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A preclinical evaluation of the possible enhancement of the efficacy of antituberculosis drugs by PheroidTM technology / L.I. Matthee

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dc.contributor.author Matthee, Leon Ignatius
dc.date.accessioned 2009-05-22T08:26:51Z
dc.date.available 2009-05-22T08:26:51Z
dc.date.issued 2007
dc.identifier.uri http://hdl.handle.net/10394/1805
dc.description Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.
dc.description.abstract With the rise of the HIV pandemic and persistent global poverty, tuberculosis (TB) was declared a global emergency, claiming thousands of lives with each passing year and putting severe pressure on the socio-economic status of affected countries. Co-infection with human immunodeficiency virus (HIV) complicates the treatment of the disease even further. The treatment of this dreadful disease currently involves administration of a combination of rifampicin (R), isoniazid (H), pyrazinamide (Z) and ethambutol (E) for the initial 2 months, followed by rifampicin and isoniazid for 4 months. The World Health Organization (WHO) strongly encourages the use of fixed-dose combination (FDC) products. FDC products containing anti-tuberculosis drugs were introduced to the market as a means to simplify treatment and to increase patient compliance. The use of FDCs is hampered by poor bioavailability when rifampicin, isoniazid, pyrazinamide and ethambutol are formulated together. Various causes have been proposed, including raw material characteristics, changes in the crystalline forms of rifampicin, degradation in the gastro-intestinal tract and inherent variability in absorption and metabolism or a combination of any of these. The discovery and development of a new regimen including four novel drugs usually takes up to 14 years and it is an extremely expensive process. Although a bouquet of drugs with novel mechanisms of action are ready for phase II and III clinical trials, the annual increase in new tuberculosis cases necessitates immediate action. The search for a means to increase bioavailability of existing drugs entered a new era when the Pheroid™ drug delivery system was developed. This technology involves the entrapment of drug molecules into stable submicron and micron sized structures, referred to as Pheroids™. Pheroids™ consist of three components, namely fatty acids, sterile water and nitrous oxide gas. Research of this system promises many advantages in the oral or transdermal delivery of drug molecules. An application of Pheroid™ technology in the treatment of tuberculosis presented itself when a Pheroid™-based combination product was tested for the possible enhancement of bioavailability of especially rifampicin in humans. However, the test formulation in the above-mentioned study had considerable stability problems. These stability problems were directly related to the instability of rifampicin when it is formulated in combination with isoniazid. The next step in the development process entailed a few changes being made to the formulation to rule out any known drug instabilities. These changes included the use of pro-Pheroid™ technology and the separation of rifampicin and isoniazid within the formulation. A pilot study was carried out to determine and compare the levels of R, H, E and Z in the plasma of mice who received a pro-Pheroid™ formulation with those who received the current 4-drug FDC (Rifafour e-275®), dissolved in water. The aim of the pilot study was to determine if the new pro-Pheroid™ formulation would also increase the absorption of rifampicin, isoniazid, ethambutol and pyrazinamide. This study also consisted of a 3-month stability study under accelerated climatic conditions and drug content and microbial growth were determined on a monthly basis. An increase (300%) in the absorption of rifampicin was found with the pro-Pheroid™ formulation, when plasma concentrations were compared with the current commercial product, Rifafour e-275®. The accelerated stability test was unfortunately hampered by some apparatus-based inconsistencies and formulation problems, which made it difficult to determine drug content after three months. This was unfortunate, but it was concluded that the drug content within the pro-Pheroid™ formulation did remain between 90% and 110% of the initial values. Furthermore, no microbial growth was detected in the formulations. Therefore, the pro-Pheroid™ formulations were regarded as stable. In conclusion, the pro-Pheroid™ formulation did succeed in delivering more of the drug molecule across the intestinal epithelia of mice. Furthermore, the proposed formulation was found to be stable at various temperatures ranging from 5°C to 40°C, when protected from light and moisture. A complete bioequivalence study in mice will be based on the experimental methods used and the data obtained from this study. The results of this study are herewith reported in the article format as described in section A. 13.7.3 of the general academic rules of the North West University. The first three chapters deal with the global burden of tuberculosis, current treatment and control strategies and the Pheroid™ drug delivery system and its application in tuberculosis treatment. Chapter 4 includes a proposed article for submission to the Open Drug Delivery Journal, and Chapter 5 gives a final summary and conclusion of this study. Results for all experiments are organized into appendices 1-3.
dc.publisher North-West University
dc.title A preclinical evaluation of the possible enhancement of the efficacy of antituberculosis drugs by PheroidTM technology / L.I. Matthee en
dc.type Thesis en
dc.description.thesistype Masters


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    This collection contains the original digitized versions of research conducted at the North-West University (Potchefstroom Campus)

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