瑞格列奈-对氨基苯甲酸-没食子酸三元共无定型的筛选及评价

Screen and evaluation of ternary co-amorphous of repaglinide-p-aminobenzoic acid-gallic acid

关键词:  瑞格列奈,没食子酸,超分子体系,溶出速率,药代动力学

Key words:  Repaglinide, Gallic  acid, Supramolecular  system, dissolution  rate, Pharmacokinetics

摘要:

目的 以瑞格列奈、没食子酸双API为模型,构建三元超分子体系,以提高瑞格列奈的生物利用度,同时为中西药结合治疗糖尿病提供新思路。方法 采用溶剂蒸发法制备三元超分子体系,应用粉末x-射线衍射、热分析、红外光谱等技术对超分子复合物进行结构表征；分别采用饱和溶解度法和桨法测定复合物的平衡溶解度和体外溶出速率；以SD大鼠为动物模型,采用LC-MS/MS法测定大鼠血浆中瑞格列奈的浓度,对瑞格列奈及其三元超分子复合物进行大鼠体内药代动力学研究。结果 成功构建了没食子酸-对氨基苯甲酸-瑞格列奈三元共无定型超分子体系,共无定型中瑞格列奈的溶解度较瑞格列奈增加了1.2倍,且溶出速率提高(P<0.01)；瑞格列奈、共无定型复合物中瑞格列奈的Cmax分别为0.17和0.32 mg·L-1,AUC0-t分别为2.81和3.58 mg·h·L-1,AUC0-∞为3.00和5.09 mg·h·L-1。结论:三元共无定型超分子体系的构建,一方面改善了西药瑞格列奈的生物利用度；另一方面,通过与具有降糖功效的天然活性成分没食子酸应用氨基酸桥梁分子对氨基苯甲酸组装成超分子体系,为中西药结合治疗糖尿病提供了新理念。

Abstract:

Objective:Used repaglinide (RG) and gallic acid (GA) as a double API model, a ternary supramolecular system was constructed to enhance the bioavailability of RG providing new ideas for the treatment of diabetes using integrated traditional Chinese active ingredient and western medicine. Methods:The ternary supramolecular system was screened by solvent evaporation. The screened supramolecular complex was characterized by powder x-ray diffraction, thermal analysis and infrared spectroscopy. The equilibrium solubility and dissolution rate of the complex were determined by saturated solubility and paddle method, respectively. The pharmacokinetic of repaglinide and its ternary supramolecular complex were evaluated through determining the concentration of repaglinide in SD rat plasma using LC-MS/MS method. Results:The GA-PABA-RG ternary coamorphous supramolecular system was successfully constructed. The solubility of RG in coamorphous was 1.2 times higher than that of pure RG; the cumulative dissolution rate increased (P<0.01). The Cmaxs of single RG and RG in the coamorphous were 0.17 and 0.32 mg·L-1, respectively. AUC0-ts were 2.81 and 3.58 mg·h·L-1 and AUC0-∞s were 3.00 and 5.09 mg·h·L-1 for single RG and RG in the coamorphous, respectively. Conclusion:The ternary coamorphous supramolecular system was constructed, in which the bioavailability of RG was improved. Moreover, western medicine RG and Chinese medicine monomer GA were linked together by PABA as a bridge molecular, provided a novel idea for the combination of Chinese medicine and western medicine in the treatment of diabetes.