INTRAVAGINAL CONTROLLED DELIVERY OF MISOPROSTOL

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Prolonged labor in the context of an unfavorable cervix can lead to maternal and fetal complications. Pharmacological intervention is often implemented in an effort to "ripen" the cervix and facilitate vaginal delivery. Use of prostaglandins for labor induction through intracervical and inravaginal administration is well documented. Recently, misoprostol has received considerable interest because of its superior clinical efficacy, ease of administration, and cost. It is administered intravaginally using the same tablets given orally for preventing gastric ulcers. The most desirable effects of misoprostol were achieved using lower and more frequent dosing regimens. This provided the incentive to prepare an earlier application to explore intravaginal, controlled release of misoprostol to optimize its safety and efficacy. Phase I objective of the revised present application is to determine feasibility of developing an intravaginal, controlled delivery system for misoprostol, and it entails (1) synthesis and characterization of absorbable gel-forming, liquid carriers, which gel on the vaginal mucosa; (2) completion of in vitro release studies to identity optimum gel-formers; (3) selection of promising formulations for studying cervical ripening in pregnant rabbits at the conclusion of an in vivo pilot study on dose range in selected carriers; (4) biochemical, biomechanical, and histological tissue evaluation to assess cervical ripening; and (5) identification of one formulation for Phase II study. This will entail completing development and scale-up studies of polymers and formulation, conducting safety and efficacy studies on large animals, and preparing an IDE application. PROPOSED COMMERCIAL APPLICATIONS: Primary outcome of a successful Phase I is demonstrating feasibility of using an absorbable gel-former for development of a delivery system for intravaginal release of misoprostol and obtaining basic data for planning Phase II. In addition to providing a means of labor induction to facilitate vaginal delivery and minimize maternal and fetal complications, the long- range impact of this technology will be its extension to other intravaginal agents.