Graduate Thesis Or Dissertation
 

Bioequivalence studies of ketoprofen : product formulation, pharmacokinetics, deconvolution, and in vitro - in vivo correlations

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/h415pc85m

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  • This thesis describes a project to produce controlled release ketoprofen beads for capsules, both at Oregon State University and in an industrial scale-up operation, that are bioequivalent to the commercial product Oruvail. A bead formulation was produced by layering drug and binders in water onto nonpareil sugar seeds in a spray coating apparatus. Ketoprofen beads manufactured in this manner will immediately release their drug content in either an in vitro or an in vivo environment. Industrially produced beads were non-homogeneous in size. Large beads in a coating batch sweep up a disproportional amount of coating material leading to a thicker coating layer and decreased drug release rates. In order to predict the effects of coating modifications, an equation was developed to accurately predict the coating thickness of any material applied to spherical particles of any size. The equation developed is suggested as a replacement for one that has been in published and cited for over 20 years, but overestimates coating thickness. The bulk of this thesis details the process of altering the drug release characteristics of the beads through application of diffusional and enteric barrier coatings, and testing for bioequivalence with Oruvail through biostudy data gathered from human volunteers. Urinary drug excretion rates were measured as a substitute for timed blood sampling of the subjects. Validity of the substitution was shown. Fed state biostudies involved beads manufactured and coated at Oregon State University. Fasted state biostudies involved beads that were industrially manufactured in a scale-up operation and coated both industrially and at Oregon State University. Deconvolution, a mathematical tool, was used to determine in vivo dissolution rates and the need for further coating modification. Statistical testing using a Two 1-Sided T test was the final arbiter of whether or not bioequivalence was concluded. Bioequivalence was achieved in subjects under a fed state and finally under fasting conditions, as required by the Food and Drug Administration, with drug beads coated with ethylcellulose to slow drug release and overcoated with an enteric bather to retard early drug release. Deconvolved in vivo dissolutions originating from biostudy data were used to develop In Vitro / In Vivo Correlations (IVIVC's). IVIVC's were used to predict in vivo biostudy data from in vitro dissolution results following coating formulation modification. A practical guide for the development and use of an IVIVC was written for pharmaceutics practitioners who have an understanding of pharmacokinetics, but may lack sufficient expertise in pharmacokinetics to develop an IVIVC.
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Déclaration de droits
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  • File scanned at 300 ppi (Monochrome, 8-bit Grayscale, 24-bit Color) using ScandAll PRO 1.8.1 on a Fi-6670 in PDF format. CVista PdfCompressor 4.0 was used for pdf compression and textual OCR.
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