title: Controlled release of metformin hydrochloride and repaglinide from sandwiched osmotic pump tablet.
abstract: The marketed compound tablet of metformin hydrochloride (MH) and repaglinide (RG) exhibits perfect multidrug therapeutic effect of type 2 diabetes. However, due to the short half life of the drugs, the tablet has to be administered 2 to 3 times a day, causing inconvenience to patient and fluctuations of plasma concentration. Here, a sandwiched osmotic pump tablet was developed to deliver the two drugs simultaneously at zero-order rate, in which MH and RG were loaded in different layers separated by a push layer. The osmotic pump tablet was prepared by a combination of three tableting procedure and film coating method. The factors including type and amount of propellant, osmotic active agents, amount of porogenic agent, coating weight, orifice diameter were optimized. The pharmacokinetic study was performed in beagle dogs, and the drug concentration in plasma samples was assayed by HPLC-MS/MS method. Simultaneous, controlled release of MH and RG in the first 12 and 8h was achieved from the optimized formulation. A significantly decreased Cmax, prolonged Tmax and satisfactory bioavailability of the osmotic pump tablet were obtained, and a good in vivo-in vitro correlation of the two drugs was also established. In summary, the sandwiched osmotic pump tablet released the MH and RG simultaneously at zero-order rate, and exhibited significant sustained release effect in vivo and good in vivo-in vitro correlation. The designed controlled release system for MH and RG proposed a promising replacement for the marked compound product in the therapy of type 2 diabetes.
authors.affiliation: State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.affiliation: Nanjing Kang Bixin Pharmaceutical Technology Co., Ltd, Nanjing 210046, PR China.
authors.forename: Chunli
authors.initials: C
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Jin
authors.affiliation: School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: lifangyin@hotmail.com.
authors.forename: Lifang
authors.initials: L
authors.lastname: Yin
mesh_terms: D000818:Animals; D002219:Carbamates / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004285:Dogs; D004338:Drug Combinations; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D009995:Osmosis; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D013607:Tablets
chemical_list: D002219:Carbamates; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D007004:Hypoglycemic Agents; D010880:Piperidines; D013607:Tablets; C072379:repaglinide; D008687:Metformin
keywords: Bioavailability; In vivo–in vitro correlation; Metformin hydrochloride; Pharmacokinetics; Repaglinide; Sandwiched osmotic pump tablets