Date of Award

1996

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

College

College of Graduate Studies

First Advisor

Jaymin Shah

Second Advisor

Kenneth Cheng

Third Advisor

Bozena Michniak

Fourth Advisor

Robert Notari

Fifth Advisor

James Wynn

Abstract

Systemic administration of prophylactic antibiotics has been reported to significantly decrease, but not eliminate postoperative infections mainly due to the failure in achieving adequate levels of antibiotics at the surgical wound. The local administration guarantees the delivery of adequate levels of antibiotics and is therefore advantageous as a prophylactic measure. Hence, the overall objective of this study was to develop a glyceryl monostearate (GMS) based biocompatible, bioerodible system to provide short term (1-3 days) local delivery of antibiotics. GMS based matrices were prepared by direct compression. Erosion enhancers were incorporated into the GMS matrix to facilitate the bioerosion and bioabsorption of the matrix when implanted in vivo. Cefazolin loaded matrices were coated with different GMS mixtures based coating. Combining 4 matrices resulted in a sequential release of cefazolin that lasted 2.5 days in vitro. The efficacy and pharmacokinetics of cefazolin delivered locally by GMS based implants were evaluated in a rat model infected subcutaneously with Staphylococcus aureus, simulating a postoperative wound infection. The prevention of abscess formation was used as a measure of efficacy as compared to a control group, in which rats did not receive any antibiotic. The efficacy of the implants was also compared to that of multiple 1M injections (1M group) of equal dose of cefazolin. There was no abscess formation in the implant group compared to 2.78 % abscess formation in the IM group and 58.33 % in the control group. The GMS implants sustained the release of cefazolin for a period of three days with little fluctuation in plasma concentrations. The release of cefazolin from the implants was nearly zero order for the entire duration. The bioerosion of the GMS implants was evaluated in an additional group of rats. Six weeks post implantation, 16.67 % of the implants had completely disappeared and the rest had a weight loss ranging between 20 - 80%, indicating the bioerodibility of the GMS implants. Overall, the research was successful in designing a delivery system that provided a prolonged delivery of cefazolin for three days, effectively prevented a staphylococcus aureus infection, and demonstrated biocompatibility in addition to significant bioerosion and biodegradation.

Rights

All rights reserved. Copyright is held by the author.

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