Designing of the fixed-dose gastroretentive bilayer tablet for sustained release of metformin and immediate release of atorvastatin

Abstract

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.

• Ammonium methacrylate copolymer
• dissolution test
• fixed-dose combination
• pharmacokinetic study
• polyethylene oxide

Declaration of interest

Ji Eun Lee, Yu Jeong Kim, Tack-Oon Oh, SungKyun Han, Eun Kyung Jeon, Kyungmin Shin, Dong-Hyun Kim and Chi Hye Park are employees at the CJ HealthCare Co., Ltd. Ju-Hee Oh and Young-Joo Lee have no conflicts of interest. This work was supported by Chungcheong institute for regional program evaluation (CIRPE) promotion project of the Ministry of Trade, Industry and Energy (MOTIE, 800-20130292, and R0001833), Republic of Korea.