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dc.contributor.advisorWilliams, Robert O., 1956-en
dc.creatorVaughn, Jason Michaelen
dc.date.accessioned2011-02-01T21:45:47Zen
dc.date.available2011-02-01T21:45:47Zen
dc.date.issued2005-08en
dc.identifier.urihttp://hdl.handle.net/2152/9770en
dc.descriptiontexten
dc.description.abstractBioavailability enhancement of poorly water soluble active pharmaceutical ingredients (API) is key for improving existing therapies and allowing for formulation of certain new chemical entities. The rate limiting step for absorption of these APIs is dependent on the dissolution rate and the APIs apparent solubility. Particle engineering processes such as evaporative precipitation into aqueous solution (EPAS) and spray freezing into liquid (SFL) were developed to enhance API dissolution and bioavailbality through the production of amorphous and nanoparticulate API. The morphology, primary API domain size and miscibility of particles produced by EPAS and SFL were investigated by several complementary and novel techniques. It was found that the SFL composition displayed amorphous character, a primary danazol particle size of 30 nm and was consistent with a solid solution. The EPAS composition was mostly amorphous with slight crystallinity, a primary danazol particle size of 500 nm and was consistent with a solid dispersion. The ability of the nanoparticulate and amorphous particles to supersaturate dispersions and how this impacts oral bioavailability was tested through in vitro and in vivo models. Through the use of a testing method for supersaturation, it was found that EPAS and SFL compositions achieve higher apparent solubilities when compared to the physical mixture and commercial Danocrine® capsules. This improvement in solubility allowed for more danazol to be available for absorption in vivo. Pulmonary delivery of SFL nanoparticulate itraconazole was evaluated for pharmacokinetic parameters and steady state trough levels compared to oral delivery of an SFL oral composition and the commercial product. Inhalation of ITZ compositions is an effective method of antifungal therapy for the treatment and prophylaxis of invasive fungal infections. High and sustained lung tissue concentrations are achieved via inhalation of an amorphous ITZ pulmonary composition while maintaining serum levels which are above the minimum lethal concentration for A. fumigatus. Histology, macrophage uptake and IL-12 induction was evaluated for aerosolized amorphous ITZ nanoparticles. Pulmonary administration of amorphous ITZ nanoparticles or excipient placebo does not cause inflammation or changes in alveolar and airway histology. Uptake of ITZ by alveolar and airway macrophages occurs following inhalation of an amorphous ITZ composition.en
dc.format.mediumelectronicen
dc.language.isoengen
dc.rightsCopyright is held by the author. Presentation of this material on the Libraries' web site by University Libraries, The University of Texas at Austin was made possible under a limited license grant from the author who has retained all copyrights in the works.en
dc.subjectSolubilityen
dc.subjectPharmaceutical ingredientsen
dc.subjectBioavailabilityen
dc.titleImproved bioavailability and site specific delivery of poorly water soluble drugs through the production of stabilized drug nanoparticlesen
dc.description.departmentPharmacyen
thesis.degree.departmentPharmacyen
thesis.degree.disciplinePharmacyen
thesis.degree.grantorThe University of Texas at Austinen
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen


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