In vitro evaluation of a system for pH-controlled peroral delivery of metformin

• Published in: Journal of controlled release 2002-04, Vol.80 (1-3), p.119-128
• Main Authors: Di Colo, G., Falchi, S., Zambito, Y.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Biological and medical sciences; Delayed-Action Preparations - administration & dosage; Delayed-Action Preparations - pharmacokinetics; Drug Delivery Systems - methods; Drug Delivery Systems - statistics & numerical data; Drug Evaluation, Preclinical - methods; Drug Evaluation, Preclinical - statistics & numerical data; Eudragit; General pharmacology; Hydrogen-Ion Concentration; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacokinetics; Interpolymer complex; Medical sciences; Metformin; Metformin - administration & dosage; Metformin - pharmacokinetics; Oral delivery system; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Poly(ethylene oxide)
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/S0168-3659(02)00022-6

Oral absorption of the antihyperglycaemic agent metformin (MF·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·HCl from matrices depended on the PEO–EUD L ratio in the coevaporate. The 1:1 (w/w) ratio was unable to control MF·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 (Mw, 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·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.