关键词: 瑞格列奈, 瑞格列奈-精氨酸复合物, 滴丸, 生物利用度

Abstract: Repaglinide(RPG)is a non-sulfonylurea oral hypoglycemic agent with the advantages of rapid onset and small side effects,but the development of new dosage forms was limited by its poorly solubility. In this paper, the Repaglinide-Arginine complex(RPG-Arg)powder were prepared by ion pair solid dispersion technology. RPG dropping pills and RPG-Arg complex dropping pills were prepared by utilizing PEG-4000 and PEG-6000 as the matrix, respectively. Taking the dissolution time of dropping pills,differences in pellet weight, and drug dissolution as the evaluated indexes,the formulation of the dropping pills was screened and the optimal ratio of PEG-4000 and PEG-6000 was found to be 4∶1(g/g). Both dropping pills were characterized by FTIR and DSC. DSC results proved that the RPG was in an amorphous- DOI:10.3969/j.issn.1000-1565.2021.03.009瑞格列奈滴丸制备及体内外评价王苗苗¹,章一¹,吴桐²,李海鹰²,杨文智²(1.保定市第一中心医院 药剂科,河北 保定 071000;2.河北大学 药学院,河北 保定 071002)摘 要:瑞格列奈是非磺酰脲类口服降糖药,具备起效迅速和副反应小的优点,但其在水中溶解度小,限制了其新剂型开发.本文采用离子对固体分散技术,获得瑞格列奈-精氨酸复合物(RPG-Arg)冻干粉.以聚乙二醇(PEG)为基质,分别制备瑞格列奈和RPG-Arg复合物滴丸.以滴丸溶散时间、丸质量差异和药物溶出为考察指标,筛选出滴丸基质配比为m(PEG-4000)∶m(PEG-6000)=4∶1.利用差示扫描(DSC)和红外光谱(FTIR)表征自制滴丸.DSC结果表明,药物以无定形态分散于基质中;FTIR结果显示,滴丸中药物、精氨酸和基质间存在氢键作用,利于药物在滴丸基质中均匀分散.RPG-Arg复合物滴丸的体外释药较原药滴丸快.大鼠分别口服10 mg/kg的自制2种滴丸,复合物滴丸达峰浓度(ρ_max)为原料药滴丸的2倍,且获得1.9倍的相对生物利用度.故RPG-Arg复合物滴丸能够改善难溶瑞格列奈溶解度并提高其生物利用度,可为瑞格列奈滴丸开发提供实验数据支持.关键词:瑞格列奈;瑞格列奈-精氨酸复合物;滴丸;生物利用度中图分类号:O625 文献标志码:A 文章编号:1000-1565(2021)03-0278-07Preparation of repaglinide dropping pills and in vitro and in vivo evaluationsWANG Miaomiao¹, ZHANG Yi¹, WU Tong², LI Haiying², YANG Wenzhi²(1.Department of Pharmacy, the First Central Hospital of Baoding,Baoding 071000,China; 2.College of Pharmacy, Hebei University, Baoding 071002, China)Abstract: Repaglinide(RPG)is a non-sulfonylurea oral hypoglycemic agent with the advantages of rapid onset and small side effects,but the development of new dosage forms was limited by its poorly solubility. In this paper, the Repaglinide-Arginine complex(RPG-Arg)powder were prepared by ion pair solid dispersion technology. RPG dropping pills and RPG-Arg complex dropping pills were prepared by utilizing PEG-4000 and PEG-6000 as the matrix, respectively. Taking the dissolution time of dropping pills,differences in pellet weight, and drug dissolution as the evaluated indexes,the formulation of the dropping pills was screened and the optimal ratio of PEG-4000 and PEG-6000 was found to be 4∶1(g/g). Both dropping pills were characterized by FTIR and DSC. DSC results proved that the RPG was in an amorphous- 收稿日期:2020-08-10 基金项目:河北省高等学校科学技术项目(ZD2018054);河北省自然科学基金资助项目(H2018201045) 第一作者:王苗苗(1987—),女,河北保定人,保定市第一中心医院主管药师,主要从事药物制剂方面的研究.E-mail:524050452@qq.com 通信作者:杨文智(1972—),男,内蒙古锡林浩特人,河北大学副教授,主要从事药物缓控释制剂方面研究.E-mail:wenzhi_yang@sina.com第3期王苗苗等:瑞格列奈滴丸制备及体内外评价state, and FTIR results showed there was hydrogen bonding between RPG, Arg and PEG matrix in their dropping pills, which was beneficial for to the uniform dispersion of the drug. The release rate of the RPG-Arg dropping pills were faster than that of the RPG dropping pills. Compared to RPG dropping pills after oral administration at an equivalent dose of 10 mg/kg in rat, the maximum plasma concentration(ρ_max)of the RPG-Arg complex dropping pills was up to twofold, and the relative bio-availability value reached to 1.9. Therefore, RPG-Arg complex dropping pills can be utilized to improve the solubility and bioavailability of RPG, which can provide basic experimental data for the development of new formulations of RPG.

Key words: repaglinide, RPG-Arg complex, dropping pills, bioavailability