田口设计筛选硝苯地平喷雾干燥分散体的处方研究

Formulation Study for Nifedipine Spray Dried Dispersion with Taguchi Design

关键词:  硝苯地平  喷雾干燥  固体分散体  溶出度

Key words:  nifedipine  spray dry  solid dispersion  dissolution

摘要:

目的 考察喷液处方对硝苯地平喷雾干燥分散体（spray dried dispersion，SDD）的表征和非漏槽条件下溶出度的影响。方法 采用minitab DOE（design of experiment）中的田口设计（Taguchi design）方法，以120 min以内的溶出度曲线下面积（AUC0~120 min）及120 min时的溶出浓度和最大浓度的比值（C₁₂₀/C_max）为评价指标，考察载体材料的种类和用量及喷雾溶液的固含量对硝苯地平SDD的药物存在状态和体外溶出度的影响。结果 硝苯地平与聚合物的比例对固体分散体中药物的存在状态和体外溶出度均有显著影响，固含量对结果影响较小。以共聚维酮为载体材料时，可以获得比醋酸羟丙甲基纤维素琥珀酸酯（HPMCAS）更高的最大溶出浓度（C_max），但是HPMCAS的抑制药物重结晶的效果明显优于共聚维酮，其中药物-HPMCAS LG 1∶4时可以获得最大的C_max和AUC_{0~120 min}。结论 硝苯地平与HPMCAS LG按照1∶4的比例配成固含量10%的溶液进行喷雾干燥，可以制得溶出度显著改善的SDD。

Abstract:

OBJECTIVE To determine the effect of solution formulation on characteristics and non-sink dissolution of nifedipine spray dried dispersion (SDD). METHODS Taguchi method in minitab software was used for experiment design. The area under dissolution curve within 120 min (AUC_{0-120 min}) and the ratio of released drug at 120 min to the maximum released drug (C₁₂₀/C_max) were applied as evaluation index to investigated the effect of polymers type, dosage and solid content of feed solution on drug state in nifedipine SDD and in-vitro dissolution. RESULTS Ratio of nifedipine to polymer had dramatic effect on drug state in SDD and in-vitro dissolution while solid content in feed solution affects a little. Copovidone based SDD got higher C_max compared with Hydroxypropyl methylcellulose acetate succinate (HPMCAS), but HPMCAS performed better in inhibiting recrystalization during dissolution test and storage. SDD with nifedipine-HPMCAS LG 1:4 could get highest C_max and AUC_{0-120 min}. CONCLUTION Spray drying solution with nifedipine-HPMCAS LG 1:4 with solid content of 10% can get great SDD with optimized dissolution.