Formulation and In-Vitro Evaluation of Mucoadhesive ...

Research J. Pharm. and Tech. 1(4): Oct.-Dec. 2008, ,

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ISSN 0974-3618

RESEARCH ARTICLE

Formulation and In-Vitro Evaluation of Mucoadhesive Buccal Tablets of Diltiazem Hydrochloride R Manivannan1*, A Balasubramaniam1, DC Prem Anand1, G Sandeep1 and N Rajkumar2. 1

Department of Pharmaceutics, J.K.K.M.M.R.F. College of Pharmacy, Komarapalayam, Pin: 638 183, Namakkal, Tamilnadu, India. 2 Department of Pharmaceutics, University College of Pharmaceutical Sciences, Kakatiya University, Warangal – 506002, Andhra Pradesh, India. *Corresponding Author E-mail: [email protected]

ABSTRACT: Mucoadhesive buccal tablets of Diltiazem hydrochloride were prepared using carbopol-934, Sodium carboxy methyl cellulose (SCMC), Hydroxy propyl methyl cellulose (HPMC), sodium alginate and guar-gum as mucoadhesive polymers. Eight formulations were developed with varying concentrations of polymers. The carbopol-934 is used as a primary polymer because of its excellent mucoadhesive property and secondary polymers like HPMC, SCMC, sodium alginate and guar-gum were used. The effect of secondary polymer loading on drug release was studied. The formulations were tested for in-vitro drug release and in-vitro swelling studies. Formulation FA2 showed maximum release of 76.98% in 8hours. Formulation FC2 showed maximum swelling index of 3.7 after 8hours. Formulation FA2 follows zero order drug release. FTIR studies show no evidence on interaction between drug and polymers. The results indicate that suitable mucoadhesive buccal tablets with desired properties could be prepared.

KEY WORDS: Buccal tablets, Diltiazem Hydrochloride, Formulation, Swelling and Evaluation. INTRODUCTION: Buccal delivery of drugs provides an attractive alternative to the oral route of drug administration, particularly in overcoming deficiencies associated with the latter mode of administration problems such as high first pass metabolism, drug degradation in harsh gastro intestinal environment can be circumvented by administering a drug via buccal route1,2&3. More over buccal drug absorption can be terminated promptly in case of toxicity by removing the dosage form from the buccal cavity. It is also possible to administer the drug to patients who cannot be dosed orally to prevent accidental swallowing. Therefore mucoadhesive dosage forms were suggested for oral drug delivery which include adhesive tablets 4,5&6, adhesive gels7&8, adhesive patches9&10. Diltiazem is a calcium channel blocker 11&12 used in the treatment of hypertension and angina (variant & classical angina) 13. Diltiazem was selected as a model drug for investigation because of its suitable properties like half-life

Received on 27.09.2008 Accepted on 18.11.2008

Modified on 12.10.2008 © RJPT All right reserved

Research J. Pharm. and Tech. 1(4): Oct.-Dec. 2008;Page 478-480

of 4.5 hrs, optimum partition coefficient (158) and molecular weight (450.98) make it suitable for administration by buccal route 14. A suitable buccal drug delivery system should posse’s good bioadhesive properties. So, that it can retain in oral cavity for desired duration and localize the dosage form in a specific region and control the release rate of drug 15. In present study, the mucoadhesive tablets were developed using hydrophilic polymers (carbopol-934, HPMC, SCMC, Sodium alginate and guar-gum) to get controlled and zero order drug release.

MATERIALS AND METHODS: Materials: Diltiazem hydrochloride was gift sample from Nicholas Primal India Ltd, Carbopol-934 by S.D.Fine chemicals Ltd, Mumbai. HPMC, SCMC, Guar-gum, PEG-6000, Magnesium Sterate were obtained from Loba Chemie Pvt. Ltd, Mumbai. All other chemicals were used are of A.R. grade. Mucoadhesive Tablets Preparation Diltiazem hydrochloride was mixed manually with different ratios of carbopol-934, HPMC, SCMC, sodium alginate and guar-gum act as a diluent [Table-1]. The

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Table 1: Formulation of Diltiazem hydrochloride Buccal batches. Formulation Ingredients FA1 FA2 FB1 FB2 Diltiazem. HCl 30 30 30 30 Carbopol 30 120 30 120 SCMC 120 30 Sodium alginate Guar gum PEG 6000 9 9 9 9 Mannitol 9 9 9 9 Mg. Sterate 2 2 2 2 Diltiazem. HCl – Diltiazem hydrochloride. , Mg. Sterate – Magnesium Sterate.

blend was lubricated with magnesium Sterate for 3-5 min and then compressed into tablets by direct compression method using 8mm flat faced punches, (Rimek Minipress, Karunavati Eng. Ltd, Ahmedabad). The mass of tablets were determined using Digital balance (Shimdazu, Japan) and thickness of tablets with a digital Screw Gauge (Mitatyo, Japan). Assay of Diltiazem Hydrochloride: Twenty tablets were taken and powdered; powder equivalent to one tablet was taken and allowed to dissolve in 100ml of water on a rotary shaker overnight. The suspension was centrifuged and supernatant liquid was collected and the absorbance was measured using UVVIS Spectrophotometer 119 (Systronics, Naroda, Ahmedabad) at 237 nm. Table 2: Mass, Thickness and Percentage drug content of Diltiazem Hydrochloride Buccal tablets. Percentage Formulation Thickness Drug Mass (mg) Code (mm) content (%) 197.32 3.525 99.96 FA1 200.65 3.043 99.22 FA2 198.65 3.107 97.35 FB1 201.15 3.145 98.28 FB2 199.15 3.432 100.12 FC1 199.26 3.480 98.47 FC2 201.26 3.621 99.77 FD1 201.56 3.762 99.06 FD2

In-Vitro Release Studies 16 : The drug release rate from buccal tablets was studied using the USP (II) dissolution test apparatus (Lab India dissolution test apparatus Disso 2000). The assembly is kept in a jacketed vessel of water maintained at 37±10C. Buccal tablet was made to stuck on bottom of the flask (so as to allow one sided release from the tablet). The beaker is filled with 250ml of mixed phosphate buffer pH 6.8. The vessel maintained at 50rpm under stirring conditions by means of paddle fabricated for purpose in dissolution apparatus. At various intervals of time, samples were withdrawn and filtered through whatmann filter paper no.42. It is replaced immediately with equal amount of fresh buffer. The samples are then analyzed U.V. spectrophotometrically at 237 nm up to 8hours.

FC1 30 30 120 9 9 2

FC2 30 120 30 9 9 2

FD1 30 30 120 9 9 2

FD2 30 120 30 9 9 2

In-Vitro Swelling Studies 17 : The tablets of each formulation were weighed individually (W1) and placed separately in Petri-dishes containing 2% Agar gel. At regular intervals (1, 2, 3, 4, 5, 6, 7 and 8 hours) the tablets were removed from Petri dishes and excess water removed carefully using filter paper. The swollen tablets were re-weighed (W2); the swelling index of each formulation calculated by using this formula. Swelling Index (S.I.) = W1-W2 / W1 FTIR Study: The buccal tablets (FA2) were compressed and powdered. The palletized powder along with potassium bromide was used for FTIR studies. The I.R. spectra were recorded using I.R. Spectrtrophotometer (Perkin-Elmer FTIR, Perkin-Elmer, USA).

RESULTS AND DISCUSSION: Mass, Thickness and Drug Uniformity: The mass and thickness of tablets were within the limits of uniformity (Table-2). The mass ranged from 197.3 to 202.5mg with R.S.D values of -3.85 to +3.89%. Thickness ranged between 3.043 to 3.767mm with R.S.D values of 0.07 to 0.12% .The drug content ranged from 99.2 to 99.9% from FA2 to FA1; 97.3 to 98.2% from FB1 to FB2; 98.4 to100.1% from FC2 to FC1 and 99 to 99.7% from FD2 to FD1. In-Vitro Drug Release Studies: The Release of Diltiazem hydrochloride from buccal tablets varied according to type and ratio of matrix forming polymers Fig: 1. The drug release was governed by amount of matrix forming polymers. The most important factor affecting the rate of release from buccal tablets is the drug and polymer ratio. As increase in the polymer concentration increases the viscosity of the gel as well as the formation of gel layer with longer diffusional path. This could cause a decrease in the effective diffusion co-efficient of drug and therefore reduction in drug release rate. In present study, the results followed this predictable behavior Fig: 1. Tablets from FA1 and FA2 (HPMC as a secondary polymer) showed drug release more than 70% in 8hours. Among the four formulations of this group, FA2 showed highest drug release and it is also highest among eight

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formulations. This is probably due to high gelling property of HPMC.

90

80

70

% cumulative Drug release

Tablets from FB1 and FB2 (SCMC as a secondary polymer) and FC1 and FC2 (sodium alginate as a secondary polymer) showed a maximum release of 75 & 57% respectively in 8hours. Tablets of FD1 and FD2 (Guar-gum as a secondary polymer) showed a maximum release of 61.6% in 8hours. In-Vitro Swelling Studies The swelling index of mucoadhesive tablets for a period of 8hours was studied. The values obtained as shown in the Fig: 2. It is evident that an increase in the amount of carbopol-934 causes decrease in swelling index, in case of SCMC and sodium alginate. Among all the formulations, FC1 showed highest value of 3.77 and FD2 with lowest value of 1.95 swelling index at end of 8hours.

0

FA1

Swelling Index (S.I)

5. 2

1.5

6. 1

0.5

7.

0 5

6

7

8

9

Time (Hrs) FA1

FA2

FB1

FB2

FC1

FC2

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Fig 2: In-Vitro Swelling Studies of Diltiazem Hydrochloride Buccal Tablets.

8.

FTIR Studies FTIR study reveals that there was no interaction took place between the drug and the polymer.

9.

CONCLUSION:

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Carbopol-934: HPMC (4:1) shows satisfactory mucoadhesive properties. Formulation FA2 using this polymer in drug and polymer ratio (4:1) showed significant swelling properties with optimum release profile and could be useful for buccal administration of Diltiazem hydrochloride. Further work is recommended to support its efficacy claims by long term Pharmacokinetic and Pharmacodynamic studies in human beings.

13. 14.

References:

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1. 2.

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Gibaldi M. The number of drugs administering buccally increasing, Clinical Pharmacology. 1985; 3: 49-56. Harris D and Robinson R. Drug Delivery via the mucous membranes of oral cavity, J Pharm Sci. 1992; 81: 110. Senel S and Hincal AA. Drug penetration enhancement via buccal route; possibilities and limitations, J Control Release. 2001; 72: 133-144.

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3

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7

8

9

FA2

FB1

FB2

FC1

FC2

FD1

FD2

Fig 1: In -Vitro drug release profiles of Diltiazem hydrochloride buccal tablets.

2.5

4

1

Time (Hrs)

3

3

30

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3.5

2

40

10

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1

50

20

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11. 12.

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