Design, Development and Evaluation of Buccal Tablets of Pregabalin

 

Srikrishna T.*, K. Mohammad Anees, S. Lakshmi Priyanka, K. Lavanya, B. Mounika, M. Murali Krishna

Department of Pharmaceutics, Narayana Pharmacy College, Chinthareddypalem, Nellore-524002 A.P., India.

*Corresponding Author E-mail: srikrishna.nlr@gmail.com

 

ABSTRACT:

The present investigation is concern with formulation and evaluation of mucoadhesive buccal tablets containing anti convulsant drug. Pregabalin 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. Nine formulations were prepared with different polymers like carbopol, HPMC, Xanthan gum with varying concentration. The tablets were tested for weight variation, hardness, drug content uniformity, swelling index and in vitro drug dissolution study. FTIR studies showed no evidence on interactions between drug and polymer. The in vitro release of Pregabalin was performed under sink conditions (Phosphate buffer PH 7.2, 370.50C) using dissolution apparatus USP type II. The best in vitro drug release profile was achieved with the formulation F6 which contains the drug, HPMC (30 mg). The formulation F6 containing 50 mg of Pregabalin exhibited 8 hrs sustained drug release i.e. 99.01%. The in vitro release kinetics studies reveal that formulation fits with Korsmeyer-Peppas model and mechanism of drug release is anolomus diffusion.

 

KEYWORDS: Bioavailability, Drug Release, Sustained Release, Pregabalin, Buccal Tablets, Carbopol.

 

 


INTRODUCTION:

The oral cavity is an attractive site for the administration of drugs because of ease of administration, avoidance of possible drug degradation in gastro intestinal tract and first-pass hepatic metabolism (1). In the oral cavity the delivery of drugs is 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.

 

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 administration (2), (3).

 

Buccal delivery involves the administration of the desired drug through the buccal mucosal membrane lining of the oral cavity. In recent years delivery of therapeutic agents through buccal mucosa has gained significant attention. Drug absorption through buccal mucosa is mainly by passive diffusion into the lipoidal membrane. In the buccal delivery the drug directly reaches to the systemic circulation through the internaljugular vein and bypasses the drugs from the hepatic first pass metabolism and gastric irritation, which leads to high bioavailability. From the technological point of view, an ideal buccal dosage form must have three properties; it must maintains its position in the mouth for a few hours, release the drug in controlled fashion and provide drug release in a unidirectional way towards mucosa. This unidirectional drug release can be achieved using bilayer devices. Moreover, buccal drug absorption can be promptly terminated in case of toxicity by removing the dosage form from the buccal cavity. It is also possible to administer therapeutic agent to patients who cannot be dosed orally to prevent accidental swallowing (4).

 

These buccal tablets are small, flat and are intended to be held between the cheek and teeth or in the cheek pouch. A suitable buccal drug delivery system should possess good bioadhesive properties so that, it can be retained in the oral cavity for the desired time duration. Various buccal mucosal dosage forms are suggested for oral delivery which includes: buccal tablets, buccal patches and buccal gels. Drug delivery via the buccal route, using bioadhesive dosage forms offers such a novel route of drug administration (5).

 

Pregabalin is a structural analogue of the inhibitory neurotransmitter γ-amino butyric acid (GABA), but it is not functionally related to it. It binds to the α-2-δ subunit of voltage- gated calcium channels, reducing the release of several excitatory releases of neurotransmitters and blocking the development of hyperalgesia and central sensitization. They constitute an important group of compounds that are used in the treatment of epilepsy and neuropathetic pain. Pregabalin has anti-hyperalgesic6, anti-convulsant, anxiolytic, analgesic and sleep modulating properties. The half-life of Pregabalin is also short 5-6 hrs which makes it suitable candidate for sustained release formulation. It has 90% of oral bioavailability, rapid absorption with in 1 hour and eliminated through kidney (6), (7).

 

MATERIALS AND METHODS:

Materials

Pregabalin, Hydroxypropyl methyl cellulose K4M, Xanthan gum, carbopol were obtained from Dr. Reddy’s Laboratories, Hyderabad, India. PVP, Saccharine Sodium, Lactose and magnesium stearate were obtained from S.D. Fine chem. Ltd, Mumbai, India. All other chemicals, reagents and solvents were used are of analytical grade.

Methods

Drug- Excipient Compatibility study using FTIR

Drug and excipients interaction was checked by comparing the FT-IR spectra of pure drug Pregabalin and FT-IR spectra of the physical mixture of drug and excipients. The IR spectra were taken from FT-IR-8400S (Shimadzu Corporation, Tokyo, Japan). In the present study, potassium bromide (KBr) pellet method was employed. The samples were thoroughly blended with dry powdered KBr crystals. The mixture was compressed to form a disc. The disc was placed in the IR Spectrophotometer and the spectrum was recorded.

 

Calibration curve of Pregabalin in 7.2 pH

Stock solution I:

10 mg of Pregabalin is taken in 100 ml volumetric flask and added to 5 ml of water. Shake well and make up the volume to 100 ml with7.2 pH to get concentration of 100µg/ml.

 

Stock solution II:

From the stock solution I, 1 ml is taken in 10 ml standard flask and make up the volume to 10 ml with 7.2 pH. From this various dilutions were made to get a final concentration of 2, 4, 6, 8, 10, 12 µg/ml.The absorbance of the above solution was measured at 210 nm using UV spectrophotometer.

 

Preparation of Buccal Tablets

Pregabalin Mucoadhesive buccal tablets were prepared by direct compression technology. The formulations composition is shown in below table. All the powders passed through a 60 mesh sieve. The required quantity of drug, various polymer mixtures and diluent were mixed thoroughly in polybags. The blend was lubricated with magnesium stearate for 3‐5mins and aerosil was added as glidant. The mixed blend was directly compressed (9mm diameter, round flat faced punches) using 12 station tablet compression machine (Saimach Pvt. Ltd. India). Each tablet contains 50 mg of Pregabalin All the tablets were stored in airtight containers for further study (8).

 

 


 

Table 1: Composition of Pregabalin Mucoadhesive buccal tablets

S.

NO

INGREDIENTS

F1 (mg)

F2 (mg)

F3 (mg)

F4 (mg)

F5 (mg)

F6 (mg)

F7 (mg)

F8 (mg)

F9 (mg)

1

Pregabalin

50

50

50

50

50

50

50

50

50

2

Carbopol

10

20

30

-

-

-

-

-

-

3

HPMC K4M

-

-

-

10

20

30

-

-

-

4

Xanthan gum

-

-

-

-

-

-

10

20

30

5

PVP

5

5

5

5

5

5

5

5

5

6

Saccharine Sodium

5

5

5

5

5

5

5

5

5

7

Mint flavour

1

1

1

1

1

1

1

1

1

8

Lactose

74

64

54

74

64

54

74

64

54

9

Magnesium Stearate

2.5

2.5

2.5

2.5

2.5

2.5

2.5

2.5

2.5

10

Aerosil

2.5

2.5

2.5

2.5

2.5

2.5

2.5

2.5

2.5


Pre-Compression Studies:

Bulk Density:

Weighed quantity of the powder (W) was taken in a graduated measuring cylinder and volume (V0) was measured. The bulk density was calculated using the formula (9).

 

Bulk density (BD)   =Weight of the powder/ Volume of powder

BD      = W/V0 g/ml

 

Tapped Density:

Weighed quantity of powder was taken in a graduated cylinder and the volume was measured (V0). Then the graduated cylinder was closed with lid, set into the density determination apparatus. The density apparatus was set for 500 taps and after that, the final reading was noted (Vf). The volume of blend was used to calculate the tapped density, Hausner’s ratio and Carr’s Index.

 

Tapped density (TD)               =    W/Vf g/ml

 

Compressibility Index (% Compressibility):

Carr’s Compressibility index i.e., % Compressibility is indirectly related to the relative flow rate, cohesiveness and particle size. It is determined by measuring both bulk density and tapped density of the powder. It is simple, fast and popular method of predicting powder flow characteristics. When the Carr’s Index ranges from 5 to 15, the materials have acceptable flow rate (9). Carr’s index was calculated by using the formula:

                       

Carr’s Index (%)   =                 (Tapped Density –Bulk Density) x   100      

                                                Tapped Density

 

Hausner’s ratio:

Hausner’s ratio indicates the flow properties of the powder and measured by the ratio of tapped density to bulk density. 

                        Hausner’s ratio was calculated by using the formula.

                        Hausner’s Ratio  = Tapped density / Bulk density

                        Hausner’s Ratio                =              Vf/V0

                                Where      V0   = Initial volume     

                                                Vf = Final volume

 

Angle of repose (θ):

Frictional force leads to improper flow these forces are measured by using angle of repose. Angle of repose is defined as the maximum angle possible between the surfaces of a pile of the powder on the horizontal plane. The angle of repose experiment is determined by using funnel and burette stand. The funnel is fixed at height on the burette stand and the powder was passed through the funnel which from a pile .this region is encircled to measure radius of the pile. The process is done for multiple times, the average value is taken. The angle of repose is calculated using the equation (10)

 

Angle of Repose (ө) = Tan-1 (h/r)

Where,

                                                h = height of the pile

                                                r = radius of the base of the pile

                                                θ = angle of repose

                    

 

Evaluation of Buccal Tablets:

Thickness and Diameter:

Six tablets from each batch were selected and measured for thickness and diameter using digital Vernier calipers. The extent to which the thickness of each tablet deviated from ± 5% of the standard value was determined.

 

Weight variation Test:

20 tablets were selected at random and average weights were determined. Then individual tablets weighed and the individual weight was compared with the average.

Average Weight of Tablets = Total Wt. of tablets/ No. of tablets

Average weight of tablets (X) = (X1+X2 +X3+…+ X20) / 20

 

Hardness Test:

Tablets should be sufficiently hard to resist breaking during normal handling, packaging and shipping, and yet soft enough to disintegrate properly after swallowing. Hardness of the tablet is controlled by (or is affected by) the degree of the pressure applied during the compression stage. Hardness is an important criterion, since it can affect disintegration and dissolution. The test measures crushing strength property defined as the compressional force applied diametrically to a tablet which just fracture (break) it. The Monsanto hardness tester was used to determine the tablet hardness. The tablet was held between a fixed and moving jaw. Scale was adjusted to zero; load was gradually increased until the tablet fractured. The value of the load at that point gives a measure of hardness of the tablet. Hardness was expressed in Kg/cm2 (11).

 

Friability Test:

The friability of the tablet was determined using Roche Friabilator. It is expressed in percentage (%). 20 tablets were initially weighed (W initial) and transferred into the Friabilator. The Friabilator was operated at 25 rpm per min for 4mins (100 revolutions). The tablets were weighed again (W final). The % friability was then calculated by

Friability= Initial Wt- Final Wt/ Initial Wt × 100

 

Assay:

Twenty tablets were selected randomly from each batch and powdered in a mortar and accurately weighed tablet powder was placed in 50 ml volumetric flask. The drug was extracted into 25 ml 7.2 Phosphate buffer with vigorous shaking on a mechanical shaker for few minutes. The volume was made up to the mark with 7.2 pH Phosphate buffer. The solution was filtered through Whattman filter paper and appropriate dilutions were further made with 7.2 pH Phosphate buffer. The dilutions samples were measured for the absorbance at 210 nm against blank (7.2 pH Phosphate buffer) and the drug content was calculated (12).

 

Swelling Study:

Three randomly chosen tablets from each formula were glued to glass beads using cyanoacrylate glue. They were weighed (W1) and placed separately in beakers containing 40 ml distilled water in a shaker at 100 rpm at 37°C. After 0.5, 1, 2, 3 and 4 hrs, remove the tablet (excess water should be removed) then reweighed it (W2) and the swelling index was calculated using the following equation:

 

Swelling index = W2-W1/W1

 

Bioadhesive strength:

Bioadhesive strength of the tablet was measured on the modified physical balance. The design used for measuring the bioadhesive strength was shown in Fig. No 12. The apparatus consist of a modified double beam physical balance in which the right pan has been replaced by a glass slide with copper wire and additional weight, to make the right side weight equal with left side pan. A taflone block of 3.8 cm diameter and 2 cm height was fabricated with an upward portion of 2 cm height and 1.5 cm diameter on one side. This was kept in beaker filled with phosphate buffer pH 7.2, which was then placed below right side of the balance (13).

 

Goat buccal mucosa was used as a model membrane and phosphate buffer pH 7.2 was used as moistening fluid. The goat buccal mucosa was obtained from local slaughter house and kept in a Krebs buffer during transportation. The underlying mucous membrane was separated using surgical blade and wash thoroughly with buffer media phosphate buffer pH 7.2. It was then tied over the protrusion in the Teflon block using a thread. The block was then kept in glass beaker. The beaker was filled with phosphate buffer pH 7.2 up to the upper surface of the goat buccal mucosa to maintain buccal mucosa viability during the experiments.

 

The one side of the tablet was attached to the glass slide of the right arm of the balance and then the beaker was raised slowly until contact between goat mucosa and buccoadhesive tablet was established. A preload of 10 mg was placed on the slide for 5 min (preload time) to established adhesion bonding between buccoadhesive tablet and goat buccal mucosa. The preload and preload time were kept constant for all formulations. After the completion of preload time, preload was removed from the glass slide and water was then added in the plastic bottle in left side arm by peristaltic pump at a constant rate of 100 drops per min. The addition of water was stopped when buccoadesive tablet was detached from the goat buccal mucosa. The weight of water required to detach buccoadhesive tablet from buccal mucosa was noted as bioadhesive strength in grams (14) (15). From the bioadhesive strength following parameter was calculated.

The results are shown in table.

 

                                         Bioadhesive strength

Force of adhesion (N) = ----------------------------× 9.81

                                                       1000

                                            Force of adhesion (N)

Bond strength (N/m2) = ---------------------------------

                                            Surface area of tablet (m2)

 

 

Fig. (1) Diagrammatic representation of the mucoadhesive force-measuring device

 

In Vitro Release Study:

In vitro release rate study of mucoadhesive buccal tablet of Pregabalin was carried out using the USP type II (paddle apparatus) method. Place the tablet in a dry bowl at the beginning of each test. Medium used for release rate study was 900ml of phosphate buffer pH 7.2 during the course of study whole assembly was maintained at 37+0.5oC. Withdraw a 5 ml of sample at time interval of 1,2,3,4 up to 8 hr and replaced with 5 ml of fresh dissolution medium. The withdrawn samples were diluted with dissolution medium and then filtered it with whattman filter paper and assayed at 210 nm spectrophotometrically (16), (17).

 

Release Kinetics:

The in vitro release data obtained was treated to zero order kinetics, first order kinetic, higuchi model and korsemeyer peppas model to know precisely the mechanism of drug release of the buccal tablets (18).

 

RESULTS:

Calibration curve of Pregabalin

Table 2: Standard calibration curve of Pregabalin using 7.2 pH

S.No

Concentration

Absorbance

1

2

0.136

2

4

0.272

3

6

0.456

4

8

0.584

5

10

0.748

6

12

0.894

 

Fig. (2) Standard calibration curve of Pregabalin in pH 7.2

 

Drug-Excipient Compatibility Study

Fig. (3) IR spectra of Pregabalin

 

Pregabalin showed peaks at 2955.508 cm-1 (C–Hstretch), 1644.495 cm-1 (N–H bend), 1545.665 cm-1  ( N–O asymmetric stretch), 1470.186 cm-1 (C–Hbend), 1368.144 cm-1 (C–H rock), 1333.857 cm-1(N–O symmetric stretch), 1278.548 cm-1 (C–Ostretch ), 933.038 cm-1 (O–H bend) and 933.038cm-1 (O–H bend)

 

 

Fig. (4) IR spectra of Pregabalin and HPMC

 

Fig. (5) IR spectra of Pregabalin and xanthanum

 

Fig. (6) IR spectra of Pregabalin and carbopol


 

Table 3:  IR spectra of Pregabalin and Pregabalin with polymer

Pregabalin

Pregabalin + HPMC

Pregabalin + Xanthan gum

Pregabalin + Carbopol

Comment

2955.508

2955.114

2955.721

2954.758

3100-3000S

1333.857

1334.000

1334.004

1334.089

1335-1250 amines group

1644.495

1643.686

1643.662

1642.734

1680-1640S alkane group

1278.548

1278.750

1278.713

1278.660 and 1162.856

1320-1000 carboxylic group

 

 

 

 

Table 4: Evaluation of Pre-Compressed granules of Pregabalin

Formulation

Bulk density (gm/m)

Tapped density (gm/m)

Compressibility index (%)

Hausner’s

ratio

Angle of repose(Θ)

F1

0.344±0.02

0.446±0.05

25.5±0.1

1.23±0.02

28.15±0.1

F2

0.342±0.01

0.493±0.009

26.4±0.2

1.65±0.01

28.44±0.4

F3

0.317±0.01

0.497±0.01

25.6±0.3

1.52±0.05

23.21±0.3

F4

0.351±0.03

0.460±0.01

23.4±0.3

1.72±0.02

30.22±0.2

F5

0.348±0.02

0.469±0.03

25.5±0.4

1.38±0.04

28.10±0.1

F6

0.310±0.03

0.460±0.04

26.6±0.1

1.24±0.01

29.18±0.4

F7

0.365±0.01

0.422±0.01

26.8±0.3

1.25±0.01

28.09±0.3

F8

0.354±0.04

0.420±0.03

26.4±0.2

1.30±0.02

30.16±0.3

F9

0.369±0.05

0.468±0.02

27.4±0.3

1.38±0.01

28.34±0.2

Note: All values are expressed as mean ± SD, n=3

 

Table 5: Evaluation of compressed granules of Pregabalin mucoadhesive buccal tablets

Batch code

Weight variation (mg)

Thickness (mm)

Hardness (kg/cm2)

Friability (%)

Assay (%)

F1

148.5±3.5

2.58 ±0.52

5.1±0.51

0.67±0.05

98.3±1.5

F2

149.2±2

2.52±0.16

5.3±0.31

0.52±0.01

99.5±2

F3

150±2.5

2.58±0.48

4.9±0.26

0.54±0.04

97.1±2.3

F4

149.4±3.2

2.48±029

5.5±0.42

0.63±0.09

98.2±1.4

F5

149.1±2.8

2.59±0.28

5.0±0.34

0.71±0.01

98.8±1.9

F6

148.5±3.4

2.56±0.46

4.8±0.65

0.65±0.13

102.3±0.9

F7

150±1.8

2.53±0.65

5.3±0.15

0.55±0.06

97.8±2.6

F8

146.5±6.1

2.50±0.3

5.4±0.23

0.65±0.02

101±2.2

F9

148.5±3.1

2.53±0.65

4.9±0.26

0.71±0.01

101.3±0.9

Note: All values are expressed as mean± SD, n = 3

 

Swelling Study:

Table 6: Results of percentage hydration

Formulation

Percentage hydration

1 hr.

2 hr.

4 hr.

8 hr.

24 hr.

F1

52.81

60.03

62.41

65.73

67.44

F2

54.17

60.90

64.51

66.36

68.48

F3

57.80

60.29

63.25

64.11

68.28

F4

58.17

61.74

64.80

67.10

70.68

F5

62.21

64.36

66.88

70.82

71.96

F6

68.35

70.28

71.59

72.56

73.37

F7

67.99

69.03

70.01

70.06

72.54

F8

67.48

68.47

69.98

71.16

72.24

F9

67.41

69.25

71.47

72.40

72.98

 


In vitro drug release Study

Table 7: In vitro drug release of Marketed formulation

Time (hrs)

% drug release

0

0

1

22.6±0.4

2

31.4±0.2

3

42.3±0.3

4

58.8±0.1

5

66.5±0.4

6

78.3±0.6

7

85.3±0.3

8

91.8±0.1

 Note: All values are expressed as mean± SD, n = 3

 

Fig. (7) In vitro drug release profile marketed formulation


Table 8: % Drug Release of Pregabalin from F1 to F9

S.No

Time

(hr)

% Drug release

F1

F2

F3

F4

F5

F6

F7

F8

F9

1

1

34.4±0.4

28.4±0.3

24.6±0.

21.2±0.3

17.5±0.1

18.4±0.3

24.9±0.

15.7±0.3

20.3±0.

2

2

44.5±0.2

36.2±0.5

32.4±0.

34.6±0.3

27.7±0.2

30.8±0.1

32.8±0.4

23.2±0..2

29.6±0.1

3

3

54.4±0.5

44.1±0.8

40.3±0.3

45.1±0.8

35.8±0.1

43.7±0.2

43.6±0.2

34.5±0.2

41.9±0.1

4

4

67.3±0.2

65.9±0.1

56.8±0.1

55.6±0.3

53.7±0.2

51.4±0.5

57.4±0.1

48.8±0.1

54.9±0.2

5

5

81.6±0.4

71.6±0.4

68.5±0.4

67.4±0.5

64.6±0.3

63.7±0.2

71.2±0.4

57.9±0.1

62.6±0.3

6

6

92.3±0.1

86.7±0.2

80.3±0.6

75.7±0.2

74.2±0..7

73.4±0.3

82.6±0.2

65.3±0.3

73.2±0.8

7

7

 

95.9±0.1

86.3±0.3

90.8±0.1

85.3±0.6

84.6±0.2

91.8±0.1

72.5±0.2

85.3±0.3

8

8

 

 

90.8±0.1

95.6±0.3

97.8±0.1

99±0.1

 

81.9±0.2

95.2±0.7

     Note: All values are expressed as mean± SD, n = 3


 

Fig. (8) In vitro drug release profile of formulation (F1 to F3)

 

Fig. (9) In vitro drug release profile of formulation (F4 to F6)


 


 

Fig. (10) In vitro drug release profile of formulation (F7 to F9)


 


Table 9: Determination of Release kinetics

S.

No

Time (hours)

Square root of time

Log time

Cum % drug release

Log cum % drug release

Cum % drug remaining

Log cum % drug remaining

1

1

1.000

0.000

17.3

1.255

82

1.924

2

2

1.424

0.301

30.8

1.490

69.1

1.829

3

3

1.722

0.477

43.4

1.640

56.3

1.742

4

4

2.000

0.602

51.4

1.711

48.6

1.678

5

5

2.439

0.778

62.7

1.797

37.3

1.492

6

6

2.818

0.913

73.4

1.866

26.6

1.415

7

7

3.132

1.000

83.6

1.916

15.4

1.199

8

8

3.464

1.079

99

1.996

1

0.000

 

Table 10: Coefficient of Correlation for kinetic drug release

 

Zero order

First order

Higuchi modal

Peppas modal

Slope

6.8137

0.1381

28.495

0.6626

r2

0.9769

0.7722

0.9631

0.9922

 

Table 11: Accelerated stability studies data of best formulation (F6)

S. No

Test

Initial

Period in months

1

2

3

1

Physical appearance

white, smooth, flat

white, smooth, flat

white, smooth, flat

white, smooth, flat

2

Hardness (kg/cm2)

4.8±0.65

4.8±0.32

4.7±0.98

4.7±0.88

3

Friability (%)

0.65±0.13

0.65±0.02

0.66±0.42

0.67±0.23

4

Assay (%)

102.3±0.9

101.8±0.4

101.4±0.1

100.8±0.4

5

Swelling studies

73.37±0.4

72.4±0.1

72.3±0.6

72.1±0.8

6

In vitro release (%)

(at 8 hour)

99±0.1

98.9±0.2

98.8±0.2

98.7±0.4

 

 


Fig. (11) Formulation of F6 – Zero order kinetics

 

Fig. (12) Formulation of F6 –First order kinetics

 

Fig. (13) Formulation of F6 – Higuchi model

 

Fig. (14) Formulation of F6 –Koresmeyer Peppas model

 

DISCUSSION:

Standard calibration curve for Pregabalin hydrochloride:

The calibration curve of Pregabalin in 7.2pH was derived from the concentration and corresponding absorbance. Values of linear regression analysis gave the equation for the line of best fit as Y= 0.075x-0.010. Linearity was observed in the concentration range between 2 to 12µg/ml. The values were show in Table.2 and represented graphically in Figure.2.

 

Drug Excipient compatibility studies:

The compatibility study was performed using FT-IR for drug polymer mixtures. The spectra of Pregabalin exhibited principal peaks at wave numbers of (C-H stretching), (C-N stretching), (C=N stretching), (C=C aromatic stretching) and (C-O stretching). From the FT-IR graphs of drug- polymer mixture, it was found that similar peaks of the drug are available. So, it proves that there is no incompatibility with the polymers. It is graphically represented in Figures 3, 4, 5and6.

 

Flow Properties:

The prepared granules of all the 9 formulation are taken to study the flow properties. The flow properties of each formulation such as bulk density, angle of repose, tapped density, compressibility index and Hausner’s ratio are determined. The flow properties of all the 9 formulation are found to be satisfactory. The results are shown in Table.4.

 

Evaluation of Tablets:

The Mucoadhesive buccal tablets are evaluated for weight variation, thickness, hardness, friability and assay. The values are in the range of 146.5mg to 150.2 mg for weight variation. Thickness and hardness values range from 2.52to 2.58 mm and 4.8 to 5.8 kg/cm2 respectively. According to Noorana tehseen et al, F2,F5, F8, F11, F14, F17  formulations are prepared by using HPMCK4M  1.25, 3.75, 7.5, 11.25, 15 and18.75. the thickness of these formulations shows 2.51, 2.62, 2.46, 2.37, 2.42, 2.55 and the hardness is 3.6, 3.7, 3.5, 3.6, 3.7, 3.8. But in our research work F4, F5, F6  formulations used 10, 20, 30 mg of HPMCK4M ,which are exhibited 2.48, 2.59, 2.56 mm thickness and hardness of these formulations was 5.5, 5.0, 4.8. These values are represented in table 13.The range of friability is 0.52 to 0.7. Results are in the range of 97.1% to 102.3% for assay. The swelling studies are found to be satisfactory. The results are shown in Table.5.

 

Release Profile of the Drug:

All the prepared batches of tablets were subjected to in vitro dissolution studies. The formulations F1, F2, F3 were prepared by using Carbopol as the polymer. The concentration of the polymer was increased in successive manner of 10 mg, 20 mg, and 30 mg. The percentage drug release was fast, where as F1 shows 92.3 % of release in 6 hours. F2 and F3 show 95.9 and 90.8% of drug release respectively in 8 hours. The results are shown in Table.8 and represented graphically in Figure.8. According to Ramasubbareddy et al. F1, F2, F3, F4 formulations which are formulated by using HPMCK4M 50mg at the end of 8hr. exhibited 56.2, 11, 23, 22% drug release. But in our research work  F4, F5, F6  formulations used 10,20,30 mg of HPMC K4M which are lower concentration than 50 mg  exhibited  95.6, 97.8, 99.9% drug release at the end of  8 hrs. Here we can observe the increased % drug release with decrease in polymer concentration. This might be due to slow hydration of matrix andits property to form thick gel layer which retard drug release than the tablet. The formulations F7, F8 and F9 were prepared by using Xanthan gum as the polymer with the concentration of 10mg, 20mg and 30 mg respectively. F7 exhibits 91.8 % of drug release in 7 hours while F8 and F9 exhibit 81.9% and 95.2 % of the release after 8 hours. The results are shown in Table.8 and represented graphically in Figure.10. Out of all the formulations, F6 was found to be the best formulation as it shows sustained release of the drug with 99.0% at the end of 8 hours of the study.

 

Drug Release Kinetics:  

Drug release date of formulation F6 was plotted as per various kinetic models. F6 was chosen on the basis of the release parameters. Table.10 show the value of correlation coefficient obtained for the various kinetic models. In vitro release mechanism was best explained by Korsemeyer Peppas equation indicated a good linearity (r2= 0.992). The release exponent n was 0.6626 for F6 formulation and n indicates diffusion constant which is the general operating release mechanism. It is know that the Peppas model is widely used to confirm whether the release mechanism is Fickian diffusion and Non- Fickian diffusion. The ‘n’ (release exponent of Korsemeyer Peppas model) value could be used to characterize different release mechanisms.

 

The interpretation of n values was done in the following manner:

• n<0.5 (0.45) - quasi-Fickian Diffusion                                    

• n=0.5 (0.45) - Diffusion mechanism

• 0.5<n<1 - Anomalous (non-Fickian) Diffusion - both diffusion and relaxation (erosion)

• n=1 (0.89) - Case 2 transport (zero order release)

• n>1 (0.89) - Super Case 2 transport (relaxation)

The mechanism of release is anomalous, that is both diffusion and erosion are involved.

 

Stability studies:

Stability studies conducted on buccal tablets of Pregabalin. Tablet was stored in High density polyethylene container at 400C / 75 % RH for 3 months.

 

Hardness:

No significant change was observed in the Hardness after storage period of 3 months at 400C / 75 % RH condition

 

Dissolution:

No significant change was observed in the percentage drug dissolved after storage period of 3 months at 400C / 75 % RH condition for buccal tablets of Pregabalin. The drug release was 98.7% at the end of 8hours.

 

Assay:

No significant change was observed in the assay value after storage period of 3 months at 40°C / 75 % RH condition for buccal tablets of Pregabalin. The drug content was 100 %.

 

CONCLUSION:

The present study was an attempt to develop bioadhesive drug delivery system for PregabalinThmaiinteresisuch  a  dosagforwamadto formulate mucoadhesive buccal tablet for Pregabalin, in order to avoid extensive first pass metabolism and for prolonged effect. Mucoadhesive formulations in the form of erodible tablets were developed to a satisfactory level in terms of drug release, bioadhesive performance, physicochemical properties and swelling index. In- vitro drug release could be obtained highest for up to 8 hours with HPMC polymer. Buccal delivery of Pregabalin is found to be a promising route for controlling the convulsion. They are found to be more advantageous in comparison to the conventional drug delivery systems containing Pregabalin hydrochloride. These results guarantee the achievement of therapeutic concentration in the actiositethdecreasodrusideffectanthimprovemenopatient compliance. Further Accelerated stability studies were carried out for 3 months, no  significant  change  in  the  physical  properties,  drug  content,  and dissolution rate of formulation  F6 was observed .As such formulation F6 developed is considered as an best formulations of Pregabalin.  Thus the study fulfilled the objective of developing efficient buccal tablets of Pregabalin.

 

ACKNOWLEDGEMENTS:

The authors are thankful to Narayana Pharmacy College, Nellore, A.P., India for providing the required support and resources.

 

REFERENCES:

1.        Rajesh BG and Joseph RR. Oral cavity as a site for bioadhesive drug delivery. Advanced Drug Delivery Reviews.13(2);1994:43-47.

2.        Amir H Shojaei. Buccal mucosa as a route for systemic drug delivery. Journal of Pharmacy and Pharmaceutical Sciences.15(30);1998:15-30.

3.        Chowdary K P R, Kamalakara G Reddy and Bhaskar P. Mucoadhesive polymers- Promising excipients for controlled release. International Journal of Pharmaceutical Excipients.3(2);2001:33-38.

4.        Sarika Pundir, Ashutosh Badola, and Deepak Sharma. Sustained release matrix technology and recent advance in matrix drug delivery system: a review. International Journal of Drug Research and Technology. 3(1);2013:12-20.

5.        Sharma A, Sharma S, and Jha KK. The study of salbutamol matrix tablets using different polymers as release retarding agent. The Pharma Research.2(1);2009:15-22.

6.        Janos B, Klara P, Odon P, and Stane S. Film coating as a method to enhance the preparation of tablets from dimenhydrinate crystals. International Journal of Pharmaceutics.5(3);2004:393-401.

7.        Ahmed E. Aboutaleb, Aly A. Abdel-Rahman, Eman M. Samy, and Marwa G. El-Naggar. Formulation and Evaluation of Verapamil Hydrochloride Buccoadhesive Tablets. Unique Journal of Pharmaceutical and Biological Sciences. 1(3);2013:48-57.

8.        Ayesha Farooqui, Dr. Syed Abdul Azeez Basha, and Asra Parveen. Formulation and Evaluation of Gastroretentive Bilayer Mucoadhesive Tablets of Verapamil Hydrochloride. International Journal Of Pharmacy and Technology. 6(2);2014:6681-6698.

9.        Tej Pratap Singh, Rakesh Kumar Singh, Jigar N Shah, and Tejal A Mehta. Mucoadhesive Bilayer Buccal Patches of Verapamil Hydrochloride: Formulation Development and Characterization. International Journal of Pharmacy and Pharmaceutical Sciences.6(4);2014:234-241.

10.     Janet A H. Methods for assessing the buccal mucosal as a route of drug delivery. Advanced Drug Delivery Reviews.12(2);1993:99-125.

11.     Khalid Mahrag Tur and Hung- Seng. Evaluation of possible mechanisms of bioadhesion. International Journal of Pharmaceutics.16(8);1998:61-74..

12.     Durgacharan Bhagwat, Pravin Kawtikwar, and Dinesh Sakarkar. Sustained release matrices of verapamil HCl using glyceryl monosterate and stearic acid. Research Journal of Pharmacy and Technology.1(4);2008:77-79.

13.     Lakade SH, and Bhalekar MR. Formulation and evaluation of sustained release matrix tablet of anti-anginal drug, influence of combination of hydrophobic and hydrophilic matrix former. Research Journal of Pharmacy and Technology.1(4); 2008:88-102.

14.     Yeduka Anjibabu, Debjit Bhowmik, Praveen Khirwadkar, K.P.Sampath Kumar, and Rajnish Kumar Singh. Design and development of buccoadhesive tablets of verapamil hydrochloride. Indian Journal of Research in Pharmacy and Biotechnology.3(1);2015:32-39.

15.     Sunil Kumar, Anil Kumar, Vaibhav Gupta, Kuldeep Malodia , and Pankaj Rakha. Oral Extended Release Drug Delivery System: A Promising Approach. Asian Journal of Pharmaceutical Technology. 2(2);2012:38-43.

16.     Ramasubba Reddy KV,Laxamanaro Potti, Rama kotaiah Mogili, prasada Rao M, and Chandra shekhar M. Formulation and Evaluation of Pregabalin sustain release tablets. International Journal Of Pharmacy Practice and Drug Research.4(2);2014:80-85.

17.     Ray Brijesh, Gupta MM. Formulation and evaluation of once daily sustained release matrix tablet of verapamil hydrochloride. Journal of Drug Delivery and Therapeutics.3(1);2013:55-58.

18.     Noorana Tehseen, Vinay Rao and Mohd Abdul Hadi. Design and Characterization of twice daily mini-tablet formulation of Pregabalin. International Journal Of Pharmacy and Pharmaceutical Sciences.4(6);2013:168-175.

 

 

 

 

 

Received on 27.12.2016             Modified on 16.02.2017

Accepted on 27.02.2017           © RJPT All right reserved

Research J. Pharm. and Tech. 2017; 10(2):579-588.

DOI: 10.5958/0974-360X.2017.00115.9