木犀草素固体分散体和自微乳制备及体内外评价

Preparation and evaluation in vitro/vivo of luteolin solid dispersion and self microemulsion formulations

关键词:  木犀草素  固体分散体  自微乳  溶解度  溶出度  药代动力学  生物利用度

Key words:  luteolin  solid dispersion  self microemulsion  solubility  dissolution  pharmacokinetics  bioavailability

摘要:

摘要：目的 筛选木犀草素固体分散体（LU-SD）和自微乳（LU-SME）最佳处方，评价两种制剂的体内药代动力学（PK）和生物利用度（F）。方法 采用喷雾干燥法制备LU-SD，以溶解度和溶出度为指标筛选合适的载体及配比，通过XRPD表征晶型稳定性；选择不同的油相、乳化剂、助乳化剂及配比制备LU-SME，以分散/储存稳定性、溶解度和溶出度为指标筛选最优处方。分别将LU-注射液、LU-混悬液、LU-SD和LU-SME进行大鼠尾静脉注射和口服灌胃给药，对比不同制剂的体内PK和生物利用度。结果 采用25%LU+75% PVP VA64处方制备的LU-SD溶解度提高了约60倍，120 min累计溶出率可达到94.3%，在模拟人体胃液（FaSSGF）中能至少在120 min内具有良好的晶型稳定性；采用30%磷脂酰胆碱（Phosal ?53 MCT）作为油相、30%辛酸癸酸聚乙二醇甘油酯（Labrasol）为乳化剂、40%聚氧乙烯蓖麻油（Kolliphor? ELP）为助乳化剂制备的LU-SME溶解度提高了约68倍，15 min最高溶出率可达到95.2%，具有较好的分散稳定性和储存稳定性。体内PK研究表明，LU-SME比LU-SD的生物利用度高，LU-SME达峰时间比LU-SD更快。结论 LU-SD和LU-SME均可显著改善LU的溶解度、溶出速率，基于本研究结果，LU-SME比LU-SD更具有提高生物利用度的优势。

Abstract:

ABSTRACT: OBJECTIVE To design different formulations of luteolin solid dispersion (LU-SD) and self microemulsion (LU-SME), and evaluate the pharmacokinetics (PK) and bioavailability (F) of the two formulations in vivo. METHODS LU-SD was prepared by spray drying method. The appropriate carrier and ratio were selected according to the solubility and dissolution rate, and the crystal stability was characterized by XRPD; Select different oil phases, emulsifiers, co-emulsifiers, and ratios for LU-SME, and screen the optimal formulation based on dispersion/storage stability, solubility, and dissolution rate. LU-injection, LU-suspension, LU-SD, and LU-SME were separately administered via tail vein injection and oral gavage administration in rats to compare the in vivo PK and bioavailability of different formulations. RESULTS The solubility of LU-SD prepared with the formulation of 25% LU+75% PVP VA64 has increased by about 60 times, and the cumulative dissolution rate at 120 min reached 94.3%. It can have good crystal stability in FaSSGF for at least 120 minutes; Using 30% Phosal 53 MCT as oil phase, 30% Labrasol as emulsifier, and 40% Kolliphor? ELP as co-emulsifier, the solubility of LU-SME increased by about 68 times, and the highest dissolution rate at 15 min reached 95.2%, and had good dispersion stability and storage stability. In vivo PK studies have shown that LU-SME has higher bioavailability than LU-SD, the peak time of LU-SME is shorter than that of LU-SD. CONCLUSION Both LU-SD and LU-SME can significantly improve the solubility and dissolution rate of luteolin. Based on the results of this study, LU-SME has a greater advantage in improving bioavailability than LU-SD.