Alternative Formulations of Tenofovir and UC781

描述（由申请人提供）：这份名为“替诺福韦和UC781的替代配方”的U19申请是为了响应RFA-AI-08-001“HIV局部杀微生物剂的临床前/临床综合计划”而提交的，寻求资助四个项目和三个核心。该提案中概述的研究包括配方研究，临床前和动物模型测试以及早期（探索性IND）临床研究，以支持非核苷类逆转录酶抑制剂（NNRTI） UC781和核苷酸类逆转录酶抑制剂替诺福韦的薄膜配方的开发。该计划包括一个转化研究项目，开发UC781和替诺福韦的薄膜配方（项目1，Lisa Rohan）；在尾尾猕猴模型中进行产品分布、安全性、有效性和药代动力学研究（项目2，Dorothy Patton），比较替诺福韦和UC781薄膜和凝胶制剂的有效性和安全性的早期人体研究（项目3，Sharon Hillier），以及UC781和替诺福韦凝胶和薄膜制剂的药代动力学的探索性IND研究（项目4，Craig Hendrix）。这四个高度相关的科学项目将由行政和协议管理核心（核心A， Sharon Hillier），微生物学/病毒学核心（核心B， Bernard Moncla, Charlene Dezzutti, Charles Isaacs）和制药和监管核心（核心C， David Friend, Jill Schwartz）提供支持。Pharmaceutical Core将把持有UC781和替诺福韦作为局部杀微生物剂（CONRAD）的专有开发权利的非营利组织与生产薄膜配方的商业实体合并。拟议研究的完成将支持以薄膜和凝胶形式提供高效抗hiv药物（如UC781和替诺福韦）的可行性。通过整合早期安全性评估、药代动力学、药效学和对先天免疫的影响，并通过开发新的杀微生物剂功效模型，提出了一种新的局部杀微生物剂剂型，从而与IPCP计划的目标相关。在完成拟议的研究后，薄膜配方可以过渡到1期临床研究

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.