N. G. Raghavendra Rao * et al. /International Journal Of Pharmacy&Technology. Available Online through.

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1 Available Online through ISSN: X Research Article DEVELOPMENT AND EVALUATION OF TABLETS-FILLED-CAPSULE SYSTEM FOR CHRONOTHERAPEUTIC DELIVERY OF MONTELUKAST SODIUM N. G. Raghavendra Rao *, Mohd Abdul Hadi, Mansoori Wahid, M. R. Munde, Shrishail M. Ghurghure PG Department of Pharmaceutics, Luqman College of Pharmacy, Gulbarga , Karnataka, India. Received on Accepted on ABSTRACT: Montelukast is a leukotrine receptor antagonist used for the maintenance treatment of asthma, chronic asthma attacks, and to relieve symptoms of seasonal allergies. Montelukast biological half life is 2.5 to 5.5 hrs, there by decreasing bioavailability upto 64%. So in order to improve the bioavailability and efficacy we have designed tablets-filled-capsule system. The system comprises of different doses of immediate release tablets (IRT) and sustained release tablets (SRT) contained in a HPMC capsule. The drug-loaded core tablets were produced by wet granulation procedure using alcoholic solution of PVP K-30 as a binder. Different composition of IRT prepared with varying amount of sodium starch glycolate (as a disintegrant), and SRT was prepared with different ratios of ethyl cellulose to HPMC and number (5 of tablets in a HPMC capsule) were used to obtain different drug release rates. The prepared tablets were subjected for post-compression parameters. The compatibility of drug with other ingredients was checked by FTIR and DSC studies. FTIR and DSC results revealed that there was no interaction between dug and other excipients. All the pre and post-compressional parameter are evaluated were prescribed limits and results were within acceptable limits. The in-vitro performance of our best tablet-filled-capsule system showed the desired behavior, the drug contained in the IRT (immediate release tablets) dissolved within the first 45 min, whereas the drug contained in the sustained release tablets was released over a period of 10 to 12 hrs. Based on the release kinetic parameters calculated, it can be concluded that tablets containing HPMC and EC were particularly suitable approaching to sustain or prolong release over hrs time periods. From this, study it can IJPT March-2011 Vol. 3 Issue No Page 1702

2 be concluded that, tablets-filled-capsule systems containing montelukast sodium shows both sustained release as well as immediate release may improve the bioavailability and efficacy. Keywords: sustained release, montelukast sodium, tablets filled capsule system, immediate release, hydroxy propyl methyl cellulose, ethyl cellulose. INTRODUCTION: Chronotherapeutics refers to a clinical practice of synchronizing drug delivery in a manner consistent with the body s circadian rhythm including disease states to produce maximum health benefit and minimum harm. Asthma is a chronic obstructive lung disease characterized by airways, inflammation and hyperactivity. In most patients, the condition worsens at night with acute exacerbation being most common. Clinical and epidemiological studies verify that asthma is several hundred folds more likely at night than during the day with disturbance of sleep. The worsening of asthma at night commonly referred to as nocturnal asthma (NA). It is a variable exacerbation of the underlying asthma conditions associated with increases in symptoms, need for medication, airway responsiveness, and/or worsening of lung function. Generally a reduction in peak flow or forced expiratory volume in one second of at least 20% is implicit in this definition. Approximately two-thirds of asthmatics suffer from night time symptoms. In a large study involving 8,000 asthmatics it is observed that 70% awakened one night per week, 64% awakened 3 nights per week and 39% had their sleep disturbed on a nightly basis. The patients who self-characterized their asthma as mild, 26% has nightly awakenings and 53% of asthma deaths occurred during the night time hours. A drug delivery system administered at bed time but releasing drug during morning hours would be ideal in this case. The possibility of deferring the drug release for a programmed time interval after oral administration of the dosage form is to perform chronotherapy is quite appealing for those diseases the symptoms of which recur mainly at night times or in the early morning, such as asthma 1, 2. The montelukast sodium is a leukotrine receptor antagonist (LTRA) used for the maintenance treatment of asthma, chronic asthma attacks and to relive symptoms of seasonal allergies 3. The main drawback of conventional montelukast formulation is that it undergoes hepatic first pass metabolism. Thus, it shows plasma or biological half- IJPT March-2011 Vol. 3 Issue No Page 1703

3 life 2.5 to 5.5 hrs 4, there by decreasing bioavailability upto 64% 5. The present work describes such delivery system, which will improve the biological half-life as well as bioavailability of montelukast. This makes montelukast sodium a candidate for incorporation in sustained release dosage form and was used as a model drug. Multi-particulate (MP) modified release drug delivery systems have several performance advantages vs. single unit dosage forms. After ingestion, MP units are released from the capsule in the stomach, predictably transit to the small intestine 6 and spread along the gastro-intestinal tract resulting in a consistent drug release with reduced risk of local irritation. MP formulations generally have a more reliable in-vivo dissolution performance when compared to a single unit dosage form, resulting in more uniform bioavailability and clinical effect 7. Sustained-release preparations provide an immediate dose required for normal therapeutic response, followed by the gradual release of drug in amounts sufficient to maintain the therapeutic response for a specific extended period of time. The major advantage of this category is that, it provides drug levels that are devoid of the peak-and-valley effect which are characteristic of the conventional intermittent dosage regimen. Sustained-release dosage forms are designed to complement the pharmaceutical activity of the medicament in order to achieve better selectivity and longer duration of action 8. The purpose of this study was to develop a sustained-release montelukast sodium dosage form using a tablet-filled-capsule system (TFCS) to be administered in the evening hours to achieve an elevated montelukast sodium level overnight when the risk of asthma was found to be maximum. Our TFCS comprises of immediaterelease tablets (IRT) and sustained-release tablets (SRT) in a capsule made from HPMC, a water soluble polymer. We aimed to reduce the size of the montelukast sodium tablet such that it could be enclosed in a capsule, and then deploy tablets with different release properties, within the one TFCS. Inclusion of IRT permits the development of rapid acting TFCS dosage forms with optimal pharmacokinetic profiles for fast action. In this study, for the IRT we investigated the influence of superdisintegrant content on the immediate montelukast sodium release profile, and for SRT we investigated the influence of different ratios of ethyl cellulose and HPMC on drug release 9. We thus IJPT March-2011 Vol. 3 Issue No Page 1704

4 aimed to develop a better understanding of the factors that can regulate montelukast sodium release from IRT and SRT. The major objectives of this study were: i] To develop and to evaluate novel multifunctional tablets-filledcapsule systems, in order to achieve a fast/slow drug release. ii] To investigate formulation parameters affecting invitro performance. iii] To obtain a tablets-filled-capsule formulation, which has the ability to release the drug at a sustained or prolong release. MATERIALS AND METHODS: Montelukast Sodium was obtained as a gift sample by Zydus health care, (east Sikkim), and Morepen Pharma Pvt. Ltd, Solan (H.P). Sodium starch glycolate (SSG) was obtained from signet, Mumbai. HPMC (5 cps), sodium lauryl sulphate (SLS) and magnesium stearate, and lactose were purchased from S.D fine Chem. Lab, Mumbai, Ethyl cellulose, Talc was purchased from Loba Chemie Pvt. Ltd, Mumbai. PVP-K-30 was purchased from Himedia Chem. Lab, Mumbai. HPMC capsules were obtained as a gift samples from ACG Associated capsules Pvt Ltd, Mumbai. Preparation of TFCS sustained release dosage form: The qualitative and quantitative composition of the different formulations of the TFCS can be seen in Table 1. Table 1: Composition of tablets-filled-capsule system (quantities in mg). FC F1 F2 F3 F4 Ingredients IRT-1 (2 Tab) SRT-1 (3 Tab) IRT-2 (2 Tab) SRT-2 (3 Tab) IRT-3 (2 Tab) SRT-3 (3 Tab) IRT-4 (2 Tab) SRT-4 (3 Tab) M S SSG HPMC (5cps) Ethyl cellulose Lactose Total weight in mg/tab IJPT March-2011 Vol. 3 Issue No Page 1705

5 NOTE: FC: Formulation code, **All the IRT and SRT formulations contain sufficient quantity of 10% alcoholic solution of PVP-K-30 and 1.2 mg and 1.2 mg of Magnesium stearate and talc. Sustained-release component (SRT) 1,10 : The SRT contained various ethyl cellulose to HPMC ratio (60:40, 70:30, 80:20, 85:15) as controlling agents. The ingredients consisting of MS, lactose, HPMC (5 cps), ethyl cellulose were passed through 60 mesh (250 µm) separately and dry mixed. The dry mixing was carried at a slow speed for 10 min and the blend was granulated with 10% w/v alcoholic solution of PVP K-30 for 5 min. The resulting wet mass was immediately passed through a 16 mesh screen (1000 µm). The granules obtained were dried for 1 hrs in a thermostatic hot air oven maintained at C to a moisture content of 2 to 3 %. The dried granules were passed through the same sieve (1000 µm) to break the lumps and blended with magnesium stearate and talc. The lubricated granules were compressed into tablets weighing 120mg using 6.3 mm round convex punches in a rotary tablet press (Rimek mini press, model RSB-4, M/S: Karnavathi engineering, Ahmedabad) to a hardness of 3 kg/cm 2. Immediate release component (IRT): In this IRT various concentrations (0%, 2.5%, 5%, 10%) of SSG because of its disintegration properties was used to obtain an immediate release of the drug. The ingredients consisting of montelukast sodium, HPMC (5cps), lactose and intra granular portion of SSG were passed through 60 mesh (250 µm) separately and dry mixed. The dry mixing was carried out at a slow speed (50 rpm) for 10 min and the blend was granulated with 10% w/v alcoholic solution of PVP K-30 at a high speed (150 rpm) for 5 min. The resulting wet mass was immediately passed through the 16 mesh screen (1000 µm). The granules obtained were dried for 1 hrs in a thermostatic hot air oven maintained at to a moisture content of 2 to 3%. The dried granules were passed through the same sieve (1000 µm) to break the lumps and blended with extra granular portion of SSG, required amount of fines, magnesium stearate and talc. The lubricated granules were compressed into tablets weighing 120 mg using 6.3 mm round convex punches in a rotary tablet press (Rimek mini press, model RSB-4, M/s Karnavathi Engineering, Ahmedabad) to a hardness of 3 kg/cm 2. Tablets-filled-capsule system (TFCS): The tablets-filled-capsule system comprises of 2 immediate-release and 3 sustained-release tablets (Fig 1). IJPT March-2011 Vol. 3 Issue No Page 1706

6 HPMC CAPSULE (size 0) SUSTAINED-RELEASE TABLETS (6.3mm) IMMEDIATE-RELEASE TABLETS (6.3mm) Fig 1: Tablets-filled-capsule system Evaluation of granules 11 : Angle of repose: The fixed funnel and free standing cone methods employ a funnel that is secured with its tip at a given height, h, which was kept 2 cm above graph paper that is placed on a flat horizontal surface. With r being the radius, of base of conical pile, angle of repose can be determined by following equation: θ = tan -1 (h/r) Where, θ is the angle of repose h is height of pile, r is radius of base of the pile Bulk density and tapped density: Both loose bulk density and tapped bulk density were determined. A quantity of 2 gm of granules from each formula, previously light shaken for the break of any agglomerates formed, was introduced into the 10ml of measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall down its own weight from the hard surface from a height of 2.5cm at 2 sec intervals. The tapping was continued until no further change in the volume was noted. LBD and TBD were calculated using the following formulas: LBD: Weight of the powder/volume of the packing. TBD: Weight of the powder/tapped volume of the packing. Compressibility index: The compressibility index of the granules was determined by carr s compressibility index. Carr,s index (%) = [(TBD-LBD) * 100] / TBD Where, LBD: Weight of the powder/volume of the packing. IJPT March-2011 Vol. 3 Issue No Page 1707

7 TBD: Weight of the powder/tapped volume of the packing. Hausner s ratio: Hausner s ratio can be determined by the following equation, Hausner s ratio = TBD / LBD Where, TBD -Tapped bulk densities and LBD - Loose bulk densities. Evaluation of tablets: Hardness test: The hardness of the tablets was determined using Monsanto hardness tester. It is expressed in kg/cm 2. Six tablets were randomly picked from each formulation and the mean and standard deviation values were calculated. Friability: A friability test was conducted on the tablets using Friabilator. Twenty tablets were selected from each batch and any loose dust was removed with the help of a soft brush. The tablets were initially weighed (W initial ) and transferred into Friabilator. The drum was rotated at 25 rpm for 4 minutes after which the mini-tablets were removed. Any loose dust was removed from the tablets as before and the tablets were weighed again (W final ). The percentage friability was then calculated by, Winitial - Wfinal F = x100 W initial % Friability of tablets less than 1% is considered acceptable. Weight variation: The weight variation test was conducted by weighing 20 randomly selected tablets individually, calculating the average weight and comparing the individual tablet weights to the average. The specification of weight variation is 10%. Uniformity of thickness: The tablet thickness was measured using screw guage. Estimation of drug content 2, 12 : Five tablets weighted and crushed in a mortar then weighed powder contain equivalent to 10 mg of drug transferred in 100ml of 0.5% of SLS solution to give a concentration of 100µg/ml.Take 15ml of this solution and diluted it upto 100ml with 0.5% of SLS solution to give a concentration of 15µg/ml.Absorbance measured at 342nm using UV-Visible Spectrophotometer. IJPT March-2011 Vol. 3 Issue No Page 1708

8 Estimation of montelukast sodium 2,12 : Preparation of standard calibration curve of MS: The standard calibration curve for MS was prepared using 0.5 % SLS solution. Standard solution: 25 mg of MS was dissolved in 25 ml 0.5 % of SLS solution to give a concentration of 1 mg/ ml (1000 µg/ml). Stock solution: From standard solution take 5 ml of solution in 50 ml of 0.5 % of SLS solution to produce the 50 µg/ml concentrations and take from the 50 µg/ml of the solution aliquots of 1, 2, 3, 4, and 5 ml of stock solution was pipette out in 10 ml volumetric flask. The volume was made up to mark with SLS solution to produce concentration as 5, 10, 15, 20, and 25 µg/ml of montelukast respectively. The absorbance of prepared solution of MS as measured at 342 nm in Shimadzu UV/visible 1700 spectrophotometer against 0.5 % of SLS solution as blank. Dissolution testing 2, 12 : Dissolution rate of MS from all formulations was performed using Electrolab dissolution apparatus (USPXXIII) with paddle. The dissolution fluid was 900 ml distilled water with 0.5% SLS at a speed of 50 rpm and a temperature of 37 0 C were used in each test. Samples of dissolution medium (5ml) were withdrawn through a filler of 0.5 mm at different time intervals suitably diluted and assayed for montelukast sodium by measuring absorbance at 342 nm. The dissolution experiments were conducted in triplicate. For all tests 5ml samples of the test medium were collected at set intervals (1, 2, 3, 4, 6, 8, 10 and 12 hrs) and were replaced with equal volume of 0.5 % SLS in distilled water. RESULTS AND DISCUSSION: MS is rapidly absorbed and excreted in the urine. In order to develop an optimized sustained release dosage forms, we tested TFCS comprising different release profile of tablets (IRT and SRT) in a HPMC capsule (size 0). Evaluation of granules: Granules of all the formulations [both IRT and SRT] were subjected for various pre-compressional evaluations such as LBD, TBD, and compressibility index, Angle of repose and hausner ratio. For IRT granules the LBD ranged from 0.51 to 0.52 and TBD ranged from 0.57 to 0.59 whereas for SRT granules LBD ranged from 0.52 IJPT March-2011 Vol. 3 Issue No Page 1709

9 to 0.55 and TBD ranged from 0.62 to The LBD and TBD of IRT granules were found to be much lower than SRT granules which may be attributed to the absence of EC in the formulation. Granules prepared with HPMC alone showed compressibility index values ranging from to %, whereas granules prepared with HPMC and EC showed compressibility index values ranging from to 15.4 %. Angle of repose of granules of all formulations ranged from to All these results were given in Table 2 indicate that the formulated granules possessed satisfactory flow properties and compressibility. Table-2: Evaluation of granules. Type of granules Angle of repose (degree) ± SD, n=3 Bulk density (gm/cc) ± SD, n=3 Tapped density (gm/cc) ± SD, n=3 Carr s index (%) ± SD, n=3 Hausner s ratio ± SD, n=3 IRT ± ± ± ± ± SRT ± ± ± ± ± IRT ± ± ± ± ± SRT ± ± ± ± ± IRT ± ± ± ± ± SRT ± ± ± ± ± IRT ± ± ± ± ± SRT ± ± ± ± ± Physical properties of the compressed tablets: Table 3 lists the physical properties (thickness, diameter, hardness, friability, average weight and drug content) of the compressed tablets. In all the formulations, hardness test indicated good mechanical strength ranges from 2.80 to 3.10 kg/cm 2. Friability is less than 1% indicated that tablets had a good mechanical resistance. Thickness of the tablets ranges from 2.77 to 3.26 mm, diameter of the tablets was found to be 6.3 mm, average weight of the tablets ranges from to mg and the drug content of the tablets ranges from to 98.73%. IJPT March-2011 Vol. 3 Issue No Page 1710

10 Table-3: Evaluation of tablets. Tablet code Thickness (±SD), n=6 Diameter (mm) (±SD), n=6 Hardness (kg/cm 2 ) (±SD), n=6 Friability (%) Average weight (mg) (±SD), n=20 Drug Content (%) (±SD), n=6 IRT ± ± ± ± ± 0.34 SRT ± ± ± ± ± 0.64 IRT ± ± ± ± ± 0.50 SRT ± ± ± ± ± 0.74 IRT ± ± ± ± ± 0.57 SRT ± ± ± ± ± 0.42 IRT ± ± ± ± ± 0.46 SRT ± ± ± ± ± 0.27 Influence of sodium starch glycolate on release of montelukast from immediate release tablets: SSG which is used as a superdisintegrant was compressed here along with HPMC (a water soluble polymer) in IRT at different concentrations (0%, 2.5%, 5%, 10%) to have an immediate release of the drug. A separate in-vitro dissolution testing was performed for only IRT tabs to assess the effect of disintegrants content on release of montelukast sodium, and we found that the time taken for complete drug release from the different IRT is ranges from 45 min to 105 min. The results were shown in Table 4. The maximum drug release observed from IRT-4 around % within 45 min. And the results (Fig 2) showed that the drug release time decreased with increase in the level of sodium starch glycolate in IRT. IJPT March-2011 Vol. 3 Issue No Page 1711

11 Table-4: In-vitro release study of Immediate-release tablets (IRT). Percentage amount of drug released* Time (min) IRT-1 IRT-2 IRT-3 IRT Fig 2: In-vitro drug release profile of immediate-release tablets (IRT). IJPT March-2011 Vol. 3 Issue No Page 1712

12 Influence of ethyl cellulose on release of montelukast from sustained release tablets: In order to evaluate the influence of ethyl cellulose content on the release of montelukast sodium from SRT a separate in-vitro dissolution testing was carried out. The results of in-vitro drug release studies of SRT were given in Table 5 and graphical representation was shown in Fig 3. These results demonstrate that the dissolution rate and extent of drug release decreased with increasing ethyl cellulose content in the tablets. Hence, the most suitable sustained-release tablet seems to be SRT-4 releasing 99.94% of montelukast sodium within 12 hrs. Table: 5 In-vitro release study of sustained-release tablets (SRT). Percentage amount of drug released* Time (hrs) SRT-1 SRT-2 SRT-3 SRT Fig 3: In-vitro drug release profile of sustained-release tablets (IRT). IJPT March-2011 Vol. 3 Issue No Page 1713

13 The IRT and SRT were filled into the 0 sized HPMC capsule [as TFCS]. Further, the in-vitro drug release study was carried out for these TFCS formulations. The results revealed that formulation F4 was releasing 40.54% of montelukast within an hour as an immediate release phase and the sustained release phase was prolonged for a period of 12 hrs, and it was found to be the most suitable combination to have an immediate as well as sustained release of drug. The drug release results of TFCS were given in Table 6 and graphical representation was shown in Fig 4. Hence, it was considered as the best formulation releasing montelukast sodium both as an immediate and sustained-release phase. Table-6: In-vitro release study of tablets-filled-capsule system formulations (TFCS). Percentage amount of drug released* Time (hrs) F-1 F-2 F-3 F Fig 4: In-vitro drug release profile of tablets-filled-capsule system formulations (TFCS). IJPT March-2011 Vol. 3 Issue No Page 1714

14 The in-vitro release profile of this TFCS coincided with the profile expected from the combination of two IRT and three SRT. The TFCS undergoes four processes as follows: (a) the HPMC capsule dissolves rapidly, and has no influence on the release rate of montelukast from the TFCS; (b) once dissolved, the HPMC capsule releases the IRT and SRT subunits; (c) montelukast is released rapidly from the IRT; and (d) montelukast is released from the SRT over hrs. Using different types of tablets, the TFCS can be designed to yield the desired stable drugrelease profiles, thereby improving patient compliance. Drug excipients interaction studies: Drug taken for the present study of formulation is MS. It has got tertiary hydroxyl groups which have exhibited a broad peak around 3300 cm -1 and a carboxylic acid peak which is in the form of a salt has exhibited a strong peak near 1700 cm -1. Numbers of aromatic C-H peaks are also observed between 2900 cm -1 to 3000 cm -1. These are the characteristic absorption peak of montelukast sodium (Figs 5-10). Fig 5: IR Spectra of pure montelukast sodium. Fig 6: IR Spectra of PVP-K-30. IJPT March-2011 Vol. 3 Issue No Page 1715

15 Fig 7: IR Spectra of Ethyl cellulose. Fig 8: IR Spectra of HPMC Fig 9: IR Spectra of IRT-4. IJPT March-2011 Vol. 3 Issue No Page 1716

16 Fig 10: IR Spectra of SRT-4. The IRT-4 contains MS, HPMC and PVP-K-30. The HPMC contains number of hydroxyl groups in a molecule which is indicated by broad hump at 3500 cm -1 which is the expected place wherein many hydroxyl groups can observe. Similarly, to above instead of aromatic C-H number of aliphatic C-H are observed near 2900 cm -1. In PVP-K-30 there are no functional groups which can absorb above 3000 cm -1. However, a strong peak at 1650 cm -1 is observed due to cyclic imide bond at 1650 cm -1. This absorption peak can vary between 1700 to 1650 cm -1. In the IRT-4 spectrum all the expected IR absorption peaks are observed indicating that during the formulation process the drug has not undergone neither chemical reaction with the polymer used or not undergone any of hydrogen bonding. Hence, in the formulation drug remains in its original form. So, this formulation can be used for its application. The drug will be available in its free state for its action. In SRT-4 along with HPMC, PVP-K-30, ethyl cellulose was also taken for its preparation of formulation. The ethyl cellulose exhibited expected peaks for the carboxylate residue and carboxylate carbonyl groups. The strong absorption peak is absorbed at 3400 cm -1 and another peak at 1700 cm -1 corresponding to the carboxylate and carbonyl residues. In SRT-4 formulation HPMC, EC, PVP-K-30 along with drug MS obtained all its characteristics peaks of drug in its original state indicating that chemical reaction has not taken place between the drug and polymers also amongst the polymers suggesting that drug is present in the formulation in its original form. IJPT March-2011 Vol. 3 Issue No Page 1717

17 DSC studies: To study the thermal stability of the drug it is subjected for DSC (Figs 11-13) studies in the range of 30 0 C to C. During the process of study it is observed that the drug starts melting at C with in the range of less than 1 0 C i.e. at C. It melts completely indicating that the drug has got thermally stability upto 139 to C. When the same drug is taken in IRT-4 formulation along with HPMC and PVP-K-30 the increase in the thermal stability is observed nearly 10 0 C. When the formulation was taken for the study the slow melting process starts at C. But suddenly increases after 6 0 C to C. Suggesting that it is a mixture but not a single reacted product. So, in the process of formulation drug has not undergone any chemical reaction. But remained in the form of a mixture. It is property of chemical substances whenever they are not in pure form prolonged melting process is observed instead of sharp melting. Fig 11: DSC of pure montelukast sodium. Fig 12: DSC of IRT-4. IJPT March-2011 Vol. 3 Issue No Page 1718

18 Fig 13: DSC of SRT-4. In SRT-4 formulation wherein along with HPMC and PVP-K-30, ethyl cellulose also has been added. In this case, formulation behaves in the same fashion as earlier i.e. the melting process starts at C and melts sharply at C suggesting that in the formulation mixture the addition of one more polymer in the system slightly reduces the melting process. Same observation is made in the second peak wherein the melting process starts at C and completes at C. These observations are in line with the observations made for the presence of drug in unreacted form in the formulation. CONCLUSION: A novel multifunctional tablets-filled-capsule system for sustained release dosage form was developed by filling tablets into an empty HPMC capsule shell which releases 25 to 30% of the total dose within 45 min and 100% of the total dose upto 12 hrs. This technology may be achieved by fast/slow delivery system. This is characterized by an initial rapid release phase, corresponding to the drug release contained in IRT (immediate release tablets) followed by a period of slow release, corresponding to the drug release of SRT (sustain release tablets). The proposed fast/slow delivery devices show a wide flexibility in the modulation of the delivery program. The two different release phases can be easily adjusted in a wide range of values of both delivery rate and ratio of IJPT March-2011 Vol. 3 Issue No Page 1719

19 the dose fractions, on the basis of the pharmacokinetics and therapeutic needs, to perform the desired in-vivo profile. ACKNOWLEDGEMENTS: Authors thank Morepen Pharma Pvt. Ltd. Solan (Delhi) and Zydus health care, (East Sikkim) for providing a gift sample of Montelukast sodium and ACG Associated capsules Pvt Ltd, Mumbai, respectively for providing the HPMC capsules. The authors are also thankful to Dr. M. G. Purohith, Emeritus professor, Luqman College of pharmacy, Gulbarga for their valuable suggestion in carrying out this research work. The authors are also thankful to Dr. M. A. Mujeeb, Chairman, Luqman College of Pharmacy, Gulbarga, for providing the facilities to carry out the research work. REFERENCES: 1. Shivakumar, H.N., Sarasija Suresh, Desai, B.G., Design and evaluation of PH sensitive Mini-tablets for chronotherapeutic delivery of theophylline. Indian Journal of pharmaceutical science-2007; 69: Janugade, B.U., Patil, S.S., Patil, S.V., Lade, P.D. Formulation and evaluation of press-coated montelukast sodium tablets for pulsatile drug delivery system. International journal of chem. Tech research 2009, Vol 1, no-3, Martindale, the Complete Drug Reference, 33 rd Edition, Page No Clark s Analysis of Drugs and Poisons. Edited by Anthony Moffat, David, M. Osseiton, and Brain Widdop. 3 rd Edition, 2004:P.No Khosla, R., Feely L.C. & Davis S.S., Int. J. Pharm., 53, (1989). 7. Riis T., Bauer-Brandl, A., Wagner, T., Kranz, H. 2. Eur J. Pharm and BioPharm, 65; (2007). 8. Rakesh, Patel, Ashok, Baria. Formulation development and process optimization of theophylline sustainedrelease matrix tablet. International journal of pharmacy and pharmaceutical sciences, Vol-1, Issue-2, Oct-Dec IJPT March-2011 Vol. 3 Issue No Page 1720

20 9. Mako to Ishida, Kenichi Abe., Munoru, Hashezime., and Masco Kawamura. A novel approach to sustained pseudoephedrine release-differentially coated Mini-tablets in HPMC capsules. International Journal of pharmaceutics 2008; 359: Carla, M. Lopes., Jose Manual Souza, lobo, Jaao, F., Pinto, Paulo., Costa. Compressed Mini-Tablets as a biphasic delivery system. International Journal of Pharmaceutics, 2006; 323: Bhupendra, G., Prajapati, Patel Krunal, R. Design and In-vitro evaluation of Nicorandil sustained release matrix tablets based on combination of hydrophilic and hydrophobic matrix system. International journal of Pharmaceutical Sci Review and Research, Vol 1; issue 1, March-April 2010; Raghavendra Rao, N.G., Suryakar, V.G. Kethan Thube. Development of mucoadhesive films for buccal administration of montelukast. International journal of pharmacy and technology. March 2010, Vol-2, issue no-1, Corresponding Author: Dr.N.G Raghavendra Rao, Professor and HOD, PG Dept of Pharmaceutics, Luqman College of Pharmacy, Old Jewargri Road, Gulbarga , Karnataka. ngraghu@rediffmail.com IJPT March-2011 Vol. 3 Issue No Page 1721