Designing Optimal Microbicide Delivery Integrating Rheology and Acceptability

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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.