A doença periodontal é uma patogenia que afeta as estruturas de suporte dos dentes com formação da bolsa periodontal, e caso não tratada, em estágios mais avançados o periodonto é destruído, ocasionando perda do dente. O tratamento concerne em duas etapas, à remoção mecânica do biofilme e cálculo dentário por raspagem e alisamento radicular e utilização de antimicrobianos. Ainda é comum a utilização de antimicrobiano de ação sistêmica, embora, tenha eficácia reduzida e frequentes efeitos adversos. Em face disto, justifica-se o desenvolvimento de sistemas de liberação sustentada de fármaco intrabolsa periodontal a fim de sanar os inconvenientes da terapia sistêmica. Contudo, aspectos como espaço anatomofisiológico e fluído gengival crevicular intrínsecos à bolsa, são limitações pertinentes durante o desenvolvimento. Portanto, este trabalho teve como objetivo desenvolver sistemas e formulações precursoras de fase líquido cristalina baseados em monolinoleato de glicerila (MLG) e cremophor (CREM) com gelificação in situ em fase líquido cristalina. Por meio de planejamento fatorial 32 foram obtidos 9 sistemas sem adição de fármaco e 9 formulações contendo metronidazol com diferentes razões de MLG/CREM e %H2O. Quando caracterizados por microscopia de luz polarizada e espalhamento de raios-X a baixo ângulo, os sistemas e formulações com menor razão MLG/CREM e conteúdos de água de 5, 10 e 15% apresentaram organização micelar isotrópica. Eles também apresentaram rápida erosão no ensaio de captação de água, inviabilizando sua transição para mesofase. Os sistemas e formulações com média e alta razão MLG/CREM e conteúdos de água de 5, 10 e 15% apresentaram coexistência de fases em transição líquido cristalina. Apresentaram rápida captação de água com transição para fase cúbica. Contudo, com exceção do sistema e formulação com alta razão MGL/CREM e 15% de água, os demais sistemas e formulações, apresentaram propriedades de fluxo ideais para fácil aplicação por seringa acoplada a agulha, e comportamento viscoelástico adequado para promover espalhabilidade e retenção no interior da bolsa. Os sistemas e formulações com média e alta razão de MLG/CREM apresentaram melhor mucoadesão. Dentre as formulações, apenas a com média razão de GML/CREM e 5% de água, apresentou perfil bi-modal de liberação mantendo concentrações de metronidazol acima do MIC por 6 dias, característica desejável para sistemas de liberação intrabolsa periodontal. Portanto, todos os resultados advogam a favor desta formulação como potencial candidata ao emprego clínico como sistema de liberação de fármaco intrabolsa periodontal. / Periodontal disease is a chronic infection that affects the structural supports of the tooth with periodontal pocket formation. If untreated, the periodontium may be destroyed, which can cause the tooth loss in the latest stages of the disease. The treatment for this infection comprises two stages, the mechanical removal of plaque and calculus by scaling and root planing and the use of antimicrobials. It is still common to use systemic antimicrobials, even though it has a reduced efficacy and frequent adverse effects. For the reason, justified the development of systems for sustained release of drug intra-pocket periodontal in order to solve the drawbacks of systemic therapy. The main limitations for the development of these systems are the anatomical and physiological aspects of the periodontal pocket, which includes the limited size and the depth area and the natural irrigate flow of the gingival crevice fluid (GCF). So, this study aimed to develop precursor liquid crystalline systems and formulations based on glyceryl monolinoleate (GML) and cremophor (CREM), with in situ gelation to liquid crystalline phases. Through a 32 factorial design 9 systems without drug and 9 formulations containing metronidazole were obtained. Different ratios of GML / CREM and water percentage were evaluated. When characterized by Small-Angle X-ray Scattering and Polarized Light Microscopy, lower ratio GML / CREM with 5, 10 and 15% H2O produce isotropic micellar organization. They also showed high erosion during water uptake, thus, precluding in situ crystalline transition. Medium and high ratio GML / CREM with 5, 10 and 15% H2O indicated the coexistence of regions in transition to the crystalline phase. They showed characteristic peaks of cubic phases, rapid water uptake, higher viscosity and increased mucoadhesion. Moreover, with the exception of the formulation containing high ratio and high water content, other systems and formulations with medium ratio GML / CREM and 5, 10, 15% of water and high ratio and 5 and 10% of water had flow properties ideal for easy application through needle fitted syringes, viscoelastic behavior appropriate to promote spreadability and might favor retention within the periodontal pocket. However, only the formulation with higher ratio and the lowest water content presented a bimodal release profile of metronidazole, maintaining concentrations above the MIC for 5 days, with the release of 100% of the drug added to the formulation. These are desirable features for delivery systems designed for periodontal pockets. Therefore, all results advocate in favor of the formulation with high ratio of GML / CREM and 5% of water as a potential candidate for clinical use as drug delivery system for the periodontal pocket.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-07-20T14:31:38Z No. of bitstreams: 1 nelsonluisgoncalvesdiasdesouza.pdf: 3525241 bytes, checksum: ae329dc7143339666d6c67da1adb3e54 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-07-22T15:21:04Z (GMT) No. of bitstreams: 1 nelsonluisgoncalvesdiasdesouza.pdf: 3525241 bytes, checksum: ae329dc7143339666d6c67da1adb3e54 (MD5) / Made available in DSpace on 2016-07-22T15:21:04Z (GMT). No. of bitstreams: 1 nelsonluisgoncalvesdiasdesouza.pdf: 3525241 bytes, checksum: ae329dc7143339666d6c67da1adb3e54 (MD5) Previous issue date: 2011-03-18 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A bovinocultura é uma das principais atividades pecuaristas que é desenvolvida no Brasil, sua importância e refletida no desenvolvimento econômico e social do país. Essa atividade é responsável pelo desenvolvimento de empregos sendo esses tanto diretamente na fazenda (produção de gado para corte ou leiteiro) ou no beneficiamento desses produtos. Sua importância e tão relevante que o número de cabeças de gado presentes no país já ultrapassa o dos habitantes. Devido a sua relevância os fatores que afetam sua produtividade e de extrema importância. Um dos fatores que podem influenciar sua produção é a ocorrência de doenças ou deficiências nutricionais que, contudo podem ser resolvidas utilizando medicamentos ou suplementos alimentares. Porém a aplicação dessas drogas se torna difícil e caro devido à necessidade da manipulação frequente do rebanho. Uma das formas de se contornar essa dificuldade é a utilização de sistemas de liberação controlada. Esses sistemas podem ser concebidos de diversas maneiras, uma dessas formas é uso de polímeros biodegradáveis e biocompatíveis como matriz para a liberação do medicamento. Assim esse trabalho num primeiro momento estuda a estabilidade físico-química de dois polímeros, quitosana e poli(caprolactona), ao entrarem em contato com o ambiente ruminal com o objetivo de analisar seu uso como matriz para sistemas de liberação. Para avaliação da estabilidade dos polímeros foi utilizado às técnicas vibracionais: absorção no infravermelho e Raman; termogravimétricas: TG e DSC e espectroscopia eletrônica. Num segundo momento o presente trabalho prevê a construção de sistemas de liberação utilizando esses polímeros juntamente com o coacervato de cálcio de modo a liberar um extrato fúngico entre 8 e 12 horas. No fim do trabalho foi possível verificar uma maior estabilidade do polímero PCL (poli(-caprolactona)) que foi utilizado para a construção do sistema de liberação, já a quitosana apresentou uma baixa estabilidade e por esse motivo não se construiu nenhum sistema a partir da mesma. Os dispositivos construídos a partir do PCL e coacervato se mostraram versáteis podendo-se obter diferentes taxas de liberação dependendo da proporção entre eles, seu formato e área superficial. / The cattle industry is one of the main activities developed in Brazil, and its importance is reflected in the country economic and social development. This activity is responsible for developing jobs which come from the farm (production of cattle for beef or dairy) until the high technology industry of dairy products. Because of this, the factors which affect its productivity are extremely important. One factor that influences its production is the occurrence of diseases or nutritional deficiencies, which can be solved using drugs or food supplements; however, the application of these drugs becomes difficult and expensive due to the need for frequent handling of the herd. One way of circumventing this difficulty is the use of controlled delivery systems. These systems can be designed in different ways; one of those ways is the use of biodegradable and biocompatible polymers as a matrix for drug release. Therefore, this work presents the study of the physical and chemical stability of both polymers, chitosan and poly(-caprolactone), in the ruminal environment in order to examine their use as a matrix for delivery systems. To evaluate the stability of polymers it has been used vibrational techniques (infrared absorption and Raman), thermogravimetric (TG and DSC) as well as electronic spectroscopy. In a second step this work involves the construction of delivery systems using these polymers and calcium polyphoshate coacervate to produce a blend in order to release a fungal extract between 8 and 12 hours. At the end of the study it has been shown the great stability of the PCL polymer, which was used to build a delivery system, already chitosan has showed a low chemical stability and therefore it was not use to build system delivery. The devices constructed from PCL and coacervate showed to be versatile can generate different release rates depending on the ratio between its constituents, their shape and surface area.

Au laboratoire, une méthode originale d'encapsulation par transacylation entre l'alginate de propylène-glycol (PGA) et une protéine a été mise au point. Cette méthode est basée sur la création de liaisons amides entre les fonctions amines libres de la protéine et les groupes esters du PGA dans une phase aqueuse émulsionnée (E/H) après alcalinisation. Les microparticules obtenues, stables, biocompatibles et biodégradables, sont potentiellement intéressantes pour la délivrance de substances actives en thérapeutique ou en cosmétique.Le premier objectif de ce travail est d'étudier l'influence des propriétés physicochimiques des deux biopolymères (protéine et PGA) et de leurs solutions, ainsi que l'effet des paramètres de préparation sur la réaction de transacylation et sur les propriétés des microparticules obtenues. Pour cela, la sérumalbumine humaine (HSA) a servi de protéine modèle et les microparticules ont été préparées dans différentes conditions physicochimiques puis caractérisées. Différents liens ont été établis entre les propriétés physicochimiques des solutions initiales des deux polymères et les propriétés fonctionnelles des microparticules obtenues.Le deuxième objectif est de remplacer le PGA, seul polysaccharide utilisable jusqu'à présent pour la microencapsulation par transacylation, par d'autres polysaccharides naturels, dans la préparation de microparticules. Etant donné ses propriétés intrinsèques limitantes, le remplacement du PGA par d'autres esters polysaccharidiques parait avantageux dans le domaine d'application des microparticules.Dans ce travail, le PGA a été remplacé par une série d'esters semi-synthétiques d'alginate puis par d'autres polysaccharides estérifiés naturels (pectines) ou semi-synthétiques (esters polypectiques et esters de l'acide hyaluronique). Les conditions optimales pour l'utilisation de chaque ester ont été alors déterminées. / In our laboratory, an original method of microencapsulation was developed, based on the use of a transacylation reaction, creating covalent bonds between proteins and propylene glycol alginate (PGA). The covalent bonds are created after alkalization of the aqueous phase of a W/O emulsion, without using bifunctional crosslinking reagent.The resulting microparticles, which are stable, biocompatible and biodegradable, have potential applications for the delivery of active compounds for therapeutics or cosmetics.The first aim of this work is to study the influence of the physicochemical properties of the two polymers (protein and PGA) and of their solutions, as well as the effect of the preparation parameters on the transacylation reaction and on microparticle characteristics. For this purpose, human serum albumin (HSA) was picked as a model protein and microparticles were prepared using several physicochemical conditions then characterized. Several relationships were established between the physicochemical properties of the initial solutions of the two polymers and the functional properties of the resulting microparticles.The second purpose is to replace the PGA, only polysaccharide used for microencapsulation by transacylation so far, by other natural polysaccharides in the preparation of microparticles. Given its limiting intrinsic properties, the replacement of PGA by other polysaccharidic esters seems advantageous in the field of microparticle applications.In this work, the PGA was successfully replaced by a series of semisynthetic alginate esters, and then by other polysaccharidic esters, either natural esters (pectin) or semisynthetic esters (polypectate esters and hyaluronate esters). The optimal conditions for the use of each ester were then determined.

The objective of this work is to analyse the possibility of use of micro -- needles technology as the method of drug delivery in the Czech Republic. The characteristics of this product (application, connection with drug, etc.) suggest three possible target groups: patients, health care providers or pharmaceutical companies. One of the goals is to analyse legal requirements on such products, evaluate current market situation and according to this information choose the best group for the product consumption. Also product itself presents a challenge and there are several designs of micro -- needle or needleless drug applicators. Combined together, this study aims to find, whether is the Czech market able to accept new method of drug delivery, in which form and how can patient reach this technology.

Charles University in Prague, Faculty of Pharmacy in Hradci Králové Department of: Pharmaceutical Technology Supervisor: PharmDr. Ondřej Holas, Ph.D. Consultant: Mgr. Jana Kubačková Student: Kateřina Kučerová Title of thesis: Preparation and evaluation of lipid based nanoparticles as drug carriers Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) are promising drug delivery systems. Their capability to encapsulate both hydrophilic and lipophilic molecules, biocompatibility and biodegradability of lipids make them a suitable alternative for well-established drug carries. The aim of this thesis was to determine suitable ratios of composition of nanoparticles with acceptable properties (especially reduced size and polydispersity, high zeta potential absolute values), to investigate status and thermodynamic behaviour of the nanoparticles and lipids used and to examine drug encapsulation efficiency. Nanoprecipitation method was used to prepare nanoparticles from stearic acid as a solid lipid and in the case of NLC preparation isopropyl myristate as a liquid lipid was used. Kolliphor® P 188 as a surfactant and Span® 20 as a co-surfactant were the best choice to meet intended characteristics. It was shown that usually lower the concentration of surfactant and co-surfactant was the...

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of: Pharmaceutical Technology Supervisor: PharmDr. Ondřej Holas, Ph.D. Consultant: Mgr. Jana Kubačková Student: Lenka Voldřichová Title of thesis: Lipid based nanoparticles: drug delivery platform Lipic nanoparticles, as newly developed dosage forms, can overcome many drawbacks of conventional dosage forms. Their potential can be utilized in particular for prolonged, controlled and targeted release. They can also increase the bioavailability of drugs, especially those with poor solubility and also allow targeting, which causes increased accumulation of lipid nanoparticles in certain tissues compared to other tissues. nanoparticles suitable for drug encapsulation. The particles were prepared by the emulsion evaporation method. Their characterization was performed using a Zetasizer, which measured the particle size and the zeta potential. The properties of the formulations were evaluated in terms of nanoparticle size, polydispersity, zeta potential, and formulation properties. Differencial scanning calorimetry analysis was also performed on selected formulations. The selected final formulation was composed of 25 mg glycerol monostearate, 10 mg isopropyl myristate, 15 mg lecithin and Kolliphor P188 0,1% solution....

Platelet preparations are a source of various autologous growth factors and have numerous applications in tissues engineering. The aim of this work was to development electrospun nanofiber scaffolds with platelet preparations. Scaffolds based on the adhesion of platelets on nanofiber meshes were developed. The scaffolds were able to enhance chondrocyte proliferation in vitro. The main disadvantage of this system is the burst release of growth factors immediately after adhesion. To overcome this, we developed coaxially electrospun scaffolds with incorporated alpha granules. Alpha granules are novel platelet preparations with high amounts of growth factors. This system was able to stimulate chondrocyte proliferation and maintain TGF- 1 concentrations for 7 days. Additionally, a novel drug delivery system with coaxially incorporated liposomes was developed. Liposomes incorporated into nanofibers remain intact and can be used for the delivery of various molecules. The ability to maintain HRP activity was compared to systems based on coaxial electrospinning with liposomes, coaxial electrospinning without liposomes and blend electrospinning. When compared to other systems, coaxial electrospinning with liposomes preserves enzyme activity twice as long. These results clearly indicate the potential of...

ABSTRACT<p><p>This project aimed at developing a drug delivery system (DDS) able to enhance the stability and<p>residence time in vivo of antibodies (Abs). The system will deliver drug by the subcutaneous<p>route (SC), while ensuring accurate control of the drug release and the resulting plasmatic level. This technology platform will allow to reduce frequency of injection, potentially decrease side effects and maintain high concentration of Abs which will improve life of patient having chronic disease such as autoimmune and inflammatory disease. Biodegradable synthetic polymer-based formulations (polylactide-co-glycolide (PLGA)) were selected as carriers for encapsulated Abs. This was because they offer good protection for the Abs and allow sustained release of the Abs for a controlled period of time. After the evaluation of different encapsulation methods such as the water-oil-in-water (w/o/w) and the solid-in-oil-inwater<p>(s/o/w) processes, the encapsulation of the Ab in solid state (s/o/w) appeared to be more appropriate for producing Ab-loaded PLGA microspheres (MS). It allowed us to maintain the<p>Ab in a monomeric conformation and to avoid the formation of unsoluble aggregates mainly present at the water/oil interface. The first part of the project was the optimization of both the method for producing the Ab solid particles (spray-drying process) and the encapsulation of these Ab solid particles into the polymeric MS (s/o/w process) by design of experiment (DoE). These optimizations were carried out using a bovine polyclonal immunoglobulin G (IgG) as model molecule. In further optimization of the spray-drying process by (DoE), aqueous Ab solutions were spray-dried using a mini Spray-Dryer assembly with a 0.7 mm spray nozzle. In accordance with the particle size (d(0.5) ~5 μm), the stability (no loss of monomer measured by<p>size exclusion chromatography (SEC) and the yield of the spray-drying process (> 60 % w/w), the process parameters were set of follow: 3 mL/min as liquid feed flow rate, 130°C /75°C as inlet temperature (inlet T°) / outlet temperature (outlet T°), 800 L/h as atomization flow rate and<p>30 m3/h as drying air flow rate. For the s/o/w, the methylene chloride (MC) commonly used for<p>an encapsulation process was replaced by ethyl acetate (EtAc), which was considered as a more<p>suitable organic solvent in terms of both environmental and human safety. The effects of several processes and formulation factors were evaluated on IgG:PLGA MS properties such as: particle size distribution, drug loading, IgG stability, and encapsulation efficiency (EE%). Several formulations and processing parameters were also statistically identified as critical to get reproducible process (e.g. the PLGA concentration, the volume of the external phase, the emulsification rate, and the quantity of IgG microparticles). The optimized encapsulation<p>method of the IgG has shown a drug loading of up to 6 % (w/w) and an encapsulation efficiency<p>of up to 60 % (w/w) while preserving the integrity of the encapsulated antibody. The produced MS were characterized by a d(0.9) lower than 110 μm and showed burst effect lower than 50 %(w/w). In the second part of the project, the optimized spray-drying and s/o/w processes<p>developed with the IgG were applied to a humanized anti-tumor necrosis factor (TNF) alpha<p>MAb to confirm the preservation of the MAb activity during these processes. The selected s/o/w method allowed us to produce MAb-loaded PLGA MS with an appropriate release profile up to 6 weeks and MAb stability. In order to maintain the Abs’ activity, both during encapsulation and<p>dissolution, the addition of a stabilizer such as trehalose appeared to be crucial, as did the<p>selection of the PLGA. It was demonstrated that the use of a PLGA characterized by a 75:25<p>lactide:glycolide (e.g. Resomer ® RG755S) ratio decreased the formation of low molecular weight species during dissolution, which led to preserve Abs activity through its release from the<p>delivery system. Furthermore, the release profile was adjusted according to the type of polymer<p>and its concentration. E.g. 10 % w/v RG755S allowed Ab MS with a release time of 6 weeks to<p>be obtained. The optimization of both the formulation and the encapsulation process allowed<p>maximum 13 % w/w Ab-loaded MS to be produced. It was demonstrated that the Ab-loaded PLGA MS were stable when stored at 5°C for up to 12 weeks and that the selection of the appropriate type of PLGA was critical to assuring the stability of the system. The better stability observed when using a PLGA characterized by a 75:25 lactide:glycolide ratio was attributed to<p>its slower degradation rate. Finally, the sustained release of Ab from the developed MS and the preservation of its activity was confirmed in vivo in a pharmacokinetic (pK) study realized in<p>rats. In conclusion, the application of the concept of entrapment into a polymer matrix for<p>stabilization and sustained release of biological compounds was demonstrated through this work.<p><p><p><p>RÉSUMÉ<p><p>Ce projet a pour but de développer un système de délivrance de médicament capable d’augmenter la stabilité et le temps de résidence in vivo des anticorps. Ce système sera administré par voie sous-cutanée et permettra un control précis de la libération du produit et de son niveau plasmatique. Cette plateforme technologique nous permettra de réduire la fréquence d’injection, de réduire potentiellement les effets secondaires et de maintenir des concentrations élevées en anticorps tout en améliorant la vie des patients atteints de maladies chroniques autoimmunes ou inflammatoires. Les formulations à base de polymères synthétiques, biodégradables (PLGA) ont été sélectionnés comme véhicules pour encapsuler les anticorps. Ils offrent en effet une bonne protection pour les anticorps and permettent une libération contrôlée de ceux-ci pendant une période définie. Après l’évaluation de différents méthodes d’encapsulation tels que les procédés d’eau-dans-huile-dans-eau (w/o/w) et solide-dans-huile-dans-eau (s/o/w), l’encapsulation des anticorps sous forme solide apparaissait plus apporpriée pour produire des microsphères de polymère chargées en anticorps. Cette technique nous permettait de maintenir l’anticorps sous sa forme monomérique et d’éviter la formation d’agrégats insolubles qui apparaissaient principalement à l’interface eau/huile. La première partie du projet a été d’optimiser à la fois la méthode nous permettant d’obtenir les anticorps sous forme de particules solides (spray-drying) et la méthode d’encapsulation de ces particules d’anticorps dans les microsphères de polymères. Cela a été réalisé par des plans d’expérience en utilisant une IgG bovine polyclonale comme molécule modèle. Durant l’optimisation du procédé de spray-drying,<p>les solutions aqueuses d’anticorps ont été atomisées en utilisant le mini Spray-Dryer assemblé avec une buse de pulvérisation d’un diamètre de 0.7 mm. En accord avec la taille particulaire (d(0.5) ~5 μm), la stabilité (absence de perte en monomère mesurée par chromatographie d’exclusion de taille et le rendement d’atomisation (> 60 % w/w), les paramètres d’atomisation ont été fixés: 3 mL/min pour le débit de liquide, 130°C /75°C pour la température d’entrée / température de sortie, 800 L/h pour le débit d’air d’atomisation et 30 m3/h pour le débit d’air de séchage. Pour le s/o/w, le dichlorométhane communément utilisé dans les procédés d’encapsulation a été remplacé par l’acétate d’éthyle qui est considéré comme un meilleure solvant organique en terme d’environnement et de sécurité. Les effets de plusieurs paramètres de fabrication ou de formulation ont été évalués sur les propriétés des microsphères polymériques d’anticorps (distribution de taille particulaire, taux de charge en anticorps, stabilité de l’anticorps et efficacité d’encapsulation). Plusieurs paramètres de fabrication et de formulation ont été statistiquement identifiés comme critiques pour obtenir un procédé reproductible (par exemple. La concentration en PLGA, le volume de phase externe, la vitesse d’émulsification et la quantité d’anticorps). La méthode d’encapsulation ainsi optimisée permettait d’obtenir un taux<p>de charge jusqu’à 6% (w/w) avec une efficacité d’encapsulation jusqu’à 60 % (w/w) tout en<p>préservant l’intégrité de l’anticorps encapsulé. Les microsphères produites étaient caractérisées<p>par un d(0.9) inférieur à 110 μm et montraient une libération après 24 h inférieure à 50 % (w/w).<p>Dans le seconde partie du projet, les procédés d’atomisation et d’encapsulation développés avec<p>l’IgG ont été appliqués à un anticorps monoclonal anti-TNF alpha humanisé pour confirmer la<p>conservation de l’activité de l’anticorps pendant ces procédés. La méthode s/o/w sélectionnée<p>permettait de produire des microsphères de PLGA chargées en anticorps avec un profil de libération jusqu’à 6 semaines et un maintien de la stabilité de l’actif. Afin de maintenir l’activité de l’anticorps, à la fois pendant le procédé d’encapsulation et pendant la libération, l’ajout d’un stabilisant tel que le tréhalose est apparu crucial ainsi que le choix du type de PLGA. Il a été démontré que l’utilisation du PLGA caractérisé par un ratio lactide :glycolide de 75 :25 (par exemple, Resomer ® RG755S) diminuait la formation d’espèces de faible poids moléculaire<p>pendant la dissolution. Cela contribuait à préserver l’activité de l’anticorps durant la libération à partir des microsphères. De plus, le profil de libération était modulé en fonction du type de polymère et de sa concentration. Par exemple, l’utilisation d’une solution à 10 % w/v RG755S conduisait à la production de microsphères d’anticorps avec un temps de libération sur 6<p>semaines. L’optimisation de la formulation et du procédé d’encapsulation a permis de produire<p>des microsphères avec des taux de charge en anticorps de maximum 13 % w/w. Il a été démontré<p>que ces microsphères, stockées à 5°C, étaient stables jusqu’à 12 semaines et que la sélection du<p>type de PLGA était critique pour assurer la stabilité du système. La meilleure stabilité a été<p>obtenue en utilisant le PLGA caractérisé par un ratio lactide :glycolide de 75 :25. Cela a été<p>attribué à sa plus faible vitesse de dégradation. Enfin, la libération contrôlée de l’anticorps à<p>partir de ces microsphères et la conservation de son activité ont été confirmées in vivo lors d’une<p>étude pharmacocinétique réalisée chez le rat. En conclusion, ce travail a permis de démontrer<p>l’application du concept d’ « emprisonnement » des composés biologiques dans des matrices<p>polymériques afin de les stabiliser et contrôler leur libération. / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

L’objectif de ce travail de recherche est le développement d’un biomatériau original permettant la libération retardée de principes actifs afin de résoudre les problématiques de diffusion trop rapide ou incontrôlée souvent rencontrées avec les systèmes de délivrance classiques. Un assemblage « hybride » composé de liposomes incorporant le principe actif, eux-mêmes incorporés dans un hydrogel physique de chitosane a été mis au point dans le cadre de ce travail. Pour élaborer ce système, une suspension de liposomes préformés est ajoutée à une solution de chitosane avant sa gelification. Une caractérisation des différents composants ainsi qu’une optimisation de ce processus d’élaboration ont été effectuées au cours de cette thèse. Les propriétés de relargage ont été étudiées via l’incorporation d’une molécule hydrosoluble jouant le rôle de modèle de principe actif. La carboxyfluorescéine (CF), dosable par fluorescence, a permis de confirmer le concept de « relargage retardé » : la quantité de CF libérée au cours du temps est plus élevée lorsque cette dernière est directement incorporée dans l’hydrogel, par rapport au cas où elle est intégrée dans l’assemblage « hybride ». Sur la base de ces résultats, l’incorporation et le relargage de deux principes actifs, la rifampicine (RIF), un antibiotique à large spectre, et la lidocaïne, un anesthésique local anti-arythmique, ont également été étudiées. Ce travail a permis de confirmer les résultats obtenus pour la molécule modèle, à savoir un retard au relargage significatif pour les assemblages par rapport aux hydrogels sans liposome. Diverses caractérisations ont également été menées pour examiner les propriétés rhéologiques et la morphologie de ces assemblages. Ces résultats représentent une avancée intéressante pour la valorisation de tels assemblages « hybrides » dans le domaine biomédical, et mettent en évidence le rôle des liposomes en tant que « réservoirs » de principes actifs au sein même de ces assemblages. / This work deals with the development of an original biomaterial in view of its application as drug delayed-release device in biomedical area. To overcome classic issues that may be encountered with common drug delivery systems such as the “burst effect” or fast outside diffusion of drugs, a « hybrid » system composed of liposomes entrapped within a chitosan physical hydrogel was developed. Its elaboration process consists in the addition of a suspension of pre-formed phosphatidylcholine liposomes within a chitosan solution before gelation process. A characterization of different components of the system and an optimization of the elaboration process were achieved. The release properties were firstly investigated using a water-soluble fluorescent model molecule, carboxyfluorescein (CF). The concept of delayed-release was confirmed. Indeed, the release of CF, assayed by fluorescence spectroscopy, was found to be higher in the “drug-in-hydrogel” systems in comparison with the “drug-in-liposomes-in-hydrogels” ones. Based on these results, the release of two drugs, rifampicin (RIF), a broad spectrum antibiotic, and lidocaine (LID), a local anaesthetic and anti-arrhythmic drug, were also studied. This work corroborated the data obtained for the model molecule, that is to say a significant delayed release for « hybrid » systems in comparison to hydrogels without liposome. Various characterizations were carried out to examine rheological properties and morphologies of assemblies. These first results showed that such systems could be a step forward in drug delivery, and highlighted the use of liposomes as drug « reservoirs » within assemblies.

Yes / Vat photopolymerization has garnered interest from pharmaceutical researchers for the fabrication of personalised medicines, especially for drugs that require high precision dosing or are heat labile. However, the 3D printed structures created thus far have been insoluble, limiting printable dosage forms to sustained-release systems or drug-eluting medical devices which do not require dissolution of the printed matrix. Resins that produce water-soluble structures will enable more versatile drug release profiles and expand potential applications. To achieve this, instead of employing cross-linking chemistry to fabricate matrices, supramolecular chemistry may be used to impart dynamic interaction between polymer chains. In this study, water-soluble drug-loaded printlets (3D printed tablets) are fabricated via digital light processing (DLP) 3DP for the first time. Six formulations with varying ratios of an electrolyte acrylate …