Combination Therapy using an Innovative Bioadhesive Polymeric Transmucosal Delive

使用创新生物粘附聚合物跨粘膜输送的联合疗法

• 批准号: 8812524
• 负责人: GITA SHANKAR
• 金额: $ 51.38万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-16 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8812524
• 关键词: Acyclovir; Antiviral Agents; Buffers; Cavia; Cell Culture Techniques; Characteristics; Clinical Trials; Combined Modality Therapy; Contraceptive Agents; Development; Development Plans; Dose; Drug Formulations; Drug Kinetics; Elements; Environment; Epithelial Cells; Epithelium; Excretory function; Exhibits; Female; Funding; Gel; HIV; HIV-1; Human Herpesvirus 2; Hypersensitivity; Infection; International; Lactobacillus; Legal patent; Life; Metabolism; Methods; Modeling; Mus; Oryctolagus cuniculus; Pharmaceutical Preparations; Phase; Placebos; Polymers; Predisposition; Property; Relative (related person); Research; Research Personnel; Risk; SIV; Safety; Sexually Transmitted Diseases; Simplexvirus; Surface; Syringes; Tenofovir; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Vagina; Virus Diseases; Woman; Work; absorption; base; biocompatible polymer; condoms; genital herpes; hydroxyethylcellulose; in vivo Model; innovation; irritation; microbicide; mouse model; mucoid; nonhuman primate; novel; novel strategies; pandemic disease; pre-clinical; preclinical safety; prototype; research study; residence; scaffold; scale up; topical antiviral; transmission process; vaginal microbicide

PROJECT SUMMARY/ABSTRACT 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.

项目总结/摘要 局部阴道组合杀微生物剂将有助于遏制艾滋病毒和单纯疱疹病毒大流行的传播， 使妇女能够保护自己免受艾滋病毒/单纯疱疹病毒感染，并可能免受其他性传播疾病的感染。 特别是在避孕套被认为不可接受或无法获得的情况下。杀微生物剂必须 无刺激性，不增加感染。几种杀微生物剂的临床试验都失败了， 有效性，可能是由于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，可能会延长阴道杀微生物剂的驻留时间 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，其本身可作为杀微生物剂，并将其与抗病毒药物结合使用 化合物将延长抗病毒药物的停留时间并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开发一种组合杀微生物剂 生物粘附聚合物将两种治疗剂递送到阴道表面，同时保护阴道表面。 脆弱的组织和创造一个低pH值的环境，有助于阻止人类免疫缺陷病毒（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的原则产品，为控制 HIV-1感染，结合起来，将上级目前的凝胶制剂。进行了初步研究 SRI研究人员的研究表明，SR-2 P与替诺福韦不会引起任何阴道刺激。 对于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， 生物粘附性和pH缓冲特性，并将药物释放到阴道上皮。中试批次 在生产过程中，我们将生产足够的药物产品，用于随后的安全性和有效性研究。安全 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， 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 将在几种模型中测试SR-2 P与替诺福韦和阿昔洛韦联合使用和不联合使用的杀微生物剂安全性和有效性， vivo.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;以及证明SR-2 P无刺激性的临床前安全性实验 并且不会引起组织过敏。 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， 有助于减少艾滋病毒和HSV感染的进一步传播。