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This study seeks to develop smart hydrogel formulations for injectable controlled drug delivery from Pluronics to enhance patients compliance, decrease side effects, reduce dose and frequency. A biocompatible copolymer, Pluronic F127 was probed as the main ingredient for the injectable systems owing its low gelation concentration and ease of modification the system properties through excipients addition. The matrix properties were studied through a series of thermal, rheological and structural (SAXS/SANS) experiments as a function of concentration and shear rate, covering both static and dynamic environments. It has shown that gelled viscosity (and structure) can be critically controlled by shear rate and the structures recorded do not match those predicted for sheared colloids. Two further Pluronics F68 and F108, were studied showing similar but shifted gelation properties to F127. Effects of additives were studied by introducing different Mw PEGs and a model hydrophobic drug ‘ibuprofen’ to a F127 20% formulation. PEGs addition effects on the system properties and gelation transition were largely dependent on the Mw used in the blend, which became more prominent with increasing chain length. Ibuprofen’s addition has resulted in reduced gelation temperature and smaller hard spheres without having a great effect on the system rheological properties compared to neat gels. Blends containing both additives PEG and ibuprofen exhibited a synergistic effect, where comparisons show that Ibuprofen had the largest effect on the blends lowering gelation boundaries and slightly increasing the size of the hard spheres indicating the necessity of full characterisation of the formulation with any API.

L’optimisation de l’incorporation et de la libération de principes actifs dans les produits formulés constitue un des enjeux majeurs des industries pharmaceutiques et cosmétiques. L'objectif principal de notre étude est de proposer un modèle prédictif de la diffusion de petites sondes au sein des émulsions concentrées. Pour cela, il a fallu considérer à la fois la formulation d’émulsions concentrées stables et leur caractérisation rhéologique et structurelle ainsi que la prédiction des paramètres de transfert des sondes au sein des émulsions concentrées. On entend par paramètres de transfert, tous les paramètres permettant de caractériser les différents mécanismes de transfert de sondes dans les émulsions concentrées pris en compte dans notre système, à savoir le coefficient de diffusion dans les phases continue et dispersée, le coefficient de transfert à l’interface eau/huile, le coefficient de partage à l’équilibre de la sonde entre les deux phases de l’émulsion. Une nouvelle approche de caractérisation de la structure des émulsions concentrée a permis l’obtention des paramètres importants de structure (taille des gouttes et épaisseur du film de la phase continue). L’étude détaillée des mécanismes et processus diffusionnels est réalisée avec la prise en compte des résultats liés à la caractérisation structurelle du système d’étude. Ainsi, un modèle de diffusion fondé sur une approche phénoménologique est proposé pour prédire l'évolution des profils de concentration de la sonde dans les émulsions concentrées. Les cinétiques expérimentales de libération des sondes sont comparables à celles simulées par le modèle sans paramètres ajustables. Cette comparaison montre une bonne adéquation entre le modèle de diffusion et l’expérience / In the field of controlled release technology for new drugs, models that can predict its delivery during application are important for device design. The main objective of this work is to develop a predictive model able to describe the drug delivery from highly concentrated water-in-oil emulsions. These systems consist of deformed droplets dispersed in a continuous film. Their structure’s characteristics make them favourable for their use as releasing devices. A combination of different transfer mechanisms has been implemented in a mathematical model in order to simulate release experiments under different operating conditions (volume fraction, oil/surfactant ratio). A sensitivity analysis has been performed to point out the most relevant parameters affecting the drug’s release: drug partition and diffusion coefficients. Partition coefficient of the drug for different surfactant concentrations has been obtained through a predictive thermodynamic model UNIFAC, and the diffusion coefficient using Chang and Wilke equations in addition to the Stefan- Maxwell development. An original and simple technique has been used to determine indirectly the mean droplet size of the concentrated emulsions, through measurements of continuous phase’s thickness by analysis of incoherent polarized steady light transport through emulsion samples. In a general view, the diffusion model proposed for small drug diffusion in concentrated emulsions, which was first proposed for diluted emulsions, predicts successfully the evolution of mandelic acid concentrations during release experiments undertaken in perfect sink conditions

Doctor of Philosophy / Department of Chemistry / Viktor Chikan / The research work in this thesis aims at investigating the basic physic-chemical properties of magnetic and metal nanoparticles (NPs) for biomedical applications such as magnetic hyperthermia and controlled drug release. Magneto-plasmonic properties of magnetic NPs are important to evaluate potential applications of these materials. Magnetic property can be used to control, monitor and deliver the particles using a magnetic field while plasmonic property allows the tracking of the position of the particles, but aggregation of NPs could pose a problem. Here, the aggregation of NPs is investigated via the Faraday rotation of gold coated Fe[subscript]2O[subscript]3 NPs in alternating magnetic fields. In addition, the Faraday rotation of the particles is measured in pulsed magnetic fields, which can generate stronger magnetic fields than traditional inductive heaters used in the previous experiments. In the second project, the formation of protein-NPs complexes is investigated for hyperthermia treatment. The interactions between gold and iron-platinum NPs with octameric mycobacterial porin A from Mycobacterium smegmatis (MspA) and MspA[superscript])cys protein molecules are examined to assemble a stable, geometrically suitable and amphiphilic proteins-NPs complex. Magnetic NPs show promising heating effects in magnetic hyperthermia to eliminate cancer cells selectively in the presence of alternating magnetic field. As a part of investigation, the heating capacity of a variety of magnetic NPs and the effects of solvent viscosity are investigated to obtain insight into the heating mechanism of these particles. Finally, the controlled drug release of magnetic NPs loaded liposomes by pulsed magnetic field is investigated. The preliminary data indicate about 5-10% release of drug after the application of 2 Tesla magnetic pulses. The preliminary experiments will serve as the initial stage of investigation for more effective magnetic hyperthermia treatment with the help of short magnetic pulses.

Cristais líquidos são sistemas que se apresentam em um estado intermediário entre o estado sólido e líquido. A monoleína é um lipídio polar com capacidade de formar diferentes tipos de cristais líquidos liotrópicos na presença de água, caracterizados como fase lamelar, cúbica e hexagonal. Devido à capacidade de controlar a liberação dos fármacos incorporados e às propriedades mucoadesivas, estes sistemas são considerados potenciais veículos para a liberação controlada de fármacos na mucosa bucal. Sabendo que o desenvolvimento da cárie e doença periodontal está relacionado com a formação do biofilme, é necessário seu controle e prevenção para manutenção da saúde bucal. Dentre os agentes químicos disponíveis para prevenir e/ou diminuir a formação do biofilme, cloreto de cetilpiridínio (CCP), polihexametileno biguanida (PHMB) e Triclosan® têm sido amplamente utilizados. Em vista disso, o objetivo deste estudo foi desenvolver e caracterizar sistemas líquido-cristalinos de fase lamelar e cúbica formados por monoleína e água contendo antimicrobianos com aplicabilidade bucal. Os sistemas foram desenvolvidos usando monoleína e água e os antimicrobianos avaliados foram o CCP, o PHMB e o Triclosan®. A formação das fases líquido-cristalinas com e sem a presença de cada fármaco estudado foi identificada por microscopia de luz polarizada. Além disso, foi avaliado o intumescimento dos sistemas contendo os fármacos estudados após contato com saliva artificial; a atividade antimicrobiana e o perfil de liberação in vitro, bem como o tempo de permanência e a força de mucoadesão ex vivo em mucosa de bochecha de porco. Foi possível obter os sistemas líquido-cristalinos para os fármacos avaliados, e o intumescimento de todos os sistemas foi caracterizado como cinética de segunda ordem. Os resultados do perfil de liberação e da atividade antimicrobiana in vitro para PHMB e Triclosan® foram favoráveis para aplicação bucal, no entanto, o CCP não é adequado para veiculação neste sistema. O perfil de liberação dos fármacos à partir desses sistemas foi influenciado pelas propriedades físico-químicas e concentração dos fármacos, bem como pelo intumescimento. Ainda, a fase lamelar apresentou maior tempo de permanência que a fase cúbica e a força de mucoadesão média da fase lamelar foi de 1,02 ± 0,50 N e da fase cúbica foi de 0,45 ± 0,10 N. Logo, os sistemas líquido-cristalinos de monoleína e água são um interessante veículo com potencial para liberação controlada dos antimicrobianos PHMB e Triclosan® na mucosa bucal com o objetivo de otimizar a eficácia destes fármacos. / Liquid crystals are systems which are in an intermediate state between solids and liquids. Monoolein is a polar lipid capable of forming different types of lyotropic liquid crystals in aqueous environment, which can be classified into lamellar, cubic and hexagonal mesophases. Due to its ability to control drug release and its mucoadhesive properties, these systems have been considerated as potential vehicle to control drug release on buccal mucosa. Based on the knowledge that the development of caries and periodontal disease is related to the biofilm formation, it is necessary their control and prevention to maintain the buccal health. Among the available chemical agents to prevent and/or reduce biofilm formation, cetylpyridinium chloride (CPC), polyhexamethylene biguanide (PHMB) and Triclosan® have been widely used. Based on these facts, the objective of this study was to develop and characterize liquid-crystalline systems formed by monoolein and water, containing antimicrobial agents with buccal applicability. The systems were developed using monoolein and water, and the antimicrobial agents evaluated were CCP, PHMB and Triclosan®. The liquid-crystalline phases with and without the presence of each drug was identified by polarized light microscopy. Furthermore, it was evaluated the swelling of the systems containing the drugs studied after contact with artificial saliva; the in vitro antimicrobial activity and its release profile, as well as the residence time and ex vivo mucoadhesion strength on pig cheek mucosa. It was possible to obtain liquid-crystalline phases for all drugs, and the swelling of all systems was characterized according to second-order kinetics. The results of release profile and antimicrobial activity in vitro to PHMB and Triclosan® were favorable for buccal application, however CCP is not suitable to be released from these systems. The drug release profile from these systems was influenced by the physicochemical properties and loading of the drugs, as well as by swelling. Furthermore, the lamellar phase showed greater residence time that the cubic phase and the mucoadhesion strength average of lamellar phase was 1.02 ± 0.50 N and for cubic phase was 0.45 ± 0.10 N. Thus, the liquid crystalline systems forming by monoolein and water are an interesting vehicle with potential to control release of the PHMB and Triclosan® on the buccal mucosa in order to optimize the drug effectiveness.

The objective of this research is to explore the use of ionic liquds in crystal engineering and drug delivery. Ionic liquids have a wide range of applications in pharmaceutical field due to their unique physicochemical propertie ssuch as chemical, thermal stability, low melting point, nonvolatility, nonflamability, low toxicity and recyclability which offer unique and interesting potential for pharmaceuitcal applications. Currently, many research groups are working on the development of ionic liquids to use in this field but there is need to develop systematic understanding about new techniques for synthesis and applications of ionic liquids to obtain new crystal form and potential of drug ionic salts. The synthesis of fifteen phosphonium ionic liquids under microwave irradiation and their physicochemical properties was investigated. The reaction time was significantly reduced compared to conventional methods, and higher yields were reported. The crystallisation of pharmaceutical drugs such as sulfathiazole, chlorpropamide, phenobarbital and nifedipine were investigated using imidazolium ionic liquids. The supramolecular complex of sulfathiazole and phenobarbital with imidazolium ionic liquids and polymorphic change in chlorpropamide was achieved. The ionic liquids provides unique environment for the crystallisation. The imidazolium salts of ibuprofen and diclofenac were synthesised and evaluated for physicochemical properties and their pharmaceutical performances especially transdermal absorption. The investigation of physicochemcal properties and pharmaceutical performance of imidazolium drug salts indicated opportunity to optimise lipophilicity and other physicochemical properties such as molecular size, osmolality, viscosity to achieve desired skin deposition and permeation. This study will provide a new approach to design of new drug salts develop using the interdisciplinary knowledge of chemical synthesis and drug delivery.

Esse trabalho apresenta resultados de modificações estruturais, caracterizações e aplicações de derivados de quitosana como carreadores de fármacos. Derivados anfifílicos de quitosana, contendo grupos hidrofílicos e grupos hidrofóbicos, foram caracterizados por técnicas de espectroscopia de ressonância magnética nuclear (RMN1H), espectroscopia na região do infravermelho (IV), espectroscopia na região do UV-Vis, técnicas termoanalíticas (termogravimetria (TGA), termogravimetria derivada (DTG), análise térmica diferencial (DTA) e calorimetria exploratória diferencial (DSC)), fluorescência no estado estacionário, espalhamento dinâmico de luz (DLS) e microscopia eletrônica de transmissão (MET). Os resultados de caracterização mostraram que as sínteses propostas foram realizadas com sucesso. A determinação da concentração de agregação crítica (CAC) e os estudos de DLS e MET confirmam que os derivados se auto-organizam em solução aquosa formando agregados com diâmetros variando entre 230 a 500 nm. Esses valores, associados aos potenciais zeta obtidos (+14,1 mV a +44,8 mV), demonstram que os agregados são estáveis em solução, característica fundamental para aplicação no transporte de fármacos. A capacidade de encapsulamento do fármaco quercetina por esses derivados foi avaliada por estudos de incorporação utilizando a espectroscopia UV-Vis. Os resultados obtidos demonstraram que o comportamento dos derivados depende de parâmetros como o grau de hidrofilicidade e grupo hidrofílico, grau de hidrofobicidade e pH do meio de encapsulamento, possibilitando controlar a quantidade de fármaco contida nos carreadores. A atividade biológica dos agregados formados pelos derivados de quitosana foi testada em células de adenocarcinoma de mama (MCF-7) e os resultados indicaram baixa toxicidade dos carreadores, além de potencialização do efeito terapêutico do fármaco. Estudos de microscopia confocal de varredura a laser evidenciaram que agregados marcados com proteína verde fluorescente com afinidade por quitosana (CAP-sfGFP) foram internalizados pelas células MCF-7. Resultados de hemocompatibilidade indicaram que os polímeros apresentam baixa destruição de glóbulos vermelhos do sangue e liberação de hemoglobina. Portanto, esses derivados possuem características adequadas para aplicação no transporte e liberação controlada de fármacos. / This thesis presents results of structural modifications, characterizations and applications of chitosan derivatives as drug carriers. Amphiphilic derivatives of chitosan containing hydrophilic and hydrophobic groups were characterized by nuclear magnetic resonance spectroscopy (RMN1H), infrared spectroscopy (IV), uv-vis spectroscopy, thermoanalytical techniques (thermogravimetry (TGA), derivative thermogravimetry (DTG), differential thermal analysis (DTA) and differential exploratory calorimetry (DSC)), fluorescence, dynamic light scattering (DLS) and transmission electron microscopy (MET). The characterization results showed that the proposed syntheses were successfully performed. The critical aggregation concentration (CAC), DLS and MET studies confirmed that the derivatives self-assembled in aqueous solution forming aggregates with diameters ranging from 230 to 500 nm. These values, associated with zeta potentials (+14.1 mV to +44.8 mV), demonstrate that the aggregates were stable in solution. The ability to encapsulate quercetin by these derivatives was assessed by incorporation studies using UV-Vis spectroscopy. The results showed that the behavior of the derivatives depends on parameters such as the degree of hydrophilicity and hydrophilic groups, degree of hydrophobicity and pH of the encapsulation medium. The biological activity of the aggregates formed by the chitosan derivatives was tested in breast cancer cells (MCF-7) and the results indicated low toxicity of the carriers, in addition to improving the therapeutic effect of the drug. Confocal laser scanning microscopy studies showed that aggregates stained with chitosan-affinity protein (CAP-sfGFP) were internalized by MCF-7 cells. Hemolysis assays showed good hemocompatibility of chitosan derivatives. Therefore, the derivatives have suitable characteristics for application as drug delivery systems.

Transdermal drug delivery systems (TDS) are pharmaceutical devices that are designed to deliver specific drugs to the human body by diffusion through skin. The TDS effectiveness suffers from crystallization in the patch when they are kept in storage for more than two years. It has been reported that there are two types of crystals in the patch: needle and aggregate, and growth of drug crystals in TDS generally occurs only in the middle third of the polymer layer. In our study, fluorescence microscopy, EDS (SEM) and Raman microspectroscopy were used to further characterize the crystals. The results show that the needle crystals most probably contain estradiol and acrylic resin conjugate. The FTIR spectrum of the model sample proved the occurrence of a reaction between estradiol and acrylic resin. Crystal growth in an unstressed matrix of a dissolved crystallizable drug component was simulated using a kinetic Monte Carlo model. Simulation using Potts model with proper boundary condition gives the crystals in the middle of matrix in the higher temperature. Bond fluctuation model is also being implemented to study representative dense TDS polymer matrix. This model can account for the size effect of polymer chain on the crystal growth. The drug release profile from TDS was also studied by simulating the diffusion of drug molecules using Monte Carlo techniques for different initial TDS microstructure. The release rate and profile of TDS depend on the dissolution process of the crystal. At low storage temperature, the grains are evenly distributed throughout the thickness of the TDS patch, thus the release rate and profile is similar to the randomly initiated system. Further work on stress induced crystallization is currently under development. Although the study was specifically done for drug in a polymer medium, the techniques developed in this investigation is in general applicable to any constrained crystallization in a polymer medium.

Chemotherapy is one of the most important treatments for cancer. However, systemic toxicity, drug resistance and unstable kinetics of the drug in the blood are serious problems of chemotherapy. The use of biodegradable polymers for controlled release of anticancer drugs has gained popularity in recent years. Controlled release of drugs from polymeric carriers has some advantages such as improvement in the efficiency of treatment, reduction in systemic toxicity and prevention of the drug resistance that is developed by the cancer cells. In this study, poly(D,L-lactide-co-glycolide) microparticles were used as carriers for the controlled release of all-trans-Retinoic acid, tamoxifen, tamoxifen citrate and idarubicin. It was aimed to prepare a drug carrier system for controlled release of hydrophobic anticancer drugs. The empty and drug loaded poly (D,L-lactide-co-glycolide) microparticles were prepared by solvent extraction/evaporation technique with single emulsion (oil/water). Optimized microparticles were characterized by using inverted light microscopy and scanning electron microscopy to examine their morphology and sizes. Drug content of microparticles and the amount of released drug were determined spectrophotometrically. In vitro toxicity of the microparticles on MCF-7 human breast cancer cells was investigated. It was revealed that the microparticles were smooth and spherical in shape. Their sizes differed in the range of 2-20 &micro / m. atRA-loaded microparticles showed approximately 90% encapsulation efficiency and it was confirmed that changing in drug/polymer ratio affected the extend of drug content. Increase in drug content caused a slower release pattern. Moreover, although the empty microparticles caused some toxicity, atRA-loaded PLGA microparticles showed slight cell growth inhibition.

In tissue engineering applications, use of biodegradable and biocompatible materials are essential. As the tissue regenerate itself on the material surface, the material degrades with enzymatic or hydrolytic reactions. After a certain time, natural tissue takes the place of the artificial support. Poly(&epsilon / -caprolactone) (PCL) is one of the preferable polymers used in the restoration of the bone defects due to its desirable mechanical properties and biocompatibility. Addition of inorganic calcium phosphate particles in PCL structures can improve the mechanical properties as well as osteoconductivity / and presence of an antibiotic can prevent infection that may occur at the defect site. In this study, three forms of biodegradable hard tissue supports which are bone fillers, bone regenerative membranes and 3D scaffolds were designed and prepared. As biodegradable bone fillers, composite microspheres containing gelatin and &beta / -tricalcium phosphate (&beta / -TCP) were prepared and characterized. Synthesized &beta / -TCP particles were coated with gelatin at different weight ratios and the effects of &beta / -TCP/Gelatin ratio on the morphology of the microspheres were evaluated. Also, a model antibiotic, gentamicin, was loaded to these microspheres and release behaviours of the drug and its antibacterial effect on E.Coli was determined. The selected composition of these microspherical bone fillers were used as additives in the preparation of bone regenerative membranes and scaffolds. For this purpose, microspheres were added into PCL solution and processed by either solvent casting or freeze-drying in order to prepare bone regenerative membranes or scaffolds, respectively. For every material, the ratio of constituents (microsphere and PCL) was altered in order to obtain optimum properties in the resulted hard tissue support structure. The effects of the ratio of the microspheres to PCL in terms of morphological, mechanical and degradation properties of composite films, as well as in vitro antibiotic release and antibacterial activities against E.Coli and S.Aureus were investigated. For scaffolds, the effects of the ratio of the microspheres to PCL on the morphological, mechanical, pore size distribution, degradation properties and in vitro antibiotic release were examined.