Design Strategies for Film Dosing Forms

项目1概要 妇女愿意使用杀微生物剂产品与减少用药频率有关， 产品的便利性和吸引力。阴道膜已被确定具有许多属性， 女人们都很渴望将该平台的谨慎和紧凑特性与其他优势相结合 例如使用方便、减少渗漏、增强药物释放和减少先天性 免疫屏障，薄膜提供了一种剂型，可以提高患者的可接受性和产品 功效以安全和有效的方式按需向阴道递送药物制剂的可行性 在评价达匹韦林膜的两个独立的临床试验中， 和替诺福韦薄膜。达匹韦林薄膜的人体研究表明， 与凝胶和环剂型一致。此外，胶片的药物组织水平与使用 阴道内环使用，其在离体攻击试验中显示与保护相关。 尽管该平台用于按需应用程序的可行性已得到证明，但其 作为延长释放产品的使用还有待探索。项目1的目标是设计一个 整合酶抑制剂MK-2048的非性交依赖性阴道膜， 组织药物水平，有效地防止艾滋病毒的性获得一个星期后， 单一应用。在非人类灵长类动物模型的初步研究中， 显示出能够在靶组织中保留显著水平的MK-2048长达96小时 在两次单独的性交行为后给药。在项目1内，将探讨三项战略， 显影每周给药的MK-2048薄膜。主要的策略包括改变膜的几何形状， 本发明还提供了用于延长MK-2048的释放的赋形剂组合物。在该策略中，对产品进行迭代评估 NHP模型（核心B）中的保留和释放将用于优化递送概况和 MK-2048在阴道中的保护水平（项目2，核心C）。即使在环境中， 性的背景也将在这一模式中得到确认。将按比例放大已显影的胶片（项目4）， 在人体临床试验中进行评估（项目3）。此外，在项目1中，基于替代纳米技术 将探讨如何利用这部电影扩大保护范围。我们小组以前曾使用过 纳米颗粒与薄膜平台结合，以克服阴道给药的挑战。纳米颗粒 含有MK-2048将被开发并纳入电影平台，以提供增强的组织 保持和定位。最后，一个高度新颖和创新的方法，以增加电影保留将是 这种策略是基于微/纳米粒子与薄膜平台的结合，以实现 增强阴道产品保留。MK-2048薄膜的成功设计， 保护窗口将为保护妇女免受艾滋病毒感染提供一个方便的选择。

PROJECT 1 SUMMARY 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 desireable. Combining the discreet and compact nature of this platform with other advantages such as preceived 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 feasability of on-demand delivery of pharmacetucial 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. Human 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 feasiblity 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 following 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 achievment 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 clincial 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.