T.J. Roseman

Design criteria for controlled release delivery systems of carboprost methyl

Abstract Permeabilities of carboprost methyl (15(s)-15 methyl prostaglandin F 2 α methyl ester) were determined for a series of synthetic polymeric membranes. Membrane compositions consisted of a polyurethane ether and a series of poly(co-ethylene) vinyl acetate copolymers with vinyl acetate concentrations varying from 9% w/w to 60% w/w. Permeability increased as a function of the percent vinyl acetate in the copolymer. The increase in permeability was mainly due to an increase in the solubility of carboprost methyl in the polymer. Diffusion coefficients were independent of vinyl acetate concentrations above 9% w/w. The highest permeability and solubility value was associated with the polyurethane polymer. Membranes of identical composition yielded different transport rates depending upon the method of preparation (casted versus blown) and transport rates were inversely related to the thickness of the membrane. Permeability was shown to be a key parameter in determining the sequencing of polymeric membranes in the design of laminated controlled release delivery systems for carboprost methyl.

Menses induction in rhesus monkeys using a controlled-release vaginal delivery system containing (15S)15-methyl prostaglandin F2α methyl ester*

Polymeric controlled-release vaginal delivery systems were designed for (15S)15-methyl prostaglandin (PG)F2 alpha methyl ester (carboprost methyl). The drug was incorporated into a highly permeable reservoir membrane that was bound to a relatively nonpermeable support membrane. The rate of drug release was controlled by coating the reservoir membrane with a less permeable rate-controlling membrane. Vaginal devices were prepared with in vitro steady-state release rates from 5 to 180 microgram/hour. The release curves were characterized by an initial, transient rapid release of the drug, followed by a linear zero-order release phase. Pregnancy was terminated in rhesus monkeys following a 24-hour treatment with vaginal devices having release rates of carboprost methyl of 45 microgram/hour or greater. Successful menses induction was associated with peripheral plasma concentrations of (15S)15-methyl PGF2 alpha between 2000 and 3000 pg/ml. Peripheral plasma concentrations of progesterone declined very rapidly to less than 1.0 ng/ml in monkeys in which pregnancy was terminated. These studies demonstrate the feasibility of manufacturing controlled-release vaginal delivery systems containing carboprost methyl for use in early pregnancy termination.