Chitosan hydrogels and microspheres as electro-responsive drug delivery vehicles

The research described in this thesis was undertaken to formulate chitosan hydrogels and microspheres and to investigate the in vitro and in vivo electro-responsive drug release from the hydrogels and microspheres. Hydrogels of medium molecular weight and high molecular weight chitosan were prepared by N-acetylation of chitosan. The gels were homogeneous, clear and transparent. Swelling ratios and loading efficiencies (for the two model drugs, diclofenac sodium and metformin hydrochloride) of medium and high molecular weight hydrogels were similar. The hydrogels stimulated with pulses of 0.4 mA electrical electric current (30 min on and 30 min off; 6 cycles) released more drugs compared to unstimulated gels. More drug was released during the pulse 'on' periods than during the pulse 'off’. However, a definite 'on-off’ release was not evident from the in vitro release study. The high molecular weight hydrogels were generally found to be more sensitive to electric current than medium molecular weight gels and released more drugs. In addition, the higher the drug concentration in the gels, the greater the release. Thus for the in vivo release studies in male Wistar rats, high molecular weight gels loaded with the higher concentration of diclofenac sodium was used. The subcutaneously implanted hydrogels stimulated with 0.4 mA electric pulses released more drug during electric application compared to the electric 'off' periods, though it was not statistically significant. Microspheres of low molecular weight chitosan were prepared by crosslinking with various concentrations of glutaraldehyde and subsequently spray drying the solution. The particles obtained were 2-5 μm in diameter and had surface charge of 35-42 mV. Compared to the higher crosslinked particles, lower crosslinked microspheres had higher entrapment efficiencies for the model drugs and released more drugs when electro-stimulated. As for hydrogels, the electro-stimulated microspheres release more drug than the control microspheres in both in vitro and in vivo experiments. Drug diffusion out of the microspheres along a concentration gradient which occurred under passive conditions meant that a definite 'on-off’ release profile was not obtained. Further work must be conducted to optimise the hint of pulsatile release observed in the experiments