Alternative Formulations of Tenofovir and UC781

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DESCRIPTION (provided by applicant): This U19 application entitled "Alternative Formulations of Tenofovir and UC781" submitted in response to RFA-AI-08-001 "Integrated Preclinical/Clinical Program for HIV Topical Microbicides" seeks funding to support four projects and three cores. The research outlined in this proposal includes formulation research, preclinical and animal model testing and early (exploratory IND) clinical studies supporting development of film formulations of the nonnucleoside reverse transcriptase inhibitor (NNRTI), UC781 and the nucleotide reverse transcriptase inhibitor, tenofovir. The program includes a translational research project to develop film formulations of UC781 and tenofovir (Project 1, Lisa Rohan); product distribution, safety, efficacy and pharmacokinetic studies in the pigtailed macaque model (Project 2, Dorothy Patton), early human studies comparing the efficacy and safety of film and gel formulations of tenofovir and UC781 (Project 3, Sharon Hillier) and exploratory IND studies of the pharmacokinetics of gel vs film formulations of UC781 and tenofovir (project 4, Craig Hendrix). These four highly interrelated scientific projects will be supported by an Administrative and Protocol Management Core (Core A, Sharon Hillier), a Microbiology/Virology Core (Core B, Bernard Moncla, Charlene Dezzutti, Charles Isaacs), and a Pharmaceutical and Regulatory Core (Core C, David Friend, Jill Schwartz). The Pharmaceutical Core will consolidate the non-profit organization holding the proprietary rights to the development of UC781 and tenofovir as topical microbicides (CONRAD) with a commercial entities that produce film formulations. Completion of the proposed studies will support the feasibility of delivering highly potent anti-HIV drugs such as UC781 and tenofovir in film and gel formulations. The proposed work is relevant to the goals of the IPCP program by advancing a novel dosage form for topical microbicides through the integration of early assessment of safety, pharmacokinetics, pharmacodynamics, and impact on innate immunity, and through the development of novel models of microbicide efficacy. Upon completion of the proposed studies, the film formulations could be transitioned to Phase 1 clinical studies RELEVANCE: Topical microbicides are products which are being developed to reduce the transmission of sexually transmitted viruses including HIV. The studies proposed in this multi-project application will establish the feasibility, safety, and efficacy of delivering UC781 and tenofovir, compounds which have potent activity against HIV, in a film formulation. These novel film formulations will be compared to gel formulations of the same drugs. PROJECT 1: Title: Dosage Form Design Strategies For Delivery Of UC781 And Tenofovir Project Leader: ROHAN, L PROJECT 1 DESCRIPTION (provided by applicant): Microbicide product development has become an essential focus in the HIV prevention field. These products are applied prior to sexual intercourse to prevent HIV acquisition have the potential to become the first line of defense in combating the spread of HIV. However, acceptable formulations of microbicide candidates are required if this approach is to succeed. Although a number of potential microbicide drug candidates have been identified, little attention has been given to product formulation. The reverse transcriptase inhibitors tenofovir (TFV) and UC781 have significant activity against HIV. Although gel vaginal products are currently being evaluated in the clinic for these candidates, ultimately, it may be necessary to develop multiple dosage platforms to provide users with products that they can readily use within the constraints of their social environment, personal choice, and environmental conditions. In this program, quick dissolve vaginal films will be developed for TFV, UC781, and a combination of the two. Film dosage forms are easily applied, are inexpensively manufactured, are easily transportable, and eliminate the need for product applicators. This project also addresses a formulation issue with UC781 which impacts all dosage form types. UC781 has very low aqueous solubility and undergoes oxidative degradation. This attribute makes formulation difficult. In this project, the use of complexation and co-crystallization as a means for solubilization and stabilization of UC781 will be explored. Successful solubilization/stabilization of this compound will provide a basis for more efficient incorporation of UC781 into a dosage form. Ultimately a panel of dispersed film and gel formulations and formulations implementing these delivery strategies will be evaluated in a thorough product comparison. The most promising formulations will be advanced to monkey safety and efficacy testing in Project 2 and ultimately scaled up through Core C and brought forward to human studies in Projects 3 and 4. This project also includes evaluation of the potential for the use of melt extrusion which provides certain benefit from a manufacturing and economic standpoint, for the production of TFV and UC781 film products. Manufacture by hot melt extrusion will be compared with aqueous solvent casting technology. RELEVANCE: This project is essential to the overall program goal of designing alternative safe and effective dosage forms for the delivery of UC781, TFV, and their combination. Polymeric film drug delivery systems for intra-vaginal application will be developed for these reverse transcriptase inhibitors. Formulation strategies to address solubility and stability issues related with UC781 and alternate film manufacturing techniques will be studied.