Designing optimal microbicide delivery integrating rheology and acceptability

描述(申请人提供)：今年可能会增加250万人，在已经感染艾滋病毒/艾滋病的大约3500万人的基础上，其中50%是妇女。局部杀微生物剂为这些妇女提供了防止性传播感染(STI)的手段，包括艾滋病毒。然而，除了对当前杀微生物剂的生物效力的担忧外，用户对其使用的接受度和坚守程度并不理想。据估计，一种即使药效有限的杀微生物剂每年也可以预防数百万新的艾滋病毒病例。阴道杀菌剂剂型的设计向配方科学家提出了挑战。安全有效的产品是必要的，但不足以保证遵守。用户可接受性既取决于材料的物理属性，也取决于行为因素。必须在开发早期确定和解决推动接受度的制约因素。必须在临床前评估该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有效药物成分(API)，然后在1-3天内缓慢释放API以维持疗效。这种剂型可以被认为是一个暂时的阴道环/横隔膜，随着API(S)的慢慢侵蚀而释放出来。这些产品将是目前软胶囊技术的改编。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。人类的感知数据将在整个设计过程中进行评估和指导。卡拉胶将用于开发热稳定性软凝胶，与目前的明胶胶囊不同，这种软凝胶不会在热带环境中融化。软凝胶(‘胚珠’)的两相性质将允许包含第二种成分。我们的R21目标为这一新的交付系统提供了概念验证，而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，如粘附性或输送益生菌。 在这里，我们提出了一种新的杀微生物剂递送系统，旨在克服现有产品的生物学(HIV中和不足)和行为(可接受性和依从性差)缺陷。通过设计具有最佳药效和最佳使用效果(可接受性/依从性)的配方，通过这些方法生产的杀微生物剂对艾滋病毒/艾滋病大流行的影响可能比目前正在开发的杀菌剂更大。此外，通过开发一种多种因素(形状、质地、大小和多阶段交付)发挥核心作用的阴道产品设计方法，我们增加了女性在使用杀微生物剂方面的选择。重要的是，我们的产品类型灵活-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。 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，因此对妇女主动和受控的预防方案的需求很大。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既能有效防止艾滋病毒传播又能被使用者接受的产品--如果产品粘稠或凌乱，女性就不会使用它们，即使她们在实验室工作。在这里，我们将用户可接受性纳入优化过程的早期，以制作同时最大化药物输送和用户可接受性的配方，而不是仅将可接受性作为配方过程中的事后考虑。

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.