Prediction of the appropriate size of drug molecules that could be released by a pulsatile mechanism from pH/thermoresponsive microspheres obtained from preformed polymers

Preparation of cross-linked pH/thermoresponsive microspheres from preformed polymers is still lacking in literature since copolymers possessing both temperature- and pH-sensitive units together with a cross-linkable moiety in appropriate ratios are required. Moreover, choosing of the appropriate drugs able to be loaded and then released in a pulsatile manner is randomly performed. Here, we report the synthesis of pH/thermoresponsive cross-linked microspheres based on N-isopropylacrylamide and N-alloc-ethylenediamine. A chromatographic method was developed to predict the appropriate size of drug molecules that could be loaded and then released in a pulsatile manner. Accordingly, it was established that common drugs (salicylic acid, benzoic acid, nicotinic acid, lidocaine and diclofenac), with molecular weights ranging between 100 and 1000 g mol-1, could be loaded and released in a pulsatile manner. Biologic molecules with higher molecular weights (heparin, lysozyme and bovine serum albumin) are completely excluded from the pores of cross-linked pH/thermoresponsive microspheres both below and above the volume phase transition temperature.