脂质包裹与环糊精包合的协同矫味研究  

Synergetic taste masking of lipid coating and β-cyclodextrin inclusion

作　　者：李雪[1,2] 郭桢[2,3] 郝结兵 李彪 刘从镖 郭涛[2] 李海燕[2] 石森林[1] 汪六一 张继稳[1,2] 

机构地区：[1]浙江中医药大学,浙江杭州310000 [2]中国科学院上海药物研究所,上海201203 [3]英国Bradford大学 [4]海南卫康制药(潜山)有限公司,安徽安庆246000

出　　处：《药学学报》2014年第3期392-398,共7页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81373358)

摘　　要：本文以对乙酰氨基酚为模型药物,研究脂质包裹与β-环糊精(β-CD)包合对难溶性苦味药物的协同矫味。通过建立动力学模型,计算药物在介质、脂质包裹微粒和分子包合等不同制剂单元中的分布,以控制产生苦味的游离药物浓度为目的,在制备、表征对乙酰氨基酚脂质微球基础上,确定β-CD用量,获得协同矫味给药体系,对其进行1H核磁共振(1H NMR)和分子模拟表征,并采用电子舌评价其矫味效果。结果脂质微球呈现一级释放,其速率常数为0.001 270 s-1,据此确定β-CD与对乙酰氨基酚的用量比为6.74∶1(w/w)。协同矫味给药体系中对乙酰氨基酚1H NMR特征峰的化学位移值均增大,且酚羟基上的氧及亚胺基上的氮分别与β-CD中羟基上的氢形成分子间氢键。电子舌实验结合主成分分析(PCA)得到的苦味顺序为:协同矫味给药体系≈脂质微球<β-CD包合物<对乙酰氨基酚原料药,确证了脂质包裹与β-CD分子包合的协同矫味效果。综上,脂质包裹微球以物理包裹方式阻滞药物释放,β-CD通过分子间氢键对游离对乙酰氨基酚进行包合,有效降低产生苦味的游离药物浓度,实现了协同矫味。Paracetamol was used as a model drug in this study to investigate the synergetic effects of lipid coating and β-cyclodextrin （β-CD） inclusion for masking the bitter taste of poorly soluble drugs. To control the concentration as low as possible of the free drug which produced a bitter taste, a kinetic model was established to calculate the drug distribution theoretically among the free drug in medium, lipid coated particles and molecular inclusion on the basis of the preparation and characterization of the lipid microspheres, so as to select the proper amount of β-CD. Finally, the synergetic drug delivery systems were prepared and characterized by 1H nuclear magnetic resonance （1H NMR）, molecular simulation and the electronic tongue. As a result, the drug release rate constant （k） of the lipid mierospheres coated with octadecanol was determined as 0.001 270 s^-1. Then, thesynergetic drug delivery systems were prepared with the ratio of 6.74 ： 1 （w/w） for βl-CD and paracetamol. The chemical shift values for the fingerprint peaks of paracetamol all increased and hydrogen bonds were formed between the oxygen on the phenolic hydroxyl group, the nitrogen on the imino in paracetamol and the hydrogens on the hydroxyl groups in β-CD. The results tested by the electronic tongue indicated that the paracetamol, lipid microspheres, βl-CD inclusion and their mixture showed different taste characteristics, with the bitterness order of the synergetic drug delivery systems ≈ lipid microspheres 〈 β-CD inclusion 〈 paracetamol, which confirmed the synergetic taste masking effects of lipid coating and fl-CD molecular inclusion. In summary, the synergetic taste masking was jointly achieved through the retard of the drug release by the lipid coating and the inclusion of the free paracetamol by fl-CD through hydrogen bonds.

关 键 词：矫味 脂质微球 Β-环糊精 电子舌 对乙酰氨基酚 

分 类 号：R943[医药卫生—药剂学]