Witika Bwalya A, Stander Jessé-Clint, Smith Vincent J, Walker Roderick B
Division of Pharmaceutics, Faculty of Pharmacy, Rhodes University, Makhanda 6140, South Africa.
Department of Chemistry, Faculty of Science, Rhodes University, Makhanda 6140, South Africa.
Pharmaceutics. 2021 Jan 20;13(2):127. doi: 10.3390/pharmaceutics13020127.
Currently, the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS) can only be treated successfully, using combination antiretroviral (ARV) therapy. Lamivudine (3TC) and zidovudine (AZT), two compounds used for the treatment of HIV and prevention of disease progression to AIDS are used in such combinations. Successful therapy with 3TC and AZT requires frequent dosing that may lead to reduced adherence, resistance and consequently treatment failure. Improved toxicity profiles of 3TC and AZT were observed when combined as a nano co-crystal (NCC). The use of stimuli-responsive delivery systems provides an opportunity to overcome the challenge of frequent dosing, by controlling and/or sustaining delivery of drugs. Preliminary studies undertaken to identify a suitable composition for a stimulus-responsive in situ forming hydrogel carrier for 3TC-AZT NCC were conducted, and the gelation and erosion time were determined. A 25% Pluronic F-127 thermoresponsive hydrogel was identified as a suitable carrier as it exhibited a gelation time of 5 min and an erosion time of 7 days. NCC-loaded hydrogels were evaluated using in vitro dissolution and cytotoxicity assays. In vitro dissolution undertaken using membrane-less diffusion over 168 h revealed that 3TC and AZT release from NCC-loaded hydrogels was complete and followed zero-order kinetic processes, whereas those loaded with the micro co-crystal and physical mixture were incomplete and best described using the Korsmeyer-Peppas kinetic model. The release of AZT and 3TC from the physical mixture and MCC-loaded gel exhibited a value for of 0.595 for AZT release from the physical mixture and 0.540 for the MCC technology, whereas the release exponent for 3TC was 0.513 for the physical mixture and 0.557 for the MCC technology indicating that diffusion and erosion controlled 3TC and AZT release. In vitro cytotoxicity assay data revealed that the addition of NCC to the thermoresponsive hydrogel resulted in an improved cell viability of 88.0% ± 5.0% when compared to the cell viability of the NCC of 76.9% ± 5.0%. The results suggest that the use of a thermoresponsive nanosuspension may have the potential to be delivered as an intramuscular injection that can subsequently increase bioavailability and permit dose reduction and/or permit use of a longer dosing frequency.
目前，导致获得性免疫缺陷综合征（艾滋病）的人类免疫缺陷病毒（HIV）只能通过联合抗逆转录病毒（ARV）疗法成功治疗。拉米夫定（3TC）和齐多夫定（AZT）这两种用于治疗HIV和预防疾病进展为艾滋病的化合物被用于此类联合治疗中。用3TC和AZT进行的成功治疗需要频繁给药，这可能导致依从性降低、产生耐药性，进而导致治疗失败。当3TC和AZT组合成纳米共晶（NCC）时，观察到其毒性特征有所改善。使用刺激响应性给药系统提供了一个机会，通过控制和/或维持药物递送来克服频繁给药的挑战。已开展初步研究，以确定用于3TC - AZT NCC的刺激响应性原位形成水凝胶载体的合适组成，并测定了凝胶化和侵蚀时间。一种25%的泊洛沙姆F - 127热响应性水凝胶被确定为合适的载体，因为它的凝胶化时间为5分钟，侵蚀时间为7天。对载有NCC的水凝胶进行了体外溶出度和细胞毒性测定。在168小时内使用无膜扩散进行的体外溶出度研究表明，载有NCC的水凝胶中3TC和AZT的释放是完全的，并且遵循零级动力学过程，而载有微共晶和物理混合物的水凝胶的释放不完全，最好用考斯迈尔 - 佩帕斯动力学模型来描述。从物理混合物和载有微共晶的凝胶中释放的AZT和3TC，物理混合物中AZT释放的n值为0.595，微共晶技术中为0.540，而物理混合物中3TC的释放指数为0.513，微共晶技术中为0.557，这表明扩散和侵蚀控制了3TC和AZT的释放。体外细胞毒性测定数据显示，与NCC的细胞活力76.9%±5.0%相比，将NCC添加到热响应性水凝胶中可使细胞活力提高至88.0%±5.0%。结果表明，使用热响应性纳米混悬液有可能作为肌肉注射给药，随后可提高生物利用度，并允许减少剂量和/或延长给药频率。
