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    In Vitro Dissolution, Supersaturation, and Permeation to Predict In Vivo Oral Drug Absorption

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    Adhikari_umaryland_0373D_11364.pdf
    Embargo:
    2023-01-01
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    2.292Mb
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    Author
    Adhikari, Asmita
    Advisor
    Polli, James E.
    Date
    2022
    Type
    dissertation
    
    Metadata
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    Abstract
    Most new drug candidates are poorly water soluble, and as such have limited absorption and bioavailability. The current research focuses on two major aspects of oral drug absorption research (i) characterization of spray dried dispersions (SDDs) of a poorly soluble drug to elucidate the factors that impact overall formulation performance and absorption, and (ii) development and utilization of an in vitro dissolution-permeation model to predict in vivo human absorption and performance of various drugs representing different Biopharmaceutic Classification System (BCS) classes. The first aim was to characterize itraconazole (ITZ) SDDs from three grades (L, M and, H) of hydroxypropyl methylcellulose acetate succinate (HPMCAS) polymer based on supersaturation kinetics and molecular interactions that contributed to the overall SDD performance and drug absorption. A combination of in vitro and solution state drug-polymer interaction studies was used. Results indicated that a high supersaturating concentration, and rate and extent of supersaturation caused the largest increase in absorption. We concluded that such stronger hydrophobic interactions between drug and polymer were relative detriment to ITZ absorption for ITZ and HPMCAS SDDs. Conventional dissolution testing has been modified in terms of in vitro design and medium composition. Biorelevant media closely simulate the composition of human gastrointestinal fluids but are challenging to prepare and contain multiple components. The second aim was to assess the similarity of dissolution profiles from biorelevant media. Results indicated favorable interday repeatability, interanalyst repeatability, and interlaboratory reproducibility suggesting this approach could be incorporated into clinically relevant dissolution models. An in vitro model that can capture the dynamic interplay between dissolution and permeation is sought for poorly soluble drugs, with potential to guide the drug development process and product life cycle management. The third aim was to characterize and utilize a dissolution-hollow fiber membrane (D-HFM) system to correlate in vitro and in vivo parameters for several BCS classes drugs. Model predictions and experimental D-HFM system studies were performed using drug solutions and drug products. Results indicated close agreement between predicted and observed drug permeation profiles, and between the D-HFM system derived in vitro and in vivo permeation constants and absorption profiles.
    Description
    University of Maryland, Baltimore. Pharmaceutical Sciences. Ph.D. 2022.
    Keyword
    amorphous solid dispersions
    dissolution
    permeation
    supersaturation
    Absorption
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/19155
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    Theses and Dissertations School of Pharmacy
    Theses and Dissertations All Schools

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