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Development, validation and application of Calu-3 cell line for nasal drug absorption studies: pilot studies on drug candidates with small molecular weight.

Wang, Shu. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 119-139). / Abstracts in English and Chinese. / Table of contents --- p.i / Abstract --- p.v / 摘要 --- p.viii / Acknowledgements --- p.x / List of tables --- p.xi / List of figures --- p.xiii / List of abbreviations --- p.xvi / Chapter Chapter One. --- Introduction --- p.1 / Chapter 1.1 --- Overview of nasal drug delivery --- p.2 / Chapter 1.1.1 --- Structure and permeability of the nasal mucosa --- p.3 / Chapter 1.1.2 --- Pathways of drug permeation across nasal mucosa --- p.6 / Chapter 1.1.3 --- Models for nasal drug permeation studies --- p.7 / Chapter 1.1.3.1 --- In vitro models --- p.7 / Chapter 1.1.3.2 --- In situ models --- p.13 / Chapter 1.1.3.3 --- In vivo animal models --- p.16 / Chapter 1.1.4 --- Factors affecting drug absorption across nasal mucosa --- p.19 / Chapter 1.1.4.1 --- Biological factors --- p.20 / Chapter 1.1.4.2 --- Physicochemical properties of drugs --- p.25 / Chapter 1.1.4.3 --- Formulation factors --- p.29 / Chapter 1.1.5 --- Profile of a suitable drug candidate for nasal delivery --- p.33 / Chapter 1.2 --- Physicochemical properties and human pharmacokinetics of the four drug candidates --- p.35 / Chapter 1.2.1 --- Rizatriptan --- p.35 / Chapter 1.2.2 --- Meloxicam --- p.37 / Chapter 1.2.3 --- Lomoxicam --- p.39 / Chapter 1.2.4 --- Nebivolol --- p.40 / Chapter 1.3 --- Scope of the current study --- p.44 / Chapter Chapter Two. --- Preliminary validation of Calu-3 cell line model as an in vitro model for nasal drug permeation screening --- p.45 / Chapter 2.1 --- Introduction --- p.45 / Chapter 2.2 --- Materials --- p.46 / Chapter 2.2.1 --- Chemicals --- p.46 / Chapter 2.2.2 --- Materials for cell culture --- p.46 / Chapter 2.2.3 --- Instruments --- p.47 / Chapter 2.3 --- Methods --- p.47 / Chapter 2.3.1 --- Cell culture --- p.47 / Chapter 2.3.2 --- Cytotoxicity studies by MTS/PES assay --- p.48 / Chapter 2.3.2.1 --- Optimization of MTS/PES assay for the initial cell seeding density and the incubation time --- p.49 / Chapter 2.3.2.2 --- Cytotoxicity studies of non-physiological pH and osmolarity on Calu-3 cells by MTS/PES assay --- p.49 / Chapter 2.3.3 --- Integrity of Calu-3 cell monolayers --- p.50 / Chapter 2.3.3.1 --- Transepithelial electrical resistance (TEER) --- p.50 / Chapter 2.3.3.2 --- Permeabilities of marker compounds --- p.51 / Chapter 2.3.3.3 --- Effect of osmolarity on the Calu-3 cell monolayers --- p.53 / Chapter 2.3.4 --- Inter-passage variation --- p.53 / Chapter 2.3.5 --- Statistical analysis --- p.54 / Chapter 2.4 --- Results and discussions --- p.54 / Chapter 2.4.1 --- Cell culture --- p.54 / Chapter 2.4.2 --- Cytotoxicity studies by MTS/PES assay --- p.55 / Chapter 2.4.2.1 --- Optimization of MTS/PES assay for the initial cell seeding density and the incubation time --- p.55 / Chapter 2.4.2.2 --- Cytotoxicity studies of non-physiological pH and osmolarity on Calu-3 cells by MTS/PES assay --- p.57 / Chapter 2.4.3 --- Integrity of Calu-3 cell monolayers --- p.58 / Chapter 2.4.3.1 --- Transepithelial electrical resistance (TEER) --- p.59 / Chapter 2.4.3.2 --- Permeabilities of marker compounds --- p.60 / Chapter 2.4.3.3 --- Effect of osmolarity on the Calu-3 cell monolayer --- p.63 / Chapter 2.4.4 --- Inter-passage variation --- p.65 / Chapter 2.5 --- Conclusion --- p.66 / Chapter Chapter Three. --- Permeation studies of selected drug candidates using the Calu-3 cell line model --- p.68 / Chapter 3.1 --- Introduction --- p.68 / Chapter 3.2 --- Materials --- p.69 / Chapter 3.2.1 --- Chemicals --- p.69 / Chapter 3.2.2 --- Materials for cell culture --- p.69 / Chapter 3.2.3 --- Instruments --- p.69 / Chapter 3.3 --- Methods --- p.70 / Chapter 3.3.1 --- HPLC assay development and validation for the drug candidates --- p.70 / Chapter 3.3.2 --- Stabilities of the drug candidates in loading solutions at different pHs --- p.71 / Chapter 3.3.3 --- Cell culture --- p.71 / Chapter 3.3.4 --- Cytotoxic effects of the drug candidates on Calu-3 cells by MTS/PES assay --- p.71 / Chapter 3.3.5 --- Permeation studies of drug candidates using Calu-3 cell line model --- p.72 / Chapter 3.3.5.1 --- Effect of concentration on the permeabilities of drug candidates across Calu-3 cell line model --- p.72 / Chapter 3.3.5.2 --- Effect of pH on the permeabilities of drug candidates across Calu-3 cell line model --- p.73 / Chapter 3.3.5.3 --- Effect of osmolarity on the permeabilities of drug candidates across Calu-3 cell line model --- p.73 / Chapter 3.3.6 --- Permeation studies of drug candidates in artificial membrane model at different pHs --- p.73 / Chapter 3.3.7 --- Correlation of the permeabilities of drug candidates between Calu-3 cell line model and artificial membrane model --- p.74 / Chapter 3.3.8 --- Statistical analysis --- p.75 / Chapter 3.4 --- Results and discussions --- p.75 / Chapter 3.4.1 --- HPLC methods for the drug candidates --- p.75 / Chapter 3.4.2 --- Stabilities of the drug candidates in loading solutions at different pHs --- p.75 / Chapter 3.4.3 --- Cytotoxic effects of the drug candidates on Calu-3 cells by MTS/PES assay --- p.76 / Chapter 3.4.4 --- Permeation studies of drug candidates in Calu-3 cell line model --- p.81 / Chapter 3.4.4.1 --- Effect of concentration on the permeabilities of drug candidates across Calu-3 cell line model --- p.81 / Chapter 3.4.4.2 --- Effect of pH on the permeabilities of drug candidates across Calu-3 cell line model --- p.84 / Chapter 3.4.4.3 --- Effect of osmolarity on the permeabilities of drug candidates across Calu-3 cell line model --- p.87 / Chapter 3.4.5 --- Permeation studies of drug candidates in artificial membrane model at different pHs --- p.88 / Chapter 3.4.6 --- Correlation of the permeabilities of drug candidates between Calu-3 cell line model and the artificial membrane model --- p.92 / Chapter 3.5 --- Selection of drug candidate for further in vivo studies --- p.93 / Chapter 3.6 --- Conclusion --- p.93 / Chapter Chapter Four. --- In vivo absorption studies of the most promising drug candidate --- p.95 / Chapter 4.1 --- Introduction --- p.95 / Chapter 4.2 --- Materials --- p.96 / Chapter 4.2.1 --- Chemicals --- p.96 / Chapter 4.2.2 --- Instruments --- p.96 / Chapter 4.3 --- Methods --- p.97 / Chapter 4.3.1 --- HPLC conditions --- p.97 / Chapter 4.3.2 --- Preparation of standard solutions --- p.97 / Chapter 4.3.3 --- Calibration curves --- p.98 / Chapter 4.3.4 --- Sample preparations --- p.98 / Chapter 4.3.5 --- Validation of the assay method --- p.98 / Chapter 4.3.5.1 --- Specificity --- p.98 / Chapter 4.3.5.2 --- Precision and accuracy --- p.99 / Chapter 4.3.5.3 --- Recovery --- p.99 / Chapter 4.3.5.4 --- Sensitivity --- p.99 / Chapter 4.3.5.5 --- Stability --- p.99 / Chapter 4.3.6 --- Animals --- p.100 / Chapter 4.3.7 --- Drug administration --- p.102 / Chapter 4.3.8 --- Data analysis --- p.102 / Chapter 4.4 --- Results and discussions --- p.103 / Chapter 4.4.1 --- Validation of the assay method --- p.103 / Chapter 4.4.1.1 --- Specificity --- p.103 / Chapter 4.4.1.2 --- "Precision, accuracy and linearity" --- p.105 / Chapter 4.4.1.3 --- Recovery --- p.106 / Chapter 4.4.1.4 --- Sensitivity --- p.107 / Chapter 4.4.1.5 --- Stability --- p.108 / Chapter 4.4.2 --- "In vivo absorption studies through the nasal, intravenous and oral routes in rat model" --- p.108 / Chapter 4.4.3 --- Preliminary correlation between permeabilities of compounds in Calu-3 cell line model and their nasal bioavailabilities in animal models --- p.111 / Chapter 4.5 --- Conclusion --- p.113 / Chapter Chapter Five. --- Overall conclusion --- p.114 / Chapter Chapter Six. --- Future studies --- p.117 / References --- p.119

Identiferoai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_326669
Date January 2009
ContributorsWang, Shu., Chinese University of Hong Kong Graduate School. Division of Pharmacy.
Source SetsThe Chinese University of Hong Kong
LanguageEnglish, Chinese
Detected LanguageEnglish
TypeText, bibliography
Formatprint, xvi, 139 leaves : col. ill. ; 30 cm.
RightsUse of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/)

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