Release kinetics of benzoic acid and its sodium salt from a series of poly(N-isopropylacrylamide) matrices with various percentage crosslinking.

Swelling and concomitant drug-release kinetics from a series of poly(N-isopropylacrylamide) (PNIPA) matrices were examined. Scanning electron microscopy indicated a decrease in polymer pore/mesh size above the lower critical solution temperature (LCST) with increasing percentage crosslinker. The release of sodium benzoate (NaB) or benzoic acid (BA) were investigated above and below the LCST of the gels and compared to the drug-loaded gel-swelling rates. The release rate of NaB increased with increasing percentage crosslinker above the LCST in contrast to a decrease in release rate with increasing crosslinker seen previously with non-thermoresponsive hydrogel systems. As the percentage crosslinker increased, there was therefore a decrease in the ability to thermally control the release of this small model drug. In contrast to the crosslinker-dependent pattern apparent with NaB, drug-PNIPA hydrophobic binding controlled the swelling rate of BA-loaded hydrogels. As a result, all the BA-loaded systems showed similar diffusion controlled swelling and release patterns, effectively independent of the inherent-swelling rates of the hydrogels. The crosslinking content of the hydrogel and the physicochemical nature of the loaded drug were therefore shown to be important in thermal control of drug release from PNIPA hydrogels.

Preparation and release of model drugs from thermally sensitive poly(N-isopropylacrylamide) based macrospheres.

Emulsion polymerization was employed to prepare poly(N-isopropylacrylamide) hydrogel spheres, which exhibited an LCST of 32 degrees C. The hydrogels were loaded with model drugs (benzoic acid (BA), sodium benzoate and diltiazem HCl (DHCl)) and release investigated at 25 degrees C and 37 degrees C. The temperature at which gel formation occurred was vital for successful hydrogel preparation, macrosphere formation not occurring when the temperature was close to the LCST. Sphere size increased on decreasing the stirring rate and on slowing the rate of addition of the aqueous phase. Pulsatile delivery was investigated using BA and DHCl. For both compounds a pulse was observed with a change in temperature. Pulsed release of the smaller model drug of lowest solubility, BA, was more successful. Drug release from hydrogel spheres was, therefore, found to be dependent on the physicochemical properties of the drugs, with pulsatile release of low molecular weight compounds, by temperature cycling, difficult to control.

Drug-polymer interactions and their effect on thermoresponsive poly(N-isopropylacrylamide) drug delivery systems.

Potential interactions between model drugs (benzoates, diltiazem, cyanocobalamin, dextrans) and a thermoresponsive poly(N-isopropylacrylamide) (PNIPA) hydrogel and corresponding linear polymer were investigated. The influence of the drugs on the equilibrium swelling level of the hydrogel was examined and drug-hydrogel binding isotherms were established where appropriate. Differential scanning calorimetry (DSC) was used to investigate the influence of the drugs on the lower critical solution temperature (LCST) of the linear polymer solution. Phase solubility studies were preformed to investigate binding. Drug-polymer co-precipitated blends were also prepared and analysed by X-ray diffraction (XRD), thermal analysis and Fourier transform infrared (FT-IR) spectroscopy. Hydrophobic binding was apparent between PNIPA and the aromatic ring/ester side chain of the unionised benzoate. The effect of this binding on hydrogel swelling was clarified in terms of the influence of the binding on the LCST of the system. The drug release rates of the benzoates from the hydrogel were shown to be dependent on drug binding properties. Ionisation of the benzoate prevented such hydrophobic binding, with a weaker salting out effect apparent with sodium benzoate. Significant interactions between diltiazem, cyanocobalamin (Vitamin B12) or the dextrans and PNIPA were not apparent. High concentrations of the hydrophilic drugs did, however, interfere with the magnitude of hydrogel equilibrium swelling. Hydrophobic binding, the salting out effect and the influence of the drugs on hydrogel swelling under non-sink conditions were therefore shown to be important effects which depended on the chemical nature of the drug present.

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.