Release pattern of three new polymers in Ketoprofen controlled-release tablets

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1 African Journal of Pharmacy and Pharmacology Vol. 6(9), pp , 8 March, 2012 Available online at DOI: /AJPP ISSN Academic Journals Full Length Research Paper Release pattern of three new polymers in Ketoprofen controlled-release tablets Syed Umer Jan 1 *, Gul Majid Khan 2, Haroon Khan 2, Asim-ur-Rehman 2, Kamran Ahmad Khan 2, Shefaat Ullah Shah 2, Kifayat Ullah Shah 2, Amir Badshah 3 and Izhar Hussain 4 1 Department of Pharmacy, University of Balochistan, Quetta, Pakistan. 2 Faculty of Pharmacy, Gomal University, D. I. Khan, Pakistan. 3 Department of Pharmacy, University of Peshawar, Pakistan. 4 Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad, Pakistan. Accepted 24 February, 2012 The objective of the study was to formulate and evaluate sustained release polymeric tablets of ketoprofen for the release rate, release patterns and the mechanism involved in the release process of the drug. Formulations with three different types of newly synthesized polymers and one grade of ethyl cellulose ether derivatives (FP100 premium) in several drug-to-polymer ratios (D:P ratio 10:1, 10:2 and 10:3) were compressed into tablets using the direct compression method. They were examined for their physical properties and appearance. Tablets dimensional tests (thickness, diameter) and Q.C tests (hardness, friability, disintegration) were performed according to the USP methods. For in vitro drug release studies of Ketoprofen controlled release (CR) tablets, the USP Method-1 (Rotating Basket Method) was used with Pharma test dissolution apparatus (D Hainburg, Germany). The medium used for dissolution was phosphate buffer having a ph of 7.4 kept at constant temperature of 37±1 C. In order to analyze the drug release kinetics from each of the prepared matrices, five different mathematical models were applied to the release data including zero order kinetics, first order kinetics, Higuchi kinetics, Hixson Crowell kinetics and Korsmeyer Peppas equations were applied to the release data. The results obtained from different parameters showed that polymers: Polyglycolide, PGA-cocaprolactone, PGA-co-pentadecalactone and Ethocel FP100 premium can be used successfully in order to develop directly compressed prolonged release tablets of slightly soluble drugs such as ketoprofen. Particle size of polymer is a determining factor in controlling the release of ketoprofen from tablets. Ethocel standard FP100 polymers extend the release rates of drug more efficiently than the conventional granular form of the other three polymers. Further, the three new polymers and Ethocel FP100 could efficiently extend the release of the drugs as compared to the reference conventional formulation. Key words: Polymers, Ketoprofen, controlled-release preparations. INTRODUCTION Efforts have been made in drug delivery system, e.g. targeted drug delivery system in which the drug is active in targeted area of the body to which it is targeted and sustained release formulation in which the drug is released over a period of time in controlled manner and specific time interval from the product (Drug Delivery, *Corresponding author: suj55@yahoo.com. Tel: ). Ketoprofen is a drug belonging to the group of nonsteroidal anti-inflammatory drugs (NSAIDs). It is a propionic acid derivative and is used in the treatment of rheumatoid arthritis. Its chemical formula is given as 2- benzoyl-3-phenyl propionic acid (Liversidge, 1981). Like other NSAIDs, ketoprofen is used in clinics as an antiinflammatory and analgesic drug for the treatments of rheumatoid arthritis and osteoarthritis (Therapeutic Drug Volume, 1991). Ketoprofen has advantages over other NSAIDs because it has no or very little addictive potential and also has no effect on sedation and depression of

2 602 Afr. J. Pharm. Pharmacol. respiration (Green, 2001). NSAIDs including ketoprofen have poor tolerability profile having some adverse effects (Evans, 1996). Due to inhibition of COX-1, various side effects are produced; whereas, on the inhibition of COX-2, their therapeutic effects are developed (Villegas et al., 2004). Some common adverse effects are gastrointestinal tract complaints such as nausea, vomiting and epigastric discomfort. Certain nervous system disorders include headache, drowsiness and dizziness, and also lower gastro intestinal tract infection (Vavra, 1987). Certain studies were performed in mice, rats and dogs, etc, in which rats were found to exhibited gastrointestinal tract (GIT) and renal system toxicity (Kantor, 1986). Dogs were also found to be susceptible for ulceration and irritation of GIT but no carcinogenic effect was found in standard screening assays (Kantor, 1986). To overcome these adverse effects, it was thought to prepare controlled release matrix formulations of ketoprofen using three newly synthesized polymers along with one ethyl cellulose ether derivatives (Ethocel FP100 premium) for comparison. Ethocel standard FP premium is the new product; it exists in a very fine particle form, thus allowing the use of direct compression to incorporate into the controlled release matrix (Khan and Zhu, 2001a, Wahab et al., 2011). The new polymers, if made into fine particles will give more extended release which can be used as polymers of choice in CR formulations in future. We also studied other viscosity grades of polymer Ethocel, and data is already published, (Jan et al., 2011) and only one grade compared (FP 100) with the newly synthesized polymers. The objective of the study was to formulate and evaluate sustained release polymeric tablets of ketoprofen for the release rate, release patterns and the mechanism release rate, release patterns and the mechanism involved in the release process of the drug. METHODOLOGY Material and chemicals Monobasic potassium phosphate, NaOH, (Merck, Germany), ketoprofen, lactose, magnesium stearate (BDH Chemical Ltd, Pool England), polymers polyglycolic acid (PGA), PGA-co-caprolactone, PGA-co-pentadecalactone and Ethocel FP100 Premium, Pharma test dissolution apparatus (D-63512, Hainburg), UV-Visible spectrophotometer (UVIDEC-1601 Shimadzu, Japan), single punch tablet machine (Erweka AR 400, Germany), hardness tester (Erweka Apparatus TB24, Germany), friability tester (Erweka TA3R, Germany). Construction of standard calibration curve 20 mg of ketoprofen was taken in a 100 ml volumetric flask for the preparation of stock solutions in 100 ml phosphate buffer (ph 7.4). The drug was dissolved using ultra-sonifier. This stock solution was used for further dilutions. 50 ml of this stock solution was taken in a 100 ml volumetric flask and 50 ml of the buffer was added to increase the volume to 100 ml. The concentration of the drug in this first dilution was 0.1 mg/ml. Then from this dilution, 50 ml was taken and further diluted to 100 ml, where the buffer the drug concentration in solution was 0.5 mg/ml. Similarly 0.025, and mg/ml dilutions were prepared in the same way. These dilutions were then analyzed at 258 nm using UV visible spectrophotometer. Formulation development 200 mg tablet of ketoprofen containing 100 mg drug and three new types of polymers and Ethocel FP100 premium grade at drug to polymer ratio of 10:1, 10:2, and 10:3 were developed. Lectose was used as filler and 0.5% magnisium stearate was used as a lubricant. The formulations are given in Table 1. Preparation of tablets The drug and polymer were weighed and mixed using mortar and pestle, and then filler was added and mixed. All these ingredients were passed through 30 mesh sieve screen. Lubricant was added in the end, then again passed twice through the same sieve, and were directly compressed in tablets using single punch tablet machine (Erweka AR 400, Germany). Physical characterization of the tablets After the tablet preparation, the quality control tests were carried out for each formulation. These tests includes, hardness test performed for ten tablets according to USP method, using hardness tester (Erweka, Germany).The dimensional tests of the tablets were performed using Vernier caliper according to USP method. The friability test was carried out in a friabilator on 20 tablets from each formulation. Disintegration test was performed on six tablets from each formulation, using disintegration apparatus. All the physical tests performed were within established ranges. In vitro drug release study For dissolution study, Pharma test dissolution apparatus (D Hainburg, Germany) was used. Rotating basket (USP method I) was adopted for the dissolution study of all tablet formulations. For ketoprofen, the dissolution media used was 7.4 ph phosphate buffer. Temperature of dissolution medium was maintained at 37± 0.5 C and the rotating speed was 100 rpm. Samples of 5 ml were taken at time intervals of 0.5, 1, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, , 12.0, 18.0 and 24 h and filtered using filter paper of 0.45 µm. Then all samples were observed spectrophotometrically (UV visible spectrophotometer 1601, Shimadzu) and their respective absorbances were noted. Then, the percent release was calculated for all tablets from the standard curves. Drug release kinetics investigation The following kinetic models and equations were applied on the data obtained from in vitro dissolution studies of different matrix tablets formulations to determine the release kinetics (Table 2). Statistical analysis Statistical analysis were performed, using computer based excel program for calculation of mean and standard deviation.

3 Jan et al. 603 Table 1. Ketoprofen tablet formulation. D:P ratio Drug Polymer Filler (lactose) Lubricant Co-excipients 10:1 100 mg 200 mg Ketoprofen-polymer matrices PGA 0.5% PGA-co-CL PGA-co-PDL 10 mg 89 mg 1 mg Ethocel 100 FP 10:2 100 mg PGA PGA-co-CL PGA-co-PDL Ethocel 100 FP 20 mg 79 mg 1 mg :3 100 mg PGA PGA-co-CL PGA-co-PDL Ethocel 100 FP 30 mg 69 mg 1 mg Table 2. Kinetic models and equations applied on the data of in vitro dissolution studies. 1 Zero-order kinetics W = K 1t (Xu and Sunada, 1995) 2 First-order kinetics In (100-W) = In100 K 2t (Xu and Sunada, 1995) 3 Higuchi-kinetics W = K 4t 1/2 (Higuchi, 1963) 4 Hixson-Crowell kinetics (100 - W) 1/3 = 100 1/3 - K 3t (Xu and Sunada, 1995) 5 Korsmeyer-Peppas equation Mt/M = K 5 t n (Ritger and Peppas, 1987) RESULTS AND DISCUSSION Drug release studies Drug release studies were carried out on all formulations after the dissolution study conducted on each formulation. The release profile of ketoprofen tablets containing different types of polymers, that is, PGA, PGAco-caprolactone, PGA-co-pentadecalactone and Ethocel FP100 premium in different ratios of 10:1, 10:2 and 10:3, is given in Figures 1 to 3. Figure 4 shows comparison of conventional tablets of ketoprofen and reference SR tablets of Ketoprofen with the prepared ketoprofen matrix tablets with drug to polymer ratio of 10:2 of different polymers. From the Figures 1, 2 and 3, it can be observed that the prepared matrix formulations of ketoprofen showed reduced release profiles from that of the standard conventional tablets of the respective drugs. These figures also showed that the release profile is more decreased in case of the tablets containing FP premium grades of Ethocel 100 as compared to other polymers which have comparatively larger particles. It can be observed from these figures that those formulations containing three new polymers showed about 95 to 98% release of the drug from tablet in 24 h; whereas, in case of Ethocel FP100 premium it showed less release in 24 h. Swelling of the matrix tablets occurred during the dissolution. This may be due to hydrating property of the polymer which eventually leads to the swelling of the tablet. Due to this swelling phenomena, the polymer s glass transition temperature (Tg), the dissolution solvent provides a stress due which there is relaxation response in the polymer-chains and this create an increase in the distance between the polymer-chains (Khan and Zhu, 2001a). An increase in the molecular volume is produced in the hydrated polymer, due to which free volume is diminished because of the presence of microspores. This could be a shift in release mechanism of the drug from polymer. A lot of other researchers and investigators also observed the same results when they were performing their studies (Khan and Zhu, 2001). In vitro drug release kinetics Drug release kinetics for each matrix was analyzed using the modals discussed earlier. Tables 3, 4 and 5 show the release kinetics of ketoprofen tablets having different drug to polymer ratio of 10:1, 10:2 and 10:3. The n value

4 Percentage Release Percentage Release 604 Afr. J. Pharm. Pharmacol. 120 Release profile of Ketoprofen + Polymers (10:1) hr 0.5hr 1hr 1 1.5hr 2hr 2 3hr 3 4hr 4 5hr 5 6hr 6 8hr 8 10hr 12hr 16hr 24hr Time Elapsed Time Elapsed (h) Poly(glycolide).PGA PGA-co-Pentadecalactone PGA-co-Caprolactone Ethocel FP100 Premium Figure 1. Comparison of percent drug release from varying polymers at drug to polymer ratio 10: Release profile of Ketoprofen + Polymers (10:2) hr 0.5hr 1hr 1.5hr 2hr 3hr 4hr 5hr 6hr 8hr 10hr 12hr 16hr 24hr Time Elapsed Time Elapsed (h) Poly(glycolide).PGA PGA-co-Pentadecalactone PGA-co-Caprolactone Ethocel FP100 Premium Figure 2. Comparison of percent drug release from varying polymers at drug to polymer ratio 10:2. was also greater than 0.5. it indicates that the ketoprofen formulations shows anomalous-non Fickian drugdiffusion. These results confirming with the findings of Amit (2010), in whose investigation on zidovudine release from guar gum matrix tablets, shows a higher value of n, that is, n > 0.5. Here, the author (Amit) concluded that

5 Percentage Release Jan et al Release profile of Ketoprofen + Polymers (10:3) hr 0.5hr 1hr 1.5hr 2hr 3hr 4hr 5hr 6hr 8hr 10hr 12hr 16hr 24hr Time Elapsed Time Elapsed (h) Poly(glycolide).PGA PGA-co-Caprolactone PGA-co-Pentadecalactone Ethocel FP100 Premium Figure 3. Comparison of percent drug release from varying polymers at drug to polymer ratio 10:3. (h) Figure 4. Comparison of percent drug release from varying polymers at drug to polymer ratio 10:2 along with conventional dosage form and SR Tablet. mechanism of the drug release was a result of coupling of two mechanisms, that is, erosion and diffusion. The formulation containing Ethocel standard FP100 premium showed better release kinetics as compared to other formulations containing different grades of polymers.

6 606 Afr. J. Pharm. Pharmacol. Table 3. Release kinetics of controlled release tablets of Ketoprofen + PGA, PGA-co-CL, PGA-co-PDL and Ethocel FP100 at drug to polymer ratio (D:P) of 10:1 in ph 7.4 phosphate buffer. Formulation ketoprofen + polymers W = k1t (100-w) = ln100-k2t (100-w)1/3= 1001/3-k3t W = k4t1/2 Mt / M = k5 tn k1 ± S D r1 k2 ± SD r2 k3 ± SD r3 k4± SD r4 k5 ± SD r5 n Controlled release tablets of Ketoprofen - PGA 10: ± ± ± ± ± Controlled release tablets of Ketoprofen - PGA-co-CL 10: ± ± ± ± ± Controlled release tablets of Ketoprofen - PGA-co-PDL 10: ± ± ± ± ± Controlled release tablets of Ketoprofen - Ethocel FP100 Premium 10: ± ± ± ± ± Table 4. Release kinetics of controlled release tablets of Ketoprofen + PGA, PGA-co-CL, PGA-co-PDL and Ethocel FP100 at drug to polymer ratio (D:P) of 10:2 in ph 7.4 phosphate buffer. Formulation ketoprofen + polymers W = k 1t (100-w) = ln100-k 2t (100-w) 1/3 = 100 1/3 - k 3t W = k 4t 1/2 M t / M = k5 t n k1 ± S D r1 k2 ± SD r2 k3 ± SD r3 k4 ± SD r4 k5 ± SD r5 n Controlled release tablets of ketoprofen - PGA 10: ± ± ± ± ± Controlled release tablets of ketoprofen - PGA-co-CL 10: ± ± ± ± ± Controlled release tablets of ketoprofen - PGA-co-PDL 10:2 453 ± ± ± ± Controlled release tablets of ketoprofen - Ethocel FP100 Premium 10: ± ± ± ± ± Conclusion The results obtained from different parameters showed that polymers: polyglycolide, PGA-cocaprolactone, PGA-co-pentadecalactone and Ethocel FP100 Premium can be used successfully in order to develop directly compressed prolonged release tablets of slightly soluble drugs such as ketoprofen. Particle size of polymer is a determining factor in controlling the release of ketoprofen from tablets. Ethocel standard FP100 polymers extend the release rates of drug more efficiently then the conventional granular form of the other three polymers. Further, the three new polymers and Ethocel FP100 could efficiently extend the release of the drugs as compared to the reference conventional formulation. The new polymers, if

7 Jan et al. 607 Table 5. Release kinetics of controlled release tablets of Ketoprofen + PGA, PGA-co-CL, PGA-co-PDL and Ethocel FP100 at drug to polymer ratio (D:P) of 10:3 in ph 7.4 phosphate buffer. Formulation ketoprofen + polymers W = k1t (100 - w) = ln100 - k2t (100-w)1/3 = 1001/3 - k3t W = k4t1/2 Mt / M = k5 tn k1 ± S D r1 k2 ± SD r2 k3 ± SD r3 k4 ± SD r4 k5 ± SD r5 n Controlled release tablets of ketoprofen - PGA 10: ± ± ± ± ± Controlled release tablets of ketoprofen - PGA-co-CL 10: ± ± ± ± ± Controlled release tablets of ketoprofen - PGA-co-PDL 10: ± ± ± ± ± Controlled release tablets of ketoprofen - Ethocel FP100 Premium 10: ± ± ± ± ± made into fine particles will give more extended release which can be used as polymers of choice in CR formulations in the future. ACKNOWLEDGEMENTS The authors are thankful to Dr. Gillian A. Hutcheon and Dr. Elsie Gaskell, Senior Lecturers in School of Pharmacy and Chemistry, Liverpool John Moores University, Liverpool, UK, for providing me facilities for polymer synthesis. We are also thankful to the HEC Pakistan for providing me the training facility in Liverpool UK, for polymer synthesis. REFERENCES Amit SY (2010). Design and evaluation of Guar gum based controlled release matrix tablets of Zidovudine. J. Pharm. Sci. Technol., 2(3): Drug Delivery (2007). Available at: Evans JM, MacDonald TM (1996). Tolerability of topical NSAIDs in the elderly. Do they really convey a safety advantage? Drugs Ageing, 9: Green GA (2001). Understanding NSAIDs: from aspirin to COX-2. Clin. Corner Sports Med., 3: Higuchi T (1963). Mechanism of Rate of Sustained-Action Medication. Theoretical Analysis of Rate of Solid Drugs Dispersed In Matrices. J. Pharm. Sci., 52: Jan SU, Khan GM, Khan KA, Rehman A, Khan H (2011). Invitro release pattern of Ketoprofen using ethyl cellulose ether derivatives. J. Appl. Pharm., 01(03): Liversidge GG (1981). Ketoprofen. In Analytical Profiles of Drug Substances Volume 10, K. Florey (ed.), Academic Press, London, UK. pp Therapeutic Drugs (1991). Dollery C. Churchill Livingstone, London, UK, 2: Kantor TG (1986). Ketoprofen: a review of its pharmacologic and clinical properties. Pharmacotherapy, 6: Khan GM, Zhu JB (2001). Evaluation of Ethocel Premium ethylcellulose derivatives with different molecular weighs as controlled release matrix forming functional polymers for Ibuprofen. Sciences, 1: Ritger RL, Peppas NS (1987). A simple equation for disposition of solute release ll: Fickian and anomalous release from swellable devices. J. Control Release, 5: Vavra (1987). Ketoprofen. In Nonsteroidal Anti-Inflammatory Drugs, A. J. Lewis, D. E. First (eds.), Marcel Dekker Inc., New York, USA, pp Villegas I, La Casa C, de la, Lastra AA, Motilva V, Herrerías JM, Martin MJ (2004). Mucosal damage induced by preferential COX-1 and COX-2 inhibitors: role of prostaglandins and inflammatory response. Life Sci., 74: Wahab A, Khan GM, Akhlaq M, Khan NR, Hussain A, Zeb A, Rehman A, Shah KU (2011). Pre-formulation investigation and in vitro evaluation of directly compressed ibuprofen- Ethocel oral controlled release matrix tablets: A kinetic approach. Afr. J. Pharm. Pharm., 5(19): Xu GJ, Sunada H (1995). Influence of formulation changes on drug release kinetics from hydroxypropyl methylcellulose matrix tablets. Chem. Pharm. Bull., 43: