Thesis (Ph.D) - University of Queensland, 2007. / Includes bibliography.

L’amélioration de la solubilité des principes actifs peu solubles est devenue l’un des principaux challenges de l’industrie pharmaceutique. Bien que présentant une structure chimique potentiellement idéale pour interagir avec la cible, elles échouent dans l’efficacité in vivo : après administration, elles ne peuvent se dissoudre dans les milieux aqueux biologiques et par conséquent ne peuvent être transportées sur leur site d’action pour atteindre la concentration efficace, amenant à un échec thérapeutique. De nombreuses stratégies très intéressantes ont été proposées pour surmonter ce sérieux obstacle.Les dispersions solides sont étudiées depuis plus de 40 ans et ont conduit à de très nombreuses publications mais jusqu’à aujourd’hui peu de produits ont été commercialisés principalement pour des raisons de stabilité physico-chimique. Celles-ci ont pour but de présenter le principe actif sous sa forme amorphe : cette dernière présentant un état d’énergie plus élevé et par conséquent une solubilisation facilitée. Dans le même temps, le système doit rester stable durant le stockage, ainsi la recristallisation ou tout autre changement entraînant une modification du profil de libération doivent être évités. Différentes techniques de production peuvent être utilisées pour préparer ce genre de systèmes polymériques tels que l’extrusion en phase chauffante ou l’atomisation-séchage. Le principal objectif de ce travail a été d’améliorer la solubilité des principes actifs peu solubles par formation de dispersions solides utilisant les deux techniques les plus utilisées : l’extrusion en phase chauffante et l’atomisation-séchage. Dans cette étude, le kétoprofène a été incorporé dans des matrices polymériques hydrophiles pour augmenter sa solubilité apparente. Les deux techniques ont été employées et l’Eudragit® E a été considéré comme une matrice intéressante pour plusieurs raisons : c’est un polymère thermoplastique, offrant une stabilité thermique suffisante pour l’extrusion en phase chauffante, il se dissout rapidement en milieu acide et peut interagir avec les groupements acides de par ses nombreux azotes ternaires. Des mélanges binaires « principe actif – Eudragit®E » ainsi que des mélanges ternaires « principe actif – Eudragit®E - PVP », « principe actif – Eudragit®E - PVPVA », « principe actif – Eudragit®E - HPMC » ont été étudiés et caractérisés Les systèmes obtenus ont été caractérisés par macro/microscopie optique, microscopie électronique à balayage, diffraction laser, analyse calorimétrique différentielle modulée, diffraction des rayons X et l’étude du profil de libération in vitro en milieu acide (HCl 0.1M). Les libérations ont été intentionnellement réalisées en condition « non sink » afin d'évaluer le potentiel des formulations à produire des solutions sur-saturées et la durée de ces dernières. Tous les systèmes présentent un profil de libération du kétoprofène beaucoup plus rapide comparé au produit commercial et à la dissolution du principe actif pur. De plus, des solutions sur-saturées peuvent être obtenues et restent stables au moins 2 h. Cependant, en fonction des polymères utilisés, différents profils de libération ont été obtenus indiquant que l’utilisation de matrices polymériques pour l’accélération de la libération de principes actifs peu solubles peut être très complexe puisqu’elle n’est pas seulement influencée par la composition du système mais aussi potentiellement par leur structure interne et notamment par l’homogénéité/hétérogénéité de la distribution des excipients.[...]. / Poor aqueous solubility has become a property of numerous new drug candidates causing major concern. Despite a potentially ideal chemical structure allowing for interaction with the target, these substances fail to be effective in vivo: upon administration, they cannot dissolve sufficiently in the aqueous fluids of the body and, thus, cannot be transported to their site of action to reach therapeutically effective concentrations. Various interesting strategies have been proposed to overcome this crucial hurdle.Solid dispersions have been studied for more than 40 years and lead to numerous interesting research articles. However, today, only a few products have reached the market principally due to problems with the physico-chemical stability. The idea is to transform the crystalline raw material into a physical state having a greater energy in order to increase the driving force for drug dissolution. At the same time, the system should be stable during long term storage, thus, re-crystallization or other system changes, resulting in altered drug release rates, must be avoided. Different manufacturing techniques can be used to prepare such polymeric drug delivery systems, including hot-melt extrusion and spray-drying.The main objective of this work has been to improve drug solubility by forming solid dispersions using the two most employed techniques: hot-melt extrusion and spray-drying. In this study ketoprofen has been incorporated into hydrophilic polymeric matrices to increase its apparent aqueous solubility. Both techniques have been applied and Eudragit® E has been considered to be an interesting matrix former in this case, as it is thermoplastic, provides sufficient thermal stability for hot-melt extrusion, rapidly dissolves at acidic pH and can interact with acidic drugs due to its multiple tertiary ammonium groups. Binary “drug-Eudragit®E” as well as ternary “drug-Eudragit®E-PVP”, “drug-Eudragit®E-PVPVA”, “drug-Eudragit®E-HPMC” combinations were investigated and characterized using X-ray diffraction, mDSC, SEM, optical macro/microscopy, and drug release measurements in 0.1 M HCl before and after storage. Drug release has been intentionally monitored under non-sink conditions, in order to evaluate the potential of the formulations to provide super-saturated solutions and the life-time of the latter. In all cases ketoprofen release was much faster compared to a commercially available product and the dissolution of the drug powder (as received). More important, super-saturated solutions could have been obtained, which were stable for at least 2 h. [...]

In this thesis, new empirical correlations that predict the behaviour of Cupric-Chloride droplets undergoing spraying and drying processes are developed. Cupric-Chloride is a chemical compound with the formula CuCl2 that is present as slurry or aqueous solution within the Copper-Chlorine (Cu-Cl) thermo-chemical cycle for generation of hydrogen. An experimental study examines the effects of inlet air and liquid temperatures, pressure, concentration, nozzle diameter, and liquid flow rate on the outlet air temperature, particle size, particle size distribution, morphology, moisture content, bulk density, and flowability. The analysis examines a single droplet of CuCl2 solution in a continuum drying media. The validation of the model involves comparisons with experimental data from previous studies of different fluids based on non-dimensional analysis. The study provides new information about the effects of different concentrations of water in the CuCl2 slurry drying at low to moderate air temperatures.Analytical correlations of heat and mass transfer are developed for the aqueous solution, subject to various drying conditions. The analysis is performed for moist air in contact with a sprayed aqueous solution of Copper (II) Chloride Dihydrate [CuCl2 ·(2H2O)]. Validation of the model is performed by comparisons with experimental results. / UOIT

Thesis (Ph. D.)--University of Canterbury, 2009. / Typescript (photocopy). "January 2009." Includes bibliographical references (p. 215-236). Also available via the World Wide Web.

The aim of this study was to prepare biologically active insulin-loaded alginate microparticles by spray drying. Particles were produced from three alginate feed concentrations of 1, 1.5 and 2% w/v, with respective insulin loadings of 11.8, 7.8 and 5.8 mg/g of alginate and investigated in terms of mass yield, moisture content, particle size, morphology and encapsulation efficiency. The mass yield of the system was determined to be between 15 and 30%, with approximately 3% of the initial dry mass ending up in the exhaust filter. The moisture content of the particles was found to be between 4.9 and 11.1% and the mean size ranged between 1.2 and 1.6 μm. Particulate morphologies were observed to be mostly spherical with some ‘divots’ present on the surface. Lastly, the encapsulation efficiency determined by absorbance assay was approximately 40%. Particles produced from a 2% alginate feed were further assayed by determining the release of insulin in simulated gastrointestinal conditions and looking at the insulin and alginate distribution within spray dried particles. A steep release profile was observed in the first 120 min of the simulation in a gastric pH of 1.2 and a longer, more sustained release is observed in intestinal conditions, where an additional 20% of the total insulin in the particles is released over 600 min. Fluorescent labels revealed that insulin and alginate are concentrated towards the periphery of the particles. The residual bioactivity of insulin was assessed by an in vitro bioactivity assay, which was developed using Fast Activated Cell Based ELISA (FACE™) AKT kits specific for phosphylated AKT. The bioactivity of insulin in the particles after spray drying was determined to be 87.9 ± 15.3%. / Thesis (Master, Chemical Engineering) -- Queen's University, 2009-09-20 20:32:29.103

This thesis work aims to improve the thermal stability of vesicular stomatitis virus (VSV) through spray drying and investigates differences in thermal stability in a matrix between enveloped and non-enveloped viral vectors. The spray drying process was used to dry and encapsulate the VSV vector within the glassy amorphous phase of a matrix of carbohydrate excipients, which imparted increased thermal stability. Viral activity was maintained when the powders were stored for 30 days at 37 °C, in contrast to the liquid control that lost all activity after 15 days. The best excipients for enhancing thermal stability of VSV were trehalose and a 3:1 blend of trehalose and dextran. Immunogenic response from the spray dried trehalose-VSV particles was detected through an in vivo study with Female BALB/c mice after storing the vaccine for 15 days at 37 °C. Two enveloped viral vectors, VSV and influenza, and a non-enveloped viral vector, human type 5 adenoviral vector (AdHu5) were spray dried with the same formulations to observe how excipients enhance thermal stability and encapsulate the different groups of viruses. The thermal stability of both enveloped viral vectors was enhanced the most when spray dried with trehalose or a 3:1 trehalose/dextran blend, and exhibited the greatest activity loss when spray dried with a mannitol/dextran blend, determined by in vitro TCID50 assays measuring GFP expression. Conversely, the best performing excipient formulation for the non-enveloped viral vector was a mannitol/dextran blend. This led to the hypothesis that the encapsulation mechanism differs between the two groups of viruses. The glass transition temperature (Tg) of the spray dried formulations (without virus) stored at 37 °C for 10 days was measured to infer the potential molecular mobility of the viral vector within the primarily amorphous matrix. Formulations containing dextran exhibited the smallest depression in Tg after storage, indicating minimal increase in molecular mobility over time. RNA leakage from aged spray dried powders containing VSV was quantified to investigate the encapsulation mechanism of enveloped viral vectors and followed a similar trend to the in vitro activity tests. VSV with poor performing excipients yielded the least detectable RNA/pfu after three days of storage at 45°C, suggesting that the lipid envelopes ruptured and released viral RNA which denatured during storage. This work demonstrates that the VSV vector can be thermally stabilized through spray drying but highlights that different carbohydrates interact differently with enveloped versus non-enveloped viral vectors, providing a guideline for future work with the advent of new vaccines. / Thesis / Master of Applied Science (MASc) / Most vaccines lose their activity when stored at room temperature and therefore are required to be stored at temperatures between 4 °C and -80°C to maintain vaccine potency. The refrigeration required to meet these temperatures is costly and limits the distribution of vaccines to resource poor areas in the world where refrigeration technology is uncommon. Spray drying, a process that rapidly dries a solution to form a dry powder, was used to trap vaccines within a sugar matrix to protect the vaccine from heat and structural changes that would otherwise deactivate it. The spray dried powders demonstrated higher thermal stability than liquid samples, which decreases the need for refrigeration during transportation and storage. Thermal stability trends for spray dried powders produced with various sugars and categories of viruses are presented.

Spray drying is the process by which the solids are recovered from a liquid solution or slurry by spraying the liquid into a stream of heated drying gas under certain conditions which permit recovery of a dry, granular product. Some of the factors which govern the characteristics of the product are: (a) the physical and chemical nature of the substance; (b) the amount of drying gas used; (c) the size of the droplets; (d) the temperature of the inlet drying gas; (e) the concentration of the solution; (f) the temperature of the solution; and (g) the rate of solidification of the substance. It was the purpose of this investigation to design and construct an adequate, laboratory-size spray dryer, together with the necessary auxiliary equipment, and to study the effects of variation in the degree of atomization, the amount of drying air, and the concentration of the solution on the drying conditions and the physical characteristics of the dried material. Only inorganic materials were used in this investigation. Preliminary tests were made with magnesium sulfate and sodium sulfate in order to get the dryer to function properly. Four tests were made, using sodium sulfate solutions, in order to determine the effect of the degree of atomization. Three tests were made, using sodium sulfate solutions, in order to determine the effect of the amount of drying air. Five tests were made, using sodium chloride solutions, in order to determine the effect of concentration of solution. One test was made using a ten per cent (by weight) solution of sodium bicarbonate. The physical characteristics of the dried materials determined were total water content and moisture content, bulk density, particle size, and the nature of the particles. It was found that magnesium sulfate dried as a mixture of hydrates; that the two-fluid nozzle used did not give much variation in the degree of atomization above an air pressure of 20 pounds per square inch gauge; that the moisture content of the spray-dried sodium sulfate distinctly varied with the amount of drying air, but the bulk density or particle size did not; that the bulk density and moisture content of the spray-dried sodium chloride did not vary appreciably with the concentration of the solution dried, while the particle size seemed to vary erratically with the concentration; and that sodium bicarbonate solution when spray dried gave sodium bicarbonate which was to some extent decomposed to sodium carbonate. / Master of Science

Compostos de origem vegetal podem apresentar inúmeros efeitos benéficos à saúde, havendo, entretanto, uma necessidade de desenvolver formulações que permitam viabilizar seu uso farmacêutico, alimentício, nutracêutico ou cosmecêutico. Syzygium aromaticum, conhecido popularmente como cravo da Índia, é uma espécie vegetal aromática com marcada atividade antioxidante, analgésica e antimicrobiana. A baixa solubilidade e estabilidade química, assim como a volatilidade dos principais compostos associados às atividades biológicas da planta justificam o desenvolvimento de formulações que melhorem suas propriedades físico-químicas e características de liberação. Formulações lipídicas têm sido cada vez mais usadas para o aumento da solubilidade de compostos no trato gastrointestinal e para o aumento da biodisponibilidade. O principal objetivo deste projeto foi investigar a produção de formulações lipídicas sólidas contendo compostos bioativos de S. aromaticum e avaliar o efeito da composição da formulação e das variáveis operacionais nas propriedades físico-químicas das partículas, estabilidade e permeação intestinal in vitro. O processo de extração dos compostos a partir da matéria-prima vegetal também foi estudado. A formulação lipídica foi otimizada com respeito ao tipo e a proporção dos lipídeos, do emulsificante e dos carreadores de secagem. Os processos de emulsificação e secagem também foram criteriosamente estudados. Os resultados mostraram que a composição da formulação teve efeitos significativos nas propriedades físico-químicas do produto e no desempenho da secagem. A formulação lipídica otimizada mostrou ser mais estável que a formulação não lipídica em condições de armazenamento de alta umidade. Com relação à permeação intestinal in vitro, utilizando eugenol como marcador, não foram observadas diferenças significativas entre estas duas formulações. Este projeto permitiu obter informações relevantes sobre a secagem por spray drying de formulações lipídicas contendo extratos vegetais. Esta rota tecnológica representa uma estratégia interessante na obtenção de formulações lipídicas estáveis que promovam o aumento da biodisponibilidade oral de compostos bioativos. / Plant-derived compounds can provide important benefits to human health. However, these compounds should be properly formulated in order to facilitate their pharmaceutical, nutraceutical, food or cosmetic applications. Syzygium aromaticum commonly known as Indian clove, is an aromatic tree with antioxidant, antimicrobial and analgesic properties. The poor water solubility and the volatility of the compounds associated to the biological activities, justify the development of formulations that improve its physicochemical and release properties. Lipid based formulations have gained special attention for oral delivery due to the improvement of solubility in the intestinal tract and increase of bioavailability. The main objective of this project was to investigate the production of solid lipidic formulations containing bioactive compounds of S. aromaticum and to test the effect of the formulation composition and the process variables on the physhicochemical properties of the particles, stability and in vitro intestinal permeation. The extraction methods of the compounds from the plant were also studied. The lipid formulation was optimized with regard to the type and proportion of the solid lipid, the surfactant and the drying carrier. The emulsification and the drying processes were carefully evaluated. Results showed that the formulation composition had significant effects on the physicochemical properties of the product and on the drying performance. The optimized lipid formulation was more stable than the formulation without lipids in high humidity stress storage conditions. With regard to the in vitro intestinal permeation using eugenol as marker compound, not significant differences were observed between the samples. This project allowed to obtain relevant information about the spray drying process of lipid formulations containing plant extracts. This technique could be an interesting strategy to obtain stable lipid formulations than enhance the oral bioavailability of bioactive compounds

O presente trabalho teve como principal objetivo o estudo da interação de complexos de cobre e de zinco contendo fármacos anti-inflamatórios não-esteróides (FAINEs) com o biopolímero quitosana. Foram preparados alguns complexos já reportados na literatura como os complexos de cobre com indometacina, ibuprofeno e naproxeno e os complexos de zinco com indometacina, para os quais foram incluídos estudos adicionais de caracterização. Também foram sintetizados complexos inéditos de cobre com cetoprofeno e de zinco com ibuprofeno e meloxicam. Estudou-se a interação de alguns dos metalofármacos com microesferas de quitosana reticuladas com glutaraldeído, preparadas pelo método de coacervação. Investigou-se também materiais obtidos por spray-drying, resultantes da interação dos metalofármacos de Cu-ibuprofeno e Cu-indometacina, e do fármaco indometacina, com quitosana. Esses materiais foram submetidos a ensaios preliminares de avaliação macroscópica da lesão intestinal in vivo. Os compostos e materiais obtidos foram caracterizados por análise elementar, espectroscopia eletrônica, espectroscopia vibracional FTIR, difratometria de raios X de pó (DRX), e análise térmica (TG/DTG/DSC). / The present work aimed the study of interactions between copper and zinc complexes containing non-steroidal anti-inflammatory drugs with the chitosan biopolymer. Complexes already reported in the literature such as copper with indomethacin, ibuprofen and naproxen and zinc with indomethacin were prepared and additional characterization studies were performed. New complexes of copper and zinc with ketoprofen, ibuprofen and meloxicam were also synthesized. The interactions of some metallodrugs with microspheres of chitosan cross-linked with glutaraldeyde, prepared by the coacervation method were studied. Materials prepared by spray-drying method, resulting from the interactions of copper-ibuprofen and copper-indomethacin metallodrugs, and from the Indomethacin drug, with chitosan were also investigated. These materials were submitted to preliminary assays to evaluate the macroscopic intestinal damage in vivo. The compounds and materials were basically characterized by elemental analysis, electronic spectroscopy, FTIR vibrational spectroscopy, powder X-rays diffractometry, and thermal analysis (TG/DTG/DSC).

A Lippia sidoides é planta largamente difundida nas práticas da medicina popular no Brasil, sendo utilizada como anti-séptico de uso tópico, fato justificável pela presença de timol. Como estratégia para a obtenção de novos produtos com atividade antimicrobiana, a partir de fonte vegetal, o presente estudo visou o desenvolvimento tecnológico de extratos secos padronizados e a encapsulação do óleo essencial dessa planta, através da técnica de secagem por atomização (spray drying). Para obtenção dos extratos secos padronizados, utilizou-se metodologia capaz de avaliar a qualidade da matéria-prima vegetal, das ações de transformação, dos produtos intermediários e do produto final. A solução extrativa foi obtida a partir das folhas secas e moídas dessa planta, empregando-se o método de extração por maceração dinâmica, avaliando-se alguns fatores que influenciavam sua eficiência. A solução extrativa selecionada foi submetida à secagem por atomização, investigando-se a combinação de adjuvantes tecnológicos sobre o desempenho do equipamento e sobre características físico-químicas do produto obtido. Além disso, avaliou-se a atividade antifúngica in vitro dos extratos secos, confirmando-se o efeito antimicrobiano dos mesmos. Para a encapsulação do óleo essencial de Lippia sidoides, utilizou-se a técnica de spray drying (método físico) e a inclusão molecular com -ciclodextrina (método químico) com subseqüente secagem por spray drying. Na microencapsulação por spray drying foi utilizado um conteúdo de óleo de 20 e 25% em relação ao material de parede. Como material de parede foram empregadas diferentes proporções de maltodextrina DE 10 e goma-arábica, sendo as emulsões de alimentação atomizadas até à concentração de 60% de sólidos totais. A eficiência da encapsulação foi avaliada através da quantidade específica de óleo essencial encapsulado nas micropartículas, sendo obtido valor máximo de 65%, dependente das condições experimentais empregadas. Observou-se existir teor de sólidos ótimo (50%) e relação entre o aumento da retenção de óleo total e as maiores concentrações de goma-arábica nas emulsões de alimentação, sendo que todas as micropartículas demonstraram atividade antifúngica. A inclusão molecular do óleo essencial, através de sua complexação com moléculas de -ciclodextrina exibiu eficiência de encapsulação de até 70%. As diferentes proporções de óleo essencial e -ciclodextrina testadas influenciaram esses resultados, sendo que menores retenções foram observadas quando maiores quantidades de óleo foram adicionadas às suspensões de alimentação. Pelas análises térmicas foi possível demonstrar a mais alta estabilidade térmica dos produtos encapsulados (micropartícula/complexo de inclusão) comparados ao óleo essencial original. Os dados adquiridos durante os estudos de desenvolvimento de produtos secos, a partir de Lippia sidoides, indicaram o potencial desses como agentes antimicrobianos naturais para fins medicinais, representando assim, alternativa para o aproveitamento da espécie vegetal pelo setor farmacêutico. / Lippia sidoides is an aromatic shrub widely used in a folk medicine in Brazil as local antiseptic, justified by thymol presence as the major constituent of its essential oil. As strategy for production of new antifungal herbal products, the present study aimed the technological development of Lippia sidoides standardized spray dried extracts as well as the encapsulation of its essential oil by spray drying/ molecular inclusion. In order to obtain the standardized dried extract, process control parameters of manufacturing operations were established and they were continuously tracked to provide reproducibility from batch-to-batch and to assure productsquality. Extraction (maceration) from Lippia sidoides leaves was used to produce thymol-containing liquid extracts. Optimal extraction conditions were determined and the selected extractive solution was spray dried. Effect of different carrier ratios on physicochemical and antifungal properties of dried extracts was evaluated. Lippia sidoides dried extract showed an important antifungal effect against the tested strains. Lippia sidoides essential encapsulation was carried out by spray drying technique (physical method) and molecular inclusion within -cyclodextrin (chemical method) followed by spray drying of the slurries in order to produce inclusion complex in a powder form. For microencapsulation by spray drying, maltodextrin DE 10 and gum arabic in different were used as carrier. Content of essential oil related to carrier was 20 and 25% in weight and the emulsions were atomized from 30% up to 60% of total solid concentration. Encapsulation efficiency was estimated through determination of the content of essential oil in the microcapsules and a maximum value obtained was 65%, depending on experimental parameters adopted. An optimal solid content of the encapsulating composition (50%) was observed. The increase of gum arabic amount in the infeed emulsion was related to the increase in the total oil retention in the microparticles. Antifungal activities of microparticles were evaluated, evidencing their potential as important antifungal agent. For inclusion complex formation between essential oil and -cyclodextrin, the encapsulation efficiency was up to 70%. The entrapment ability was influenced by the different essential oil: -cyclodextrin ratios tested. A decreasing tendency in the total oil content was observed, when the initial amount of added oil was increased. The greater thermal stability of the encapsulated products (microparticles/ inclusion complexes) in comparison to the original oil was confirmed by thermal analysis. The finding acquired during the development of Lippia sidoides dried products indicated their potential as natural antimicrobial agent for medicinal propose and provided evidences which support the use of such plant specimen by pharmaceutical industry.