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Development of co-loaded fusidic acid and rifampicin polymeric microspheres and nanofibers : phase characterization and in vivo evaluation in a rodent model of orthopaedic infection

University of British Columbia

The overall goal of this project was to develop and characterize a biodegradable, polymeric formulation using poly (D,L-lactic acid-co-glycolic acid) (PLGA) for the controlled delivery of fusidic acid (FA) and rifampicin (RIF) to orthopaedic surgical sites to achieve high localized concentrations above the MIC of potential microorganisms to prevent implant-associated infections. Our primary formulation strategy using PLGA microspheres was inappropriate for the controlled delivery of either agent due to a phase separation phenomena of the solid drugs from PLGA. The phase separation, lead us to investigate the solid state properties of FA and the phase behavior of FA and RIF in microspheres. Four distinct solid forms of FA (Form I-IV), and an amorphate were identified. Form IV and amorphous FA had significantly greater intrinsic dissolution rates, and the interconversion of both Form IV and amorphous FA to Form III in aqueous mileau suggests a risk of interconversion upon exposure to moisture if FA is formulated in the solid state. The phase separation of FA and RIF from PLGA microspheres was characterized by drug microdomains localized on the microsphere surface (for FA), or a dimpled microsphere surface (for RIF). Novel micromanipulation techniques allowed the visualization of the phase separation events for FA and RIF, which was correlated with the compatibility between each drug and PLGA. When co-loaded, FA and RIF phase separate in a single event, intermediate to each drug alone. Suface distribution of drug microdomains, and drug release, was dependent on the weight fraction of FA. A more suitable controlled release formulation was PLGA nanofibers prepared using electrospinning. The drug-loaded formulations were defect-free and had a biphasic drug release profile. All dual-loaded formulations showed direct antimicrobial activity in vitro against 4 Gram positive microorganisms. Furthermore, lead formulations containing 10% (w/w) FA/SF and 5% (w/w) RIF were able to prevent the adherence of methicillin resistant S. aureus to a titanium implant in an in vivo rodent model of implant-associated infection. The data in this thesis contributes to the understanding of drug phase separation from PLGA, and drug-loaded electrospun nanofibers provide a preclinical proof-of-principle for the prevention of implant-associated infections.

Text

2012-07-23

Attribution-NonCommercial-NoDerivs 3.0 Unported

http://hdl.handle.net/2429/42800

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/3.0/