Designing Optimal Microbicide Delivery Integrating Rheology and Acceptability

项目总结/摘要 为你的项目写一个科学家和外行都能理解的简洁的总结。如果你的申请得到资助，你的摘要将成为 NIH CRISP数据库中的公共文件。不要包含机密或专有信息。 今年，在已经感染艾滋病毒的大约3500万人的基础上，可能还会增加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。 包括艾滋病毒在内的性传播感染。然而，除了对生物功效的关注之外， 目前的杀微生物剂、使用者对其使用的接受度和坚持度是次优的。据估计 一种效力有限的杀微生物剂每年可以预防数百万新的艾滋病毒病例。的 阴道杀微生物剂剂型的设计对制剂科学家提出了挑战。安全有效 产品是必要的，但不足以确保遵守。用户可接受性取决于 材料的物理性质和行为因素。驱动接受度的约束必须是 在开发早期就已识别并解决。必须评估产品对女性的可接受性 临床前我们提出了合理的临床前设计和开发一种能够提供 立即有效剂量的活性药物成分（API），然后缓慢释放API 在1-3天的时间内维持功效。这种剂型可以被认为是暂时的阴道给药， 当API缓慢腐蚀时释放API的环/隔膜。这些产品将适应当前 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 胶囊在形状和坚固性（质地）上变化。人类感知数据将在整个过程中进行评估， 指导设计过程。卡拉胶将用于开发热稳定的软胶囊， 目前的明胶胶囊在热带环境中不会融化。软胶囊的两相性质（“胚珠”） 将允许包含第二组分。我们的R21目标提供了这一新的概念验证 输送系统，R33目标将优化可接受性和生物物理功能。R33将 还探索潜在的高阶功能，如粘膜粘附或益生菌的递送。 在这里，我们提出了一种新的microbide输送系统，旨在克服生物（不足） HIV中和）和行为（接受性和依从性差）缺陷。通过 设计用于最佳功效和最佳使用（可接受性/依从性）的制剂， 通过这些方法生产的杀微生物剂可能对艾滋病毒/艾滋病流行病产生更大的影响， 目前正在开发的管道。此外，通过开发阴道设计的方法， 产品的多个因素（形状，质地，尺寸和多阶段交付）发挥着核心作用，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 多种质地、大小、形状和抗病毒策略-以适应用户的偏好范围。

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.