Film Antiretroviral Microbicide Evaluation

 说明(由申请人提供)：妇女使用杀微生物剂产品的意愿与减少给药频率以及产品的便利性和吸引力有关。阴道电影被认为具有许多女性想要的属性。将这一平台的谨慎和紧凑特性与其他优势相结合，如感知的易用性、减少泄漏、增强药物释放和减少对先天免疫屏障的干扰，薄膜提供了一种可能导致患者接受性和产品功效提高的剂型。在评估达匹韦林药膜和替诺福韦药膜的两个不同的临床试验中，已经说明了使用药膜以安全和可接受的方式将药物按需递送到阴道的可行性。对达匹韦林薄膜的人体研究表明，经阴道给药情况与凝胶和 环状剂型。此外，药膜的药物组织水平与阴道内环使用的药物组织水平相匹配，这在体外激发试验中被证明与保护有关。虽然这个平台用于按需应用的可行性已经被证明，但其作为扩展发布产品使用的能力还有待探索。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的阴道膜，达到在单一应用后一周内达到有效抗性感染艾滋病毒的宫颈阴道组织药物水平。在非人类灵长类动物模型的初步研究中，一种原型MK-2048膜被证明能够在两次单独的性交行为后在靶组织中保留显著水平的MK-2048，长达96小时。在项目1中，将探索三种策略来开发每周管理的MK-2048电影。主要策略包括修改薄膜几何结构和赋形剂组成，以延长MK-2048的释放。在这一战略中，将使用NHP模型(核心B)中产品保留和释放的迭代评估来优化MK-2048在阴道中的给药概况和保护水平的实现(项目2，核心C)。即使在性行为的背景下，维持保护水平的能力也将在这一模式中得到证实。开发的胶片将被放大(项目4)，并在人体临床试验中进行评估(项目3)。此外，在项目1中，将探索以纳米技术为基础的替代战略，以延长薄膜的保护窗口。我们小组之前曾使用纳米颗粒与薄膜平台相结合来克服阴道给药的挑战。含有MK-2048的纳米颗粒将被开发并合并到薄膜平台中，以提供增强的组织保持和靶向。最后，将开发一种非常新颖和创新的方法来增加胶片保留率。这一策略是基于微米/纳米管与薄膜平台的结合，以实现增强的阴道产品保留率。成功设计一种MK-2048薄膜，提供延长的保护窗口，将为预防妇女感染艾滋病毒提供一种方便的选择。

 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.