The purpose of this exploratory study was to determine which of the three training-delivery systems is the most frequently selected by training professionals in Virginia and which training methods are selected to support the chosen delivery systems. The study also examined the extent to which internal and external factors contributed to the selection of the delivery systems and the training methods. Qualitative research methodology was employed in analyzing the results of 12 in-depth interviews with purposively selected training professionals in Virginia in order to answer the research questions. This study found that (a) the training professionals chose instructor-led classroom for 46% of their programs, the blended method for 32%, and online for 22%; (b) they used a wide variety of training methods to support the program objectives and meet the audience’s needs; and (c) external factors more frequently impacted selection decisions than did internal factors, but one internal factor that impacted selection decisions was the training professionals’ understanding of instructional systems design. The external factors that had the greatest impact on the training system chosen were workplace constraints such as immediacy and scalability and the size and geographical dispersion of the audience. That is, for large and/or dispersed audiences coupled with time constraints, the online delivery system was chosen most often. Likewise, mandatory programs were most likely to be offered online. The following conclusions were drawn: (a) a shift is taking place from instructor-led-classroom delivery to blended delivery, (b) instructor-led classroom incorporates methodologies that extend beyond the lecture format, (c) companies are using emerging technologies in training and development, and (d) training and development continues to add value to the workforce, which is a powerful competitive advantage. / Ph. D.

No / A novel approach for identifying synergistic mixtures of skin penetration enhancers promises to transform development of transdermal products, including patches.

研究目的：本論文之研究主要旨在採用兩種非甾體抗炎藥--布洛芬（IBP）及氟比洛芬（FBP）來考察一項新型的納米粒子製備技術--瞬時納米沉澱技術（FNP）。IBP和FBP具有不同理化性質，但其親油性屬大部分藥物所具的典型親油性 （log P = 2-5）。研究證實IBP和FBP有治療阿爾茨海默氏病的潛在藥效，但在血液中廣泛與血漿蛋白結合，導致其腦血管通透性很低。因此，本研究的另一目的為考察FNP製備的納米處方是否能改善此類藥物的大腦遞送。 / 方法：應用FNP，用多入口渦旋混合器（MIVM）將藥物載入聚乙二醇-聚乳酸（PEG-PLA）的納米粒中。通過改變關鍵工藝流程變量考察了變量對納米粒物理性質及穩定性的影響。使用動態光散射儀測定了納米粒粒徑和粒徑分佈，使用zeta 電位分析測定了粒子表面電荷，使用原子力顯微鏡（AFM）確定了納米粒形態，使用x射線光電子能譜（XPS）分析了粒子表面化學成分，使用高效液相色譜測定了的處方載藥量和包封率。使用MDCK和Caco-2細胞株評估了優化後納米處方的細胞通透性，使用健康小鼠進行了優化后纳米處方的体内腦攝取實驗。 / 結果：IBP和FBP納米粒的粒徑均在30-100 nm的範圍內，粒徑分佈均低於或接近0.2。AFM結果顯示，納米粒具有近球狀形態。由多次線性回歸分析各工藝流程變量對IBP納米粒粒徑的影響所得相對重要性的結果為：PLA對PEG之分子量比 > 過飽和比 > 藥物對聚合物比 > 雷諾數。用相同統計方法分析FBP樣品所得結果顯示，PLA對PEG之分子量比亦為影響粒子粒徑的最重要變量。最穩定的IBP納米處方可以在懸浮液狀態下穩定超過1個月，而FBP納米處方為2天。IBP和FBP納米粒的載藥量和包封率均分別超過25%和70%。XPS，AFM和zeta電位測定結果共同表明納米粒中的PEG均偏重位於粒子表面，而相比之下，IBP納米粒中的PEG較FBP納米粒更加偏向於分佈於粒子表面。優化後的IBP納米粒由聚山梨醇酯80包裹後，與IBP溶液相比，顯著增加了IBP的健康小鼠腦攝取量。 / 結論：應用FNP及MIVM製備的聚合物IBP和FNP納米粒，粒徑小，粒徑分佈窄，重現性高，且有較高的載藥量和包封率。納米粒的粒徑主要取決於所採用的共聚物。IBP 納米粒子明顯優越的物理穩定性可歸功於粒子表面較高的PEG濃度。用聚山梨醇酯80包裹納米粒子對於提高IBP的大腦遞送有決定性作用。 / Objectives: The present thesis work was primarily aimed at assessing a relatively novel nanoparticle (NP) production technology termed flash nanoprecipitation (FNP) using two non-steroidal anti-inflammatory drugs, ibuprofen (IBP) and flurbiprofen (FBP), with different physiochemical properties and lipophilicity typical of most drugs (log P = 2-5). Both model drugs were proven to be of potential benefits to the treatment of Alzheimer’s disease, but exhibited poor brain delivery in vivo which could be ascribed to their extensive binding with plasma proteins in the blood. Therefore another aim of the present thesis was to determine whether FNP-produced NP formulations could enhance the delivery of these drugs into the brain. / Methods: Drugs were loaded into NPs of polyethylene glycol (PEG)-polylactic acid (PLA) copolymers of different molecular weights (MWs) by FNP using a four-stream multi-inlet vortex mixer (MIVM). The influence of several key processing variables on the physical properties and stability of the NPs was investigated. The NP preparations were characterized for particle size and size distribution by dynamic light scattering (DLS) sizing analysis; surface charges by zeta potential measurement; particle morphology by atomic force microscopy (AFM); surface composition by x-ray photoelectron spectroscopy (XPS); and drug loading (DL) and encapsulation efficiency (EE) by high performance liquid chromatography. Optimal IBP NP samples were assessed in vitro for cellular permeability using Caco-2 and MDCK cell lines and in vitro for brain uptake in normal mice. / Results: Both IBP and FBP NPs exhibited mean particle size in the range of 30-100nm and polydispersity below or around 0.2. The particles were nearly spherical in shape, as examined by AFM. Multiple linear regression analysis revealed that the relative impact of the processing variables on the particle size of IBP NPs followed the order: PLA-to-PEG MW ratio > supersaturation ratio > drug-to-copolymer ratio > Reynolds number. Similar statistical analysis for FBP NPs also indicated PLA-to-PEG MW ratio being the most significant determinant of particle size. The most stable IBP and FBP NPs in suspension form could last for over 1 month and 2 days respectively. NPs with DLs > 25% and EEs > 70% could be obtained by FNP. XPS in conjunction with AFM and zeta potential analysis revealed that PEG was located more on the surfaces of both IBP and FBP NPs than in the core, but the surface PEG density was higher for the IBP NPs. Coating of optimal IBP NPs with polysorbate 80 significantly improved the brain uptake of IBP in normal mice, compared to IBP solution. / Conclusion: Polymer-stabilized IBP and FBP NPs with particle size below 100 nm and narrow size distribution can be consistently generated by FNP using the MIVM. The copolymer used is the most important determinant of particle size. The superior physical stability of the IBP NPs can be ascribed to their relatively high surface PEG density. High DLs and EEs are achievable with the FNP process. Nanoparticle coating with polysorbate 80 is critical to enhancing the delivery of IBP to the brain in normal mice. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Zhang, Xinran. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 205-245). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese. / Table of Contents --- p.I / Acknowledgements --- p.VI / Abstract --- p.VIII / 摘要 --- p.X / List of Figures --- p.XII / List of Tables --- p.XVII / List of Abbreviations --- p.XIX / Chapter Chapter One --- Introduction / Chapter 1.1 --- Rationale of the study --- p.1 / Chapter 1.2 --- General review of nanoparticulate drug carrier systems --- p.4 / Chapter 1.2.1 --- Background of nanoscience --- p.4 / Chapter 1.2.2 --- Applications of nanoparticulate drug delivery systems --- p.4 / Chapter 1.2.2.1 --- Improved delivery of poorly water soluble drugs --- p.5 / Chapter 1.2.2.2 --- Targeted drug delivery --- p.6 / Chapter 1.2.2.3 --- Drug delivery across the blood brain barrier --- p.8 / Chapter 1.2.2.4 --- Other drug delivery applications --- p.10 / Chapter 1.2.3 --- Types of nanoparticulate drug delivery systems --- p.10 / Chapter 1.2.3.1 --- Nanocrystals --- p.10 / Chapter 1.2.3.2 --- Solid lipid nanoparticles --- p.11 / Chapter 1.2.3.2.1 --- Preparation methods --- p.12 / Chapter 1.2.3.2.2 --- Drug delivery --- p.12 / Chapter 1.2.3.3 --- Polymeric nanoparticles --- p.14 / Chapter 1.2.3.3.1 --- Preparation methods --- p.15 / Chapter 1.2.3.3.2 --- Drug delivery --- p.17 / Chapter 1.2.4 --- Characterization of nanoparticulate drug delivery systems --- p.20 / Chapter 1.2.4.1 --- Particle size and size distribution --- p.21 / Chapter 1.2.4.2 --- Morphology --- p.21 / Chapter 1.2.4.3 --- Zeta potential --- p.23 / Chapter 1.2.4.4 --- Surface chemical composition --- p.23 / Chapter 1.2.4.5 --- Crystallinity --- p.24 / Chapter 1.3 --- Flash Nanoprecipitation technique --- p.25 / Chapter 1.3.1 --- Mechanism and evolution --- p.25 / Chapter 1.3.2 --- Applications --- p.30 / Chapter 1.4 --- Ibuprofen and flurbiprofen --- p.32 / Chapter 1.4.1 --- General characteristics --- p.32 / Chapter 1.4.2 --- Physicochemical properties --- p.33 / Chapter 1.4.3 --- New therapeutic indications --- p.34 / Chapter 1.5 --- Scope of the thesis --- p.36 / Chapter Chapter Two --- Influence of Processing Variables on the Physical Properties and Stability of Ibuprofen and Flurbiprofen Nanosuspensions / Chapter 2.1 --- Introduction --- p.38 / Chapter 2.2 --- Materials and Methods --- p.39 / Chapter 2.2.1 --- Materials --- p.39 / Chapter 2.2.2 --- Solubility of ibuprofen and flurbiprofen in water and acetone mixtures --- p.39 / Chapter 2.2.3 --- Nanoparticle formulation preparation --- p.40 / Chapter 2.2.3.1 --- Determination of the minimum Reynolds number (Re) for homogenous mixing --- p.40 / Chapter 2.2.3.2 --- Effects of processing parameters on particle size and size distribution of ADCP-protected IBP and FBP nanoparticles. --- p.41 / Chapter 2.2.4 --- Particle size and size distribution measurement --- p.42 / Chapter 2.2.5 --- Statistics --- p.42 / Chapter 2.2.6 --- Assessment of nanosuspension stability --- p.42 / Chapter 2.3 --- Results and discussion --- p.43 / Chapter 2.3.1 --- Solubilities of ibuprofen and flurbiprofen in water and acetone mixtures --- p.43 / Chapter 2.3.2 --- Determination of the minimum Re for homogenous mixing --- p.44 / Chapter 2.3.3 --- Effects of processing parameters on particle size and size distribution of the ADCP-protected IBP and FBP nanoparticles. --- p.47 / Chapter 2.3.3.1 --- Effect of solvent type --- p.47 / Chapter 2.3.3.2 --- Effect of PLA-to-PEG MW ratio --- p.64 / Chapter 2.3.3.3 --- Effect of supersaturation --- p.64 / Chapter 2.3.3.4 --- Effect of Re --- p.70 / Chapter 2.3.3.5 --- Effect of drug-to-ADCP ratio --- p.71 / Chapter 2.3.4 --- Effects of processing parameters on the stability of ADCP-stabilized IBP and FBP nanoparticles --- p.72 / Chapter 2.3.4.1 --- Three-day stability --- p.72 / Chapter 2.3.4.2 --- Long-term stability --- p.83 / Chapter 2.4 --- Summary --- p.85 / Chapter Chapter Three --- Drying of Ibuprofen Nanoparticle Suspensions / Chapter 3.1 --- Introduction --- p.86 / Chapter 3.2 --- Materials and Methods --- p.88 / Chapter 3.2.1 --- Materials --- p.88 / Chapter 3.2.2 --- Preparation of IBP nanoparticle formulations with hydrophilic stabilizers or at refrigerated temperature --- p.89 / Chapter 3.2.3 --- Dialysis of nanoparticle formulations --- p.89 / Chapter 3.2.4 --- Freeze-thawing of selected nanoparticle preparations --- p.89 / Chapter 3.2.5 --- Freeze-drying of nanoparticle formulations --- p.90 / Chapter 3.2.6 --- Reconstitution --- p.90 / Chapter 3.2.7 --- Hydrogen bonding coacervate precipitation --- p.91 / Chapter 3.3 --- Results and discussion --- p.91 / Chapter 3.3.1 --- Preparation and dialysis of IBP nanoparticle formulations with hydrophilic stabilizers --- p.92 / Chapter 3.3.2 --- Freeze-drying using cryoprotectants and lyoprotectants --- p.94 / Chapter 3.3.3 --- Freeze-drying with different concentrations of glucose, sucrose and PVA --- p.101 / Chapter 3.3.4 --- Freeze-drying of nanoparticles prepared under other processing conditions --- p.105 / Chapter 3.3.5 --- Hydrogen bonding coacervate precipitation --- p.108 / Chapter 3.4 --- Summary --- p.110 / Chapter Chapter Four --- Physicochemical Characterization of Ibuprofen and Flurbiprofen Nanoparticles / Chapter 4.1 --- Introduction --- p.111 / Chapter 4.2 --- Materials and Methods --- p.112 / Chapter 4.2.1 --- Materials --- p.112 / Chapter 4.2.2 --- Encapsulation efficiency (EE) and drug loading (DL) of IBP nanoparticles --- p.112 / Chapter 4.2.3 --- HPLC analysis of IBP and FBP --- p.113 / Chapter 4.2.4 --- Nanoparticle morphology --- p.114 / Chapter 4.2.4.1 --- SEM --- p.114 / Chapter 4.2.4.2 --- AFM --- p.114 / Chapter 4.2.5 --- Zeta potential measurement --- p.115 / Chapter 4.2.6 --- Surface composition analysis --- p.115 / Chapter 4.3 --- Results and discussion --- p.116 / Chapter 4.3.1 --- Encapsulation efficiency (EE) and drug loading (DL) of IBP nanoparticles --- p.116 / Chapter 4.3.2 --- Nanoparticle morphology --- p.121 / Chapter 4.3.3 --- Surface charges of the nanoparticles --- p.126 / Chapter 4.3.4 --- Surface composition of nanoparticles --- p.128 / Chapter 4.4 --- Summary --- p.145 / Chapter Chapter Five --- Cellular Permeability and In Vivo Brain Uptake of Ibuprofen Nanoparticles / Chapter 5.1 --- Introduction --- p.146 / Chapter 5.2 --- Materials and methods --- p.148 / Chapter 5.2.1 --- Materials --- p.148 / Chapter 5.2.2 --- Methods --- p.148 / Chapter 5.2.2.1 --- Cellular permeability study --- p.148 / Chapter 5.2.2.1.1 --- Cell culture --- p.148 / Chapter 5.2.2.1.2 --- Cell viability study --- p.149 / Chapter 5.2.2.1.3 --- MDCK and Caco-2 cell monolayer permeability assay --- p.150 / Chapter 5.2.2.2 --- In vivo brain uptake study --- p.151 / Chapter 5.2.2.2.1 --- HPLC-UV analysis --- p.151 / Chapter 5.2.2.2.2 --- Preparation of calibration samples --- p.151 / Chapter 5.2.2.2.3 --- Sample preparation --- p.152 / Chapter 5.2.2.2.4 --- Validation of assay methods --- p.153 / Chapter 5.2.2.2.5 --- Animal experiments --- p.154 / Chapter 5.2.2.2.6 --- Data Analysis --- p.155 / Chapter 5.3 --- Results and discussion --- p.155 / Chapter 5.3.1 --- Cellular permeability study --- p.155 / Chapter 5.3.1.1 --- Cell viability study --- p.155 / Chapter 5.3.1.2 --- MDCK and Caco-2 cell monolayer permeability assay --- p.157 / Chapter 5.3.2 --- In vivo brain uptake study --- p.158 / Chapter 5.3.2.1 --- Method validation --- p.158 / Chapter 5.3.2.2 --- Brain uptake of IBP nanoparticles --- p.159 / Chapter 5.4 --- Summary --- p.166 / Chapter Chapter Six --- Conclusions and Future Studies / Chapter 6.1. --- Conclusions --- p.167 / Chapter 6.2. --- Future studies --- p.172 / Appendices --- p.174 / References --- p.205

Background. Danshen, the dried root of Salvia miltiorrhiza Bge, is used for treating coronary heart disease. In China, numerous pharmaceutical dosage forms of Danshen are commercially available. Although the pharmacological effects of different components of Danshen are well identified, its absorption as well as pharmacokinetics studies are still insufficient and inconsistent. The current study aims to: (1) screen for the major absorbable active components of Danshen; (2) interpret the absorption mechanism and pharmacokinetics characteristics of the identified components; (3) develop an improved oral drug delivery system for the identified components of Danshen. / Conclusion. Both danshensu and SAB have limited intestinal permeability and oral bioavailabilities. Our results demonstrated the usefulness of sodium caprate as a potential absorption enhancer for danshensu and SAB in Danshen product. / Methods. Six major active components in commercially available Danshen products were identified and quantified. In vitro human Caco-2 cell monolayer model, rat in situ intestinal perfusion model as well as rat in vivo pharmacokinetic model were used to investigate the intestinal absorption and pharmacokinetics profiles of the identified Danshen components. Effect of the absorption enhancer on the oral absorption and bioavailabilities of the studied Danshen components was further evaluated. / Results. Danshensu, salvianolic acid B (SAB) and protocatechuic aldehyde (PCA) were identified as the major components in Danshen products. Investigations using in vitro, in situ and in vivo model found that both danshensu and SAB had poor permeabilities and low bioavailabilities (Danshensu: 11.09%; SAB: 3.90%), which may be due to their absorption via the paracellular transport pathways. Studies of PCA suggested that it may have a intestinal first pass metabolism with an oral bioavailability of only 18.02%. It was found that the permeabilities of both danshensu and SAB were significantly increased upon addition of sodium caprate, a paracellular absorption enhancer. The oral bioavailabilities of both danshensu and SAB in pure compound form as well as Danshen extract form were also increased in the presence of sodium caprate in rats. / Zhou, Limin. / Advisers: Zuo Zhong; Moses S.S. Chow. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3457. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

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

Thesis (M.Sc.), Memorial University of Newfoundland, School of Pharmacy, / Typescript. Bibliography: p. 141-166.

Acute liver failure is a major cause of death in the world, and effective treatments are greatly needed. Liver macrophages (Kupffer cells) play a major role in the pathology of acute liver failure, and drug delivery vehicles that can target therapeutics to Kupffer cells have great therapeutic potential for treating acute liver failure. Microparticles, formulated from biodegradable polymers, are advantageous for treating acute liver failure because they can passively target therapeutics to Kupffer cells. However, existing biomaterials are not suitable for the treatment of acute liver failure because of their slow hydrolysis and acidic degradation products. In this dissertation, I present the development of a new class of biodegradable materials, termed aliphatic polyketals, which have considerable potential as drug delivery vehicles for the treatment of acute liver failure because of their neutral degradation products and tunable hydrolysis kinetics. The anti-inflammatory enzyme, superoxide dismutase (SOD), was delivered using polyketal microparticles to the liver for treating acute liver Failure. Our results demonstrated that polyketal microparticles significantly improved the efficacy of SOD in treating LPS-induced acute liver damage in vivo, as evidenced by decreased levels of serum alanine transaminase, which corresponds to the extent of damage in the liver, and serum level of tumor necrosis factor-alpha, which corresponds to the secretion of pro-inflammatory cytokines. The completion of this thesis research demonstrates the ability of polyketal-based drug delivery systems for treating acute inflammatory diseases and creates a potential therapy for enhancing the treatment of acute liver failure.

M. Tech. Pharmaceutical Sciences / Following the discovery of an active pharmaceutical ingredient, attempts were made to improve its delivery to the site of action and thereby its effectiveness. Insulin and other therapeutic proteins are administered almost exclusively parenterally because of their poor absorption after oral administration, but this route is associated with disadvantages including pain, discomfort and lipohypertrophy at the site of injection. A suitable absorption enhancer which could effectively improve the absorption of poorly absorbable drugs from the gastrointestinal tract would contribute to the development of an effective oral drug delivery system for these drugs. One such attempt was the formulation of the active ingredient into an appropriate dosage form for a specific route of administration to improve other properties such as manufacturability, stability and bioavailability. Formulation studies led to the development of substances called excipients, which were incorporated into dosage forms, in addition to the active pharmaceutical ingredient, to improve the properties of the final product. Aloe vera gel previously showed the ability to increase the bioavailability of vitamins and to enhance the in vitro transport of a macromolecular drug across intestinal epithelial cell monolayers. However, the effect of leaf materials from aloes, indigenous to South Africa, on drug transport across intestinal epithelia has not previously been investigated. The aim of this study is to evaluate the in vitro drug transport enhancement potential of the gel and whole leaf extract of Aloe ferox, Aloe marlothii, Aloe speciosa and compare them with that of Aloe vera across Caco-2 cell monolayers, as well as across excised rat intestinal tissues.

Chronic diseases can often be managed by constantly delivering therapeutic amounts of drug for prolonged periods. A controlled release for extended duration would replace the need for multiple and frequent dosing. Local drug release would provide added benefit as a lower dose of drug at the target site will be needed as opposed to higher doses required by whole body administration. This would provide maximum efficacy with minimum side effects. Nonetheless, a problem with the known implantable drug delivery devices is that the delivery rate cannot be controlled, which leads to drug being released in an unpredictable pattern resulting in poor therapeutic management of patients. This dissertation is the result of development of an implantable drug delivery system that is capable of long-term zero order local release of drugs. The device can be optimized to deliver any pharmaceutical agent for any time period up to several years maintaining a controlled and desired rate. Initially significant efforts were dedicated to the characterization, biocompatibility, and loading capacity of nanoporous metal surfaces for controlled release of drugs. The physical characterization of the nanoporous wafers using Scanning electron microscropy (SEM) and atomic force microscopy techniques (AFM) yielded 3.55 x 10⁴ nm³ of pore volume / μm² of wafer surface. In vitro drug release study using 2 - octyl cyanoacrylate and methyl orange as the polymer-drug matrix was conducted and after 7 days, 88.1 ± 5.0 % drug was released. However, the initial goal to achieve zero order drug release rates for long periods of time was not achieved. The search for a better delivery system led to the design of a perforated microtube. The delivery system was designed and appropriate dimensions for the device size and hole size were estimated. Polyimide microtubes in different sizes (125-1000 μm) were used. Micro holes with dimensions ranging from 20-600 μm were fabricated on these tubes using photolithography, laser drilling, or manual drilling procedures. Small molecules such as crystal violet, prednisolone, and ethinyl estradiol were successfully loaded inside the tubes in powder or solution using manual filling or capillary filling methods. A drug loading of 0.05 – 5.40 mg was achieved depending on the tube size and the drug filling method used. The delivery system in different dimensions was characterized by performing in vitro release studies in phosphate buffered saline (pH 7.1-7.4) and in vitreous humor from the rabbit’s eye at 37.0 ± 1.0°C for up to four weeks. The number of holes was varied between 1 and 3. The tubes were loaded with crystal violet (CV) and ethinyl estradiol (EE). Linear release rates with R²>0.9900 were obtained for all groups with CV and EE. Release rates of 7.8±2.5, 16.2±5.5, and 22.5±6.0 ng/day for CV and 30.1±5.8 ng/day for EE were obtained for small tubes (30 μm hole diameter; 125 μm tube diameter). For large tubes (362-542 μm hole diameter; 1000 μm tube diameter), a release rate of 10.8±4.1, 15.8±4.8 and 22.1±6.7 μg/day was observed in vitro in PBS and a release rate of 5.8±1.8 μg/day was observed ex vivo in vitreous humor. The delivery system was also evaluated for its ability to produce a biologically significant amounts in cells stably transfected with an estrogen receptor/luciferase construct (T47D-KBluc cells). These cells are engineered to produce a constant luminescent signal in proportion to drug exposure. The average luminescence of 1144.8±153.8 and 1219.9±127.7 RLU/day, (RLU = Relative Luminescence Units), yet again indicating the capability of the device for long-term zero order release. The polyimide device was characterized for biocompatibility. An automated goniometer was used to determine the contact angle for the device, which was found to be 63.7±3.7degreees indicating that it is hydrophilic and favors cell attachment. In addition, after 72 h incubation with mammalian cells (RAW 267.4), a high cell distribution was observed on the device’s surface. The polyimide tubes were also investigated for any signs of inflammation using inflammatory markers, TNF-α and IL-1β. No significant levels of either TNF-α or IL-1β were detected in polyimide device. The results indicated that polyimide tubes were biocompatible and did not produce an inflammatory response. / text

Telephone nursing (TpN) care is delivered in a wide range of settings and provides a variety of services to individuals and populations across the age span. Although a viable specialty practice, there is little evidence regarding how the process of care delivery contributes to successful outcomes. To study the effects of TpN care, and to develop appropriate clinical and education interventions, a solid understanding of the process is needed. This study utilized grounded theory method to identify and describe the core concepts of the TpN process, the relationships among these concepts, and the factors influencing the process. Study findings were validated through peer and participant review. Based on interviews with ten telephone nurses from four sites, the following components were identified and organized into a conceptual model of the TpN process. The process generally proceeds through three phases, gathering information to cognitive processing to output. Throughout these phases, the nurse engages in a goal oriented parallel process focusing on both explicit (e.g., verbal, physical) and implicit (non-verbal, contextual) dimensions. Inherent to this parallel process is a two-way interpreting process in which information from the caller is translated into health care language for processing and then health care information is translated back into the language of the caller to identify and meet their needs. Factors influencing the process include prioritization and the level of complexity of the call, resources of the nurse and the organization, and the nurse's desire for validation of the service and the appropriateness of the output. The model highlights the need for research further delineating how implicit information is gathered and processed and how it influences output. Research is also needed on the value of implicit output and on the effects of feedback regarding output on nurse performance and satisfaction. The model suggests that more nursing education should be focused on the sub-processes within the three phases, the interpreting process, and implicit aspects of the process. Finally, the model suggests that formal feedback regarding the quality of call output should be provided and the value of implicit nursing output should be recognized.