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Queen Mary University of LondonQueen Mary University of London
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School of Engineering and Materials Science
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PhD Thesis: Polymer-drug formulations for controlled release via supercritical assisted impregnation

Author: GONG, Kenan

Year: 2008

Supervisor(s): Ihtesham Rehman

In this study, different polymer matrices were employed to convert model drugs into the amorphous state. The polymers included synthetic polymers, such as poly(vinyl pyrrolidine) (PVP), poly(sebacic anhydride) (PSA), hydroxypropyl methylcellulose, and natural polymer, chitosan. They were chosen on the basis of hydrophilicity, crystallinity, molecular weight and functional groups present. Controlled drug release was achieved by manipulating the experimental parameters of supercritical impregnation process for a range of polymer-drug combinations.

PVP-indomethacin composites (DCs) were produced in supercritical CO­­­­2 under the conditions of 15.2 MPa and 75°C, with formation of a complete amorphous indomethacin dispersion. The accumulated drug dissolution (ca. 97%) from DCs was enhanced compared to that from the unprocessed pure crystalline drug (ca. 63%) within the experimental timeframe (4 hrs). Subsequently, chitosan-indomethacin, PSA-indomethacin and HPMC indomethacin composites with a total amorphous dispersion of the drug were obtained under the conditions, 20.7 MPa/70°C, 17.2 MPa/130°C and 17.2 MPa/130°C, respectively (all at polymer-drug weight ratio 4:1). Extended (sustained) drug release was found in the DCs based on the chitosan and PSA, i.e. more than 90% drug dissolved from chitosan-indomethacin DCs via a two-step diffusion controlled release mechanism in 24 hrs. In contrast, ca. 96% drug release at a constant rate was observed for PSA composites during an 80 hrs period (zero order release) controlled by polymer surface erosion.

The work also covered a study to enhance the dissolution of chlorhexidine diacetate from a patented and commercialized polymeric system poly(ethylmethacrylate)/tetrahydrofurfuryl-methacrylate, by modifying the microstructure of polymer matrix using supercritical impregnation technique. The supercritical treated drug delivery system was significantly foamed and drug release (fitted with 1/3 power of time) was enhanced by ca. 7 times.