matrix tablet after dissolution showedthat the solvent front enters the matrix and moves slowlytoward the center of the tablet The drug diffuses out of thematrix after it comes in contact with dissolution mediumThe images of the tablet showed a network in the swollenpolymer through which the drug diffused to the surroundingmedium Thus it was concluded that the drug was releasedfrom a matrix by diffusion mechanism (Figures 6 and7)

A comparative study was performed on the availablemarketed formulation of extended release tablet and capsulecontaining venlafaxine hydrochloride equivalent to venlafax-ine 375mgThe results obtained from the in vitro drug releasestudy showed that optimized formulations FC8 showedmore sustained-release action than that of tablet (marketed-1) and capsule (marketed-2) with respect to time of 18 hr(Figure 8)

Figure 6 Scanning electron microscopy of optimized formulationFC8 of tablet surface before dissolution

Figure 7 Scanning electron microscopy of optimized formulationFC8 of tablet surface after dissolution

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

FC8Marketed-1

Marketed-2

Figure 8 Comparison of drug release of optimized formulation(FC8) versus marketed formulations for 18 hr

The drug release was found to follow first-order kineticswith 119903 = 09935 and 09904 for marketed-1 (tablet) andmarketed-2 (capsule) respectively while optimized formula-tion FC8 followed the Peppasmodel with value of 119903 = 09962119899 = 04473 and 119896 = 252788 So the best-fit model was foundto be the Peppas model for optimized formulation FC8 Themarketed formulations of tablet and capsule showed morethan 90of drug release in 14 hrwhile optimized formulationFC8 showed only 8258 of drug release in 14 hr

The data obtained from in vitro dissolution studies werefitted to zero-order first-order Higuchi and Korsmeyer-Peppas equations All release kinetic models were applied

10 Scientifica

Table 9 Stability studies of venlafaxine hydrochloride floating tablets of optimized formulation (FC8)

Characteristic Initial 1st month 2nd month 3rd monthHardness (kgcm2) 667 plusmn 098 602 plusmn 056 642 plusmn 020 630 plusmn 088Drug content () 9891 plusmn 018 9834 plusmn 002 9812 plusmn 142 9800 plusmn 027Floating lag time (seconds) 72 plusmn 265 76 plusmn 126 84 plusmn 245 90 plusmn 326Total floating time (hours) 2450 plusmn 074 2416 plusmn 112 2418 plusmn 226 2408 plusmn 034Swelling index () 16152 16082 16064 16018Buoyancy on disturbing Float Float Float FloatMatrix integrity Very good Very good Very good Very good in vitro release 18 hours 9692 plusmn 083 9443 plusmn 138 9398 plusmn 042 9300 plusmn 156Mean plusmn SD 119899 = 3 FC formulation code

(a) (b)

Figure 9 In vitro floating studies of optimized formulation (FC8) (a) after 80 sec and (b) after 24 hr

on the formulation codes FC1 FC2 FC3 FC4 FC5 FC6FC7 FC8 FC9 FC10 FC11 FC12 and FC13 due to theirsatisfactory release behavior The best-fit model was found tobe the matrix for formulation codes FC1 FC2 and FC5 andPeppas for formulation codes FC3 FC4 FC6 FC7 FC8 FC9FC10 FC11 FC12 and FC13The selection criteria for the bestmodel were based on goodness of fit of the data and residualsum of squares The details of the best-fit model of differentformulation codes are given in Table 10

For confirming the diffusion mechanism of optimizedformulation FC8 the data was fitted to the Korsmeyerequation which showed the exponent value 119899 = 04473Because the optimized formulation FC8 had the exponentvalue (119899) less than 05 it was suggested that the releasemechanism of venlafaxine hydrochloride indicates swellingand diffusion mechanism of floating tablets which followedthe Fickian diffusion (Case I transport) This kinetic dataanalysis was done by using ldquoPCP Disso V208rdquo Software(Poona College of Pharmacy Pune India)

The optimized formulation FC8 was suggested for stabil-ity study based on in vitro floating lag time total floating timein vitro drug dissolution studies and its physical propertiesThe floating tablets were investigated at 400∘C75 RH in

aluminum foil packaging for three monthsThe increased lagtime indicates the possibility of reaction of sodium bicarbon-ate with moisture during the study period However therewas the very little effect on the duration of the floating andmatrix integrity of the tablets Some drug degradation wasfound but it was not statistically significant Decreased drugrelease was found from the formulation but drug releasedcompiled the official standard of release since more than80 of the drug was released (Table 9) Thus it was foundthat the floating tablets of venlafaxine hydrochloride werealmost stable under these storage conditions for at least threemonths

The in vitro studies with BaSO4-containing floating

tablets showed a floating lag time of 112plusmn200 seconds hard-ness of 660 plusmn 003 kgcm2 and thickness of 399 plusmn 001mmThe intragastric behavior of the BaSO

4-loaded tablet in the

albino rabbit was observed by using a radiographic imagingtechnique Radiographic images were taken after 1 3 and6 hr showing that the tablet had altered its position in thestomachThis provided evidence that the tablets were floatingon the gastric fluid After 4 hr of the tablet administrationthe swelling of the tablet is visualized very well together withthe white dry core and translucent swelling layer around it

Scientifica 11

Table 10 Drug release kinetics for floating-bioadhesive tablets

S number Formulation code (FC) Best-fit model 119877 value Parameters for Korsmeyer-Peppas equation

1 FC1 Matrix 09948 119899 = 04817

119896 = 242487

2 FC2 Matrix 09942 119899 = 05125

119896 = 213988

3 FC3 Peppas 09966 119899 = 04919

119896 = 210756

4 FC4 Peppas 09914 119899 = 05500

119896 = 169021

5 FC5 Matrix 09968 119899 = 04877

119896 = 229187

6 FC6 Peppas 09941 119899 = 05430

119896 = 171357

7 FC7 Peppas 09966 119899 = 06472

119896 = 130990

8 FC8 Peppas 09962 119899 = 04473

119896 = 252788

9 FC9 Peppas 09942 119899 = 03266

119896 = 374233

10 FC10 Peppas 09910 119899 = 03279

119896 = 396415

11 FC11 Peppas 09972 119899 = 04974

119896 = 213024

12 FC12 Peppas 09933 119899 = 03702

119896 = 332823

13 FC13 Peppas 09934 119899 = 03466

119896 = 366938

Note each sample was analyzed in triplicate (119899 = 3)119896 kinetic constant119899 exponent value

due to the swellable polymers HPMCK4MCR and Carbopol934PNF

Hence examination of the sequential radiographicimages of the GIT during the study clearly indicated that thetablet remained buoyant and altered its position in the gastriccontents for more than 6 hr So prolonged gastric retentiontime (GRT) of more than 6 hr is achieved (Figures 10(a)ndash10(c))

The objective of the in vivo studies was to provide theproof of concept that the floating capability of the floatingtablet was useful for the increasing the gastric residence timeof the dosage form For facilitating the trials on the rabbitsthe dosage form did not contain any drug and the scope waslimited to the observation of the behavior of the system in thestomach

4 Conclusion

The present study was carried out to develop the floating-bioadhesive drug delivery of venlafaxine hydrochloride using

HPMC K4MCR and Carbopol 934PNF polymers as the car-rier Optimized formulation FC8 gave satisfactory results forvarious physiochemical evaluations for tablets like hardnessweight variation floating lag time and uniformity of contentIn vitro dissolution studies of the optimized formulation FC8showed the sustained release for 18 hr followed by the Fickiandiffusion and an in vivo study indicated increased gastricresidence time by the floating principle and was considereddesirable for improving the bioavailability of the drug Allthese results also indicated that a low amount of floatingagent and high amount of hydrophilic polymer favored thesustained release of venlafaxine hydrochloride from the float-ing gastroretentive tablet formulations Developed sustained-release oral formulation for prolonged release would be asignificant advantage for the patient and may result in fewerside effects due to reduction of the blood concentrationfluctuations especially in long-term therapy Thus results ofthe current study clearly indicate a promising potential of thevenlafaxine hydrochloride floating system as an alternativeto the conventional dosage form However further clinical

12 Scientifica

(a)

(b)

(c)

Figure 10 Radiographic images showing the presence of BaSO4loaded floating tablet in the stomach at different time periods (the tablet is

indicated with an arrow) Images were taken after (a) 1 hr (b) 3 hr and (c) 6 hr after tablet administration

studies are needed to assess the utility of this system forpatients suffering from depression

Competing Interests

The authors declare that there are no competing interestsThe authors do not have a direct financial relation with thecommercial identities mentioned in the research paper thatmight lead to competing interests for any of the authors

Acknowledgments

The authors are thankful to Ranbaxy Research Lab Ltd Gur-gaon Haryana India for providing venlafaxine hydrochlo-ride as a gift sample and Arihant Trading CompanyMumbaiIndia and Colorcon Asia Pvt Ltd Goa India for providingthe polymer samples They also wish to thank Dr P KJain Radiologist VardhmanMedical Centre Jhansi India forextending radiography

Scientifica 13

References

[1] O Berton and E J Nestler ldquoNew approaches to antidepressantdrug discovery beyond monoaminesrdquo Nature Reviews Neuro-science vol 7 no 2 pp 137ndash151 2006

[2] E J Nestler M Barrot R J DiLeone A J Eisch S J Gold andLMMonteggia ldquoNeurobiology of depressionrdquoNeuron vol 34no 1 pp 13ndash25 2002

[3] E Richelson ldquoPharmacology of antidepressantsrdquo Mayo ClinicProceedings vol 76 no 5 pp 511ndash527 2001

[4] httpwwwdrugbankcadrugsDB00285[5] P Blier E Saint-Andre C Hebert C De Montigny N Lavoie

and G Debonnel ldquoEffects of different doses of venlafaxine onserotonin and norepinephrine reuptake in healthy volunteersrdquoInternational Journal of Neuropsychopharmacology vol 10 no1 pp 41ndash50 2007

[6] S M Holliday and P Benfield ldquoVenlafaxine a review of itspharmacology and therapeutic potential in depressionrdquo Drugsvol 49 no 2 pp 280ndash294 1995

[7] B Omprakash S Ajay G Santosh and P Amin ldquoFormulationdevelopment of venlafaxine hydrochloride extended releasetablet and invitro characterizationsrdquo International Journal ofPharmTech Research vol 4 no 4 pp 1777ndash1784 2012

[8] E AMuth J AMoyer J T Haskins T H Andree andG EMHusbands ldquoBiochemical neurophysiological and behavioraleffects of Wy-45233 and other identified metabolites of theantidepressant venlafaxinerdquo Drug Development Research vol23 no 2 pp 191ndash199 1991

[9] B Cusack A Nelson and E Richelson ldquoBinding of antide-pressants to human brain receptors focus on newer generationcompoundsrdquo Psychopharmacology vol 114 no 4 pp 559ndash5651994

[10] B N Singh and K H Kim ldquoFloating drug delivery systems anapproach to oral controlled drug delivery via gastric retentionrdquoJournal of Controlled Release vol 63 no 3 pp 235ndash259 2000

[11] P Bhardwaj R Singh and A Swarup ldquoStomach specific drugdelivery systemmdasha brief reviewrdquo Inventi Rapid NDDS no 3 pp1ndash9 2012

[12] R B Umamaheshwari S Jain D Bhadra and N K JainldquoFloating microspheres bearing acetohydroxamic acid for thetreatment of Helicobacter pylorirdquo Journal of Pharmacy andPharmacology vol 55 no 12 pp 1607ndash1613 2003

[13] S K Jain AMAwasthi N K Jain andG P Agrawal ldquoCalciumsilicate based microspheres of repaglinide for gastroretentivefloating drug delivery preparation and in vitro characteriza-tionrdquo Journal of Controlled Release vol 107 no 2 pp 300ndash3092005

[14] D Chaurasia K Kaushik P Bhardwaj H Chaurasia S K Jainand S Shobhna ldquoDevelopment and in vitro characterizationof floating microspheres bearing tramadol HClrdquo Acta PoloniaePharmaceuticamdashDrug Research vol 68 no 5 pp 795ndash801 2011

[15] P Bhardwaj H Chaurasia D Chaurasia S K Prajapati andS Singh ldquoFormulation and in-vitro evaluation of floatingmicroballoons of indomethacinrdquo Acta Poloniae Pharmaceuti-camdashDrug Research vol 67 no 3 pp 291ndash298 2010

[16] L Lachman H A Liberman and J L Kanig The Theoryand Practice of Industrial Pharmacy Varghese Publishin HouseBombay India 3rd edition 1991

[17] M E Aulton PharmaceuticsThe Science of Dosage formDesignElsevier Science Ltd Philadelphia Pa USA Churchill Living-stone London UK 2nd edition 2002

[18] M Jaimini A C Rana andY S Tanwar ldquoFormulation and eval-uation of famotidine floating tabletsrdquo Current Drug Deliveryvol 4 no 1 pp 51ndash55 2007

[19] A A Deshpande N H Shah C T Rhodes and W MalickldquoDevelopment of a novel controlled-release system for gastricretentionrdquo Pharmaceutical Research vol 14 no 6 pp 815ndash8191997

[20] G S Sonar D K Jain and D M More ldquoPreparation and invitro evaluation of bilayer and floating-bioadhesive tablets ofrosiglitazone maleaterdquo Asian Journal of Pharmaceutical Sciencevol 2 no 4 pp 161ndash169 2007

[21] B R Matthews ldquoRegulatory aspects of stability testing inEuroperdquo Drug Development and Industrial Pharmacy vol 25no 7 pp 831ndash856 1999

[22] R Gupta S K Prajapati S Pattnaik and P Bhardwaj ldquoFor-mulation and evaluation of novel stomach specific floatingmicrospheres bearing famotidine for treatment of gastric ulcerand their radiographic studyrdquo Asian Pacific Journal of TropicalBiomedicine vol 4 no 9 pp 729ndash735 2014

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

8 Scientifica

Table7Sw

ellingbehavior

ofmatrix

tablets

Form

ulationcode

Initialweight(mg)

Initialthickn

ess(mm)

Initialdiam

eter

(mm)

Finalw

eight(mg)

Finalthickness(m

m)

Finald

iameter

(mm)

Swellin

gindex

FC1

23411plusmn305

397plusmn001

898plusmn001

55259plusmn311

442plusmn10

81816plusmn038

13603

FC2

24020plusmn435

398plusmn002

897plusmn002

57852plusmn13

2450plusmn074

1852plusmn12

014084

FC3

24418plusmn16

9397plusmn001

899plusmn001

60710plusmn506

456plusmn089

1873plusmn14

814867

FC4

25010plusmn17

1399plusmn002

897plusmn001

6372

2plusmn340

461plusmn12

11885plusmn092

15478

FC5

23958plusmn10

1398plusmn001

898plusmn002

57848plusmn225

453plusmn14

21862plusmn13

41414

5FC

625009plusmn18

9396plusmn001

899plusmn002

64886plusmn413

463plusmn12

71889plusmn088

1594

5FC

725558plusmn329

397plusmn002

897plusmn001

6816

8plusmn267

466plusmn054

1893plusmn15

316672

FC8

25017plusmn12

3399plusmn002

899plusmn001

65425plusmn328

462plusmn028

1899plusmn067

16152

FC9

25421plusmn353

398plusmn001

898plusmn001

67817plusmn14

4464plusmn078

1914plusmn025

16678

FC10

2596

7plusmn442

399plusmn002

897plusmn002

70367plusmn287

468plusmn038

1927plusmn14

417099

MeanplusmnSD

119899=3FC

form

ulationcode

Scientifica 9

Table 8 Detachment forces of different formulations

S numberFormulation code (FC) Detachment force (dynescm2)1 FC1 123452 FC2 131743 FC3 147534 FC4 156725 FC5 110426 FC6 159657 FC7 167808 FC8 142189 FC9 1402110 FC10 1362411 FC11 1437812 FC12 1452613 FC13 14065

the concentration of Carbopol decreased value of forces wasdecreased (ie FC5) Hence it was also concluded from theresults that the values of detachment forces were increasedmuchmore in case of Carbopol 934PNF compared to HPMCK4MCR because the Carbopol was highly bioadhesive ascompared to HPMC

Bioadhesion is a surface phenomenon inwhich amaterialof synthetic or natural origin adheres or sticks to a biologicalsurface usually mucus membrane Many hydrophilic poly-mers adhere to mucosal surfaces as they attract water fromthe mucus gel layer adhering to the epithelial surface This isthe simplest mechanism of adhesion and it has been definedas ldquoadhesion by hydrationrdquo The hydrogen bonding presentbetween the adherent polymer and mucus is involved inmucoadhesion at themolecular level As the concentration ofbioadhesive polymers increased then the hydrogen bondingbetween the mucus membrane and adherent polymer at themolecular level increased therefore detachment forces werealso found to be increased

Surface morphology of the optimized formulation FC8was examined by scanning electronmicroscopy (SEM) It wasobserved from the SEM photographs that the drug is releasedfrom the matrix tablet by the diffusion process The surfacemorphology of the matrix tablet after dissolution showedthat the solvent front enters the matrix and moves slowlytoward the center of the tablet The drug diffuses out of thematrix after it comes in contact with dissolution mediumThe images of the tablet showed a network in the swollenpolymer through which the drug diffused to the surroundingmedium Thus it was concluded that the drug was releasedfrom a matrix by diffusion mechanism (Figures 6 and7)

A comparative study was performed on the availablemarketed formulation of extended release tablet and capsulecontaining venlafaxine hydrochloride equivalent to venlafax-ine 375mgThe results obtained from the in vitro drug releasestudy showed that optimized formulations FC8 showedmore sustained-release action than that of tablet (marketed-1) and capsule (marketed-2) with respect to time of 18 hr(Figure 8)

Figure 6 Scanning electron microscopy of optimized formulationFC8 of tablet surface before dissolution

Figure 7 Scanning electron microscopy of optimized formulationFC8 of tablet surface after dissolution

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

FC8Marketed-1

Marketed-2

Figure 8 Comparison of drug release of optimized formulation(FC8) versus marketed formulations for 18 hr

The drug release was found to follow first-order kineticswith 119903 = 09935 and 09904 for marketed-1 (tablet) andmarketed-2 (capsule) respectively while optimized formula-tion FC8 followed the Peppasmodel with value of 119903 = 09962119899 = 04473 and 119896 = 252788 So the best-fit model was foundto be the Peppas model for optimized formulation FC8 Themarketed formulations of tablet and capsule showed morethan 90of drug release in 14 hrwhile optimized formulationFC8 showed only 8258 of drug release in 14 hr

The data obtained from in vitro dissolution studies werefitted to zero-order first-order Higuchi and Korsmeyer-Peppas equations All release kinetic models were applied

10 Scientifica

Table 9 Stability studies of venlafaxine hydrochloride floating tablets of optimized formulation (FC8)

Characteristic Initial 1st month 2nd month 3rd monthHardness (kgcm2) 667 plusmn 098 602 plusmn 056 642 plusmn 020 630 plusmn 088Drug content () 9891 plusmn 018 9834 plusmn 002 9812 plusmn 142 9800 plusmn 027Floating lag time (seconds) 72 plusmn 265 76 plusmn 126 84 plusmn 245 90 plusmn 326Total floating time (hours) 2450 plusmn 074 2416 plusmn 112 2418 plusmn 226 2408 plusmn 034Swelling index () 16152 16082 16064 16018Buoyancy on disturbing Float Float Float FloatMatrix integrity Very good Very good Very good Very good in vitro release 18 hours 9692 plusmn 083 9443 plusmn 138 9398 plusmn 042 9300 plusmn 156Mean plusmn SD 119899 = 3 FC formulation code

(a) (b)

Figure 9 In vitro floating studies of optimized formulation (FC8) (a) after 80 sec and (b) after 24 hr

on the formulation codes FC1 FC2 FC3 FC4 FC5 FC6FC7 FC8 FC9 FC10 FC11 FC12 and FC13 due to theirsatisfactory release behavior The best-fit model was found tobe the matrix for formulation codes FC1 FC2 and FC5 andPeppas for formulation codes FC3 FC4 FC6 FC7 FC8 FC9FC10 FC11 FC12 and FC13The selection criteria for the bestmodel were based on goodness of fit of the data and residualsum of squares The details of the best-fit model of differentformulation codes are given in Table 10

For confirming the diffusion mechanism of optimizedformulation FC8 the data was fitted to the Korsmeyerequation which showed the exponent value 119899 = 04473Because the optimized formulation FC8 had the exponentvalue (119899) less than 05 it was suggested that the releasemechanism of venlafaxine hydrochloride indicates swellingand diffusion mechanism of floating tablets which followedthe Fickian diffusion (Case I transport) This kinetic dataanalysis was done by using ldquoPCP Disso V208rdquo Software(Poona College of Pharmacy Pune India)

The optimized formulation FC8 was suggested for stabil-ity study based on in vitro floating lag time total floating timein vitro drug dissolution studies and its physical propertiesThe floating tablets were investigated at 400∘C75 RH in

aluminum foil packaging for three monthsThe increased lagtime indicates the possibility of reaction of sodium bicarbon-ate with moisture during the study period However therewas the very little effect on the duration of the floating andmatrix integrity of the tablets Some drug degradation wasfound but it was not statistically significant Decreased drugrelease was found from the formulation but drug releasedcompiled the official standard of release since more than80 of the drug was released (Table 9) Thus it was foundthat the floating tablets of venlafaxine hydrochloride werealmost stable under these storage conditions for at least threemonths

The in vitro studies with BaSO4-containing floating

tablets showed a floating lag time of 112plusmn200 seconds hard-ness of 660 plusmn 003 kgcm2 and thickness of 399 plusmn 001mmThe intragastric behavior of the BaSO

4-loaded tablet in the

albino rabbit was observed by using a radiographic imagingtechnique Radiographic images were taken after 1 3 and6 hr showing that the tablet had altered its position in thestomachThis provided evidence that the tablets were floatingon the gastric fluid After 4 hr of the tablet administrationthe swelling of the tablet is visualized very well together withthe white dry core and translucent swelling layer around it

Scientifica 11

Table 10 Drug release kinetics for floating-bioadhesive tablets

S number Formulation code (FC) Best-fit model 119877 value Parameters for Korsmeyer-Peppas equation

1 FC1 Matrix 09948 119899 = 04817

119896 = 242487

2 FC2 Matrix 09942 119899 = 05125

119896 = 213988

3 FC3 Peppas 09966 119899 = 04919

119896 = 210756

4 FC4 Peppas 09914 119899 = 05500

119896 = 169021

5 FC5 Matrix 09968 119899 = 04877

119896 = 229187

6 FC6 Peppas 09941 119899 = 05430

119896 = 171357

7 FC7 Peppas 09966 119899 = 06472

119896 = 130990

8 FC8 Peppas 09962 119899 = 04473

119896 = 252788

9 FC9 Peppas 09942 119899 = 03266

119896 = 374233

10 FC10 Peppas 09910 119899 = 03279

119896 = 396415

11 FC11 Peppas 09972 119899 = 04974

119896 = 213024

12 FC12 Peppas 09933 119899 = 03702

119896 = 332823

13 FC13 Peppas 09934 119899 = 03466

119896 = 366938

Note each sample was analyzed in triplicate (119899 = 3)119896 kinetic constant119899 exponent value

due to the swellable polymers HPMCK4MCR and Carbopol934PNF

Hence examination of the sequential radiographicimages of the GIT during the study clearly indicated that thetablet remained buoyant and altered its position in the gastriccontents for more than 6 hr So prolonged gastric retentiontime (GRT) of more than 6 hr is achieved (Figures 10(a)ndash10(c))

The objective of the in vivo studies was to provide theproof of concept that the floating capability of the floatingtablet was useful for the increasing the gastric residence timeof the dosage form For facilitating the trials on the rabbitsthe dosage form did not contain any drug and the scope waslimited to the observation of the behavior of the system in thestomach

4 Conclusion

The present study was carried out to develop the floating-bioadhesive drug delivery of venlafaxine hydrochloride using

HPMC K4MCR and Carbopol 934PNF polymers as the car-rier Optimized formulation FC8 gave satisfactory results forvarious physiochemical evaluations for tablets like hardnessweight variation floating lag time and uniformity of contentIn vitro dissolution studies of the optimized formulation FC8showed the sustained release for 18 hr followed by the Fickiandiffusion and an in vivo study indicated increased gastricresidence time by the floating principle and was considereddesirable for improving the bioavailability of the drug Allthese results also indicated that a low amount of floatingagent and high amount of hydrophilic polymer favored thesustained release of venlafaxine hydrochloride from the float-ing gastroretentive tablet formulations Developed sustained-release oral formulation for prolonged release would be asignificant advantage for the patient and may result in fewerside effects due to reduction of the blood concentrationfluctuations especially in long-term therapy Thus results ofthe current study clearly indicate a promising potential of thevenlafaxine hydrochloride floating system as an alternativeto the conventional dosage form However further clinical

12 Scientifica

(a)

(b)

(c)

Figure 10 Radiographic images showing the presence of BaSO4loaded floating tablet in the stomach at different time periods (the tablet is

indicated with an arrow) Images were taken after (a) 1 hr (b) 3 hr and (c) 6 hr after tablet administration

studies are needed to assess the utility of this system forpatients suffering from depression

Competing Interests

The authors declare that there are no competing interestsThe authors do not have a direct financial relation with thecommercial identities mentioned in the research paper thatmight lead to competing interests for any of the authors

Acknowledgments

The authors are thankful to Ranbaxy Research Lab Ltd Gur-gaon Haryana India for providing venlafaxine hydrochlo-ride as a gift sample and Arihant Trading CompanyMumbaiIndia and Colorcon Asia Pvt Ltd Goa India for providingthe polymer samples They also wish to thank Dr P KJain Radiologist VardhmanMedical Centre Jhansi India forextending radiography

Scientifica 13

References

[1] O Berton and E J Nestler ldquoNew approaches to antidepressantdrug discovery beyond monoaminesrdquo Nature Reviews Neuro-science vol 7 no 2 pp 137ndash151 2006

[2] E J Nestler M Barrot R J DiLeone A J Eisch S J Gold andLMMonteggia ldquoNeurobiology of depressionrdquoNeuron vol 34no 1 pp 13ndash25 2002

[3] E Richelson ldquoPharmacology of antidepressantsrdquo Mayo ClinicProceedings vol 76 no 5 pp 511ndash527 2001

[4] httpwwwdrugbankcadrugsDB00285[5] P Blier E Saint-Andre C Hebert C De Montigny N Lavoie

and G Debonnel ldquoEffects of different doses of venlafaxine onserotonin and norepinephrine reuptake in healthy volunteersrdquoInternational Journal of Neuropsychopharmacology vol 10 no1 pp 41ndash50 2007

[6] S M Holliday and P Benfield ldquoVenlafaxine a review of itspharmacology and therapeutic potential in depressionrdquo Drugsvol 49 no 2 pp 280ndash294 1995

[7] B Omprakash S Ajay G Santosh and P Amin ldquoFormulationdevelopment of venlafaxine hydrochloride extended releasetablet and invitro characterizationsrdquo International Journal ofPharmTech Research vol 4 no 4 pp 1777ndash1784 2012

[8] E AMuth J AMoyer J T Haskins T H Andree andG EMHusbands ldquoBiochemical neurophysiological and behavioraleffects of Wy-45233 and other identified metabolites of theantidepressant venlafaxinerdquo Drug Development Research vol23 no 2 pp 191ndash199 1991

[9] B Cusack A Nelson and E Richelson ldquoBinding of antide-pressants to human brain receptors focus on newer generationcompoundsrdquo Psychopharmacology vol 114 no 4 pp 559ndash5651994

[10] B N Singh and K H Kim ldquoFloating drug delivery systems anapproach to oral controlled drug delivery via gastric retentionrdquoJournal of Controlled Release vol 63 no 3 pp 235ndash259 2000

[11] P Bhardwaj R Singh and A Swarup ldquoStomach specific drugdelivery systemmdasha brief reviewrdquo Inventi Rapid NDDS no 3 pp1ndash9 2012

[12] R B Umamaheshwari S Jain D Bhadra and N K JainldquoFloating microspheres bearing acetohydroxamic acid for thetreatment of Helicobacter pylorirdquo Journal of Pharmacy andPharmacology vol 55 no 12 pp 1607ndash1613 2003

[13] S K Jain AMAwasthi N K Jain andG P Agrawal ldquoCalciumsilicate based microspheres of repaglinide for gastroretentivefloating drug delivery preparation and in vitro characteriza-tionrdquo Journal of Controlled Release vol 107 no 2 pp 300ndash3092005

[14] D Chaurasia K Kaushik P Bhardwaj H Chaurasia S K Jainand S Shobhna ldquoDevelopment and in vitro characterizationof floating microspheres bearing tramadol HClrdquo Acta PoloniaePharmaceuticamdashDrug Research vol 68 no 5 pp 795ndash801 2011

[15] P Bhardwaj H Chaurasia D Chaurasia S K Prajapati andS Singh ldquoFormulation and in-vitro evaluation of floatingmicroballoons of indomethacinrdquo Acta Poloniae Pharmaceuti-camdashDrug Research vol 67 no 3 pp 291ndash298 2010

[16] L Lachman H A Liberman and J L Kanig The Theoryand Practice of Industrial Pharmacy Varghese Publishin HouseBombay India 3rd edition 1991

[17] M E Aulton PharmaceuticsThe Science of Dosage formDesignElsevier Science Ltd Philadelphia Pa USA Churchill Living-stone London UK 2nd edition 2002

[18] M Jaimini A C Rana andY S Tanwar ldquoFormulation and eval-uation of famotidine floating tabletsrdquo Current Drug Deliveryvol 4 no 1 pp 51ndash55 2007

[19] A A Deshpande N H Shah C T Rhodes and W MalickldquoDevelopment of a novel controlled-release system for gastricretentionrdquo Pharmaceutical Research vol 14 no 6 pp 815ndash8191997

[20] G S Sonar D K Jain and D M More ldquoPreparation and invitro evaluation of bilayer and floating-bioadhesive tablets ofrosiglitazone maleaterdquo Asian Journal of Pharmaceutical Sciencevol 2 no 4 pp 161ndash169 2007

[21] B R Matthews ldquoRegulatory aspects of stability testing inEuroperdquo Drug Development and Industrial Pharmacy vol 25no 7 pp 831ndash856 1999

[22] R Gupta S K Prajapati S Pattnaik and P Bhardwaj ldquoFor-mulation and evaluation of novel stomach specific floatingmicrospheres bearing famotidine for treatment of gastric ulcerand their radiographic studyrdquo Asian Pacific Journal of TropicalBiomedicine vol 4 no 9 pp 729ndash735 2014

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Scientifica 9

Table 8 Detachment forces of different formulations

S numberFormulation code (FC) Detachment force (dynescm2)1 FC1 123452 FC2 131743 FC3 147534 FC4 156725 FC5 110426 FC6 159657 FC7 167808 FC8 142189 FC9 1402110 FC10 1362411 FC11 1437812 FC12 1452613 FC13 14065

the concentration of Carbopol decreased value of forces wasdecreased (ie FC5) Hence it was also concluded from theresults that the values of detachment forces were increasedmuchmore in case of Carbopol 934PNF compared to HPMCK4MCR because the Carbopol was highly bioadhesive ascompared to HPMC

Bioadhesion is a surface phenomenon inwhich amaterialof synthetic or natural origin adheres or sticks to a biologicalsurface usually mucus membrane Many hydrophilic poly-mers adhere to mucosal surfaces as they attract water fromthe mucus gel layer adhering to the epithelial surface This isthe simplest mechanism of adhesion and it has been definedas ldquoadhesion by hydrationrdquo The hydrogen bonding presentbetween the adherent polymer and mucus is involved inmucoadhesion at themolecular level As the concentration ofbioadhesive polymers increased then the hydrogen bondingbetween the mucus membrane and adherent polymer at themolecular level increased therefore detachment forces werealso found to be increased

Surface morphology of the optimized formulation FC8was examined by scanning electronmicroscopy (SEM) It wasobserved from the SEM photographs that the drug is releasedfrom the matrix tablet by the diffusion process The surfacemorphology of the matrix tablet after dissolution showedthat the solvent front enters the matrix and moves slowlytoward the center of the tablet The drug diffuses out of thematrix after it comes in contact with dissolution mediumThe images of the tablet showed a network in the swollenpolymer through which the drug diffused to the surroundingmedium Thus it was concluded that the drug was releasedfrom a matrix by diffusion mechanism (Figures 6 and7)

A comparative study was performed on the availablemarketed formulation of extended release tablet and capsulecontaining venlafaxine hydrochloride equivalent to venlafax-ine 375mgThe results obtained from the in vitro drug releasestudy showed that optimized formulations FC8 showedmore sustained-release action than that of tablet (marketed-1) and capsule (marketed-2) with respect to time of 18 hr(Figure 8)

Figure 6 Scanning electron microscopy of optimized formulationFC8 of tablet surface before dissolution

Figure 7 Scanning electron microscopy of optimized formulationFC8 of tablet surface after dissolution

0000

20000

40000

60000

80000

100000

120000

0 5 10 15 20

Cum

ulat

ive

dru

g re

leas

e

Time (hr)

FC8Marketed-1

Marketed-2

Figure 8 Comparison of drug release of optimized formulation(FC8) versus marketed formulations for 18 hr

The drug release was found to follow first-order kineticswith 119903 = 09935 and 09904 for marketed-1 (tablet) andmarketed-2 (capsule) respectively while optimized formula-tion FC8 followed the Peppasmodel with value of 119903 = 09962119899 = 04473 and 119896 = 252788 So the best-fit model was foundto be the Peppas model for optimized formulation FC8 Themarketed formulations of tablet and capsule showed morethan 90of drug release in 14 hrwhile optimized formulationFC8 showed only 8258 of drug release in 14 hr

The data obtained from in vitro dissolution studies werefitted to zero-order first-order Higuchi and Korsmeyer-Peppas equations All release kinetic models were applied

10 Scientifica

Table 9 Stability studies of venlafaxine hydrochloride floating tablets of optimized formulation (FC8)

Characteristic Initial 1st month 2nd month 3rd monthHardness (kgcm2) 667 plusmn 098 602 plusmn 056 642 plusmn 020 630 plusmn 088Drug content () 9891 plusmn 018 9834 plusmn 002 9812 plusmn 142 9800 plusmn 027Floating lag time (seconds) 72 plusmn 265 76 plusmn 126 84 plusmn 245 90 plusmn 326Total floating time (hours) 2450 plusmn 074 2416 plusmn 112 2418 plusmn 226 2408 plusmn 034Swelling index () 16152 16082 16064 16018Buoyancy on disturbing Float Float Float FloatMatrix integrity Very good Very good Very good Very good in vitro release 18 hours 9692 plusmn 083 9443 plusmn 138 9398 plusmn 042 9300 plusmn 156Mean plusmn SD 119899 = 3 FC formulation code

(a) (b)

Figure 9 In vitro floating studies of optimized formulation (FC8) (a) after 80 sec and (b) after 24 hr

on the formulation codes FC1 FC2 FC3 FC4 FC5 FC6FC7 FC8 FC9 FC10 FC11 FC12 and FC13 due to theirsatisfactory release behavior The best-fit model was found tobe the matrix for formulation codes FC1 FC2 and FC5 andPeppas for formulation codes FC3 FC4 FC6 FC7 FC8 FC9FC10 FC11 FC12 and FC13The selection criteria for the bestmodel were based on goodness of fit of the data and residualsum of squares The details of the best-fit model of differentformulation codes are given in Table 10

For confirming the diffusion mechanism of optimizedformulation FC8 the data was fitted to the Korsmeyerequation which showed the exponent value 119899 = 04473Because the optimized formulation FC8 had the exponentvalue (119899) less than 05 it was suggested that the releasemechanism of venlafaxine hydrochloride indicates swellingand diffusion mechanism of floating tablets which followedthe Fickian diffusion (Case I transport) This kinetic dataanalysis was done by using ldquoPCP Disso V208rdquo Software(Poona College of Pharmacy Pune India)

The optimized formulation FC8 was suggested for stabil-ity study based on in vitro floating lag time total floating timein vitro drug dissolution studies and its physical propertiesThe floating tablets were investigated at 400∘C75 RH in

aluminum foil packaging for three monthsThe increased lagtime indicates the possibility of reaction of sodium bicarbon-ate with moisture during the study period However therewas the very little effect on the duration of the floating andmatrix integrity of the tablets Some drug degradation wasfound but it was not statistically significant Decreased drugrelease was found from the formulation but drug releasedcompiled the official standard of release since more than80 of the drug was released (Table 9) Thus it was foundthat the floating tablets of venlafaxine hydrochloride werealmost stable under these storage conditions for at least threemonths

The in vitro studies with BaSO4-containing floating

tablets showed a floating lag time of 112plusmn200 seconds hard-ness of 660 plusmn 003 kgcm2 and thickness of 399 plusmn 001mmThe intragastric behavior of the BaSO

4-loaded tablet in the

albino rabbit was observed by using a radiographic imagingtechnique Radiographic images were taken after 1 3 and6 hr showing that the tablet had altered its position in thestomachThis provided evidence that the tablets were floatingon the gastric fluid After 4 hr of the tablet administrationthe swelling of the tablet is visualized very well together withthe white dry core and translucent swelling layer around it

Scientifica 11

Table 10 Drug release kinetics for floating-bioadhesive tablets

S number Formulation code (FC) Best-fit model 119877 value Parameters for Korsmeyer-Peppas equation

1 FC1 Matrix 09948 119899 = 04817

119896 = 242487

2 FC2 Matrix 09942 119899 = 05125

119896 = 213988

3 FC3 Peppas 09966 119899 = 04919

119896 = 210756

4 FC4 Peppas 09914 119899 = 05500

119896 = 169021

5 FC5 Matrix 09968 119899 = 04877

119896 = 229187

6 FC6 Peppas 09941 119899 = 05430

119896 = 171357

7 FC7 Peppas 09966 119899 = 06472

119896 = 130990

8 FC8 Peppas 09962 119899 = 04473

119896 = 252788

9 FC9 Peppas 09942 119899 = 03266

119896 = 374233

10 FC10 Peppas 09910 119899 = 03279

119896 = 396415

11 FC11 Peppas 09972 119899 = 04974

119896 = 213024

12 FC12 Peppas 09933 119899 = 03702

119896 = 332823

13 FC13 Peppas 09934 119899 = 03466

119896 = 366938

Note each sample was analyzed in triplicate (119899 = 3)119896 kinetic constant119899 exponent value

due to the swellable polymers HPMCK4MCR and Carbopol934PNF

Hence examination of the sequential radiographicimages of the GIT during the study clearly indicated that thetablet remained buoyant and altered its position in the gastriccontents for more than 6 hr So prolonged gastric retentiontime (GRT) of more than 6 hr is achieved (Figures 10(a)ndash10(c))

The objective of the in vivo studies was to provide theproof of concept that the floating capability of the floatingtablet was useful for the increasing the gastric residence timeof the dosage form For facilitating the trials on the rabbitsthe dosage form did not contain any drug and the scope waslimited to the observation of the behavior of the system in thestomach

4 Conclusion

The present study was carried out to develop the floating-bioadhesive drug delivery of venlafaxine hydrochloride using

HPMC K4MCR and Carbopol 934PNF polymers as the car-rier Optimized formulation FC8 gave satisfactory results forvarious physiochemical evaluations for tablets like hardnessweight variation floating lag time and uniformity of contentIn vitro dissolution studies of the optimized formulation FC8showed the sustained release for 18 hr followed by the Fickiandiffusion and an in vivo study indicated increased gastricresidence time by the floating principle and was considereddesirable for improving the bioavailability of the drug Allthese results also indicated that a low amount of floatingagent and high amount of hydrophilic polymer favored thesustained release of venlafaxine hydrochloride from the float-ing gastroretentive tablet formulations Developed sustained-release oral formulation for prolonged release would be asignificant advantage for the patient and may result in fewerside effects due to reduction of the blood concentrationfluctuations especially in long-term therapy Thus results ofthe current study clearly indicate a promising potential of thevenlafaxine hydrochloride floating system as an alternativeto the conventional dosage form However further clinical

12 Scientifica

(a)

(b)

(c)

Figure 10 Radiographic images showing the presence of BaSO4loaded floating tablet in the stomach at different time periods (the tablet is

indicated with an arrow) Images were taken after (a) 1 hr (b) 3 hr and (c) 6 hr after tablet administration

studies are needed to assess the utility of this system forpatients suffering from depression

Competing Interests

The authors declare that there are no competing interestsThe authors do not have a direct financial relation with thecommercial identities mentioned in the research paper thatmight lead to competing interests for any of the authors

Acknowledgments

The authors are thankful to Ranbaxy Research Lab Ltd Gur-gaon Haryana India for providing venlafaxine hydrochlo-ride as a gift sample and Arihant Trading CompanyMumbaiIndia and Colorcon Asia Pvt Ltd Goa India for providingthe polymer samples They also wish to thank Dr P KJain Radiologist VardhmanMedical Centre Jhansi India forextending radiography

Scientifica 13

References

[1] O Berton and E J Nestler ldquoNew approaches to antidepressantdrug discovery beyond monoaminesrdquo Nature Reviews Neuro-science vol 7 no 2 pp 137ndash151 2006

[2] E J Nestler M Barrot R J DiLeone A J Eisch S J Gold andLMMonteggia ldquoNeurobiology of depressionrdquoNeuron vol 34no 1 pp 13ndash25 2002

[3] E Richelson ldquoPharmacology of antidepressantsrdquo Mayo ClinicProceedings vol 76 no 5 pp 511ndash527 2001

[4] httpwwwdrugbankcadrugsDB00285[5] P Blier E Saint-Andre C Hebert C De Montigny N Lavoie

and G Debonnel ldquoEffects of different doses of venlafaxine onserotonin and norepinephrine reuptake in healthy volunteersrdquoInternational Journal of Neuropsychopharmacology vol 10 no1 pp 41ndash50 2007

[6] S M Holliday and P Benfield ldquoVenlafaxine a review of itspharmacology and therapeutic potential in depressionrdquo Drugsvol 49 no 2 pp 280ndash294 1995

[7] B Omprakash S Ajay G Santosh and P Amin ldquoFormulationdevelopment of venlafaxine hydrochloride extended releasetablet and invitro characterizationsrdquo International Journal ofPharmTech Research vol 4 no 4 pp 1777ndash1784 2012

[8] E AMuth J AMoyer J T Haskins T H Andree andG EMHusbands ldquoBiochemical neurophysiological and behavioraleffects of Wy-45233 and other identified metabolites of theantidepressant venlafaxinerdquo Drug Development Research vol23 no 2 pp 191ndash199 1991

[9] B Cusack A Nelson and E Richelson ldquoBinding of antide-pressants to human brain receptors focus on newer generationcompoundsrdquo Psychopharmacology vol 114 no 4 pp 559ndash5651994

[10] B N Singh and K H Kim ldquoFloating drug delivery systems anapproach to oral controlled drug delivery via gastric retentionrdquoJournal of Controlled Release vol 63 no 3 pp 235ndash259 2000

[11] P Bhardwaj R Singh and A Swarup ldquoStomach specific drugdelivery systemmdasha brief reviewrdquo Inventi Rapid NDDS no 3 pp1ndash9 2012

[12] R B Umamaheshwari S Jain D Bhadra and N K JainldquoFloating microspheres bearing acetohydroxamic acid for thetreatment of Helicobacter pylorirdquo Journal of Pharmacy andPharmacology vol 55 no 12 pp 1607ndash1613 2003

[13] S K Jain AMAwasthi N K Jain andG P Agrawal ldquoCalciumsilicate based microspheres of repaglinide for gastroretentivefloating drug delivery preparation and in vitro characteriza-tionrdquo Journal of Controlled Release vol 107 no 2 pp 300ndash3092005

[14] D Chaurasia K Kaushik P Bhardwaj H Chaurasia S K Jainand S Shobhna ldquoDevelopment and in vitro characterizationof floating microspheres bearing tramadol HClrdquo Acta PoloniaePharmaceuticamdashDrug Research vol 68 no 5 pp 795ndash801 2011

[15] P Bhardwaj H Chaurasia D Chaurasia S K Prajapati andS Singh ldquoFormulation and in-vitro evaluation of floatingmicroballoons of indomethacinrdquo Acta Poloniae Pharmaceuti-camdashDrug Research vol 67 no 3 pp 291ndash298 2010

[16] L Lachman H A Liberman and J L Kanig The Theoryand Practice of Industrial Pharmacy Varghese Publishin HouseBombay India 3rd edition 1991

[17] M E Aulton PharmaceuticsThe Science of Dosage formDesignElsevier Science Ltd Philadelphia Pa USA Churchill Living-stone London UK 2nd edition 2002

[18] M Jaimini A C Rana andY S Tanwar ldquoFormulation and eval-uation of famotidine floating tabletsrdquo Current Drug Deliveryvol 4 no 1 pp 51ndash55 2007

[19] A A Deshpande N H Shah C T Rhodes and W MalickldquoDevelopment of a novel controlled-release system for gastricretentionrdquo Pharmaceutical Research vol 14 no 6 pp 815ndash8191997

[20] G S Sonar D K Jain and D M More ldquoPreparation and invitro evaluation of bilayer and floating-bioadhesive tablets ofrosiglitazone maleaterdquo Asian Journal of Pharmaceutical Sciencevol 2 no 4 pp 161ndash169 2007

[21] B R Matthews ldquoRegulatory aspects of stability testing inEuroperdquo Drug Development and Industrial Pharmacy vol 25no 7 pp 831ndash856 1999

[22] R Gupta S K Prajapati S Pattnaik and P Bhardwaj ldquoFor-mulation and evaluation of novel stomach specific floatingmicrospheres bearing famotidine for treatment of gastric ulcerand their radiographic studyrdquo Asian Pacific Journal of TropicalBiomedicine vol 4 no 9 pp 729ndash735 2014

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

10 Scientifica

Table 9 Stability studies of venlafaxine hydrochloride floating tablets of optimized formulation (FC8)

Characteristic Initial 1st month 2nd month 3rd monthHardness (kgcm2) 667 plusmn 098 602 plusmn 056 642 plusmn 020 630 plusmn 088Drug content () 9891 plusmn 018 9834 plusmn 002 9812 plusmn 142 9800 plusmn 027Floating lag time (seconds) 72 plusmn 265 76 plusmn 126 84 plusmn 245 90 plusmn 326Total floating time (hours) 2450 plusmn 074 2416 plusmn 112 2418 plusmn 226 2408 plusmn 034Swelling index () 16152 16082 16064 16018Buoyancy on disturbing Float Float Float FloatMatrix integrity Very good Very good Very good Very good in vitro release 18 hours 9692 plusmn 083 9443 plusmn 138 9398 plusmn 042 9300 plusmn 156Mean plusmn SD 119899 = 3 FC formulation code

(a) (b)

Figure 9 In vitro floating studies of optimized formulation (FC8) (a) after 80 sec and (b) after 24 hr

on the formulation codes FC1 FC2 FC3 FC4 FC5 FC6FC7 FC8 FC9 FC10 FC11 FC12 and FC13 due to theirsatisfactory release behavior The best-fit model was found tobe the matrix for formulation codes FC1 FC2 and FC5 andPeppas for formulation codes FC3 FC4 FC6 FC7 FC8 FC9FC10 FC11 FC12 and FC13The selection criteria for the bestmodel were based on goodness of fit of the data and residualsum of squares The details of the best-fit model of differentformulation codes are given in Table 10

For confirming the diffusion mechanism of optimizedformulation FC8 the data was fitted to the Korsmeyerequation which showed the exponent value 119899 = 04473Because the optimized formulation FC8 had the exponentvalue (119899) less than 05 it was suggested that the releasemechanism of venlafaxine hydrochloride indicates swellingand diffusion mechanism of floating tablets which followedthe Fickian diffusion (Case I transport) This kinetic dataanalysis was done by using ldquoPCP Disso V208rdquo Software(Poona College of Pharmacy Pune India)

The optimized formulation FC8 was suggested for stabil-ity study based on in vitro floating lag time total floating timein vitro drug dissolution studies and its physical propertiesThe floating tablets were investigated at 400∘C75 RH in

aluminum foil packaging for three monthsThe increased lagtime indicates the possibility of reaction of sodium bicarbon-ate with moisture during the study period However therewas the very little effect on the duration of the floating andmatrix integrity of the tablets Some drug degradation wasfound but it was not statistically significant Decreased drugrelease was found from the formulation but drug releasedcompiled the official standard of release since more than80 of the drug was released (Table 9) Thus it was foundthat the floating tablets of venlafaxine hydrochloride werealmost stable under these storage conditions for at least threemonths

The in vitro studies with BaSO4-containing floating

tablets showed a floating lag time of 112plusmn200 seconds hard-ness of 660 plusmn 003 kgcm2 and thickness of 399 plusmn 001mmThe intragastric behavior of the BaSO

4-loaded tablet in the

albino rabbit was observed by using a radiographic imagingtechnique Radiographic images were taken after 1 3 and6 hr showing that the tablet had altered its position in thestomachThis provided evidence that the tablets were floatingon the gastric fluid After 4 hr of the tablet administrationthe swelling of the tablet is visualized very well together withthe white dry core and translucent swelling layer around it

Scientifica 11

Table 10 Drug release kinetics for floating-bioadhesive tablets

S number Formulation code (FC) Best-fit model 119877 value Parameters for Korsmeyer-Peppas equation

1 FC1 Matrix 09948 119899 = 04817

119896 = 242487

2 FC2 Matrix 09942 119899 = 05125

119896 = 213988

3 FC3 Peppas 09966 119899 = 04919

119896 = 210756

4 FC4 Peppas 09914 119899 = 05500

119896 = 169021

5 FC5 Matrix 09968 119899 = 04877

119896 = 229187

6 FC6 Peppas 09941 119899 = 05430

119896 = 171357

7 FC7 Peppas 09966 119899 = 06472

119896 = 130990

8 FC8 Peppas 09962 119899 = 04473

119896 = 252788

9 FC9 Peppas 09942 119899 = 03266

119896 = 374233

10 FC10 Peppas 09910 119899 = 03279

119896 = 396415

11 FC11 Peppas 09972 119899 = 04974

119896 = 213024

12 FC12 Peppas 09933 119899 = 03702

119896 = 332823

13 FC13 Peppas 09934 119899 = 03466

119896 = 366938

Note each sample was analyzed in triplicate (119899 = 3)119896 kinetic constant119899 exponent value

due to the swellable polymers HPMCK4MCR and Carbopol934PNF

Hence examination of the sequential radiographicimages of the GIT during the study clearly indicated that thetablet remained buoyant and altered its position in the gastriccontents for more than 6 hr So prolonged gastric retentiontime (GRT) of more than 6 hr is achieved (Figures 10(a)ndash10(c))

The objective of the in vivo studies was to provide theproof of concept that the floating capability of the floatingtablet was useful for the increasing the gastric residence timeof the dosage form For facilitating the trials on the rabbitsthe dosage form did not contain any drug and the scope waslimited to the observation of the behavior of the system in thestomach

4 Conclusion

The present study was carried out to develop the floating-bioadhesive drug delivery of venlafaxine hydrochloride using

HPMC K4MCR and Carbopol 934PNF polymers as the car-rier Optimized formulation FC8 gave satisfactory results forvarious physiochemical evaluations for tablets like hardnessweight variation floating lag time and uniformity of contentIn vitro dissolution studies of the optimized formulation FC8showed the sustained release for 18 hr followed by the Fickiandiffusion and an in vivo study indicated increased gastricresidence time by the floating principle and was considereddesirable for improving the bioavailability of the drug Allthese results also indicated that a low amount of floatingagent and high amount of hydrophilic polymer favored thesustained release of venlafaxine hydrochloride from the float-ing gastroretentive tablet formulations Developed sustained-release oral formulation for prolonged release would be asignificant advantage for the patient and may result in fewerside effects due to reduction of the blood concentrationfluctuations especially in long-term therapy Thus results ofthe current study clearly indicate a promising potential of thevenlafaxine hydrochloride floating system as an alternativeto the conventional dosage form However further clinical

12 Scientifica

(a)

(b)

(c)

Figure 10 Radiographic images showing the presence of BaSO4loaded floating tablet in the stomach at different time periods (the tablet is

indicated with an arrow) Images were taken after (a) 1 hr (b) 3 hr and (c) 6 hr after tablet administration

studies are needed to assess the utility of this system forpatients suffering from depression

Competing Interests

The authors declare that there are no competing interestsThe authors do not have a direct financial relation with thecommercial identities mentioned in the research paper thatmight lead to competing interests for any of the authors

Acknowledgments

The authors are thankful to Ranbaxy Research Lab Ltd Gur-gaon Haryana India for providing venlafaxine hydrochlo-ride as a gift sample and Arihant Trading CompanyMumbaiIndia and Colorcon Asia Pvt Ltd Goa India for providingthe polymer samples They also wish to thank Dr P KJain Radiologist VardhmanMedical Centre Jhansi India forextending radiography

Scientifica 13

References

[1] O Berton and E J Nestler ldquoNew approaches to antidepressantdrug discovery beyond monoaminesrdquo Nature Reviews Neuro-science vol 7 no 2 pp 137ndash151 2006

[2] E J Nestler M Barrot R J DiLeone A J Eisch S J Gold andLMMonteggia ldquoNeurobiology of depressionrdquoNeuron vol 34no 1 pp 13ndash25 2002

[3] E Richelson ldquoPharmacology of antidepressantsrdquo Mayo ClinicProceedings vol 76 no 5 pp 511ndash527 2001

[4] httpwwwdrugbankcadrugsDB00285[5] P Blier E Saint-Andre C Hebert C De Montigny N Lavoie

and G Debonnel ldquoEffects of different doses of venlafaxine onserotonin and norepinephrine reuptake in healthy volunteersrdquoInternational Journal of Neuropsychopharmacology vol 10 no1 pp 41ndash50 2007

[6] S M Holliday and P Benfield ldquoVenlafaxine a review of itspharmacology and therapeutic potential in depressionrdquo Drugsvol 49 no 2 pp 280ndash294 1995

[7] B Omprakash S Ajay G Santosh and P Amin ldquoFormulationdevelopment of venlafaxine hydrochloride extended releasetablet and invitro characterizationsrdquo International Journal ofPharmTech Research vol 4 no 4 pp 1777ndash1784 2012

[8] E AMuth J AMoyer J T Haskins T H Andree andG EMHusbands ldquoBiochemical neurophysiological and behavioraleffects of Wy-45233 and other identified metabolites of theantidepressant venlafaxinerdquo Drug Development Research vol23 no 2 pp 191ndash199 1991

[9] B Cusack A Nelson and E Richelson ldquoBinding of antide-pressants to human brain receptors focus on newer generationcompoundsrdquo Psychopharmacology vol 114 no 4 pp 559ndash5651994

[10] B N Singh and K H Kim ldquoFloating drug delivery systems anapproach to oral controlled drug delivery via gastric retentionrdquoJournal of Controlled Release vol 63 no 3 pp 235ndash259 2000

[11] P Bhardwaj R Singh and A Swarup ldquoStomach specific drugdelivery systemmdasha brief reviewrdquo Inventi Rapid NDDS no 3 pp1ndash9 2012

[12] R B Umamaheshwari S Jain D Bhadra and N K JainldquoFloating microspheres bearing acetohydroxamic acid for thetreatment of Helicobacter pylorirdquo Journal of Pharmacy andPharmacology vol 55 no 12 pp 1607ndash1613 2003

[13] S K Jain AMAwasthi N K Jain andG P Agrawal ldquoCalciumsilicate based microspheres of repaglinide for gastroretentivefloating drug delivery preparation and in vitro characteriza-tionrdquo Journal of Controlled Release vol 107 no 2 pp 300ndash3092005

[14] D Chaurasia K Kaushik P Bhardwaj H Chaurasia S K Jainand S Shobhna ldquoDevelopment and in vitro characterizationof floating microspheres bearing tramadol HClrdquo Acta PoloniaePharmaceuticamdashDrug Research vol 68 no 5 pp 795ndash801 2011

[15] P Bhardwaj H Chaurasia D Chaurasia S K Prajapati andS Singh ldquoFormulation and in-vitro evaluation of floatingmicroballoons of indomethacinrdquo Acta Poloniae Pharmaceuti-camdashDrug Research vol 67 no 3 pp 291ndash298 2010

[16] L Lachman H A Liberman and J L Kanig The Theoryand Practice of Industrial Pharmacy Varghese Publishin HouseBombay India 3rd edition 1991

[17] M E Aulton PharmaceuticsThe Science of Dosage formDesignElsevier Science Ltd Philadelphia Pa USA Churchill Living-stone London UK 2nd edition 2002

[18] M Jaimini A C Rana andY S Tanwar ldquoFormulation and eval-uation of famotidine floating tabletsrdquo Current Drug Deliveryvol 4 no 1 pp 51ndash55 2007

[19] A A Deshpande N H Shah C T Rhodes and W MalickldquoDevelopment of a novel controlled-release system for gastricretentionrdquo Pharmaceutical Research vol 14 no 6 pp 815ndash8191997

[20] G S Sonar D K Jain and D M More ldquoPreparation and invitro evaluation of bilayer and floating-bioadhesive tablets ofrosiglitazone maleaterdquo Asian Journal of Pharmaceutical Sciencevol 2 no 4 pp 161ndash169 2007

[21] B R Matthews ldquoRegulatory aspects of stability testing inEuroperdquo Drug Development and Industrial Pharmacy vol 25no 7 pp 831ndash856 1999

[22] R Gupta S K Prajapati S Pattnaik and P Bhardwaj ldquoFor-mulation and evaluation of novel stomach specific floatingmicrospheres bearing famotidine for treatment of gastric ulcerand their radiographic studyrdquo Asian Pacific Journal of TropicalBiomedicine vol 4 no 9 pp 729ndash735 2014

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Scientifica 11

Table 10 Drug release kinetics for floating-bioadhesive tablets

S number Formulation code (FC) Best-fit model 119877 value Parameters for Korsmeyer-Peppas equation

1 FC1 Matrix 09948 119899 = 04817

119896 = 242487

2 FC2 Matrix 09942 119899 = 05125

119896 = 213988

3 FC3 Peppas 09966 119899 = 04919

119896 = 210756

4 FC4 Peppas 09914 119899 = 05500

119896 = 169021

5 FC5 Matrix 09968 119899 = 04877

119896 = 229187

6 FC6 Peppas 09941 119899 = 05430

119896 = 171357

7 FC7 Peppas 09966 119899 = 06472

119896 = 130990

8 FC8 Peppas 09962 119899 = 04473

119896 = 252788

9 FC9 Peppas 09942 119899 = 03266

119896 = 374233

10 FC10 Peppas 09910 119899 = 03279

119896 = 396415

11 FC11 Peppas 09972 119899 = 04974

119896 = 213024

12 FC12 Peppas 09933 119899 = 03702

119896 = 332823

13 FC13 Peppas 09934 119899 = 03466

119896 = 366938

Note each sample was analyzed in triplicate (119899 = 3)119896 kinetic constant119899 exponent value

due to the swellable polymers HPMCK4MCR and Carbopol934PNF

Hence examination of the sequential radiographicimages of the GIT during the study clearly indicated that thetablet remained buoyant and altered its position in the gastriccontents for more than 6 hr So prolonged gastric retentiontime (GRT) of more than 6 hr is achieved (Figures 10(a)ndash10(c))

The objective of the in vivo studies was to provide theproof of concept that the floating capability of the floatingtablet was useful for the increasing the gastric residence timeof the dosage form For facilitating the trials on the rabbitsthe dosage form did not contain any drug and the scope waslimited to the observation of the behavior of the system in thestomach

4 Conclusion

The present study was carried out to develop the floating-bioadhesive drug delivery of venlafaxine hydrochloride using

HPMC K4MCR and Carbopol 934PNF polymers as the car-rier Optimized formulation FC8 gave satisfactory results forvarious physiochemical evaluations for tablets like hardnessweight variation floating lag time and uniformity of contentIn vitro dissolution studies of the optimized formulation FC8showed the sustained release for 18 hr followed by the Fickiandiffusion and an in vivo study indicated increased gastricresidence time by the floating principle and was considereddesirable for improving the bioavailability of the drug Allthese results also indicated that a low amount of floatingagent and high amount of hydrophilic polymer favored thesustained release of venlafaxine hydrochloride from the float-ing gastroretentive tablet formulations Developed sustained-release oral formulation for prolonged release would be asignificant advantage for the patient and may result in fewerside effects due to reduction of the blood concentrationfluctuations especially in long-term therapy Thus results ofthe current study clearly indicate a promising potential of thevenlafaxine hydrochloride floating system as an alternativeto the conventional dosage form However further clinical

12 Scientifica

(a)

(b)

(c)

Figure 10 Radiographic images showing the presence of BaSO4loaded floating tablet in the stomach at different time periods (the tablet is

indicated with an arrow) Images were taken after (a) 1 hr (b) 3 hr and (c) 6 hr after tablet administration

studies are needed to assess the utility of this system forpatients suffering from depression

Competing Interests

The authors declare that there are no competing interestsThe authors do not have a direct financial relation with thecommercial identities mentioned in the research paper thatmight lead to competing interests for any of the authors

Acknowledgments

The authors are thankful to Ranbaxy Research Lab Ltd Gur-gaon Haryana India for providing venlafaxine hydrochlo-ride as a gift sample and Arihant Trading CompanyMumbaiIndia and Colorcon Asia Pvt Ltd Goa India for providingthe polymer samples They also wish to thank Dr P KJain Radiologist VardhmanMedical Centre Jhansi India forextending radiography

Scientifica 13

References

[1] O Berton and E J Nestler ldquoNew approaches to antidepressantdrug discovery beyond monoaminesrdquo Nature Reviews Neuro-science vol 7 no 2 pp 137ndash151 2006

[2] E J Nestler M Barrot R J DiLeone A J Eisch S J Gold andLMMonteggia ldquoNeurobiology of depressionrdquoNeuron vol 34no 1 pp 13ndash25 2002

[3] E Richelson ldquoPharmacology of antidepressantsrdquo Mayo ClinicProceedings vol 76 no 5 pp 511ndash527 2001

[4] httpwwwdrugbankcadrugsDB00285[5] P Blier E Saint-Andre C Hebert C De Montigny N Lavoie

and G Debonnel ldquoEffects of different doses of venlafaxine onserotonin and norepinephrine reuptake in healthy volunteersrdquoInternational Journal of Neuropsychopharmacology vol 10 no1 pp 41ndash50 2007

[6] S M Holliday and P Benfield ldquoVenlafaxine a review of itspharmacology and therapeutic potential in depressionrdquo Drugsvol 49 no 2 pp 280ndash294 1995

[7] B Omprakash S Ajay G Santosh and P Amin ldquoFormulationdevelopment of venlafaxine hydrochloride extended releasetablet and invitro characterizationsrdquo International Journal ofPharmTech Research vol 4 no 4 pp 1777ndash1784 2012

[8] E AMuth J AMoyer J T Haskins T H Andree andG EMHusbands ldquoBiochemical neurophysiological and behavioraleffects of Wy-45233 and other identified metabolites of theantidepressant venlafaxinerdquo Drug Development Research vol23 no 2 pp 191ndash199 1991

[9] B Cusack A Nelson and E Richelson ldquoBinding of antide-pressants to human brain receptors focus on newer generationcompoundsrdquo Psychopharmacology vol 114 no 4 pp 559ndash5651994

[10] B N Singh and K H Kim ldquoFloating drug delivery systems anapproach to oral controlled drug delivery via gastric retentionrdquoJournal of Controlled Release vol 63 no 3 pp 235ndash259 2000

[11] P Bhardwaj R Singh and A Swarup ldquoStomach specific drugdelivery systemmdasha brief reviewrdquo Inventi Rapid NDDS no 3 pp1ndash9 2012

[12] R B Umamaheshwari S Jain D Bhadra and N K JainldquoFloating microspheres bearing acetohydroxamic acid for thetreatment of Helicobacter pylorirdquo Journal of Pharmacy andPharmacology vol 55 no 12 pp 1607ndash1613 2003

[13] S K Jain AMAwasthi N K Jain andG P Agrawal ldquoCalciumsilicate based microspheres of repaglinide for gastroretentivefloating drug delivery preparation and in vitro characteriza-tionrdquo Journal of Controlled Release vol 107 no 2 pp 300ndash3092005

[14] D Chaurasia K Kaushik P Bhardwaj H Chaurasia S K Jainand S Shobhna ldquoDevelopment and in vitro characterizationof floating microspheres bearing tramadol HClrdquo Acta PoloniaePharmaceuticamdashDrug Research vol 68 no 5 pp 795ndash801 2011

[15] P Bhardwaj H Chaurasia D Chaurasia S K Prajapati andS Singh ldquoFormulation and in-vitro evaluation of floatingmicroballoons of indomethacinrdquo Acta Poloniae Pharmaceuti-camdashDrug Research vol 67 no 3 pp 291ndash298 2010

[16] L Lachman H A Liberman and J L Kanig The Theoryand Practice of Industrial Pharmacy Varghese Publishin HouseBombay India 3rd edition 1991

[17] M E Aulton PharmaceuticsThe Science of Dosage formDesignElsevier Science Ltd Philadelphia Pa USA Churchill Living-stone London UK 2nd edition 2002

[18] M Jaimini A C Rana andY S Tanwar ldquoFormulation and eval-uation of famotidine floating tabletsrdquo Current Drug Deliveryvol 4 no 1 pp 51ndash55 2007

[19] A A Deshpande N H Shah C T Rhodes and W MalickldquoDevelopment of a novel controlled-release system for gastricretentionrdquo Pharmaceutical Research vol 14 no 6 pp 815ndash8191997

[20] G S Sonar D K Jain and D M More ldquoPreparation and invitro evaluation of bilayer and floating-bioadhesive tablets ofrosiglitazone maleaterdquo Asian Journal of Pharmaceutical Sciencevol 2 no 4 pp 161ndash169 2007

[21] B R Matthews ldquoRegulatory aspects of stability testing inEuroperdquo Drug Development and Industrial Pharmacy vol 25no 7 pp 831ndash856 1999

[22] R Gupta S K Prajapati S Pattnaik and P Bhardwaj ldquoFor-mulation and evaluation of novel stomach specific floatingmicrospheres bearing famotidine for treatment of gastric ulcerand their radiographic studyrdquo Asian Pacific Journal of TropicalBiomedicine vol 4 no 9 pp 729ndash735 2014

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

12 Scientifica

(a)

(b)

(c)

Figure 10 Radiographic images showing the presence of BaSO4loaded floating tablet in the stomach at different time periods (the tablet is

indicated with an arrow) Images were taken after (a) 1 hr (b) 3 hr and (c) 6 hr after tablet administration

studies are needed to assess the utility of this system forpatients suffering from depression

Competing Interests

The authors declare that there are no competing interestsThe authors do not have a direct financial relation with thecommercial identities mentioned in the research paper thatmight lead to competing interests for any of the authors

Acknowledgments

The authors are thankful to Ranbaxy Research Lab Ltd Gur-gaon Haryana India for providing venlafaxine hydrochlo-ride as a gift sample and Arihant Trading CompanyMumbaiIndia and Colorcon Asia Pvt Ltd Goa India for providingthe polymer samples They also wish to thank Dr P KJain Radiologist VardhmanMedical Centre Jhansi India forextending radiography

Scientifica 13

References

[1] O Berton and E J Nestler ldquoNew approaches to antidepressantdrug discovery beyond monoaminesrdquo Nature Reviews Neuro-science vol 7 no 2 pp 137ndash151 2006

[2] E J Nestler M Barrot R J DiLeone A J Eisch S J Gold andLMMonteggia ldquoNeurobiology of depressionrdquoNeuron vol 34no 1 pp 13ndash25 2002

[3] E Richelson ldquoPharmacology of antidepressantsrdquo Mayo ClinicProceedings vol 76 no 5 pp 511ndash527 2001

[4] httpwwwdrugbankcadrugsDB00285[5] P Blier E Saint-Andre C Hebert C De Montigny N Lavoie

and G Debonnel ldquoEffects of different doses of venlafaxine onserotonin and norepinephrine reuptake in healthy volunteersrdquoInternational Journal of Neuropsychopharmacology vol 10 no1 pp 41ndash50 2007

[6] S M Holliday and P Benfield ldquoVenlafaxine a review of itspharmacology and therapeutic potential in depressionrdquo Drugsvol 49 no 2 pp 280ndash294 1995

[7] B Omprakash S Ajay G Santosh and P Amin ldquoFormulationdevelopment of venlafaxine hydrochloride extended releasetablet and invitro characterizationsrdquo International Journal ofPharmTech Research vol 4 no 4 pp 1777ndash1784 2012

[8] E AMuth J AMoyer J T Haskins T H Andree andG EMHusbands ldquoBiochemical neurophysiological and behavioraleffects of Wy-45233 and other identified metabolites of theantidepressant venlafaxinerdquo Drug Development Research vol23 no 2 pp 191ndash199 1991

[9] B Cusack A Nelson and E Richelson ldquoBinding of antide-pressants to human brain receptors focus on newer generationcompoundsrdquo Psychopharmacology vol 114 no 4 pp 559ndash5651994

[10] B N Singh and K H Kim ldquoFloating drug delivery systems anapproach to oral controlled drug delivery via gastric retentionrdquoJournal of Controlled Release vol 63 no 3 pp 235ndash259 2000

[11] P Bhardwaj R Singh and A Swarup ldquoStomach specific drugdelivery systemmdasha brief reviewrdquo Inventi Rapid NDDS no 3 pp1ndash9 2012

[12] R B Umamaheshwari S Jain D Bhadra and N K JainldquoFloating microspheres bearing acetohydroxamic acid for thetreatment of Helicobacter pylorirdquo Journal of Pharmacy andPharmacology vol 55 no 12 pp 1607ndash1613 2003

[13] S K Jain AMAwasthi N K Jain andG P Agrawal ldquoCalciumsilicate based microspheres of repaglinide for gastroretentivefloating drug delivery preparation and in vitro characteriza-tionrdquo Journal of Controlled Release vol 107 no 2 pp 300ndash3092005

[14] D Chaurasia K Kaushik P Bhardwaj H Chaurasia S K Jainand S Shobhna ldquoDevelopment and in vitro characterizationof floating microspheres bearing tramadol HClrdquo Acta PoloniaePharmaceuticamdashDrug Research vol 68 no 5 pp 795ndash801 2011

[15] P Bhardwaj H Chaurasia D Chaurasia S K Prajapati andS Singh ldquoFormulation and in-vitro evaluation of floatingmicroballoons of indomethacinrdquo Acta Poloniae Pharmaceuti-camdashDrug Research vol 67 no 3 pp 291ndash298 2010

[16] L Lachman H A Liberman and J L Kanig The Theoryand Practice of Industrial Pharmacy Varghese Publishin HouseBombay India 3rd edition 1991

[17] M E Aulton PharmaceuticsThe Science of Dosage formDesignElsevier Science Ltd Philadelphia Pa USA Churchill Living-stone London UK 2nd edition 2002

[18] M Jaimini A C Rana andY S Tanwar ldquoFormulation and eval-uation of famotidine floating tabletsrdquo Current Drug Deliveryvol 4 no 1 pp 51ndash55 2007

[19] A A Deshpande N H Shah C T Rhodes and W MalickldquoDevelopment of a novel controlled-release system for gastricretentionrdquo Pharmaceutical Research vol 14 no 6 pp 815ndash8191997

[20] G S Sonar D K Jain and D M More ldquoPreparation and invitro evaluation of bilayer and floating-bioadhesive tablets ofrosiglitazone maleaterdquo Asian Journal of Pharmaceutical Sciencevol 2 no 4 pp 161ndash169 2007

[21] B R Matthews ldquoRegulatory aspects of stability testing inEuroperdquo Drug Development and Industrial Pharmacy vol 25no 7 pp 831ndash856 1999

[22] R Gupta S K Prajapati S Pattnaik and P Bhardwaj ldquoFor-mulation and evaluation of novel stomach specific floatingmicrospheres bearing famotidine for treatment of gastric ulcerand their radiographic studyrdquo Asian Pacific Journal of TropicalBiomedicine vol 4 no 9 pp 729ndash735 2014

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Scientifica 13

References

[1] O Berton and E J Nestler ldquoNew approaches to antidepressantdrug discovery beyond monoaminesrdquo Nature Reviews Neuro-science vol 7 no 2 pp 137ndash151 2006

[2] E J Nestler M Barrot R J DiLeone A J Eisch S J Gold andLMMonteggia ldquoNeurobiology of depressionrdquoNeuron vol 34no 1 pp 13ndash25 2002

[3] E Richelson ldquoPharmacology of antidepressantsrdquo Mayo ClinicProceedings vol 76 no 5 pp 511ndash527 2001

[4] httpwwwdrugbankcadrugsDB00285[5] P Blier E Saint-Andre C Hebert C De Montigny N Lavoie

and G Debonnel ldquoEffects of different doses of venlafaxine onserotonin and norepinephrine reuptake in healthy volunteersrdquoInternational Journal of Neuropsychopharmacology vol 10 no1 pp 41ndash50 2007

[6] S M Holliday and P Benfield ldquoVenlafaxine a review of itspharmacology and therapeutic potential in depressionrdquo Drugsvol 49 no 2 pp 280ndash294 1995

[7] B Omprakash S Ajay G Santosh and P Amin ldquoFormulationdevelopment of venlafaxine hydrochloride extended releasetablet and invitro characterizationsrdquo International Journal ofPharmTech Research vol 4 no 4 pp 1777ndash1784 2012

[8] E AMuth J AMoyer J T Haskins T H Andree andG EMHusbands ldquoBiochemical neurophysiological and behavioraleffects of Wy-45233 and other identified metabolites of theantidepressant venlafaxinerdquo Drug Development Research vol23 no 2 pp 191ndash199 1991

[9] B Cusack A Nelson and E Richelson ldquoBinding of antide-pressants to human brain receptors focus on newer generationcompoundsrdquo Psychopharmacology vol 114 no 4 pp 559ndash5651994

[10] B N Singh and K H Kim ldquoFloating drug delivery systems anapproach to oral controlled drug delivery via gastric retentionrdquoJournal of Controlled Release vol 63 no 3 pp 235ndash259 2000

[11] P Bhardwaj R Singh and A Swarup ldquoStomach specific drugdelivery systemmdasha brief reviewrdquo Inventi Rapid NDDS no 3 pp1ndash9 2012

[12] R B Umamaheshwari S Jain D Bhadra and N K JainldquoFloating microspheres bearing acetohydroxamic acid for thetreatment of Helicobacter pylorirdquo Journal of Pharmacy andPharmacology vol 55 no 12 pp 1607ndash1613 2003

[13] S K Jain AMAwasthi N K Jain andG P Agrawal ldquoCalciumsilicate based microspheres of repaglinide for gastroretentivefloating drug delivery preparation and in vitro characteriza-tionrdquo Journal of Controlled Release vol 107 no 2 pp 300ndash3092005

[14] D Chaurasia K Kaushik P Bhardwaj H Chaurasia S K Jainand S Shobhna ldquoDevelopment and in vitro characterizationof floating microspheres bearing tramadol HClrdquo Acta PoloniaePharmaceuticamdashDrug Research vol 68 no 5 pp 795ndash801 2011

[15] P Bhardwaj H Chaurasia D Chaurasia S K Prajapati andS Singh ldquoFormulation and in-vitro evaluation of floatingmicroballoons of indomethacinrdquo Acta Poloniae Pharmaceuti-camdashDrug Research vol 67 no 3 pp 291ndash298 2010

[16] L Lachman H A Liberman and J L Kanig The Theoryand Practice of Industrial Pharmacy Varghese Publishin HouseBombay India 3rd edition 1991

[17] M E Aulton PharmaceuticsThe Science of Dosage formDesignElsevier Science Ltd Philadelphia Pa USA Churchill Living-stone London UK 2nd edition 2002

[18] M Jaimini A C Rana andY S Tanwar ldquoFormulation and eval-uation of famotidine floating tabletsrdquo Current Drug Deliveryvol 4 no 1 pp 51ndash55 2007

[19] A A Deshpande N H Shah C T Rhodes and W MalickldquoDevelopment of a novel controlled-release system for gastricretentionrdquo Pharmaceutical Research vol 14 no 6 pp 815ndash8191997

[20] G S Sonar D K Jain and D M More ldquoPreparation and invitro evaluation of bilayer and floating-bioadhesive tablets ofrosiglitazone maleaterdquo Asian Journal of Pharmaceutical Sciencevol 2 no 4 pp 161ndash169 2007

[21] B R Matthews ldquoRegulatory aspects of stability testing inEuroperdquo Drug Development and Industrial Pharmacy vol 25no 7 pp 831ndash856 1999

[22] R Gupta S K Prajapati S Pattnaik and P Bhardwaj ldquoFor-mulation and evaluation of novel stomach specific floatingmicrospheres bearing famotidine for treatment of gastric ulcerand their radiographic studyrdquo Asian Pacific Journal of TropicalBiomedicine vol 4 no 9 pp 729ndash735 2014

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of