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Date of Award
1993
Document Type
Dissertation - Pacific Access Restricted
Degree Name
Doctor of Philosophy (Ph.D.)
Department
Graduate School
First Advisor
Ravindra Vasavada
First Committee Member
Madhukar Chaubal
Second Committee Member
Richard P. Dodge
Third Committee Member
Michael Mergener
Fourth Committee Member
Donald Sorby
Abstract
Polymethyl methacry late-antibiotic implants for the local treatment of osteomyelitis have been used in hospitals in the U.S. since the 1970s. This treatment requires a second surgery for removal of t he depleted implant. The purpose of this study is to investigate a new biodegradable implant system based upon poly(ortho esters) (POE) which can release tobramycin sulfate (TS) over a 21-day period (the usual clinical treatment period) with simultaneous and subsequent degradation of polymer in the tissues to harmless constituents.
The POE-TS disks without any excipients showed a similar drug release pattern regardless of TS loading ( 4%, 8%, 12%, w/ w) and thickness (148, 244, 433 pm): 20%-60% TS-release within the first 24 hours followed by less than 10% release during the following 20 days with less than 3% weight loss of the polymer. These formulations did not meet therapeutic requirements of either drug release or polymer degradation rate. POE d egradation is known to be acid sensitive. To achieve uniform and high TS release over 21 days, various concentrations of lactic acid (LA), sorbic acid (SA), oleic acid (OA) and palmitoleic acids (PA) were incorporated in the 244pm-disks of 8% TS. The disks with LA demonstrated a pseudo zero-order TS release. With SA, OA & PA, the TS release was multi-phasic and the rate of polymer degradation was found to be acid concentration dependent. The TS release from these disks could be attributed to burst effect, polymer erosion and diffusion. Among these formulations, disks with 0.2% LA and 0 .9% OA gave the best release rate of 2mg TS/ day/ g implant; they achieved desirable therapeutic level of TS release and POE degradation.
No physical or chemical interactio ns were detected by DSC, NMR and JR. Comparisons of POE weight loss and molecular weight loss with different acid catalysts revealed extremely different kinetics of acid catalysis. Uniform distribution of the drug in the disks was concluded based on content uniformity studies. Aqueous and solid state stability of TS were found to be suitable for clinical usage.
Pages
132
Recommended Citation
Du, Jie. (1993). Investigation of tobramycin-poly (ortho ester) implantable systems for the treatment of osteomyelitis. University of the Pacific, Dissertation - Pacific Access Restricted. https://scholarlycommons.pacific.edu/uop_etds/2256
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