Ionic Liquids of tenofovir prodrugs for improved oral bioavailability and antiviral efficacy

替诺福韦前药离子液体可提高口服生物利用度和抗病毒功效

• 批准号: 10699620
• 负责人: Abhijit A Date
• 金额: $ 23.03万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-24 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699620
• 关键词: ABCB1 gene; Acids; Anions; Anthelmintics; Anti-Retroviral Agents; BLT mice; Biodistribution; Biological Availability; Brain; Cations; Chronic Hepatitis B; Clinical; Cost Savings; Cryptococcosis; Data; Developed Countries; Development; Diphosphates; Dose; Drug Kinetics; Drug Utilization; Electrostatics; Encapsulated; Enhancers; Evaluation; FDA approved; Formulation; Fumarates; Gastrointestinal tract structure; Goals; HIV; HIV Infections; HIV-1; HIV/AIDS; Hepatitis B Therapy; High Pressure Liquid Chromatography; Hydrolysis; Hydrophobicity; Infection; Liquid substance; Mediating; Metabolic; Metformin; Methods; Modeling; Mus; Nature; Oleic Acids; Oral; Oral Administration; Patients; Permeability; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Play; Polymers; Predisposition; Prodrugs; Research; Role; Salts; Sodium; Solubility; Temperature; Tenofovir; Testing; Therapeutic; Time; Tissues; Treatment Cost; Vagina; Vertebral column; Viral Physiology; amphiphilicity; anti-viral efficacy; antiretroviral therapy; aqueous; benzimidazole; biodegradable polymer; chemical stability; clinical development; efficacy evaluation; efficacy testing; hydrophilicity; improved; improved outcome; in vivo; in vivo evaluation; inter-individual variation; low and middle-income countries; lymph nodes; melting; mouse model; nanomicelles; nanopolymer; novel; novel strategies; pre-exposure prophylaxis; premature

PROJECT SUMMARY Tenofovir prodrugs, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF) are cornerstones of the first-line therapy in HIV/AIDS patients and there are at least 15 FDA-approved antiretroviral products that contain either TDF or TAF. However, due to their hydrophilic nature, low permeability, and premature hydrolysis or activation, TDF and TAF both have a considerably low oral bioavailability of 25% and 40% respectively. Given that these drugs need to be administered for the lifetime of HIV patients, strategies to improve oral bioavailability leading to optimal drug utilization and reduced therapeutic dose need to be developed. Transformation of ionizable, highly hydrophilic or hydrophobic drugs into ionic liquids (ILs), low- melting organic salts with a melting point < 100°C, has emerged as a novel and pharmaceutically viable approach to improving pharmaceutical processability, solubility, permeability, and oral bioavailability of drugs. Our preliminary data show that it is possible to transform ionizable hydrophobic drugs such as anthelmintic benzimidazoles, and hydrophilic ionizable drugs such as metformin hydrochloride into low-melting ILs using pharmaceutically acceptable fatty anion such as sodium docusate. Our preliminary further show that the developed ILs can be efficiently packaged into polymeric nanomicelles further leading to improved oral delivery and in vivo efficacy. Hence, we hypothesize that the transformation of TDF and TAF into amphiphilic ionic liquids (ILs) using generally regarded as safe (GRAS) fatty permeation enhancers and their subsequent incorporation into polymeric nanomicelles will improve oral bioavailability and in vivo antiviral efficacy. Our preliminary data show that TDF and TAF can be rapidly and efficiently converted to amphiphilic ILs using GRAS fatty permeation enhancers such as decanoic acid, undecylenic acid, oleic acid, and salcaprozic acid. Aim 1 will focus on the development, characterization, and pharmacokinetic evaluation of polymeric nanomicelles containing TDF-ILs or TAF ILs. Aim 2 will focus on the in vivo antiviral efficacy evaluation of oral polymeric nanomicelles containing TDF IL in humanized BLT mouse model of HIV infection compared to pure TDF or TAF to establish the proof of concept. The successful completion of this proposal is expected to lead to the development of clinically viable pharmaceutical formulations containing ILs of tenofovir prodrugs to achieve effective long-term management of HIV infection.

项目概要 替诺福韦前药、富马酸替诺福韦二吡呋酯 (TDF) 和富马酸替诺福韦艾拉酚胺 (TAF) HIV/艾滋病患者一线治疗的基石，至少有 15 种经 FDA 批准的抗逆转录病毒药物 然而，由于其亲水性、低渗透性和低渗透性，含有 TDF 或 TAF 的产品。 过早水解或活化，TDF 和 TAF 的口服生物利用度都相当低，均为 25%，并且 鉴于这些药物需要在 HIV 患者的一生中使用，因此应采取以下策略： 提高口服生物利用度，从而实现最佳药物利用并减少治疗剂量 开发了将可电离的、高亲水性或疏水性药物转化为低离子液体（IL）的技术。 熔化熔点 < 100°C 的有机盐，已成为一种新颖且在药学上可行的方法 提高药物的药物加工性、溶解度、渗透性和口服生物利用度。 初步数据表明，可以转化可电离的疏水性药物，例如驱虫药 使用苯并咪唑和亲水性电离药物（例如盐酸二甲双胍）将其转化为低熔点离子液体 药学上可接受的脂肪阴离子如多库酯钠。 开发的 IL 可以有效地包装到聚合物纳米胶束中，进一步改善口服给药 因此，我们发现 TDF 和 TAF 转化为两亲离子。 使用普遍认为安全的 (GRAS) 脂肪渗透促进剂的液体 (IL) 及其后续产品 掺入聚合物纳米胶束将提高口服生物利用度和体内抗病毒功效。 初步数据表明，使用 GRAS 可以将 TDF 和 TAF 快速有效地转化为两亲性 IL 脂肪渗透促进剂，例如癸酸、十一碳烯酸、油酸和柳卡普酸（Aim 1）。 专注于聚合物纳米胶束的开发、表征和药代动力学评价 目标 2 将重点关注口服聚合物的体内抗病毒功效评估。 与纯 TDF 或 TAF 相比，在 HIV 感染的人源化 BLT 小鼠模型中含有 TDF IL 的纳米胶束 建立概念验证预计该提案的成功完成将导致 开发含有替诺福韦前药 IL 的临床上可行的药物制剂，以实现 对艾滋病毒感染进行有效的长期管理。