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

项目摘要 替诺福韦前药，富马酸替诺福韦二异丙酯（TDF）和富马酸替诺福韦艾拉酚胺（TAF）， 艾滋病毒/艾滋病患者一线治疗的基石，至少有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， 由于TDF和TAF的过早水解或活化，它们的口服生物利用度都相当低，为25%， 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， 改善口服生物利用度导致最佳药物利用和降低治疗剂量， 开发将可电离的、高亲水性或疏水性药物转化为离子液体（IL）、低- 熔化熔点< 100°C的有机盐已成为一种新颖且药学上可行的方法 涉及改善药物的药物加工性、溶解性、渗透性和口服生物利用度。我们 初步数据表明，有可能将可电离的疏水药物如驱虫药 苯并咪唑和亲水性可电离药物如盐酸二甲双胍， 药学上可接受的脂肪阴离子，如多库酯钠。我们的初步调查进一步表明 开发的IL可以有效地包装到聚合物纳米胶束中 和体内功效。因此，我们假设TDF和TAF转化为两亲性离子型聚合物是可能的。 使用通常被认为是安全的（GRAS）脂肪渗透增强剂的液体（IL）及其随后的 掺入聚合物纳米胶束中将改善口服生物利用度和体内抗病毒功效。我们 初步数据表明，TDF和TAF可以使用GRAS快速有效地转化为两亲性离子液体 脂肪渗透增强剂，例如癸酸、十一碳烯酸、油酸和水杨酸。目标1将 专注于聚合物纳米胶束的开发，表征和药代动力学评价 含有TDF-IL或TAF IL。目的2：评价口服聚合物的体内抗病毒效果 与纯TDF或TAF相比，在人源化BLT小鼠HIV感染模型中含有TDF IL的纳米胶束 建立概念验证。这一提案的顺利完成预计将导致 开发含有替诺福韦前药的IL的临床上可行的药物制剂， 艾滋病毒感染的长期有效管理。

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.