Sustained release from hot-melt extruded matrices based on ethylene vinyl acetate and polyethylene oxide

• Published in: European journal of pharmaceutics and biopharmaceutics 2012-11, Vol.82 (3), p.526-533
• Main Authors: Almeida, A., Brabant, L., Siepmann, F., De Beer, T., Bouquet, W., Van Hoorebeke, L., Siepmann, J., Remon, J.P., Vervaet, C.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biological Availability; Calorimetry, Differential Scanning; Crystallization; Delayed-Action Preparations; Dogs; Drug Carriers - chemistry; Drug Compounding; Ethylene vinyl acetate; General pharmacology; Hot Temperature; Hot-melt extrusion; Male; Medical sciences; Metoprolol - administration & dosage; Metoprolol - chemistry; Metoprolol - pharmacokinetics; Models, Theoretical; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyethylene Glycols - chemistry; Polyethylene oxide; Polyvinyls - chemistry; Porosity; Spectrum Analysis, Raman; Sustained release; Tomography, X-Ray; Viscosity
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2012.08.008

In vitro and in vivo characterization of EVA and PEO based hot-melt extruded matrices. The aim of the present study was to evaluate the importance of matrix flexibility of hot-melt extruded (HME) ethylene vinyl acetate (EVA) matrices (with vinyl acetate (VA) contents of 9%, 15%, 28% and 40%), through the addition of hydrophilic polymers with distinct swelling capacity. Polyethylene oxide (PEO 100K, 1M and 7M) was used as swelling agent and metoprolol tartrate (MPT) as model drug. The processability via HME and drug release profiles of EVA/MPT/PEO formulations were assessed. Solid state characteristics, porosity and polymer miscibility of EVA/PEO matrices were evaluated by means of DSC, X-ray tomography and Raman spectroscopy. The processability via HME varied according to the VA content: EVA 40 and 28 were extruded at 90°C, whereas higher viscosity EVA grades (EVA 15 and 9) required a minimum extrusion temperature of 110°C to obtain high-quality extrudates. Drug release from EVA matrices depended on the VA content, PEO molecular weight and PEO content, matrix porosity as well as pore size distribution. Interestingly, the interplay of PEO leaching, matrix swelling, water influx and changes in matrix porosity influenced drug release: EVA 40- and 28-based matrices extruded with PEO of higher MW accelerated drug release, whereas for EVA 15- and 9-based matrices, drug release slowed down. These differences were related to the distinct polymer flexibility imposed by the VA content (lower VA content presents higher crystallinity and less free movement of the amorphous segments resulting in a higher rigidity). In all cases, diffusional mass transport seems to play a major role, as demonstrated by mathematical modeling using an analytical solution of Fick’s second law. The bioavailability of EVA 40 and 28 matrices in dogs was not significantly different, independent of PEO 7M concentration.