title: 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.
authors.affiliation: a Department of Life and Nanopharmaceutical Science , College of Pharmacy, Kyung Hee University , Seoul , Republic of Korea and.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Oh
authors.affiliation: b R&D Center, CJ HealthCare Co., Ltd. , Gyeonggi-Do , Republic of Korea.
authors.forename: Ji
authors.initials: J
authors.lastname: Eun Lee
authors.affiliation: b R&D Center, CJ HealthCare Co., Ltd. , Gyeonggi-Do , Republic of Korea.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jeong Kim
authors.affiliation: b R&D Center, CJ HealthCare Co., Ltd. , Gyeonggi-Do , Republic of Korea.
authors.forename: Tack-Oon
authors.initials: TO
authors.lastname: Oh
authors.affiliation: b R&D Center, CJ HealthCare Co., Ltd. , Gyeonggi-Do , Republic of Korea.
authors.forename: SungKyun
authors.initials: S
authors.lastname: Han
authors.affiliation: b R&D Center, CJ HealthCare Co., Ltd. , Gyeonggi-Do , Republic of Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Jeon
authors.affiliation: b R&D Center, CJ HealthCare Co., Ltd. , Gyeonggi-Do , Republic of Korea.
authors.forename: Kyungmin
authors.initials: K
authors.lastname: Shin
authors.affiliation: b R&D Center, CJ HealthCare Co., Ltd. , Gyeonggi-Do , Republic of Korea.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: b R&D Center, CJ HealthCare Co., Ltd. , Gyeonggi-Do , Republic of Korea.
authors.forename: Chi
authors.initials: C
authors.lastname: Hye Park
authors.affiliation: a Department of Life and Nanopharmaceutical Science , College of Pharmacy, Kyung Hee University , Seoul , Republic of Korea and.
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D019540:Area Under Curve; D000069059:Atorvastatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003692:Delayed-Action Preparations; D004285:Dogs; D004338:Drug Combinations; D065546:Drug Liberation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D008687:Metformin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012995:Solubility; D013607:Tablets
chemical_list: D003692:Delayed-Action Preparations; D004338:Drug Combinations; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D013607:Tablets; D008687:Metformin; D000069059:Atorvastatin
keywords: Ammonium methacrylate copolymer; dissolution test; fixed-dose combination; pharmacokinetic study; polyethylene oxide