Designing optimal microbicide delivery integrating rheology and acceptability

描述（由申请人提供）：今年可能会增加250万人，大约3500万人已经感染艾滋病毒/艾滋病，其中50%是妇女。局部杀微生物剂为这些妇女提供了预防性传播感染（STI），包括艾滋病毒的手段。然而，除了对当前杀微生物剂的生物功效的关注之外，用户对它们的使用的接受和坚持是次优的。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。阴道杀微生物剂剂型的设计对配方科学家提出了挑战。安全有效的产品是必要的，但不足以确保依从性。用户可接受性取决于材料的物理特性和行为因素。必须在开发的早期识别和解决驱动接受的约束。必须在临床前评估产品对女性的可接受性。我们建议合理的临床前设计和开发一种剂型，该剂型提供立即有效剂量的活性药物成分（API），然后在1-3天内缓慢释放API以维持疗效。该剂型可被认为是暂时的阴道环/隔膜，其在缓慢侵蚀时释放API。这些产品将是目前软胶囊技术的适应。然而，与目前的明胶胶囊不同，我们将开发一系列形状和硬度（质地）不同的非明胶胶囊。人类感知数据将在整个过程中进行评估，并指导设计过程。卡拉胶将用于开发热稳定的软胶囊，与目前的明胶胶囊不同，它不会在热带环境中融化。软胶囊（“胚珠”）的两相性质将允许包含第二组分。我们的R21目标提供了这种新输送系统的概念验证，R33目标将优化可接受性和生物物理功能。R33还将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杀微生物剂输送系统，旨在克服目前产品的生物（艾滋病毒中和不足）和行为（可接受性和依从性差）缺陷。通过设计具有最佳功效和最佳使用（可接受性/坚持性）的配方，通过这些方法生产的杀微生物剂可能比目前正在开发的杀微生物剂对艾滋病毒/艾滋病流行病产生更大的影响。此外，通过开发一种设计阴道产品的方法，其中多个因素（形状，质地，大小和多阶段交付）起着核心作用，我们增加了妇女在使用杀微生物剂方面的选择。最重要的是，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-以适应一系列用户的喜好。 公共卫生相关性：在全球范围内，艾滋病毒是一种异性恋疾病，因此对妇女发起和控制的预防方案有强烈的需求。杀微生物剂有很强的潜力来满足这一需求，但前提是配方科学家能够制造出有效预防艾滋病毒传播的产品，同时又能被使用者接受--如果产品粘粘的或凌乱的，女性就不会使用它们，即使她们在实验室工作。在这里，我们在优化过程的早期将用户可接受性纳入其中，以使制剂同时最大限度地提高药物输送和用户可接受性，而不是仅将可接受性视为制剂过程中的事后考虑。

DESCRIPTION (provided by applicant): 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 a 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 microbicide 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 than 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. PUBLIC HEALTH RELEVANCE: Globally, HIV is a heterosexual disease, so there is a strong demand for women initiated and controlled prevention options. Microbicides have strong potential to meet this need, but only if formulation scientists can make products that effectively prevent HIV transmission while being acceptable to users - if products are sticky or messy, women will not use them, even if they work in the lab. Here, we incorporate user acceptability early in the optimization process to make formulations that maximize drug delivery and user acceptability at the same time, instead of considering acceptability only as an afterthought in the formulation process.