二氢丹参酮I自微乳的制备及其肝靶向性研究  

Preparation and liver targeting of dihydrotanshinone I self-microemulsion

作　　者：许宁 牛霞 李桂玲[1] XU Ning;NIU Xia;LI Gui-ling(Department of Pharmaceutics,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院北京协和医学院医药生物技术研究所制剂研究室,北京100050

出　　处：《中国医药生物技术》2024年第5期420-431,共12页Chinese Medicinal Biotechnology

摘　　要：目的 构建难溶性天然活性物质二氢丹参酮I(DHI)自微乳药物递送系统(DR),以提高DHI的溶解度,并使其具备一定的被动肝靶向性。方法 以药物在其中的溶解度为指标,初步筛选出油相、乳化剂和助乳化剂种类,并通过伪三元相图的绘制和星点设计-响应面优化法筛选出DR的最佳处方,之后对DR进行形貌表征、体外释放考察、稳定性评价及肝靶向性和肠滞留性研究。结果 DR最佳处方组成为DHI 3 mg(0.1%)、中碳链三甘油酯614.4mg(20.5%)、聚氧乙烯氢化蓖麻油944.1mg(31.5%)、PEG4001438.6mg(48%)。DR在室温下为红色澄清溶液,载药量为(1.240±0.014)mg/ml,显著提高了DHI的溶解度(40 ng/ml)。DR加水后形成微乳体系,呈淡蓝色乳光,TEM透镜观察可见粒子为均一的类球形,通过粒度仪测定其粒径为(104.50±0.45)nm,多分散系数(PDI)为0.241±0.004,Zeta电位为(–10.600±0.462)m V。体外释放结果显示,与DHI原料药相比,DR的释放速度和累积释放率提高了3~4倍,不同分散介质及稀释倍数(20~1000倍)对所形成微乳体系的粒径和PDI无明显影响。室温放置3个月后,DR的外观、粒径、PDI及含量均未见明显变化,表明其稳定性良好。体内分布研究表明,DR与原料药相比表现出显著的肝靶向性和肠道滞留性。结论 DHI自微乳给药系统制备工艺简单,性质稳定,显著提高了DHI的溶解度和体外释放速率,同时具有肝靶向性和肠道滞留性,可为DR用于治疗肝脏疾病提供一定的理论依据。Objective To construct a self-microemulsion drug delivery system(DR)for the insoluble natural active substance dihydrotanshinone I(DHI),with the aim of improving the solubility of DHI and enhancing its certain passive liver targeting capabilities.Methods Using the solubility of the drug as an indicator,the types of oil phase,emulsifiers,and co-emulsifiers were preliminarily screened.Then,through the drawing of pseudo-ternary phase diagrams and the optimization method of star point design-response surface,the optimal prescription for DR was selected.Subsequently,the morphology of the DR was characterized,its in vitro release was examined,its stability was evaluated,and its liver targeting and intestinal retention was studied.Results The optimal prescription composition of DR was DHI 3 mg(0.1%),medium-chain triglycerides 614.4 mg(20.5%),polyoxyethylene hydrogenated castor oil 944.1 mg(31.5%),and PEG4001438.6 mg(48%).DR was a red clear solution at room temperature with a drug loading of(1.240±0.014)mg/ml and the solubility of DHI(40 ng/ml)was significantly was improved.After water was added,DR formed a microemulsion system with a light blue opalescence.The results from TEM observation revealed that the particles were uniform spherical shapes.Particle size measurements by a particle size analyzer showed a particle diameter of(104.50±0.45)nm,polydispersity index(PDI)of 0.241±0.004,and Zeta potential of(–10.600±0.462)mV.In vitro release results showed that compared to the raw DHI,the release rate and cumulative release rate of DR were increased by 3-4 times,and different dispersion media and dilution multiples(20-1000 times)had no significant effect on the particle size and PDI of the formed microemulsion system.After being stored at room temperature for 3 months,there were no significant changes in the appearance,particle size,PDI,and content of DR to indicate its good stability.In vivo distribution studies showed that DR exhibited significant liver targeting and intestinal retention as compared with the raw mat

关 键 词：二氢丹参酮I 自微乳给药系统 星点设计-响应面法 肝靶向性 肠道滞留性 

分 类 号：R283.6[医药卫生—中药学]