FORMULATION AND INVITRO EVALUATION OF BUCCAL …
Transcript of FORMULATION AND INVITRO EVALUATION OF BUCCAL …
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Naresh et al. World Journal of Pharmacy and Pharmaceutical Sciences
FORMULATION AND INVITRO EVALUATION OF BUCCAL
TABLETS OF TAPENTADOL HYDROCHLORIDE
P. Naresh*, S.Sujatha
*Department of Pharmaceutics, Malla Reddy Institute of Pharmaceutical Sciences,
Maisammaguda, Secunderabad.
ABSTRACT
The present investigation is concerned with formulation and evaluation
of buccal tablets containing a centrallyacting opioid analgesic drug,
TapentadolHCl to circumvent the first pass effect and to improve its
bioavailability with reduction in dosing frequency and dose related
side effects. The tablets were prepared by direct compression method.
The formulations were developed with varying concentrations of
polymers like Carbopol 934, HPMC-K4M, sodium alginate,
xanthangum, and polyvinylpyrrolidone-K30 (PVP). The prepared
formulations were evaluated for their physicochemical characteristics,
swelling index, surface pH, buccoadhesive strength, drug content
uniformity and in-vitro drug release studies. Formulation (F8) showed
maximum drug release of 99% in 8 hours. The in-vitrorelease kinetics
studies reveal that all formulations fits well with zero order kinetics followed by Korsmeyer-
Peppas, first order and then Higuchi’s model.
KEYWORDS: Tapentadol hydrochloride, opioid analgesic, buccoadhesive tablets, HPMC
K4M, zero order kinetics.
INTRODUCTION
Among the various routes of drug delivery, oral route is the most suitable and most widely
accepted one by the patients for the delivery of the therapeutically active drugs. But, after
oral drug administration many drugs are subjected to pre systemic clearance in liver, which
often leads to a lack of correlation between membrane permeability, absorption and
bioavailability [1-4]
. Within the oral route, the oral cavity is an attractive site for drug delivery
*Correspondence for
Author
P. Naresh
Department of
Pharmaceutics, Malla Reddy
Institute of Pharmaceutical
Sciences, Maisammaguda,
Secunderabad
Article Received on
11 August 2014,
Revised on 03 September
2014,
Accepted on 25 September
2014
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 2.786
Volume 3, Issue 10, 1228-1243. Research Article ISSN 2278 – 4357
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due to ease of administration and avoids possible drug degradation in the gastrointestinal tract
as well as first pass hepatic metabolism [5]
. In the, oral cavity the delivery of drugs are
classified into three categories: 1.Sublingual delivery, which is systemic delivery of drugs
through the mucosal membranes lining the floor of the mouth; 2.buccal delivery it is the drug
administration through mucosal membranes lining the cheeks (buccal mucosa); and 3. Local
delivery it is the drug delivery into the oral cavity [6,7]
. Among these routes, buccal delivery is
suitable for administration of retentive dosage forms because of an excellent accessibility, an
expanse of smooth muscle and immobile mucosa. So, buccal delivery of drugs is attractive
alternative to the oral route of drug administration8.Buccal delivery involves the
administration of drug through buccal mucosal membrane (the lining in the oral cavity).
Buccal drug delivery is the safer method of drug utilization because; drug absorption is
terminated in case of toxicity by removing the dosageform from the buccal cavity. The drug
directly reaches to the systemic circulation through the internal jugular vein and bypasses the
drugs from the hepatic first pass metabolism, which leads to high bioavailability [9]
. The other
advantages of buccal drug delivery include: low enzymatic activity, suitable for drugs or
excipientsthat mildly and reversibly damage or irritate the mucosa, painless drug
administration, easy drug withdrawal, possible to include the permeation enhancer/enzyme
inhibitor or pH modifier in the formulation.
A suitable buccal drug delivery system should be flexible and should possess good
bioadhesive properties, so that itcan be retained in the oral cavity for the desired duration. In
addition, it should release the drug in a controlled and predictable manner to elicit the
required therapeutic response[10]
. Various buccal mucosal dosage forms are suggested for oral
delivery which includes: buccal tablets, buccal patches and buccal gels.
Tapentadol is a centrally-acting opioid analgesic, having a potency between morphine and
tramadol. Tapentadol has been approved as immediate release tablets in 50 mg, 75 mg and
100mgformulation by the United States Food and drug administration[10]
.
The approval was based on data from clinical studies involving more than 2,100 patients that
showed that tapentadol provided significant relief of moderate to severe acute pain in adults
18 years of age or older as compared to placebo and is generally well tolerated.
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Tapentadol undergoes extensive hepatic first pass metabolism with an oral bioavailability of
32%. The terminal elimination half life is 4 hours after oral administrationand peak effect is
attained after 1 hr. Duration of action is 4-6 hrs.
MATERIALS AND METHODS
MATERIALS
Tapentadol hydrochloride was obtained as a gift sample from LobaChemPvt.Ltd,Mumbai.
Sodium alginate , xanthangum and Hydroxy propyl methyl cellulose K4M ,Starch, carbopol,
SSG, Talc, Magnesium stearate and other excipients were obtained from Richer
pharmaceuticals, Hyderabad.
METHODS
DIRECT COMPRESSION
Tapentadol hydrochloride buccal tablets were prepared by direct compression method. The
buccal tablets were prepared by using Carbopol 934 P (CP 934 P) as primary
mucoadhesivepolymer because of its excellent mucoadhesive properties. HPMCK4M,
plasidoneS-630, and sodium alginate were used as secondary polymers. The above said
polymers were used in different ratios in the formulation of buccal tablets. The composition
of different formulations is represented in Table 1. All the ingredients of the formulation
were passed through a sieve # 85 and were blended in a glass mortar with a pestle to obtain
uniform mixing. The blended powder was compressed into tablets on a pilot press, nine
station tablet punching machine (ChamundaPharmapvtLtd,Ahmadabad).
EVALUATION PARAMETERS
1. Bulk density: It is the ratio of total mass of powder to the bulk volume of powder. It was
measured by pouring the weighed powder into a measuring cylinder and the volume was
noted. It is expressed in gm/ml. (Table no: 2)
Bulk density = Weight of powder / Bulk volume
2. Tapped density: It is the ratio of total mass of powder to the tapped volume of powder. It
is determined by placing a graduated cylinder containing known weight of powder,
mechanical tapper apparatus operated for fixed number of taps until the powder bed volume
has reached a minimum volume. (Table no: 2)
Tapped density = Weight of powder / Tapped volume
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3. Carr’s index (i)
It is measured by using values of bulk density and tapped density.(Table no: 2)
Carr’s Index = density Tapped
density Bulk -density Tapped×100
4.Hausner’s ratio
Hausner’s ratio is the ratio of tapped density to bulk density.(Table no: 2)
Hausner’s Ratio = DensityBulk
Density Tapped
5.Angle of repose
The frictional forces in a loose powdercan be measured by the angle of repose, θ.(Table no:
2)
= tan-1
(h/r)
Where h=height of the heap
r=radius of the heap
It is determined by pouring the powder a conical on a level, flat surface, measured the
included angle with the horizontal.
6. Hardness: The hardness of the tablet was determined by using a Monsanto hardness
tester. It is expressed in kg / cm2
.
7. Thickness: The thickness of the tablets was measured by Digital Vernier Caliper. It is
expressed in mm.
8. Weight variation: Ten tablets were selected randomly from the lot and weighed
individually to check for weight variation. The following %deviation in weight variation is
allowed.
9. Friability (F): The friability of the tablet was determined using Roche Friabilator. It is
expressed in %. 10 tablets were initially weighed and transferred into the friabilator. The
friabilator was operated at 25 rpm for 4 mins. The tablets were weighed again. Friability of
tablet should not exceed 1%.
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10. Content uniformity: Three tablets of each formulation were powdered using a mortar
and a pestle. Aliquots of the crushed tablets equivalent to 50 mg of Tapentadol hydrochloride
were weighed and required amount of distilled water was added to extract the drug. This
suspension was shaken for 6 hours and volume was made up to 100 ml with distilled water,
filtered throughWhatmann filter paper No.1, 2 ml of filtrate were diluted to 50 ml with
distilled water. The samples were analyzed in spectrophotometer at 220 nm.
11. Surface pH[11]
The surface pH of the buccal tablets was determined in order to find out the possibility of any
side effects in buccal environment. As an acidic or alkaline pH may cause irritation to the
buccal mucosa, it was determined to keep the surface pH as close to buccal pH as possible,
The tablet was allowed to swell by keeping it in contact with 5 ml of phosphate buffer
containing 2% w/v agar medium (pH6.8±0.01) for 2 h at room temperature. The pH was
measured by bringing the electrode in contact with the surface of the tablets and allowing it to
equilibrate for 1minute. A mean of three readings were recorded.
12. Swelling index: Three tablets from each batch were weighed individually and placed
separately in a thoroughly cleaned Petri dish containing 5 ml of pH 7.2 phosphate buffer. At
regular intervals the tablets were removed and weight was noted. The swollen tablets were
reweighed and swelling index was calculated by using the formula:
Swelling index = [(W2-W1)/W1] × 100
Where, W1- Initial weight of Tablet,
W2- Weight of swollen tablet at time(t).
13.MeasurementofBioadhesive strength[12]
Modified physical balance method was used fordetermining the ex-vivobioadhesive strength.
FreshPorcine buccal mucosa obtained from a localslaughterhouse was stored in pH 6.6
phosphate bufferat 40Cupon collection. The experiment was performedwithin 3 hours of
procurement of the mucosa. Theporcine buccal mucosa was fixed to the stainless steelpiece
with cyanoacrylate adhesive and placed in abeaker; then pH 6.6 phosphate buffer was added
intothe beaker up to the upper surface of the porcinebuccal mucosa to maintain buccal
mucosal viabilityduring the experiment. Then the tablet was attached tothe upper clamp of
the apparatus and the beaker wasraised slowly to establish contact between porcinebuccal
mucosa and the tablet. A preload of 50 gm was placed on the clamp for 5mins to establish
adhesivebond between the tablet and porcine buccal mucosa.After completion of preload
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time, preload wasremoved from the clamp and water was added into thebeaker from burette
at a constant rate. The weight ofwater required to detach the tablet from porcine
buccalmucosa was noted as mucoadhesive strength andexperiment was repeated with fresh
mucosa in anidentical manner. (Table No. 4)
14. In-vitro dissolution studies: The dissolution studies were performed using USP 24 type
II paddle apparatus, employing paddle stirrer rotating at 75 rpm, 500 ml of phosphate buffer
pH 6.8 as a dissolution medium at 37 ± 0.5ºC. 5 ml aliquots of dissolution medium was
withdrawn at specified time intervals and the volume of the dissolution medium was
maintained by adding the same volume of fresh dissolution medium. The absorbance of the
withdrawn samples was measured spectrophotometrically at 220 nm.
15. Stability studies: The stability studies were conducted for satisfactory formulation as
ICH guidelines. The satisfactory formulation sealed in aluminum packaging and kept in
humidity chamber containing 30±2°C with 65±5% RH for 2months.Samples were analyzed
for drug content and in vitro drug release profile.(Table no: 6)
16. FTIR studies: In the present study FTIR usedas a tool to evaluate physical and chemical
stability of prepared buccal tablets. The buccoadhesive tablets were compressed and
powdered. The pelletized powder along with KBr was used for FTIR studies. The IR spectra
were recorded using Fourier TransformInfrared spectrophotometer (company). The IR
spectrum of pure TapentadolHCl and pelletized powder of tablets were taken, interpreted and
compared with eachother.(Figure 1, 2)
17. Drug release kinetics: To analyze the mechanism of drug release from the tablets, the
results of in vitro release data were plotted in various kinetic models like zero order, Higuchi
model and Korsmeyer- peppas.
RESULTS AND DISCUSSION
Table No 1: Formulation of Different Batches
INGREDIENTS F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
TAP 50 50 50 50 50 50 50 50 50 50 50 50
LACTOSE 42 57
PVPK-90 4 4
CP 4 4
HPMC K4M 21 30 7.5 15 22.5 30 7.5 15 22.5 7.5
SOD.ALGINATE 24
7.5 7.5
TALC 5 5
STARLAC
72.5 65 57.5 50 57.5 57.5 50 50
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SSG
3 3 3 3 3 3 3 3 3 3
ASPARTAME
2 2 2 2 2 2 2 2 2 2
PLASIDONE S-630
6 6 6 6 6 6 6 6 6 6
Mg.STEARATE
3 3 3 3 3 3 3 3 3 3
AEROSIL
6 6 6 6 6 6 6 6 6 6
HPMC E5
15 7.5 7.5 22.5
STARCH
57.5 50
GUAR GUM
XANTHAN GUM
CARBOPOL
15 22.5
Total tablet weight 150 150 150 150 150 150 150 150 150 150 150 150
EVALUATION PARAMETERS
Tablets of different formulations were subjected to various physicochemical evaluation
parameters such as weight variation, hardness, friability, thickness, drug content, and
diameter. The results of these studies were found to be within the limits and given in Table
no.3
COMPATIBILITY STUDY
The standard spectrum of TapentadolHCl shown in fig.1was compared by FTIR spectrum of
physical mixtures fig 2, fig3. FTIR studies proved that the drug is compatible with excipients.
IN-VITRO DISSOLUTION STUDIES
Dissolution is carried out in USP 2 type apparatus at 50rpm in the volume of 500ml
dissolution media (phosphate buffer pH 6.8) for 8hours. The dissolution rate was found to
decrease linearly with increasing concentration of Sustained release agent. Formulations F1,
F2, and F3 which contained Sodium alginate shows % drug release of 85.11%, 77.55%,and
92.5% Formulations F4, F5, and F6 which contained HPMC shows % drug release of
91.83%, 98.88%, and 82.16% respectively. Formulations F8, F9, F10and F17 which
contained HPMCK4M % drug release of 99%, 88.11%, 87.55, and 88.61% respectively. The
% drug release of all the formulations and the comparative release profile in fig.4.
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Table No 2:Pre-compression studies of the blend
FORMULATION BULKDENSITY TAPPEDDENSITY CARR'SINDEX ANGLE OF REPOSE HAUSNER'S RATIO FLOWABILITY
F1 0.212 0.241 12.3 26.8 1.14 Good
F2 0.306 0.361 15.9 27.5 1.18 Good
F3 0.274 0.309 12.8 28 1.13 Good
F4 0.339 0.386 12.4 28.5 1.14 Good
F5 0.322 0.363 11.2 29.7 1.13 Good
F6 0.318 0.359 11.2 29.4 1.13 Good
F7 0.519 0.607 12.6 27.1 1.17 Good
F8 0.519 0.593 14.6 27.5 1.5 Good
F9 0.419 0.478 11.3 29.8 1.14 Good
F10 0.478 0.565 12.5 28.6 1.18 Good
F11 0.333 0.346 12.8 28.1 1.14 Good
F12 0.423 0.398 15.3 26.8 1.18 Good
Table No 3: Post compression studiesof TapentadolHClbuccal tablets
FORMULATION WEIGHT VARIATION THICKENESS HARDNESS FRIABILITY DRUG CONTENT
F1 150.2 ± 0.836 1.59 ± 0.083 5.04 ± .0547 0.671±0.12 97.5±0.21
F2 148.6 ± 0.836 1.69 ± 0.054 5.16 ± 0.0547 0.675±0.08 98.42±0.11
F3 149.6 ± 0.894 1.49 ± 0.083 5.12 ± 0.0836 0.684±0.09 98.20±0.17
F4 150.2 ± 1.095 1.49 ± 0.054 5.22 ± 0.0836 0.675±0.18 98.74±0.23
F5 149 ± 0.707 1.49 ± 0.083 5.26 ± 0.0547 1.64±0.20 98.88±0.21
F6 149.6 ± 0.547 1.59 ± 0.054 5.32 ± 0.0836 0.699±0.08 98.95±0.19
F7 150.4 ± 0.894 1.39 ± 0.054 5.38 ± 0.0447 0.671±0.31 98.38±0.20
F8 149.4 ± 0.547 1.49 ± 0.083 5.36 ± 0.0707 0.675±0.11 97.68±0.18
F9 149 ± 1.224 1.49 ± 0.089 5.42 ± 0.0836 0.666±0.25 98.2±0.23
F10 150.2 ± 0.447 1.49 ± 0.054 5.46 ± 0.0547 0.704±0.09 96±0.20
F11 151 ± 0.707 1.59 ± 0.054 5.36 ± 0.0547 0.662±0.12 98.16±0.16
2 150.6 ± 0.894 1.59 ± 0.054 5.30 ± 0.0707 0.675±0.08 98.35±0.17
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Table No4: Surface pH and Bioadhesive Strength
FORMULATION SURFACE pH BIOADHESIVE STRENGTH(g)
F1 5.9 18.37
F2 5.8 20.3
F3 6.03 28.72
F4 5.5 24.5
F5 5 27.6
F6 6.12 19.8
F7 5.2 30.1
F8 6.1 32.5
F9 5.9 29.5
F10 6.19 26.82
F11 5.8 24.5
F12 5.9 20.5
Swelling index
Table 5: swelling index of the formulations
T
i
m
e
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
0 0 0 0 0 0 0 0 0 0 0 0 0
1
14.2
7 ±
0.01
37.47
±
0.042
107.
14±0
.042
12.4
7 ±
0.04
2
31.24
±
0.024
13.34
±
0.013
50.0
9 ±
0.13
4
35.71
±
0.011
21.4
2±0.
18
14.26
±
0.016
13.3
3 ±
0.02
1
26.65
±
0.011
2
28.5
0 ±
0.05
4
56.25
±
0.08
128.
5±0.
021
12.4
7 ±
0.04
3
62.50
±
0.017
26.65
±
0.011
92.4
8 ±
0.04
5
57.14
±
0.014
35.7
1±0.
020
28.57
±
0.023
26.6
6 ±
0.01
5
40.02
±
0.042
3
50.0
8 ±
0.08
3
81.23
±
0.021
12.4
7 ±
0.04
4
81.25
±
0.015
46.55
±
0.016
85.71
±
0.014
50±
0.01
4
50.03
±
0.042
40.0
5 ±
0.05
2
53.32
±
0.011
4
64.2
6 ±
0.01
3
106.1
8 ±
0.075
12.4
7 ±
0.04
5
100.1
9 ±
0.450
66.65
±
0.011
107.1
4±
0.014
64.2
±0.0
45
64.27
±
0.016
53.3
3 ±
0.02
1
73.74
±
0.016
5
78.5
±
0.07
0
118.5
9 ±
0.020
12.4
7 ±
0.04
6
118.7
4 ±
0.028
80.26
±
0.062
121.4
2 ±
0.014
78.5
2±0.
023
85.71
±
0.015
66.6
5 ±
0.01
9
93.34
±
0.011
6
92.8
0 ±
0.08
131.2
3 ±
0.025
12.4
7 ±
0.04
7
125.0
6 ±
0.104
106.6
5 ±
0.013
142.8
5 ±
0.019
100
±0.0
18
107.1
2 ±
0.016
86.6
5 ±
0.01
4
106.6
4 ±
0.024
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STABILITY STUDIES
Table No .6: Stability studies: Drug content
S.NO Parameters Initial 1
month
2
month
3
month
Limits as per
specification
1 400C/75% RH
% Release 98.95 98.92 98.81 98.70 Not less than 85 %
2 400C/75% RH
Assay Value 98.65 98.58 98.42 98.33
Not less than 90 %
Not more than 110 %
Figure :1Ftir of tapentadol
Figure : 2 Ftir of tapentadol with excipients
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Figure :3Ftir of tapenadol table
%Cumulative drug release profile of selected formulations
Kinetic model Fit Formulation of F8
Zero order
Time(minutes) Zero order
0 0
30 18.27
60 35.05
120 46.22
180 51.55
240 62.11
300 67.77
360 72.77
420 84.61
480 99
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Time(minutes) First order
30 1.912
60 1.812
120 1.73
180 1.685
240 1.578
300 1.508
360 1.435
420 1.187
480 0
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Higuchi model
sqrt time %CDR
0 0
5.47 18.27
7.74 35.05
10.95 46.22
13.41 51.55
15.49 62.11
17.39 67.77
18.97 72.77
20.49 84.61
21.9 99
Korsmeyer-peppas model
Log time Log %CDR
1.477121255 1.261
1.77815125 1.544
2.079181246 1.664
2.255272505 1.712
2.380211242 1.793
2.477121255 1.831
2.556302501 1.861
2.62324929 1.927
2.681241237 1.995
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RELEASE KINETICS
Different models like zero order, first order, higuchi's, and peppas plots were drawn for
formulation F-8. The regression coefficient (r2) value for zero order, first order, higuchi's, and
peppas plots (figures no: 5-8 ) for formulation F-8 was found to be 0.936, 0.673, 0.980, and
0.971 respectively. The formulation F-8 follows zero order release and peppas plot. Since
the regression coefficient of peppas was 0.971 and slope ‘n’ value is less than 0.5 which
confirms that the drug release through the matrix was fickian diffusion.
STABILITY STUDIES
F8 formulation was subjected to stability studies. It was suggested that there was no
significant change physical parameters such as weight variation, hardness, friability,
thickness; drug content. This is shown in table no 6.
CONCLUSION
From the above mentioned results it can be concluded that the formulation of buccal tablets
of Tapentadol hydrochloride were prepared by direct compression method by using polymers
like HPMCK4M,PVP-K30,PlasidoneS-630, either alone or combinations.Among all the
formulations,the formulation F8 showed satisfactory results with good swelling index and
bucco-adhesive strength.The optimized formulation was showing good stability in
accelerated conditions. Buccal tablets of Tapentadol hydrochloride could be promising one as
they, increase bioavailability, minimize the dose, reduces the side effects and improves
patient compliance hence, Tapentadolhydrochloride might be a right and suitable candidate
for oral controlled drug delivery via Buccaltablets for the therapeutic use.
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ACKNOWLEDGMENT
Authors wish to thank Malla Reddy Institute of Pharmaceutical Sciences, Secunderabad,
Telangana, for providing research laboratory to carryout this project work. The authors also
wish to show theirdeep gratitude to Richer Pharmaceuticals, Hyderabad for providing the gift
sample ofTapentadol HCL.
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