Floating Osmotic Drug Delivery System of Ranitidine Hydrochloride: Development and Evaluation—A Technical Note

Abstract

Under certain circumstances prolonging the gastric retention of a delivery system is desirable for achieving greater therapeutic benefit of the drugs. For example, drugs that are absorbed in the proximal part of the gastrointestinal tract (1), and drugs that are less soluble in or are degraded by the alkaline pH may benefit from prolonged gastric retention (2). In addition, for local and sustained drug delivery to the stomach and proximal small intestine to treat certain conditions, prolonged gastric retention of the therapeutic moiety may offer numerous advantages including improved bioavailability and therapeutic efficacy, and also the possible reduction of dose size (3). Gastroretentive drug delivery systems (GRDDS) can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of drugs. Various GRDDS reported in literatures provide controlled delivery of drugs in matrix and/or reservoir type systems. The release of drugs from reservoir/matrix type systems is affected by hydrodynamic conditions of the absorption site and also results in bioavailability fluctuation due to gastric pH variation. Osmotic drug delivery system (ODDS) utilizes the principles of osmotic pressure for controlled delivery of drugs (4). Drug release from these systems is independent of pH and other physiological parameters to a large extent and exhibit significant in vitro–in vivo correlation (5). Drug delivery from ODDS follows zero-order kinetics hence provides better control over in-vivo performance. Ranitidine hydrochloride (RH) is a histamine H2-receptor antagonist. It is widely prescribed in active duodenal ulcers, gastric ulcers, Zollinger–Ellison syndrome, gastroesophageal reflux disease, and erosive esophagitis (6). The recommended adult oral dosage of ranitidine is 150 mg twice daily or 300 mg once daily. The effective treatment of erosive esophagitis requires administration of 150 mg of ranitidine four times a day (6). A frequent dosage schedule for patients often leads to poor patient compliance; thus a sustained release dosage form of RH is desirable. The short biological half-life of drug (2.5–3 h) also favours for development of a sustained release formulation. A traditional oral sustained release formulation of RH releases most of the drug at the colon; due to less solubility of RH in small intestine, thus the drug have absorption window in the colon or in stomach. Ranitidine is absorbed only in the initial part of the small intestine and has 50% absolute bioavailability (6). Moreover, colonic metabolism of ranitidine is partly responsible for the poor bioavailability of ranitidine from the colon (7). These properties of RH do not favour the traditional approach to sustained release delivery. Hence, clinically acceptable sustained release dosage forms of RH prepared with conventional technology may not be successful. With all these considerations in mind, we designed floating osmotic drug delivery system (FODDS) of RH. FODDS consists of an osmotic core (containing drug, osmotic agent and excipients), an inner semipermeable membrane (SPM), and an outer compression coating of gelling agent containing gas generating agent and an orifice drilled through both membranes for delivery of drug. When system comes in contact with gastric environment, gas generating agent, generate CO2 by reacting with the surrounding fluid, the gas generated is trapped and protected within the gel (formed by hydration of gelling agent), thus decreasing the density of tablet. As the density of tablet falls below 1 (density of water), the tablet becomes buoyant. At the same time, the osmotic core also draws surrounding fluid across semipermeable membrane because of osmotic pressure gradient and form saturated solution of the drug. This pressure is relieved by the flow of saturated solution of drug through the delivery orifice.