formulation and invitro evaluation of buccal …

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1228

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.


1242


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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