Anti-HIV-1 Composite Cellulose Acetate Phthalate Film

性状（由申请人提供）：邻苯二甲酸乙酸纤维素（CAP），用于制药行业片剂和胶囊的肠溶薄膜包衣，是一种HIV-1进入抑制剂，可阻断病毒上的CXCR 4/CCR 5辅助受体结合位点，并诱导病毒包膜上的“死端”gp 41六螺旋束。吸附的CAP是唯一的候选局部杀微生物剂，具有从生理液体中吸附HIV-1的能力，防止病毒与靶细胞接触。HIV-1和微粒化CAP之间的相互作用导致病毒解体和包膜糖蛋白脱落，从而导致感染性丧失。CAP还a）灭活疱疹病毒HSV-1、HSV-2、巨细胞病毒、淋病奈瑟氏球菌、阴道毛滴虫、杜克雷嗜血杆菌、沙眼衣原体、苍白密螺旋体和与细菌性阴道病相关的细菌; B）分别保护小鼠和恒河猴免受HSV-2和SIV的阴道感染。因此，CAP具有组合杀微生物剂的期望特性。CAP有一个既定的安全记录，是广泛可用的大量和廉价。为了进一步利用这些性质，有必要开发一种相称的递送系统，该系统简单、便宜、适于大规模生产，具有最小的处置问题。这些要求通过可分散的CAP膜来满足，所述可分散的CAP膜在水的存在下可转化成含有微粉化CAP的凝胶。需要进一步的工作来优化薄膜并将其投入大规模工业生产。这将在本提案的框架内完成。CAP膜也适用于递送除CAP之外的杀微生物剂。已为此目的选择羟丙基-β-环糊精（HP-β-CD）锌指抑制剂（ZnFI）和逆转录酶抑制剂UC 781。它们将扩大HIV-1抑制的目标。本提案的目标将在所有三个项目的框架内实现：l）通过CAP/HP-beta- CD/ZnFI/UC 781组合在体外和人类宫颈组织模型中预防初级HIV-1分离株和不同分支的感染; II）a）评估CAP膜以及ZnFI和UC 781组合膜的安全性和-猴阴道施用后杀微生物剂的分布，和B）评估CAP膜和组合膜对抗致病性X4和R5猿猴/人嵌合HIV-1病毒（SHIV）感染的功效; III）中试临床试验，其通过与上述项目和技术与监管核心的反复合作，将确保建立有效的基于CAP的杀微生物膜的大规模商业生产的先决条件。

DESCRIPTION (provided by applicant): Cellulose acetate phthalate (CAP), used in the pharmaceutical industry for enteric film coating of tablets and capsules, is an HIV-1 entry inhibitor blocking the CXCR4/CCR5 coreceptor binding sites on the virus and eliciting "dead-end" gp41 six-helix bundles on the virus envelope. Micronized CAP is the only candidate topical microbicide with the capacity to adsorb from physiological fluids HIV-1, preventing virus contact with target ceils. The interaction between HIV-1 and micronized CAP leads to virus disintegration and shedding of envelope glycoproteins, resulting in loss of infectivity. CAP also a) inactivates herpesviruses HSV-1, HSV-2, cytomegalovirus, Neisseria gonorrhoeae, Trichomonas vaginalis, Haemophilus ducreyi, Chlamydia trachomatis, Treponema pallidum and bacteria associated with bacterial vaginosis; b) protects mice and rhesus monkeys against vaginal infection by HSV-2 and SIV, respectively. Thus, CAP has the desired properties of combination microbicides. CAP has an established safety record, is widely available in large quantities and is inexpensive. To take further advantages of these properties, it is necessary to develop a commensurate delivery system which is simple, inexpensive, amenable to mass production, with a minimum of disposal problems. These requirements are met by a dispersible CAP film convertible in the presence of water into a gel containing micronized CAP. Further work is needed to optimize the film and bring it into large-scale industrial production. This will be accomplished within the framework of this proposal. CAP films are also suited for delivery of microbicides other than CAP. Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) zinc finger inhibitors (ZnFI) and the reverse transcriptase inhibitor UC781 have been selected for this purpose. They will widen the targets for HIV-1 inhibition. The aims of this proposal will be accomplished within the framework of all three projects: l) Prevention of infection by primary HIV-1 isolates and distinct clades in vitro and in human cervical tissue models by CAP/HP-beta- CD/ZnFI/UC781 combinations; II) a) Assessing the safety of CAP films and ZnFI and UC781 combination films and --microbicide distribution after vaginal application in monkeys and b) Evaluating the efficacy of the CAP film and combination films against infection with pathogenic X4 and R5 simian/human chimeric HIV-1 viruses (SHIV); III) Pilot Clinical Trials, which by iterative collaboration with the above projects and the Technology & Regulatory Core, will assure the establishment of prerequisites for large-scale commercial production of efficacious CAP-based microbicidal films.