Alternative Formulations of Tenofovir and UC781

描述（由申请人提供）：本U19申请题为“替诺福韦和UC 781的替代制剂”，提交了对RFA-AI-08-001“艾滋病毒局部杀微生物剂的临床前/临床综合计划”的回应，寻求资金支持四个项目和三个核心。本提案中概述的研究包括制剂研究、临床前和动物模型试验以及早期（探索性IND）临床研究，支持开发非核苷类逆转录酶抑制剂（NNRTI）UC 781和核苷酸类逆转录酶抑制剂替诺福韦的薄膜制剂。该计划包括一个转化研究项目，以开发UC 781和替诺福韦的薄膜制剂（项目1，丽莎罗汉）;猪尾猕猴模型中的产品分布、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UC 781的薄膜和凝胶制剂的功效和安全性的早期人体研究（项目3，Sharon Hillier）和UC 781和替诺福韦的凝胶与薄膜制剂的药代动力学的探索性IND研究（项目4，克雷格亨德里克斯）。这四个高度相关的科学项目将得到行政和方案管理核心（核心A，Sharon Hillier）、微生物学/病毒学核心（核心B，Bernard Moncla，Charlene Dezzutti，Charles Isaacs）以及药物和监管核心（核心C，大卫朋友，Jill Schwartz）的支持。药物核心将巩固非营利组织持有的专有权利，以开发UC 781和替诺福韦作为局部杀微生物剂（CONRAD）与商业实体，生产薄膜制剂。拟议研究的完成将支持以薄膜和凝胶制剂提供高效抗艾滋病毒药物（如UC 781和替诺福韦）的可行性。拟议的工作是相关的IPCP计划的目标，通过推进局部杀微生物剂的新剂型，通过整合的安全性，药代动力学，药效学和对先天免疫的影响的早期评估，并通过开发新的杀微生物剂疗效模型。在完成拟定研究后，薄膜制剂可转入I期临床研究 相关性：局部杀微生物剂是正在开发的用于减少性传播病毒（包括HIV）传播的产品。这项多项目申请中提出的研究将确定以薄膜制剂形式提供UC 781和替诺福韦（具有强效抗HIV活性的化合物）的可行性、安全性和有效性。这些新的薄膜制剂将与相同药物的凝胶制剂进行比较。 项目1： 标题：用于递送UC 781和替诺福韦的剂型设计策略 项目负责人：罗汉，L 项目1描述（由申请人提供）：杀微生物剂产品开发已成为艾滋病毒预防领域的一个重要焦点。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，如果这种方法要取得成功，就需要可接受的候选杀微生物剂配方。虽然已经确定了一些潜在的杀微生物剂候选药物，但很少关注产品配方。逆转录酶抑制剂替诺福韦（tenofovir，TFV）和UC 781对HIV具有显著的活性。虽然凝胶阴道产品目前正在评估在临床上为这些候选人，最终，它可能是必要的开发多个剂量 平台，为用户提供他们可以在社交网络的限制范围内随时使用的产品。 环境、个人选择和环境条件。在该计划中，将为TFV、UC 781以及两者的组合开发快速溶解阴道膜。薄膜剂型易于施用，制造成本低，易于运输，并且消除了对产品施用器的需要。该项目还解决了UC 781的配方问题，该问题影响所有剂型类型。UC 781具有非常低的水溶性，并且经历氧化降解。这一属性使公式化变得困难。在本项目中，将探索使用络合和共结晶作为UC 781的增溶和稳定的手段。该化合物的成功溶解/稳定化将为更有效地将UC 781掺入剂型提供基础。最终，将对一组分散的薄膜和凝胶制剂以及实施这些递送策略的制剂进行全面的产品比较。最有希望的制剂将在项目2中进行猴安全性和有效性测试，并最终通过核心C扩大规模，并在项目3和4中进行人体研究。该项目还包括评估使用熔融挤出的潜力，从生产和经济角度来看，熔融挤出为TFV和UC 781薄膜产品的生产提供了一定的好处。将热熔挤出制造与水溶剂浇铸技术进行比较。 相关性：该项目对于设计用于递送UC 781、TFV及其组合的替代安全有效剂型的总体计划目标至关重要。将开发用于阴道内应用的聚合物膜药物递送系统用于这些逆转录酶抑制剂。将研究解决与UC 781和替代薄膜制造技术相关的溶解度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.