Effect of Drug Physicochemical Properties on Swelling/deswelling Kinetics and Pulsatile Drug Release from Thermoresponsive Poly(N-isopropylacrylamide) Hydrogels

The effect of drug physicochemical properties on swelling/deswelling kinetics and pulsatile drug release from a thermoresponsive hydrogel was examined. Hydrogels were loaded with drug and thermally triggered swelling/deswelling and release experiments were performed. Two series of drugs of contrasting hydrophilicity and varying physicochemical properties were examined. Benzoic acid (BA), its methyl and propyl esters, and diltiazem base were used as model hydrophobic drugs. Sodium benzoate (NaB), diltiazem HCl (DHCl), vitamin B12 (VB12) and various dextrans (MW 4300, 10,200, 42,000, 68,800) were used as model hydrophilic agents of increasing size. The hydrogel swelling rate was slowed by the presence of the hydrophobic drugs and this decreased rate was solubility dependant for the benzoates. The hydrophilic series increased the rate of swelling compared to the unloaded system. In all cases, the magnitude and rate of hydrogel contraction were proportional to the extent of swelling prior to temperature switch. Drug release was by diffusion below the lower critical solution temperature (LCST), while a solubility-dependent drug pulse release on temperature switch was observed for the hydrophobic series. Effectiveness of thermal control of hydrophobic drug release increased with increasing solubility. The hydrophilic series produced a molecular size-dependent drug pulse on temperature switch above the LCST. Pulsatile on-off drug release was shown with DHCl, VB12 and the various dextrans. Drug solubility, size and chemical nature were shown to be of particular importance in the control of hydrogel swelling and drug release from thermosensitive hydrogels.