Ketorolac tromethamine (KT), (±)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (in 1:1 ratio), is a potent nonsteroidal anti-inflammatory drug (NSAID) without an opioid effect. It is a pyrrolizine carboxylic acid derivative, chemically related to indomethacin and tolmetin (1).
KT is indicated for the short-term management of moderately severe acute pain that would otherwise require treatment with an opioid analgesic. Like other NSAIDs, KT inhibits the activity of the enzyme cyclo-oxygenase, leading to decreased formation of precursors of prostaglandins and thromboxanes from arachidonic acid associated with gastrointestinal side effects (1). Oral KT is indicated only for the continuation of therapy following initial parenteral administration. Because of its short half-life (4–6 h), KT must be dosed frequently to maintain its therapeutic effect (2). Therefore it may be advantageous to administer sustained-release formulations to reduce side effects and improve patient compliance.
Previous studies on the risk of gastrointestinal bleeding associated with NSAIDs in animals (3) and in humans (4) proved that bermoprofen and flurbiprofen, respectively, formulated as sustained-release products were effective and well tolerated with fewer gastrointestinal side effects.The aim of controlled drug therapy is improved efficiency in treatment—that is, achieving the desired effect and maintaining it for an extended period of time. Objectives of sustained-release formulations include minimizing or eliminating patient compliance problems, minimizing drug accumulation in body tissues with chronic dosing, eliminating either local and systemic side effects, reducing or eliminating drug in blood?level fluctuactions (thereby allowing better disease state management), and improving the bioavailability of some drugs. A potential advantage is that the average cost of treatment over an extended time period may be lower than that of a conventional form (5).
Many investigators have studied the effect of using various techniques to prolong KT release. Genc and Hegazy reported on the preparation of sustained-release wax matrix formulations of KT with Compritol (6). The authors investigated the effect of cellulose matrices on controlling the release of KT and reported that by mixing the drug with an optimum amount of nonionic hydroxy propylmethylcellulose (HPMC) or methylcellulose and anionic sodium carboxymethyl cellulose polymers, excellent release profiles close to zero order were obtained (7). Vatsaraj et al. prepared KT swelling-controlled matrix tablets using three cellulose derivatives (8). Rokhade et al. reported on the preparation of controlled-release KT microspheres using gelatin and carboxymethyl cellulose sodium (9).
Eudragit (Rohm Pharma, Darmstadt, Germany) copolymers have been used to prolong KT release in a matrix formulation (10). Eudragit RL and Eudragit RS are insoluble in water and digestive juices. They are capable of swelling, and because of their permeability, the active ingredients are released by diffusion. They are pH-independent, which means that drug release takes place independently of individual variation. Eudragit polymers also have been used by other researchers to prolong the release of diclofenac and ketoprofen (11–13).
The aim of this study was to prepare sustained-release pellets of KT, that would be given twice per day and that would maintain the effective therapeutic concentration for as long as 12 h. The method would involve a simple microencapsulation technique using Eudragit RL and Eudragit RS and nonpareil seeds as carrier.
Materials. The following materials were used in this study: KT and propyl gallate (Dr. Reddy's Laboratories, Hyderabad, India); nonpareil seeds, mesh size 18–20 (Mendel, a Penwest company, Germany); Eudragit RS 100 powder and Eudragit RL/RS 12.5% solution; talc powder (Tardy, Italy); dibutyl phthalate and tetrahydrofuran (Merck, Darmstadt, Germany); methanol and isopropanol (BDH, Poole, England). Other chemicals and reagents were of analytical grade.
Preparation of KT pellets.
KT pellets were prepared using nonpareil seeds as an inert carrier. Nonpareil particles were first pan coated (Erweka AR400 apparatebau GmbH, Heusenstamm, Germany) successively with RS 100 solution in isopropyl alcohol (12.5%) until they became visually insoluble in water. KT was then applied onto nonpareil coated pellets in a conventional stainless steel pan using the following formula: