International Journal of Innovative Pharmaceutical Sciences and Research

International Journal of Innovative Pharmaceutical Sciences and Research www.ijipsr.com FORMULATION AND EVALUATION OF MODIFIED REALEASE CAPSULES OF BUDESONIDE 1 K.Veera Kumari*, 2 Dr. Appa Rao, 3 Dr.Shaik.Harun Rasheed 1,2 Department of Pharmaceutics, Victoria College of Pharmacy, Nallapadu, Guntur, A.P, INDIA. 3 Department of Pharmaceutics, DCRM College of Pharmacy, Inkollu, Prakasam, A.P, INDIA. Abstract Controlled release formulation of Budesonide modified release capsules was formulated by suspension layering by matrix layer formulation method using aqua coat ECD, acetyl tri butyl citrate, eudragit L30D55 and triethyl citrate. Infrared spectra of the drug along with the polymers reveal that there is no interaction between drug and polymers. Preformulation studies were done initially and found to be within the limits. The study was carried out by solution/suspension matrix layering, first drug and polymer solutions were mixed, coating was done on the sugar spheres and further enteric coating was done on the polymer matrix coated pellets. Different trails were conducted with various percentages of polymers and other excipients in the first (drug loading) and second stage (during enteric coating) and the formulation was finally optimized based on the Cumulative % drug release. The evaluation test results are found to be within pharmacopieal specifications. The in-vitro dissolution tests were performed for all trails. Dissolution profile of formulation F9 matched with the innovator s product and was found to be satisfactory. Stability studies both accelerated and long term stability studies were conducted for two months. During this study, the formulation F9 was found to be stable and no differences in the assay, moisture content and release characteristics were noticed. Keyword: Budesonide, Controlled release formulation, modified release capsules, enteric coating, Aqua coat ECD, Eudragit L30D55 Corresponding Author: K.Veera Kumari Department of Pharmaceutics Victoria College of Pharmacy Nallapadu, Guntur, A.P, INDIA Email: veerakumarikambhampati@gmail.com Mobile: +91-9440431070 Available online: www.ijipsr.com September Issue 2209

INTRODUCTION Pharmaceutical Oral solid dosage forms have been used widely for decades mainly due to their convenience of administration and their suitability for delivery of drugs for systemic effects The salient aspect of conventional methods of drug delivery including tablets, capsules, and liquids is the fluctuation in concentration between dosages [1]. Some drug fluctuations cause no problems, but some drugs that cause toxic reaction when administered above a narrow therapeutic concentration range, such a variation can cause considerable side effects. Thus ideal goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body and then maintain the desired drug concentration. i.e., the drug delivery system should deliver the drug at a rate dictated by the needs of the body over a specified period of treatment. The overall action of a drug molecule is dependent on its inherent therapeutic activity and the efficiency with which it is delivered to the site of action. An increasing appreciation of the latter has led to the evolution and development of novel drug delivery systems (NDDS), aimed at performance enhancement of potential drug molecules. Novel drug delivery systems (NDDS) are the key area of pharmaceutical research and development. The reason is relatively low development cost and time required for introducing a NDDS ($20-50 million and 3-4 years, respectively) as compared to new chemical entity (approximately $500 million and 10-12 years, respectively) [2]. The focus in NDDS includes design of NDDS for new drugs on one hand and on the other NDDS for established drugs to enhance commercial viability. Oral route remains one of the most natural routes of drug administration and has seen remarkable accomplishments in the last couple of decades towards optimization of oral delivery of drug molecules. Oral ingestion is one of the oldest and most extensively used routes of drug administration, providing a convenient method of effectively achieving both local and systemic effects [3]. Available online: www.ijipsr.com September Issue 2210

Modified release drug delivery system: The oral route of drug delivery is typically considered the preferred and most patient convenient means of drug administration. Consequently, much effort is directed during drug discovery to identify orally active candidates that will provide reproducible and effective plasma concentrations in vivo. The reality is that many compounds are either incompletely or ineffectively absorbed after oral administration (i.e. bioavailability is an issue), or that the required dosing frequency is too short to enable once or twice daily administration (ie. Pharmacokinetic half-life is an issue) [5]. Modified release formulation technologies offer an effective means to optimize the bioavailability and resulting blood concentration time profiles of drugs that otherwise suffer from limitations. Modified release refers to controlled, delayed and extended release systems for oral administration as well as oral delivery system s designed specifically to modify the release of poorly water soluble drugs [4]. Sustained release systems include any drug delivery system that achieves slow release of drug over an extended period of time. If the system can provide some control, whether this is of a temporal or spatial nature, or both of drug release in the body, or in other words, the system is successful maintaining constant drug levels in the target cells or tissues, it is considered a controlled release system [6]. Potential advantages of controlled drug therapy All controlled release products share the common goal of improving drug therapy over that achieved with their non-controlled counter parts. This improvement in drug therapy is represented by several potential advantages, which include: Avoid patient compliance problems. Reduction in frequency of dosing. Employ minimum total drug. Minimize or eliminate local side effects. Minimize or eliminate systemic side effects. Cure or control condition more promptly. Available online: www.ijipsr.com September Issue 2211

Reduce fluctuations in drug level. Improve bioavailability of some drugs. Minimize drug accumulation with chronic dosing. Improve efficacy in treatment. Make use of special effects e.g. sustained release aspirin for morning relief of arthritis by dosing before bedtime. Mups for CR Systems Oral modified drug delivery systems can be classified into two broad groups: 1. Single Unit dosage forms. 2. Multiple unit particles. Multiple unit particles (MUPS), such as granules, pellets, or mini tablets The concept of MUPS was initially introduced in 1950s. The production of MUPS is a common strategy to control the release of drug as shown by the reproducibility of the release profiles when compared to the ones obtained with SUDFS. The concept of MUPS is characterized by the fact that the dose is administered as a number of sub units, each one containing the drug. Then the dose is sum of the quantity of the drug in each sub unit and the functionality of individual sub-units. In contrast to Monolithic dosage forms multiple unit dosage forms offer several advantages. Controlled release systems can be developed by multi-unit dosage forms. The capsule comprised of a multiple unit pellets when administered, freely disperse in the GIT as a sub unit, each pellet acting as a separate drug delivery unit. Thus, maximizing drug absorption and reducing the peak plasma fluctuations, consequently, potential side effects can be minimized without imparting drug bioavailability [7]. Methods of preparation of multiple unit dosage forms To understand the complete strategy of the multiple unit dosage forms, it is necessary to have a brief idea regarding how pellets are prepared and principles involved in it. Pelletization This technique is referred to an agglomeration process that convert fine powder or granules of bulk drug or excipient in to small, free flowing, spherical or semi spherical pellets Available online: www.ijipsr.com September Issue 2212

where size range typically from 0.5-1.5mm [8]. The most widely used Pelletization processes in pharmaceutical industries are, Extrusion Spheronization Spherical Agglomeration Liquid-induced agglomeration Spray drying and spray congealing Melt-induced agglomeration. Cryopelletization MATERIALS Aquacoat ECD (30%), Acetyl tributyl citrate, Eudragit L30 D55, Triethyl citrate, Tween 80, Talc, and Sugar spheres. METHOD Standard Calibration Curve of Budesonide A 100 mg of Budesonide was transferred to a 100 ml of standard flask and then dissolved in to the required quantity of phosphate buffer ph 7.5 and then make up to the volume in 100 ml of standard flask. From this stock solution the aliquots of 5µg, 10µg, 15µg, 20µg, and 25µg/ml were withdrawn and volume made up to 10ml. The absorbance of the concentration was measured at 244nm using UV- spectrophotometer. Drug excipients compatibility study: In this study, the active pharmaceutical ingredient and excipients were mixed separately and stored at different conditions for a time period of 1 month. The physical properties (colour change) were monitored regularly. The change in the colour in any mixture was the basis for disregarding the study. Available online: www.ijipsr.com September Issue 2213

Solution/suspension layering by matrix layer formulation Drug and polymer matrix layering on sugar spheres: The required quantity of sugar spheres (18/20#) were weighed and transferred into a fluidized bed processor and required quantity of acetyl tributyl citrate and talc were dissolved in specified volume of water. Required volume of aqua coat ECD was added to above solution under continuous stirring. Later required quantity of budesonide was dispersed in above suspension by stirring. This suspension was sprayed on sugar spheres by bottom spray technique. This drug-polymer layered pellets were further used for enteric coating. Enteric Coating by Using Eudragit L30 D55 The required quantity of drug-polymer matrix layered pellets were loaded into the FBC and required quantity of triethyl citrate, tween 80 and eudragit L30 D55 were dissolved in specified volume of water under continuous stirring for 20 min. Later required quantity of talc was added to the above solution and sprayed on drug-polymer matrix layered pellets in bottom spray FBC. Table:1 Composition of drug and polymer matrix coated pellets for the formulation trial (F1-F9) Name of the excipient Weight of the Excipients (gm/500gm batch) % of polymer F1 F2 F3 F4 F5 F6 F7 F8 F9 Budesonide 4.25 4.25 4.25 4.25 4.25 4.25 4.25 4.25 4.25 Aqua coat ECD 30% 10 11.66 13.33 15.0 16.66 16.66 16.66 16.66 16.66 Acetyl tri butyl citrate 0.24 0.29 0.36 0.40 0.40 0.40 0.45 0.475 0.50 Talc 0.225 0.28 0.34 0.40 0.375 0.40 0.425 0.45 0.50 Sugar spheres 460.38 455.88 451.84 448.64 458.07 454.13 450.06 448.05 444.60 Purified water q.s q.s q.s q.s q.s q.s q.s q.s q.s Note: # the material balance would become 600gm only after enteric coating step. Available online: www.ijipsr.com September Issue 2214

* Aquacoat ECD is a 30% suspension contained ethyl cellulose (30%), sodium lauryl sulphate (0.9-1.7%), cetyl alcohol (1.7-3.3%), (FMC Biopolymers). Table:2 Composition of enteric coated pellets for the formulation trials (F1-F9) Name of the excipient Weight of the Excipients (gm/500gm batch) % of polymer F1 F2 F3 F4 F5 F6 F7 F8 F9 Eudragit D30 L55 83.33 91.66 100 103.33 83.33 91.66 100 103.3 110.0 Tri ethyl citrate 1.75 2.062 2.4 2.79 1.75 2.062 2.40 2.79 3.3 Talc 5.0 6.05 6.60 7.75 5.0 6.05 7.2 7.75 8.58 Tween 80 0.15 0.178 0.21 0.232 0.15 0.178 0.21 0.232 0.264 Water q.s q.s q.s q.s q.s q.s q.s q.s q.s Evaluation of formulation (capsules): Average Fill Weight of Capsule: Weigh an intact capsule. Open the capsule without losing any part of the shell and remove the contents as completely as possible. Weigh the shell. The weight of the contents is the difference between the weighings. Repeat the procedure with a further 19 capsules. Determination of the average weight = (Weight of 20 capsules (g)/20)*1000=...mg Dissolution studies: Dissolution studies were carried out by using USP Type-2 (Paddles with sinker) with 0.1N HC1 and ph 7.5 phosphate buffers as a dissolution medium. The samples were withdrawn for 2hours for 0.1N Hcl as a dissolution medium and 1-8 hours for ph 7.5 phosphate buffer and samples were analyzed by using HPLC and dissolution data was compared with the innovator product. Available online: www.ijipsr.com September Issue 2215

RESULTS AND DISCUSSION Table:3 Calibration curve of Budesonide Figure:1 Calibration curve of Budesonide in Phosphate Buffer in ph 7.5 S. Concentration Absorbance at 1 5 0.080 2 10 0.162 3 15 0.242 4 20 0.321 5 25 0.391 Figure:2 FT-IR spectrum of Budesonide Figure :3 FTIR Spectrum of Eudragit D30 L55 Available online: www.ijipsr.com September Issue 2216

Figure :4 FTIR Spectrum of F9 Table: 4 drug excipients compatibility study: S.No Drug + Excipient Initial After 1 month After 1 month Compatible at at 1. Drug White powder NCC NCC Yes 2. Drug +Aquacoat ECD White suspension NCC NCC Yes 3. Drug+ Talc White powder NCC NCC Yes 4. Drug+ Acetyl tri butyl citrate White suspension NCC NCC Yes 5. Drug+ Eudragit L30 D55 6. Drug+ Triethyl citrate White suspension White suspension NCC NCC Yes NCC NCC Yes 7. Drug+ Tween 80 White powder NCC NCC Yes * NCC-No Colour Change Compatibility studies at different temperatures and relative humidity showed that the drug itself was stable at higher temperature and relative humidity, as well as compatible with all the above excipients Average fill weight: Weight of 20 capsules /20*1000 The Average fill weight of capsule was found to be= 7173.7mg/20 = 359.7mg Available online: www.ijipsr.com September Issue 2217

Dissolution studies: Table: 5 cumulative% drug release of budesonide MR capsules in the formulation trails and innovator product (3mg): Fig: 5 Dissolution Profile comparison of Formulation F1-F3 Fig: 6 Dissolution Profile comparison of Formulation F4-F6 Available online: www.ijipsr.com September Issue 2218

Fig : 7 Dissolution Profile comparison of Formulation F1-F3 Fig:8 Dissolution Profile comparison of Optimized Formulation F9 and Innovator CONCLUSION The study was undertaken with an aim to formulate budesonide modified release capsules. The drug budesonide is corticosteroid and currently used for the treatment of Crohn s disease. Before going to develop the formulation, a detail product literature review was carried out to know about the innovator s type of dosage form available in market, weights, all other parameters and excipients used product and the patent status of the drug. The study was carried out by solution/suspension matrix layering, first drug and polymer solutions were mixed, coating was done on the sugar spheres; further enteric coating was done on the polymer matrix coated pellets. Different trails were conducted with various percentages of polymers and other excipients in the first (drug loading) and second stage (during enteric coating) and the formulation was finally optimized based on the Cumulative % drug release. The optimized pellets were evaluated for tests like average fill weight, assay and content uniformity. The in-vitro dissolution tests were performed for all trails. Dissolution profile of formulation F9 matched with the innovator s product and was found to be satisfactory. Stability studies were also performed; both accelerated and long term stability studies were conducted for two months. During this study, the formulation F9 was found to be stable and no differences in the assay, moisture content and release characteristics were noticed. Available online: www.ijipsr.com September Issue 2219

REFERENCES 1. Vyas.P, Kharr, R.K., Controlled drug delivery- Concept and Advances. 1 st ed. Delhi: Vallabh Prakashan Publishers; 2002. 5-25. 2. Joseph, R.R., Vincent, H.L.L., editors. Controlled drug delivery: Fundamentals and applications. 2 nd ed. New York. Marcel Decker, Inc: 1987.29:12-35. 3. Florence, Juergen.S, Mathias.W- ph sensitive polymer blends used as coating materials to control drug release from spherical beads: Elucidation of the underlying Mass Transport Mechanisms. Pharma. Res.2005: 22:7. 4. Ghebre-Selassie. Pharmaceutical Pelletization Technology. New York. Marcel Deckker Inc.1989: 37:1-165 5. Thomas W.Y.L, Joseph, R.R. Controlled release drug delivery system. In: Alfonso, R.G. editor. Remingtons: The science and practice of pharmacy, 20 th ed. Philadelphia; Lippincott Williams and Wilkilns; 2000; 1: 903-930. 6. Schaefer, T. Holm, P.Kristensen, H.G., Melt Pelletization in a high shear mixer. Effect of Process variables and binder. Acta. Pharm. Nord. 1992; 4: 133-140. 7. Chien, Y.W. Novel Drug delivery Systems, 2 nd ed. New York: Marcel Dekker, Inc; 1992 : 50: 43-98. 8. Gamlen M.J. Pellet manufacture for controlled release. Manuf. Chem. 1985; 56: 55-59. 9. David, M.S., Chang, S.K. Dinesh, V.P., James, A.w., Diffuse- interface theory for structure formation and release behavior in controlled drug delivery system. 2007: 3: 851-864. Available online: www.ijipsr.com September Issue 2220