阿瑞匹坦三元超饱和固体分散体的制备及性能考察

Preparation and performance investigation of Aprepitant ternary supersaturated solid dispersion system

关键词:  阿瑞匹坦  三元聚合物  过饱和递药系统  热熔挤出

Key words:  Aprepitant  ternary polymer  supersaturated drug delivery system  hot melt extrusion

摘要:

目的：为了提高难溶性药物阿瑞匹坦(Aprepitant,APR)的溶解度,解决其酸中溶出、碱中结晶沉淀的问题,选择不同功能的聚合物载体,采用热熔挤出技术制备三元固体分散体,并对其进行性能考察；方法：采用溶剂-熔融法制备二元固体分散体,以溶出度和溶出速度为指标,筛选具有增溶功能的载体材料。通过介质转移法考察各聚合物在不同浓度的药物溶液中的抑晶性能,筛选出最佳的沉淀抑制剂。确定药载比,将APR、溶出促进剂及沉淀抑制剂以不同比例混合,采用热熔挤出技术制备三元固体分散体,以溶出度和抑晶时间为指标,优选出三元固体分散体处方。经XRD确认药物在载体中的存在状态,考察该三元固体分散体在模拟肠液中的动态溶解度和加速条件下的物理稳定性。结果：亲水性聚合物PVP K30制备的二元固体分散体溶出速度快,增溶效果佳,肠溶性聚合物HPMCAS显示出优越的抑晶作用,延长了APR的过饱和点,质量比为1:1:3(APR:PVP K30:HPMCAS)的三元固体分散体在酸中迅速完全释放(120min溶出95%),相对于原料药显著提高了溶出度和溶出速率,当介质pH转为6.8后,三元固体分散体完全释放并在6h内维持溶液处于高过饱和的稳定状态,药物以无定形形式存在于载体基质中,同时能在加速条件下保持至少三个月的无定形状态。结论：基于不同聚合物的理化特性,本研究制备的三元固体分散体通过协调溶出速率和结晶抑制效果,不仅显著提高APR的溶解度,并能解决APR在胃中溶出、肠中沉淀析晶的问题,具有良好的溶出特性。

Abstract:

OBJECTIVE To improve the solubility of the insoluble drug aprepitant, solve the problem of solubilization in acid and crystallization and precipitation in alkali of aprepitant, select polymer carriers with different functions, prepare ternary solid dispersions by hot-melt extrusion technique, and investigate their performance; Method Binary solid dispersions were prepared by solvent-melt method, and the solubility and dissolution rate were used as indicators to screen the solubilization-enhancing carrier materials. The crystallization inhibition performance of each polymer in different concentrations of drug solutions was investigated by the medium transfer method, and the best precipitation inhibitor was screened. The ternary solid dispersions were prepared by hot melt extrusion technique, and the ternary solid dispersion prescriptions were preferably selected with the indexes of solubility and crystal inhibition time. The presence of the drug in the carrier was confirmed by X-ray diffraction analysis, and the dynamic solubility and physical stability of the ternary solid dispersion in simulated intestinal fluid under accelerated conditions were investigated. RESULTS The binary solid dispersion prepared by hydrophilic polymer PVP K30 showed fast dissolution and good solubilization, the enterosoluble polymer HPMCAS showed superior crystal inhibition and prolonged the supersaturation point of aprepitant, and the ternary solid dispersion with a mass ratio of 1:1:3 (APR: PVP K30: HPMCAS) was rapidly and completely released in acid (95% dissolution at 120 min). The ternary solid dispersions were completely released and maintained the solution in a highly supersaturated stable state at 6h when the pH of the medium was shifted to 6.8, which significantly increased the dissolution degree and dissolution rate relative to the APR, and the drug existed in the carrier matrix in an amorphous form, while being able to maintain the amorphous state for at least three months under accelerated conditions. Conclusion Based on the physicochemical properties of different polymers, the ternary solid dispersion prepared in this work not only significantly improved the solubility of aprepitant by coordinating the dissolution rate and crystallization inhibition effect, but also solved the problem of aprepitant dissolution in stomach and precipitation in intestine, with good dissolution characteristics.