Yuan Yue, Che Xin, Zhao Mingyi, Wang Yan, Liu Yajun, Schwendeman Anna, Li Sanming
School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China and.
J Microencapsul. 2015;32(3):273-80. doi: 10.3109/02652048.2015.1010461. Epub 2015 Mar 12.
The goal of this study was to develop a parenteral microemulsion formulation of cyclosporine A (CyA). The CyA solubility in caprylic capric triglyceride (GTCC), ethyl oleate and soybean oil were determined. The pseudo-ternary diagrams of oil (GTCC), surfactant (Solutol® HS-15), cosurfactants (ethanol/polyethylene glycol 400 [PEG 400] mixture) and water were constructed to identify boundaries for microemulsion existence. The CyA was added at 3, 6 and 9% w/w to the optimal microemulsion composition. Microemulsion particle size, solution viscosity and conductivity were examined. The microemulsion stability and haemolytic potential were examined after dilution in 5% dextrose solution for injection to 1 mg/mL CyA. Microemulsion stability was examined after a three-month storage at 4 and 25 °C. The GTCC was selected as an oil phase for CyA microemulsion based on solubility results. The optimum CyA microemulsion formulation consisted of 2.5% CyA, 9% GTCC, 24% Solutol® HS 15, 8% PEG 400, 4% ethanol and 52.5% water based on weight percent. The average particle sizes of the optimized blank and drug-loaded microemulsions were 68.7 nm and 71.6 nm, respectively and remained unchanged upon 25-fold dextrose dilution. The results of microemulsion physical and CyA chemical were confirmed by a three-month stability study at 4 and 25 °C. In vitro haemolysis studies indicated that CyA microemulsions were well tolerated by erythrocytes. The novel microemulsion formulation of CyA was developed that is suitable for parenteral administration. This new formulation could potentially have less vehicle-associated side effects that current commercial formulation of CyA based on Cremophor® EL and ethanol solution.
本研究的目的是开发一种环孢素A(CyA)的肠胃外微乳剂配方。测定了CyA在辛酸癸酸甘油三酯(GTCC)、油酸乙酯和大豆油中的溶解度。构建了油相(GTCC)、表面活性剂(Solutol® HS - 15)、助表面活性剂(乙醇/聚乙二醇400 [PEG 400]混合物)和水的伪三元相图,以确定微乳剂存在的边界。将CyA按3%、6%和9%(w/w)添加到最佳微乳剂组合物中。检测了微乳剂的粒径、溶液粘度和电导率。在5%葡萄糖注射液中稀释至1mg/mL CyA后,检测微乳剂的稳定性和溶血潜力。在4℃和25℃储存三个月后检测微乳剂的稳定性。基于溶解度结果,选择GTCC作为CyA微乳剂的油相。基于重量百分比,最佳的CyA微乳剂配方由2.5% CyA、9% GTCC、24% Solutol® HS 15、8% PEG 400、4%乙醇和52.5%水组成。优化后的空白微乳剂和载药微乳剂的平均粒径分别为68.7nm和71.6nm,在25倍葡萄糖稀释后保持不变。在4℃和25℃进行的三个月稳定性研究证实了微乳剂物理性质和CyA化学性质的结果。体外溶血研究表明,红细胞对CyA微乳剂耐受性良好。开发了适合肠胃外给药的新型CyA微乳剂配方。与基于聚氧乙烯蓖麻油® EL和乙醇溶液的CyA现有商业配方相比,这种新配方可能具有更少的与载体相关的副作用。
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