Improved oral bioavailability of poorly water soluble drugs using rapid freezing processes

dc.contributor.advisorWilliams, Robert O., 1956-en
dc.creatorOverhoff, Kirk Alanen
dc.date.accessioned2011-08-16T20:43:43Zen
dc.date.available2011-08-16T20:43:43Zen
dc.date.issued2006-12en
dc.descriptiontexten
dc.description.abstractA growing number of therapeutic compounds currently being developed by pharmaceutical companies are poorly water soluble leading to limited and/or erratic bioavailability. The rate limiting step for absorption of these compounds is dependent on the dissolution and apparent solubility. Nanoparticle formation has been exploited as a method to improve the bioavailability of these poorly water soluble active pharmaceutical ingredients (API) by increasing the dissolution rates and apparent solubilities. The influence of hydrophilic stabilizers in powder compositions prepared by the spray freezing into liquid (SFL) process using either an emulsion feed dispersion or organic co-solvent feed solutions on enhancing the wetting and dissolution properties of nanostructured aggregates containing itraconazole (ITZ). Subsequently, an in vivo pharmacokinetic study was conducted comparing the SFL processed powder to commercial Sporanox®. An ultra-rapid freezing (URF) technology has been developed to produce high surface area powders composed of solid solutions of an active pharmaceutical ingredient (API) and a polymer stabilizer. Rapid freezing technologies are known to enhance the physico-chemical properties of APIs and thus increase bioavailability. However, the effect of the different freezing geometries and rates in the URF process are unknown. Therefore, this study investigated how solvent properties and thin film geometry of the droplet affect the freezing rate and thus the physico-chemical properties of micronized danazol powders. Amorphous nanoparticles containing tacrolimus (TAC) in a solid dispersion were prepared using the Ultra-rapid Freezing (URF) process. The objective of this study was to assess the effects of combinations of polymeric stabilizers on the maximum degree and extent of supersaturation of TAC. An attempt to establish if an in vitro-in vivo correlation exists between supersaturation and improved pharmacokinetic parameters for orally dosed TAC was performed. Enteric solid dispersions could overcome limitations of premature precipitation of supersaturated solutions by 1.) delaying dissolution until the compound enters the intestines where absorption is favored and 2.) increasing the apparent solubility at higher pH to increase the driving force for absorption. The objective of the study is to investigate the influence of composition parameters including drug:polymer ratio and polymer type, and particle structure of enteric solid dispersions on the release of ITZ.en
dc.description.departmentPharmaceutical Sciencesen
dc.format.mediumelectronicen
dc.identifier.urihttp://hdl.handle.net/2152/13125en
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.subjectFrozen drugsen
dc.subjectPolymeric drug delivery systemsen
dc.subjectFK-506 (Drug)--Designen
dc.subjectPolymeric drugs--Developmenten
dc.subjectDrug developmenten
dc.subjectDrugs--Solubilityen
dc.subjectDrugs--Bioavailabilityen
dc.subjectNanoparticlesen
dc.titleImproved oral bioavailability of poorly water soluble drugs using rapid freezing processesen
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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