Semester

Spring

Date of Graduation

2004

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Paula Jo Meyer-Stout.

Abstract

Useful for drug delivery systems, natural polymer matrix systems, such as gelatin, have been formulated for localized drug delivery. The main limitations of gelatin are its extensive swelling, rapid dissolution and drug release. To slow drug release, chemical cross-linking agents have been used to form relatively non-soluble networks. Sucrose and fructose were used as cross-linking agents in a gelatin-based matrix. Additional studies evaluated two process variables: casting and curing (ambient or refrigerated temperatures, vacuum drying and lyophilization) methods. The optimized gelatin/sugar matrices were then compared to varying concentrations of gelatin/formaldehyde matrices. Matrix erosion studies were completed to monitor percent swelling and maintenance of physical integrity. Thermal analysis studies were performed to thermally characterize the matrices. Optimized formulations were loaded with drug and the release profiles of these matrices were characterized and compared. Qualitative and quantitative studies were completed, under sink and non-sink conditions. Diffusion based models were applied for identification of the mechanisms controlling drug release from these matrices.;The use of native sugars as cross-linking agents enhances matrix performance and overall stability while decreasing the risks associated with aldehydes. It was determined that lyophilization provided optimum matrix curing. The use of ethanol as a dispersing agent offered little advantage over water. Comparison of gelatin/sugar and gelatin/formaldehyde matrices demonstrated that the sugars decrease the swelling of the matrix, but do not maintain the prolonged erosion time seen with the gelatin/formaldehyde matrices. Visual release studies revealed that an initial burst followed by a gradual release is seen until there is no dye in the matrix. Visual studies also demonstrated that two different solutes transport out of the matrices at different rates. In vitro release and modeling studies revealed that the dye release appears to be diffusion-controlled, with minimal affect of swelling on release kinetics.;These studies demonstrate the viability of the use of sucrose and fructose, in combination with lyophilization, as cross-linking agents for gelatin-based systems. While these sugars could not replace formaldehyde in formulations needed for extended sustained release delivery (>2 day), the sugars offer a better alternative in formulations requiring an extended release of drug over 12--48 hours.

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