Film Antiretroviral Microbicide Evaluation

薄膜抗逆转录病毒杀菌剂评价

• 批准号: 9089929
• 负责人: Sharon L. Hillier
• 金额: $ 404.4万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089929
• 关键词: AIDS prevention; Achievement; Adherence; Anti-Retroviral Agents; Biological Assay; Blood; Centers for Disease Control and Prevention (U.S.); Cervical; Characteristics; Chemicals; Clinical Research; Clinical Trials; Coitus; Cold Chains; Contraceptive Agents; Data; Development; Dosage Forms; Dose; Drug Delivery Systems; Drug Kinetics; Evaluation; Excipients; Extravasation; Family suidae; Female; Film; Formulation; Frequencies; Gel; Genital system; Geometry; Goals; HIV; HIV Infections; HIV Integrase Inhibitors; Hour; Human; Immune; In Vitro; Inflammation Mediators; Injectable; Integrase Inhibitors; Interview; Laboratory Animal Models; Lead; Link; Macaca; Macaca nemestrina; Male Condoms; Marketing; Modeling; Modification; Mucous Membrane; Mucous body substance; Nanotechnology; Nature; Oral; Pamphlets; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Preclinical Testing; Production; Program Evaluation; Research Personnel; Risk; Safety; TMC120-R147681; Tail; Tenofovir; Tissues; Vagina; Vaginal Ring; Vaginal delivery procedure; Woman; base; cervicovaginal; computerized; contraceptive effectiveness; cost; design; human female; human tissue; in vivo; innovation; iterative design; manufacturing scale-up; meetings; microbicide; nanoparticle; nanopattern; nonhuman primate; novel; pharmacokinetic model; phase 1 study; predictive modeling; prevent; programs; prototype; reproductive tract; scale up; sex; simian human immunodeficiency virus; sound; uptake; wasting; willingness

 DESCRIPTION (as provided by applicant): The willingness of a woman to use a microbicide product has been linked to reduction of dosing frequency and product convenience and appeal. Vaginal films have been identified to possess a number of attributes which women find desirable. Combining the discreet and compact nature of this platform with other advantages such as perceived ease of use, reduced leakage, enhanced drug release, and decreased disturbance of innate immune barriers, films offer a dosage form which may lead to enhanced patient acceptability and product efficacy. The feasibility of on-demand delivery of pharmaceutical agents to the vagina in a safe and acceptable manner using a film has been illustrated in two separate clinical trials evaluating a dapivirine film and a tenofovir film. Huma studies of the dapivirine film showed that the vaginal delivery profile was consistent with gel and ring dosage forms. Further, drug tissue levels for film matched those achieved with intravaginal ring use which were shown to be associated with protection in an ex vivo challenge assay. Although the feasibility of utility of this platform for on-demand applications has been demonstrated, its ability to be modified for use as an extended release product has yet to be explored. The Project 1 goal is to design a non-coitally dependent vaginal film for the integrase inhibitor MK-2048 that achieves cervicovaginal tissue drug levels that are effective against the sexual acquisition of HIV for one week following a single application. In preliminary studies in the nonhuman primate model, a prototype MK-2048 film was shown to have the ability to retain significant levels of MK-2048 in the target tissue up to 96 hours post film administration followin two separate acts of coitus. Within Project 1, three strategies will be explored to develop a weekly administered MK-2048 film. The primary strategy involves modification of film geometry and excipient composition to extend the release of MK-2048. Within this strategy iterative evaluation of product retention and release in the NHP model (Core B) will be used to optimize the delivery profile and achievement of protective levels of MK-2048 in the vagina (Project 2, Core C). The ability to maintain protective levels even in the context of sex will also be confirmed in this model. The developed film will be scaled up (Project 4) and evaluated in human clinical trials (Project 3). Additionally within Project 1 alternative nanotechnology based strategies for extending the window of protection with the film will be explored. Our group has previously used nanoparticles combined with the film platform to overcome vaginal drug delivery challenges. Nanoparticles containing MK-2048 will be developed and incorporated into the film platform to provide enhanced tissue retention and targeting. Finally, a highly novel and innovative approach to increase film retention will be developed. This strategy is based on the combination of micro/nanopatterns with the film platform to achieve enhanced vaginal product retention. Successful design of an MK-2048 film which provides an extended window of protection would offer a convenient option for protection against HIV infection in women.

 描述（由申请人提供）： 女性使用杀菌剂产品的意愿与减少用药频率以及产品的便利性和吸引力有关，已确定阴道膜具有女性认为所需的许多特性。该平台的谨慎性和紧凑性以及其他优点，例如易于使用、减少泄漏、增强药物释放和减少对先天免疫屏障的干扰，薄膜提供了一种可以提高患者可接受性和产品功效的剂型。两项独立的临床试验评估了达匹韦林薄膜和替诺福韦薄膜，这表明使用薄膜以安全且可接受的方式按需将药剂递送至阴道的效果。与凝胶一致并且 此外，膜的药物组织水平与阴道内使用环所达到的水平相匹配，这在离体激发试验中显示与保护相关，尽管该平台用于按需应用的可行性已得到证明。 ，其作为缓释产品进行修改的能力仍有待探索。项目 1 的目标是为整合酶抑制剂 MK-2048 设计一种非性交依赖性阴道薄膜，以达到有效的宫颈阴道组织药物水平。在非人类灵长类动物模型中的初步研究中，原型 MK-2048 薄膜在单次施用后一周内能够抵抗 HIV 的性传播，其能够在目标组织中保留显着水平的 MK-2048，最高可达 96。在项目 1 中，在两次独立的性交行为后的薄膜施用后数小时内，将探索三种策略来开发每周施用的 MK-2048 薄膜，主要策略包括修改薄膜的几何形状和赋形剂成分以延长药物的释放。 MK-2048。在该策略中，NHP 模型（核心 B）中的产品保留和释放的迭代评估将用于优化 MK-2048 在阴道中的递送曲线和实现的保护水平（项目 2，核心 C）。即使在性行为的情况下也能维持保护水平，所开发的薄膜也将在项目 1 中扩大规模（项目 4）并在人体临床试验中进行评估（项目 3）。我们的团队将探索基于替代纳米技术的策略，以延长薄膜的保护范围，以克服阴道药物输送的挑战，并将开发含有 MK-2048 的纳米粒子，并将其纳入薄膜平台中。最后，将开发一种高度新颖和创新的方法来增加薄膜保留，该策略基于微/纳米图案与薄膜平台的结合，以实现增强的阴道产品保留。 MK-2048 薄膜提供了更长的保护窗口，将为女性预防艾滋病毒感染提供便捷的选择。