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

项目总结 替诺福韦前体药物富马酸替诺福韦(TDF)和富马酸替诺福韦丙氨酰胺(TAF) HIV/AIDS患者一线治疗的基石和至少15种FDA批准的抗逆转录病毒药物 含有TDF或TAF的产品。然而，由于它们的亲水性、低渗透性和 过早水解或激活，TDF和TAF的口服生物利用度都相当低，仅为25%和 分别为40%。鉴于这些药物需要在艾滋病毒患者的一生中使用，采取的策略是 提高口服生物利用度，实现最佳药物利用，减少治疗剂量 发展起来的。将可电离的、高度亲水或疏水的药物转化为离子液体(ILS)，低成本 熔点为&lt；100°C的有机盐熔化已成为一种新的、在药学上可行的方法 旨在改善药物的可加工性、溶解性、渗透性和口服生物利用度。我们的 初步数据显示，有可能将驱虫药等可电离疏水药物 苯并咪唑和盐酸二甲双胍等亲水可电离药物制成低熔点ILS 药学上可接受的脂肪阴离子，如十二烷基磺酸钠。我们的初步结果进一步表明， 开发的ILS可以有效地包装成聚合物纳米胶束，进一步改善口服给药 和体内疗效。因此，我们假设TDF和TAF向两亲性离子的转变 使用通常被认为是安全的(GRAS)脂肪渗透促进剂的液体(ILS)及其后续 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效果。我们的 初步数据表明，利用GRAS可以快速有效地将TDF和TAF转化为两亲性ILS 脂肪渗透促进剂，如癸酸、十一烯酸、油酸和磺胺丙酸。目标1将 关注聚合物纳米胶束的发展、表征和药动学评价 含有TDF-ILS或TAF ILS。目的2将重点放在口服聚合物的体内抗病毒效果评价 含有TDFIL的纳米胶束在人源化BLT小鼠HIV感染模型中与单纯TDF或TAF的比较 确立概念证明。这项提案的成功完成预计将导致 开发临床可行的药物制剂，包括替诺福韦前药ILS以实现 有效的长期管理艾滋病毒感染。

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.