Development and Evaluation of Sustained Release matrix Tablet of Nicorandil Mamta Arora, Delhi Institute of Pharmaceutical Sciences and

Research, New Delhi, India ABSTRACT The objective of the current study was to develop a matrix sustained release dosage form. The choice of the drug has been made by taking into consideration, the pharmacokinetic parameters of the Nicorandil, which makes it an ideal candidate for the preparation of sustained release dosage form. Matrix system are monolithic devices in which a drug is dispersed and embedded in a mass of retarding material. Drug release is dependent upon the properties of the drug and the retardant substance. Matrix system was chosen for the formulation of sustained release as it has the advantage of simple processing and low cost of fabrication. Combinations of various polymers are being used for fabrication of the matrix system. A survey of literatures showed that these materials have been extensively characterized for formulation of sustained release dosage form. Various combinations of these polymers have been used to formulate an ideal matrix formulation.The effect of change of drug : polymer ratio on in vitro profile has also been studied. The formulation was tested for the various physico-chemical parameters. As 80% of the drug is absorbed from the small intestine, mucoadhesive systems can also be added to localize the drug at a particular site this would significantly improve the extent of drug absorption. Key words: Xanthan Gum; Stearyl alcohol; matrix; controlled release matrices INTRODUCTION An appropriately designed controlled drug delivery system can be a major advance towards solving problems concerning the targeting of a drug to a specific organ or tissue and controlling the rate of drug delivery to the target tissue. Controlled or sustained release (SR) preparations using alternative routes have been formulated but the oral route still remains the most desirable. For obvious reasons, water soluble drugs are more difficult to deliver orally in sustained or controlled release manner than the lipophilic drugs. Various attempts have been made to regulate the release process by

incorporating hydrophobic fillers. The present study focuses on oral controlled release dosage forms. The use of controlled release technology in the formulation of pharmaceutical products has become increasingly popular in the last few years. The First theoretical formulation of sustained release dosage form was described in 1996 [1] Controlled release may be defined as a technique by which active chemicals are made available to a specified target at a rate and duration designed to accomplish an intended effect. More specifically, an oral controlled release drug delivery system is a dosage form that controls drug release into the absorption site in the gastrointestinal tract (GIT). It controls the drug absorption rate to achieve the desired plasma profiles defined by the steady state pharmacology. A typical controlled release system is designed to provide constant or nearly constant drug levels in plasma with reduced fluctuation via slow release of drug over an extended period of time. A pharmaceutical model of SR preparation involving first process for drug release, absorption and elimination with change in their relative rates for different drugs was developed in 1966[2] The advantage of an ideal Controlled release dosage form over an immediate release product include improved patient compliance due to a reduced dosing frequency, avoidance of side effects, a greater selectivity of pharmacological activity and a more constant therapeutic effect, as well as an increase of cost effectiveness. Nicorandil is a nicotinamide ester and a vasodilator agent with a compound and balanced mechanism of action as a potassium channel activator with nitrate effects. Aim of this study was to formulate and to optimize matrix tablet of Nicorandil, an anti-anginal drug. The drug was first introdued in 1979[3,4] as a coronary vasodilator for angina pectoris is currently being used for prevention and long-term treatment of unstable angina. The drug is 100% bioavailable on oral administration[5] . Matrix tablet was chosen for formulation of sustained release as it has the advantage of simple processing and low cost of fabrication[6] Once daily sustained release matrix tablets of Nicorandil by wet granulation method was developed in 2003[7] Nicorandil was analyzed by HPTLC method[8]. Polymers and their applications in various sustained release systems, including matrix formulations were reviewed in 1988[9]

MATERIALS AND METHODS Xanthan gum and HPMC were purchased from Colorcon Asia Pvt. Ltd, Stearyl alcohol was purchased from CDH (P) Ltd, New Delhi and ethanol from Binra Brothers , New Delhi. Guar Gum and Carbopol were gift samples from ranbaxy Lab. Ltd. Gurgaon. Chloroform was purchased from CDH (P) Ltd. New Delhi, Ammonia and Methanol were purchased from Loba Chemie Pvt. Ltd. Mumbai. Nicorandil was kind gift from cadila Healthcare Ahmedabad. All chemicals were of analytical quality. Formulation of Layered Matrix Tablets Matrix tablet of Nicorandil were prepared varying the type and proportions of various polymers until a formulation could be optimized for desired sustained release action [stearyl Alcohol with guar gum, Xanthan Gum, and Carbopol, Hydroxy Ethyl Cellulose(HEC) and Hydroxyl Propyl Methyl Cellulose (HPMC)] (Table 1) . the drug load in all tablets was 15 mg/tablet. Tablet weight was adjusted to 150 mg. Combination of Stearyl Alocohol with Xanthan Gum Nicorandil and Xanthan Gum were accurately weighed and dry mixed. To this mixture ethanol was added dropwise and dough was prepared. This mass was passed through sieve no. 16 followed by sieve of mesh no. 20 to get the granules of desired size. Then stearyl alcohol was accurately weighed and kept in oven to form its semisolid mass. This mass was passed through sieve no. 16 followed by sieve of mesh no. 20 to get the granules of desired size. First of all, stearyl alocohol granules were poured in dye then granules of Nicorandil and Xanthan Gum were poured then again granules of stearyl alcohol were added to dye in order to form triple layer matrix tablet of Nicorandil. Compression was performed on a single station tabletting machine with 8 mm round punches to prepare tablets of weight 150 mg. Physico-chemical Evaluation of Tablets Weight variation, hardness, diameter and drug content of the tablet were found out. Each tablet was weighed and the average weight was determined. Strong Cobb hardness tester was used to test the hardness of the matrix

tablet. The diameter of the tablet was determined using a Screw gauge micrometer. The drug content of the tablets was determined by preparing the standard curve of the drug in distilled water. The tablets were placed in 50 ml of distilled water in a beaker and kept on a shaker (200 rpm) overnight at 37o C. after 24 hrs, the aliquots from the filtered solution were analyzed spectrophotometrically at 262.5 nm. The drug content was represented as average drug loading (Table 2) In - Vitro release studies The in vitro dissolution studies were performed on a tab India dissolution apparatus (Disso 2000), Lab India Pvt. Ltd. Mumbai. The formulation coded as A1 was evaluated for its release profile using USP type 11 apparatus. Dissolution Medium was SGF for the first two hours and SLF for the rest of the time. Sample volume and replacement volume was 10 ml. Temperature was maintained at 37+0.5 o C, speed was 50 rpm, paddle depth was 25 mm, Dissolution medium volume was 900 ml and amber colored sampling bottle were used. The samples were analyzed using double beam spectrophotometer(Shimadzu 1601). The absorption maximum in pH 1.2 and ph 6.8 was 262 nm. Plots were drawn between the % amount of drug released versus time for all the matrix tablets (Figure1) In -Vivo Evaluation Based on in vitro performance, the selected formulation coded as A1 was evaluated in rabbits to compare the blood level profiles of the formulation with profiles obtained after oral administered aqueous solution of the drug in rabbits. Rabbits of 2.0-2.5 kg of either sex were kept in normal housing conditions and were fed with commercially available diet, sprouted grams and cabbage. Rabbits were starved 24 hrs before the administration of the sample. Two groups were formed, each containing six animals. First group was given the matrix tablets and second group was given the aqueous drug solution. Blood samples were withdrawn from the marginal ear vein at given intervals in a syringe having 0.4 ml of sodium citrate and then transferred to apphindroffs tubes, 0.5 ml of ethyl acetate was added. The samples were centrifuged at 3000 rpm for 40 minutes at 4 o C . The plasma obtained was separated and and kept frozen until analyzed.

Table 1. Formula for the Matrix Tablet.

Constituents Formulation Code A1 Stearyl 100 Alcohol Xanthan 100 Gum Guar Gum Carbopol HEC HPMC Nicorandil 15

A2 100 100 15

A3 100 100 15

A4 100 100 15

A5 100 100 15

Table 2. Physico- Chemical evaluation of layered matrix formulations: Formulation Average Code hardness (kg/cm) A1 6.52+0.1 6 A2 6.38+0.1 8 A3 6.43+0.5 4 A4 6.41+0.4 4 A5 6.35+0.3 5 Friability Average weight(mg ) 0.49 147.9+0.5 7 0.42 148.4+0.4 8 0.45 146.8+1.0 3 0.48 148.5+0.6 7 0.46 152.4+0.5 8 Disinteg Average drug Thickness -ration content(mg) (mm) Time 14.8+10.06 3.74+0.07 14.98+0.18 15.05+0.07 15.0+0.16 15.04+0.12 3.68+0.16 3.84+0.14 3.84+0.06 3.72+0.11

Table 3 : Regression Coefficients for Zero order, First order and Higuchi plots of in vitro release study Formulation Code Zero Order First Order Higuchi Regression Regression Regression Coefficient Coefficient Coefficient A1 0.9546 0.249 0.9742 A2 0.5534 0.7115 0.6415 A3 0.5918 0.7004 0.7136 A4 0.5207 0.6982 0.5636 A5 0.4561 0.7257 0.4588 Based on Physico-chemical properties, tablet A1 possessed the need of an ideal matrix tablet. So, it was selected as the optimized tablet and was further subjected to in- vivo studies. In- Vivo Evaluation The batch of matrix tablet A1 was selected for in vivo studies. Twelve healthy albino rabbits were selected for the studies, which were divided into 2 groups. First group was given the optimized formulation of matrix tablet (A1) containing 15 mg of the drug; the second group was given the aqueous solution of drug equivalent to 5 mg/4ml. The blood samples were withdrawn from the marginal ear vein of the animals. Results and Discussion: Gums from natural sources hydrate and swells on contact with water and these have been used for preparation of single unit sustained release dosage forms.[10] There have been numerous attempts at matrix systems impregnating active principles in wax. [11,12,13] All the tablets were subjected to in vitro release study. The comparative in vitro release profile of tablets is shown in Figure 1. From the in vitro release data, kinetics of drug release was found for Zero order, first order and Higuchi type release kinetics. The regression coefficients of each of this kinetics were calculated and compared (Table 3). The data revealed that the release pattern of the patches was best fitted for Higuchi kinetics because the

Higuchi regression coefficient values predominate over the zero and first order values

Figure 1. Comparative Drug release profile of all matrix formulations

Figure 2. Comparative plot of in vivo release profile for A1 and Aqueous solution of drug.

Table 4. Plasma Concentration in Rabbits after administration of A1 and aqueous solution of drug. S. No. Time Plasma Concentration of Nicorandil (ng/l) (hrs.) Aqueous Solution A1 1 0 0.00+ 0.00 0.00+ 0.00 2 2 66.34+ 1.02 66.59+ 1.34 3 4 68.21+ 0.23 72.58+ 1.02 4 8 81.54+ 1.48 71.93+ 0.25 5 16 73.49+ 0.69 76.45+ 0.97 6 22 81.42+ 0.98 78.18+ 1.55 7 24 90.08+ 1.36 99.65+ 1.36 8 41 24.10+ 1.65 65.32+ 1.92

Table 5 . Comparative Pharmacokinetic Data for the formulations A1 and aqueous solution of the drug. Data A1 Drug Solution Conclusions It is concluded from this study that among the various formulations of Nicorandil, formulation coded as A1 found to be better during physicochemical characterization and in vivo release studies. Acknowledgements The authors would like to thank Cadila Healthcare for the donation of Nicorandil. One of the author (Mamta Arora) wishes to thank AICTE for financial support. References 1. Robinson, J.R .; Eriksen, S.P. Theoretical formulation of sustained release dosage forms. J.Pharm. Sci. 1966, 55, 1254-1263 2. Kruger-Thiemer,E.;Eriksen,S.P Mathematical model for sustained release preparations and its analysis. J.Pharm. Sci. 1966,55,12491253. 3. Tiara, N.;Satoh,K.;Yanagiswar,T.; Imai, Y.;Hiwatari, M. Pharmacological profile of a new coronary vasodilator drug, 2nicotinamidoethyl nitrate (SG-75) Clin. Exp. Pharmacol.Physiol.1979,6,301-316. 4. Uchida,Y.;Yoshimoto,N.;Murao,S.Effect of 2-nicotinamidethyl nitrate (SG-75) on coronary circulation. Japan Heart J. 1978.19,112-124. 5. Frydman,A. Pharmacokinetic profile of Nicorandil in humans an overview. J. Cardivasc.pharmacol.1992,20(3),534-544. 6. Qui,Y.; Hui, H.W.; Cheskin, H. Formulation development of sustained release hydrophilic matrix tablets of zileuton. Pharm. Dev. Techno. 1997,2 (3), 197-204. Cmax(ng/l) 90.08 99.65 Tmax(hrs.) 24.00 24.00 AUC 2727.29 3132.25

7. Reddy, K.R. Development of once daily-sustained release matrix tablets of nicorandil by wet granulation method: Formulation and in vitro Evaluation. AAPS Pharm Sci. Tech. 2003,4(4), article 61. 8. Patel, C.N. Development of a simple and sensitive method for the determination of content uniformity of Nicorandil tablets. Indian J. Pharm. Sci. 2002, 64 (4), 362-366. 9. Ranga Rao, K.V.; Padmalatha Devi, K. Swelling controlled release systems: recent developments and applications. Int. J. Pharm. 1998, 48, 1-13. 10. Nakano, M.; Ogata, A. Examination of natural gums as matrices for sustained release of theophylline. Chem. Bull. 1984, 32(2), 782-785. 11.Draper, E.B.; Becker, C.H. some wax formulations of a sulfa ethyl thiadiazole produced by aqueous dispenser for prolonged release medication. J. Pharm. Sci. 1966, 55, 376. 12. Raghunathan, Y.; Becker, C.H. Spray congealed formulations of sulfa ethyl thiadazole and waxes for prolonged release medication: effect of modifiers. J. Pharm. Sci.. 1968, 57, 1748. 13.Cusimano, A.G.; Becker, C.H. Spray congealed formulations of sulfaethylthiadiazole and waxes for prolonged release medication: effect of wax. J. Pharm. Sci. 1968, 57, 1104.