Oh Ju-Hee, Eun Lee Ji, Jeong Kim Yu, Oh Tack-Oon, Han SungKyun, Jeon Eun Kyung, Shin Kyungmin, Kim Dong-Hyun, Hye Park Chi, Lee Young-Joo
a Department of Life and Nanopharmaceutical Science , College of Pharmacy, Kyung Hee University , Seoul , Republic of Korea and.
b R&D Center, CJ HealthCare Co., Ltd. , Gyeonggi-Do , Republic of Korea.
Drug Dev Ind Pharm. 2016;42(2):340-9. doi: 10.3109/03639045.2015.1096279. Epub 2015 Oct 15.
Patients with type 2 diabetes mellitus have a high risk of cardiovascular disease mainly caused by dyslipidemia. Metformin and atorvastatin are preferentially used to treat type 2 diabetes mellitus and dyslipidemia, respectively. The aim of this study was to develop a once-a-day fixed-dose combination tablet containing metformin and atorvastatin. For this purpose, we designed gastroretentive bilayer tablets consisting of 500 mg metformin in a sustained release layer and 10 mg atorvastatin in an immediate release layer. In addition, we modified the formulation to maintain a dual release pattern for the kinetically different layers for once-daily dosing. The gastroretentive bilayer tablet was developed using polyethylene oxide as a swellable polymer and ammonium methacrylate copolymer as a granule-coating polymer with minimal use of excipients. In vitro release patterns of metformin and atorvastatin from the developed formulation were similar to those of the reference drugs, Glucophage XR for metformin and Lipitor for atorvastatin, with satisfactory dissolution similarity factor (f2) values. The pharmacokinetic study showed the sustained and immediate absorptions of metformin and atorvastatin, respectively, in beagle dogs. The 90% confidence intervals of the ratios of ln values of AUCs of test formulation F3 and respective reference formulations of metformin and atorvastatin were 0.93-1.12 and 0.89-1.17, respectively, compared with their respective reference drugs. This formulation could contribute to improving the compliance and therapeutic outcome of patients with metabolic diseases.
2型糖尿病患者患心血管疾病的风险很高，主要由血脂异常引起。二甲双胍和阿托伐他汀分别优先用于治疗2型糖尿病和血脂异常。本研究的目的是开发一种含有二甲双胍和阿托伐他汀的每日一次固定剂量复方片剂。为此，我们设计了胃滞留双层片，其缓释层含有500毫克二甲双胍，速释层含有10毫克阿托伐他汀。此外，我们对制剂进行了改良，以维持动力学不同层的双释放模式，实现每日一次给药。胃滞留双层片采用聚环氧乙烷作为溶胀性聚合物，甲基丙烯酸铵共聚物作为颗粒包衣聚合物，辅料用量最少。所开发制剂中二甲双胍和阿托伐他汀的体外释放模式与参比药物（二甲双胍的格华止XR和阿托伐他汀的立普妥）相似，具有令人满意的溶出相似性因子（f2）值。药代动力学研究表明，在比格犬中，二甲双胍和阿托伐他汀分别呈现持续和即时吸收。与各自的参比药物相比，受试制剂F3与二甲双胍和阿托伐他汀各自参比制剂的AUC的ln值之比的90%置信区间分别为0.93 - 1.12和0.89 - 1.17。该制剂有助于提高代谢疾病患者的依从性和治疗效果。
