| Description |
Controlled release drug delivery systems are polymeric devices which are implanted at or near the intended site of action for the purpose of drug delivery at controlled rates for extended periods. In this thesis, various types of drug delivery devices including monolithic, reservoir, and combined monolithic-reservoir devices were prepared and the release kinetics evaluated as a function of device design and composition. Emphasis is placed on progesterone as a model hydrophobic drug. The hydrogel devices were prepared from hydroxyethyl methacrylate (HEMA) and copolymers of HEMA with methoxyethyl methacrylate (MEMA), methoxyethosyethyl methacrylate (MEEMA), or methacrylate (MMA). Hydrogels prepared from chitosan were investigated also. Initial work emphasized drug transport studies in hydrogel films. For these studies, an equation was developed to describe the special case of solute transport under the condition of a high membrane-water partition coefficient and low solubility in the permeation solvent. Several solute-membrane combinations were investigated which may be summarized as follows: (i) an increase in the initiator content leads to a small decrease in progesterone permeability coefficients probably due to increased crosslinking of the polymers; (ii) estriol permeability coefficients in pHEMA crosslinked with ethylene glycol dimethacrylate were smaller than progesterone due to a decrease in the solute membrane partition coefficient; (iii) progesterone and estriol permeability coefficients decrease with increases in weight percent of MMA in copolymers of HEMA and MMA due to a decrease in the water content. At high mole fractions of MMA, the permeability coefficients are relatively constant suggesting that a solution-diffusion mechanism is operative; (iv) partition coefficients for both estriol and progesterone produce a maximum when plotted as function of weight percent MMA. This was interpreted in terms of a domain structure for the HEMA-MMA copolymers; and (v) hydrogels prepared from chitosan are, in general, more permeable than pHEMA for the same solutes, however, chitosan permeabilities were found to be sensitive to the charge of the solute due to charge-charge interactions in the film. Existing equations which describe solute release rates from cylindrical monolithic devices were evaluated and a new equation developed which includes the effects of drug released from the planer ends of the device. The conditions under which the release from the planer ends can be neglected were developed from the release data. Drug release from cylindrical monolithic hydrogel devices containing progesterone were evaluated. It was found that the rate of water influx strongly influences the initial release rates. It was postulated that the initial release rates. It was postulated that the initial release rates should decrease due to a crossflow of solute and solvent within the water-filled channels or pores of the film. It was found, also that the permeability coefficients were dependent upon the initial drug load. This effect was probably due to changes in polymer structure which arise during precipitation of the solute. That this effect was not an artifact of the release studies was confirmed from transport studies on drug depleted films. The release of drugs from reservoir and the combined reservoir-monolithic devices were, in general, consistent with those expected based on the transport studies. However, when the swelling of the monolithic core material was strongly affected by the barrier layer, the release rates were significantly lower than predicted values. The final portion of this thesis deals with the mechanisms of solute permeation in pHEMA-based hydrogels using the methods of irreversible thermodynamics. From this study, it was found that hydrogels are highly selective membranes. The selectivity is increased by crosslinking. The results of the study emphasize the porous nature of solute transport in the films. However, for certain solutes, transport within and through the polymer segments contributes to the total solute permeability. |
