David R Swanson

Nifedipine gastrointestinal therapeutic system

Convenient once-a-day dosage regimens are highly desirable in general, and especially for the treatment of asymptomatic diseases such as essential hypertension. Nifedipine is an insoluble, short-acting calcium channel blocker that presents a difficult technical challenge for formulation in a constant 24-hour delivery dosage form. Once-a-day dosage forms have been developed based on the gastrointestinal therapeutic system (GITS) push-pull osmotic pump configuration in three strengths with different drug delivery rates (mg/hour) per dose (mg), as 1.7/30, 3.4/60, and 5.1/90. The delivery rates of drug from these systems are controlled by their drug loading, composition of osmotic components, membrane properties, and dimensions. The release rates are independent of pH in the range from gastric pH = 1.2 to intestinal pH = 7.5. The release rates are independent of stirring rate and therefore unlikely to be influenced by motility in the gastrointestinal tract. The drug release rate from the nifedipine GITS dosage form in vivo in the gastrointestinal tract of dogs has been found to be equal to the release rate in vitro, indicating that the in vitro test is predictive of in vivo delivery. Following administration of the nifedipine GITS dosage forms to human subjects, absorption rates, calculated from resulting plasma concentrations, indicate that the cumulative amount of drug absorbed in humans over 24 hours is proportional to the amounts of drug delivered in vitro. Plasma concentrations are therefore predictable and remain relatively constant throughout the 24-hour dosing interval.

Use of osmotically active therapeutic agents in monolithic systems

Abstract The functionality of a new class of monolithic systems for the controlled release of drugs is discussed. The systems consist of uniformly dispersed particles of osmotically active therapeutic agents (drugs) in biocompatible polymeric matrices. The drug particles are encapsulated by polymers to form a multiplicity of microcapsules throughout the matrix. These osmotic film systems display zero-order drug delivery kinetics. The principal energy source governing the release of agents is osmotic in nature. When such a film is placed in an aqueous infinite sink, the film imbibes water into the outermost layer of the dispersion at a rate dictated by permeability of the polymer. Water transport into the film continues until volumetric rupture of the drug-containing capsules occurs, after which time saturated drug solution is pumped through channels created by the rupture. This process repeats itself in a serial fashion until the system is exhausted of agent. Due to the osmotic functionality of these systems, reduction of the thermodynamic activity of water outside the system can proportionally reduce the release of agent. In this paper the effects of varying drug particle size, osmotic pressure gradients, system area, drug type, polymer type, and temperature upon the drug release kinetics are presented. Application of this new technology has allowed the fabrication of several useful drug therapeutic systems.