Designing Optimal Microbicide Delivery Integrating Rheology and Acceptability

项目摘要/摘要 对你的项目写一个科学家和外行都能理解的简洁总结。如果您的应用程序得到了资金支持，则您的摘要将成为 美国国立卫生研究院CRISP数据库中的公共文件。不要包含机密或专有信息。 今年，在已经感染的大约3500万人的基础上，可能会增加250万人 艾滋病毒/艾滋病，其中50%是妇女。局部杀微生物剂为这些妇女提供了一种防止性行为的手段 传播感染(STI)，包括艾滋病毒。然而，除了对沙门氏菌生物功效的担忧外， 目前的杀微生物剂，用户对其使用的接受度和坚持程度都不是最理想的。据估计， 一种即使药效有限的杀微生物剂每年也可以防止数百万新的艾滋病毒病例。这个 阴道杀菌剂剂型的设计向配方科学家提出了挑战。安全有效 产品是必要的，但不足以保证遵守。用户的可接受性取决于 物质的物理性质和行为因素。推动接受度的约束必须是 在开发的早期确定和解决。必须评估该产品对女性的接受度 临床前的。我们建议合理的临床前设计和开发一种能够提供 立即有效剂量的有效药物成分(API)，然后是API的缓释 在1-3天内保持药效。这种剂型可以被认为是一种临时性阴道 当空气污染指数(S)慢慢被侵蚀时释放出来的环/隔膜。这些产品将是对当前 软胶囊技术。然而，与目前的明胶胶囊不同，我们将开发一系列非明胶 胶囊的形状和硬度(质地)各不相同。人类感知数据将在整个过程中和 指导设计流程。卡拉胶将用于开发耐热软凝胶，不同于 目前的明胶胶囊，在热带环境下不会融化。软凝胶的两相特性(‘胚珠’) 将允许包括第二个组件。我们的R21目标提供了这一新的概念验证 R33目标将优化可接受性和生物物理功能。R33将 还要探索潜在的更高层次的功能，如粘液黏附或益生菌的输送。 在这里，我们提出了一种新的微生物输送系统，旨在克服生物(不足) 现有产品的缺陷(艾滋病毒中和)和行为缺陷(可接受性和依从性差)。通过 设计具有最佳疗效和最佳使用功能的配方(可接受性/依从性)； 通过这些方法生产的杀微生物剂可能会对艾滋病毒/艾滋病大流行产生更大的影响 目前正在开发的项目。此外，通过开发一种设计阴道的方法 在多种因素(形状、质地、大小和多阶段交付)起核心作用的产品中，我们 增加妇女在使用杀微生物剂方面的选择。重要的是，我们的产品类型是灵活的-允许 多种纹理、大小、形状和抗病毒策略-以适应一系列用户偏好。

PROJECT SUMMARY / ABSTRACT Write a succinct summary of your project that both a scientist and a lay person can understand. If your application is funded, your abstract becomes a public document in the NIH CRISP database. Don't include confidential or proprietary information. This year perhaps 2.5 million people will be added to the approximately 35 million already infected with HIV/AIDS, 50% of whom are women. Topical microbicides offer these women a means to prevent sexually transmitted infections (STIs), including HIV. However, in addition to concerns about the biological efficacy of current microbicides, user acceptance of and adherence to their use is suboptimal. It has been estimated that a single microbicide with even limited efficacy could prevent millions of new HIV cases annually. The design of vaginal microbicide dosage forms has challenged formulation scientists. Safe and efficacious products are necessary, but not sufficient to assure adherence. User acceptability depends both on the physical properties of the material and behavioral factors. Constraints that drive acceptance must be identified and addressed early in development. The acceptability of the product to women must be evaluated preclinically. We propose the rational preclinical design and development of an dosage form that delivers an immediate efficacious dose of active pharmaceutical ingredient (API) followed by the slow release of API over a period of 1-3 days to maintain efficacy. This dosage form can be thought of as a temporal vaginal ring/diaphragm that releases API(s) as it slowly erodes away. These products will be an adaptation of current softgel capsule technology. However, unlike current gelatin capsules, we will develop a range of non-gelatin capsules varying in shape and firmness (texture). Human perceptual data will be assessed throughout and guide the design process. Carrageenan will be used for the development of heat-stable softgels that, unlike current gelatin capsules, will not melt in tropical environments. The two-phase nature of softgels ('ovules') will permit the inclusion of a second component. Our R21 goals provide for proof-of-concept of this new delivery system, and the R33 goals will optimize both acceptability and biophysical functionality. The R33 will also explore potential higher-order functionality, like mucoadhesion or delivery of probiotics. Here, we propose a new microbide delivery system, designed to overcome both biological (insufficient HIV neutralization) and behavioral (poor acceptability and adherence) deficiencies of current products. By designing formulations that function for optimal efficacy and optimal use (acceptability / adherence), microbicides produced via these methods are likely to have a greater impact on the HIV/AIDS pandemic that those currently in the development pipeline. Also, by developing a methodology for design of vaginal products where multiple factors (shape, texture, size, and multi-stage delivery) play a central role, we increase the options women have in microbicide use. Critically, our product type is flexible - allowing for multiple textures, sizes, shapes and antiviral strategies - to accommodate a range of user preferences.