ISSN: Original Article FORMULATION AND IN VITRO EVALUATION OF SUSTAINED RELEASE ISRADIPINE MATRIX TABLETS BY USING HYDROPHILIC POLYMERS

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1 Available online at International Journal of Pharmacy and Pharmaceutical Science Research Universal Research Publications. All rights reserved ISSN: Original Article FORMULATION AND IN VITRO EVALUATION OF SUSTAINED RELEASE ISRADIPINE MATRIX TABLETS BY USING HYDROPHILIC POLYMERS Arup Ratan Deb *1, Padmakana Malakar 2, Nilufa Yeasmin 2 1 Department of Pharmaceutics, Moonray Institute Pharmaceutical Sciences, Mahbubnagar, India 2 Department of Pharmaceutical Chemistry, Azad College of Pharmacy, Hyderabad, India Correspondence Author: ARUP RATAN DEB Department of Pharmaceutics, Moonray Institute Pharmaceutical Sciences, Raikal, Shadnagar, Mahbubnagar, A.P, Phone: ard.pharma11@gmail.com Received 15 August 2013; accepted 21 August 2013 Abstract The purpose of this study was to formulate and evaluate an efficient sustained release formulation of Isradipine designed to provide 24 hours drug release profile using varying proportion of hydrophilic polymers viz; Lactose monohydrate and HEC as matrix-forming material. In vitro release studies were performed using USP type II apparatus. Compatibility of drug with various excipients was also studied which shows suitable results. Prepared matrix tablets showed satisfactory physicochemical properties where drug content was 98.24% to %, thickness was 3.33 mm to 3.55 mm, hardness was 7.52±0.171 to 8.94±0.285 kg/cm 2, friability was less than 1% and % weight variation was within the standard pharmacopoeial limits of ±7.5% of the weight. Dissolution study revealed that all six formulations were able to sustain the drug release up to 24 hours. The dissimilarity factor (f 1 ) and similarity factor (f 2 ) were found to be 5 and 63 respectively for the comparison of dissolution profiles of formulation F6 and innovator product. Mathematical analysis of the release kinetics of the optimized formulation (F6) was best fitted in zero order kinetics (R 2 = ). The dissolution profiles of formulation F6 and innovator product in multi media were compared by calculating similarity factor (f 2 ) which were found to 56, 71, 67 in ph 4.5 acetate buffer, ph 6.8 phosphate buffer, 0.1N HCl respectively. The stability data reveals that the F6 showed a negligible change in drug content after storage in various conditions for two months according to ICH guidelines Universal Research Publications. All rights reserved Keywords: Isradipine, Matrix tablets, Lactose monohydrate, HEC, Sustained release. 1.0 INTRODUCTION Oral route is the most preferred route for administration of drugs. Tablets are the most popular oral formulations available in the market and preferred by the patients and physicians alike. In long-term therapy for the treatment of chronic disease conditions, conventional formulations are required to be administered in multiple doses, and therefore have several disadvantages [1]. Sustained-release oral delivery systems are designed to achieve therapeutically effective concentrations of drug in the systemic circulation over an extended period of time, thus achieving better patient compliance and allowing a reduction of both the total dose of drug administered and the incidence of adverse side effects [2]. Among the different approaches studied with this aim, matrix systems still appear as one of the most attractive from both the economic as well as the process development and scale-up points of view [3]. Isradipine is a dihydropyridine-class calcium channel antagonist. It binds to calcium channels with high affinity and specificity and inhibits calcium flux into cardiac and smooth muscle [4]. Isradipine is almost completely absorbed from the gastrointestinal tract after oral doses but undergoes extensive first-pass metabolism; the bioavailability is reported to be 15 to 24%. Peak plasma concentrations occur about 2 hours after oral dosage. About 70% of an oral dose is reported to be excreted as metabolites in urine, the remainder in faeces. The terminal elimination half-life is often stated to be about 8 hours although a value of less than 4 hours has also been reported [5, 6]. An obstacle to more successful use of Isradipine therapy is the high incidence of dizziness, flushing, headache, hypotension, peripheral oedema, tachycardia, and palpitations that often diminish on continued therapy. Side 118

2 effects and the need for administration two or three times per day when larger doses are required can decrease patient compliance. A sustained-release (SR) formulation that would maintain plasma levels of the drug for 24 hours might be sufficient for once-daily dosing of Isradipine. SR products are needed for Isradipine to prolong its duration of action and to improve patient compliance. Hence, in the present work, an attempt has been made to formulate the extended-release matrix tablets of Isradipine and tested for controlled delivery of drug using hydrophilic matrix material. 2.0 MATERIALS AND METHODS 2.1 Materials Isradipine was a gift sample from Glaxo Smith Kline Pharmaceuticals Ltd., (Nashik, India). HPMC (Hydroxy Propyl Methyl Cellulose) E50, HPMC 5 cps, HEC and HPC- LF were purchased from S. D. Fine Chem. Labs, (Mumbai, India). All other reagents and chemicals used were of analytical grade. 2.2 Methods Drug excipients compatibility study The pure drug and along with its formulation excipients were subjected to compatibility studies and studies were carried out by mixing definite proportions of drug and excipients. These mixtures were kept in a 5ml glass white colored vials and packed properly which are stored at 40 o C ±2 o C &75± 5%RH. 15gm of blend is prepared which is filled in 3 vials. Observations for physical appearance are made at initial, 2 week and 4week Preparation of Isradipine matrix tablets Six matrix embedded formulations of Isradipine were prepared by wet granulation method using varying proportion of polymers. The composition of various formulations of the tablets with their codes is listed in Table 1. Weighed the required quantities of lactose monohydrate and HEC as per given in the table separately and pass through #30 mesh followed by mixing. Prepare the drug Table 1. Compilation of Isradipine extended release matrix Tablets SL. F1 F2 F3 F4 F5 F6 CONTENTS NO. (mg/tab) (mg/tab) (mg/tab) (mg/tab) (mg/tab) (mg/tab) DRY MIX 1 Lactose mono hydrate HEC DRUG SOLUTION 3 Isradipine HPMC 5 cps IPA Q.S Q.S Q.S Q.S Q.S Q.S 6 DCM Q.S Q.S Q.S Q.S Q.S Q.S BINDER SOLUTION 7 HPC- LF PEG Purified water Q.S Q.S Q.S Q.S Q.S Q.S LUBRICANTS 10 Lactose monohydrate Aerosil Magnesium stearate Average weight (mg) solution and binder solution separately by using appropriate amount of Isradipine (10 mg) and other excipients. Co sifted mixture is loaded into Fluid Bed Processor CPM-HO (Pam Glatt Pvt. Ltd., Mumbai, India) top spray granulation bowl and prepared drug solution was added for granulation. Granulation was carried out at inlet temperature C, compressed using a 16 station rotary press CM D3-16 (Cadmch Machinery co. Pvt.Ltd, Ahmadabad, India) at a constant compression force equipped with a 8-mm standard concave punches at a compression force required to produce tablets of about 7 9 kg/cm 2 hardness. All the tablets were stored in airtight containers for further study. Prior to compression, granules were evaluated for their flow and compressibility characteristics. 2.3 Precompression Parameters Bulk and Tapped density [7] Both bulk and tapped densities were determined and expressed in gm/cm 3. The bulk density and tapped density product temperature C, spray rate gm/min, atomisation air pressure bar and blower drive speed 15-20%. Granules were dried at temperature at C until the LOD was obtained and were sized through #30 mesh. Magnesium stearate was added as lubricant; the appropriate amount of the mixture was weighed and then were calculated using the following equations. Bulk density = Tapped density = Compressibility index [8] The Compressibility index of the powder blend was determined by Carr s Compressibility index. The formula for Carr s index is as below. Carr s index (I) =

3 2.3.3 Hausner ratio [9] The Hausner ratio is an index of ease of powder flow. It is calculated by following equation. Hausner ratio = Angle of repose [10] The angle of repose of powder blend was determined according to fixed funnel and free standing cone method. Angle of repose (θ) was calculated using the following equation. tanθ = h/r Loss on drying 1.0g of sample of Isradipine was accurately weighed and the powder was kept in a moisture balance apparatus for 3 min. At 105ºC and the moisture content was calculated. 2.4 Post compression Parameters The prepared matrix tablets were characterized immediately after preparation for hardness, weight variation, thickness, friability and drug content. The weight variation of the tablets was evaluated (n=20) tablets using an electronic balance. The hardness of the tablets (n=6) was tested using a Monsanto hardness tester (Campbell Electronics, India). Friability (n=10) was determined in a Roche friabilator (Campbell Electronics, India) for 4 minutes at a speed of 25 rpm. The thickness of the tablets was measured by vernier caliper [11-13] Assay Assay is an indicative of the amount of the drug present in the dosage form. Here it gives the insight information about the substances of the process and about effect of changes. Decrease in assay % was insignificant and within limits for the formulations. Mobile phase: Prepared a mixture of 400ml Water, 500 ml of methanol, and 100 ml of tetrahydrofuran, (50:40:10) were mixed well. Filter through 0.45µm nylon membrane filter and degassed. Diluent: Mobile phase was used as diluent. Standard Stock solution preparation (2mg/mL): Transferred an accurately weighed amount of 20mg of working standard into a 100ml volumetric flask. 10ml of Acetonitrile added and sonicated for 5 minutes. Diluted to volume with diluent and mixed well. Preparation of diluted standard solution: Pipette 5ml of above standard stock solution into a 100ml volumetric flask and dilute to volume with dilute and filtered through 0.45 m nylon membrane filter. Test preparation: Transferred 5 tablets into 200mL of volumetric flask, 20 ml of acetonitrile added sonicated about 15 minutes. Diluted to volume with diluent and mixed well filtered through 0.45 µm nylon membrane filter. Chromatographic system Column : Kromasil C x 4.6 mm, 5 µm Flow rate : 1.7mL/min Wave length : 326 nm Column oven temperature : Ambient Injection volume : 25µL Run time : 15 minutes Procedure: Inject 25 µl portion of the dissolution medium as blank, standard preparation, test preparation into the chromatogram, record the chromatogram and measure the response for the analyte peak. Calculations for Assay Assay (mg/tab) = A T *Ws*TD*P*Avg Wt / A S *SD*W T *100 ASSAY (%) = Assay (mg/tab) *100 / L Where, A T = peak area of Isradipine for test preparation. A S = peak area of Isradipine for standard preparation. Ws = weight of Isradipine working standard taken in mg. P = potency of Isradipine working standard calculated as API. L = labeled amount of Isradipine working standard calculated as API. W T = weight of Isradipine tablet taken. SD = Sample dilution and TD= Test dilution In-vitro release studies The In-vitro release study was carried out using United States Pharmacopoeia (USP) XXIV or type II dissolution apparatus (Electrolab Ltd.). The rotating paddle method was used to study the drug release from matrix tablets. The dissolution medium consisted of 1000 ml of 0.2% LDAO (Lauryl Dimethyl Amine Oxide) in water. The release was performed at 37ºC± 0.5ºC, with rotation speed of 50 rpm. Samples (10 ml) were withdrawn at predetermined time intervals (2, 4, 6, 8, 10, 12, 16 & 24 hrs) and volume was replaced with the fresh medium. Preparation of Dissolution media (0.2% of 30% Lauryl Dimethyl amine oxide): Transferred 66.0 ml of 30 % Lauryl Dimethyl amine oxide in to 10 Lt of dearerated water and mixed well. Analysis of Samples by HPLC Method: Mobile phase: Prepared a mixture of 400ml Water, 500 ml of methanol, and 100 ml of tetrahydrofuran, (50:40:10) were mixed well. Filter through 0.45µm nylon membrane filter and degassed. Diluent: Dissolution media was used as diluent. Standard Stock solution preparation (2mg/mL): Transferred an accurately weighed amount of about 20mg of working standard into a 100ml volumetric flask 50ml of diluent added and sonicated for 5 minutes. Diluted to volume with diluents and mixed well. Preparation of diluted standard solution: Pipette 5ml of above standard stock solution into a 100ml volumetric flask and dilute to volume with dilute and filtered through 0.45 m nylon membrane filter. Test preparation: Transfer each tablet into each six dissolution vessels containing 1000ml of dissolution media. Withdraw the 10 ml of the sample from the dissolution at 2, 4, 6, 8, 10,12,16,24 hours. Chromatographic system: Column : Kromasil C x 4.6 mm, 5 µm Flow rate : 1.0 ml/min Wave length : 326 nm Column oven temperature : Ambient Injection volume : 25µL Run time : 8 minutes Procedure: Injected 25 µl portion of the dissolution medium as blank, standard preparation, test preparation into the chromatogram, record the chromatogram and measure the response for the analyte peak. 120

4 Table 2. Results of Compatibility study INITIAL FINAL OBSERVATION SL. RATIO NAME OF EXCIPIENT OBSERVATIO AT 40 C/75% RH NO. API: EXPT N 2 nd week 4 th week CONCLUSION 1 API (Isradipine) --- Yellow Yellow Yellow Compatible 2 API + Lactose monohydrate 1:1 Yellow Yellow Yellow Compatible 3 API + HEC 1:1 Yellow Yellow Yellow Compatible 4 API + HPMC 5cps 1:1 Yellow Yellow Yellow Compatible 5 API + HPC 1:1 Yellow Yellow Yellow Compatible 6 API + PEG-400 1:1 Yellow Yellow Yellow Compatible 7 API + Aerosil 1:0.5 Yellow Yellow Yellow Compatible 8 API + Magnesium stearate 1:0.5 Yellow Yellow Yellow Compatible Table 3. Precompression parameters of Granules Formulation Code Bulk Density (gm/cm 3 ) Tapped Density (gm/cm 3 ) Compressibility Index (%) Hausner s Ratio Angle of Repose (θ) F ± ± ± ± ± F ± ± ± ± ±1 1.8 F ± ± ± ± ± F ± ± ± ± ± F ± ± ± ± ± Loss on drying F ± ± ± ± ± All values are mean ± SD, n=3 densities & tapped densities for all the batches were found Calculations: Quantity of Isradipine dissolved in n th time interval as % of Labeled Amount = A T *Ws * P *5 * 1000 * 100 / A S * 100* 100 * 100 * L in the range of 0.364± to 0.353± g/cm3 and 0.385±0.024 to 0.367±0.014 g/cm3 respectively. The results of bulk density & tapped density were showed good flow properties of powder. This was further supported by Where, A T = peak area of Isradipine for test preparation, lower values compressibility index & Hausner s ratio. The in the nth time interval % Compressibility index was found to be in the range of A S = peak area of Isradipine for standard preparation ±0.537 to ±2.422 % for all the formulations Ws = weight of Isradipine working standard taken in mg. indicating good flow property. The values of Hausner s P = potency of Isradipine working standard calculated as ratio for all batches were below which indicates good API. flow property of the powder. The values of angle of repose L = labeled amount of Isradipine working standard for all the formulations were came below 31 which again calculated as API, n = 2, 4, 6, 8, 12, 16, 20 and 24 hrs indicate good flow property. Moisture content of less than Drug release kinetics 2% indicates optimum drying of granules. The details are The release kinetics such as zero order, first order, Higuchi, mentioned in Table 3. Korsmeyer-Peppas and Hixon-Crowell were determined 3.3 Tablet characteristics [16]. All the tablets with different proportion of polymer Stability Studies composition were within the weight range with SD values The optimized formulation of Isradipine extended release Tablets of all the batches passes the weight tablets was subjected to Accelerated stability at 40 C and variation test as the % weight variation was within the 75 % RH for period of two months. After each month tablet standard pharmacopoeial limits of ±7.5% of the weight. sample was analyzed for drug release profile [17]. The weights of all the tablets were found to be uniform 3.0 RESULTS AND DISCUSSION with low standard deviation values. The mean thickness of 3.1 Drug excipients compatibility study the tablets was uniform in all the batches and was found to From the above Drug Excipient compatibility studies be in the range of 3.33 mm to 3.55 mm. The hardness of data, it is clear that Isradipine is compatible with all the tablets of each batch ranged between 7.52±0.171 to excipients tested above. Physical observation of sample 8.94±0.285 kg/cm 2. This ensures good handling was done every week for any color change or lump characteristics for all batches. The Percentage friability for formation; the results of the physical observation are shown all formulations was found to be less than 1% in all the in Table 2. formulations ensuring that the tablets were mechanically 3.2 Precompression parameters stable. The percentages of drug content for all the batches The powder of all the formulations (F-1 to F-6) was were found to be in the range of 98.24% to % of evaluated for bulk density, tapped density, compressibility Isradipine, it complies with official specifications. The index, Hausner s ratio and angle of repose. The bulk details are mentioned in Table 4.

5 Table 4. Physical properties of the matrix tablets Formulation Code Hardness (kg/cm 2 ) Thickness (mm) Friability (%) Weight Variation (%) Drug Content (%) F1 8.76± ± ± ±0.30 F2 7.93± ± ± ±0.32 F3 8.03± ± ± ±1.10 F4 8.94± ± ± ±0.50 F5 7.74± ± ± ±0.27 F6 7.52± ± ± ± All values are mean ± SD Table 5. Comparative dissolution profile of F1 to F6 and Innovator product Sl. No. Time (hr) Mean % Drug Dissolved F1 F2 F3 F4 F5 F6 Innovator Table 6. Similarity factor (f 2 ) and Dissimilarity factor (f 1 ) of formulation F1 to F6 FORMULA F1 F2 F3 F4 F5 F6 Similarity factor (f 2 ) Dissimilarity factor (f 1 ) Table 7. Calculation of f 1 and f 2 of F6 with Innovator product DISSOLUTION PROFILE COMPARISON TIME (hrs) REFERENCE (R) F6 (T) [R-T] [R-T] 2 f 2 VALUE f 1 VALUE TOTAL In-vitro release studies The compressed tablets were evaluated for dissolution release profiles. It is carried out for 24 hrs study using USP-II (Paddle Type) apparatus. All the formulations were subjected to in vitro dissolution studies by comparing with marketed product (Reference-DYNACIRC). Filler was selected as lactose and HEC was selected as polymer to extend the release. Among all the six formulations, the release profile of trial F6 was found to be similar to the Marketed Product release profiles. The dissolution data of formulations and innovator are tabulated in Table 5. and Fig. 1. The dissolution profiles of formulations F1 to F6 and innovator product were compared by calculating differential factor (f1) and similarity factor (f2) in Table 6. Fig 1. Comparative dissolution profile of Formulation with Innovator and Table 7. The f1 and f2 were found to be 5 and 63 respectively for the comparison of dissolution profiles of 122

6 Table 8. Kinetics of Innovator product (R) and Test product (F6) Square Q 100-Q LOG Q LOG (100-Q ) Sl. Time LOG Root of No. (Hr) Time R F6 R F6 R F6 R F6 Time FORMULA ZERO ORDER FIRST ORDER HIGUCHI KORSEMEYER PEPPAS R 2 K 0 R 2 K 1 R 2 K R 2 n Reference F formulation F6 and innovator product. Hence these two products were considered to be similar. 3.5 Drug release kinetics In order to study the drug release mechanism of the examined tablet (F6), the dissolution profiles were analysed according to the zero-order, first-order, Higuchi s square root equations and Korsemeyer Peppas equation (Table 8. and Fig 2. to Fig 5.). Based on the n value of 0.87 obtained for F6 formulation, the drug release was found to follow Anomalous (non-fickian) diffusion. This value indicates a coupling of the diffusion and erosion mechanism (Anomalous diffusion) and indicates that the drug release was controlled by more than one process. Also, the drug release mechanism was best explained by Zero order equation, as the plots showed the highest linearity (r 2 = ), followed by Higuchi s equation (r 2 = ). As the drug release was best fitted in zero order kinetics, it indicated that the rate of drug release is concentration independent. Even the innovators product was found to follow the same pattern with highest linearity (r 2 = ) for zero order equation. Fig 2. Comparative Zero Order release profile of Reference and Test Formulation (F6) Fig 4. Comparative Higuchi release profile of Reference and Test Formulation (F6) Fig 5. Comparative Korsemeyer Peppas release profile of Reference and Test Formulation (F6) The r 2 value for Higuchi plot was found to be indicating that drug release included diffusion as one of the release mechanisms Testing Robustness of Test Formulation in Multi Media The dissolution profiles of formulation F6 and innovator product in multi media were compared by calculating similarity factor (f2). The f2 were found to 56, 71, and 67 in ph 4.5 acetate buffer, ph 6.8 phosphate buffer and 0.1N HCl respectively (Table 9. and Fig 6. to Fig 8.). As all these values are above 50, hence these two formulations are comparable. Fig 3. Comparative First Order release profile of Reference and Test Formulation (F6) Fig 6. Comparative dissolution profile of F6 with Innovator in ph 4.5 Acetate buffer 123

7 Table 9. Dissolution of F6 and Innovator product in multi media % Drug Release in ph 4.5 Acetate Buffer Sl. No. Time (hrs) % Drug Release in ph 6.8 Phosphate Buffer % Drug Release in 0.1N HCL R T R T R T f 2 Value Table 10. Accelerated stability data of F6 Formulation Sl. No. Time (hrs) % Drug Dissolved after 1 month % Drug Dissolved after 2 month Fig 7. Comparative dissolution profile of F6 with Innovator in ph 6.8 Phosphate buffer Fig 8. Comparative dissolution profile of F6 with Innovator in 0.1N HCl Fig 9. Dissolution profile of F6 after 1 and 2 Months 124

8 3.7. Accelerated stability studies The stability study for the selected formulation F6 was performed as per ICH guidelines. Stability study is carried out for 2 months at 40 C; 75%RH, according to ICH guidelines. The tablets were tested for release during the stability period and confirmed that results were found within the limits (Table 10). The stability data reveals that the F6 showed (Fig 9.) a negligible change in drug content after storage in various conditions for two months according to ICH guidelines. 4. CONCLUSION Formulation F6 containing Isradipine 10 mg per tablet and developed employing Lactose Monohydrate and Hydroxy ethyl Cellulose in dry mix is similar and equal to the innovator product in respect of all tablets properties and dissolution profile. No significant change was observed in the drug content, physical properties and dissolution rate of these tablets after the storage period of 2 months at 40 o c and 75%RH. Hence the study resulted in the development of Isradipine Matrix Release Extended tablets comparable to the innovator product for Isradipine fulfilling the objective of the study. The identified formula shall be utilized for the formulation development and other studies for successful launching of the product as it was proved to be stable and robust, cost effective compared to osmotic device. ACKNOWLEDGMENT The authors are thankful to GSK Pharmaceuticals Ltd., Nashik, India for providing Isradipine as gift sample and Moonray Institute of Pharmaceutical Sciences, Shadnagar, India for providing necessary facilities to carry out this work. REFERNCES 1. Y W Chien, Novel Drug Delivery Systems, 6 th ed. New York: Marcel Dekker; (1992) J M Vergnaud, Controlled drug release from oral dosage forms, London: Ellis Horwood Limited; L. Lachman, H. A. Lieberman, J. L. Kanig, The theory and practice of Industrial Pharmacy, 3 rd ed. Lea and Febiger: Philadelphia; (1986) Vijaya Kumar Bonthal, Buchi Babu Pabbu, Garrepally Prasad, Formulation and Evaluation of Isradipine Buccal Tablets, Research J. Pharm. and Tech. (2012) 5(9): G. M. Shenfield, The pharmacokinetics of isradipine in hypertensive subjects, Eur J Clin Pharmacol. (1990) 38: F. L. S. Tse, J. M. Jaffe, Pharmacokinetics of PN (Isradipine), a new calcium antagonist, after oral administration in man, Eur J Clin Pharmacol. (1987) 32: G.S. Bangale, Natural mucoadhesive materials based buccal tablets of Nitrendipine formulation and in-vitro evaluation, J. Pharm. Res. (2011) 4(1): L. Lachman, H.A. Lieberman, J.L. Kanig, The Theory and Practice of Industrial Pharmacy, 3rd ed. Bombay: Varghese Publishing House; (1987) S.K. Kar, R.N. Panigrahy, A.M. Mahale, Design and development of Indomethacin matrix tablet with ph modulated release kinetics, Int. J. Compreh. Pharma. (2011) 1(6): M.J. Swarbrick, A. Camarrata, Textbook of Physical Pharmacy, 3rd ed. Bombay: Varghese Publishing House, (1991) A.Martin, Micromeritics. In: Physical Pharmacy. ed. Philadelphia, PA: Lippincott Williams & Wilkins.(2001) J.Wells, Pharmaceutical Preformulation: The physiochemical properties of drug substances. In: Aulton, ME. ed. Pharmaceutics the science of dosage form design London:Churchill Livingstone.(2002) Ngangbam Birjit Singh, V. Venu, R. Sambath kumar, P. Perumal, Formulation and in- vitro evaluation of controlled release matrix tablets of Isradipine. IJPRD. (2011) 4(04): B. Wilson, H.S. Patel, M.S Sajeev, G. Vinothapooshan, Design and evaluation of sustained release matrix tablets of Levofloxacin for effective treatment of microbial infections. Int. J. Drug Dev. (2011) 3: Aditya et. al., Design and evaluation of controlled release mucoadhesive buccal tablets of Lisinopril. Int. J. Curr. Pharm. Res. (2010) 2(4): M. Chandira, Formulation and evaluation of mucoadhesive oral tablet of Clarithromycin. T. Pharm. Res. (2009) 2: Cartensen J.T., Drug Stability: Principle and Practices, 2 nd ed. New Work: Marcel Dakker; (1995) Source of support: Nil; Conflict of interest: None declared 125