119 Indomethacin sustained release pellets prepared by extrusion-spheronization G.M. Mahrous 1 *, M.A. Ibarhim 2 , M. El-Badry 1 , F.K. Al-Anazi 1, 2 1 Department of Pharmaceutics, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia 2 Kayyali Chair for Pharmaceutical Industry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia *Correspondence: gmmarous@ksu.edu.sa, gmmahroos@yahoo.com Gastrointestinal side effects may interrupt essential therapy with indomethacin, a non-steroidal anti-infammatory drug. Formulation of this drug into sustained release multiparticulate form may reduce some of these side effects by avoiding contact of drug crystals with gastrointestinal mucosa at high concentrations, as may happen with immediate release dosage forms. Indomethacin (IM) sustained release pellets containing 5 or 10 % w/w of the drug were prepared using an extrusion-spheronization technique. Different concentrations of hydrophilic polymers, polyeth- ylene glycol 4000 (PEG 4000), hydroxypropyl methylcellulose E5 LV premium (HPMC) and polyvinyl pyrrolidone (PVP K30), were mixed at different concentrations (5,10 and 20 %) with Avicel PH 101 to prepare the sustained release formulae. Moreover, a mixer torque rheometer was used to quantitatively determine the suitable moisture content in the pastes before the extrusion process. The resulting pellets were characterized for content, particle size, shape and dissolution profle. The studies on the effect of the polymers used on Avicel rheological properties revealed that the magnitude of torque for the system was decreasing as the polymer concentration increased. The in vitro release of IM from the prepared Avicel pellets was found to be dependent upon the type and concentration of the added polymer. The rank order of IM release in the presence of the investigated polymers was as follows: PEG > HPMC > PVP. Furthermore, the magnitude of IM release rate from the pellet formulations was found to be dependent on the magnitude of the peak torque of the pellet forming paste, which in turn depends on the type and concentration of the added polymer. Increasing IM loading from 5 to 10 % has led to an increase in dissolution rates. At least two of the prepared pellet formulations showed dissolution profles similar to the commercial product Bonidon 75 SR capsules. In conclusion, the formulation of IM sustained release pellets successfully controlled the drug release which might be benefcial in lowering the risk of side effects and improving patient convenience as an advantage of the pellets as a drug delivery system. Key words: Indomethacin – Pellets – Extrusion-spheronization – Hydrophilic polymers – Kinetics. J. DRUG DEL. SCI. TECH., 20 (2) 119-125 2010 The interest in pellets as dosage forms has been increasing continu- ously. Pellets as a drug delivery system offer therapeutic advantages such as less irritation of the gastro-intestinal tract and a lowered risk of side effects due to dose dumping [1]. In addition, technological advantages, for example better fow properties, less friable dosage form, narrow particle size distribution, ease of coating and uniform packing can be achieved with pellets. The pellets in the form of spheri- cal granules with a diameter of 0.1-2 mm as a “multiple unit” form of the drug are easier to assess than “single unit” form tablets. As a drug delivery system, pellets ensure less irritation of the gastro-intestinal tract and a lower risk of side effects [1-2]. Indomethacin (IM) is a non-steroidal anti-infammatory drug used in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and other disorders. The oral administration of conventional dosage forms of indomethacin can cause serious systemic side effects and gastric irritation [3]. Moreover, dosage regimens involving con- ventional oral dosage forms require drug administration three or four times daily to maintain adequate therapeutic effectiveness, with the inherent problems associated with patient compliance. Additionally, the conventional dosage forms do not protect patients against morning joint stiffness which is common in rheumatoid disease states [4]. Thus the development and clinical use of sustained or controlled release dosage forms of indomethacin may have several advantages over the use of conventional capsule formulations, e.g. reduction of the side effect, prolongation of drug action and improvement of bioavailability and patient compliance [5]. It has been shown that the rheological properties of wet masses can be successfully monitored by a mixer torque rheometer [6-8]. The use of the mixer torque rheometer (MTR) as an upfront analytical tool can greatly reduce the number of develop- ment batches. This equipment has been shown to be an excellent tool for the evaluation of wet granulated systems and as a scale-up tool for high shear granulations [9]. Several authors have compared the rheological properties of different microcrystalline cellulose (MCC) systems [10-12], but the rheological properties of polymeric addi- tives on microcrystalline cellulose have not hitherto been extensively studied. The amount of water added at the maximum torque should be comparable with that found for the optimum production of pellets during spheronization [10]. Extrusion and spheronization is currently one of the techniques used to produce pharmaceutical pellets. With each production technique, pellets with specifc characteristics are obtained. The preparation of spherical granules or pellets by extrusion and spheronization is now a more established method because of its advantages over the other methods [13-14]. The main purpose of this study is to produce a sustained release IM multiparticulate formulation using extrusion-spheronization technique. I. MATERIALS AND METHODS 1. Materials Indomethacin (IM) was purchased from Avocado Research Chemicals Ltd. (Heysham, Lancs, United Kingdom). Hydroxypro- pyl methylcellulose low viscosity grade, Methocel E5 PREM LV, (HPMC) was kindly donated by DOW (Midland, MI, United States). Polyethylene glycol 4000 (PEG 4000) was purchased from Koch-Light Laboratories Ltd. (Colnbrook, Bucks, United Kingdom). Polyvinyl pyrrolidone (PVP K30) was purchased from Fluka chemica (Buch, Switzerland). Microcrystalline cellulose (Avicel PH101) was purchased from Serva Feinbiochemica (Heidelberg, Germany). Bonidon 75 SR capsules (Mepha Ltd. Aesch-Basel, Switzerland). All other materials and solvents used are of reagent or analytical grade and they were used without further purifcation.