Gastroretentive systems for prolonged release of metformin based on osmotically driven expansion
Abstract
Metformin is a relatively old drug mainly used to treat type 2 and gestational diabetes, which needs to be administered two or three times a day in high doses. It has a high aqueous solubility and is poorly absorbed following oral intake. Aiming to achieve a gastroretentive formulation for prolonged release of this drug, an expandable device based on an osmotically driven mechanism (ORODS, Organ-Retentive Osmotically Driven System) was developed.
The system consists of an osmotic unit obtained from tubular dialysis membranes filled with an osmotic agent, and one or more drug release units containing metformin. Osmotic units were fabricated using dialysis membranes with different cutoffs (3.5–5 and 12–14 kD) and different osmotic agents, namely sodium chloride or mannitol. Drug release units were obtained by tableting metformin in admixture with high-viscosity hypromellose (Methocel® K15M) to give prolonged-release hydrophilic matrix systems. Multi-layered matrices having drug-free external layers were also designed, which led to a range of different release rates.
The assembled ORODS devices were loaded into hard-gelatin capsules suitable for oral administration and, when in contact with pH 1.2 fluid, rapidly expanded thanks to osmotic water inflow, thus potentially preventing transit through the open pylorus in an in vivo setting. Metformin-containing units ultimately dissolved and/or eroded, while the osmotic units shrank and disassembled thereby ideally allowing for physiological emptying of the device from the stomach and intestinal elimination.
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Materials
Metformin hydrochloride (Metapharmaceutical, ES, Mw = 165.62 g/mol, solubility in water at 25 °C, 50 mg/mL, d50 = 79 µm, SPAN = 2.1); dicalcium phosphate dihydrate and magnesium stearate (VWR International S.r.l. IT), hypromellose (HPMC, Methocel® K15M, Colorcon, UK); ethyl cellulose (EC, Ethocel®, Colorcon, UK); acetone (VWR International S.r.l. IT); dialysis tubular membrane made of regenerated cellulose having 10 mm flat width and cutoffs of 3.5–5.0 or 12–14 kD (Spectrum Labs™ Repligen, Spectra/Por™ 2, CA, USA); sodium chloride (NaCl, VWR International S.r.l., IT, Mw = 58.44 g/mol, solubility in water at 25 °C, 360 mg/mL); mannitol (Mannogem XL®, SPI Pharma, USA, Mw = 182.17 g/mol, solubility in water at 25 °C, 220 mg/mL); potassium chloride (KCl); hydrochloric acid (HCl) 37% (VWR International S.r.l., IT), hard-gelatin capsules (Capsugel® ConiSnap® Size 00, Lonza, BE); acrylic glue (Loctite, DE).
Micol Cirilli, Saliha Moutaharrik, Luca Palugan, Martina Edith Coldani, Alessandra Buscarini, Giovanna Bruni, Andrea Gazzaniga, Alessandra Maroni, Anastasia Foppoli, Matteo Cerea, Gastroretentive systems for prolonged release of metformin based on osmotically driven expansion, International Journal of Pharmaceutics, Volume 681, 2025, 125856, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125856.
Read also our introduction article on Mannitol here:
