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.
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.
