Thesis (M.Sc.)--University of Alberta, 2010. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Master of Science in Pharmaceutical Sciences. Title from pdf file main screen (viewed on February 17, 2010). Includes bibliographical references.

The influence of water soluble and insoluble stabilizing excipients on the physical stability of coated dosage forms was investigated in this study. The effect of the excipients on the thermal and physico-mechanical properties, and water vapor permeability of free films was studied, as was the influence of these excipients on the physical stability and release kinetics of coated pellets. The effect of water-soluble proteins, bovine serum albumin (BSA) and Type B gelatin, on the physical aging of Eudragit[trademark] RS/RL 30 D films was investigated. It was found that ionic interactions occurred above the isoelectric point of BSA and caused unstable films which showed accelerated decreases in drug release rate. The adjustment of the pH of the dispersion below the isoelectric point of BSA resulted in electrostatic repulsive charges that stabilized the drug release rate from coated dosage forms at both ambient and accelerated conditions. The addition of gelatin to the coating dispersion increased the drug release rate due to the formation of gel-domains through which the drug was able to easily diffuse. The influence of silicon dioxide on the stability of Eudragit[trademark] RS/RL 30 D films was investigated. Colloidal grades showed enhanced incorporation in the acrylic matrix; however, unstable films were formed. The addition of silicon dioxide with a larger particle size increased the permeability of the film and stabilization in drug release rate was attributed to constant water vapor permeability values of free films. The influence of ethylcellulose on the physical aging of Eudragit[trademark] NE 30 D coated pellets was studied. The two polymers were found to be substantially immiscible and the drug release rate of coated pellets was constant at both ambient and accelerated conditions which correlated to stabilizations in both the physico-mechanical properties and water vapor permeability of free films. Blending both Eudragit[trademark] NE 30 D and RS 30 D resulted in the formation of coherent films without the need of plasticizer. The two polymers were found to be miscible and both films and coated dosage forms were stable when stored below the glass transition temperature of the polymer blend. When films were stored above this temperature, instabilities occurred as a result of the further coalescence and densification of the polymer blend.

Chronic pulmonary disorders, marked by excessive extracellular matrix deposition (ECM) or fibrosis, are the most resistant to present clinical therapies resulting in prognoses of 50% life expectancy three years from diagnosis. Inadequacies of current treatments may be attributable to limitations in non-invasive therapeutic administration modalities. However, with the use of polyketal microparticles (PKMs), a novel drug delivery vehicle, a myriad of therapeutic schemes may be explored. Polyketals are a new polymeric family characterized by tissue biocompatibility, rapid hydrolysis, and benign degradation byproducts making it attuned for pulmonary applications. Potential treatments such as siRNA, oligo nucleotides, enzymes and other biomolecules can be encapsulated within PKMs and administered non-invasively via inhalation. For this study, we selected a model therapeutic peptide, Ac-SDKP, with established anti-fibrotic properties as the load for PKMs. For lung dysfunctions accompanied by fibrotic scarring, Ac-SDKP possesses promise in restoring the normal ECM framework. To assess PKMs viability as a pulmonary drug delivery vehicle three objectives were initially defined: 1) Synthesize particles possessing aerodynamic properties conducive for aerosolization 2) Optimization of the therapeutic load, Ac-SDKP, in PKMs to levels that will translate to clinical dosing concentrations, and 3) Determine the biocompatibility of the PKMs in the lung. Optimization of the Ac-SKDP loading within PKMs and size analysis revealed that a solid in oil in water double emulsion particle synthesis technique produced the most ideal microspheres. Based on previous reports, the loading efficiency attained, when locally dispensed, should reach clinical dosing requirements. Synthesized particles were compatible with aerosolization criteria; i.e., diameters below 3 μm and low polydispersities. In addition, we evaluated PKM tissue biocompatibility using a murine lung model. Examination of bronchoalveolar lavage fluid demonstrated only a slight inflammatory response to intratracheal particle injections of PKMs whereas PLGA, a commonly used biomaterial, elicited a significantly higher response. Histological assessment of the lungs following particle injection verified PKMs biocompatibility superiority. In conclusion, small-diameter PKMs are a suitable delivery system for pulmonary drug delivery, capable of delivering small peptide therapeutics and evading the local inflammatory response. The present work will enable expansion of therapeutic avenues capable of combating chronic lung disease.

Introduction: Embolic agents are used to block blood flow of hypervascular tumours, ultimately resulting in target tissue necrosis. However, this therapy is limited by the formation of new blood vessels within the tumour, a process known as angiogenesis. Targeting angiogenesis led to the discovery of anti-angiogenic factors, large molecular weight proteins that can block the angiogenic process. The aim of this research is development of poly (vinyl alcohol) (PVA) aqueous solutions that cross-link in situ to form a hydrogel that functions as an embolic agent for delivery of macromolecular drugs. Methods: PVA (14 kDa, 83% hydrolysed), functionalised by 7 acrylamide groups per chain, was used to prepare 10, 15, and 20wt% non-degradable hydrogels, cured by UV or redox initiation. Structural properties were characterised and the release of FITCDextran (20kDa) was quantified. Degradable networks were then prepared by attaching to PVA (83% and 98 % hydrolysed) ester linkages with an acrylate end group. The effect on degradation profiles was assessed by varying parameters such as macromer concentration, cross-linking density, polymer backbone and curing method. To further enhance the technology, radiopaque degradable PVA was synthesised, and degradation profiles were determined. Cell growth inhibition of modified PVA and degradable products were also investigated. Results: Redox initiation resulted in non-degradable PVA networks of well-controlled structural properties. Increasing the solid content from 10 to 20wt% prolonged the release time from few hours to ~ 2 days but had no effect on the percent release, with only a maximum release of 65% achieved. Ester attachment to the PVA allowed flexibility in designing networks of variable swelling behaviors and degradation times allowing ease of tailoring for specific clinical requirements. Synthesis of radiopaque degradable PVA hydrogels was successful without affecting the polymer solubility in water or its ability to polymerize by redox. This suggested that this novel hydrogel is a potential liquid embolic with enhanced X-ray visibility. Degradable products had negligible cytotoxicity. Conclusion: Novel non-degradable and radiopaque degradable PVA hydrogels cured by redox initiation were developed in this research. The developed PVA hydrogels showed characteristics in vitro that are desirable for the in vivo application as release systems for anti-angiogenic factors.

Introduction: Embolic agents are used to block blood flow of hypervascular tumours, ultimately resulting in target tissue necrosis. However, this therapy is limited by the formation of new blood vessels within the tumour, a process known as angiogenesis. Targeting angiogenesis led to the discovery of anti-angiogenic factors, large molecular weight proteins that can block the angiogenic process. The aim of this research is development of poly (vinyl alcohol) (PVA) aqueous solutions that cross-link in situ to form a hydrogel that functions as an embolic agent for delivery of macromolecular drugs. Methods: PVA (14 kDa, 83% hydrolysed), functionalised by 7 acrylamide groups per chain, was used to prepare 10, 15, and 20wt% non-degradable hydrogels, cured by UV or redox initiation. Structural properties were characterised and the release of FITCDextran (20kDa) was quantified. Degradable networks were then prepared by attaching to PVA (83% and 98 % hydrolysed) ester linkages with an acrylate end group. The effect on degradation profiles was assessed by varying parameters such as macromer concentration, cross-linking density, polymer backbone and curing method. To further enhance the technology, radiopaque degradable PVA was synthesised, and degradation profiles were determined. Cell growth inhibition of modified PVA and degradable products were also investigated. Results: Redox initiation resulted in non-degradable PVA networks of well-controlled structural properties. Increasing the solid content from 10 to 20wt% prolonged the release time from few hours to ~ 2 days but had no effect on the percent release, with only a maximum release of 65% achieved. Ester attachment to the PVA allowed flexibility in designing networks of variable swelling behaviors and degradation times allowing ease of tailoring for specific clinical requirements. Synthesis of radiopaque degradable PVA hydrogels was successful without affecting the polymer solubility in water or its ability to polymerize by redox. This suggested that this novel hydrogel is a potential liquid embolic with enhanced X-ray visibility. Degradable products had negligible cytotoxicity. Conclusion: Novel non-degradable and radiopaque degradable PVA hydrogels cured by redox initiation were developed in this research. The developed PVA hydrogels showed characteristics in vitro that are desirable for the in vivo application as release systems for anti-angiogenic factors.

Thesis (Ph. D.)--University of Texas at Austin, 2006. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--Lund University.

Thesis (Ph. D.)--Lund University.

Thesis (Ph.D)--Biomedical Engineering, Georgia Institute of Technology, 2009. / Committee Chair: Murthy, Niren; Committee Member: Bellamkonda, Ravi; Committee Member: Davis, Michael; Committee Member: May, Sheldon; Committee Member: Milam, Valeria. Part of the SMARTech Electronic Thesis and Dissertation Collection.

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 213-223).