Department of Chemistry, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
Int J Pharm. 2020 Jun 15;583:119361. doi: 10.1016/j.ijpharm.2020.119361. Epub 2020 Apr 22.
Aripiprazole (ARP) is an antipsychotic drug approved for the treatment of schizophrenia. It is poorly water-soluble and undergoes extensive hepatic metabolism and P-gp efflux, which lead to poor bioavailability and increased dose-related side effects. This study focuses on the preparation of mixed micelles (MM) to enhance the aqueous solubility, oral bioavailability, and blood-brain barrier permeation of ARP. For this purpose, Soluplus and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were selected for micelle preparation (ARP-MM). Micelles with borneol as penetration enhancer were also considered (ARP-B-MM). The optimized formulations have sizes of ca 50 nm, defined in distilled water, narrow size distribution (polydispersity index ≤0.1), and high encapsulation efficiency (greater than98%). Both formulations can be freeze-dried without losing their chemical-physical characteristics and are stable during storage for three months. The mixed micelles resulted stable in enzyme free-simulated gastric fluid (SGF, pH 1.2), simulated intestinal fluid (SIF, pH 6.8), and in serum. The in vitro ARP release was evaluated in the same biorelevant media, (SGF and SIF), and it disclosed that both micelles can give prolonged drug release. Furthermore, ARP solubility is greatly increased when loaded into mixed micelles. The absorption and efflux of ARP-loaded micelles were studied in vitro, employing two artificial membranes (Parallel Artificial Membrane Permeability Assay for the intestinal, PAMPA-GI, and the blood-brain barrier, PAMPA-BBB), to simulate the intestinal and brain epithelium, and the brain microvascular endothelial cell line hCMEC/D3. ARP-MM and ARP-B-MM increase the effective permeability of ARP by a factor of about three in the case of PAMPA-GI and about two for PAMPA-BBB. Furthermore, the P-gp mediated efflux was decreased by about six times in the case of ARP-MM and by about four times in the case of ARP-B-MM, compared to unformulated ARP. Finally, both ARP-loaded mixed micelles ameliorate the bioavailability of ARP, as demonstrated by the increase of the pharmacokinetic parameters, such as Cmax, AUC and t1/2.
阿立哌唑（ARP）是一种抗精神病药物，已被批准用于治疗精神分裂症。它的水溶性差，会经历广泛的肝代谢和 P-糖蛋白外排，导致生物利用度差和剂量相关的副作用增加。本研究专注于制备混合胶束（MM）以提高 ARP 的水溶解度、口服生物利用度和血脑屏障渗透性。为此，选择 Soluplus 和 D-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS）来制备胶束（ARP-MM）。还考虑了含有冰片作为渗透增强剂的胶束（ARP-B-MM）。优化的配方在去离子水中的粒径约为 50nm，粒径分布窄（多分散指数≤0.1），包封效率高（大于 98%）。两种配方都可以在不失去理化特性的情况下冷冻干燥，并在储存三个月内保持稳定。混合胶束在无酶模拟胃液（SGF，pH1.2）、模拟肠液（SIF，pH6.8）和血清中均稳定。在相同的生物相关介质（SGF 和 SIF）中评估了 ARP 的体外释放，结果表明两种胶束都可以延长药物释放。此外，将 ARP 载入混合胶束后，其溶解度大大提高。采用两种人工膜（用于肠道的平行人工膜透过性测定，PAMPA-GI，和血脑屏障，PAMPA-BBB），模拟肠道和脑上皮以及脑微血管内皮细胞系 hCMEC/D3，研究了载药胶束的吸收和外排。与未包载的 ARP 相比，ARP-MM 和 ARP-B-MM 使 ARP 的有效透过率在 PAMPA-GI 中的增加了约三倍，在 PAMPA-BBB 中的增加了约两倍。此外，与未包载的 ARP 相比，ARP-MM 和 ARP-B-MM 使 P-糖蛋白介导的外排减少了约六倍和四倍。最后，载药混合胶束均改善了 ARP 的生物利用度，表现在药代动力学参数如 Cmax、AUC 和 t1/2 的增加。
