利格列汀二甲双胍缓释片的制备及其体内外评价

Preparation and in vitro and in vivo evaluation of linagliptin/metformin sustained-release tablets

目的通过筛选处方以及工艺,制备与参比制剂体外溶出行为一致的利格列汀二甲双胍缓释片,并开展2种制剂在比格犬体内的药代动力学研究。方法以溶出度、片剂硬度和片重差异为考察因素,通过单因素实验,对处方中缓释骨架材料、粘合剂、增塑剂的用量以及制备工艺等进行考察,筛选出最优处方,并将自制制剂和参比制剂在4种介质中的溶出曲线以及在比格犬体内的药代动力学进行比较。结果盐酸二甲双胍作为主药,用聚氧乙烯作为缓释骨架材料,用羟丙甲纤维素为粘合剂,硬脂酸镁为润滑剂,制成缓释型片芯。利格列汀为主药,聚乙二醇为增塑剂,羟丙甲纤维素为包衣材料,作为包衣液,使用包衣机进行包衣,制得利格列汀二甲双胍缓释片。通过比较自制制剂与参比制剂在4种溶出介质中的溶出曲线,可知二者的溶出曲线相似性因子f2>50。对犬体内药动学实验数据进行分析,参比制剂与自制制剂中2种主药在犬体内的C_(max)相当,说明在相同时间内二者可以达到同样的有效浓度。结论利格列汀二甲双胍缓释片的自制制剂与参比制剂体内外溶出行为一致,制备方法简单可行,可满足大生产的需要。

Objective:To prepare the sustained-release tablets of linagliptin and metformin with the same dissolution behavior as the reference preparation in vitro by screening the formulation and process,and to carry out the pharmacokinetics study of the two preparations in beagle dogs.Methods:With dissolution,tablet hardness and tablet weight difference as factors of investigation,the dosage and preparation process of sustained-release matrix materials,adhesives,plasticizers in the formulation were investigated through single factor experiment,and the optimal formulation was selected.The dissolution curves of self-made preparation and reference preparation in four media and the pharmacokinetics in beagle dogs were compared.Results:Metformin hydrochloride was used as the main drug,polyoxyethylene as the sustained-release skeleton material,hydroxypropyl methylcellulose as the adhesive,and magnesium stearate as the lubricant to prepare the sustained-release core.The sustained-release tablets of linagliptin and metformin were prepared by using linagliptin as the main drug,polyethylene glycol as the plasticizer,hydroxypropyl methylcellulose as the coating material.By comparing the dissolution curves of self-made preparation and reference preparation in four dissolution media,it was seen that their dissolution curve similarity factor f2 was greater than 50.The pharmacokinetic experimental data in dogs were analyzed.The C_(max) of the two main drugs in the reference preparation and the self-made preparation in dogs was equivalent,indicating that they could reach the same effective concentration in the same time.Conclusion:The dissolution behavior of linagliptin metformin sustained-release tablets prepared by ourselves is consistent with that of reference tablets in vitro and in vivo,and the preparation method is simple and feasible,which can meet the needs of large-scale production.