Practical Formulations of HIV-1 Entry Inhibitors

本申请的中心假设是，当HIV-i与靶细胞融合时， 当适当配制和适当使用时，联合使用可以预防阴道或阴道炎。 艾滋病毒i的直肠传播。在研究项目II中，我们将重点关注杀微生物剂的关键问题 制剂和递送。我们意识到最近大规模试验的经验表明， 遵守是当今杀微生物剂研究和开发中的一个非常重要的问题。具体为 现在严重关注的是，在性交前使用的杀微生物剂是否 是一个真正实用的主张;临床试验中的依从性差可能很容易转化为有限的使用 如果任何产品获得许可证。因此，研究项目二的目标是开发持久的， 用于基于入口通道的杀微生物剂的不依赖性交的递送方法， 每天施用一次的持续释放半固体制剂，和控制释放阴道环 其可以在原位提供活性化合物的连续和恒定的供应持续一段时间， 应用单个器械后数周/数月。这两种截然不同的配方策略是 在这个项目中，由于广泛接受的共识， 将需要提高杀微生物剂产品的质量，以满足妇女不同的社会和文化偏好。 项目二有四个具体目标： 含有小分子进入抑制剂CMPD 167、BMS-C和 AMD 3465。2)开发含有肽的新型控释阴道环（“插入棒”环） 进入抑制剂T-124 Q。3)开发含有复方制剂的控释阴道环 抑制剂的4)开发小分子进入抑制剂的缓释半固体制剂 CMPD 167、BMS-C、AMD 34&5和T-1249，单独使用和联合使用，每日一次。 项目负责人是R。卡尔·马尔科姆博士，Mark Mitchnick博士和A.大卫伍夫森， 博士作为共同调查员。本项目的阴道环制剂部分将在 在英国贝尔法斯特女王大学药学院， 将在Particle Sciences Inc.美国宾夕法尼亚州。这两个团体都有相当多的专业知识， 各自的制定任务。

The central hypothesis of the application is that specific inhibitors of HIV-i fusion with target cells, when used in combination and when properly formulated and used appropriately, could prevent the vaginal or rectal transmission of HIV-i. In Research Project II, we will focus on the critical issue of microbicide formulation and delivery. We are conscious of recent experience from large-scale trials indicating that compliance is a very significant issue in microbicide research and development today. Specifically, there are now serious concerns whether a microbicide intended for use immediately prior to sexual intercourse is a truly practical proposition; poor compliance in clinical trials may easily translate to the limited usage should any product make it to licensure. Therefore, the aim of Research Project II is to develop longlasting, coitally-independent delivery methods for entry inhibitor-based microbicides, in the form of sustained release semi-solid formulations that are applied once daily, and controlled release vaginal rings that can provide a continuous and constant supply of the active compound(s) in situ for a period of weeks/months after application of a single device. These two very different formulation strategies are deliberately being pursued within this project on account of the widely accepted consensus that a number of microbicide products will be required to meet the differing social and cultural preferences of women. There are four specific objectives within Project II: i) To develop controlled-release matrix and reservoirtype vaginal ring devices containing each of the small molecule entry inhibitors CMPD 167, BMS-C and AMD3465. 2) To develop novel controlled release vaginal rings ('rod-insert' rings) containing the peptide entry inhibitor T-124Q. 3) To develop controlled release vaginal rings containing combination entry inhibitors. 4) To develop sustained-release semi-solid formulations of the small molecule entry inhibitors CMPD 167, BMS-C, AMD34&5 and T-1249, both alone and in combination, for once-daily application. The Project Leader will be R. Karl Malcolm, Ph.D., with Mark Mitchnick, Ph.D. and A. David Woolfson, Ph.D. acting as co-investigators. The vaginal ring formulation component of the Project will be conducted at the School of Pharmacy, Queen's University Belfast, UK, while the semi-solid formulation component will be conducted at Particle Sciences Inc. PA, US. Both groups have considerable expertise in their respective formulation tasks.