Practical Formulations of HIV-1 Entry Inhibitors

该应用的中心假设是，当HIV-I的特定抑制剂与靶细胞融合时， 配合使用，如果配方正确，使用得当，可以防止阴道或 HIV-I的直肠传播。在研究项目II中，我们将重点关注杀菌剂的关键问题 配方和交付。我们意识到最近大规模试验的经验表明 遵从性是当今杀微生物剂研发中的一个非常重要的问题。具体地说，有 现在严重关注性交前使用的杀微生物剂 是一个真正实用的命题；临床试验中依从性差很容易转化为有限的使用 是否有任何产品获得许可。因此，研究项目II的目标是开发长效的， 以以下形式的基于进入抑制剂的杀微生物剂的社区独立给药方法 每日使用一次的缓释半固体制剂和控释阴道环 可在原位连续、持续供应活性化合物(S)一段时间 在单一设备应用后的几周/几个月。这两种截然不同的表述策略是 在这个项目中被刻意追求，因为广泛接受的共识是 将需要大量杀微生物剂产品，以满足妇女不同的社会和文化偏好。 在项目II中有四个具体目标：i)开发受控释放基质和储层类型 含有小分子进入抑制剂CMPD 167、BMS-C和 AMD3465。2)开发含有多肽的新型控释阴道环(‘杆状插入’环) 进入抑制剂T-124Q。3)研制含有联合进入的控释阴道环 抑制剂。4)开发小分子进入抑制剂的缓释半固体制剂 CMPD 167、BMS-C、AMD34&5和T-1249，单独或组合使用，每日一次。 项目负责人将是R.Karl Malcolm博士、Mark Mitchnick博士和A.David Woolfson， 博士担任联合调查员。将进行项目的阴道环配方部分 在英国贝尔法斯特女王大学药学院，而半固体配方成分 将在美国宾夕法尼亚州粒子科学公司进行。这两组人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.