Combination Therapy using an Innovative Bioadhesive Polymeric Transmucosal Delive

描述（由申请人提供）：局部阴道复合杀微生物剂将有助于遏制艾滋病毒和HSV流行病的传播，使妇女能够保护自己免受艾滋病毒/HSV感染，并可能免受其他性传播疾病，特别是当避孕套被认为是不可接受的或不可用的时候。杀微生物剂必须是无刺激性的，并且不会增加感染。几种杀微生物剂在临床试验中失败，因为缺乏有效性，可能是因为在阴道表面的停留时间有限。长时间的表面接触是必不可少的。生物粘合剂被归类为生物相容性聚合物，可以延长阴道杀微生物剂的停留时间，从而最大限度地减少频繁给药的需要，并且它们的聚合物支架也可以帮助溶解药物。开发一种无毒的生物粘合剂，它本身就可以作为杀微生物剂，并将其与抗病毒化合物相结合，既可以延长抗病毒药物的停留时间，又可以增加进一步的保护性能。 我们建议使用我们的专利，创新，双元素SR-2 P生物粘附聚合物开发一种组合杀微生物剂，将两种治疗药物输送到阴道表面，同时保护这个脆弱的组织并创造一个低pH环境，有助于阻断人类免疫缺陷病毒（HIV）-1感染。我们将测试这种新的配方都单独，其固有的杀微生物特性，并制定它与替诺福韦和阿昔洛韦，以证明一个安全和有效的证明原则的产品，用于控制HIV-1感染，在组合，将是上级到目前的凝胶制剂。SRI研究人员进行的初步研究表明，SR-2 P与替诺福韦不会引起任何阴道刺激。 为 R21阶段，我们将首先优化SR-2 P与和不与替诺福韦和阿昔洛韦具有强大的生物粘附和pH缓冲特性，并释放药物到阴道上皮。在中试批次生产中，我们将生产足够的制剂用于后续安全性和有效性研究。将在阴道刺激模型中研究SR-2 P单独使用和与药物联合使用的安全性，以证明该制剂无毒且无刺激性。为了在R33阶段进一步开发SR-2 P，我们将在几种体内模型中测试SR-2 P与替诺福韦和阿昔洛韦的杀微生物剂安全性和有效性。同时，我们将对两种形式进行加速稳定性研究。使用标准临床前安全性和毒理学方法，我们将进行阴道药代动力学/吸收;分布、代谢、排泄和毒性研究;以及临床前安全性实验，以证明SR-2 P无刺激性，不会引起组织超敏反应。 我们预计这些研究将证明SR-2 P是一种安全有效的杀微生物剂，可以帮助减少HIV和HSV感染的进一步传播。

DESCRIPTION (provided by applicant): A topical vaginal combination microbicide will help contain the spread of the HIV and HSV pandemic by allowing women to protect themselves against HIV/HSV infection and possibly from other sexually transmitted diseases, especially when condoms are considered unacceptable or are unavailable. The microbicide must be nonirritating and not enhance infection. Several microbicides have failed clinical trials because of lack of efficacy, possibly from limited residence time on the vaginal surface. Prolonged surface contact is essential. Bioadhesives, which are classified as biocompatible polymers, may lengthen vaginal microbicide residence time, thus minimizing the need for frequent dosing, and their polymer scaffold can also help solubilize drugs. Developing a nontoxic bioadhesive that acts as a microbicide on its own and combining it with antiviral compounds will both lengthen residence time for the antiviral medication and add further protective properties. We propose to develop a combination microbicide using our patented, innovative, dual-element SR-2P bioadhesive polymer to deliver two therapeutics to the vaginal surface while simultaneously protecting this delicate tissue and creating a low-pH environment that aids in blocking human immunodeficiency virus (HIV)-1 infection. We will test this novel formulation both alone, for its inherent microbicidal properties; and formulate it with tenofovir and acyclovir, to demonstrate a safe and effective proof-of-principle product for the control of HIV-1 infections that, in combination, will be superior to current gel formulations. Preliminary studies performed by SRI researchers indicate that the SR-2P with tenofovir does not elicit any vaginal irritation. For the R21 phase, we will first optimize SR-2P with and without tenofovir and acyclovir to have strong bioadhesive and pH buffering properties, and to release drugs to the vaginal epithelium. In pilot batch manufacturing, we will produce sufficient drug product to test in subsequent safety and efficacy studies. Safety of SR-2P alone and in combination with the drugs will be investigated in a vaginal irritation model to demonstrate that the formulation is nontoxic and nonirritating. To develop SR-2P further in the R33 phase, we will test microbicide safety and efficacy of SR-2P with and without tenofovir and acyclovir in several models in vivo. Concurrently, we will perform accelerated stability studies on both forms. Using standard preclinical safety and toxicology methods, we will conduct vaginal pharmacokinetics/absorption; distribution, metabolism, excretion, and toxicity studies; and preclinical safety experiments to demonstrate that SR-2P is nonirritating and causes no tissue hypersensitivity. We anticipate that these studies will demonstrate that SR-2P is a safe and efficacious microbicide that can help reduce the further spread of HIV and HSV infections.