Sustained Drug Delivery - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/27201/10/10_chapter...

Sustained Drug Delivery:

It is the dosage form that modifies the drug release by prolongs therapeutics action of drug.

The concentration of drug in body releases slowly once it reach maximum level so it will take

prolonged time to fall under the therapeutic range. The major goal of sustained release dosage

form is to keep the therapeutic blood or tissue level of the drug for a prolonged period and

generally it can be achieved by obtaining ‘zero order’ release from the drug or dosage form as

shown in figure 1.1

It can be formulated when a polymer either natural or synthetic, is prudently joined with a

drug in such manner that drug is released from the dosage form over a prolonged time 1, 2. So it is

required continuous release of drug in order to retain the constant plasma levels as per figure 1.1

and 1.2.

Figure 1.1: Drug levels in the blood with Conventional drug delivery systems

Figure 1.2: Drug levels in the blood with Controlled drug delivery systems

The hypothetical drug blood level and hypothetical plasma concentration patterns of drug

from both formulations traditional and controlled are given in Figure 1.3 and 1.4.

Figure 1.3: Hypothetical drug blood level – time curves for a conventional solid

dosage form and a multiple action product.

Figure

1.4: Hypothetical plasma concentration- time profiles from conventional multiple dosing

and single doses of sustained controlled release formulation.

1.1.1. Merits of Sustained release product: 3, 4

� Enhanced Patient compliance.

• By minimizing number of daily doses.

• Minimizing dosing at night time.

• Minimizing patient carefulness time.

• Affordable to patients as number of tablets required for patients can be minimized by

formulating with sustain dosage form.

• Minimizing systemic as well as local side effects and gastrointestinal irritation.

� Enhanced treatment efficiency.

• Optimized therapy.

• Maintain constant blood concentration.

• Minimizing drug level fluctuation so constant pharmacological response.

• Reduced accumulation of drug.

1.1.2. Demerits of Sustained release product:

� Dose dumping: It may chances release of excess quantity of active substance or drug at

the initially and may lead to toxicity due to excess quantity (toxic quantity) of the active

substance or drug in the body.4,5

� Development Costs: The inert materials and equipment required for this formulation is

expensive.

� Release rate: Food and GIT transit time effect the release pattern of drug so fluctuation

between the releases rate of doses.

� Cannot crush or chew products: Sustain release formulation can’t be chewed or

crushed as drug product loses its release characteristics.

� Minimize potential for accurate dose adjustment.

� Require patient education for sustain release product.

� More likely to first pass metabolism.

� Minimizing systemic availability.

� Irregular or poor correlation between in vitro and in vivo.

� Stability problems: It may chances to get either slower or faster release rate than

estimated after time interval of stability

1.1.3. Drug properties relevant to Sustained release formulation:

Table 1.1: Properties of drug to be considered for Sustained Release

Drug Suitable Drug not Suitable

Physicochemical 4,6

1. Low molecular size compounds

2. Compounds which are highly water

soluble and pH independent

3. Compounds which are non-aqueous

soluble.

4. Unionized (at least 0.1 to 5%) in GIT

5. Compounds with very weak acid and

moderately weak acid.

6. Compounds with very weak base and

moderately weak bases.

Pharmacokinetic/Pharmacodynamic

1. Compounds having short half-

to5 h.

2. Compounds having good absorption

all areas of Gastrointestinal tract

1.1.4. Principle of sustained release drug delivery:

As shown in below pattern

into body.

Low molecular size compounds

Compounds which are highly water

aqueous

Unionized (at least 0.1 to 5%) in GIT

Compounds with very weak acid and

Compounds with very weak base and

1. Compounds having large molecular

weight

2. low aqueous soluble compounds

3. Largely in ionized form in the GIT

4. Strong bases having pKa more than

11.0

5. Strong acids having pKa less than

2.5

/Pharmacodynamic7

-life from 2

Compounds having good absorption from

tract

Compounds that show

1. Slow absorption

2. Carrier mediated transport

3. Site definite absorption

4. Irritation in GIT

5. First pass metabolism

6. Those inhibit metabolism

7. Large dose

8. Drug’s metabolites are actives too

Principle of sustained release drug delivery:

As shown in below pattern conventional drug delivery release drug substance immediately

Compounds having large molecular

low aqueous soluble compounds

Largely in ionized form in the GIT

more than

having pKa less than

. Drug’s metabolites are actives too

conventional drug delivery release drug substance immediately

The absorption pool characterizes that drug solution present at the site of absorption, and the

term Kr, Ka and Ke represents first order release constant, absorption and elimination respectively.

For conventional dosage form immediate drug release indicates that Kr>>>>Ka. In another word

drug absorption through biological membrane is the rate limiting step. And drug

release represents Kr<<< Ka, means drug release from the conventional dosage form is the rate

limiting step. And this kinetics can be represented as following.

For formulating sustained drug delivery the major objectives is to deliver the rate at a

predetermined rate and maintain a persistent drug blood level. The constant drug level can be

achieved by constant intravenous infusion as supplying continuous drug

It refers that for providing constant drug release the dosage form should refers

described in formula 1.1,

Kr° = Rate In = Rate Out = K

Where,

Kr° : Zero-order rate constant for drug release

Ke : First-order rate constant for overall drug elimination

Cd : Desired drug level in the body

Vd : Volume space in which the drug is distributed

Zero order release rate consta

Vd are attained from appropriately designed single dose pharmacokinetic study. For m


represents first order release constant, absorption and elimination respectively.


drug absorption through biological membrane is the rate limiting step. And drug with no immediate


limiting step. And this kinetics can be represented as following.



intravenous infusion as supplying continuous drug to the patient a

It refers that for providing constant drug release the dosage form should refers zero

° = Rate In = Rate Out = Ke C

d V

d-------------------------- (1.1)

e constant for drug release-Amount/time

order rate constant for overall drug elimination-time-1

Cd : Desired drug level in the body – Amount/volume, and

Vd : Volume space in which the drug is distributed-Liters

ero order release rate constant can be calculated by this equation. The value

Vd are attained from appropriately designed single dose pharmacokinetic study. For m


represents first order release constant, absorption and elimination respectively.


with no immediate




the patient at a fixed rate.

zero-order kinetics as

The values of Ke, Cd and

Vd are attained from appropriately designed single dose pharmacokinetic study. For majority of

drugs, there is more complex elimination kinetics and also other factors that affect the drug

disposition and due to this it affects the nature of the release kinetics which is essentially for preserve

constant drug blood level.

1.1.5. Mechanism of Sustained drug delivery

Sustained drug delivery classified in different categories depending upon their drug

release mechanism:

� Dissolution controlled release

o Encapsulation dissolution control

o Matrix dissolution control

� Diffusion controlled release

o Reservoir devices

o Matrix devices

� Diffusion and dissolution systems

� Ion-exchange resins

� Osmotically controlled release

� Gastroretentive systems

Altered density formulation

o High density approach

o Low density approach (Floating system)

Swelling and expanding systems

Bioadhesive systems

1.1.5.1. Dissolution controlled release

Release of drug based on dissolution controlled mechanism can be accomplished by

encapsulating drug with polymers which are relatively insoluble. One of the regular methods

used to prepare sustained formulation is to add a drug in hydrophobic polymers such

polyethylene, polypropylene, wax

propyl methylcellulose, methylcellulose,

methylcellulose. The availability of drug is controlled by the penetration of dissolution fluid into

matrices through polymer membrane and depends on porosity of matrices. The mechanism for

the dissolution controlled release can be understand by the following figure.

Figure 1.5: Dissolution controlled mechanism

1.1.5.2. Diffusion controlled release:

Like dissolution controlled drug release by diffusion controlled release through the

polymer membrane can be achieved by encapsulating drug in polymer matrices or by dispersing

the drug in polymer matrix. The availability of drug through diffusion controlled by

through the polymer, and this represents mainly

used to prepare sustained formulation is to add a drug in hydrophobic polymers such

wax and ethyl cellulose; or hydrophilic matrices such as,

propyl methylcellulose, methylcellulose, hydroxyl propyl cellulose and sodium carboxy

The availability of drug is controlled by the penetration of dissolution fluid into


the dissolution controlled release can be understand by the following figure.

gure 1.5: Dissolution controlled mechanism

Diffusion controlled release:



drug in polymer matrix. The availability of drug through diffusion controlled by

, and this represents mainly non-zero-order rate as increase in

used to prepare sustained formulation is to add a drug in hydrophobic polymers such as

such as, hydroxyl

and sodium carboxy

The availability of drug is controlled by the penetration of dissolution fluid into




drug in polymer matrix. The availability of drug through diffusion controlled by partitioning

as increase in diffusional

resistance as well as decrease in diffusion area. The diffusion con

understand by following figure.

Figure 1.6: Diffusion controlled release mechanism

1.1.6. Polymers in sustained drug delivery:

For formulating sustained drug delivery polymers play a vital role and they are classified

as below:

Classification of polymers:

A. Non-biodegradable hydrophobic polymers:

Non-biodegradable hydrophobic polymers

eliminated or extracted intact from the site of administration and serve essentially

as rate limiting barriers to the transport and release of drug form the device.

E.g. Polyethylene vinyl acetate, ethyl cellulose. cellulose acetate.

B. Hydrogels:

as well as decrease in diffusion area. The diffusion controlled mechanism can also be

Figure 1.6: Diffusion controlled release mechanism

Polymers in sustained drug delivery:


Classification of polymers:

biodegradable hydrophobic polymers:

biodegradable hydrophobic polymers are inert in the environment of use are


rate limiting barriers to the transport and release of drug form the device.

E.g. Polyethylene vinyl acetate, ethyl cellulose. cellulose acetate.

trolled mechanism can also be


are inert in the environment of use are


Hydrogels are swells when coming in contact with water but will not dissolve in water.

They are inert removed intact from the site of administration and function by forming a rate

limiting barrier to the transport and release of drugs.

E.g. Poly hydroxyethyl methacrylate (p-HEMA), cross-linked polyvinyl alcohol

(PVA), cross-linked polyvinyl pyrrolidone, polyacrylamide and dextran etc.

C. Soluble polymers:

These are the polymers that soluble in water and will not cross link. Soluble polymers can

be used as alone or in combination with other hydrophobic polymers to provide devices that

slowly erode over time.

E.g. Polyethylene glycol, uncross-linked polyvinyl alcohol, polyvinyl pyrrolidone (PVP),

Hydroxy propylmethyl cellulose (HPMC),

D. Biodegradable polymers:

Biodegradable polymers slowly remove from the site of administration; and be achieved

by chemical reaction occurs in body such as hydrolysis and lead to disappear the biodegradable

polymer at the site of administration.

E.g. Polylactic acid, polyglycolic acid (PGA), polycaprolactone (PCL),

E. Mucoadhesive polymers:

Mucoadhesive polymers develop adhesive on hydration and show the property of

bioadhesion, i.e. adhesion to a biological membrane or tissue by interfacial forces.

The terms mucoadhesion means polymer attached to the mucin layer of mucosal tissue.

E.g. Methylcellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose,

1.1.7. Drug release mechanisms for polymeric drug delivery:

For preparing sustained drug release two major polymer categories have been studied i.e.

reservoir type and matrix type. The reservoir type represents encapsulation of drug in a polymer

shell while matrix type represent that drug is entrapped within the polymer. The release of drug

through this polymer may be diffusion controlled or dissolution controlled. Different polymers

used for the development of sustained release are summarized in table 1.2.

Table 1.2:Polymer used in oral controlled release technologies

Method of achieving

controlled release

Polymer used Examples of

dosage forms

Matrix or Embedding

Hydrophilic Carriers Methyl Cellulose, Sodium CMC,

Carboxymethyl cellulose,

Polyacrylic acid, HPMC,

Hydroxyethyl cellulose,

Methacrylate Hydrogels,

Polyethylene Glycols, Galactose

Mannate, Sodium Alginate

Multilayer tablets

with slow

releasing cores

Compressed-coated

tablets

Hydrophobi

c Carriers

Soluble

carrier

Glycerides, waxes, fatty

alcohols, fatty Acids

Matrix tablets Insoluble

carrier

Polyethylene, polyvinyl chloride,

polyvinyl acetate, waxes23,

calcium sulfate

Reservoir Type

Coating with insoluble

Membrane

Ethyl cellulose Granules, pellets,

Tablets

Osmotic Systems Vapor permeable walls

- Tenite 808A polyethylene

- Kynar 460 polyvinylidene

• Vapor permeable

capsules

• Vapor permeable

Fluoride

HPMC , HPC, Sodium CMC

Ethyl cellulose

tablets

• Single and

bilayer tablets

Ion-exchange Resins Dowex® 50, Amberlite® IRC

50 With polystyrene-based

polymeric backbone

Controlled

release capsules

Chewable tablets

Chewable gums

Liquid suspension

Gastric retention

Systems

HPMC, Agar, Carrageenans,

Alginic acid, Oils, Porous

calcium silicate, Superporous

hydrogels, Ion-exchange resin

beads coated with bicarbonate,

Ethyl cellulose for coatings

Compressed

tablets

Gelatin capsules

1.2. MICROSPHERES: 8, 9

Microspheres are solid spherical particle having dispersed drug either in solution or

microcrystalline form and size of the microspheres ranging from 1 to 1000 micrometer.

Microencapsulation is a fast growing technology for the development of sustained formulation.

In this process relatively thin layer of coating is applied to small drug particles of solid or liquid

droplets. By formulating microspheres sustainedrelease characteristics of drug can be

accomplished by coating the drug with release retardant polymer.

Microcapsule Microsphere

Figure 1.3: Difference between microcapsule and microsphere

1.2.1. Polymer used in microsphere:

II. Synthetic Polymer:

III. Non-biodegradablePolymers: e.g. Poly methyl methacrylate (PMMA), Acrolein,

Glycidyl methacrylate

IV. Biodegradable polymers: e.g. Glycolides,Lactides & their copolymers, Poly

alkylcyano acrylates, PolyAnhydrides.

1. Natural Polymer: Natural polymers foundfrom different sourceslike proteins,

carbohydrates andchemically modified carbohydrates.

Proteins: Albumin,Gelatin, and Collagen

Carbohydrates: Agarose, Carrageenan,Chitosan, Starch

Chemically modifiedCarbohydrates: PolyDextran, PolyStarch.

1.2.2. Methods of Preparation of microspheres: 9, 10

1. Solvent removed technique:-

• Emulsion – solvent evaporation technique.

i) Oil inWater (o/w)

ii) Water inOil (w/o)

iii) Water in oil inWater Oil Water (W/O/W)

• Emulsion solvent extraction.

• Emulsion solvent diffusion.

2. Coacervation and phase separation technique.

a) With temperature modification.

b) Using incompatible polymer.

c) With addition of non solvent.

d) With addition of salt.

e) Interaction of polymer with polymer.

f) Using evaporation of solvent.

3. Cross – linking technique.

a) Chemical cross linking.

b) Thermal cross linking.

c) Ionic cross linking method

4. Polymerization Technique.

a) Normal polymerization.

b) Vinyl polymerization.

c) Interfacial polymerization.

5. Spray congealing & spraydrying.

6. Freeze drying technique.

7. Precipitationtechnique.

8. Multi orificecentrifugal process

9. PanCoating.

10. Air suspensioncoating.

11. Melt dispersiontechnique

1.2.2.1. Ionotropic gelationmethod: 11-13

Ionotropic gelation can be established by capacity of polyelectrolytes that cross link to

form hydrogel beads with presence of counter ion and is referred as gelispheres. Gelispheres

have tendency to swell in stimulated fluid and capacity to release drug for prolonged time due to

relaxation of polymer also due to hydrophilic nature of gelispheres. Gelispheres can be

formulated by placing the drug and polymer solution to counter ion solution with continue

stirring.

Figure

1.8: Basic technique of Gelispheres preparation

Figure 1.9: Formulation of Gelispheres by polyelectrolytecomplexation technique

Natural polymer has more interest for the development of ionotropic gelation technique.

There are so many semisynthetic polymers like chitosan,gum can be used for the preparation of

microspheres using encapsulation technique. In the chemical structure natural polyelectrolytes

comprises certain anions/cations those have capacity to form meshworkstructure with merging

counter ions.

1.2.3. Factors affectingIonotropic gelation method:

I. Polymer and crosslinking electrolyte concentration

Polymer andelectrolyte concentration have key result on preparation of beads developed

by ionotropicgelation method and also depends on concentrationof both calculated fromnumber

of crosslinking units.

II. Temperature

The bead size also sometimes depends on temperature as well as total time consumed for

crosslinking.

III. pH of crosslinking solution

pH of crosslinkingsolution also significant factor considering for the formulation because

pH having influence on reactionrate, size andshape of beads.

IV. Drug concentration

The ratio of drug with polymer can be considered as important factors for the parameters

like drug entrapment efficiency. When the drug with polymer ratio is more than one than it may

be chances for bursting effect. The ratio also effect on morphology of gelispheres.

V. Gas forming agent concentration

Porous gelispheres can be prepared by using gas inducing agent that also effect on

morphology of microspheres. There are widely available agent that produces gases like calcium

and sodium bicarbonate.

1.3. BIODEGRADABLE POLYMER: 14,15

Biodegradable polymers are in vivo degradable, that can be degraded by enzymatically or

non-enzymatically, and produce biocompatible or nontoxic by-products. These polymers have

the capacity to metabolize using enzymes and also eliminated through normal

physiologicalpathways. They are separated into three collections on the basis of their availability

source i.e. natural, semi synthetic and synthetic. Most generally available natural biodegradable

polymers likegelatin, alginate, andchitosan and so widely used for microspheres. Biodegradation

is the process in which compounds can be redistributed in environment cycle as carbon, sulphur,

nitrogen etc. The release of drug from the biodegradablepolymer can be maintained by so many

factors like kinetics of biodegradation, drug characteristics and compatibility of drug to polymer

and also morphology of devices.

1.3.1. Mechanism of drug release from Biodegradable polymer: 16, 17

The drugrelease mechanism form the erodible polymers can be happen by one of the

mechanism as shown in Figure 1.10 and 1.11.

As per mechanism1, the drug is ready to available for connect with polymeric backbone

with alabile bond; this bond hadgreater action toward hydrolysis than thepolymer reactivity to

breakdown. As per mechanism 2, the drug available in the core and is coated with biodegradable

ratecontrolling membrane. This isreservoir type mechanism and it erodes to eliminate the drug.

Mechanism 3 represents a uniformly dispersion of drug in the biodegradablepolymer and

dissolution of drug for as per mechanism III is by erosion,diffusion, or combination ofboth.

Figure 1.10: Possible drug release mechanism for polymeric drug delivery.

Figure 1.11: Diagram for the drugrelease mechanism from the biodegradable polymer

1.4. MELT GRANULATION TECHNIQUE: 19

Melt granulation is technique through which fine solid particle are agglomerates by

kneading, agitation and layering using molten binding liquid. After solidifying dry agglomerates

are formed at room temperature. Melt granulation is most widely used techniques for the

development of meltagglomeration. There are no proper justifications for distinguish between

pelletization and melt granulation. So granulation may be considered as pelletizationprocess

when agglomerates of extremely spherical and narrowsize are produced.

In this techniques the polymer melted at their meltable temperature and drug is added to

the molten solution. The drug meltable solution was cooled at room temperature for

solidification. From the solidification granules can be formed by sizing of different granules

using different sieves. The meltable solution also prepared by using hot air or heatingjacket.

Most widely used meltable binders melts at 50 to 80°C.

1.4.1. Mechanism of melt granulation: 19

The melt granulation process comprises of three combined phases:

I. Wetting andnucleation,

II. Coalescencestep,

III. Attrition andbreakage.

I. Wetting and nucleation step:

During the this step the liquid bridges are formed when meltable binders come into contact

with the powder bed and it may lead to the formation of small agglomerates.

a) Immersion

Immersion of the melt granulation occurs when the meltable granules size is more than

that of fine solid particle. Immersion can be accomplished by the depositionof solid fine

particlesonto the droplet surfaces ofmolten binder. (Figure 1.8)

b) Distribution

In this case a molten bindingliquid is dispersed over the surfaces of solid fine particles.

So nuclei are producedby the collision betweenthe wetted particles. Normally, smaller droplet

size as well as reduced viscosity of binder along with high shearingforces are suitable conditions

for the development of nucleation bythe distributionmethod. (Figure 1.8)

II. Coalescence step:

It exhibits nuclei that haveresidual liquid surface to increase success fulfusion ofnuclei.

The surface liquid have ability to increase plasticity tothe nuclei and is important for supporting

the deformation ofnuclei surface for coalescence as well as enhancing granulation efficiency.

III. Attrition-breakage step:

Attrition andbreakage is nothing but one type of granulation fragmentation technology in

which materials are dried by tray cooling to room temperature withoutthe use of tumblingprocess

for the drying. Furthermore, breakage is identical that have characteristics role for influencing

the final properties of granules that performed by meltgranulation.

Figure 1.12: Modes ofagglomeration(a)Distribution (b)Immersion

1.4.2. Requirements of melt granulation:

Usually, 10–30% w/w meltable binder can be used for the development of product.

� Polymer used for melt granulation have melting point in range of 50–100ºC.

� Hydrophilic meltable binders are considered for the development of fast release product

whereas the hydrophobicmeltable binders are utilized for development of prolonged-

release product.

� Solid particles should have melting points at least 20°C greater thanfrom the

maximumprocessing temperature.

1.4.3. Meltable binders:

• It must be solid at normal room temperature and melt within range of 40 and 80°C,

• Physical and chemical stable

There are two type of Meltable binder

1) Hydrophilic Meltable binders [Table 1.3]

2) Hydrophobic Meltable binder [Table 1.4]

Table 1.3 Hydrophilic meltablebinders in the meltgranulation technique.

Hydrophilicmeltable binder Typicalmelting range (°C)

Gelucire 44-50

Poloxamer 50.9

PolyethyleneGlycol

2000 42-53

3000 48–63

6000 49-63

8000 54-63

10000 57-64

20000 53-66

Stearate 6000 WL1644 46-58

Table 1.4 Hydrophobic meltablebinders in the meltgranulation technique.

Hydrophobicmeltable binder Typicalmelting range (°C)

Beeswax 56-60

Carnauba wax 75-83

Glyceryl behenate 67-75

Glyceryl monostearate 47-63

Glyceryl palmitostearate 48-57

Glyceryl stearate 54-63

HydrogenatedCastor oil 62-86

MicrocrystallineWax 58-72

ParaffinWax 47-65

StearicAcid 46-69

StearicAlcohol 56-60

1.5.1. Tramadol Hydrochloride (TM): 20

ChemicalName: (±) cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)

CyclohexanolHydrochloride.

ChemicalStructure:

MolecularFormula: C16H25O2N . HCl

Molecular weight: 299.8

Melting point: 180 to 184°C

Description: white, bitter, crystalline and odorless powder.

Solubility: Readily soluble in water and ethanol

PKa: 9.41

PartitionCoefficient 1.35 atpH 7.

1.5.2. Mechanism ofAction:

TM has the action against opioid analgesic. Two possible mechanism can considered as

binding of parent as well as M1metabolite to µ-opioidreceptors and weak inhibition ofreuptake

of nor epinephrine andserotonin. Opioid management of TM is because of less binding attraction

of the parentmolecule and more attraction binding of theO-demethylated metaboliteM1 to µ-

opioidreceptors. As per model developed from animal, M1 having the great potency upto 6 times

greater than that of TM ingenerating analgesia As well as 200 times extra potency in µ-

opioidbinding. In humans the effect of analgesia starts probably form 1 h afteradministration and

reaches peakin approximately 2 to3 h.

1.5.3. Pharmacokinetics:

The TM effect ofanalgesia is because ofboth M1metabolite as well as parent drug. TM is

taken as aracemate and both the [-]and [+] formsof both TM andM1 are detectedin the

circulation. The TM pharmacokinetics can be understand by following figure 1.13.

� Absorption:

TM is capable of fast and nearly completelyabsorbed after oral administration. The oral

bioavailability for TM is approximately 75% for 100 mg dose. The mean peakplasma

concentration ofTM and M1 found at 2 and 3 h, respectively, after administration of TM product

in healthy adults. The plasma steady-state concentrations is observed for bothTM as well as M1

within two dayswith q.i.d. dosing. There is noevidence ofself-induction.

� Distribution

The volume ofdistribution in the body for the female as well as males ofTM was 2.9

and2.6 lit/kg respectively, when the 100 mg of TM is taken as intravenously. The plasmaprotein

binding for theTM is approximately 20% inbody and also observed that binding isindependent of

concentration upto 10µg/ml.

Figure 1.13: Mechanism action for Tramadol Hydrochloride

: Mechanism action for Tramadol Hydrochloride

� Metabolism

After the drug administration nearly 60% of TM is eliminated asmetabolites. Nearly 30%

of the TM is removed through urine as unchangeddrug, whereas 60% of theTM is separated for

metabolism. There are number of enzymes available in body capable for metabolism in body like

CYP2D6, CYP3A4, as well as by N - and O - demethylationand glucuronidation orsulfation in

liver.

� Elimination

The Major elimination for TM through liver and kidneys also play role for elimination of

TM.

1.5.4. Side effects of TM:

The major side effect of TM is swelling of eyes, face, throat, mouth, hands, feet, ankles or

lower legs. It was also found that sometimes difficult in breathing. Other side effects like

diarrhea, constipation, nausea, heartburn, vomiting. TM having the effect on skin like hives, rash,

itching, sweating and chills. It also effect on central neuron like headache, drowsiness, insomnia,

nervousness and agitation.

Figure 1.14: Adverse effects of TM. Red color indicates more adverse, necessary for

1.5.5. Indications and usage:

The major indication for TM is thesevere pain management.


immediate contact.

The major indication for TM is thesevere pain management.


1.5.6. Dosage andAdministration:

For the ages above 17 years dosing of TM should be started initially as 25 mg/day and

increase dose of TM to 25 mg every 3 days toreach 100 mg/day. After reaching 100 mg dose

further dosing of TM can be raised by 50 mg for every 3 days to reach200 mg/day (50 mg q.i.d.).

After reaching 200 mg doseof TM further can be increased upto 100 mg as needed.TM does

should not be exceed from 400 mg/day.

1.6. Chitosan: 21, 22

Chitosan, a natural linear biopolyaminosaccharide, polymer derived from chitin using

alkaline deacetylation. Chitin is found to be major element available in protective cuticlesof

crustaceans suchas shrimps, crabs,lobsters, prawns also cellwalls of certainfungi such as

aspergillus andmucor. To prepare chitin, demineralised the crab and shrimp hells in

diluteHydrochloric acid (HCl), then deproteinated using dilute NaOH, followed by decolourised

with potassium permangate KMnO4) as shown in figure 1.12. The chitin is then deacetylated by

boiling in a concentrated NaOH solution to become chitosan. Pharmaceutical grade chitosan is

deacetylated within 90 and 95% where as food grade between 75 and 80%. Chitosan is

structurally represented as Figure 1.11.

Figure 1.15: Chitosan Chemical Structure Molecular formula: (C6H11NO4)n

CAS registry no: 9012-76-4

Synonyms; 2-Amino-2-deoxy-(1,4)-β-D-glucopyranam

Chemical name: Poly-β-(1-4)-2-Amino-2-deoxy--D-Glucose

Appearance: White to light yellow flake

pKa: 6.2- 7.0

Solubility:

Chitosan is soluble at pH less than 7.0 in dilute acids. Chitosan dissolve rapidly in dilute

solution of most organic acid. Chitosan is insoluble in pH more than 6.5 in alkaline solution.

Chitosan can precipitated in + 3 alkaline and have capacity to form gel at reduced pH

Figure 1.1

Because of readily available free amine groups inch

also have capacity to interact with

1.6.1. Important characteristics of Chitosan to be considered in the pharmaceutical

formulations.

� Molecular weight

• Low molecular weight

• High molecular weight

Figure 1.16: Synthesis of Chitosan from chitin

Because of readily available free amine groups inchitosan, it carry a +ve charged ion

also have capacity to interact with –ve charged surfaces or polymers andundergoes chelation

Important characteristics of Chitosan to be considered in the pharmaceutical

molecular weight – 10,000

High molecular weight – 1000,000

carry a +ve charged ion and

undergoes chelation.

Important characteristics of Chitosan to be considered in the pharmaceutical

� Viscosity

At conc. of 1.25% in dilute acetic acid has a viscosity of

• 1200 cps – good quality

• 160 cps – medium quality

• 161 cps – low quality

� Degree of deacetylation:

Commercial deacetylated chitin is approximately 80 – 85% deacetylated. Degree

ofdeacetylation is important and it should be 80 – 85% (or) higher for the development of soluble

product.

� Density: between 1.35 and 1.40 g/cc3

� pH: 4.0 – 6.0

� Glass transition temperature: 203ºC

� Viscosity: There are different types of viscosity grades available for Chitosan. Chitosan

was observed to be good viscosity promoting agent when product developed in acidic

condition. It also behave as apseudo-plasticmaterial, that mean to say that with

increasingshear rate viscosity of Chitosandecreased.

� Deacetylation: The degree ofdeacetylation is important characteristics and it should be

more than 80-85% for development more soluble product.

� Particle size distribution: <30 µm

� pKa: ~6.5

� Storage condition: Chitosan should be placed in a tightly closedcontainer in a cool as

well as dry place. The PhEur 2005 specifies that chitosan should be stored at room

temperature of 2ºC-8ºC.

� Incompatibility: Chitosan is incompatible with strong oxidizing agent.

1.6.2. Application: 23

• Chitosan can be used in biomedical and pharmaceutical formulations because Chitosan

have properties like lowtoxicity, biodegradability ans well as good biocompatibility.

• In case of pharmaceutical applications chitosan can be utilizes as a vehiclefor directly

compressedtablets24, asDisintegrant25,binder26, granulatingaaAgent27, in

groundmixtures28. Chitosan also having properties as a drug carrierfor sustained release

development29 and co-grindingdiluent for the improvement of dissolutionrate and

bioavailabilityof water insolubledrugs.

• As chitosan has interaction between negatively charged mucosal surface so can be used

in mucoadhesive formulation.

• Because of properties like film forming can be used for preparation of contact lenses.

• Chitosan membranes can be usedartificial kidney.

• Chitosan possess carrier for microsphere drug delivery so used for sustained and

controlled drug delivery.

• Reaction of chitosan withmultivalent anion so crosslinking between chitosan molecules.

This effect mostly in developemt of chitosanmicrosphere as shown in figure 1.13.

• Chitosan also have characteristics for filmforming and has been utilized for

developmentof contact lenses.

• Chitosan membrane also used in artificial kidney membranes.

• Chitosan have suitable properties for the preparation of microspheres as a carrier.

Microspheres prepared using chitosan can used for formulation of sustained and

controlled

release

product.

Chitosan

microspheres

having

characteristic

s to improve

bioavailabilit

y of

degradable

substances.

Figure 1.17:

Method of

preparation of chitosan microspheres

Formation of crosslinking between polymer functional groups reduces hydrophlilicity

and due to decreasing permeation rate for biologicalfluids through the hydratedmatrix. Physical

bonds formation between polymer molecules can be attained by ionotropic gelation that involves

interaction of polymer with opposite charged ions. Cross-linking can also been achieved by

adding agents for the formation of chemical bonds but has the main disadvantage is chemicals

having more toxicity like formaldehyde. BY crosslinking with ionization has an advantage that

can avoid toxicity. Chitosan has now growing interest in ionization technology because their

network forming capacity as shown in figure below.

Figure 1.18: Formation of cross

1.7. Sodium Tripolyphosphate (Na

Tripolyphosphate (TPP) has different synonyms like Sodium triphosphate,

triphosphoric acid, pentasodium salt, sodium tripolyphosphate (Na

triphosphate, pentasodium Tripolyphosphate.

TPP is free from toxic and carrying anion which having capacity to crosslinks with

positively chargedamine groups by ionic

Figure 1.19: Chemical structure of sodium tripolyphosphat

TPP is an broadly researched cross

When Chitosan interact with TPP it will form good spherical complex and have excellent

properties like pH-responsive drug

characteristics that they can improve product stability and can be utilized for development of

controlleddrug delivery.

1.8. Glyceryl Palmitostearate:

• Chemical Name: Glycerin

oxohexadecyl)-oxy]-1,3-propanediyl dioctadecanoate and 1,2,3

• Empirical Formula:

andtriglycerides of C16 and C18 fatty

• Description: Glyceryl palmitostearate available

: Formation of cross-linked gels by use of polyelectrolyte complexion

Sodium Tripolyphosphate (Na-TPP)


pentasodium salt, sodium tripolyphosphate (Na-TPP), pentasodium

triphosphate, pentasodium Tripolyphosphate.


by ionicinteraction.

: Chemical structure of sodium tripolyphosphate:

TPP is an broadly researched cross-linking agent with five bonding sites on the molecule.


e drugrelease properties. The TPP and Chitosan complexes have

they can improve product stability and can be utilized for development of

: 30-32

Glycerin palmitostearate; glycerol palmitostearate; 2

propanediyl dioctadecanoate and 1,2,3-propane triol.

Glyceryl palmitostearate is a combination

triglycerides of C16 and C18 fattyacids.

palmitostearate available as a fine whitepowder with a

linked gels by use of polyelectrolyte complexion


TPP), pentasodium


e:.

linking agent with five bonding sites on the molecule.


The TPP and Chitosan complexes have

they can improve product stability and can be utilized for development of

; glycerol palmitostearate; 2-[(1-

propane triol.

palmitostearate is a combination of mono-,di-,

powder with a faint odor.

• BoilingPoint: 200°C

• Melting Point:52-55° C

• Solubility: Easily soluble in chloroform as well as dichloromethane; whereas practically

insoluble inethanol (95%), mineraloil, and water.

• Storage condition: Glyceryl palmitostearate should be stored at a temperature of 5–

158C in an airtight container, protected from light and moisture.

• Functional category: Biodegradable material; coating agent; gelling agent; release

modifying agent; sustained-release agent; diluents in tablet capsule formulation;

lubricant; taste-masking agent.

• Application in pharmaceutical formulation or technology:

Glyceryl palmitostearate is widely used in oralsolid-dosage pharmaceutical formulations

aslubricant. Tablet disintegration and strengths depends on mixing time of glyceryl

palmitostearate, as increase the blending time, increases disintegration time of tablets and also

decreases strength of tablet. It is used as a lipophilicmatrix for preparation of sustained-release

product. Tablet formulations maybe developed by granulation or any hot-melttechnique, the

former producing tablets that have the faster release profile. Release rate decreases with

increased glyceryl palmitostearate content. Glyceryl palmitostearate is used to form

microspheres, which may be used in capsules or compressed to form tablets,) pellets, coated

beads and biodegradablegels. It is also used for taste-masking. See Table 1.5

Table 1.5: Uses of glyceryl palmitostearate

Sr. No. Use Concentration

1 Matrix for sustained release 10.0-25.0

2 Tablet masking 2.0-6.0

3 Tablet lubricant 1.0-3.0

1.9. Glyceryl Behenate : 33-35

• Synonyms: Compritol 888 ATO; 2,3-dihydroxypropyldocosanoate; docosnoic acid, 2,3-

dihydroxypropylester; E471; glycerol behenate; glyceryl monobehenate.

• Chemical Name: Docosanoic acid, monoester with glycerin

• Functional Category: Coating agent; tablet binder; tablet and capsule lubricant.

• Melting point: 65-77°C

• Solubility: soluble in chloroform & dichloromethan when heated, practically glyceryl

behanate is not soluble in 95% ethanol, hexane, mineraloil, and alo in water.

• Applications in Pharmaceutical Formulation or Technology:

Glyceryl behenate have its effect in foods, cosmeteics, as well as oral pharmaceutical

development. In cosmetics, glyceryl behanate widely used for viscosity enhancing polymer for

the manufacturing of emulsions; see Table 1.6. In pharmaceutical preparations, it is can be

widely utilized as lubricant and also observed have characteristics like lipidic coating. It also is

having properties for encapsulation of different drugs like retinoids. It also observed that can be

used as matrixagent for sustained products; mainly have the more effect with watersoluble drugs

for their sustained effect. Like glyceryl palmitostearate, behanate also having properties like

lubricant for oral soliddosage formulations. Because of its low melting point glyceryl behnate

can be utilized for ho-melt coating agent.

Table 1.6: Uses of Glyceryl Behenate

Lipophilic matrix/coating for sustained released tablets and capsules

>10.0

Tablet and capsule lubricant 1.0-3.0

Viscosity increasing agent in silicone gels (Cosmetics) 1.0-15.0

Viscosity increasing agentin w/o or o/w emulsion (cosmetics) 1.0-5.0

Storage Condition: Glyceryl behenate should be stored in a tight container, at a temperature less

than 35ºC.

K.S.Y Hemant et al36 studied microspheres for the drugs amoxicillin trihydrate and

Metronidazole with chitosan used as mucoadhesive polymer. Here microspheres were developed

by cross linking using sodium tripolyphosphate. The influence of formulation parameters were

evaluated on particle size, swelling studies, content uniformity, and mucoadhesive studies.

Release of drug from chitosan microspheres were evaluated in 0.1N HCl at 370±0.50C. The

chitosan microspheres indicated good mucoadhesive property and showing sustained effect. The

spherical shape of microspheres confirmed with SEM. Further concluded that prepared

microspheres can be used in the treatment of gastric ulcer.

Maryam Amidi et al 37 studied chitosan containing drug delivery systems that improve drug

absorption of the formulation from the mucosal sites. Chitosan is a mucoadhesivepolysaccharide

and have capacity that can open the tight junctions among epithelial cells for chemical alteration,

resulted in a development of great range of chitosan derivatives used for improve the drug

absorption rate. This review offers the physicochemical properties of chitosan and their uses for

the preparation of product like protein and antigen that can be delivered through mucosal and

parenteral administrations discussed.

Preeti K. Suresh et al38 prepared metronidazole loaded chitosan microspheres prepared with

external gelation technique using tripolyphosphate as the cross-linker. The drug and polymer

ratios were studied at three levels: 1:4, 1:5 and 1:6 (by weight) and also studied concentration of

tripolyphosphate at three levels: 6, 12 and 18 (%). The prepared microspheres were evaluated

size of particle, morphology of microspheres, entrapmentefficiency, swelling, erosion,

bioadhesion and drug release profile. Microspheres with size ranging from ~ 800 µm with

spherical in nature produced. Drug entrapment efficiency, percentage swelling, erosion and

biosdhesion was found to be in the range of 60-75%, 10-25%, 5-15% and 43-59% respectively.

Devika R. Bhumkar et al39 evaluated pH effect on cross-linking belongings of chitosan with Na

tripolyphosphate. She prepared microspheres with ionotropic gelation method using chitosan and

concluded that cross-linked particles having capacity to modify with adjusting the pH of chitosan

solution. At lower pH chitosan was cross-linked ionically whereas at higher pH chitosan cross-

linked by deprotonation mechanism. The swelling behavior of chitosan microspheres depends on

pH of TPP, and concluded that chitosan cross-linked showed higher swelling ability at lower pH.

S. Senthil kumar et al40 prepared clobazam loaded chitosan microspheres with ionic gelation

method using Natripolyphosphate as the crosslinking agent. Microspheres were evaluated for

size of microspheres, particle size distribution, drug content, encapsulationefficiency and in-vitro

drugrelease. The surface characteristics of the developed microspheres were confirmed by SEM.

From drug release data concluded that as increasing the crosslinking density the drug release rate

decreased. The physical form of microspheres also confirmed by DSC and XRD and confirmed

that clobazam existed as a molecular dispersion in the polymeric microsphere matrix in an

amorphous state.

Magdalena Gierszewska et al41 studied the crosslinking efficiency condition when the

formulation prepared with chitosan. He studied the influence of molecular structure of chitosan.

Various crosslinking conditions like pH and crosslinking time were studied. The drug form and

surface morphology of microsphere were conformed using X-ray device and SEM. The effect of

crosslinking was confirmed by atomic force microscopy (AFM). Finally he concluded that pH of

crosslinking TPP solution are playing more important role on surface smoothness and roughness

of of the microspheres.

Emmanuel Chinedum Ibezim et alc42 formulated chitosan with tripolyphosphate microparticles

for the controlled drug delivery of pyrimethamine. Chitosan was ionically cross-linked along

with tripolyphosphate at controlled temperatures i.e. 25oC, 40oC, and 50oC and also with varying

cross-linking times i.e. 30 min, 2 h and 4 h respectively was taken to form microparticles. The

yield of microparticles found 0.3515 to 0.7749 g per 100 ml of crosslinking solution. The

entrapmentefficiency of microspheres was found 25.55 to 99 %. And concluded that

microspheres prepared at ambient temperature and 30 min cross linking time having the highest

efficiency.

Aliasgar J. Kundawala et al43 formulated isoniazid microspheres for pulmonary delivery using

chitosan as polymer. Tripolyphospate was used for crosslinking of chitosan based microspheres

to attain sustained drug release. Chitosan microspheres were developed by spray drying method.

The developed microspheres were confirmed for their microspheres size, droplet shape, drug

release characteristics and in vitro drug deposition at pulmonary. The developed cross linked

microspheres was having entrapment efficiency of 72 to 88 % and microspheres particle size was

found from 3.6 to 5.2 µm and fine particle fraction of 67 %.

Obaidat AA et al44 prepared controlled drug release formulation contains tramadol using

glyceryl behenate. This investigation revealed that glyceryl behenate having tendency to

formulate sustain release product and is a suitable waxy material that can be utilized for the

development of sustained the drug release product. He investigated this development with the

use ofwater soluble drug like tramadol.

Tiwari S et al45 studied impact of concentration of hydrophobic and hydrophilic polymer the

drug release rate. He taken tramadol as model drug and hydrophilic and hydrophobic polymers

are hydrogenated castor oil; ethyl cellulose on were studied. Wet granulation was used for the

development of hydrophilic matrix tablets whereas melt granulation technique was used for the

development of hydrophobic (wax). He concluded that hydrophobic materials having more

sustained effect when compared with hydrophilic polymer. Tables prepared with hydrogenated

castor oil were observed to be mist and formulation was more suitable for drugs which are

greatly water soluble in order to achieve sustained effect.

Shu XZ et al 46 prepared complex beads of tripolyphosphate with chitosan for controlled release

drug delivery. A innovative method was used to improve the mechanical strength of bead of

tripolyphosphate(TPP)/ chitosan formulated under cooled condition at 4˚C in the existence of

gelatin. The pH effects of TPP cross-linking have capacity to modify the drug release behavior of

beads. And concluded that beads prepared with chitosan and tripolyphosphate was having

significant effect in the terms of development of prolonged release formulation.

D. Singh et al47 formulated gentamicin sulphate microspheres for controlled release using

chitosan as rate controlling polymer. The independent variables was designated for formulation

of microspheres were drug concentration (X1), cross linking agent (X2) and polymer (chitosan)

concentration (X3) whereas dependent variables designated were entrapment efficiency (Y1) and

average diameter (Y2) of microspheres. It was concluded that formulation containing 10 mg

gentamicin, 2% (w/v) tripolyphosphate and 3% (w/v) chitosan, was recognized for maximizing

drug entrapment (80.04±2.24%) and minimizing average particle size to optimum level

(18.64±0.61µm). Surface smoothness of droplets was confirmed by SEM and confirmed that

microspheres with smooth spherical surface with size from 11.42±0.56µm to 26.34±0.72µm.

R. Jayakumar et al48 prepared microspheres of phosphorus for controlled release using chitosan

as drug retardant polymer. Tripolyphosphate was used for the complexion with chitosan at lower

pH as 4.0 and confirmed by SEM. The effect of pH solution was studied by taking into

consideration of drug release profile using indomethasin as model drug and was taken into two

different concentrations i.e. 0.3% as lower and 0.6% as higher w/w. From the data of in vitro

profile concluded that with increasing buffer solution pH the drug release increased. In another

word in vitro release was observed more at pH 7.4 and in vitro release observed lower at pH 1.4,

the reason for these characteristics was phosphorous ionization groups and solubility of IM was

greater at basic medium.

Akanksha Garud et al49 prepared metronidazole mucoadhesive microcapsules using chitosan as

drug retardant polymer. Tripolyphosphate was used as cross-linking agent with linkage of

chitosan. The prepared microcapsules characterized for different parameters like size, shape,

particle size, entrapment efficiency. They concluded that swelling of chitosan microcapsules

depends on cross-linking characteristics with tripolyphosphate. The developed microcapsules

showed greater mucoadhesive tendency at intestinal pH 7.4 whereas lower tendency at pH 1.2.

The in vitro release was observed to be slow and also for prolonged time.

Hui Liu et al 50 investigated characteristics of ionically cross-linked chitosan nanoparticles. They

concluded that nanoparticles can be developed only inside suitable zone of TPP and chitosan

concentrations. The surface zetapotential and droplet size have the significant impact of ratio as

well as concentration of chitosan with TPP. The droplets characteristics also can be modified by

factors like addition of salt form and solution of pH. From the data inferred that developed

formulation was stable.

J. Berger et al51 reviewed interactions in covalently and ionically crosslinked chitosan hydrogels

for biomedical applications. The formulated linkages have characteristics to permit water as well

as other compounds absorption and maintain the diffusion release characteristics without

dissolution. This type of formulation pH induced can be developed by placing another polymer.

Ionically prepared crosslinked hydrogels have more swelling tendency in the terms of pH

change.

Mahaparale PR et al 52 prepared sustained release metronidazole succinate matrices with using

two different meltable binders for the formulation one is Compritol888 ATO and another is

PrecirolATO 05. Matrices were formulated by melt granulation technique. From the drug release

study it was concluded that matrices formulated from mixture of two waxes showed more

sustained release effect than the formulation prepared using compritol and precirol alone.

J.K patel et al53 reviewed chitosan based nanoparticle in drug delivery. Several polymeric

nanoparticlulate systems have been developed and evaluated in recent year, using both natural as

well as systemic polymers. The formulation developed using different polymers having their

own benefits and disadvantages. From the natural polymers, the nanoparticles formulation were

developed with chitosan and evaluated. Somasundaram Ramachandran et al 54 formulated

famotidine microspheres using biodegradable polymer as chitosan for increase bioavailability

and decrease dose frequency of the famotidine. Chitosan containing microspheres were

developed by simpleemulsification technique with glutaraldehyde ascrosslinking. Several

process parameters such as emulsification speed and stirringtime and formulation variables like

drug/polymer ratio, volume of glutaraldehyde and surfactant volume were evaluated. The

developed microspheres studied for different parameters and the surface morphology of

microspheres were confirmed by SEM. From data it was concluded that droplets having smooth

surface. The in vitro release data showed that famotidine release was upto 24 h.

Lian-Yan Wang et al 55 prepared chitosan microspheres holding insulin for enhancement of

release behavior. In this study Lian-Yan developed suitable method for the development of even

sized microspheres using emulsion technique. Lian-Yan also optimized process variables for the

uniform sized droplets. Lian-Yan also evaluated parameters like protein’s chemicalstability, in

vitro release characteristics and encapsulationefficiency was matched with different alternative

method of microspheres containing chitosan. From these data equally parallel chitosan droplets

were developed.

M.D.Dhanaraju et al 56 prepared Lamivudin microspheres using chitosan as release controlling

polymer. They developed microspheres using crosslinking technique with glutaraldehyde. The

developed microspheres were examined for physicalcharacterization. From the data,

encapsulationefficiency was observed to be 54.83-63.70 %w/w, size of droplets was measured

from of 5 to 40 µm and said that approximately 68% of the droplets was lying between 27 to 37

µm sizes. From the investigation M.D. Dhanaraju concluded that in vitro release of lamivudine

was managed by crosslinking density.

Rajesh Pandey et al 57 prepared alginate–chitosan microspheres for check the integrity on anti-

tubercular drug activity. Three an anti-tubercular drugs (ATDs), rifampicin, isoniazid and

pyrazinamide, were studied the efficacy of anti-tubercular activity by preparing microspheres.

Microspheres were evaluated for their physical characterization. Form the result drug

encapsulation efficiency was found from 65% to 85% and drug loadingefficiency was 220–280

mg in microspheres. The developed microspheres were administrated to guinea pigs for evaluate

sustain effect in plasma and organ for seven days and nine days respectively. From the result

concluded that drug encapsulated as microspheres increase the bioavailabilty up to 13- to 15

fold.

Sanju Dhawan et al 58 developed microspheres to study the impact on mucoadhesive

characteristics by using chitosan. Microspheres developed with different techniques with

different crosslinking agent like glutaraldehyde and tripolyphosphate. The strength of the

interface among chitosan and mucin microspheres was reliant on microspheres preparation and

the addition of mucin quantity. Adsorption of mucus level was directly related to the entire +ve

zeta potential values presented in microspheres. Finally concluded that microspheres formulated

with thermal crosslinking and glutaraldehyde exposed more stable in acid HCl when

microspheres developed with emulsificationionotropic gelation using tripolyphosphate as

crosslinking agent.

Rajesh R. Dubey et al 59 studied two-stage optimization process for development of

microspheres containing chitosan. Chitosan containing microspheres were developed with

chemicaldenaturation technique. The developed microspheres droplets were confirmed for their

physical representation like surface characteristics, particle size of droplets, particle

sizedistribution, drug entrapmentefficiency, drug content, and in vitro release. From the result

concluded that morphology of the microspheres was dependent on process constraints. Rahesh

also concluded that average microspheres size was depends on polymer solution, the stirring rate.

Kiran S. Bhise et al 60 studied effect of two major characteristics like dissolution medium and

oppositely charged polymer in microspheres formulated with chitosan. For this naproxen was

selected as model drug. They studied effect on erosion, swelling and drug release. Also studied

effect of buffer pH and drug : polymer ratio on water uptake, drug release and matrix erosion

were studied. The rapid drug release of naproxen was found on matrices that comprising 100%

polymer so it may lead to reduce the matrix cohesiveness of matrix; whereas, in vitro release

observed to be minimum for matrices developed by using optimum κ-carrageenan. The reason

for getting slower in vitro release for naproxen was confirmed by its poor solubility at different

pH.

Sanat Kumar Basu et al 61 prepared tramadol microspheres containing chitosan and gelatin B

the microspheres was prepared by ionotropic gelation method. Ionotropicgelation was developed

using Na-tripolyphosphate. The prepared microspheres were studied for their physical

characterization. All the microspheres exhibited initial burst release then maintaining the

sustained effect. The release of drug followed as fickian diffusion mechanism. The physical

properties of drug from the microspheres were confirmed by DSC and XRD analysis and

confirmed that drug present in matrix.

Soheila Honary et al 62 studied effect of mucoadhesive characteristics on molecular weight of

chitosan. The microspheres were developed with use of combination of alginate and chitosan.

Three different chitosan molecular concentrations were selected for optimization of investigation

like minimum, medium and maximum and studied the effect on particle size and drug release.

The microparticle was prepared by directly spraying alginate solution onto the chitosan and

calcium chloride solution at desired conditions. From the results indicated that formulation

prepared with high molecular weight of chitosan having smaller and uniform particle size. And

the formulation containing high molecular weight having stronger electrostatic and hydrogen

bonding confirmed by FTIR and DSC study.

Hailong Peng et al 63 prepared resveratrol microspheres with chitosan as drug coating materials

for controlled release. Vanillin was selected for cross-linking with chitosan. The microspheres

were formulated by emulsion chemical cross-linking method. The prepared microspheres exhibit

smaller particles with smoother surface and the size distribution between 53 and 311 lm. The

encapsulation efficiency of Res within microspheres was up to 93.68%.

Kesari Asha et al 64 formulated zidovudine microspheres for controlled release using chitosan as

rate controlling agent. Gluteraldehyde was used as a crosslinking agent. Microspheres were

developed by emulsification method. The developed microspheres were confirmed for their

physical characterization like shape and size of microspheres droplets, drug

entrapmentefficiency, drug content and in vitro release. Form the data microspheres was

spherical and uniform small particle size with free flowing. The percent entrapment efficiency of

the microspheres were found to be 72-94 % and drug release was spread over 12 hrs. The

physical state of the Zidovudin in microspheres were confirmed by X-ray and indicated that drug

is present as crystalline form.

Lourdes O et al 65 studied effect on sustain release on the formulation prepared with melt

granulation method using hydrophilic matrices. Theophylline was selected as model drug to

investigate the impact of hydrophilic polymers on formulation. From the result of dissolution

profile concluded that formulation having HPMC K4 M, Gelucire or PEG showed similar

dissolution profile with marketed approved products. Drug release found to be relatively lower

when microspheres formulated with lipophilic binders.

Paradkar et al 66 studied the effect of formulation developed by two different methods like

direct compression and melt granulation method to study the impact on in vitro release

characteristics. The formulation prepared with metformin and glyceryl behenate (Compritol)

were selected as meltable binders. The effect of diluents like lactose andMCC on in vitro release

characteristics also studied. From the data it was confirmed that glyceryl behanate showed good

sustained effect when the formulation prepared with melt granulation. And concluded that

glyceryl behanate was good waxy materials utilized for controlling the drug release behavior.

Amaral et al 67 prepared naproxen matrix tablet with hydrophilic and hydrophobic hydrogenated

castor oil. They investigated impact of hydrophilic concentration as well as hydrophobic

concentration on in vitro release characteristics. Lactose and dicalcium phosphate was used as

filler. Matrices formulated with HPMC and hydrogenated castor oil exhibit that concentration of

polymer was inversely depended on in vitro release characteristics. Drug release was moderated

by adding proper diluents. And finally concluded that lipid matrices were suitable for attaining

sustained release for highly water soluble drug.

Jiping L et al 68 studied the effect of different process like holt melt extrusion with melt

granulation. Jiping also studied granules properties with the formulation prepared by two

techniques. The tablets prepared by different methods were studied for their drug release

characteristics. From the result of drug release characteristics it was found as slower tablet

prepared with melt extrusion having slow frug release whe tanlet prepared with melt granulation

method.

Shimpi et al 69 investigated the impact of Gelucire for developing of multiunitfloating system of

highlywater soluble drug like Diltiazem hydrochloride. The diltiazem granules were prepared by

using melt granulation technique with the use of Gelucire. From the granules tables was

developed using tablet press machine. Afetr developing the tablet studied for tablets parameters

and also confirm the floating ability of tablets. Prepared matrices were studied for DSC, HSPM,

SEM and in-vitro release. Aged samples presented phase transformation of Gelucire 43/01 that

causes increase in release of drug.

Kamble et al 70 prepared ibuprofen matrix tablet using wax. Matrices were formulated by melt

solidification techniques. With adding more amount of wax to the matrices increase integrity and

increase prolongation of drug release. Cetyl alcohol and Palmitic acid mixures was used to

improve matrix integrity and release of drug form the DSC concluded that various solidification

and erosion characteristics of waxes are responsible on drug retardant properties.

Paradkar et al 71 prepared flurbiprofen matrix tablet with cetyl alcohol. Melt solidification

technique was used to develop matrices of flurbiprofen. The process involved for formulation of

matrices was emulsification technique. The mixture of flurbiprofen cetylalcohol melted at

significant temp (50ºC) and solidified. Impact of cetylalcohol amount and agitation speed was

also optimized observed. Form the drug release behavior it was summarized that invitro release

from the cetyl alcohol followed zero order.

Chauhan et al 72 prepared floating risedronate sodium matrices using Gelucire 39/01 as meltable

binders. The matrices were formulated by melt solidification and prepared tablets were studied

for their invitro floating characteristics and invitro release. Ageing of matrices evaluated for

DSC, HSPM, SEM and invitro release. The Ageing is responsible for alterations in physical

properties of Gelucire that is impact on drug release characteristics.

Mahaparale PR et al 74 prepared metoprolol succinate matrices for sustained release. Matrices

prepared by melt granulation technique Compritol and PrecirolATO were utilized as

meltablebinders for the development of matrices. The developed tablets were evaluated for

different characteristics. From the drug release data it was conformed that matrices prepared with

combination of both meltable binders having more drug retardant efficiency when compared

with the formulation prepared with alone meltable binders.

Feng QL et al 74 prepared sodium ferualte matrix tablet prepared by solid method. Compritol

888 ATO was utilized by means of meltable binders for the development of melt granulation.

From the tablet properties it was exposed that tablet developed with dispersion based observed to

be have significant effective than from the direct compressionmethod. Invitro release behavior

was studied for the tablets prepared with both process and concluded that tablets prepared with

direct compression completed full drug release within 12 hour while tablet prepared from solid

dispersion sustained the drug release upto 24 h.

Jannin V et al 75 prepared theophylline matrix tablet by melt granulation method. precirol ATO

05 was used as meltable binders for the development of melt granulation. They also studied the

effect of poloxomers on dissoluition behavior and also developed stable formulation that have

capacity to release drug in controlled manner with precirol. From the drug release data concluded

that drug release can be improved with hydrophilicpolymers with the generation of a

porousnetwork into inert lipidmatrix.

M.C. Gohel et al 76 prepared diclofenac sodium microspheres using chitosan as drug retardant

polymer. Microspheres were formulated by coacervation phase separation method.

Glutaraldehyde was used as cross-linking agent with chitosan. They evaluated conditions for

preparations, factors affecting the in-vitro drug release from hard gelatin capsules in phosphate

buffer (pH 6.5) and drug release mechanism were identified. From the results concluded that

prepared microspheres showed good spherical morphology and release mechanism from the drug

followed to the Higuchi mechanism.

J.K.Patel et al 77 developed Metoclopramide mucoadhesive microspheres. Chitosan was used to

develop mucoadhesion in the formulation and also as coating materials. The microspheres were

developed by emulsification phaseseparation technology and glutaraldehyde was selected as

crosslinking polymer. Microspheres were evaluated for both formulation and process

optimization, like volume of crosslinking agent, time for crosslinking and speed of rotation.

Mucoadhesive properties of microspheres were depended on polymer ratio. From the drug

release it was exposed that invitro of drug was diffusioncontrolled and followed non-Fickian

diffusion.

B. Arul et al 78 formulated chitosan microspheres containing isoniazid. The microspheres were

formulated by glutaraldehyde cross-linking method using various concentrations of chitosan. The

prepared microspheres investigated for drug content, PSD studies and compared with marketed

tablets. The percentage of entrapment obtained was 60%. Stability studies were carried out at

different temperatures and found that all the formulation was more stable at 4o and room

temperature.

Dong Yanga et al 79 studied impact of the meltgranulation on the dissolution features of

griseofulvin. Granules were developed in small scale process at the temperature range at 60 °C

and the RPM range for impeller was designed approximately 20,000. Dong also investigated

formulation characterization for robust composition like impact of drug loading, concentration of

binder, selection of filler, and also impact of HPMC on release of griseofulvin. Dong developed

composition with factorialdesign. From the factorial data exposed that availability of more

HPMC decrease dissolution of griseofulvin, and also availability of starch promote the

dissolution of griseofulvin.

M.U. Uhumwangho et al 80,developed acetaminophen granules using meltgranulation. The

waxes used were goat wax, carnuba wax and glyceryl monostearate. The acetaminophen release

data were analyzed for their in vitro mechanism with mathematicalmodels (release kinetics)

namely, – zero order, firstorder, and third one was Higuchisquare root. The developed granules

was showed zero order acetaminophen release for first 55% and after this acetaminophen release

depends on firstorder for last 45%.

Nirav V Patel et al 81 developed instant release tablets of oxcarbazepine by meltgranulation

technology. The oxcarbazepine granules were developed with PEG4000 as a melting polymer.

Nirav also used filler for the instant release oxcarbazepine tablets like lactose monohydrate

having the hydrophilic tendency. From the investigation nirav investigated impact of disintegrant

on dissolution and also studied the impact of starch for the promotion of dissolution rate.

Kapil Kalra et al 82 investigated effect on dissolution characteristics and solubility behavior for

the tablet developed by meltgranulation using rifapentine as drug. Rifapentine granules were

developed using different variables of polyethyleneglycol and different variables of poloxomers.

From the drug release data it was conformed that matrices developed with polyethyleneglycol

and different variables of poloxomers having more drug retardant efficiency when compared

with the other marketed formulation.

Dhruvita Patel et al 83 developed two layered tablet for metformin along with pioglitazone with

meltgranulation technology. The matrices consist of two layers, form this one layer having the

fast release effect and this layer contains pioglitazone whereas other layer having retardant effect

the release and this layer contains metformin. Dhrivita has developed matrices for use in

diabetes mellitus. She investigated impact of hydrophilic as well as hydrophobic compounds on

invitro release of metformin.

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