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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.
191

The factors affecting liquid and semi-solid mucoadhesion to the oral cavity and oesophagus

Young, Simon A. January 2000 (has links)
No description available.
192

Development and characterization of biodegradable microspheres containing selected antimycobacterials

Bain, David F. January 1998 (has links)
Prolonged therapy required to effectively treat mycobacterial infection frequently results in severe dose-limiting side-effects and drug resistance due to patient non-compliance with protracted dosage regimens. Biodegradable poly-a-hydroxy acid microspheres and microcapsules containing rifampicin (RIF) and isoniazid (INH) respectively have been prepared with the intention of providing high sustained site-specific concentrations to overcome some of the shortcomings of existing oral treatments. Due to the high dose, hydrophilicity and instability of both drugs, formulation strategies to attain high drug loading and methodologies to characterize in vitro drug release during ongoing decomposition were required. Stability indicating HPLC assays to quantify drug release have been developed, validated and applied to monitor drug release based on cumulative quantification of drug and degradates. A mathematical correction for serial decompositions associated with RIF was made based on the terminal pseudo equilibrium observed during stability studies. An isocratic HPLC assay was prospectively developed for the quantification of both drugs and their major metabolites in biological samples. Further preformulation studies confirmed the absence of significant polymorphs for both drugs when recrystallized from solvents later used in formulation development. Furthermore, thermal analysis revealed only modest interaction between the drugs and Resomer®. The high and moderate water solubilities of INH (145 mgmL-1) and RIF (1 mgmL-1) determined the selection of spray-drying (SD) and emulsion solvent evaporation (ESE) for RIF, whereas preparation of INH microcapsules relied solely on the former technique. Examination of the effects of varying RIF: polymer ratio, phase volumes and continuum presaturation with selected poly(L-lactide) and poly(D, L-lactide-co-glycolide) (PDLGA) Resomer® identified optimum conditions to maximize drug loading during a comparison of aqueous ESE with spray-drying with a range of nine further amorphous Resomer® polymers. Although yields were generally higher with ESE (85-90 %), SD (45- 75 %) was considered a superior preparation technique on the basis of the rapid production of microspheres of high and predictable drug loading (100 % of that attempted), with monodisperse granulometry and superior morphology. Release profiles were typically asymptotic characterized by a rapid `burst' of release followed by a slow release of residual entrapped RIF, irrespective of the preparative technique or polymer used. Poor yields (7.2 %) when SD low molecular weight (MW) PDLGA (8 kD) were greatly enhanced (74.8 %) by reduction in drying temperature and substitution of chloroform: dichloromethane (CFM: DCM) (1: 1) cosolvent with DCM. These conditions were adopted as the optimum parameters for further studies of blends of low (2 kD, R104) and moderate (11 kD, R202H) MW poly(D, L-lactide) (PDLLA); materials which demonstrated excellent sprayability and dramatically modulated the release of drug when combined compared to their use alone. Drug release showed a remarkable dependence on blend, dramatic acceleration being observed between 44 and 48 %w/w R104. Release over this range showed a marked dependence on medium temperature and led to the proposal of an autohydration mechanism linked to the hydrophilicity and glass transition (T9) of the blend which accounted for the sigmoidal profiles observed. First order dependence of release allowed calculation of Arrhenius derived activation energies of drug release in glassy anhydrous and rubbery plastic matrices of 630 and 320 J mol-1. Hydration and thermal studies supported the postulated diffusion mechanism, whereas granulometric and morphological examinations demonstrated that erosion did not contribute significantly. The criticality of matrix composition was further highlighted when interchange with nominally identical polymer, R202H, shifted the critical composition to 30 %w/w R104. Moreover, this observation contested the batch-to-batch reproducibility of commercial polymer. Substitution of DCM with halothane (HAL) and acetone (ACT) had a profound influence on the properties of compositionally identical ('R104: R202'H, 30: 70) microspheres, particularly release kinetics. This was attributed to the more rapid drying kinetics with the poor solvent, ACT, and the generation of a porous matrix. Consequently, drug was largely released during the 'burst' phase. Superior solvents, HAL and DCM resulted in enhanced matrix coherence at the expense of considerable residual solvent burdens (6 - 12.5 %), which allowed extensive matrix relaxation as solvent was lost with first order kinetics. This ageing process was followed by the development of an endotherm associated with the Tg as the matrix stabilized with a resultant increase in the induction period and a general retardation of drug release. Extension of the concept of blending R104 as release 'initiator' to a range of MW PDLGA of 50: 50 and 75: 25 comonomer ratio as release 'modulator' was of limited success generating release profiles reminiscent of each polymer when used alone. The magnitude of the 'burst' correlated to the precipitation kinetics of the predominant complementary PDLGA polymer as determined by cloud-point titration. Due to the more hydrophilic nature of the copolymers, at the critical concentration uncontrolled hydration resulted in a single rapid release phase. Spray-dried biodegradable INH microcapsules were prepared by a two stage process whereby SD cores of drug or in combination with biodegradable albumin or casein were subsequently coated with PDLGA by SD. The highly crystalline, aggregated and irregular morphology of SD drug resulted in poor coating efficiency and a rapid release of encapsulated drug. Protein microspheres of superior sphericity allowed more effective coating and hence slower INH release. It is concluded that SD has excellent industrial potential for the preparation of biodegradable poly-a-hydroxy acid microspheres for high dose drugs to be delivered directly to their site of action, e. g., intra-pulmonary. Indeed, the granulometry of these particles and, in particular, the hydrophilic character of blends of PDLLA described have considerable potential for the sustained delivery of drugs in the low volumes of fluid that prevails in the lung. These formulations might offset some of the limitations of current oral antimycobacterial therapy.
193

Metered atomisation for respiratory drug delivery

Clark, Andrew Reginald January 1991 (has links)
An investigation into the factors affecting the metered atomisation of superheated liquids has been carried out. The investigation was aimed primarily at developing an understanding of the factors which affect the performance of. respiratory drug delivery systems (Suspension Pressurised Metered Dose Inhalers). Initial investigations used a semi-empirical sizing technique, representing the human airways, to identify the major variables (formulation and geometric) which affect the performance of the MDI system. Computer models were developed to describe both continuous and metered discharge from a superheated-liquid aerosol generator. These models were based on the concept of thermal and dynamic equilibrium, but they were improved and extended, to describe metered discharge, by including empirical corrections obtained from continuous discharge experiments. Experimental investigations using 'instrumented inhalers' were used to confirm the validity of the computer model. The experimental investigations encompassed the use of conventional CFC's and the new non-chlorinated propellants 134A and 227. The computer models and droplet correlation function developed during these investigations represent powerful tools for use in the design of both current and future HFC/HFA powered metered dose inhaler delivery systems.
194

Studies of some molecular reorganisations in the solid state and in colloidal media by vibrational spectroscopy

Dennis, Andrew C. January 2000 (has links)
No description available.
195

Curdlan 1,3-Beta-Glucans: A New Platform for Polymer Drug Delivery

Lehtovaara, Benjamin 18 April 2011 (has links)
1,3-β-glucans are a class of natural polysaccharides with unique pharmacological properties and the ability to form triple helical structures and resilient gels. Curdlan and other 1,3-β-glucans have found application pharmacologically in the treatment of cancers and acceleration of wound healing in humans and in the impartation of infection resistance in animal husbandry. Structurally, these polysaccharides have found application in food science as thermal gels, in nanostructure formation as helical scaffolds, and in drug delivery as nanocarriers for drugs and as inclusion complexes with polynucleotides. A literature review of the important work on Curdlan research reveals two streams of research: investigation of the pharmacological significance of these polymers and their application in increasing host immunocompetency and investigation of the nature of the triple helix and its application in a variety of fields from food gels to drug delivery. Two significant contributions to the field of Curdlan research have been completed including 1) The development of a Curdlan nanoparticle drug delivery platform and 2) A new multi-component liquid crystalline hydrogel providing a new route to form polynucleotide inclusion complexes with Curdlan for gene delivery. The developed nanoparticle platform exhibited high encapsulation of chemotherapeutic drugs and a 24-hour controlled release with a particle size of 109.9 nm. The liquid crystalline hydrogel exhibited homogeneous inclusion of DNA into amorphous and crystalline phases of Curdlan and delayed and triggered release of polynucleotide content. This work has been a significant demonstration of the potential of Curdlan as a new polymer for multi-functional drug delivery.
196

Design of Coated Magnetic Iron-Oxide Nanogels for Drug Delivery Systems

Rahmani, Sara January 2011 (has links)
Intelligent and more advanced therapeutic agents, capable of sensing and responding to their environment, are required to treat more complicated and complex diseases. Among all recently developed therapeutic agents, hydrogels are not only intelligent to sense and respond to external stimulus, but also they can be synthesized and designed in the cellular and sub-cellular size scale, which enhance their therapeutic ability. Most body physiological processes are regulated as a consequence of pH gradient in different compartments of the body; besides, changes in pH are also associated with disease or damaged sites within the body. A unique feature of hydrogels is that they can provide a network for loading and release of drugs. Therefore, the drug loaded within pH-responsive nanogels are able to locally release onto the target sites because of their small size, and capability to sense and respond to environmental changes. The goal of this research is to design and implement novel pH-responsive magnetic nanogels for drug delivery that respond to changes in pH. Semi-continuous emulsion polymerization was conducted to synthesize polyampholyte nanogels comprising of methacrylic acid (MAA) and 2-(diethylamino) ethyl methacrylate (DEAEMA) in the presence and absence of steric stabilizer poly (ethylene glycol) methacrylate (PEGMA). The synthesized nanogels demonstrated swelling behavior at both acidic and basic pHs. Herein, procaine hydro chloride (PrHy) was utilized as cationic drug to investigate the release behavior from synthesized nanogels under different conditions. PrHy was loaded within nanogels through hydrophobic interaction and hydrogen bonding, as confirmed by isothermal titration calorimetry. The release study of PrHy molecules from nanogels was conducted by applying the versatile and easy technique of drug selective electrode, in which the concentration of released drug was measured as a function of time. In order to facilitate the purification and enhance the detection of nanogels, iron oxide particles (Fe3O4) were co-precipitated within nanogels to form magnetic nanogels. Subsequently, layer-by-layer coating of polyelectrolytes were performed to control and eliminate the initial burst release of PrHy from nanogel by increasing the diffusion barrier and manipulating the permeability of nanogels. For the purpose of this research low molecular weight chitosan (CS) was used as polycation and poly (sodium 4-styrenesulfonate) (PSS) was acted as polyanion to coat magnetic nanogels. The more layers was applied, the more reduction in burst release was observed, which was revealed by using drug selective electrode to measure the concentration of the released drug from coated nanogels. Besides, layer-by-layer coating prolonged the time require to reach the steady state drug release. Therefore, this synthesized polyampholyte coated iron-oxide nanogels demonstrate great potential for use in controlled drug delivery systems.
197

Development of stat-3 targeting siRNA nano-carriers for cancer therapy

Alshamsan, Aws 11 1900 (has links)
In many tumors, persistently-active signal transducer and activator of transcription 3 (STAT3) imparts several oncogenic features such as survival, proliferation, angiogenesis, and immune escape. Therefore, STAT3 targeting in cancer and cancer-exposed dendritic cells (DCs) is important for cancer therapy. Our objective is developing delivery modalities of STAT3-targeting small interfering RNA (siRNA) using lipid-modified polyethylenimine (PEI) polyplexes and poly(D,L lactic-co-glycolic) acid (PLGA) nanoparticles (NPs), and evaluating the therapeutic outcomes in vitro and in vivo. Significant increase in siRNA condensation, protection, and cellular uptake by B16.F10 melanoma was seen by stearic-acid-modified PEI (PEI-StA) compared to unmodified PEI. Moreover, PEI-StA increased the STAT3 silencing potency of siRNA compared to PEI. STAT3 knockdown was accompanied with significant induction of interleukin-6 (IL-6) secretion and reduction of vascular endothelial growth factor (VEGF) production and cytotoxicity evidenced by increased Caspase 3 activity in vitro and in vivo, and significant inhibition in tumor growth. Analysis of tumor microenvironment showed CD3+ cells infiltration corresponding to STAT3 knockdown. The levels of CD4+ helper cells, CD8+ cytotoxic cells, and NKT cells significantly increased. DC infiltration and activation significantly increased in tumor mass following STAT3 knockdown as evidenced by high expression of CD86 and CD40. Moreover, IFN-, IL-12, and TNF- significantly increased following STAT3 knockdown by PEI-StA compared to PEI, suggesting Th1-type immunity. Allogenic capacity of DCs isolated from siRNA-treated mice was evidenced by the high T cell proliferation and IL-2 production in mixed lymphocytes reaction (MLR). Then, we explored STAT3 knockdown in DCs exposed to tumor derived factors (TDFs). We investigated encapsulation of siRNA complexes (PEI or PEI-StA) into PLGA NPs (PLGA-P and PLGA-PS). PLGA-P and PLGA-PS had an average diameter of ~ 370 nm and zeta potential of ~ -16 mV. Uptake and endosomal localization was confirmed. After TDFs exposure, DCs showed high STAT3 and low CD86 expression. STAT3 silencing by PLGA-P and PLGA-PS restored DC functionality as evidenced by upregulation of CD86, IL-12, and TNF- and MLR activity. PLGA significantly reduced PEI-associated toxicity. Therefore, STAT3 targeting in B16 cells by siRNA polyplexes of PEI and PEI-StA, or in DCs by PLGA-P and PLGA-PS provide potential strategies for cancer therapy. / Pharmaceutical Sciences
198

Preparation and evaluation of novel drug alginate granule systems using paracetamol as model drug

Mukhopadhyay, Debashis, n/a January 2006 (has links)
Purpose: The aim of this thesis was to investigate a novel method of preparing crosslinked alginate matrices. Current methods use large quantities of water and hence are not suitable for large scale manufacturing of drug alginate particulate systems. Moreover, the current processes offer little scope for control of the crosslinking process. The aim was to overcome these problems through studies of paracetamol alginate granular matrices prepared by the novel method and to explore if these granules could be used to improve the taste of paracetamol. Methods: The novel method involves preparation of dried drug alginate granules (moisture content: <5-6 %) using conventional granulation followed by crosslinking treatment of the dried granules with calcium chloride or a combination of calcium and magnesium ion solution in a crosslinking bath. The effect of the process (shear rate, binder quantity) to prepare untreated granules, composition of the raw materials (drug particle size and type of alginate) and subsequently the crosslinking treatment process variables (Ca�⁺ ion concentration, agitation rate, time and temperature of Ca�⁺ solution) on the physicochemical properties of granule systems were studied using factorial designs together with supporting studies. The granules were characterized using sodium and calcium content analysis, drug release studies (mainly sub-60s release) matrix swelling rate and equilibrium swelling studies, tensile strength studies, ion permeation studies, SEM and X Ray analysis and gravimetric studies. Sensory studies correlating sub-60 s drug release (determined using a specially designed apparatus) and human taste scores (measured using an analogue scale) were then undertaken. Selected formulations were evaluated for taste improvement and to determine if mucoadhesion led to an increased unpalatability of paracetamol. Results: Of the crosslinking treatment factors, the calcium concentration had the greatest effect on crosslinked granules. Although other treatment factors also affected the granule properties, alteration of the salt concentration allowed considerable control over the crosslinking process (not possible in the conventional method) in addition to providing a mechanistic understanding of the crosslinking process in the dried state. The use of low calcium concentrations (< 20 mg/ml, CaCl₂. 2H₂O) during treatment led to granule erosion (hence drug loss) due to overall incomplete crosslinking but led to a reduction in the short-term drug release compared to the granules treated with intermediate (100- 250 mg/ml) or high calcium concentrations (>400 mg/ml) due to reduction in the granule porosity after crosslinking. Although intermediate calcium concentrations led to complete crosslinking and longer release times (T 85 %: 25 min) high calcium crosslinking restricted the crosslinking to the surface of the granules leading to faster drug release (T 85 %: 8 min) with low calcium granules showing intermediate crosslinking and drug release rates (T 85 %: 18 min). High calcium treatment limited drug loss during crosslinking (95 % recovered compared to 83 % recovery at intermediate calcium concentration) without affecting the short-term drug release much. Low calcium granules showed the lowest drug recovery (< 70 %) and slowest sub-60s drug release followed closely by intermediate and high calcium treated granules. The granule preparation factors (shear rate, binder quantity) and type of alginate used, considerably affected the sub-60s drug release by affecting surface porosity especially when a low shear rate was used. However, these factors only slightly reduced the drug loss during crosslinking treatment phase (about 4 % increase in drug recovery). Smaller drug particle size had a slightly larger incremental effect on drug recovery (about 8 % increase in the drug recovery) during crosslinking treatment due to better embedding of the drug particles inside the untreated granule matrix. This was true as long as the particle size of the drug was > 98 [mu]m. Below this size drug recovery remained unaffected by changes in drug particle size. Although granule surface porosity considerably affected the sub-60s drug release, its effect on drug release (long-term) was much less. A linear correlation was observed between the sub-60s drug release and sensory scores despite high individual variability. Both granule formulations evaluated showed taste improvement and mucoadhesion did not lead to an increase in the bitter taste of the uncrosslinked paracetamol alginate granules. Conclusions: Unlike the traditional method, the new technique of preparation of crosslinked drug alginate particulate systems uses very little water and allows greater control over the the crosslinking process compared to the swollen state crosslinking. The novel process of preparation is versatile, and should be scalable. It offers the formulator a platform to prepare a matrix, reservoir or a combination of these two systems using alginates and other drugs and polymers as well. Adequate short-term control over paracetamol release, very little loss of paracetamol during treatment (< 5 % loss), reduction in mucoadhesion of the granules and lastly improvement of the taste of paracetamol is possible using alginate based systems especially if high calcium is used during the crosslinking treatment. Hence, it is likely that these taste-improved granules could be used to prepare tablets without the need for a protective film coating to improve taste. Finally, this research established the utility of short-term drug release in taste improvement research and characterization of solid controlled release dosage forms.
199

Liposomes in drug delivery :

Er, Yan. Unknown Date (has links)
Liposomes are used as biocompatible carriers of drugs, peptides, proteins, plasmic DNA, antisense oligonucleotides or ribozymes, for pharmaceutical, cosmetic, and biochemical purposes. They are considered as effective drug delivery systems due to their colloidal size, easily controllable surface and membrane properties, large carrying capacity of drugs and biocompatibility. / This study was concerned with the stability of liposomes, their interaction at solid-liquid interfaces and their release of hydrophilic drug compounds. Either conventional liposomes containing lecithin and cholesterol, and Stealth® liposomes containing polyethylene glycol (PEG) 5000-lipids or PEG2000-lipids were investigated. Steric hindrance introduced by PEG chains proved to be influential in controlling liposome stability, interaction and drug release processes. Electrostatic forces were shown to be essential to the mechanisms and kinetics of liposome adsorption and colloidal stability, but not influential for the release of guanosine, used as a model hydrophilic drug. / Findings from this research improve the understanding of liposome interaction during drug delivery, give insight into the actions of liposomes in the body and may form the basis for improved liposome formulation. In addition, this research has developed a more comprehensive understanding of the role of PEG in controlling the colloidal stability, interfacial interactions of liposomes and drug transport kinetics across the lipid bilayers of liposomes. / Thesis (PhDAppliedScience)--University of South Australia, 2005.
200

Development of acid-cleavable polymeric nano/microparticles for delivery of therapeutics

Chan, Yannie Ka Yan, Chemical Sciences & Engineering, Faculty of Engineering, UNSW January 2007 (has links)
For controlled drug delivery applications, an ideal carrier system should release its drug payload only at the site where the therapeutic activity is required. One elegant strategy for site-selective release of drugs is to utilize the acidic sites in the body, for example, tumor sites and intracellular endocytic compartments. The objective of this thesis is to develop a series of new acid-cleavable polymeric nanoparticles for pH-triggered delivery oftherapeutics. Four new acid-cleavable benzaldehyde acetal crosslinkers have been designed and synthesized. They were then used in the generation of acid-labile polymeric nanoparticle drug carrier systems via various synthetic strategies and drug loading approaches for the delivery of therapeutics with different nature: (l) the coreshell poly(butyl acrylate)-g-poly(polyethylene glycol acrylate) nanoparticles, synthesized via the reversible addition-fragmentation chain transfer (RAFT)-mediated dispersion polymerization, were used for the delivery of hydrophobic drugs; (2) the core-crosslinked poly(hydroxyethyl acrylate)-b-poly(butyl acrylate) copolymer micelles, synthesized via the RAFT-mediated chain-extension polymerization, were used for the delivery of an antitumor drug, doxorubicin; (3) the poly(hydroxyethyl methacrylate) microgel particles, synthesized via the inverse-emulsion polymerization, were used for the delivery of biomacromolecular drugs. The designed physiochemical features such as the size, surface chemistry, cytotoxicity and the pH-triggered drug release properties of the developed carrier systems have been assessed. The synthesized systems offered release of the drug payload at slightly acidic conditions. The structural integrity of the polymeric carriers remained intact in the physiological, neutral pH conditions. The results support the potential value of the developed systems to be used for acidic-site delivery of therapeutics e.g. tumor sites and intracellular compartments. The content of this thesis has been published as three peer-reviewed international journal articles.

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