Alternative Formulations of Tenofovir and UC781

描述(由申请人提供)：这份名为“替诺福韦和UC781的替代制剂”的U19申请是为了响应RFA-AI-08-001“艾滋病毒局部杀菌剂临床前/临床综合计划”而提交的，该申请寻求资金支持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支持开发非核苷类逆转录酶抑制剂UC781和核苷酸逆转录酶抑制剂替诺福韦薄膜制剂的早期(探索性IND)临床研究。该计划包括一个翻译研究项目，以开发UC781和替诺福韦薄膜制剂(项目1，Lisa Rohan)；在辫子猴模型中进行产品分布、安全性、疗效和药代动力学研究(项目2，Dorothy Patton)；比较替诺福韦和UC781薄膜和凝胶制剂的疗效和安全性的早期人体研究(项目3，Sharon Hillier)；以及UC781和替诺福韦凝胶制剂与替诺福韦薄膜制剂的药代动力学探索性IND研究(项目4，Craig Hendrix)。这四个高度相关的科学项目将得到一个行政和方案管理核心(核心A，Sharon Hillier)、一个微生物学/病毒学核心(核心B，Bernard Moncla、Charlene Dezzutti、Charles Isaacs)和一个制药和管理核心(核心C，David Friend、Jill Schwartz)的支持。制药核心公司将把拥有UC781和替诺福韦作为局部杀菌剂(Conrad)开发专有权的非营利性组织与生产薄膜制剂的商业实体合并。拟议研究的完成将支持在薄膜和凝胶配方中提供高效抗艾滋病毒药物的可行性，如UC781和替诺福韦。这项拟议的工作与IPCP计划的目标相关，通过整合安全性、药动学、药效学和对天然免疫的影响的早期评估，以及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。在建议的研究完成后，薄膜制剂可以过渡到第一阶段临床研究 相关：局部杀微生物剂是正在开发的产品，用于减少包括艾滋病毒在内的性传播病毒的传播。在这项多项目应用中提出的研究将确定在薄膜配方中提供UC781和替诺福韦的可行性、安全性和有效性，这两种化合物具有强大的抗艾滋病毒活性。这些新的薄膜配方将与相同药物的凝胶配方进行比较。 项目1： UC781和替诺福韦的剂型设计策略 项目负责人：罗翰、L 项目1说明(申请人提供)：杀微生物剂产品开发已成为艾滋病毒预防领域的一个基本重点。这些产品在性交前使用，以防止艾滋病毒感染，有可能成为抗击艾滋病毒传播的第一道防线。然而，如果这一方法要取得成功，则需要可接受的候选杀微生物剂配方。尽管已经确定了一些潜在的杀微生物剂候选药物，但对产品配方的关注很少。逆转录酶抑制剂替诺福韦(TFV)和UC781具有显著的抗HIV活性。尽管凝胶阴道产品目前正在为这些候选药物进行临床评估，但最终可能有必要开发多种剂量。 平台为用户提供他们可以在其社交网络的限制内随时使用的产品 环境、个人选择和环境条件。在这个项目中，将为TFV、UC781以及这两种药物的组合开发快速溶解阴道薄膜。薄膜剂型易于涂抹，制造成本低，易于运输，并且不需要产品涂抹器。该项目还解决了UC781的配方问题，该问题影响到所有剂型。UC781在水中的溶解度很低，可进行氧化降解。这一属性使表述变得困难。在本项目中，将探索使用络合和共结晶作为UC781的增溶和稳定手段。该化合物的成功增溶/稳定将为将UC781更有效地并入剂型提供基础。最终，一组分散的薄膜和凝胶配方以及实施这些输送策略的配方将在彻底的产品比较中进行评估。最有希望的配方将在项目2中进行猴子安全性和有效性测试，并最终通过核心C扩大规模，在项目3和4中提交人体研究。该项目还包括对熔融挤出使用的潜力进行评估，这从制造和经济角度为TFV和UC781薄膜产品的生产提供了一定的好处。将热熔融挤压制造技术与水溶液浇注技术进行比较。 相关性：该项目对于为UC781、TFV和它们的组合设计替代的安全有效的剂型的总体计划目标至关重要。针对这些逆转录酶抑制剂，将开发用于阴道内给药的聚合物薄膜给药系统。将研究解决与UC781和替代薄膜制造技术相关的溶解性和稳定性问题的配方策略。

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.