Western University of Health Sciences, College of Pharmacy, 309 E. Second St., Pomona, California, 91766, USA.
Western University of Health Sciences, Graduate College of Biomedical Sciences, Pomona, California, USA.
AAPS PharmSciTech. 2018 May;19(4):1802-1809. doi: 10.1208/s12249-018-0989-0. Epub 2018 Apr 3.
The aim of this study was to develop a proliposomal formulation of lipopeptide antibiotic drug daptomycin (DAP) for oral delivery. Thin film hydration was the selected method for preparation of proliposomes. Different phospholipids including soy-phosphatidylcholine (SPC), hydrogenated egg-phosphatidylcholine (HEPC), and distearoyl-phosphatidylcholine (DSPC) were evaluated in combination with cholesterol. The inclusion of surface charge modifiers in the formulation such as dicetyl phosphate (DCP) and stearylamine (SA) to enhance drug encapsulation was also evaluated. Particle size, surface charge, and encapsulation efficiency were performed on daptomycin-hydrated proliposomes as part of physical characterization. USP type II dissolution apparatus with phosphate buffer (pH 6.8) was used for in vitro drug release studies. Optimized formulation was evaluated for in vivo pharmacokinetics after oral administration to Sprague-Dawley rats. Proliposomes composed of SPC exhibited higher entrapment efficiency than those containing HEPC or DSPC. The highest entrapment efficiency was achieved by positively charged SPC-SA proliposomes, showing an encapsulation efficiency of 92% and a zeta potential of + 28 mV. In vitro drug release of optimized formulation demonstrated efficient drug retention totaling for less than 20% drug release within the first 60 min and only 42% drug release after 2 h. Pharmacokinetic parameters after single oral administration of optimized proliposomal formulation indicated a significant increase in oral bioavailability of DAP administered as SPC-SA proliposomes when compared to drug solution. Based on these results, incorporation of charge modifiers into proliposomes may increase drug loading and proliposomes an attractive carrier for oral delivery of daptomycin.
本研究旨在开发一种用于口服递释的脂肽抗生素药物达托霉素（DAP）的前体脂质体制剂。薄膜水化法被选为前体脂质体的制备方法。不同的磷脂，包括大豆磷脂酰胆碱（SPC）、氢化卵磷酯酰胆碱（HEPC）和二硬脂酰基磷脂酰胆碱（DSPC），与胆固醇一起进行了评估。还评估了在制剂中加入表面电荷修饰剂，如双十六烷基磷酸酯（DCP）和硬脂胺（SA），以增强药物包封。作为物理特性部分，对达托霉素水化前体脂质体进行了粒径、表面电荷和包封效率的测定。采用 USP 型 II 溶出仪，以磷酸盐缓冲液（pH 6.8）进行体外药物释放研究。对优化后的制剂进行了口服给予 Sprague-Dawley 大鼠后的体内药代动力学评价。由 SPC 组成的前体脂质体表现出比含有 HEPC 或 DSPC 的前体脂质体更高的包封效率。带正电荷的 SPC-SA 前体脂质体获得了最高的包封效率，包封效率为 92%，zeta 电位为+28 mV。优化后的制剂的体外药物释放研究表明，药物保留效率很高，在前 60 分钟内总释放不到 20%的药物，2 小时后仅释放 42%的药物。单次口服给予优化的前体脂质体制剂后的药代动力学参数表明，与药物溶液相比，以 SPC-SA 前体脂质体给予的 DAP 的口服生物利用度显著增加。基于这些结果，将电荷修饰剂掺入前体脂质体中可能会增加药物载药量，使前体脂质体成为达托霉素口服递释的有吸引力的载体。
