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Somnath Sakore and Bhaswat Chakraborty, Int J Pharm Biomed Res 2013, 4(1), 21-26                          22              ...
Somnath Sakore and Bhaswat Chakraborty, Int J Pharm Biomed Res 2013, 4(1), 21-26                         23               ...
Somnath Sakore and Bhaswat Chakraborty, Int J Pharm Biomed Res 2013, 4(1), 21-26                                          ...
Somnath Sakore and Bhaswat Chakraborty, Int J Pharm Biomed Res 2013, 4(1), 21-26                                25        ...
Somnath Sakore and Bhaswat Chakraborty, Int J Pharm Biomed Res 2013, 4(1), 21-26                                  26      ...
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Formulation and Evaluation of Enalapril Maleate SR Matrix Tablets


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Formulation and Evaluation of Enalapril Maleate SR Matrix Tablets

  1. 1. Available online at International Journal of PHARMACEUTICAL AND BIOMEDICAL Int J Pharm Biomed Res 2013, 4(1), 21-26 RESEARCH ISSN No: 0976-0350 Research article Formulation and evaluation of enalapril maleate sustained release matrix tablets Somnath Sakore*, Bhaswat Chakraborty Cadila Pharmaceuticals Ltd, Research & Development, Survey no. 1389, Trasad Road, Dholka, Ahmedabad- 387 810, Gujarat, India Received: 06 Dec 2012 / Revised: 30 Dec 2012 / Accepted: 10 Jan 2013 / Online publication: 31 Jan 2013 ABSTRACTGALLEY PROOF The aim of the present research work was to develop and evaluate the sustained release matrix tablets of enalapril maleate. The tablet was formulated using HPMC KM and HPMC K15 M polymers by wet granulation method. In vitro drug release study was carried out in simulated gastric fluid (0.1 N HCl) for the first 2h and in phosphate buffer (pH 6.8) for the next 3h following USP apparatus II paddle method. An independent model method, Lin Ju and Liaw’s similarity factor (ƒ2) were used to compare various dissolution profiles. In order to describe the enalapril maleate release kinetics from individual tablet formulations, the corresponding dissolution data were fitted in various kinetic dissolution models: zero order, first order, Higuchi, Korsmeyer Peppas and Hixon Crowell. The results indicated that the drug release characteristics from HPMC polymer matrices follow Higuchi square root time kinetics and the mechanism of drug release was both diffusion and erosion. Key words: Oral dosage form, Controlled drug release, Half-life, HPMC KM, Release kinetics 1. INTRODUCTION utilization of existing conventional equipment and methods [3]. HPMC most widely used as the gel forming agent in the Oral dosage forms has long been the most popular and formulations of solid, liquid, semisolid and controlled release convenient route of drug delivery. Various types of modified dosage forms. The adjustment of the polymer concentration, release formulations have been developed to improve the the viscosity grades and the addition of different types and patient compliance and also clinical efficacy of the drug. The levels of excipients to the HPMC matrix can modify the drug sustained release oral dosage forms have been demonstrated release rates [4]. to improve therapeutic efficacy by maintaining steady state Drug release from dosage form like tablets capsules, and drug plasma concentration. granules shows complex interaction between mechanisms Nonionic cellulose ethers and hydroxypropyl methyl like wetting, capillary penetration, swelling, disintegration cellulose (Hypromellose, HPMC) have been widely studied diffusion, dissolution, erosion etc. These processes are for their application in oral sustained release formulations mainly depends on type, quantity and properties of the drug [1]. Such hydrophilic polymers are most popular because of and excipients as well as manufacturing processes. Polymer their flexibility to get a desirable drug release profile, cost dissolution, erosion in solvent is an important area in drug effectiveness and broad regulatory acceptance [2]. HPMC has delivery system, which allows for optimization of design and always been a first choice for formulation of hydrophilic processing of drug dosage form as well as selection of matrix systems, because of providing robust mechanism, suitable excipients. The ideal drug delivery system is one choice of viscosity grades, nonionic nature, consistent which provides the drug only when and where required and reproducible release profiles, cost effectiveness and in minimum dose is required to give the desired therapeutic. When the dosage form introduced into the solvent, swelling occur allowing increased mobility of drug and it *Corresponding Author. Tel: +91 2714 221481 Fax: +91 2714 220315 Email: diffuses out of polymer in the surrounding fluid. Various mathematical models can be applied to the dissolution profile ©2013 PharmSciDirect Publications. All rights reserved.
  2. 2. Somnath Sakore and Bhaswat Chakraborty, Int J Pharm Biomed Res 2013, 4(1), 21-26 22 to describe the mechanism and kinetics of dissolution compression. Prior to compression, the granules were process, whereas, it is quite difficult to create mathematical evaluated for several tests. In all formulations, the amount of equations due to different dissolution curves shows very the active ingredient is equivalent to 20mg of enalapril different shapes. maleate (Table 1). The hypertensive patients are more prone to morning surge in blood pressure and hypertensive attacks during morning hours between 5 a.m. to 9 a.m. The development Table 1 Formulation of HPMC K4M and K15 M based enalapril maleate sustained sustained release tablets of enalapril are expected to avoid release matrices acute overdose, and to prevent morning hypertension [5]. The Formulation Enalapril maleate HPMC K4M HPMC K15M other advantages of sustained release dosage forms are code (mg) (mg) (mg) patient compliance, reduction of local and systemic side F1 20 -- 15 F2 20 15 15 effects, minimization of peaks and valleys in drug blood F3 20 20 15 levels [6]. F4 20 20 10 Enalapril, an orally-active, long-acting, nonsulphydryl F5 20 15 15 F6 20 15 10 angiotensin-converting enzyme (ACE) inhibitor, is F7 20 12.5 12.5 extensively hydrolyzed in vivo to enalapril at its bioactive F8 20 15 17.5 F9 20 10 15 form. Bio activation probably occurs in the liver. Metabolism F10 20 10 12.5 beyond activation to enalapril is not observed in man. F11 20 15 20 Administration with food does not affect the bioavailability of enalapril; excretion of enalapril and enalapril at is primarily renal. Enalapril reduces blood pressure inGALLEY PROOF hypertensive patients by decreasing systemic vascular 2.3. Angle of repose resistance. The blood pressure reduction is not accompanied by an increase in heart rate. Furthermore, cardiac output is The angle of repose of granules was determined by the slightly increased and cardiovascular reflexes are not funnel method. The accurately weighed granules were taken impaired [7]. in funnel. The height of the funnel was adjusted in such a In the present work, enalapril maleate sustained release way that the tip of the funnel just touched the apex of the matrix system has been developed using HPMC KM and heap of the granules. The granules were allowed to flow from HPMC K15 M polymers by wet granulation method. In order the funnel on the surface. The diameter and height of the to compare the dissolution profiles, Lin Ju and Liaw’s heap formed from the granules were measured. The angle of similarity factor (ƒ2) was used. In order to describe the repose was calculated using following formula [8]: release kinetics and the mechanism of drug release, Tan Ѳ= h/r ………………………………………. Eqn.(1) dissolution data were fitted in various kinetic dissolution Where, “h” is height of the heap and “r” is the radius of the models: zero order, first order, Higuchi, Korsmeyer Peppas heap of granules. and Hixon Crowell. 2.4. Carr’s compressibility index 2. MATERIALS AND METHODS The Carr’s compressibility Index was calculated from 2.1. Chemicals and reagents Bulk density and tapped density of the granules. A quantity of 2g of granules from each formulation, filled into a 10mL Enalapril maleate was a gift sample from Cadila of measuring cylinder. Initial bulk volume was measured, and Pharmaceuticals, Ahmedabad. All other chemicals used were cylinder was allowed to tap from the height of 2.5cm. The of analytical reagent grades. tapped frequency was 25±2 per min to measure the tapped volume of the granules. The bulk density and tapped density 2.2 Preparation of tablets were calculated by using the bulk volume and tapped volume. Carr’s compressibility index was calculated by using Different tablets formulations were prepared by wet following formula [9]: granulation technique. All powders were passed through 60 Carr’s compressibility index (%) = mesh. Required quantities of drug and polymers were mixed [(Tapped density-Bulk density) X100]/Tapped density thoroughly, and sufficient quantity of isopropyl alcohol and ……….. Eqn.(2) methylene dichloride was added slowly as granulating fluid. Dummy granules were added to improve flow property of 2.5. Evaluation of tablets granules. The granules were passed through 22/44 mesh and dried at room temperature for 12h. Magnesium stearate was The weight of tablets was evaluated on 20 tablets using an added as lubricant. Lactose was used as diluents, Starch paste electronic balance. The flow properties were measured by is used as binder for granules. Finally were subjected to Carr’s compressibility index, Friability was determined using
  3. 3. Somnath Sakore and Bhaswat Chakraborty, Int J Pharm Biomed Res 2013, 4(1), 21-26 23 6 tablets in Roche friability tester at 25rpm. Hardness of the Q0= is the initial concentration of drug tablets was evaluated using an ERWEKA hardness tester k= is the first order rate constant (Erweka GmbH, Germany). The hardness of all the t =release time formulation was between 4-6kg/cm2. (iii) Higuchi kinetics 2.6. In vitro dissolution studies Q=kt1/2………………………...…Eqn.(5) Where, In vitro drug release studies from the prepared matrix k= Release rate constant tablets were conducted using USP type II apparatus at 37°C t=release time, Hence the release rate is proportional to the at 50rpm. Dissolution mediums used were 900mL of 1.0N reciprocal of the square root of time. HCl and phosphate buffer of pH 6.8. The release rates from matrix tablets were conducted in HCl solution (pH 1.2) for 2h (iv) Hixon Crowell cube root law and changed to phosphate buffer (pH 6.8) for further time Q 01/3- Q t1/3=K HC t………...……Eqn.(6) periods. The samples were withdrawn at desired time periods Q t= the amount of drug release at time t from dissolution media and the same were replaced with Q 0= initial amount of drug in tablets fresh dissolution media of respective pH. The samples were K HC= rate constant for Hixon Crowell. analyzed by HPLC. The amounts of drug present in the samples were calculated with the help of appropriate (v) Korsmeyer-Peppas calibration curves constructed from reference standards. Drug First 60% in vitro release data was fitted in equation of dissolved at specified time periods was plotted as percent Korsmeyer et al. to determine the release behavior from release versus time curve. controlled release polymer matrix system. The equation isGALLEY PROOF also called as power law, 2.7. Dependent-model method (Data analysis) Mt /M∞ =Kt n …………………… Eqn.(7) Where, In order to describe the enalapril maleate release kinetics Mt = amount of drug released at time t from individual tablet formulations, the corresponding M∞ = amount of drug released after infinite time dissolution data were fitted in various kinetic dissolution Mt /M∞ = fraction solute release models: zero order, first order, Higuchi, Korsmeyer Peppas t = release time and Hixon Crowell. When these models are used and K = kinetic constant incorporating structural and geometric analyzed in the preparation, the rate constant obtained from characteristics of the polymer system these models is an apparent rate constant. The release of n = diffusional exponent that characterizes the mechanism of drugs from the matrix tablets can be analysed by release the release of traces. kinetic theories [10-14]. The magnitude of the release exponent “n” indicates the To study the kinetics of drug release from matrix system, release mechanism (i.e. Fickian diffusion, Non Fickian, the release data were fitted into Zero order as cumulative supercase II release). For matrix tablets, values of n of near amount of drug release vs. time (Eqn.3), first order as log 0.5 indicates Fickian diffusion controlled drug release, and an cumulative percentage of drug remaining vs. time (Eqn.4), n value of near 1.0 indicates erosion or relaxational control Higuchi model as cumulative percent drug release vs. square (case II relaxational release transport, non Fickian, zero order root of time (Eqn.5), Hixon-Crowell cube root law as cube release) [15-16]. root of percent drug remaining vs time (Eqn.6). To describe Values of n between 0.5 and 1 regarded as an indicator of the release behavior from the polymeric systems, data were both diffusion and erosion as overall release mechanism fitted according to well known exponential Korsmeyer – commonly called as anomalous release mechanism [17]. The Peppas equation as log cumulative percent drug release vs values of n and k are inversely related. A very high k values log of time equation (Eqn.7). may suggest a burst drug release from the matrix [18,19]. (i) Zero order kinetics 2.8. Independent-model method (Data analysis) Qt=K0t……………………………Eqn.(3) Where, The dissolution profile was statistically analyzed by using Q= Amount of drug release in time t dissolution similarity factor (f2), which was calculated by the K0 = Zero order rate constant expressed in unit of following formula: concentration /time t = Release time ƒ2 = 50 × log {[1 / (1 + (Σ (Rt - Tt) 2) / n)] 1/2 × 100}…Eqn.(8) (ii) First order kinetics Where, Log Q=Log Q0-kt/2.303…………Eqn.(4) n=Number of dissolution time that Where, Rt=Reference dissolution value at time t
  4. 4. Somnath Sakore and Bhaswat Chakraborty, Int J Pharm Biomed Res 2013, 4(1), 21-26 24 Tt = Test dissolution value at time t F1, F2, F3, F4, F5, F6, F7, and F8 were found to be out of the In vitro release profile of test formulation was compared target release profile during first 1h. The drug release was with the desired theoretical dissolution profile. The f2 value comparatively slower than the target profile. This might be between 50-100 ensures sameness and equivalence between due to use of higher proportion of HPMCK4M to two dissolution profiles. HPMCK15M polymers. However F9 and F10 showed the proper dissolution profiles which were required for target 3. RESULTS AND DISCUSSION release profile of enalapril maleate for 5h. 3.1. Physical characteristics of granules and tablets The granules of different formulations were evaluated for angle of repose, Carr’s compressibility index etc (Table 2). The results of Angle of repose and Carr’s compressibility Index (%) ranged from 22-27 and 16-24, respectively. Which showed that granules from all the formulations having good flow property. The hardness and percentage friability ranged from 4-6kg/cm2 and 0.64-0.81% respectively. Table 2 Physical properties of enalapril maleate granules and tabletsGALLEY PROOF Formulation code Friability (%) Angle of repose Carr’s index F1 0.64 22 16 F2 0.72 24 20 Fig.1. Zero order release plot for enalapril maleate matrix tablets F3 0.69 23 18 F4 0.67 25 19 F5 0.71 23 21 F6 0.63 28 24 F7 0.69 27 23 5 F8 0.66 23 17 F1 4.5 F9 0.73 22 16 F2 F10 0.63 25 15 4 Log % Drug Remaining F3 F11 0.62 22 17 3.5 F4 3 F5 2.5 F6 2 F7 1.5 F8 3.2. In vitro dissolution studies 1 F9 0.5 F10 Enalapril maleate sustained release tablets were prepared 0 F11 by using HPMC polymers. The release profiles of enalapril 0 2 4 6 maleate sustained release tablets were plotted as Fig.1-5. The Time (h) release rate of enalapril maleate mainly controlled by the Fig.2. First order release plot for enalapril maleate matrix tablets hydration and swelling properties of HPMC which forms a gel layer that controls the water penetration and drug diffusion. The effect of polymer concentration on drug release could be clearly seen from the variation of the dissolution profiles. It was found that drug release from F1 and F2 composed of HPMC single polymer was no longer than 2.5h, and significantly higher drug release rate than other formulation which were prepared by using combination of HPMC K4M and HPMC K15 M. Formulations F3 to F11 shows different release rate profile up to 5h period. Formulation F3 and F8 shows less than 70% drug release in 2h. However other formulation shows more than 80% of drug release within first 2h, which is due to higher amount of drug release retarding polymers. The release rate decreased significantly and the drug release prolonged as the polymer concentration was increased. The release profiles were Fig.3. Higuchi release plot for enalapril maleate matrix tablets compared with target release profiles. The release profiles of
  5. 5. Somnath Sakore and Bhaswat Chakraborty, Int J Pharm Biomed Res 2013, 4(1), 21-26 25 viscosity of the polymers which is higher as the molecular weight polymer increases. If the viscosity of the polymer increases the gel layer viscosity also increases so that the gel layer becomes resistant to diffusion and erosion. The release rate therefore decreases. Different levels of methyl and hydroxypropoxy substitution resulted in intrinsically different hydration rates, which affected the performance of the polymer in the initial stages of tablet hydration. When glassy polymer comes into contact with water or any other medium with which it is thermodynamically compatible, the solvent penetrates into the free spaces on the surface between macromolecular chains. When enough Fig.4. Hixon Crowell release plot for enalapril maleate matrix tablets solvent has entered into the matrix, the glass transition temperature of the polymer drops to the level of the experimental temperature (which is usually 37°C). The presence of solvent in the glassy polymer causes stresses, 5 which are then accommodated by an increase in the radius of F1 4.5 the gyration and end to end distance of the polymer F2 4 molecules. i.e., the polymer chains get solvated. The solvent F3 3.5 molecules move into the glassy polymer matrix. The F4 thickness of the swollen or rubbery region increases withGALLEY PROOF 3 Log % Release F5 2.5 time in the opposite direction. This phenomenon is a F6 2 characteristic for that particular polymer/solvent system. F7 F8 1.5 1 3.3. Influence of ionic strengths on drug release F9 F10 0.5 0 The release rate of drug is known to be affected by F11 ‐1.5 ‐1 ‐0.5 0 changing the pH of dissolution medium although HPMC Log time hydration and gel formation is not affected by changes in pH. Fig.5. Korsmeyer Peppas release plot for enalapril maleate matrix tablets Bravo et al [20], studied the effect of pH on diclofenac sodium release from HPMC matrices. Study showed the release rate of diclofenac sodium was extremely slow in acidic pH, since after 2h only 1% of drug was released and The hydration rate of HPMC depends on the nature of the showed faster drug dissolution rates at pH 6.8. substituent like hydroxypropyl group contents. HPMC K4M Various attempts have been made to quantify the and HPMC K15M are having viscosity 4000cps and influence of the solution containing phosphate and chloride 15000cps respectively, which forms a strong viscous gel in ions at different ionic strengths on dissolution rates from contact with aqueous media, which controls the release rate HPMC SR tablets. In this study effect of phosphate buffer on of enalapril maleate. For formulation F3, F4, F8 containing drug release from HPMC matrices have been studied. No highest amount of polymer shows more controlled release of significant changes in drug dissolution in buffer compared to drug in both pH 1.2 and distilled water. This may be owing to water medium observed for enalapril maleate. a more rigid complex formed by presence of higher proportion of HPMC K4M and HPMC K15M which helped 3.4. Release kinetics in retaining the drug in matrix and did not allow rapid diffusion of drug from matrix. The best fit with higher correlation coefficient was found The rate and amount of drug release were decreased with with Higuchi model which indicates that the amount of drug increasing the amount of HPMC polymers. This polymers release is proportional to the square root of total amount of ability to retard the drug release rate is depends on its drug in tablet and solubility of drug in polymer matrix and viscosity. The increase in polymer content decreases the total time. (Fig.3) The rate of release can be altered by increase or porosity therefore drug release extended for prolonged period decrease in the drug solubility and concentration of drug in because decreased porosity have lower lateral area. The matrix system. The drug release mechanism based upon release rate decreased significantly and drug release retarded entrance of the surrounding medium into a polymer matrix as the polymer proportion was increased. where it dissolves and leaches out the soluble drug, leaving a The drug release became sustained with increasing HPMC shell of polymer and empty pores. Depletion zone moves to concentration because of poorer wetability, slower hydration the centre of the tablet as the drug released. Since the and formation of gelatinous layer. Another important factor is boundary between the drug matrix and the drug depleted
  6. 6. Somnath Sakore and Bhaswat Chakraborty, Int J Pharm Biomed Res 2013, 4(1), 21-26 26 matrix recedes with time and the thickness of the empty 4. CONCLUSIONS matrix through which drug diffuses also increases with time. As the drug passes out of a homogeneous matrix, the The sustained release tablets of enalapril maleate were boundary of the drug moves to the inside by an infinitesimal prepared successfully using HPMC polymer of different distance. viscosity. According to in vitro release studies, the release rate was decreased with increasing viscosity and amount of polymer. The results of the study clearly demonstrated that Table 3 HPMC matrix tablet formulation is an effective and Release kinetics of enalapril maleate sustained release tablet formulations promising drug delivery system for once daily administration Formulation Zero First Hixon Higuchi Korsmeyer of enalapril maleate. order order Crowell Peppas The analysis of the release profiles in the light of distinct F1 0.803 0.962 0.549 0.957 0.988 F2 0.633 0.887 0.460 0.992 0.983 kinetic models (zero order, first order, Higuchi, Korsmeyer F3 0.895 0.979 0.583 0.976 0.994 Peppas and Hixon Crowell) led to the conclusion that, the F4 0.861 0.972 0.550 0.969 0.983 F5 0.835 0.969 0.478 0.969 0.989 drug release characteristics from HPMC polymer matrices F6 0.82 0.953 0.525 0.930 0.834 follows Higuchi square root time kinetics and the mechanism F7 0.798 0.947 0.583 0.986 0.976 F8 0.900 0.967 0.593 0.974 0.966 of drug release was both diffusion and erosion. F9 0.800 0.964 0.484 0.984 0.995 F10 0.796 0.961 0.478 0.986 0.987 REFERENCES F11 0.842 0.970 0.549 0.989 0.987 [1] Rajabi-Siahboomi, A.R., Jordan, M.P., Eur Phar Rev 2000, 5, 21-23. [2] Lordi, N.G., Sustained release dosage form. In: The Theory and Practice of Industrial Pharmacy, 3rd Edn., Lea and Febiger,GALLEY PROOF Philadelphia, USA, 1986. To confirm the mechanism of drug release, dissolution [3] Reddy, K.R., Mutalik, S., Reddy, S., AAPS Pharm Sci Tech 2003, 4, Article 61. data was fitted into Korsmeyer Peppas equation (Fig.5). All [4] Bravo, S.A., Lamas, O., Salomon, C.J., J Pharm Pharmaceutical formulations showed good linearity. The correlation Sciences 2002, 5, 213-219. [5] Hermida, R.C., Ayala, D.E., Mojon, A., Farnandez, J.R., J Am Soc coefficient was found to be 0.988-0.994 with diffusional Nephrol 2011, 22, 2313-2321. coefficient n values between 0.552-0.839, which indicates [6] Kiattisak, S., Yanee, P., Helmut, V., Siriporn, O., Sci Pharm 2007, 75, both mechanisms as drug diffusion and erosion, so called 147-163. [7] Gomez, H.J., Cirillo, V.J., Irvin, J.D., Drugs 1985, 30, 13-24. anomalous diffusion. (Table 3) All formulations showed [8] Cooper, J., Gunn, C., Tutorial Pharmacy. CBS Publishers and Mathematical modeling of drug release from dosage form has Distributors, New Delhi, India 1986. [9] Martin, A., Physical Pharmacy, Lippincott Williams & Wilkins 2001. two major benefits: first, elucidation of the underlying [10] Hixon, A.W., Crowell, J.H., Ind Eng Chem 1931, 23, 923-931. transport mechanism and second the possibility to predict the [11] Higuchi. T., J Pharm Sci 1963, 52, 1145-1149. resulting drug release kinetics as a function of the design of [12] Gibaldi, M., Feldman, S., J Pharm Sci 1967, 56, 1238-1242. [13] Korsmeyer, R.W., Gurny, R., Doelker, E.M., Buri, P., Peppas, N.A., Int the formulation. Swellable matrix tablets are activated by J Pharm 1983, 15, 25-35. water, and the drug release is controlled by the interaction [14] Costa, P., Sousa, Lobo, J.M., Eur J Pharm Sci 2001, 13, 123-133. [15] Ford, J.L., Mitchell, K., Rowe, P., Armstrong, D.J., Elliott, P.N.C., among the water, the polymer, and the drug. Due to the water Rostron, C., Hogan, J.E., Int J Pharm 1991, 71, 95-104. penetration, the gel layer is exposed to continuous changes in [16] Wadher, K.J., Kakde, R.B., Umekar, M.J., Bri J Pharm Res 2011, 1, 29- its structure and thickness. 45. [17] Talukdar, M.M., Plaizier-vercammen, J., Drug Dev Ind Pharm 1993, Similarity factor f2 analysis is used to ensure the sameness 19, 1037-1046. and equivalence in drug release between two profiles. [18] Marina, L., Ali, R., Rajabi-Siaboomi , J Pharm Sci 2004, 93, 2743- 2754. Formulation F9 showed the highest value of f2 i.e. 77.22 [19] Bhavani Boddeda, P.V., Kamala Kumari, Chowdary, K.P.R., Int J which confirms that the release of drug from prepared Pharm Biomed Res 2012, 3, 44-48. [20] Bravo, S.A., Lamas, M.C., Salomon, C.J., J Pharm Sci 2002, 5, 213- formulation is similar with desired target release profile. 219.