Alternative Formulations of Tenofovir and UC781

替诺福韦和 UC781 的替代制剂

• 批准号: 8471636
• 负责人: Sharon L. Hillier
• 金额: $ 280.8万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8471636
• 关键词: AIDS prevention; Address; Animal Model; Anti-HIV Agents; Attention; Clinic; Clinical; Clinical Research; Coitus; Crystallization; Development; Dosage Forms; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Economics; Evaluation; Film; Friends; Funding; Gel; Goals; HIV; Human; Local Microbicides; Macaca nemestrina; Microbiology; Modeling; Monkeys; Natural Immunity; Nonprofit Organizations; Nucleotides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Pre-Clinical Model; Production; Protocols documentation; Research; Research Project Grants; Reverse Transcriptase Inhibitors; Rights; Safety; Social Environment; Solubility; Solvents; Techniques; Technology; Tenofovir; Testing; Translational Research; UC 781; Vagina; Vaginal Gel; Virus; Work; aqueous; base; combat; comparative efficacy; design; dosage; drug candidate; efficacy testing; melting; microbicide; non-nucleoside reverse transcriptase inhibitors; novel; pre-clinical; prevent; product development; programs; response; safety testing; scale up; transmission process; virology

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.

描述（由申请人提供）：这份题为“替诺福韦和 UC781 的替代制剂”的 U19 申请是为了响应 RFA-AI-08-001“HIV 局部杀微生物剂综合临床前/临床计划”而提交的，寻求资金支持四个项目和三个核心项目。该提案中概述的研究包括制剂研究、临床前和动物模型测试以及早期（探索性 IND）临床研究，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薄膜制剂的开发。该计划包括开发 UC781 和替诺福韦薄膜制剂的转化研究项目（项目 1，Lisa Rohan）；猪尾猕猴模型中的产品分布、安全性、功效和药代动力学研究（项目 2，Dorothy Patton），比较替诺福韦和 UC781 薄膜和凝胶制剂功效和安全性的早期人体研究（项目 3，Sharon Hillier）以及探索性 IND 研究UC781 和替诺福韦凝胶制剂与薄膜制剂的药代动力学比较（项目 4，Craig Hendrix）。这四个高度相关的科学项目将得到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）以及制药和监管核心（核心 C、大卫·弗兰德、吉尔·施瓦茨）。 Pharmaceutical Core 将把持有 UC781 和替诺福韦局部杀菌剂 (CONRAD) 开发专有权利的非营利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以薄膜和凝胶制剂形式提供高效抗 HIV 药物（例如 UC781 和替诺福韦）的可行性。拟议的工作与 IPCP 计划的目标相关，通过整合安全性、药代动力学、药效学和对先天免疫的影响的早期评估，并通过开发新的杀菌剂功效模型，推进局部杀菌剂的新剂型。完成拟议的研究后，薄膜配方可以过渡到一期临床研究 相关性：外用杀菌剂是为减少包括艾滋病毒在内的性传播病毒的传播而开发的产品。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 UC781 和替诺福韦这两种具有有效抗 HIV 活性的化合物的可行性、安全性和有效性。这些新颖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：UC781 和替诺福韦的剂型设计策略 项目负责人：ROHAN, L 项目 1 描述（由申请人提供）：杀菌剂产品开发已成为 HIV 预防领域的一个重要焦点。这些产品在性交前使用，以防止感染艾滋病毒，有可能成为对抗艾滋病毒传播的第一道防线。然而，如果这种方法要成功，就需要可接受的候选杀菌剂配方。尽管已经确定了许多潜在的杀菌剂候选药物，但很少有人关注产品配方。逆转录酶抑制剂替诺福韦 (TFV) 和 UC781 具有显着的抗 HIV 活性。尽管目前正在临床上针对这些候选者评估凝胶阴道产品，但最终可能有必要开发多种剂量 为用户提供在其社交范围内可以轻松使用的产品的平台 环境、个人选择、环境条件。在此计划中，将为 TFV、UC781 以及两者的组合开发快速溶解阴道膜。薄膜剂型易于施用，制造成本低廉，易于运输，并且无需产品涂抹器。该项目还解决了 UC781 的配方问题，该问题影响所有剂型类型。 UC781 的水溶性非常低并且会发生氧化降解。这个属性使得制定变得困难。在该项目中，将探索使用络合和共结晶作为 UC781 溶解和稳定的方法。该化合物的成功溶解/稳定将为 UC781 更有效地掺入剂型提供基础。最终，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将在彻底的产品比较中进行评估。最有前途的配方将在项目 2 中进行猴子安全性和功效测试，并最终通过 Core C 进行扩大规模，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体挤出的潜力。从制造和经济角度来看，为 TFV 和 UC781 薄膜产品的生产提供了一定的优势。热熔挤出制造将与水性溶剂浇铸技术进行比较。 相关性：该项目对于设计用于传递 UC781、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。将针对这些逆转录酶抑制剂开发用于阴道内应用的聚合物膜药物递送系统。将研究解决与 UC781 相关的溶解度和稳定性问题的配方策略以及替代薄膜制造技术。