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Skin is a dynamic and complex organ that relies on the interaction of different cell types,biomacromolecules and signaling molecules. Upon injury, a cascade of events occurs to quickly restore the skin’s integrity. Depending on the size and severity of the wound, a dressing is used to provide a temporary barrier to protect from dehydration, microorganisms and debris. Current wound dressings however, cannot accelerate wound healing beyond the natural rate, require frequent dressing changes, and cannot be easily removed without triggering additional pain ortissue destruction. Insulin, a peptide used to treat Type 1 diabetes, has been reported to improve the recovery of severe burn wounds. Yet, no one has successfully demonstrated a convenient and effective insulin delivery vehicle that can be used to accelerate burn wound healing. Poly(lactic-co-glycolic acid) microparticles, were shown to release bioactive insulin for a period of 25 days, stimulating human keratinocyte migration in vitro. A wound dressing made from poly(ethylene glycol) and alginate was formulated incorporating the insulin-loaded poly(lactic-co-glycolic acid) microparticles. Bioactive insulin release was achieved for nearly 3 weeks, along with favourable water handling and physical properties conducive for wound healing. Finally, in vivo testing confirmed that a constant dose of insulin from alginate-PEG sponge dressings loaded with 0.125mg, or 0.04mg/cm2 insulin, with dressing changes every 3 days, was sufficient to significantly improve wound healing by 25%, as compared to an alginate- PEG sponge dressing without insulin. Insulin releasing alginate-PEG sponge dressings are therefore, an effective method of improving burn wound healing and may serve as a delivery vehicle platform to incorporate other therapeutic molecules in the future. / Thesis (Ph.D, Chemical Engineering) -- Queen's University, 2012-12-20 17:50:47.872

In this dissertation, we studied two-phase microfluidics as a platform for the controlled synthesis of drug delivery polymeric nanoparticles (PNPs). The block copolymer we studied was poly(ε-caprolactone)-block-poly(ethylene oxide) (PCL-b-PEO). The anticancer drug we studied was paclitaxel (PAX). First, we explored microfluidic control of nanoparticle structure (size, morphology, and core crystallinity) on PCL-b-PEO PNPs without loaded PAX. We demonstrated the reproducible variability of PCL-b-PEO nanoparticle size and morphology. Microfluidic control of nanoparticle size and morphology was found to arise from the interplay of flow-induced particle coalescence and breakup. Next, we demonstrated the linear dependence of PCL core crystallization on flow-rate. We attributed this dependence of PCL core crystallization on flow-induced crystallization. We then used our microfluidic device to control PAX-loaded PNP structure and function (small molecule loading efficiency, diffusional release kinetics, and cytotoxicity). At low drug loading ratios (r < 0.1), we demonstrated reproducible variability of PAX-loaded PNP size and morphology. With increasing flow rate we were able to manufacture PNPs of high aggregation number. We were also able to reproducibly demonstrate the linear dependence of PCL core crystallinity on flow rate. Furthermore, PAX loading efficiency was dependent on PNP size and morphology. Formulations which consisted of cylindrical and lamellar type morphologies typically had higher PAX loading efficiencies, than formulations which consisted of spherical structures. Next, we studied diffusional PAX release, increasing core crystallinity correlated with slowing diffusional PAX release kinetics. At high drug loading ratios (r > 0.1), we demonstrated reproducible control of PAX-loaded PNP structure and function. PCL core crystallinity was a major factor influencing PNP size and morphology. Samples with high core crystallinity formed PNP structures with low internal curvature. Furthermore, core crystallization had a large influence on PAX loading efficiency; as samples with high PAX loading efficiency correlated with low PCL core crystallinity. With respect to diffusional PAX release, we found that increasing PCL core crystallinity correlated with slowing diffusional PAX release kinetics. Next, we studied the cytotoxicity of our PAX-loaded PNPs using the MCF-7 cancer cell line. Due to the complex nature of the interactions between our PAX-loaded PNPs and the cancer cells, we were not able to elucidate the exact influence of flow rate on PNP cytotoxicity. / Graduate

This thesis includes three studies on related aspects of structure and function control for drug delivery block copolymer nanoparticles manufactured in segmented gas-liquid microfluidic reactors. First, the self-assembly of a series of photoresponsive poly(o-nitrobenzyl acrylate)-b-polydimethylacrylamide copolymers is conducted in the gas-liquid segmented microfluidic reactor at various flow rates. The resulting morphologies are found to be flow-variable and distinct from nanoparticles prepared off-chip by dropwise water addition. Photocleaving of the nanoparticles formed at different flow rates reveal flow-variable photodissociation kinetics. Next, we conduct a direct comparison between a commercially-available single-phase microfluidic mixer and the two-phase, gas-liquid segmented microfluidic reactor used in our group, with respect to nanoparticle formation from a typical block copolymer identified for drug delivery applications, polycaprolactone-b-poly(ethylene oxide). The two-phase chip yields morphologies and core crystallinities that vary with flow rate; however, the same parameters are found to be flow-independent using the single-phase mixer. This study provides the first direct evidence that flow-variable structure control is a unique feature of the two-phase chip design. Finally, we investigate structure and function control for paclitaxel (PAX)-loaded nanoparticles prepared from a series of poly(6-methyl caprolactone-co-ε-caprolactone)-block-poly(ethylene oxide) copolymers with variable 6-methyl caprolactone (MCL) content. For all MCL-containing copolymers, off-chip preparations form nanoparticles with no measurable crystallinity, although PAX loading levels are higher and release rates are slower compared to the copolymer without MCL. Both off-chip and on-chip preparations yield amorphous spheres of similar size from MCL-containing copolymers, although on-chip nanoparticles showed slower release rates, attributed to more homogeneous PAX distribution due to faster mixing. / Graduate

Predicting vapor transport and aerosol dynamics in the respiratory airways is important for analyzing both environmental exposure and respiratory drug delivery. A large number of analytical models, computational studies, and experiments on vapor and aerosol transport in the respiratory tract have been conducted previously. However, a number of critical questions remain unanswered. In this study, computational fluid dynamics (CFD) is primarily employed with frequent comparisons to existing and new experimental data sets to address previously unanswered issues related to the transport of vapors and aerosol in the respiratory tract. The three objectives of this study are further described below. Objective 1: A CFD model was developed to predict the transient absorption of inhaled vapors in the respiratory tract. Results indicated that transient absorption can significantly influence the transport and uptake of vapors in the walls of the conducting airways. Objective 2: The concept of enhanced condensational growth (ECG) applied to respiratory drug delivery was tested in a representative airway model extending from the oral cavity to the end of the tracheobronchial (TB) airways. Results indicated that ECG is an effective method to provide near full lung retention of the aerosol. The CFD results also indicated that the ECG delivery approach under transient inhalation conditions increased aerosol deposition in the TB airways by only a small amount, as compared with steady state conditions. Objective 3: The effect of transient waveforms on the transport and deposition of pharmaceutical aerosols from inhalers in the upper airways was considered. Results indicated that the CFD model predictions matched the in vitro experiments to a high degree. The CFD results also indicated that it was critical to consider transient inhalation effects when assessing aerosol deposition. The stochastic individual path (SIP) modeling approach was then introduced and implemented to evaluate the transport and deposition of pharmaceutical aerosols from inhalers in medium and small TB airways. Results indicated that steady state inhalation could be used to predict deposition efficiencies in the TB airways between the 4th branch (B4) and the bronchioles (B15).

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Science in Medicine in Pharmaceutical Affairs Johannesburg, 2003 / Tshwane is one of three metropolitan municipalities in Gauteng Province and a cross border district with North West Province. Tshwane has a complex Drug Supply Management system. Gauteng Provincial Authority (GPA), North West Provincial Authority (NWPA) and City of Tshwane Metropolitan Municipality (CTMM) play significant roles. This has resulted in duplication of duties and inefficient use of resources. The aim of the study was to describe the current Drug Supply Management System in Tshwane, identify any weaknesses plus the factors responsible for the observed weaknesses and formulate recommendations for improvement. / IT2018