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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).

With the remarkable advancement in the nanoparticles (NPs)-based drug delivery systems (DDS) over the past several decades, the pharmacological properties associated with conventional free drugs delivery are improved. In this thesis, we report potential candidates for the next-generation NP-based DDS. While natural DDS are promising as they possess exceptional delivery mechanisms and selective targeting, synthetic DDS are more favorable for their low immunogenicity. Our developed natural DDS called magnetotactic bacterial cages (MBC), which is based on magnetotactic bacteria (MTB) as a guidable delivery vehicle for DNA functionalized gold nanoparticles (AuNPs). Loading DNA functionalized AuNPs in MTB aided in increasing the maximum-tolerated dose of DNA functionalized AuNPs and tackled issues related to DNA functionalized AuNPs stability and systemic delivery. Natural DDS hold great advantages; however, it is difficult to make complete prediction about their immunogenicity and toxicity on the basis of preclinical trials. Thus, we assessed the efficacy of synthetic NP-based DDS. Using inorganic platforms, we were able to develop the first visual monitoring system of bacteria-NPs interaction. The system offers simultaneous sensing and inhibition of bacteria in infected cells. The system is comprised of Au nanoclusters @lysozyme (AuNC@lys) colloids MSN loaded with antibacterial agents. The applicability of the inorganic DDS in the biomedical field has been limited by the high bioaccumulation risks. Hybrid materials combine the advantages of organic, inorganic and natural carriers, offering opportunities for enhanced stability, manipulating release behavior and combine two or more functions in a single platform. To further enhance the properties our inorganic DDS, we incorporated light-responsive organic ligands to silicabased NPs. Plasmid DNA was loaded on the light-responsive bridged silsesquioxane nanocomposites (BS NPs). Light irradiation was performed to reverse the surface charge of NPs via a photoreaction of the organic fragments (silsesquioxane) within the NPs, that resulted in the release of plasmid DNA in HeLa cancer cells. Finally, we assessed a new class of organic-inorganic DDS composed of inorganic metal ions and organic linkers, zeolite imidazolate frameworks-8 (ZIF-8). These NPs showed exceptional ability to entrap large cargo due to their tunable porosity and structural flexibility.

Drug delivery to the brain has challenged medical professionals for several decades, with 98% of small molecules and 100% of large molecules unable to cross the blood brain barrier (BBB). Biocompatible, biodegradable polymers have been extensively researched for the oral delivery of therapeutic agents, but to date has not been successfully manipulated for the formulation of an implantable device. We have therefore utilised such polymers for the formulation and design of an implantable nanoenabled multipolymeric drug delivery device (NMDDD) for the management of AIDS Dementia Complex (ADC). ADC is a central nervous system (CNS) complication of HIV, associated with a host of debilitating cognitive, motor and behavioural symptoms. ADC remains a serious manifestation of HIV/AIDS in both developing and developed countries, affecting both adults and children, with death expected within 6 months of initial diagnosis. Zidovudine (AZT), the current gold standard for the management of ADC, has demonstrated the best penetration into the CNS. It is capable of reducing viral replication in the CNS and managing neurological abnormalities associated with ADC, with clinical efficacy evidenced by the decline in morbidity and mortality of patients treated with this drug. Nanotechnology, an interdisciplinary field of research, involving the manipulation of matter on a submicron level, is receiving emerging interest for the formulation of novel drug delivery systems. As they can potentially be manipulated to react in a bioresponsive manner, nanopharmaceuticals have received much attention for site-specific drug delivery and were therefore employed in the formulation of an implantable NMDDD, with AZT employed as the model drug, for the management of ADC. Nanoparticles were prepared by means of an approach utilising controlled gelation of alginate, employing cationic crosslinking of the anionic alginate to precipitate nanoparticles. A 3-factor Box-Behnken statistical design was employed for the optimisation of nanoparticle and multipolymeric scaffold formulations. Nanoparticles measuring 68.04nm (SD<0.0002) in size with a zeta potential of -13.4mV (SD<0.0005) were formulated. Nanoparticles presented with a mean dissolution time (MDT) of 46.046 hours 30 days post exposure to phosphate buffered saline (PBS), pH 7.4. In an attempt to further retard drug release and to formulate a device for implantation in the frontal lobe of the brain, nanoparticles were dispersed within a robust multipolymeric matrix. Matrix erosion was calculated at 28%w/w (SD<0.001) for multipolymeric scaffold and a matrix resilience of 4.451%w/w (SD<0.007) was observed 30 days post exposure to PBS, indicating slow degradation of the NMDDD. MDT was reduced to 12.570 hours (SD<0.0005) with dispersion of the nanoparticles within a polymer matrix, supporting the application of the drug-loaded MDDD in the management of ADC patients. The optimised multipolymeric nanoparticulate scaffold was implanted into the frontal lobe of the rat brain, for investigation of drug release characteristics and tissue response to the device following in vivo administration.

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

Antibiotic therapy has been proven to be vital for the treatment of life-threatening bacterial infections. Oral antibiotic therapy, however, results in unwanted side effects such as the intestinal flora destruction, allowing for the colonization of foreign bacteria. This phenomenon results in the occurrence of antibioticassociated diarrhea. Probiotic supplementation has been the choice adjunctive prophylaxis for this condition allowing for the bacterial adhesion of intestinal mucosal binding sites. Probiotic bacteria are, however, susceptible to the bactericidal effects of broad-spectrum antibiotics, resulting in many probiotic formulations being prescribed two hours after the ingestion of the antibiotic formulation. This is, however, not always adhered to, with many patients taking the antibiotic and probiotic concomitantly resulting in the destruction of the probiotic bacteria. This study provides for the design, development, characterization and evaluation of an oral delivery system for the concurrent administration of antibiotics and probiotics employing a dual release mechanism or ‘Dual-Biotic System’. The premise behind the development of this system is to allow for the concurrent administration of antibiotics and probiotics where the probiotic bacteria are only released two hours after the antibiotic, in which time the antibiotic would be absorbed into systemic circulation, preventing physical interaction between the systems and thus preventing bacterial destruction. Amoxicillin was chosen as the model antibiotic in this study due to its spectrum of activity and wide utilization in oral antibiotic therapy.

Thesis (M. Pharm.)--University of the Witwatersrand, Faculty of Health Sciences, 2013. / Ocular diseases of the anterior segment are ubiquitous, especially among elderly patients. The development of novel drug delivery systems on the journey for improved treatment is therefore imperative. Aside from anatomical and physiological barriers of the eye, the actual dosage form plays a crucial role. Although liquid eye drops are the first-choice dosage form, the shortcomings do not go unnoticed. In an attempt to circumvent these drawbacks, a novel instantly soluble eye drop device was developed. The system aimed to provide an easier administration form, comfort for the patient and improve drug bioavailability to anterior chamber. This was a steer toward attaining patient-convenience and compliance which are critically challenging factors. Preformulatory studies allowed for the screening and selection of candidate components and key processing conditions. Hydrophilic polymers and excipients were selected for attainment of small, rapid disintegrating yet robust matrices via lyophilization of solutions. Design of experiments generated formulations by means of a Face centred central composite design (FCCCD) that underwent thorough physicochemical and mechanical assessment. Overall, robust rapidly disintegrating solid eye drops were produced. Fastest disintegration time was noted to be 0.200s. Drug content ranged from 79-96%. An improved permeation of formulations compared to a pure drug dispersion was seen. Mathematical modeling was conducted for better insight into the behavior of the device on the eye surface. Statistical analysis through constraint optimization yielded a single optimal formulation. Thermal and molecular transition analysis showed congruent findings with no incompatibility between components. Combinatory surface morphology and porositometric studies confirmed the presence of interconnecting pores across the matrix surface. Drug release kinetic evaluation predicted that best model fit was first-order release. Ocular irritancy studies by means of the HET-CAM test indicated that both drug-loaded and drug-free eye drops had an irritation score of 0 with the inference of good tolerability. Ex vivo permeation across excised rabbit cornea showed an improved steady state drug flux (0.00052mg.cm-2.min-1) and permeability co-efficient (1.7x10-4cm.min-1) for the optimized device compared to pure drug and a marketed eye drop preparation. In vivo analysis was conducted on the rabbit model with insertion of the device into the ocular cul-de-sac. Subsequently, ultra performance liquid chromatography (UPLC) analysis of the aspirated aqueous humour for model drug timolol maleate detection was conducted. The device demonstrated improved drug levels (Cmax = 3ug/mL) in comparison to commercial eye drops (Cmax = 1.97ug/mL) and was well tolerated. Level A point-to-point IVIVC plots indicated a R2 value of 0.84. This served to imply that the in vitro dissolution data can be compared to and may serve as a surrogate to that of in vivo pK data. Histopathological assessment on the enucleated eye ball confirmed the lack of noxious effects of the device on ocular tissue. From this study, the solid eye drop device was concluded to be safe as a drug delivery system for the anterior eye. Looking toward innovative trends and modifications, a bi-layered solid eye drop system with enhanced permeability capabilities employing low molecular weight chitosan was further fabricated for preliminary investigation.