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.

项目摘要 Tenofovir Prodrugs，替诺福韦毒素（TDF）和Tenofovir Alafenamide Fumarate（TAF）为 艾滋病毒/艾滋病患者的一线疗法的基石，至少有15个FDA批准的抗逆转录病毒 包含TDF或TAF的产品。但是，由于其亲水性，低渗透性和 过早的水解或激活，TDF和TAF的口服生物利用度为25％，并且 分别为40％。考虑到这些药物需要在艾滋病毒患者的寿命中服用，因此 改善口服生物利用度，导致最佳药物利用和降低的治疗剂量需要 发达。将高度亲水或疏水药物转化为离子液体（ILS），低 - 用熔点<100°C熔化有机盐已成为一种新颖且可行的方法 为了改善药物的药物加工，可溶性，渗透性和口服生物利用度。我们的 初步数据表明，可以转变可离子的疏水药物（例如驱虫药） 苯并咪唑和亲水性电离药物（例如二甲双胍盐酸盐）使用低融化的IL 药物可接受的脂肪阴离子，例如钠纪录。我们的初步进一步表明 开发的IL可以有效地包装到聚合物纳米细胞中，从而进一步改善口服递送 和体内效率。因此，我们假设TDF和TAF转化为两亲离子 液体（ILS）使用通常被认为是安全的（GRAS）脂肪渗透增强剂及其随后的 掺入聚合物纳米细胞将改善口服生物利用度和体内抗病毒效率。我们的 初步数据表明，TDF和TAF可以使用gras快速有效地转换为两亲性IL 脂肪渗透增强剂，例如decan酸，纯酸，油酸和盐酸。目标1意志 专注于聚合物纳米细胞的开发，表征和药代动力学评估 包含tdf-ils或taf ils。 AIM 2将集中于口服聚合物的体内抗病毒效率评估 与纯TDF或TAF相比 建立概念证明。预计该提案的成功完成将导致 开发含有替诺福韦前药的IL的临床可行的药物公式 有效的艾滋病毒感染的长期管理。