Preparation and characterisation of thermoresponsive poly[(N-isopropylacrylamide-co-acrylamide-co-(hydroxyethyl acrylate)] microspheres as a matrix for the pulsed release of drugs.

Despite the large number of publications and patents concerning pH/thermoresponsive polymers, few data are available concerning the preparation of thermoresponsive cross-linked microspheres from preformed polymers. Therefore, N-isopropylacrylamide-co-acrylamide-co-(2-hydroxyethyl acrylate) copolymers were obtained as a new thermoresponsive material with a lower critical solution temperature (LCST) around 36 degrees C, in phosphate buffer at pH 7.4, and with a cross-linkable OH group in their structure. The LCST value was determined both by UV spectroscopy and microcalorimetric analysis. These copolymers were solubilised in acidified aqueous solution below their LCST, dispersed in mineral oil, and transformed into stable microspheres by cross-linking with glutaraldehyde. The thermoresponsive microspheres were characterised by optical and scanning electron microscopy, degree of swelling, and water retention. The pore dimensions of the microspheres and the retention volumes of some drugs and typical compounds were evaluated at different temperatures by liquid chromatography. Indomethacin, as a model drug, was included in the microspheres by the solvent evaporation method. Finally, the influence of temperature and of temperature cycling on drug release was investigated.