关键词: 米格列奈钙, 米格列奈-精氨酸复合物, 溶解度, 生物利用度

Abstract: Mitiglinide calcium(MTG)is a drug for the treatment of type Ⅱ diabetes, which has the advantages of quick action and high safety. However, its low solubility in water limits the development of its solution dosage form. In this paper, the lyophilized powder of mitiglinide-arginine complex(MTG-Arg)was optimized and prepared by a single factor method using hydrotropic technology. The MTG-Arg complex powders were characterized by X-ray diffraction(XRD)and differential scanning calorimetry(DSC). XRD results show that the crystal diffraction peaks of the drug and arginine disappear, and there is strong intermolecular hydrogen bonding between the drug and arginine hydrotropic agent, which makes the drug and arginine exist in amorphous state. The results of DSC show that the melting endothermic peaks of the drug and arginine disappear, which further proves the amorphous dispersion of the drug and arginine. MTG-Arg complex has good stability and its dissolution is significantly better than that of the original- DOI:10.3969/j.issn.1000-1565.2023.03.007米格列奈-精氨酸复合物的制备与评价王苗苗¹,李航航²,贾丽丽¹,吴丽欣¹,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:米格列奈钙(MTG)是治疗Ⅱ型糖尿病药物,具有起效快和安全性高的优点,但其在水中溶解度小,限制其溶液剂型的开发.本文利用助溶制剂技术,采用单因素方法优化并制备米格列奈-精氨酸复合物(MTG-Arg)冻干粉,经粉末X线衍射(XRD)和差示扫描量热法(DSC)验证MTG-Arg复合物制备成功.XRD结果显示:复合物中药物和精氨酸的晶体衍射峰消失,两者之间存在较强分子间氢键作用,在复合物中以无定型态存在;而DSC结果显示复合物中的药物与精氨酸的晶体熔融吸热峰消失,进一步证明两者的无定形分散态.MTG-Arg复合物稳定性良好,体外溶出显著优于原药.大鼠分别灌胃含药20 mg/kg的MTG-Arg复合物溶液剂和MTG混悬剂,MTG-Arg组的大鼠血药达峰质量浓度(ρ_max)为MTG的1.8倍且获得改善的绝对生物利用度.此外,糖尿病小鼠灌胃MTG-Arg复合物溶液剂,可有效降血糖.故MTG-Arg复合物能用于制备其溶液剂,实验结果可为米格列奈钙口服溶液剂的开发提供数据支持.关键词:米格列奈钙;米格列奈-精氨酸复合物;溶解度;生物利用度中图分类号:O625 文献标志码:A 文章编号:1000-1565(2023)03-0274-07Preparation and evaluation of mitiglinide-arginine complexWANG Miaomiao¹, LI Hanghang², JIA Lili¹, WU Lixin¹, YANG Wenzhi²(1. Department of Pharmacy, First Central Hospital of Baoding,Baoding 071000,China; 2. College of Pharmacy, Hebei University, Baoding 071002, China )Abstract: Mitiglinide calcium(MTG)is a drug for the treatment of type Ⅱ diabetes, which has the advantages of quick action and high safety. However, its low solubility in water limits the development of its solution dosage form. In this paper, the lyophilized powder of mitiglinide-arginine complex(MTG-Arg)was optimized and prepared by a single factor method using hydrotropic technology. The MTG-Arg complex powders were characterized by X-ray diffraction(XRD)and differential scanning calorimetry(DSC). XRD results show that the crystal diffraction peaks of the drug and arginine disappear, and there is strong intermolecular hydrogen bonding between the drug and arginine hydrotropic agent, which makes the drug and arginine exist in amorphous state. The results of DSC show that the melting endothermic peaks of the drug and arginine disappear, which further proves the amorphous dispersion of the drug and arginine. MTG-Arg complex has good stability and its dissolution is significantly better than that of the original- 收稿日期:2022-10-20 基金项目:保定市科技计划项目(2272P009);河北省医学科研项目(20220283) 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,博士,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:米格列奈-精氨酸复合物的制备与评价drug. Rats were administrated with 20 mg/kg MTG-Arg complex solution or MTG supension, respectively. The peak concentration(ρ_max)of the complex solution was 1.8 times than that of the MTG suspension, and the absolute bioavailability of MTG-Arg was also improved. In addition, intragastric administration of MTG-Arg complex solution can effectively reduce blood glucose in diabetic mice. Therefore, MTG-Arg complex can be used to prepare its solution dosage form, and the results can provide data support for the development of oral solution of MTG.

Key words: mitiglinide calcium, mitiglinide-arginine complex, solubility, bioavailability