棕榈酸帕利哌酮酯长效注射剂的制备及体内外评价

Preparation,in vitro and in vivo Evaluation of Paliperidone Palmitate Long-acting Injection

长效混悬注射剂中药物颗粒的大小和体外释放是关键质量属性。测得棕榈酸帕利哌酮酯长效缓释注射剂(Invega Trinza^(?),参比制剂)的d(0.1)、d(0.5)和d(0.9)分别为2~3、6~8和16~19μm,并确定为自制长效注射剂粒度分布的质控标准。采用湿磨法制备棕榈酸帕利哌酮酯长效注射剂,测得自制长效注射剂的d(0.1)、d(0.5)和d(0.9)分别为(2.43±0.14)、(6.74±0.29)和(17.34±0.90)μm。以含0.489%Tween-20的0.001 mol/L盐酸为释放介质进行体外释放试验。自制长效注射剂在5 min及2、6、23 h时的累积释放率分别为(5.25±0.73)%、(47.30±1.17)%、(70.84±0.74)%及(91.24±0.55)%。并且,根据相似因子计算结果,自制制剂与参比制剂体外释放曲线具有相似性。体外表征结果表明,自制及参比制剂的外部形貌和晶型均相同。大鼠体内药动学研究表明,自制及参比制剂的t_(1/2)、t_(max)、c_(max)、AUC及MRT均无显著性差异。

The particle size and in vitro release are key quality attributes of long-acting injectable suspension.The values of d(0.1),d(0.5) and d(0.9) of paliperidone palmitate injection(Invega Trinza~?,the Reference Listed Drug) were determined as 2-3、6-8 and 16-19 μm,respectively.So,the quality control standard of particle size distribution of the self-made long-acting injection was confirmed.Paliperidone palmitate injection was prepared by wet milling method.And the values of d(0.1),d(0.5) and d(0.9) of the self-made long-acting injection were(2.43±0.14),(6.74±0.29) and(17.34±0.90)μm,respectively.The in vitro release test was carried out with 0.001 mol/L hydrochloric acid containing 0.489% of Tween-20 as the release medium.The cumulative release rates at 5 min,2 h,6 h and 23 h of the self-made long-acting injection were(5.25±0.73)%,(47.30±1.17)%,(70.84±0.74)% and(91.24±0.55)%,respectively.According to the calculated results of similarity factor,the release curves between the self-made and reference preparations were similar.The in vitro characterization results showed that the morphology and crystal form of the self-made and the reference preparations were the same.In vivo pharmacokinetic study in rats showed that there were no significant differences in t_(1/2),t_(max),c_(max),AUC and MRT between self-made and reference preparations.