桂枝、当归挥发油微囊处方优化及体内药动学研究

Formulation Optimization of the Volatile Oil Microcapsules of Cinnamomi Ramulus and Angelicae Sinensis Radix and Their Pharmacokinetics in Vivo

关键词:  Box-Behnken设计-效应面法  桂枝、当归挥发油  微囊  药动学  相对生物利用度

Key words:  Box-Behnken design-response surface method  Cinnamomi Ramulus and Angelicae Sinensis Radix volatile oil  microcapsules  pharmacokinetics  relative bioavailabilit

摘要:

目的 优化桂枝、当归挥发油微囊的处方，对处方优化后制备的微囊进行相关表征和大鼠体内药动学研究。方法 采用喷雾干燥法制备桂枝、当归挥发油微囊。以载药量和包封率为指标，通过Box-Behnken设计-效应面法优化处方。采用傅里叶变换红外光谱和扫描电镜方法对处方优化后制备的微囊进行表征。按照100 mg·kg^-1的剂量灌胃给药后采血，HPLC测定血药浓度，比较体内药动学行为。结果 最佳处方为芯材-囊材比1∶1.7，囊材浓度为10.25%，复合囊材辛烯基琥珀酸淀粉钠/麦芽糊精比为3.8∶1，高压均质压力为20 MPa，喷雾干燥进口温度为185 ℃。在该条件下，测得微囊的载药量为(18.94±1.09)%，包封率(96.03±2.91)%。傅里叶变换红外光谱和扫描电镜结果表明，挥发油已成功被包覆在囊壁材料中，微囊基本形状为球形，表面凹陷但无明显裂缝。体内药动学结果显示，微囊组的达峰时间(t_max)、半衰期(t_1/2)、清除率(CL)、时间-曲线下面积(AUC_0-t)、药物从中央室消除的一级速率常数(k₁₀)、药物从中央室向周边室转运的一级速率常数(k₁₂)、药物从周边室向中央室转运的一级速率常数(k₂₁)等药动学参数与挥发油组的差异均具有统计学意义(P<0.05或P<0.01)。药动学结果表明微囊有效延长了桂枝、当归挥发油在体内滞留时间，促进药物在体内的吸收，口服相对生物利用度提高至2.62倍。结论 Box-Behnken设计-效应面法所建立的模型能较好地优化桂枝、当归挥发油微囊的处方工艺，具有良好预测性。处方优化后制备的微囊具有良好载药性能，提高了挥发油的生物利用度。

Abstract:

OBJECTIVE To optimize the preparation technology of the volatile oil microcapsules of Cinnamomi Ramulus and Angelicae Sinensis Radix, characterize the microcapsules prepared after the formulation optimization and study pharmacokinetics characteristics in rats. METHODS Spray drying was used to prepare the volatile oil microcapsules of Cinnamomi Ramulus and Angelicae Sinensis Radix. The preparation process was optimized by Box-Behnken response surface method with the drug loading and encapsulation efficiency as indexes. The microcapsules were characterized by Fourier transform infrared spectroscopy(FT-IR) and scanning electron microscopy(SEM). Blood samples were collected after gastric administration at a dose of 100 mg·kg^-1. HPLC method was adopted in the plasma concentration determination, and pharmacokinetics behavior in vivo was also compared. RESULTS The optimal formulation: core material-capsules material ratio was 1∶1.7, capsules material concentration was 10.25%, sodium starch octenyl succinate∶maltodextrin was 3.8∶1, high pressure homogenization pressure was 20 MPa and the inlet temperature of spray drying was 185 ℃. Under the optimized conditions, the drug loading was (18.94±1.09)% and the encapsulation rate was (96.03±2.91)%, respectively. The results of FT-IR and SEM showed that the essential oils had been successfully coated in the capsule wall material. The microcapsules were basically spherical in shape, with concave surface but no obvious cracks. The main pharmacokinetic parameters such as t_max, t_1/2, CL, AUC_0-t, k₁₀,k₁₂, and k₂₁ of microcapsules had significant difference of the volatile oil(P<0.05 or P<0.01). Microcapsules effectively prolonged the circulation time of volatile oil in the body, promoted the absorption of drugs in the body and the oral bioavailability was enhanced to 2.62 times. CONCLUSION The model established by the Box-Behnken design-response surface method can be used to optimize the formulation of volatile oil microcapsules of Cinnamomi Ramulus and Angelicae Sinensis Radix with great prediction effect. The microcapsules prepared by the optimized process has good drug loading properties and the bioavailability of volatile oil is increased.