An inclusion complex between β-cyclodextrin and insoluble guest compounds has been reported by several researchers. The main purpose of forming an inclusion complex between β-CD and sparingly soluble guests is to enhance the guest’s solubility and mask its undesirable properties. Preliminary studies have shown that when conjugated with target-specific moieties, these inclusion complexes can be used in pharmaceutical applications for drug delivery. β-Sitosterol, a plant sterol, has been well documented to reduce tumor cell growth and migration as well as exhibit apoptotic characteristics. An issue with this plant sterol and most pharmaceutical compounds is their lack of solubility. In this study, we propose that an inclusion complex will enhance the solubility of this sterol and change the physicochemical properties of the sparingly soluble guest. We first prepared the β-CD:β-Sitosterol inclusion complex and characterized the samples in both solid and solution state. The complex was characterized using FT-IR, DSC, SEM and NMR. IR studies of the inclusion complex and physical mixture revealed changes in the characteristic peaks of the inclusion complex suggestive of the formation of a new compound. 1HNMR studies revealed an upfield resonance shift of β-CD internal protons (H3 and H5) as an equal molar ratio of β-Sitosterol is introduced into the β-CD mixture. 2D NOESY NMR studies suggest that the initial sites of interaction of β-CD and β-Sitosterol occur between the aliphatic tail of β-Sitosterol and H3 of β-CD. 2D ROESY NMR reveals that the cyclic head of β-Sitosterol also interacts with the cavity of β-CD suggesting that β-Sitosterol may be completely encapsulated inside β-CD’s cavity. From these initial studies, we hypothesize that the β-CD-PEG-FA will facilitate absorption of β-Sitosterol and increase the drug delivery vehicle’s solubility as a whole. Since most tumor cells over-express folic acid, inclusion of folic acid in the construct of the vehicle will direct these sterols to tumor sites. β-cyclodextrin-PEG, a precursor to the bio-conjugate for antitumor delivery of sterols, was synthesized and characterized.

A controlled assembly of natural beta-cyclodextrin modified Au NPs mediated by dopamine is demonstrated. Furthermore, a simple and sensitive colorimetric detection for dopamine is established by the concentration-dependent assembly.

La reparation de defauts osseux par les techniques de l’ingenierie tissulaire osseuse (ITO) est consideree comme une alternative aux greffes conventionnelles. L’objectif de ce projet de these fut de developper des materiaux destines a servir de scaffolds pour le comblement et la regeneration osseuse, ces derniers etant sous la forme d’hydrogels injectables d’une part, et d’eponges, d’autre part. Ces deux types de materiaux ont ete obtenus par melange de chitosane (CHT, cationique), et de polymere de cyclodextrine reticule par l’acide citrique (PCD, anionique), interagissant via des liaisons ioniques et formant des complexes polyélectrolytes. La premiere partie de la these a ete consacree au developpement et caracterisation d’une eponge CHT/PCDs qui a ete chargee avec le facteur de croissance de l’endothelium vasculaire (VEFG) dans le but de favoriser sa vascularisation. Le second volet de la these a eu pour objectif d’optimiser la formulation d’un hydrogel injectable destine a la chirurgie mini-invasive, compose de CHT et de PCD sous sa forme soluble (PCDs) et insoluble (PCDi) [CHT/PCDi/PCDs]. L'etude a ete concentree sur l’optimisation et la caracterisation des proprietes rheologiques de l’hydrogel. Enfin, une etude prospective sur le developpement de l'hydrogel/eponge composite en ajoutant une phase minerale - l'hydroxyapatite (HAp) dans la formulation a ete realisee afin d'ameliorer les proprietes mecaniques et osteoconductrices.L’eponges CHT/PCDs a ratio 3 :3 a ete obtenue par lyophilisation des hydrogels et a subi un traitement thermique (TT) afin d’ameliorer leur stabilite par la formation des liaisons covalentes. L’eponge CHT/PCDs avec un TT a 160°C a montre des proprietes de gonflement eleve (~600%) et une biodegradation ralenti induite par le lysozyme (~12% perte masse dans un mois). Sa microstructure, ses proprietes mecaniques de compression et sa cytocompatibilite avec deux types de cellules (pre-osteoblastes (MC3T3-E1) et endotheliales primaires (HUVECs) ont ete etudiees. Une porosite elevee (~87%) avec des pores interconnectes a ete observee par microtomographie de rayons X, ainsi qu’une bonne adhesion et colonisation cellulaire au sein de l’eponge par microscopie electronique a balayage (MEB). Le VEGF a ete incorpore dans l’eponge, et son profil de liberation a ete suivi, ainsi que la bio-activite du VEGF libere. La liberation du VEGF a ete rapide pendant les trois premiers jours, puis ralenti jusqu'a devenir non-detectable par la methode ELISA jusqu’a 7 jours. Le VEGF libere pendant les deux premiers jours a montre un effet pro-proliferation et pro-migration significatif sur les HUVECs.Les hydrogels injectables de CHT/PCDi/PCDs a differents ratios ont ete optimises et caracterises en fonction de leurs proprietes rheologiques, leur injectabilite, et leur cytotoxicite. L’impact de l’ajoute du PCDi dans l’hydrogel a ete clairement observe par analyses rheologiques Ainsi, l'hydrogel CHT/PCD, compose a parts egales de PCDi et de PCDs, a demontre le meilleur compromis entre stabilite structurelle, proprietes rheofluidifiantes et autoreparantes, et injectabilite. En plus, l’hydrogel a montre une excellente cytocompatibilite vis-avis les cellules pre-osteoblastes MC3T3-E1.Bases sur la formulation optimisee, l’HAp a ete incorporee a differentes concentrations dans l’hydrogel. L’ajout de la phase minerale n’a pas perturbe la formation ni la stabilite structurelle des hydrogels, mais a ameliore les proprietes viscoelastiques. Les eponges composites, elaborees par lyophilisation de ces hydrogels, ont montre que les particules de HAp etaient dispersees de maniere homogene dans la structure macroporeuse de l'eponge. Ces resultats encourageants ont montre qu'il etait possible de fournir un hydrogel injectable ou une eponge composite comme scaffold pour l’ITO [...] / Repair of bone defects by bone tissue engineering (BTE) methods is considered as an alternative to conventional grafts. The aim of this PhD project was to develop two types of BTE scaffolds for bone regeneration: one is in the form of injectable hydrogel, and the other is in the form of sponge. Both scaffolds based on the formation of polyelectrolyte complexes by mixing chitosan (CHT, cationic) and polymer of cyclodextrin (PCD, anionic). Besides developing the sponge scaffold, the vascularization of 3D scaffold (a challenge of BTE) was specially investigated in the first part of the work, for which vascular endothelial growth factor (VEFG) was loaded on the CHT/PCDs sponge to promote the vascularization. The second part of the thesis was dedicated to the elaboration of an injectable CHT/PCD hydrogel, which was intended for minimally invasive surgery. The formulation optimization of hydrogel was performed by tuning the composition ratios of two PCD components: soluble-form PCD (PCDs) and insoluble-form PCD (PCDi), in order to better reach the specific requirement (e.g. rheological properties) of injectable hydrogel for regenerative medicine. Finally, a prospective study on developing the composite hydrogel/sponge by adding a mineral phase - hydroxyapatite (HAp) in the formulation was realized to improve the mechanical and osteoconductive properties.CHT/PCDs sponges were obtained by freeze-drying the hydrogels CHT/PCDs 3:3. The thermal treatment (TT) at different temperatures was further applied on the sponge to improve the mechanical stability. The CHT/PCDs sponge treated at 160°C was opted for further study thanks to high swelling capacity (~ 600%) and moderate lysozyme-induced biodegradation rate in vitro (~ 12% mass loss 21 days). This sponge of choice was further evaluated for the microstructure, the mechanical property (compressive strength) and the cytocompatibility with pre-osteoblasts (MC3T3-E1) and endothelial cells (HUVEC). Results of X-ray microtomography showed a high porosity (~87%) in the sponge with interconnected pores. Good cell adhesion and in-growth (colonization) in the sponge were observed by scanning electron microscopy (SEM). After loading VEGF on the sponge, the release profile of VEGF and the bioactivity of released VEGF were thoroughly studied. It showed that the release of VEGF was rapid (burst) during the first two days, then slowed down up to non-detectable by ELISA method after 7 days. The released VEGF during the first two days showed a significant pro-proliferation and pro-migration effect on HUVECs.For the injectable CHT/PCDi/PCDs hydrogels, optimization of composition ratio was based on evaluating their rheological properties, injectability, and cytotoxicity. The beneficial effect of combining both PCDi and PCDs in the formula of the hydrogel was clearly observed on the properties of hydrogel. Namely, the CHT/PCD hydrogel, composed of equal quantity of PCDi and PCDs, demonstrated the best compromise between structural stability, shearthinning and self-healing properties, and injectability. An excellent cytocompatibility with preosteoblast cells (MC3T3-E1) was also confirmed for the hydrogel with this composition.Based on the optimized formulation, HAp was incorporated at different concentrations, which didn’t disturb the formation or the structural stability of the hydrogels, but improved the viscoelastic properties. The composite sponges, elaborated by lyophilization of these hydrogels, showed that the HAp particles homogeneously dispersed within the macroporous structure of the sponge. These encouraging results showed the feasibility of providing an injectable hydrogel or a composite sponge for BTE scaffold [...]

Ce projet de thèse s'inscrit dans une dynamique de développement des polyrotaxanes de cyclodextrines pour des applications biomédicales. L'objectif est d'obtenir, par une approche modulaire et convergente, des polyrotaxanes fonctionnalisés pour l'imagerie par microscopie optique dans le proche infrarouge et l'IRM. Une bibliothèque de cyclodextrines fonctionnalisées a été générée par CuAAC entre des fluorophores (BODIPY, Cyanine) ou un agent de contraste (monoamide-DOTA-Gd) et des ?-cyclodextrines mono- ou bis-azotures. Leurs propriétés d'auto-assemblage ont été étudiées sur un axe court et ont permis le développement de [3]rotaxanes fonctionnalisés pour l'IRM dont les expérimentations in vivo ont démontré l'apport bénéfique de la structure supramoléculaire pour les propriétés d'agent de contraste. L'extension de l'architecture aux polyrotaxanes multimodaux a été réalisée par l'utilisation d'un axe polyammonium. Une nouvelle classe d'axes anioniques a été développée avec l'étude cinétique et thermodynamique de l'enfilage sélectif d'une ou deux cyclodextrines sur des monomères diphosphates et montre l'intérêt des pseudo-bouchons phosphates pour le contrôle de la barrière d'activation par le pH. L'extension à une structure pseudopolyrotaxane est obtenue par la synthèse d'un poly(hexylène phosphate) et permet de valider l'utilisation du polymère pour la synthèse de composés fonctionnalisés. En perspective de ces développements, des voies de post-fonctionnalisation des polyrotaxanes, une nouvelle voie de synthèse par polymérisation de pseudo-rotaxanes et l'obtention d'une cyclodextrine pour le relargage contrôlé par stimuli acido-basiques sont abordées. / This PhD project is focused on the development of cyclodextrin-based polyrotaxanes for biomedical applications. The objective is to use a modular building-block approach to synthesize functionalized polyrotaxanes for NIR fluorescence and magnetic resonance imaging. A library of functionalized cyclodextrins was obtained by a versatile ‘click’ reaction between fluorescent probes (BODIPY, Cyanine) or contrast agent (GdDOTA-monoamide) and mono- or bis-azido α-cyclodextrins. Their self-assembly properties were first studied on short axles and allowed the development of functionalized [3]rotaxanes for MRI. In vitro and in vivo studies demonstrated the advantages of the supramolecular approach for the design of contrast agent with an enhancement of the relaxivities and better retention times in kidneys. The strategy was extended to obtain multimodal polyrotaxane architectures based on a poly(alkyl)ammonium thread. A new family of anionic threads based on alkylphosphate moieties was also developed. Thorough kinetic and thermodynamic studies revealed the ability of phosphates to act as pH-responsive stoppers enabling a selective threading of one or two cyclodextrins on small alkanediphosphate threads. Pseudopolyrotaxanes of α-CD were then obtained with poly(hexylene phosphate) and pave the way for the synthesis of functionalized ones. Finally, significant investigations in the post-functionalization of polyrotaxanes, polymerization of pseudo-rotaxanes as new synthetic pathway and pH-switchable rotaxane for controlled release were realized.

Les nanoMOFs – nanoparticles poreuses hybrides ont récemment été introduites dans le domaine de la vectorisation des médicaments afin de combiner les avantages de systèmes purement organiques ou inorganiques. Les nanoMOFs biodégradables et biocompatibles à base de trimesate de fer (MIL-100) ont été étudiées. Une méthode de synthèse «verte» a été développée et validée, ouvrant la voie à la production à grande échelle et à l’utilisation de ces matériaux pour des applications biologiques. Par la suite, les MIL-100 nanoMOFs ont été proposées comme potentiels vecteurs pour l’administration de médicaments hydrophiles antirétroviraux et anti-cancéreux, tels que les analogues nucléosidiques azydothimidines mono et triphosphates ou encore le Topotécan. Finalement, une nouvelle stratégie de modification de surface des nanoMOFs par leur recouvrement avec une couronne à base de dérivés de la β cyclodextrine, a été developpée. / Hybrid porous materials, as Metal Organic Frameworks (MOF) have been recently introduced in the drug delivery field in the attempt to combine advantages of the conventional “purely organic” or “purely inorganic” nanocarriers, such as important loading capability and controlled release.In this work the potential of biodegradable and biocompatible MOF nanoparticles made of iron trimesate (MIL-100 nanoMOF) has been investigated. A “green” synthetic procedure has been developed and validated, opening the way to the scale up synthesis of these materials for biological applications. MIL-100 nanoMOFs have been further applied to the delivery of hydrophilic drugs such as antiretroviral nucleoside analogues mono and triphosphate (azydothimidine mono and triphosphate) and the anticancer drug topotecan. Finally a new method of nanoMOFs surface modification, based on the nanoparticles coating with a β cyclodextrin-based extrenall shell, has been developed

O objetivo do presente trabalho foi obter complexos binários e ternários de sinvastatina (SNV) e ciclodextrinas (CDs) utilizando diferentes tipos de CDs, métodos de secagem e polímeros para selecionar aquele que proporcionam um maior aumento da solubilidade aquosa do fármaco. Inicialmente complexos com diferentes CDs, a α, β, γ, e hidroxi-propil-β (HPβCD) foram obtidos através da secagem em estufa. Foram empregados os seguintes ensaios para sua caracterização: solubilidade, DSC, TG e difração de raios X. Adicionalmente, foi realizada a modelagem molecular com simulações de dinâmica molecular. O complexo com γCD parece ser o mais adequado para a complexação com a SNV, pois, foi o mais estável (menor energia) na modelagem molecular, além de ter apresentado uma nova fase sólida na difração de raios X. Complexos de SNV, γCD ou HPβCD foram obtidos por diferentes métodos de secagem (estufa com circulação forçada de ar, coevaporação, liofilização e estufa a vácuo) e a caracterização foi realizada através da solubilidade, DSC, TG e difração de raios X. Todos os complexos melhoraram a solubilidade da SNV, mas quando comparados às respectivas misturas físicas, o ganho foi baixo. As curvas DSC e a difração de raios X indicam que, no máximo, pode ter ocorrido uma complexação parcial em alguns casos. O que se verifica é que mesmo o complexo que apresentou maior ganho de solubilidade (HPβCD obtido pela coevaporação), a complexação do não foi total. Complexos ternários de SNV, βCD e diferentes polímeros (polietilenoglicol 1500, polietilenoglicol 4000, povidona, copovidona, crospovidona, maltodextrina e hidroxipropil-metilcelulose) foram preparados utilizando-se a coevaporação. A caracterização dos complexos foi realizada através da solubilidade, DSC e TG. Para todos os complexos houve ganho de solubilidade, mas apenas quando foi utilizado a crospovidona e a maltodextrina, existe diferença significativa entre a solubilidade observada para a mistura física e aquela registrada para o complexo. As curvas DSC indicam que ainda existe fármaco na forma livre até mesmo nos complexos que apresentaram maior solubilidade, dessa forma, nenhum dos polímeros utilizados foi capaz de promover um complexação total da SNV. / The purpose of this study was to obtain binary and ternary complexes of simvastatin (SV) and cyclodextrins (CDs) using different types of CDs, drying methods and polymers, to select those that offer greater increase in aqueous solubility of the drug. Initially, different complexes with CDs, α, β, γ, and hydroxy-propyl-β (HPβCD), were obtained using oven drying. The following tests were performed for complexes´s characterization: solubility, DSC, TG and X-ray diffraction. Additionally, molecular modeling was performed with molecular dynamics simulations. The complex with γCD seems to be the most suitable for complexation with the SV, since it has been the most stable (lowest energy) in molecular modeling, and has presented a new solid phase in X-ray diffraction. Complex of SV, γCD or HPβCD were obtained by different drying methods (forced air circulation oven, co-evaporation, freeze drying and vacuum oven) and the characterization was performed by solubility, DSC, TG and X-ray diffraction. All the complexes improved the solubility of SV, but when compared to their physical mixtures, the gain is low. The DSC curves and X-ray diffraction indicates that, at most, a partial complexation may have happened in some cases. It was verified that even the complex that had greater increase in solubility (HPβCD obtained by co-evaporation), the complexation was not total. Ternary complexes of SV, βCD and different polymers (polyethyleneglycol 1500, polyethyleneglycol 4000, povidone, copovidone, crospovidone, maltodextrin and hydroxypropyl-methyl-cellulose) were prepared using the co-evaporation. The characterization of the complexes was performed by solubility, DSC and TG. For all complexes there was a gain of solubility, but only when crospovidone and maltodextrin were used, there was a significant difference between the solubility observed for the physical mixture and the complex. The DSC curves indicate that non comlexed drug is still present, even in the complexes that had higher solubility. Thus, none of the polymers was able to promote a total complexation of SV.

O nebivolol é um fármaco anti-hipertensivo, comercializado na forma de uma mistura equimolar dos enantiômeros RSSS e SRRR-nebivolol. Esses dois enantiômeros possuem propriedades farmacológicas distintas, o que sugere uma farmacocinética diferente entre ambos. Sendo assim, foram desenvolvidos dois métodos para a análise do nebivolol por eletroforese capilar (CE), um aquiral e outro quiral. O primeiro consistiu em um método para análise de forma farmacêutica comercial de comprimidos de nebivolol. Foram definidas as seguintes condições analíticas: capilar de sílica fundida 50 ?m de diâmetro interno (d.i) e 38 cm de comprimento efetivo (c.ef), eletrólito de corrida composto por tampão acetato de sódio 50 mM, pH 4,0, temperatura de 30 °C, tensão de 30 kV e detecção a 200 nm. O método desenvolvido permitiu a análise rápida e eficiente de comprimidos comerciais de nebivolol, sendo simples, seletivo, preciso e exato, está em conformidade com o guia de validação de métodos analíticos da ANVISA (2003), e foi aplicado para quantificação de comprimidos comerciais de nebivolol. O segundo método teve como objetivo realizar a análise enantiosseletiva da ligação do nebivolol à albumina humana do soro (HSA). Após a avaliação de diversos parâmetros, foram estabelecidas as seguintes condições analíticas: capilar de sílica fundida 50 ?m d.i e 38 cm c.ef, eletrólito de corrida composto por tampão acetato de sódio 50 mM, carboxi-metil-?-ciclodextrina 12,5 mM, 1% acetonitrila, pH 4,0, temperatura de 25 oC, tensão de 25 kV e detecção a 200 nm; e como técnica de stacking foi utilizada field amplified sample injection com plug de água (5 psi, 5 s) e injeção eletrocinética 5 kV por 30 s. Nesta condição foi obtida uma resolução de 1,58 e tempo de análise inferior a 25 minutos. No estudo de ligação à HSA foi observado que há enantiosseletividade na ligação, porém, este estudo ainda precisa ser melhor delineado em relação às concentrações de proteína e analito, bem como tempo de incubação e procedimento de filtração para separação das frações livre e ligada / Nebivolol is an anti-hypertensive drug, commercialized as a racemic mixture of RSSS and SRRR-nebivolol. Both enantiomers have distintict pharmacological properties, what suggests a different pharmacokinectis between them. Therefore, it was developed two methods for the nebivolol analysis by capillary electropforesis (CE), one of them is achiral and the other is chiral. The first method aimed the analysis of tablets. The analytical conditions were determined: silica fused capillary 50 ?m internal diameter (i.d.) and 38 cm effective length (ef. l.), running electrolyte composed by 50 mM sodium acetate buffer, pH 4.0, 30 °C temperature, 0 kV applied voltage and 200 nm UV detection. The developed method allowed a quickly and efficient tablets analysis, being simple, selective, accurate and precise, and it is also in accordance with ANVISA (2003) analytical methods validation guide, and it was applied to the quantification of nebivolol in tablets. The second method aimmed to analyze the enantiosselective nebivolol binding to HSA. After the evaluation of many parameters, it was stabilished the following analytical conditions: 50 ?m i.d. and 38 cm ef.l. fused silica capillary, running electrolyte composed by 50 mM sodium acetate buffer, 12.5 mM carboxymethyl- ?-cyclodextrin, acetonytrile 1%, pH 4.0, 25 oC, 25 kV applied voltage and 200 nm UV detection; and as stacking technique it was applied field amplified sample injection with water plug(5 psi, 5 s) and 5 kV por 30 s eletrokinect injection. At this condition, it was possible to achive 1.58 resolution and less than 25 minutes of analysis. At the HSA binding study, it was observed an enantiosselectivity on the binding; however this study still needs better desing in conserne to analyte and protein concentration, as well as, incubation time and filtration proceadure to the separion of binded and free fractions.

O grande interesse no estudo de materiais fotoluminescentes em solução aquosa é devido à possibilidade de aplicação destes sistemas em imunoensaios, na produção de lasers líquidos e como sondas estruturais de biomoléculas. Neste contexto, íons de Terras Raras (TR) e as ciclodextrinas são muito importantes, já que algumas TRs – como o európio e o térbio – apresentam a propriedade da luminescência, enquanto que as ciclodextrinas possuem uma cavidade apolar que pode incorporar moléculas (ou partes delas) em seu interior e protegê-las das moléculas do solvente. Neste projeto desenvolvemos principalmente a síntese de novos complexos luminescentes de európio e térbio com β-dicetonas, e o estudo de seus compostos de inclusão em α-ciclodextrina em solução aquosa. Foram estudados também compostos obtidos através da ligação covalente entre derivados da tetrakis(pentafluorofenil)porfirina e a β-ciclodextrina. Derivados de macrocíclos porfirínicos fotossensíveis vêm sendo empregados com muito sucesso no tratamento do câncer através terapia fotodinâmica. A ligação destes agentes em β-ciclodextrina propicia uma melhor solubilidade no meio fisiológico, característica esta que é um dos requisitos para uma melhor eficiência do tratamento. Todos os materiais obtidos foram caracterizados química e foto-fisicamente, relacionando-se a eficiência destes novos sistemas com outros já relatados na literatura. / In recent years, there has been considerable research on the study of energy transfer process by active optically ions due to their great importance in solid state devices, e.g., lasers and optic-electronic materials. These luminescent materials in aqueous solution can also be very useful as sensors or probe in biomaterials analysis. In this context, the interest on rare earth ion (RE) and cyclodextrins (CD) in the same systems are increasing, due to their compatibility with solid state and aqueous media. Some RE, like europium and terbium, present luminescent properties, while the CD’s have an apolar hydrophobic cavity that can incorporate molecules, protecting them from solvent entities and resulting in a rigid hydrophobic matrix in solution. In a part of this present work, it was performed the study of the RE complexes in aqueous solution incorporated into α-CD hydrophobic cavity. Rare Earth complexes with β-diketones were synthesized and characterized, and their solubilization in water was achieved by incorporation in α-CD. We also studied the porphyrin-type macrocycles linked to β-CD. Macrocycle tetrapyrroles are very promising molecules to be used as photosensitizer in Photodynamic Therapy. This therapy is an emergent treatment for cancer that requires a combination of oxygen, visible light and a photosensitizer, which causes damage to living tissue. The linkage of porphyrins in cyclodextrins can increase their solubility in water, making them suitable for intravenous administration and widens the possibilities of their use in medicine. Chemical and photochemical properties of all prepared compounds were performed and compared with similar results recorded for well know commercial products.

As ciclodextrinas são oligossacarídeos descobertos há mais de cem anos e utilizados para modificação de propriedades físico-químicas de moléculas, aplicadas especialmente para aumentar/modificar sua solubilidade através da formação de complexos de inclusão tipo hóspede-hospedeiro entre sua cavidade apolar e grupamentos afins das moléculas hóspedes. O sucesso na obtenção dos complexos de inclusão depende muito do método empregado e é necessário conhecer as opções disponíveis para selecionar a melhor relação entre eficiência e rendimento. Dentre as técnicas utilizadas para a obtenção destes complexos as mais destacadas são a coprecipitação, coevaporação, neutralização, liofilização, spray-drying, malaxagem, moagem e fluidos supercríticos. O objetivo do presente trabalho foi avaliar a influência da complexação do pizotifeno (PZT) com ciclodextrinas (CDs) sobre a sua fotodegradação em solução aquosa. Para isso foram utilizados diferentes tipos de CDs (α, β e γ ). Adicionalmente, um método analítico indicador de estabilidade por cromatografia líquida de alta eficiência foi desenvolvido e validado. Este método cromatográfico foi avaliado quanto a sua seletividade, linearidade, precisão intermediária, exatidão, estimativas de limites inferiores de quantificação e detecção, robustez e saturação dos filtros. A coluna cromatográfica utilizada foi uma Wakosil II 5C18 RS, 250mm x 4,6mm (5µm). A fase móvel (FM) utilizada consistiu numa mistura de solução aquosa de (NaH2PO4 + Pic B8) 2 mmol/l:acetonitrila:trietilamina (600:400:2, v/v) com pH aparente de 3,00±0,05. A vazão de trabalho utilizada foi de 1,5 ml/min e a temperatura da coluna foi mantida a 30°C. O método avaliado mostrou-se capaz de separar o PZT de seus principais produtos de degradação, preciso, exato, satisfatoriamente linear (r2>0,99, intercepto-y próximo de zero), robusto quanto ao pH, composição e vazão da FM e a condição de filtração ideal foi através de filtros de PVDF hidrofílico. A mudança na fotoestabilidade do pizotifeno puro e complexado com α, β e γ ciclodextrinas em solução aquosa foi avaliada em câmara de fotoestabilidade sob luz branca e UV por doze dias em frascos de vidro lacrados. Os complexos de inclusão conferiram ao fármaco uma velocidade de degradação no mínimo 19% menor em relação ao PZT puro e uma proteção relativa de até 1,61. A magnitude da fotoproteção foi maior para o complexo formado com β-ciclodextrina independentemente do tipo de radiação. / Cyclodextrins (CDs) are oligosaccharides discovered over one hundred years ago and used to change physicochemical properties of molecules, acting especially over its aqueous solubility through the formation of guest-host type inclusion complexes between its apolar cavity and similar structures in the guest molecule. Among the techniques employed to obtain these inclusion complexes the most commonly used are coprecipitation, coevaporation, neutralization, freeze-drying, spray-drying, kneading, grinding and precipitation from supercritical fluids. The objective of the present work was to evaluate the influence of the complexation of pizotifen (PZT) with various CDs (α, β and γ) over its photostability in aqueous solution. Also, a stability indicating high performance chromatographic method was developed and fully validated regarding its selectivity, linearity, intermediate precision, accuracy, lower limits of detection and quantification, robustness and filter saturation. The column used was a Wakosil II 5C18 RS with (250 x 4,6) mm, 5 µm particle size and kept at 30°C. The mobile phase (MP) used consisted of a mixture of a saline aqueous solution (NaH2PO4 + Sodium Octanesulfonate) 2 mmol/l:acetonitrile:tryethylamine (600:400:2 v/v) with its apparent pH adjusted to 3 and with a flow rate of 1,5 ml/min. The method was selective regarding PZT peak even among its degradation products and also precise, exact, linear (r2>0,99 and y-intercept close to zero), robust regarding MP\'s pH, composition and flow rate and the best filtration condition was with hydrophilic PVDF. Photostability changes in pure and complexed PZT in aqueous solution inside sealed glass vials were assessed for 12 days under both white and UV light in a photostability chamber regarding PZT\'s observed degradation rate, half-life and relative protection. Inclusion complexation significantly reduced PZT\'s degradation constant at least 20%, with equivalent increase in its half-life and a maximum relative protection of 1,61. The most significant protection was observed in the β-CD complex solution for both types of irradiation.

Les cannabinoides (CBs) et plus spécifiquement les agonistes des récepteurs CB2 ontdémontré leurs propriétés analgésiques, sans effet psychotrope comparés auxagonistes CB1. Les CBs sont généralement des composés lipophiles et non “drug-like”présentant une faible biodisponibilité. Afin d’évaluer de nouveaux CB2 agonistesd’origine synthétique développés par notre laboratoire, sur des modèles in vivo dedouleur neuropathique, une stratégie de formulation précoce a été mise au point et apermis le développement de quatre systèmes de délivrance d’actif. Une étudepharmacologique d’efficacité a été conduite avec notre tête de série MDA7, formulédans des complexes d’inclusion avec des cyclodextrines (CDs), des liposomes et unesolution micellaire administrés par voie parentérale. Le concept à base de CDs adémontré une plus forte activité anti nociceptive. Une étude de compréhension dumécanisme d’inclusion de MDA7 dans le complexe supramoléculaire formé avec lesCDs a été menée. Des systèmes auto-émulsionnables (SEDDS) ont également étéutilisés pour une administration orale afin d’étudier le profile pharmacocinétique deMDA7. Des nanocapsules (NCs) polymériques et cationiques ont également été développéesafin de stabiliser un phytocannabinoide, CB2, en vue d’une administration in vivo. Desétudes pour caractériser et évaluer l’influence des paramètres affectant la formation desNCs préparées par nanoprécipitation ont été conduites. Nous avons étudié lapropension des NCs développées à former des interactions ioniques avec desmacrocycles anioniques tels que les sulfobutylether-β-cyclodextrines ou, desinteractions électrostatiques avec les cucurbit[n]urils / Cannabinoids (CBs) and particularly CB2 agonists have been shown to reduce pain andinflammation without eliciting any apparent psychotropic effect conversely to CB1agonist compounds. CBs candidates are usually lipophilic non drug-like compoundswith poor bioavailability. To serve the purpose of evaluating new synthetic CB2 agonistsdeveloped by our group, on in vivo neuropathic pain models, an enabling formulationstrategy has been set up and four Drug Delivery Systems (DDS) developed. Forparenteral administration, cyclodextrin (CD)-based inclusion complexes, liposomes andsurfactants/co-solvents micellar solution have been investigated whereas Self-Emulsifying DDS (SEDDS) was selected for oral administration. A pharmacologicalstudy conducted with lead compound MDA7, formulated in CD-based DDS resulted inthe higher antinociceptive activity. A comprehensive study of the inclusion mechanismof MDA7 in the CD supramolecular complexes prepared was carried out. MDA7pharmacokinetic profile was also generated formulated in micellar solution and SEDDS.Besides, cationic polymeric nanocapsules (NCs) have been designed to serve as aprotective DDS for oral administration of a dietary phytocannabinoid CB2 agonist.Studies were undertaken to characterize and evaluate the influence of differentparameters on NCs formation prepared by nanoprecipitation. The cationic NCsdeveloped have been explored for their property to yield proportion of counterioniccondensation in the presence of macrocycles bearing anionic groups such assulfobutylether-beta-cyclodextrin or to form electrostatic interactions/host-guestcomplexion with cucurbit[n]uril.