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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
211

An Investigation into Formulation and Therapeutic Effectiveness of Nanoparticle Drug Delivery for Select Pharmaceutical Agents

Cooper, Dustin 01 May 2016 (has links)
Drug based nanoparticle (NP) formulations have gained considerable attention over the past decade for their use in various drug delivery systems. NPs have been shown to increase bioavailability, decrease side effects of highly toxic drugs, and prolong drug release. Furthermore, polymer based, biodegradable nanodelivery has become increasing popular in the field of NP formulation because of their high degree of compatibility and low rate of toxicity. Due to their popularity, commercially available polymers such as poly lactic acid (PLA), poly glycolic acid (PGA) and polylactic-co-glycolic acid (PLGA) are commonly used in the development and design of new nano based delivery systems. Nonsteriodal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of pain and inflammation. NSAIDs such as diclofenac and celecoxib function by blocking cyclooxygenase expression and reducing prostaglandin synthesis. Unfortunately, the pharmacological actions of NSAIDs can lead to the development of several adverse side effects such as gastrointestinal ulceration and bleeding. The aim of this study was to formulate and optimize diclofenac or celecoxib entrapped polymer NPs using an emulsion-diffusion-evaporation technique. NP formulations were evaluated based on specific formula parameters such as particle size, zeta potential, morphology, and entrapment efficiency. Effects of stabilizer type, stabilizer concentration, centrifugal force, drug amount, and/or emulsifier (lecithin) on nanoparticle characterization were examined for formula optimization. Results of the formulation studies showed that NPs developed using polylactide-co-glycolide (PLGA) polymers and the stabilizer didodecyldimethylammonium bromide (DMAB) demonstrated enhanced stability, drug entrapment, and reduced particle size. These findings demonstrate an effective method for polymer NP formulation of diclofenac or celecoxib. Furthermore, the results reported herein support a novel method of drug delivery that may function to reduce known adverse effects of these pharmacotherapeutic agents.
212

Assessment of co-processing of cellulose II and silicon dioxide as a platform to enhance excipient functionality

Camargo, Jhon Jairo Rojas 01 December 2011 (has links)
This thesis project studied microcrystalline cellulose II (CII), a polymorphic form of cellulose, which has lower mechanical properties, less plastic deformation, higher elastic recovery and faster disintegration properties than microcrystalline cellulose I (CI). Also, the effects of processing and silicification on CII materials were investigated. Particle modification through spray drying, wet granulation and spheronization was employed to improve CII performance. Spray-drying (SDCII) and wet granulation (WGCII) produced materials with no difference in mechanical or disintegration properties from unprocessed CII, but did show an increase in density and particle flow. Conversely, spheronization (SPCII) showed the poorest mechanical properties compared to CII. Further, SDCII showed better dilution potential than CII. Thus the advantages of SDCII were apparent when it was mixed with a poorly compressible drug (acetaminophen) because fibrous CII was converted to spheroidal particles through spray drying. The rapid disintegration of SDCII and CII compacts was due to water wicking through capillaries followed by compact bursting. Compacts of ibuprofen mixed with SDCII and Avicel® PH-102 had comparable disintegration rates and release profiles compared to ibuprofen formulated with commercial disintegrants and Avicel® PH-102, especially at levels 10% w/w. Adding fumed silica into CII particles through spray drying, wet granulation (WGCII) and spheronization (SPCII) at 2-20% w/w was also studied. Silicification increased physical properties such as true density, Hausner ratio, porosity, ejection force and specific surface area of SDCII and WGCII. Other properties such as bulk and tap densities were reduced due to the amorphous and light character of fumed silica. Spheronized CII showed no change in these properties with silicification. Silicification diminished lubricant sensitivity with magnesium stearate due to the competition of SiO2 with magnesium stearate to coat CII particles. Silicification also decreased the affinity of CII for water only at the 20% w/w level due to the few silanol groups available for water interaction compared to surface hydroxyl groups on CII alone. Particle size modification of CII was process-dependent rather than silicification-dependent. Additionally, silicification decreased the apparent plasticity and elastic recovery of SDCII and WGCII when compacted. The former effect along with increased powder porosity increased surface area and compressibility of SDCII and WGCII. Compact tensile strength of silicified CII materials was in the order: spray-dried > wet granulated > spheronized. This order was due to the combined effect of particle morphology and how fumed silica was incorporated and distributed within CII particles. Silicification did not affect the rapid disintegration properties of CII. Thus, diphenhydramine HCl and griseofulvin tablets prepared with silicified CII had faster disintegration and release than those prepared with commercial silicified CI (Prosolv®). Moreover, CII beads containing diphenhydramine HCl or griseofulvin had faster release profiles compared to beads prepared with Prosolv® SMCC 50 or Avicel® PH-101. This behavior showed that rapid disintegration is an intrinsic property of CII. Compact tensile strength decreased more for unsilicified CI and CII compacts stored at 75% RH, while silicified CI and CII compacts lost less tensile strength under the same conditions. Reprocessed CI materials containing acetaminophen (1:1mixtures) lost 35-72% of their original strength compared to silicified CII materials (15-25% loss) indicating more particle interaction upon recompression. .
213

STUDY OF THE MECHANISM OF ACTION FOR Ru(II) POLYPYRIDYL COMPLEXES AS POTENTIAL ANTICANCER AGENTS

Sun, Yang 01 January 2018 (has links)
Application of chemotherapeutic agents in current cancer treatment has been limited by adverse effects as poor selectivity results in systemic toxicity; most chemotherapy approaches also experience inherited or acquired drug resistance which lead to reduced treatment outcome. Research efforts have focused on the discovery of novel chemotherapies that overcome the limitations mentioned above. Ru(II) polypyridyl complexes with anti-cancer properties have been extensively studied as traditional cytotoxic agents and photodynamic therapy agents due to their photophysical and photochemical characteristics. Most research has focused on the design of Ru(II) polypyridyl complexes that have affinities to nucleic acids as inspired by the classic small molecule metal complex cisplatin. Though modifying the structures of ligands on the ruthenium metal center, the hydrophilicity, charge state and photochemical properties can be tuned, resulting to Ru(II) polypyridyl complexes that act through cellular targets other than DNA. Understanding the mechanism of action and identifying functional targets remain the challenging and complex research topic in the design and study of novel medication or candidates. With the development of semi-high throughput cytological profiling in a bacterial system, rapid investigation of the mechanism of action can be achieved to distinguish anti-cancer agents which possess different mechanisms of actions. Ru(II) polypyridyl complexes with different scaffolds have been studied and suggested to have anti-cancer properties through DNA damage response, and/or translational inhibition.
214

DESIGN AND ANALYSIS OF CURCUMIN CONJUGATED POLY(BETA-AMINO ESTER) NETWORKS FOR CONTROLLED RELEASE IN OXIDATIVE STRESS ENVIRONMENTS

Jordan, Carolyn T. 01 January 2018 (has links)
Oxidative stress, the imbalance of free radical generation with antioxidant defenses, leads to cellular inflammation, apoptosis and cell death. This compromised environment results in debilitating diseases, such as oral mucositis (OM), atherosclerosis, and ischemia/reperfusion injury. Antioxidant therapeutics has been a proposed strategy to ameliorate these imbalances and maintain homeostatic environments. However, the success of these approaches, specifically curcumin, has been limited due to characteristics such as hydrophobicity and high reactivity when released as bolus doses to contest to oxidative stress induced diseases. The development of a controlled release system to aid in protection of the antioxidant capacity of curcumin, as well as a tunable system to aid in proper rate of release for disease can overcome these limitations. Previously, the use of a poly(beta-amino ester) (PBAE) chemistry has been developed in Dziubla and Hilt laboratories to provide desirable properties. The dynamic mechanical analysis and efficacy in cellular protection has been studied, yet the sensitivity and responsiveness of these polymers to abnormal environments found within oxidative stress compromised environments are unknown. In this work, a series of networks were comprised of different molar ratios of modified acrylated curcumin, poly(ethylene glycol) diacrylate, and a primary diamine crosslinker to create tunable hydrolytically degradable crosslinked hydrogels. I hypothesized a consumption rate difference of free curcumin and curcumin as a released product from the crosslinked network in the presence of a free radical generating system. After the consumption profiles of each were reported differently, the experimental data was translated into a kinetic rate model to identify quantitative consumption rate parameters of curcumin and active film degradation products. The effect on the released products arose the question of curcumin consumption in other oxidizing environments. These networks were then investigated in low concentrations of a hydrogen peroxide insult, and interestingly showed sensitivity to hydrolysis by recovering significantly more curcumin at an accelerated rate of release. Identifying the sensitivity of these tunable networks to environmental stimuli, they were then presented to a series of low pH environments, which significantly reduced the degradation time, finding a dependence of rate of release on the weight loading of curcumin present within the film. To translate these responsive materials to an application-based system, the curcumin conjugated PBAE polymers were investigated as an oral rinse drug delivery system for the treatment of radiation-induced OM in a hamster model. Radiation-induced OM onset and severity was reduced with a 20 wt% microparticle loaded mucoadhesive system that releases curcumin over 24 hours, providing promising results of a therapeutic effect from curcumin when incorporated in to a controlled release delivery system. Overall, curcumin conjugated PBAE polymers show selectivity of hydrolysis in abnormal environments related to oxidative stress. This information is beneficial to the proper design and loading of antioxidant therapeutics within crosslinked polymers, giving the ability to tune release to treat and deliver based on the environment’s insult. This can advance the potential use for antioxidant therapeutics in pharmaceutical applications in the future.
215

THE DEVELOPMENT OF NOVEL NON-PEPTIDE PROTEASOME INHIBITORS FOR THE TREATMENT OF SOLID TUMORS

Miller, Zachary C. 01 January 2018 (has links)
The proteasome is a large protein complex which is responsible for the majority of protein degradation in eukaryotes. Following FDA approval of the first proteasome inhibitor bortezomib for the treatment of multiple myeloma (MM) in 2003, there has been an increasing awareness of the significant therapeutic potential of proteasome inhibitors in the treatment of cancer. As of 2017, three proteasome inhibitors are approved for the treatment of MM but in clinical trials with patients bearing solid tumors these existing proteasome inhibitors have demonstrated poor results. Notably, all three FDA-approved proteasome inhibitors rely on the combination a peptide backbone and reactive electrophilic warhead to target the proteasome, and all three primarily target the catalytic subunits conferring the proteasome’s chymotrypsin-like (CT-L) activity. It is our hypothesis that compounds with non-peptidic structures, non-covalent and reversible modes of action, and unique selectivity profiles against the proteasome’s distinct catalytic subunits could have superior pharmacodynamic and pharmacokinetic properties and may bear improved activity against solid tumors relative to existing proteasome inhibitors. In an effort to discover such compounds we have employed an approach which combines computational drug screening methods with conventional screening and classic medicinal chemistry. Our efforts began with a computational screen performed in the lab of Dr. Chang-Guo Zhan. This virtual screen narrowed a library of over 300,000 drug-like compounds down to under 300 virtual hits which were then screened for proteasome inhibitory activity in an in vitro assay. Despite screening a relatively small pool of compounds, we were able to identify 18 active compounds. The majority of these hits were non-peptide in structure and lacked any hallmarks of covalent inhibition. The further development of one compound, a tri-substituted pyrazole, provided us with a proteasome inhibitor which demonstrated cytotoxic activity in a variety of human solid cancer cell lines as well as significant anti-tumor activity in a prostate cancer mouse xenograft model. We have also evaluated the in vitro pharmacokinetic properties of our lead compound and investigated its ability to evade cross-resistance phenomena in proteasome inhibitor-resistant cell lines. We believe that our lead compound as well as our drug discovery approach itself will be of interest and use to other researchers. We hope that this research effort may aid in the further development of reversible non-peptide proteasome inhibitors and may eventually deliver new therapeutic options for patients with difficult-to-treat solid tumors.
216

TOWARDS THE RATIONAL DESIGN AND APPLICATION OF POLYMERS FOR GENE THERAPY: INTERNALIZATION AND INTRACELLULAR FATE

Mott, Landon Alexander 01 January 2019 (has links)
Gene therapy is an approach for the treatment of acquired cancers, infectious disease, degenerative disease, and inherited genetic indications. Developments in the fields of immunotherapies and CRISPR/Cas9 genome editing are revitalizing the efforts to move gene therapy to the forefront of modern medicine. However, slow progress and poor clinical outcomes have plagued the field due to regulatory and safety concerns associated with the flagship delivery vector, the recombinant virus. Immunogenicity and poor transduction in certain cell types severely limits the utility of viruses as a delivery agent of nucleic acids. As a result, significant efforts are being made to develop non-viral delivery systems that perform mechanistically similarly to viral delivery but lack immunogenic factors. Though safer, existing agents lack the efficacy inherent in the natural design of viral vectors. Clinical relevance of non-viral vectors will therefore depend on the ability to engineer optimized systems for cellular delivery in physiological environments. Progress in non-viral vector design for gene delivery requires a deep understanding of the various barriers associated with nucleic acid delivery, including cell surface interaction, internalization, endosomal escape, cytosolic transport, nuclear localization, unpackaging, etc. Further, it requires a knowledge of vector design properties (surface chemistry, charge, size, shape, etc.) and how these physical parameters affect interactions with the cellular environment. Of these interactions, charge is shown to govern how particles are internalized and subsequently processed, thereby affecting the intracellular fate and efficacy of delivery. Charge also affects the in-serum stability where negative zeta potential improves stability and circulation time. Therefore, it is important to understand the effects of polyplex charge and other parameters on the internalization and intracellular fate of polyplexes for gene therapy. In chapter 2, studies are performed to delineate the effects of polyplex charge on the cellular internalization and intracellular processing of polymer-mediated gene delivery. Charge is shown to affect the endocytic pathway involved in internalization, and the caveolin-dependent and macropinocytosis pathways lead to higher gene delivery efficacy, likely due to avoidance of acidified compartments such as late endosomes and lysosomes. In chapters 3-4, novel nanoparticles carrying DNA, RNA, and antioxidants are assessed for therapeutic effect with an emphasis on studying the internalization mechanisms and resulting effect on efficacy. Novel RNA delivery agents are shown to benefit from EGFR-targeting aptamer and nanoceria/PEI hybrids are demonstrated to provide simultaneous antioxidant and gene therapy. Finally, chapter 5 demonstrates the use of silencing RNA and CRISPR/Cas9 genome editing to study the prevalence of gene targets in vivo. The overall goal of this work is to contribute to the design and application of novel nanoparticles for gene delivery and offer insight into the engineering of novel polyplexes. It remains clear that route of internalization is key to successful gene delivery, and designing polyplexes to enter through non-acidified endocytic pathways is highly beneficial to transgene expression. This can be achieved through incorporation of surface chemistries that trigger internalization through targeted pathways and is the source of further work in the lab.
217

Pharmacokinetic and Pharmacodynamic Evaluation of Cocaine Hydrolases for the Treatment of Cocaine Overdose and Cocaine Addiction Using Rodent Models

Zheng, Xirong 01 January 2019 (has links)
Overdose and addiction are two medical complications of cocaine abuse. To date, there is no FDA approved pharmacotherapy specific for cocaine abuse. Cocaine hydrolases (CocHs) have been extensively investigated for its potential in anti-cocaine therapy. Previous studies have demonstrated that CocHs efficiently hydrolyze cocaine to generate biologically inactive metabolites both in vivo and in vitro. However, it has not been studied whether there is gender difference in the therapy using CocHs. In addition, the effectiveness of CocHs is unknown for treating cocaine toxicity when alcohol is co-administered. The main purpose of this dissertation is to characterize and evaluate efficient CocHs for cocaine overdose and cocaine addiction treatment. In the first set of studies, the effectiveness of human serum albumin-fused CocH1 were studied in male and female rats. The pharmacokinetic profiles, as well as the pharmacodynamic effects of CocH1-HSA were compared in male and female rats. The obtained data clearly demonstrated that CocH1-HSA was equally effective in both genders. The second set of studies investigated the efficiency of Fc-fused CocH5 in reversing cocaine toxicity in rats receiving simultaneous administration of cocaine and alcohol. Results showed that CocH5-Fc rapidly hydrolyzed cocaine and cocaine’s toxic metabolites in rats, and demonstrated that CocH5-Fc was efficient in treating cocaine toxicity when alcohol was simultaneously administered. In later studies to investigate the effects of CocH5-Fc for the treatment of cocaine addiction, a mathematical model was developed and validated to predict the effects of CocH5-Fc on the disposition of cocaine in rat blood and brain. This model adequately described the effects of CocH5-Fc in accelerating the elimination of cocaine and its toxic metabolites in both rat blood and brain. In conclusion, the studies within the current dissertation demonstrate the clinical potential of CocHs for the treatment of both cocaine overdose and cocaine addiction.
218

Prolonged Drug Release from Gels, using Catanionic Mixtures

Bramer, Tobias January 2007 (has links)
<p>The use of catanionic drug-surfactant mixtures was proven to be an efficient novel method of obtaining prolonged drug release from gels. It was shown that various commonly used drug compounds are able to form catanionic mixtures together with oppositely charged surfactants. These mixtures exhibited interesting phase behaviour, where, among other structures, vesicles and large worm-like or branched micelles were found. The size of these aggregates makes them a potential means of prolonging the drug release from gels, as only monomer drugs in equilibrium with larger aggregates were readily able to diffuse through the gel. When the diffusion coefficient for drug release from the formulation based upon a catanionic mixture was compared to that obtained for the drug substance and gel alone, the coefficient was some 10 to 100 times smaller.</p><p>The effects of changes in the pH and ionic strength on the catanionic aggregates was also investigated, and this method of prolonging the release was found to be quite resilient to variations in both. Although the phase behaviour was somewhat affected, large micelles and vesicles were still readily found. The drug release was significantly prolonged even under physiological conditions, that is, at a pH of 7.4 and an osmolality corresponding to 0.9% NaCl.</p><p>Surfactants of low irritancy, capric and lauric acid, may successfully be used instead of the more traditional surfactants, such as sodium lauryl sulfate (SDS), and prolonged release can still be obtained with ease.</p><p>Some attempts to deduce the release mechanism from the proposed systems have also been made using transient current measurements, dielectric spectroscopy, and modelling of the release using the regular solution theory. In these studies, the previous assumptions made concerning the mechanism responsible for the release were confirmed to a large extent. Only small amounts of the drug existed in monomer form, and most seemed to form large catanionic aggregates with the oppositely charged surfactant.</p>
219

Prolonged Drug Release from Gels, using Catanionic Mixtures

Bramer, Tobias January 2007 (has links)
The use of catanionic drug-surfactant mixtures was proven to be an efficient novel method of obtaining prolonged drug release from gels. It was shown that various commonly used drug compounds are able to form catanionic mixtures together with oppositely charged surfactants. These mixtures exhibited interesting phase behaviour, where, among other structures, vesicles and large worm-like or branched micelles were found. The size of these aggregates makes them a potential means of prolonging the drug release from gels, as only monomer drugs in equilibrium with larger aggregates were readily able to diffuse through the gel. When the diffusion coefficient for drug release from the formulation based upon a catanionic mixture was compared to that obtained for the drug substance and gel alone, the coefficient was some 10 to 100 times smaller. The effects of changes in the pH and ionic strength on the catanionic aggregates was also investigated, and this method of prolonging the release was found to be quite resilient to variations in both. Although the phase behaviour was somewhat affected, large micelles and vesicles were still readily found. The drug release was significantly prolonged even under physiological conditions, that is, at a pH of 7.4 and an osmolality corresponding to 0.9% NaCl. Surfactants of low irritancy, capric and lauric acid, may successfully be used instead of the more traditional surfactants, such as sodium lauryl sulfate (SDS), and prolonged release can still be obtained with ease. Some attempts to deduce the release mechanism from the proposed systems have also been made using transient current measurements, dielectric spectroscopy, and modelling of the release using the regular solution theory. In these studies, the previous assumptions made concerning the mechanism responsible for the release were confirmed to a large extent. Only small amounts of the drug existed in monomer form, and most seemed to form large catanionic aggregates with the oppositely charged surfactant.
220

Compression analysis as a tool for technical characterization and classification of pharmaceutical powders

Nordström, Josefina January 2008 (has links)
There are today strong incentives for an increased understanding of material properties and manufacturing processes to facilitate the development of new technologies in the pharmaceutical industry. The purpose of this thesis was to suggest methods requiring a low sample amount for characterization of technical properties of powders. Compression analysis was used to evaluate the formulation relevance of some compression equations. Using the mechanics of single granules to estimate powder functionality was part of this work. It was concluded that the formability of granular solids and the plasticity of single granules could be determined with compression analysis by using the Kawakita model for single components and binary mixtures of ductile granules. Further on, the fragmentation propensity of solid particles could be estimated from compression analysis by using the Shapiro equation, enabling indicators of both the fragmentation and the deformation propensity of particles to be derived in one single compression test. The interpretations of the compression parameters were only valid if the influence of particle rearrangement was negligible for the overall compression profile. An index indicating the extent of particle rearrangement was developed and a classification system of powders into groups dependent on the incidence of particle rearrangement was suggested as tools to enable rational interpretations of compression parameters. The application of compression analysis was demonstrated by investigating the relevance of the mechanics of granular solids for their tableting abilities. The plasticity of single gran-ules was suggested to influence both the rate of compactibility and the mode of deformation, and consequently the maximal tablet strength. The degree of granule bed deformation was shown to be a potential in line process indicator to describe the tableting forming ability. This thesis contributes to a scheme, suitable in formulation work and process control, to describe manufacturability of powders for an enhanced tablet formulation technology.

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