Abstract：
Abiraterone acetate (ABA), a biopharmaceutical class IV drug suffers from solubility and permeability pitfalls resulting in limited oral bioavailability and positive food effect, i.e. multi-fold enhancement in drug absorption in the presence of food. This poses difficulties to physicians towards the estimation of dose and dosage regimen required for efficacious therapy of prostate cancer (PCa). Nanostructured lipid carriers (NLC) have demonstrated tremendous outcomes in enhancing the oral bioavailability of various entities along with food effect attenuation. In this study, Quality by design and multivariate analysis was employed for optimization of ABA loaded NLC (ABA NLC). The optimal size, PDI and zeta potential obtained using QbD were 134.6 nm, 0.163 and -15.7 mV respectively. Ex vivo qualitative and quantitative intestinal permeability studies demonstrated improved traversion of NLC through the intestinal segments. In vitro dissolution profile in biorelevant fast and fed gastric and intestinal media revealed minimal differences for ABA NLC compared to ABA. In vivo pharmacokinetics was performed to decipher the efficacy of ABA NLC in mitigating the food effect of ABA. The studies demonstrated 14.51-fold and 1.94-fold improvement in oral bioavailability during fasted and fed state respectively as compared to free ABA. The absorption mechanism of ABA NLC using chylomicron flow blocking approach conveyed lymphatic uptake as the major mechanism. Cmax fast/fed ratio was 0.9758 whereas, AUC fast/fed ratio was 0.9386, which being nearly equivalent, confirmed the food effect attenuation. Therefore, the results of the study demonstrate optimal pharmacokinetics of ABA NLC and its utility in circumventing the fast fed variability.
摘要：
醋酸阿比特龙（ABA），生物制药IV类药物具有溶解度和渗透性缺陷，导致口服生物利用度和积极的食物效果有限，即在食物存在下药物吸收的多倍增强。这给医师估计前列腺癌(PCa)的有效治疗所需的剂量和剂量方案带来了困难。纳米结构脂质载体（NLC）在增强各种实体的口服生物利用度以及食物效应减弱方面已显示出巨大的成果。在这项研究中,通过设计和多变量分析的质量用于优化ABA负载的NLC（ABANLC）。最佳尺寸，使用QbD获得的PDI和zeta电位为134.6nm，分别为0.163和-15.7mV。离体定性和定量肠通透性研究表明改善了NLC通过肠段的翻转。在生物相关的快速和喂食的胃和肠介质中的体外溶出曲线显示，与ABA相比，ABANLC的差异最小。进行体内药代动力学以破译ABANLC在减轻ABA的食物效应中的功效。研究表明，与游离ABA相比，禁食和进食状态下的口服生物利用度分别提高了14.51倍和1.94倍。使用乳糜微粒流阻断方法的ABANLC的吸收机制以淋巴吸收为主要机制。Cmax快速/进食比为0.9758，而AUC快速/进食比为0.9386，几乎相当，证实了食物效应衰减。因此,研究结果表明ABANLC的最佳药代动力学及其在规避快速进食变异性方面的实用性。
