title: In vitro evaluation of a system for pH-controlled peroral delivery of metformin.
abstract: Oral absorption of the antihyperglycaemic agent metformin (MF x HCl) is confined to the upper part of the intestine, therefore controlled-release oral formulations of this drug should ensure a complete release during transit from stomach to jejunum. Compressed matrix tablets based on pH-sensitive poly(ethylene oxide) (PEO)-Eudragit L100 (EUD L) compounds have shown in vitro a compliance with the above requirement. The polymer compounds were prepared by a coevaporation process. The release pattern of MF x HCl from matrices depended on the PEO-EUD L ratio in the coevaporate. The 1:1 (w/w) ratio was unable to control MF x HCl release in simulated gastric fluid (SGF, pH 1.2), because the matrix material was excessively hydrophilic. Nevertheless, the release rate in SGF could be modulated by increasing the EUD L fraction in the coevaporate. With a PEO (M(w), 400 kDa)-EUD L (1:2, w/w) ratio the percent dose released in 2 h to SGF, where the coevaporate was insoluble, was around 23 or 50% with 10 or 20% loading dose. The release was then completed within the successive 2 h of elution with simulated jejunal fluid (SJF, pH 6.8) where EUD L and the coevaporate gradually dissolved. Release in SGF was controlled by matrix swelling and/or drug diffusion in matrix, whereas matrix dissolution controlled release in SJF. The unique release-controlling properties of the polymer compounds were due to PEO-EUD L macromolecular interactions. Matrices show promise of a gradual and complete release of MF x HCl from stomach to jejunum, unaffected by gastric pH fluctuations. This mode of administration might allow the use of lower therapeutic doses compared to existing immediate- or sustained-release products, thus minimising side effects.
authors.affiliation: Department of Bioorganic Chemistry and Biopharmaceutics, University of Pisa, Via Bonanno 33, 56126 Pisa, Italy. giadic@farm.unipi.it
authors.forename: G
authors.initials: G
authors.lastname: Di Colo
authors.forename: S
authors.initials: S
authors.lastname: Falchi
authors.forename: Y
authors.initials: Y
authors.lastname: Zambito
mesh_terms: D000284:Administration, Oral; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods* / Q000706:statistics & numerical data; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000706:statistics & numerical data; D006863:Hydrogen-Ion Concentration; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008687:Metformin / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D003692:Delayed-Action Preparations; D007004:Hypoglycemic Agents; D008687:Metformin