隐丹参酮滴丸制备及其体内药动学研究

Preparation and in vivo pharmacokinetics of cryptotanshinone dropping pills

目的制备隐丹参酮滴丸,并考察其体内药动学。方法熔融法制备滴丸。以PEG 4000与PEG 6000比例、基质与药物比例、冷凝温度、滴速、滴距为影响因素,成型率、质量差异为评价指标,单因素试验优化处方工艺。X射线粉末衍射进行晶型分析,在扫描电镜下观察微观形态,测定溶解度、体外释药、稳定性。18只家兔随机分为3组,分别灌胃给予隐丹参酮、物理混合物、滴丸的0.5%CMC-Na混悬液(40 mg/kg),于不同时间点采血,HPLC法测定隐丹参酮血药浓度,计算主要药动学参数。结果最优处方工艺为PEG 4000与PEG 6000比例1∶1,基质与药物比例7∶1,滴速35滴/min,冷凝温度12℃,滴距7 cm,成型率为(94.86±1.18)%,质量差异为(8.89±0.72)%。隐丹参酮在滴丸中以无定形状态存在,溶解度提高至40.55倍,45 min内累积溶出度达94.74%。滴丸在6个月内外观、水分、最大质量差异、溶散时限符合2020年版《中国药典》要求。与原料药、物理混合物比较,滴丸t max缩短(P<0.05),C_(max)、AUC_(0~t)、AUC_(0~∞)升高(P<0.01),相对生物利用度与原料药相比增加至2.70倍。结论滴丸可促进隐丹参酮体外溶出、体内吸收。

AIM To prepare cryptotanshinone dropping pills,and to investigate their in vivo pharmacokinetics.METHODS The dropping pills were prepared by melting method.With PEG 4000-PEG 6000 ratio,matrix-drug ratio,condensate temperature,dropping speed and dropping distance as influencing factors,forming rate and weight difference as evaluation indices,the formulation process was optimized by single factor test.X-ray powder diffraction was used for crystalline form analysis,the micromorphology was observed under scanning electron microscope.The solubility,in vitro drug release and stability were determined.Eighteen rabbits were randomly assigned into three groups and given intragastric administration of the 0.5%CMC-Na suspensions of cryptotanshinone,physical mixture and cryptotanshinone(40 mg/kg),respectively,after which blood collection was made at different time points,HPLC was adopted in the plasma concentration determination of cryptotanshinone,and main pharmacokinetic parameters were calculated.RESULTS The optimum formulation process was determined to be 1∶1 for PEG 4000-PEG 6000 ratio,7∶1 for PEG 4000-PEG 6000 ratio,35 drop/min for dropping speed,12℃for condensate temperature,and 7 cm for dropping distance,the forming rate and weight difference were(94.86±1.18)%,(8.89±0.72)%,respectively.Cryptotanshinone existed in the dropping pills in an amorphous state,whose solubility was increased to 40.55 times,and the accumulative dissolution reached 94.74%within 45 min.The appearance,water,maximum quality difference and disintegration time limit of dropping pills accorded with Chinese Pharmacopoeia(2020 Edition).Compared with raw medicine and physical mixture,the dropping pills demonstrated shortened t max(P<0.05)and increased C_(max),AUC_(0-t),AUC_(0-∞)(P<0.01),the relative bioavailability was enhanced to 2.70 times as compared with that of raw medicine.CONCLUSION Dropping pills can promote the in vitro dissolution and in vivo absorption of cryptotanshinone.