INTRAVAGINAL CONTROLLED DELIVERY OF MISOPROSTOL

在宫颈不良的情况下延长分娩时间可能会导致母婴并发症。药物干预通常是为了使宫颈“成熟”并促进阴道分娩。使用前列腺素通过宫颈和阴道内给药引产是有很好的文献记载的。最近，米索前列醇因其优越的临床疗效、给药方便和成本而受到极大的关注。它在阴道内服用，与口服预防胃溃疡的药片相同。米索前列醇最理想的效果是使用更低和更频繁的给药方案。这促使人们准备早期应用，探索米索前列醇在阴道内的受控释放，以优化其安全性和有效性。修订后的本申请的第一阶段目标是确定开发米索前列醇阴道内控释系统的可行性，它包括(1)合成和表征可吸收凝胶形成的液体载体，将其凝胶化在阴道黏膜上；(2)完成体外释放研究，以确定最佳凝胶形成剂；(3)在对选定载体的剂量范围进行体内初步研究后，选择适合研究怀孕兔宫颈成熟的制剂；(4)进行生化、生物力学和组织学组织学评价，以评估宫颈成熟；以及(5)确定第二阶段研究的一种配方。这将需要完成聚合物和配方的开发和放大研究，在大型动物身上进行安全性和有效性研究，并准备IDE应用。拟议的商业应用：第一阶段成功的主要结果是证明了使用可吸收凝胶形成剂开发米索前列醇阴道内释放的给药系统的可行性，并为第二阶段的规划获得了基本数据。除了提供一种促进阴道分娩和将母婴并发症降至最低的引产手段外，这项技术的长期影响将是它延伸到其他阴道内药物。

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.