MS, Pharmaceutical Affairs, Faculty of Health Sciences, University of the Witwatersrand / PEO (Polyethylene Oxide) is one of the most important biodegradable polymers used in pharmaceutical formulations, mainly because of its non-toxicity, high water-solubility and swellability, insensitivity to the pH of the biological medium and flexibility during dosage form production (Kim, 1995; Picker-Freyer, 2006; Kiss et al., 2008). The lack of studies attempting to achieve controlled drug delivery of hydrophilic drugs has provided us with motivation to use a drug of this nature but we have combined it with a PEO-electrolyte combination in order to control drug delivery. This study was aimed at modifying the physicochemical and physicomechanical properties of PEO in order to influence the hydrodynamic diffusion of its three-dimensional network. Hence, through such alteration, it was envisaged that if drug is loaded into its PEO matrix, its solubility and dissolution can be regulated in order to achieve zero-order influx of dissolution medium. The interaction between PEO and electrolytes may allow for precipitation of ions on the polymer backbone. This would lead to the attraction of water molecules to the ions. As a result, this would cause dehydration of the polymer matrix, hence minimising its mobility and relaxation. In this study, 36 PEO-electrolyte combinations were prepared by combining a high molecular weight PEO with different statistically planned combinations of electrolytes. The 36 formulations were microscopically analyzed and subjected to textural analysis. The salted-out PEO-electrolyte combinations were then further selected and analyzed. Assessment of the molecular structural transition and thermal compatibility analysis indicated minimal interaction between the electrolytes and PEO indicating that the polymer-electrolyte combination was stable enough to be employed as a medium for controlled drug release. The polymer-electrolyte combination was combined with a model drug, diphenhydramine HCl to form a tablet matrix and then subjected to dissolution. In vitro drug release varied depending on the different electrolytes and their combinations. The type of polymer, molecular weight of the polymer, concentration of the polymer, different electrolyte combinations and solubility of the drug played a significant role in controlling drug release. After optimization of the fracture force, resilience and work performed values, results have established that equal concentrations of Na2CO3 and K2HPO4 are desirable for achieving controlled release of drug from the salted-out PEO combination in a zero-order manner. Furthermore, Na2CO3 and K2HPO4 had a significant influence on controlling the release of drug from the salted-out PEO combination due to crosslinking between PEO and the electrolytes ultimately leading to zero-order release kinetics. The salting-out of PEO notably modified the physicochemical and micromechanical properties of basic PEO, which demonstrably enhanced the ability of the sample to achieve controlled drug release. The formulation strategy employed in this study where in our sample drug, diphenhydramine HCl was combined with a PEO-electrolyte combination has shown promising results in regulating drug release.

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Hydrophilic polymers in a swellable matrix tablet hydrate quickly to form a hydrogel layer on the exterior of the dosage once in contact with water or biologic fluid. The resultant hydrogel serves as a barrier to regulate water permeation into the matrix and drug diffusion from the preparation. It is therefore important to understand how the polymer is hydrated and what mechanism exists between hydrogel formation and drug dissolution from a swellable matrix tablet. In this thesis, a TA texture analyzer was utilized to monitor and characterize matrix swelling properties during dissolution process. Multiple regression models were employed to analyze the quantitative relationship between drug dissolution or hydrogel thickness and major formulation factors (polymer ratio, drug solubility). Modified release matrix tablets were prepared using four APIs with a range of aqueous solubility, i.e., acetaminophen (ACE), chlorpheniramine (CHL), ibuprofen (IBU), and pseudoephedrine hydrochloride (PSE). Two hydrophilic polymers, polyethylene oxide (PEO) and hydroxypropyl methylcellulose (HPMC) were selected and tested as primary matrix polymers for the formulations. It was found from the experiments that multiple regression model was capable of estimating drug dissolution for both PEO and HPMC matrix preparations. Based on major formulation factors the regression models provide satisfactory prediction of drug release, which could further aid in formulation development and optimization.

Hydrophilic polymers in a swellable matrix tablet hydrate quickly to form a hydrogel layer on the exterior of the dosage once in contact with water or biologic fluid. The resultant hydrogel serves as a barrier to regulate water permeation into the matrix and drug diffusion from the preparation. It is therefore important to understand how the polymer is hydrated and what mechanism exists between hydrogel formation and drug dissolution from a swellable matrix tablet. In this thesis, a TA texture analyzer was utilized to monitor and characterize matrix swelling properties during dissolution process. Multiple regression models were employed to analyze the quantitative relationship between drug dissolution or hydrogel thickness and major formulation factors (polymer ratio, drug solubility). Modified release matrix tablets were prepared using four APIs with a range of aqueous solubility, i.e., acetaminophen (ACE), chlorpheniramine (CHL), ibuprofen (IBU), and pseudoephedrine hydrochloride (PSE). Two hydrophilic polymers, polyethylene oxide (PEO) and hydroxypropyl methylcellulose (HPMC) were selected and tested as primary matrix polymers for the formulations. It was found from the experiments that multiple regression model was capable of estimating drug dissolution for both PEO and HPMC matrix preparations. Based on major formulation factors the regression models provide satisfactory prediction of drug release, which could further aid in formulation development and optimization.

Thesis (Ph.D.) -- McMaster University, 2001. / Includes bibliographical references (leaves 204-228). Also available via World Wide web.

Master of Science / Department of Chemistry / Takashi Ito / Solvent swelling of block copolymer microdomains plays an essential role in the improvement of microdomain alignment by solvent vapor annealing and in chemical separations using block copolymer monoliths. Here, investigation of the effects of solvent swelling on the molecular permeability and dimensions of cylindrical microdomains in polystyrene-block-poly(ethylene oxide) (PS-b-PEO) films is done by using single molecule tracking. These films are prepared by sandwiching benzene (with/without methanol) or THF (with/without methanol) solutions containing 5 nM sulforhodamine B (SRB) between two glass substrates. The PEO microdomains are aligned in the solution flow direction during the film preparation. The diffusional motions of individual SRB molecules are measured at different drying times to assess the microdomain radius and permeability. These parameters, on average, gradually decrease with an increase in drying time; however the trend differs slightly from one solvent system to another. A sharp decrease of microdomain radius is observed for benzene, benzene-methanol, THF and THF-methanol swollen films at initial drying condition (for example 2 days). In contrast, microdomain permeability does not decrease sharply; instead a gradual decreasing trend is seen for all solvent systems. In addition, mixing of a small amount of methanol (14% in PEO microdomains) either with benzene or with THF does not produce noticeable difference in the swelling of PEO microdoamins. Importantly, both benzene and THF offer similar microdomain swelling behavior at the same drying temperature, which is evident from the microdomain radius values, however THF shows comparatively larger microdomain permeability and better correlation between permeability and microdomain radius compared with benzene.

This work uses high-speed video imaging to study the formation of filaments, during impact and rebounding of drops with polymer additives. We use PEO of different concentrations from 10 to 1000 ppm and study how drops rebound from various different surfaces: superhydrophilic, hydrophilic, hydrophobic, and superhydrophobic. Bouncing occurs for all surfaces at low impact velocities. We specifically focus on the phenomenon of the generation of polymer filaments, which are pulled out of the free surface of the drop during its rebounding from micro-pillared or rough substrates. We map the parameter regime, in terms of polymer concentration and impact Weber number, where the filaments are generated in the most repeatable manner. This occurs for regularly pillared surfaces and drops of 100 ppm PEO concentrations, where numerous separated filaments are observed. In contrast, for superhydrophobic coatings with random roughness the filaments tend to merge forming a branching structure. Impacts on inclined surfaces are used to deposit the filaments on top of the pillars for detailed study.

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<p>Surface-induced thrombosis is a continuing issue in the development of biomaterials for blood contacting applications. Protein adsorption is a key factor in thrombosis since it occurs rapidly upon contact of a material with blood, initiating coagulation and other adverse reactions including platelet adhesion. The research presented in this thesis explores the use of a unique antithrombin-heparin covalent complex (ATH) for surface modification to provide antithrombogenicity. ATH was tethered to surfaces by various methods. Polyethylene oxide (PEO) was investigated as a linker-spacer molecule for surface attachment of ATH as well as for its antifouling properties.</p> <p>In the first phase of the work gold was used as a model substrate. ATH was attached by three different methods: direct attachment, attachment via a short chain linker, and attachment via PEO. Analogous heparin-modified surfaces were prepared for comparison. Surfaces were characterized using contact angle measurements, x-ray photoelectron spectroscopy (XPS), ellipsometry and quartz-crystal microbalance (QCM). The data suggested that the heparin moiety of ATH was directed away from the surface, in an orientation allowing ready interaction with blood components. The ATH-modified surfaces showed greater antithrombin binding than the heparin-modified surfaces as measured by radioactive labelling and Western blotting analysis. Antithrombin binding was found to occur predominantly through the active pentasaccharide sequence of the heparin moiety of ATH, demonstrating the potential of the ATH for catalytic anticoagulant function. From measurements of the ratio of total heparin to active heparin (anti-factor Xa assay), ATH-modified surfaces were shown to have greater bioactivity than heparin-modified surfaces. The adhesion of platelets to gold and modified gold surfaces was measured from flowing whole blood <em>in vitro</em> using a cone-and-plate device and was lower on all of the modified surfaces compared to bare gold. PEO-ATH surfaces were also shown to prolong plasma clotting times compared to control and heparinized surfaces.</p> <p>In subsequent work, surface modification methods were developed for polyurethane (PU) substrates. Isocyanate groups were introduced into the PU surface for attachment of PEO and ATH was attached to the “distal” end of the PEO. Surfaces using PEO of varying molecular weight and end group were investigated to determine conditions for maximum anticoagulant activity and minimum non-specific protein adsorption. Surfaces were characterized using contact angle measurements and XPS, and protein interactions were studied using radiolabelling. The optimum balance of bioactivity and protein resistance was found to occur with PEO of low to mid range MW (ie. MW 300-600). These PU-PEO-ATH surfaces showed low fibrinogen adsorption and high selectivity for antithrombin. Consistent with results using gold substrates, platelet adhesion remained low when ATH was attached to polyurethane surfaces grafted with PEO. A hetero-bifunctional amino-carboxy-PEO (PEO-COOH surface) was compared with a “conventional” homo-bifunctional dihydroxy-PEO (PEO-OH surface) with respect to their effectiveness as linkers for attachment of ATH. The PEO-COOH-ATH surface was shown to bind slightly greater amounts of antithrombin, indicating higher catalytic anticoagulant activity. Thrombin binding was measured to determine whether the surfaces could provide direct anticoagulant activity. The PEO-OH-ATH surface bound high amounts of thrombin, indicating potential for direct thrombin inhibition. It is hypothesized that the PEO properties (MW and functional end group) may have an effect on the orientation of ATH on the surface thus influencing its "preference" for catalytic vs. direct anticoagulant function.</p> <p>This thesis provides new information regarding the interactions of proteins and platelets with ATH immobilized on biomaterials. ATH-modified surfaces were superior to analogous heparin-modified surfaces with respect to antithrombin binding and catalytic anticoagulant ability. Immobilized ATH was also shown to bind thrombin, suggesting potential for direct anticoagulant activity. It can thus be seen as a unique surface modifier with dual functioning anticoagulant activity. The modification of polyurethane with ATH using PEO as a protein resistant linker-spacer, may provide a material of improved antithrombogenicity for the construction of blood contacting devices.</p> / Doctor of Philosophy (PhD)