The main complication of aortocoronary reconstruction with vein grafts is restenosis in the course of time. The aim was to assess the effect of a periadventitial polyester system releasing sirolimus on intimal hyperplasia of autologous grafts. The controlled-release system comprises a polyester mesh coated with a sirolimus-eluting copolymer of L lactic acid and ε-caprolactone system designed to be wrapped around an autologous venous graft during its implantation. In vitro sirolimus release and its effects on smooth muscle and endothelial cells were assessed. In vitro, the copolymer-coated polyester mesh released sirolimus over a period of 6 weeks. Mesh-eluted sirolimus inhibited the growth of smooth muscle and endothelial cells in seven-day in vitro experiments. After seven days of sirolimus release from the mesh, smooth muscle and endothelial cell counts decreased by 29% and 75%, respectively, with the cells maintaining high viability. We implanted v. jugularis ext. into a. carotis communis in rabbits. The vein graft was either intact, or was wrapped with a pure polyester mesh, or with a sirolimus-releasing mesh. Three and six weeks after surgery, the veins were subjected to standard histological staining and the thicknesses of the tunica intima, the media and the intima-media complex were...

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-09-05T19:49:54Z No. of bitstreams: 1 michelecamposalves.pdf: 4465106 bytes, checksum: 619948227c4d2d419bdbeb66a9cad785 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-09-06T11:36:14Z (GMT) No. of bitstreams: 1 michelecamposalves.pdf: 4465106 bytes, checksum: 619948227c4d2d419bdbeb66a9cad785 (MD5) / Made available in DSpace on 2017-09-06T11:36:14Z (GMT). No. of bitstreams: 1 michelecamposalves.pdf: 4465106 bytes, checksum: 619948227c4d2d419bdbeb66a9cad785 (MD5) Previous issue date: 2013-08-12 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Atualmente, existe um interesse crescente nas potenciais atividades de proteção à saúde do chá verde (Camellia sinensis), que é caracterizado pela presença de grandes quantidades de polifenois, sendo a maioria deles representados por catequinas. Galato de epigalocatequina (EGCG) é o componente mais abundante e ativo, sendo geralmente utilizado como biomarcador junto com a cafeína (CAF) e o ácido gálico (AG). EGCG é pouco absorvido no tratogastrointestinal e está sujeito ao metabolismo de primeira passagem pelo fígado quando administrado por via oral, forma mais comumente utilizada para o chá verde. Um sistema transdérmico poderia então ser um mecanismo de liberação alternativo. Dessa forma, o presente trabalho teve como objetivo: desenvolver e validar métodos por cromatografia em fase líquida de alta eficiência (CLAE) para a quantificação simultânea de EGCG, CAF e AG em cápsulas e emulsões contendo extrato seco de chá verde e determinar na emulsão a liberação de EGCG in vitro e sua permeação cutânea em pele humana, utilizando modelo ex vivo. Os métodos utilizaram CLAE de fase inversa e detecção em arranjo de fotodiodo. A separação foi atingida utilizando as seguintes condições: coluna octadecilsilano; fase móvel composta por água, etanol, acetato de etila e ácido acético (84:12:3:1, v/v/v/v); temperatura do compartimento para a coluna de 35 °C; e um sistema de fluxo por gradiente, alternando o fluxo entre 0.7 e 1.4 mL.min-1. Os compostos foram separados em 35 min. Os métodos foram simples, seletivos, precisos, exatos e rápidos; e mostraram a confiabilidade necessária para que fossem utilizados no controle de qualidade das formulações testadas. O método para a emulsão provou ser adequado para os ensaios de liberação in vitro e de permeação ex vivo. A taxa de liberação in vitro de EGCG foi de 8896.01 mg.cm-2, seguindo o modelo de pseudo-primeira ordem, também conhecido como modelo de Higuchi. O teste de permeação ex vivo mostrou que EGCG não é capaz de exercer suas atividades biológicas sistemicamente quando utilizado a partir da emulsão testada, permanecendo apenas no estrato córneo. / Currently, there is an increased interest in potential health-protective activities of green tea (Camellia sinensis), which is characterized by the presence of polyphenols huge amounts, being the majority of them catechins. Epigallocatechin 3- gallate (EGCG) is the most abundant and active component, been generally used as biomarker together with caffeine (CAF) and gallic acid (GA). EGCG is poorly absorbed in the gastrointestinal tract and is subject to first-pass metabolism by the liver when administered orally, the most widely used forms of green tea. A transdermal system could then be an alternative delivery mechanism. In this light, the present work aimed: to develop and validate high performance liquid chromatography (HPLC) methods for simultaneous quantification of EGCG, CAF and GA in emulsions and capsules containing dry extract green tea and to determine in emulsion the in vitro EGCG release and its human skin cutaneous permeation using ex vivo model. The methods used reversed phase HPLC and photodiode array detection. Separation was achieved using the follow conditions: octadecylsilyl column; mobile phase composed by water, ethanol, ethyl acetate and acetic acid (84:12:3:1, v/v/v/v); column temperature of 35 °C; and flow gradient syst em, alternating flow between 0.7 and 1.4 mL.min-1. The compounds were separated within 35 min. The methods were simple, selective, precise, accurate and fast; and provide the reliability required for them to be used for quality control of tested formulations. The emulsion method proved to be suitable both for in vitro release and ex vivo permeation. EGCG in vitro release rate was found to be 8896.01 μg.cm–2, following pseudo-first-order model, also known as Higuchi’s model. Ex vivo permeation testing showed that EGCG is not able to exert its biological activities systemically when used from tested emulsion, remaining only in the stratum corneum.

La principale difficulté lors de l'administration orale d'un ingrédient pharmaceutique actif (API) est de garantir que la dose clinique de l’API sera dissoute dans le volume disponible de liquides gastro-intestinaux. Toutefois, environ 40% des API sur le marché et près de 90% des molécules en cours de développement sont peu solubles dans l’eau et présentent une faible absorption par voie orale, ce qui entraîne une faible biodisponibilité. Les dispersions solides amorphes (ASD) sont considérées comme l’une des stratégies plus efficaces pour résoudre des problèmes de solubilité des principes actifs peu solubles dans l’eau et, ainsi, améliorer leur biodisponibilité orale. En dépit de leur introduction il y a plus de 50 ans comme stratégie pour améliorer l’administration orale des API, la formation et la stabilité physique des ASD font toujours l'objet de recherches approfondies. En effet, plusieurs facteurs peuvent influer sur la stabilité physique des ASD pendant le stockage, parmi lesquels la température de transition vitreuse du mélange binaire API-polymère, la solubilité apparente de l'API dans le polymère, les interactions entre l'API et le polymère et le procédé de fabrication. Cette thèse consistait en deux parties qui avaient pour objectif le développement de nouvelles formulations sous forme d’ASD d'un antirétroviral, l'Efavirenz (EFV), dispersé dans un polymère amphiphile, le Soluplus, en utilisant deux procédés différents, le séchage par atomisation (SD) et l'extrusion à chaud (HME). EFV est l’API BCS de classe II de notre choix car c’est un API qui représente un défi pour les nouvelles formulations. En effet, il a besoin d’ASD plus fortement concentrées, pour lesquelles la stabilité chimique et physique pendant le stockage et la dissolution seront essentielles. Dans le but de développer de manière rationnelle les ASDs EFV- Soluplus à forte concentration, la première partie s'est concentrée sur la construction d'un diagramme de phases EFV-Soluplus en fonction de la composition et de la température. Le diagramme de phases a été construit à partir d'une étude thermique de recristallisation d'un ASD sursaturé (85 %m EFV), générée par séchage par atomisation. À notre connaissance, il s'agit de la première étude à présenter un diagramme de phase pour ce système binaire. Ce diagramme de phases est très utile et démontre que la solubilité de l'EFV dans les solutions varie de 20 %m (25 °C) à 30 %m (40 °C). Les ASD de EFV dans le Soluplus contenant plus de 30 %m d'EFV doivent être surveillées pendant le stockage dans des conditions typiques de température. Ce diagramme de phases peut être considéré comme un outil de pré-formulation pour les chercheurs qui étudient de nouvelles ASD d'EFV dans le Soluplus afin de prédire la stabilité (thermodynamique et cinétique). Les ASD préparées par différentes techniques peuvent afficher des différences dans leurs propriétés physicochimiques. La deuxième partie de cette thèse portait sur la fabrication d’ASD par des procédés HME et SD. Cette étude montre clairement que la formation d’ASD est une stratégie de formulation utile pour améliorer la solubilité dans l'eau et la vitesse de dissolution de l'EFV à partir de mélanges binaires EFV-Soluplus. Les procédés de fabrication (HME et SD) se sont révélés efficaces pour générer des ASD dans une large gamme de compositions en EFV. L'optimisation du ratio EFV-Soluplus peut être utilisée pour adapter la libération cinétique des ASD. Le choix d’une charge EFV élevée dépassant la solubilité thermodynamique de l’EFV dans le Soluplus est possible, mais il convient de prendre en compte sa stabilité cinétique dans le temps. / The main difficulty when an Active Pharmaceutical Ingredient (API) is orally administered is to guarantee that the clinical dose of the API will be dissolved in the available volume of gastrointestinal fluids. However, about 40% of APIs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble and exhibits a poor oral absorption, which leads to a weak bioavailability. Amorphous solid dispersions (ASD) are considered as one of the most effective strategies to solve solubility limitations of poorly-water soluble compounds and hence, enhance their oral bioavailability. Despite their introduction as technical strategy to enhance oral APIs bioavailability more than 50 years ago, ASD formation and physical stability remains a subject of intense research. Indeed, several factors can influence the physical storage stability of ASD, among them, the glass transition temperature of the API-carrier binary mixture, the apparent solubility of the API in the carrier, interactions between API and carrier, and the manufacturing process. This thesis consisted of two parts that aim on developing new formulations of ASD of an antiretroviral API, Efavirenz (EFV), dispersed in an amphiphilic polymer, Soluplus, by using two different processes, Spray-drying (SD) and Hot-melt extrusion (HME). EFV is the class II BCS API of our choice because it is a challenging API for new formulations. It needs higher-dosed ASDs, for which chemical and physical stability during storage and dissolution will be critical. Aiming a rational development of high-loaded EFV-Soluplus ASDs, the first part focused on the construction of a temperature- composition EFV-Soluplus phase diagram. The phase-diagram was constructed from a thermal study of recrystallization of a supersaturated ASD (85 wt% in EFV), generated by spray drying. To our knowledge, this is the first study reporting a phase-diagram for this binary system. This phase-diagram is very useful and demonstrated that the EFV solubility in Soluplus ranges from 20 wt% (25 °C) to 30 wt% (40 °C). ASD of EFV in Soluplus containing more than 30 wt% of EFV should be monitored over storage under typical temperature conditions. This phase-diagram might be considered as a preformulation tool for researchers studying novel ASD of EFV in Soluplus, to predict (thermodynamic and kinetic) stability. ASD prepared by different techniques can display differences in their physicochemical properties. The second part of this thesis focused on the manufacturing of ASD by HME or SD processes. This study clearly shows that ASD is a useful formulation strategy to improve the aqueous solubility and the dissolution rate of EFV from EFV-Soluplus binary mixtures. HME and SD manufacturing processes demonstrated to be efficient to generate ASDs in a large range of compositions and loads of EFV. The optimization of EFV to Soluplus ratio can be used to tailor the release kinetics from ASD. The choice of a high EFV load exceeding the thermodynamic solid solubility in Soluplus is possible but it needs the consideration of its kinetic stability over time.

The main complication of aortocoronary reconstruction with vein grafts is restenosis in the course of time. The aim was to assess the effect of a periadventitial polyester system releasing sirolimus on intimal hyperplasia of autologous grafts. The controlled-release system comprises a polyester mesh coated with a sirolimus-eluting copolymer of L lactic acid and ε-caprolactone system designed to be wrapped around an autologous venous graft during its implantation. In vitro sirolimus release and its effects on smooth muscle and endothelial cells were assessed. In vitro, the copolymer-coated polyester mesh released sirolimus over a period of 6 weeks. Mesh-eluted sirolimus inhibited the growth of smooth muscle and endothelial cells in seven-day in vitro experiments. After seven days of sirolimus release from the mesh, smooth muscle and endothelial cell counts decreased by 29% and 75%, respectively, with the cells maintaining high viability. We implanted v. jugularis ext. into a. carotis communis in rabbits. The vein graft was either intact, or was wrapped with a pure polyester mesh, or with a sirolimus-releasing mesh. Three and six weeks after surgery, the veins were subjected to standard histological staining and the thicknesses of the tunica intima, the media and the intima-media complex were...

Les interactions aliment-médicaments nuisant aux processus de libération et/ou à la stabilité de leurs principes actifs doivent être caractérisées en raison de leurs conséquences adverses sur la biodisponibilité orale, l’efficacité thérapeutique et, dans le cas des agents anti infectieux, la sélection d’organismes résistants. Notre étude a évalué la relation entre l'efficacité de la libération in vitro de la chlortétracycline (CTC) et de la lincomycine (LIN) dans le liquide gastrique simulé de porc (LGSP) et la capacité de rétention d'eau (CRE) d’ingrédients couramment utilisés dans l’alimentation des porcs (tourteau de soja (TS), drèche de distillerie sèche avec solubles (DDS) et farine de viande et d'os (FVO), maïs, blé, et seigle), que l’on a fortifié avec 880 ppm de CTC ou 440 ppm de LIN. La CRE des ingrédients différait significativement (p <0,0001) et était maximale avec le TS, aussi bien dans l'eau que le LGSP. Le FVO avait une CRE significativement plus basse dans le LGSP que dans l'eau (p <.0001). Les effets du temps de trempage sur la CRE étaient négligeables pour tous les ingrédients (p> 0,50). La CRE diminue avec l'augmentation de la taille des particules pour tous les aliments, mais leurs relations différaient significativement (p<0.0001). Tous les ingrédients alimentaires testés ont diminué la vitesse et l'étendue de la dissolution des prémélanges de CTC et de LIN. Le CRE était le principal facteur qui a empêché la dissolution des deux médicaments (p <0,0001), tandis que le temps et la teneur en cendres des ingredients favorisaient significativement leur dissolution (p ≤ 0,008). En comparaison des prémélanges dissouts seuls, le DDS et le seigle ont libéré 80% de ces antibiotiques, tandis que le TS, le blé et le maïs en ont libéré entre 40 et 50%. La neutralisation du LGSP au pH intestinal porcin a diminué les proportions dissoutes d’antibiotiques, mais pas significativement (p>0.69). La CRE des ingrédients utilisés dans la fabrication d'aliments médicamenteux serait donc un indicateur prometteur des interactions aliment-prémélange médicamenteux de LIN et de CTC. Afin d'augmenter leur libération et leur potentiel thérapeutique, la formulation des aliments médicamenteux pourrait être améliorée en utilisant des ingrédients alternatifs, dont la CRE est moindre. / Food-drug interactions adversely affecting the release process and the stability of their active ingredients must be characterized because of their adverse consequences on oral bioavailability, therapeutic efficacy and, in the case of antibiotics, selection resistant organisms. Our study evaluated the relationship between the efficiency of the in vitro release of chlortetracycline (CTC) and lincomycin (LIN) in simulated pig gastric fluid (SPGF) and the water-holding capacity (WHC) of feedstuffs commonly used in pig feed (soybean meal (SBM), dry distillers' grain with solubles (DDGS) and meat and bone meal (MBM), corn (gC), wheat (gW), and rye (gR), which it was fortified with 880 ppm CTC or 440 ppm LIN. The WHC of ingredients differed significantly (p <0.0001) among feedstuffs with the highest value for SBM both in water and SPGF and lowest value for MBM. The MBM had a significantly lower WHC in SPGF than in water (p <.0001). The effects of soaking time on WHC were negligible for all feedstuffs (p> 0.50). The WHC decreased with increasing particle size for all feedstuffs, but their relationships differed significantly (p <0.0001). All the tested feedstuffs decreased the rate and extent of dissolution of the CTC and LIN premixes. WHC was the main factor that hindered the dissolution of both drugs (p <0.0001), while the time and ash content of the ingredients significantly favored their dissolution (p ≤ 0.008). Compared to the dissolved premixes alone, DDGS and gR released 80% of these antibiotics, while SBM, gW and gC released between 40% and 50%. Neutralization of SPGF at swine intestinal pH decreased the dissolved proportions of antibiotics, but not significantly (p> 0.69). The WHC of the used feedstuffs in the manufacture of medicated feed would therefore be a promising indicator of the feed-drug interactions of LIN and CTC. To increase their release and therapeutic potential, the formulation of medicated feeds could be improved by using alternative ingredients, with less WHC.

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[ES] El cáncer es una de las principales causas de muerte a nivel mundial. Los tratamientos anticancerígenos generalmente usados tienen diversos efectos secundarios producidos por su baja especificidad. Esta es una de las razones por las que se sigue en continua búsqueda de nuevos tratamientos. Dentro de estas nuevas investigaciones se encuentra el extenso campo de la nanomedicina, es decir, el estudio de nuevos materiales a escala nanométrica. Esta permite reducir dichos efectos secundarios aumentando la selectividad y especificidad de los tratamientos. Dentro de los nanomateriales se encuentran las nanopartículas de upconversion que son capaces de absorber luz en el infrarrojo cercano y emitirla en la región ultravioleta-visible. Por otro lado, desde el principio de la historia de la medicina la luz se ha empleado como forma de tratamiento teniendo un rol muy importante. Un inconveniente para dichos tratamientos suele ser la necesidad de emplear luz de la región ultravioleta-visible, pues las biomoléculas son capaces de absorber y produce daño celular. En este contexto, la presente Tesis Doctoral se centra en el estudio de nuevas formas de tratamiento anticancerígeno combinando nanomedicina y luz. Para ello se han desarrollado nuevos fármacos fototóxicos y nuevos materiales capaces de ser activados mediante luz infrarroja cercana. En primer lugar, se sintetizaron nuevas fluoroquinolonas para explorar sus propiedades fototóxicas para su uso en fotoquimioterapia (Capítulo 3 de la Tesis). Se estudiaron las características fotofísicas y fotoquímicas de los nuevos compuestos, además de su capacidad para producir mayor fototoxicidad en las células en comparación con las fluoroquinolonas como la lomefloxacina mediante la aplicación de luz ultravioleta. En base a los resultados obtenidos se realizó un estudio para determinar las diferencias entre las interacciones de algunas fluoroquinolonas dihalogenadas, incluidas las comentadas anteriormente, y biomoléculas como ADN y proteínas. La reactividad de sus intermedios fotogenerados también se estudió en el Capítulo 4. Tras conocer en profundidad la capacidad fototóxica de los nuevos fármacos, en el Capítulo 5 se llevó a cabo el diseño de un nanosistema compuesto por fluoroquinolonas y nanopartículas de conversión ascendente. Se demostró la alta capacidad fototóxica de este nuevo nanosistema. De esta manera, se generó actividad fototóxica a partir de una fluoroquinolona sin el uso de luz ultravioleta Por otro lado, la formación de profármacos abre la puerta a la administración selectiva de fármacos contra el cáncer. Los profármacos consisten en la unión fotolábil de una molécula capaz de ser activada por la luz y el fármaco de interés. Sin embargo, un conocimiento profundo de las propiedades fotofísicas y fotoquímicas del fotodisparador y de los potenciales redox de ambos miembros de la diada puede ser crucial para obtener la fotoliberación deseada. Así, en el Capítulo 6, se destacó la relevancia de estos datos utilizando un profármaco formado por un derivado de cumarina como molécula fotoactivable y colchicina como fármaco. Finalmente, en el Capítulo 7 se exploró la síntesis de un nuevo nanosistema que contiene un profármaco formado por un derivado de cumarina unido al fármaco contra el cáncer clorambucilo y nanopartículas biocomatibles de conversión ascendente. La adición de albúmina de suero humano como recubrimiento de las nanopartículas cumple la doble función de obtener nanopartículas biocompatibles y ser el lugar de carga del profármaco. / [CA] El càncer és una de les principals causes de mort a nivell mundial. Els tractaments anticancerígens generalment usats tenen diversos efectes secundaris produïts per la seva baixa especificitat. Aquesta és una de les raons per les que se segueix en contínua recerca de nous tractaments. Dins d'aquestes noves investigacions es troba l'extens camp de la nanomedicina, és a dir, l'estudi de nous materials a escala nanomètrica. Aquesta permet reduir aquests efectes secundaris augmentant la selectivitat i especificitat dels tractaments. Dins dels nanomaterials es troben les nanopartícules de upconversion que són capaços d'absorbir llum en l'infraroig proper i emetre-la en la regió ultraviolada-visible. D'altra banda, des del principi de la història de la medicina la llum s'ha emprat com a forma de tractament tenint un paper molt important. Un inconvenient per aquests tractaments sol ser la necessitat d'emprar llum de la regió ultraviolada-visible, ja que les biomolècules són capaços d'absorbir-la i produïr dany cel·lular. En aquest context, la present Tesi Doctoral es centra en l'estudi de noves formes de tractament anticancerigen combinant nanomedicina i llum. Per això s'han desenvolupat nous fàrmacs fototòxics i nous materials capaços de ser activats mitjançant llum infraroja propera. En primer lloc, es van sintetitzar noves fluoroquinolones per explorar les seves propietats fototòxiques per al seu ús en fotoquimioteràpia (Capítol 3 de la Tesi). Es van estudiar les característiques fotofísiques i fotoquímiques dels nous compostos, a més de la seva capacitat per produir major fototoxicitat en les cèl·lules en comparació amb les fluoroquinolones com la lomefloxacina mitjançant l'aplicació de llum ultraviolada. En base als resultats obtinguts es va realitzar un estudi per determinar les diferències entre les interaccions d'algunes fluoroquinolones dihalogenades, incloses les comentades anteriorment, i biomolècules com ADN i proteïnes. La reactivitat de les seves intermedis fotogenerats també es va estudiar en el Capítol 4. Després de conèixer en profunditat la capacitat fototòxica dels nous fàrmacs, en el Capítol 5 es va dur a terme el disseny d'un nanosistema compost per fluoroquinolones i nanopartícules de upconversion. Es va demostrar l'alta capacitat fototòxica d'aquest nou nanosistema. D'aquesta manera, es va generar activitat fototòxica a partir d'una fluoroquinolona sense l'ús de llum ultraviolada D'altra banda, la formació de profàrmacs obre la porta a l'administració selectiva de fàrmacs contra el càncer. Els profàrmacs consisteixen en la unió fotolábil d'una molècula capaç de ser activada per la llum i el fàrmac d'interès. No obstant això, un coneixement profund de les propietats fotofísiques i fotoquímiques del fotodisparador i dels potencials redox de tots dos membres de la diada pot ser crucial per obtenir el fotoalliberament desitjada. Així, en el Capítol 6, es va destacar la rellevància d'aquestes dades utilitzant un profàrmac format per un derivat de cumarina com a molècula fotoactivable i colquicina com a fàrmac. Finalment, en el Capítol 7 es va explorar la síntesi d'un nou nanosistema que conté un profàrmac format per un derivat de cumarina unit a l'fàrmac contra el càncer clorambucilo i nanopartícules biocomatibles de upconversion. L'addició d'albúmina de sèrum humà com a recobriment de les nanopartícules compleix la doble funció d'obtenir nanopartícules biocompatibles i ser el lloc de càrrega del profàrmac. / [EN] Cancer is one of the leading causes of death worldwide. Generally used anticancer treatments have various side effects produced by their low specificity. This is one of the reasons why the search for new treatments continues. Within these new investigations is the extensive field of nanomedicine, which can be explained as the study of new materials on a nanometric scale. It can be translated in the reduction of these side effects by increasing the selectivity and specificity of the treatments. Among the nanomaterials are upconversion nanoparticles that are capable of absorbing light in the near infrared and emit it in the ultraviolet-visible region. On the other hand, since the beginning of the history of medicine, light has been used as a form of treatment, having a very important role. A drawback for such treatments is sometimes the need to use light from the ultraviolet-visible region since biomolecules are capable of absorbing and causing cell damage. In this context, this Doctoral Thesis focuses on the study of new forms of anticancer treatment combining nanomedicine and light. For this, new phototoxic drugs and new materials capable of being activated by near infrared light have been developed. First, new fluoroquinolones were synthesized to explore their phototoxic properties for using in photochemotherapy (Chapter 3 of the Thesis). The photophysical and photochemical characteristics of the new compounds were studied, in addition to their ability to produce greater phototoxicity in cells than fluoroquinolones such as lomefloxacin by applying ultraviolet light. Based on the results obtained, a study was carried out to determine the differences between the interactions of some dihalogenated fluoroquinolones including the above commented, and biomolecules such as DNA and proteins. The reactivity of their photo-generated intermediates was also studied in Chapter 4. After a deep knowledge of the phototoxic capacity of the new drugs, design of a nanosystem composed of fluoroquinolones and upconversion nanoparticles was carried out in Chapter 5. The high phototoxic capacity of this new nanosystem was demonstrated. In this way phototoxic activity was generated from a fluoroquinolone without the use of ultraviolet light. On the other hand, the formation of prodrugs opens a door to the selective administration of anticancer drugs. Prodrugs consist of the photolabile binding of a molecule capable of being activated by light and the drug of interest. However, a knowledge of the photophysical and photochemical properties of the phototrigger as well as the redox potentials of both members of the dyad can be crucial to obtain the desired photorelease. Thus, in Chapter 6, the relevance of these data was highlighted using a prodrug formed by a coumarin derivative as a photoactivatable molecule and colchicine as a drug. Finally, in Chapter 7 the synthesis of a new nanosystem containing a prodrug formed by a derivative of coumarin linked to the anticancer drug chlorambucil, and upconversion biocompatible nanoparticles was explored. The addition of human serum albumin as a coating for the nanoparticles fulfills the dual function of obtaining biocompatible nanoparticles and being the loading site for the prodrug. / Anaya González, C. (2021). Design of New Up-conversion Systems for Anticancer Therapies [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/172665

An implantable closed-loop insulin delivery device (INsmart device) containing a glucose responsive gel has been developed within the INsmart research group, over a period of 10 years, to mimic pancreas. In this thesis, the reliability and performance capability of the INsmart device was studied for future clinical use. Investigations into the device material compatibility with insulin solution, assessed by monitoring insulin loss and degradant formation over a period of 31 days using RP-HPLC have shown that stainless steel and titanium are the most compatible materials. Polycarbonate contributes to insulin loss after 11 days, resin might not be the best material and polyurethane is the least compatible for future device designs. To study insulin delivery mechanism and kinetics from the device, fluorescently labelled human insulin (FITC-insulin) was synthesised and characterised using RP-HPLC and MS, to produce a product with predominantly di-labelled conjugate (>75%) with no unreacted FITC or native insulin. Clinically used insulin analogues were also fluorescently labelled to produce predominantly di-labelled FITC-insulin conjugate with potential future biological and in vitro applications. The drug release mechanism from the glucose sensitive gel held in the INsmart device, studied using fluorescein sodium was determined as a Fickian diffusion controlled release mechanism. The diffusion coefficient (D) for FITC-insulin in the non-polymerised dex2M-conA gel (NP gel) determined using mathematical models, QSS and TL slope methods was 1.05 ± 0.02 x 10-11 m2/s and in the cross-linked dex500MA-conAMA gel (CL gel) was 0.75 ± 0.06 x 10-11 m2/s. In response to physiologically relevant glucose triggers in the NP gel, the diffusivity of FITC-insulin increases with increasing glucose concentrations, showing a second order polynomial fit, device thus showing glucose sensitivity and graded response, mimicking pancreas. Rheological measurements further confirmed the gel glucose responsiveness demonstrated by a third order polynomial fit between FITC-insulin D and the NP complex viscosity in response to increasing glucose concentration. The knowledge of FITC-insulin diffusion kinetics in the gel has aided in making some theoretical predictions for the capability and performance of the INsmart device. Alternate device geometry and design optimisation is also explored.

CHARLES UNIVERSITY FACULTY OF PHARMACY IN HRADEC KRÁLOVÉ DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY Author: Tereza Pokorná Title of Diploma thesis Terbinafine-loaded biodegradable polymeric systems for topical administration Supervisor: PharmDr. Eva Šnejdrová, Ph.D. In the diploma thesis the released properties of solid dispersions with terbinafine, based on polyesters of D,L-lactic acid and glycol acid, branched with pentaerythritol and tripentaerythritol are studied. The theoretical part deals with solid dispersions, their classification and methods of preparation, methods of drug dissolution testing, properties, effect, use of terbinafine and preparations containing terbinafine. In the experimental part, solid dispersions were prepared by the melting method. The drug was incorporated into the polyester in the form of a hydrochloride or a base in a concentration of 10 % or 20 %. Some systems were plasticized with 30% triethyl citrate. Thin layers were formulated from solid dispersions, and drug dissolution tests were performed on phosphate buffer pH 7.4 at 37 řC. Assay of terbinafine released was performed spectrophotometrically at 223 nm and ultra-high performance liquid chromatography. Based on the results of this diploma thesis, it can be clearly stated that the suitable carrier of terbinafine...