Le développement de nouvelles formes galéniques nécessite la mise au point de protocoles avec variation d’un ensemble de paramètres jouant sur les caractéristiques du dispositif. Au niveau industriel, cela représente une perte importante de temps et d’argent. Avec le développement d’outils permettant la caractérisation des systèmes et à fortiori des mécanismes impliqués dans la libération du principe actif, l’application des modèles mathématiques se voit être de plus en plus grande permettant de prédire la sortie du principe actif hors de son système. L’un des objectifs de ce travail a été de développer un modèle mathématique mécanique réaliste permettant de quantifier la libération de vitamines à partir de matrice lipidique. Deux techniques différentes de formulation : la compression directe et une suite d’extrusion en phase chauffante/ broyage/ compression directe ont permis la préparation de comprimés à base de Compritol 888 (glyceryl dibehenate NF). L’acide nicotinique a été utilisé comme principe actif modèle hautement soluble dans le milieu environnant. Des études de dissolution ont montrée une libération plus accrue pour des comprimés ayant une charge initiale en vitamine plus importante, cela liée à une augmentation de la porosité de la matrice avec l’épuisement graduel de la vitamine. Concernant la technique de préparation, un taux de sortie beaucoup plus faible dans le cas des comprimés préparés par extrusion en phase chauffante préalable, est mesuré, dû à un emprisonnement de la vitamine par la matrice fondue. A partir de ces observations et des connaissances sur les matrices lipidiques, un modèle basé sur les lois de diffusion de Fick et sur la considération de la coexistence d’une partie du principe actif sous forme dissoute ou non dissoute a été élaboré. Ce modèle permet la prédiction de la quantité de vitamine libérée au cours du temps en fonction de l’impact de la composition, de la technique de préparation et de la taille du système. Ces simulations in-silico sont d’une grande aide pour permettre d’accélérer la production de comprimés à base de Compritol 888. Dans le cas de systèmes multiparticulaires, et encore plus dans le cas de formes enrobées, des modèles mathématiques peuvent également être établis mais montrent une complexité plus grande, notamment due à la membrane polymérique. Dans cette optique, le développement de nouveaux outils pour caractériser les systèmes est primordial. Dernièrement la technologie Terahertz voit son potentiel comme nouvel outil dans la caractérisation de systèmes enrobés croissant. Son emploi dans la détection de différence de taille et d’uniformité de films polymériques d’enrobage pour des systèmes multicouches a été réalisé sur des granules de tailles conventionnelles (1mm de diamètre). Un premier enrobage de metoprolol succinate a été réalisé sur des noyaux de sucre, suivi d’un enrobage permettant le contrôle de la fuite du principe actif à base d’un mélange de Kollicoat SR :Kollicoat IR. Des granules avec différentes tailles d’enrobage ont été étudiées par Terahertz. Une taille homogène de la couche de principe actif pulvérisée a été montré dans tous les types de pellets ; alors qu’une taille croissante de l’enrobage polymérique 46 µm, 71 µm et 114 µm a pu être appréhendée. Ces résultats, mis en corrélation avec les méthodes de dissolution traditionnelles, permettront le développement d’une formule prédisant les cinétiques de libération à partir de la lecture non destructive de l’épaisseur d’enrobage par Térahertz.[...] / Development of new galenic devices needs series experiments with variation of number parameters. For industrial, it’s a lost in time and money. Food and Drug Administration initiated since several years, Process Analytical Technology (PAT) as a tool to analyze and control pharmaceutical process. These tools can be helpful to determine drug release mechanism and allow application of mathematical model to predict drug release kinetics. One objective of this work is to develop a mechanistically realistic mathematical model allowing for the quantification of vitamin release from Compritol 888 (glyceryl dibehenate NF)-based matrix tablets, prepared either by direct compression or via hot-melt extrusion/grinding/compression. Nicotinic acid has been used as highly soluble drug in surrounding medium. Dissolution studies show vitamin release rates increased with increasing initial niacin content, due to the increased matrix porosity upon vitamin depletion. In all cases, niacin release from tablets prepared via hot-melt extrusion was slower than from tablets prepared by direct compression, due to more intense embedding of the vitamin within the lipid. Importantly, a numerical model based on Fick’s law of diffusion and considering the co-existence of dissolved and non-dissolved vitamin could successfully be used to quantify vitamin release from both types of tablets, irrespective of the initial niacin loading and tablet size. In-silico simulations can be very helpful to accelerate product optimization of Compritol 888-based matrices, saving development time and costs. For multiparticulates systems, and more again for coated forms, mathematical models are more complexes. In this goal, development of new tools to characterize devices is primordial. Technology Terahertz offers an interesting potential. This technique can be used to detect difference in size and uniformity for polymeric film from multilayer pellets of 1 mm diameter. Pellets consisting of a sugar starter core and a metoprolol succinate layer were coated with a Kollicoat® SR: Kollicoat® IR polymer blend. Pellets with several coating thickness are studied. No drug layer thickness difference between batches was observed, and the average coating thicknesses were 46 µm, 71 µm and 114 µm, for the different batches. Terahertz results compared with experimental data from dissolution methods, allow predicting coating thickness results correlated with the subsequent drug release behavior. Multiparticulates systems have important interest: they allow avoiding “dose dumping”. Dose dumping is described as an unintended, rapid drug release in a short period of time of the entire amount or a significant fraction of the drug contained in a modified release dosage form (Meyer, 2005). This phenomenon can be observed in the case of ethylcellulose-based devices in presence with ethanol rich-media. Recently, ethylcellulose:guar gum blend have been reported to provide ethanol-resistant drug release kinetics from coated dosage forms. Theophylline matrix pellets were coated with ethylcellulose: guar gum blends. These granules show no change in drug release profiles upon contact with medium containing 40% of ethanol (v/v). This is because the ethanol insoluble guar gum effectively avoids undesired ethylcellulose dissolution in ethanol-rich bulk fluids. However, so far the importance of crucial formulation parameters, including the minimum amount of guar gum to be incorporated and the minimum required guar gum viscosity, remains unclear. It was found that more than 5% guar gum (referred to the total polymer content) must be incorporated in the film coating and that the apparent viscosity of a 1% aqueous guar gum solution must be greater than 150 cPs to provide ethanol-resistance. [...]

Les mini-granules enrobées offrent un grand potentiel pour la libération contrôlée de médicament par voie orale. Cependant, les mécanismes de libération impliqués ne sont pas toujours élucidés et compris. Ainsi, l’impact de certains paramètres de formulation peut être surprenant. Par exemple, il a été démontré dans ce travail :- La libération du propranolol HCl à partir de mini-granules enrobées avec du Kollicoat SR est plus lente si les mini-granules sont composées de noyaux de sucre comparé à des noyaux de cellulose microcristalline (CMC).Généralement, la tendance inverse est observée, car les noyaux de sucre ont une activité osmotique attirant plus rapidement l’eau à l’intérieur du système et entrainant ainsi, une dissolution et diffusion de la substance active. Ce résultat inattendu est dû à une association de 2 phénomènes : (i) l’effet plastifiant dû au sucre sur le film de Kollicoat SR et (ii) la diminution de la solubilité de cette SA dans le milieu de dissolution en présence de sucre dissous.De plus, le Kollicoat SR 30 D [dispersion aqueuse de poly(vinyl pyrrolidone)] offre des possibilités intéressantes de formulation par sa haute flexibilité et ses propriétés mécaniques stables. En revanche, les mini-granules composées de noyaux de sucre ont tendance à gonfler de par le cumul de l’activité osmotique du noyau et de la SA jusqu’à l’apparition de « cracks », révélés par des images obtenues par micro tomographie à rayons X.- Lorsqu’on augmente la quantité en propranolol HCl dans le système, la cinétique de libération est augmentée, particulièrement avec les mini-granules composées de noyaux de CMC.L’opposé est souvent constaté car accroitre la quantité de SA nécessite un plus grand apport en eau afin de pouvoir tout dissoudre. Les mini-granules à base de CMC présentent probablement des « cracks » malgré un faible gonflement du système, et sont accentués par l’augmentation de la concentration en propranolol HCl.En conclusion, des nouvelles connaissances sur les mécanismes de libération à partir de mini-granules enrobées avec du Kollicoat SR ont été apportées et l’importance du type de SA et la nature du noyau composant le système ont été élucidées.- Dans une deuxième partie, des mini-granules enrobées avec un mélange de polymère (Aquacoat ECD et Eudragit NM 30 D) ont été formulées dans le but de libérer la diprophylline, SA modèle, par diffusion à travers le film de polymère et de pouvoir modéliser sa cinétique à partir de modèles mathématiques. / Polymer coated pellets offer a great potential for control drug delivery system. Nevertheless, the underlying drug release mechanisms can be complex and are not fully understood. Thus, the impact of formulation parameters can be surprising. For example, it has been demonstrated during this thesis that:- The release of propranolol HCl was slower from sugar-based pellets coated with Kollicoat SR compared to microcrystalline cellulose (MCC)-based pellets.Generally, the opposite was observed because the sugar cores are osmotically active attracting more and more water into the system leading to a fast dissolution and diffusion of the drug, especially with high water-soluble drug. This unexpected result is due to a combination of two phenomena: (i) The plasticizing effect of sugar for the film coating and (ii) Decrease in drug solubility in the release medium due to the presence of co-dissolved sugar.In addition, Kollicoat SR 30 D [an aqueous dispersion of poly(vinyl acetate) also containing small amounts of poly(vinyl pyrrolidone) and sodium lauryl sulfate] is a very interesting polymer owing to its high flexibility and stable mechanical properties. However, sugar-based pellets tend to swell by the osmotic pressure created by the high water-soluble API and the sugar until crack formation, clearly visible on the images obtained by X-ray micro tomography.- Propranolol HCl release in phosphate buffer pH 7.4 increases by increasing the drug loading into the system, especially from MCC-based pellets.The opposite was often observed since the amount of water within the drug reservoir might not be sufficient to dissolve all drug. MCC-based pellets likely presented also cracks despite a low swelling of the system, accentuated by the increase of propranolol HCl concentration.To conclude, new insights on the underlying drug release mechanisms from Kollicoat SR coated pellets were provided. The importance of the type of drug and the nature of starter cores were elucidated.- In the second part, diprophylline loaded pellets coated with a polymer blend composed of Aquacoat ECD and Eudragit NM were prepared in order to control the drug release only by diffusion through the intact polymeric film and to predict the drug kinetics using mathematical models.

Sistemas monolíticos particulados contendo os constituintes ativos veiculados na forma de grânulos revestidos - pellets - têm recebido crescente atenção nos últimos anos, em função da otimização na biodisponibilidade e segurança na liberação do fármaco. A utilização destas unidades, como componentes de comprimidos traz, como principal vantagem, a divisibilidade da forma sem a perda do perfil biofarmacêutico desejado para o fármaco. Para sua produção, é indispensável a manutenção da integridade do revestimento daquelas unidades. Uma estratégia para o alcance deste objetivo envolve a utilização de grânulos inertes deformantes, comprimidos em conjunto com os grânulos revestidos, que atuam como um sistema de amortecimento das forças de compressão. Neste trabalho investigou-se a produção de grânulos deformantes através de dois métodos de granulação por via úmida, avaliando a influência de adjuvantes sobre as características dos produtos obtidos. Empregando a técnica de extrusão/esferonização obtiveram-se grânulos com propriedades de fluxo, empacotamento e resistência mecânica aceitáveis. O efeito dos adjuvantes sobre as etapas tecnológicas foi estudado por meio de um planejamento fatorial. Testaram-se duas variedades de celulose microcristalina, os desintegrantes croscarmelose sódica e crospovidona e soluções aglutinantes aquosas e hidroetanólicas de povidona. Para o desenvolvimento dos comprimidos utilizaram-se, como modelo, grânulos revestidos gastro-resistentes contendo omeprazol. A influência da composição dos grânulos deformantes sobre a liodisponibilidade do fármaco dos comprimidos foi avaliada através de análise fatorial 23. Os grânulos deformantes protegeram o revestimento polimérico dos pellets com diferentes intensidades. / Monolythic particulate systems containing the active constituents as coated pellets became great interest due to the improvement of safety and bioavailability. The use of such units as components of tablets shows as main advantages the divisibility of the pharmaceutical dosage form without loosing the desired biopharmaceutical profile of the drug. Consequently for the tablet production, the integrity of the polymeric film must be attained. A strategic option involves the utilization of inert soft pellets, which could be compressed together with the film coated pellets, absorbing the compaction forces. In this work the production of soft pellets was investigated using two wet granulation methods and evaluating the influence of formulation adjuvants on the pellets properties. The extrusion/spheronization technique yielded pellets with acceptable flow, packing and mechanical characteristics. The influence of the adjuvants on the technological steps was carried out through a statistical designed experiment. Microcrystalline cellulose from two producers, the disintegrants sodium croscarmellose and crospovidone, and aqueous and hydroethanolic dispersions of povidone, as binder, were tested. For the tablets development omeprazol gastroresistant film coated pellets were used as model. Aiming at the study of the influence of the soft pellets composition on drug lyoavailability was performed a 23 factorial experiment. The soft pellets protected at different intensities the polymeric coating of the gastroresistant pellets.

The reduction behaviour of the olivine iron ore pellet MPBOwas studied in laboratory scale at KTH as well as in the LKABexperimental blast furnace. Initially, a newreduction-under-load, or so-called reduction/softening/melting,test equipment was developed. Experiments using differentreducing conditions, corresponding to different radialpositions of the blast furnace, were conducted. The experimentsincluded different temperature profiles, reducing atmospheresand mechanical loads applied on the sample bed to simulate thevarying conditions in the blast furnace process. The progressof reduction was investigated, as well as the processes ofsintering and contraction during reduction. A model of thecarburisation (pick-up of carbon by the reduced iron) andmelt-down process during rapid contraction was presented. Laboratory testing of MPBO pellets was compared with resultsfrom the LKAB experimental blast furnace. The reduction of ironore pellets in the experimental blast furnace was surveyed by adissection of the furnace after quenching. The high temperaturephenomena occurring when reducing the MPBO pellet, with limitedsoftening and a short temperature range of the melting process,resulting in a thin cohesive zone, were found to be the same inlaboratorytests and in the experimental blast furnace. Thereduction down through the burden of the experimental blastfurnace was similar, but not identical to the results of theRUL experiments. The differences were found to be due todifferent reducing conditions. Therefore, it was concluded thata simulation of the reduction occurring in the blast furnacecan be performed in laboratory scale, provided the experimentalconditions are correctly chosen. Finally, a modification to further improve the properties ofthe MPBO pellets was examined. With the aim to improve theblast furnace process, coating of blast furnace pellets wasinvestigated in laboratory scale, as well as in the LKABexperimental blast furnace. Olivine, dolomite and quartzitewere used as coating agents. In laboratory scale the stickingprevention action of the different coating materials wasverified, in established test methods as well as in new testmethods, modified for blast furnace conditions. Testing of thecoated pellets in the experimental blast furnace revealedseveral advantages; significantly reduced blast furnace fluedust generation, improved gas utilisation and a smoother blastfurnace operation with a potential for a lowered fuel rate. <b>Keywords:</b>Olivine, pellets, pellet testing,reduction/softening/melting, MPBO, blast furnace, reduction,quenching, dissection, coating, sticking, coated pellets.

<p>The reduction behaviour of the olivine iron ore pellet MPBOwas studied in laboratory scale at KTH as well as in the LKABexperimental blast furnace. Initially, a newreduction-under-load, or so-called reduction/softening/melting,test equipment was developed. Experiments using differentreducing conditions, corresponding to different radialpositions of the blast furnace, were conducted. The experimentsincluded different temperature profiles, reducing atmospheresand mechanical loads applied on the sample bed to simulate thevarying conditions in the blast furnace process. The progressof reduction was investigated, as well as the processes ofsintering and contraction during reduction. A model of thecarburisation (pick-up of carbon by the reduced iron) andmelt-down process during rapid contraction was presented.</p><p>Laboratory testing of MPBO pellets was compared with resultsfrom the LKAB experimental blast furnace. The reduction of ironore pellets in the experimental blast furnace was surveyed by adissection of the furnace after quenching. The high temperaturephenomena occurring when reducing the MPBO pellet, with limitedsoftening and a short temperature range of the melting process,resulting in a thin cohesive zone, were found to be the same inlaboratorytests and in the experimental blast furnace. Thereduction down through the burden of the experimental blastfurnace was similar, but not identical to the results of theRUL experiments. The differences were found to be due todifferent reducing conditions. Therefore, it was concluded thata simulation of the reduction occurring in the blast furnacecan be performed in laboratory scale, provided the experimentalconditions are correctly chosen.</p><p>Finally, a modification to further improve the properties ofthe MPBO pellets was examined. With the aim to improve theblast furnace process, coating of blast furnace pellets wasinvestigated in laboratory scale, as well as in the LKABexperimental blast furnace. Olivine, dolomite and quartzitewere used as coating agents. In laboratory scale the stickingprevention action of the different coating materials wasverified, in established test methods as well as in new testmethods, modified for blast furnace conditions. Testing of thecoated pellets in the experimental blast furnace revealedseveral advantages; significantly reduced blast furnace fluedust generation, improved gas utilisation and a smoother blastfurnace operation with a potential for a lowered fuel rate.</p><p><b>Keywords:</b>Olivine, pellets, pellet testing,reduction/softening/melting, MPBO, blast furnace, reduction,quenching, dissection, coating, sticking, coated pellets.</p>

Sistemas monolíticos particulados contendo os constituintes ativos veiculados na forma de grânulos revestidos - pellets - têm recebido crescente atenção nos últimos anos, em função da otimização na biodisponibilidade e segurança na liberação do fármaco. A utilização destas unidades, como componentes de comprimidos traz, como principal vantagem, a divisibilidade da forma sem a perda do perfil biofarmacêutico desejado para o fármaco. Para sua produção, é indispensável a manutenção da integridade do revestimento daquelas unidades. Uma estratégia para o alcance deste objetivo envolve a utilização de grânulos inertes deformantes, comprimidos em conjunto com os grânulos revestidos, que atuam como um sistema de amortecimento das forças de compressão. Neste trabalho investigou-se a produção de grânulos deformantes através de dois métodos de granulação por via úmida, avaliando a influência de adjuvantes sobre as características dos produtos obtidos. Empregando a técnica de extrusão/esferonização obtiveram-se grânulos com propriedades de fluxo, empacotamento e resistência mecânica aceitáveis. O efeito dos adjuvantes sobre as etapas tecnológicas foi estudado por meio de um planejamento fatorial. Testaram-se duas variedades de celulose microcristalina, os desintegrantes croscarmelose sódica e crospovidona e soluções aglutinantes aquosas e hidroetanólicas de povidona. Para o desenvolvimento dos comprimidos utilizaram-se, como modelo, grânulos revestidos gastro-resistentes contendo omeprazol. A influência da composição dos grânulos deformantes sobre a liodisponibilidade do fármaco dos comprimidos foi avaliada através de análise fatorial 23. Os grânulos deformantes protegeram o revestimento polimérico dos pellets com diferentes intensidades. / Monolythic particulate systems containing the active constituents as coated pellets became great interest due to the improvement of safety and bioavailability. The use of such units as components of tablets shows as main advantages the divisibility of the pharmaceutical dosage form without loosing the desired biopharmaceutical profile of the drug. Consequently for the tablet production, the integrity of the polymeric film must be attained. A strategic option involves the utilization of inert soft pellets, which could be compressed together with the film coated pellets, absorbing the compaction forces. In this work the production of soft pellets was investigated using two wet granulation methods and evaluating the influence of formulation adjuvants on the pellets properties. The extrusion/spheronization technique yielded pellets with acceptable flow, packing and mechanical characteristics. The influence of the adjuvants on the technological steps was carried out through a statistical designed experiment. Microcrystalline cellulose from two producers, the disintegrants sodium croscarmellose and crospovidone, and aqueous and hydroethanolic dispersions of povidone, as binder, were tested. For the tablets development omeprazol gastroresistant film coated pellets were used as model. Aiming at the study of the influence of the soft pellets composition on drug lyoavailability was performed a 23 factorial experiment. The soft pellets protected at different intensities the polymeric coating of the gastroresistant pellets.

Sistemas monolíticos particulados contendo os constituintes ativos veiculados na forma de grânulos revestidos - pellets - têm recebido crescente atenção nos últimos anos, em função da otimização na biodisponibilidade e segurança na liberação do fármaco. A utilização destas unidades, como componentes de comprimidos traz, como principal vantagem, a divisibilidade da forma sem a perda do perfil biofarmacêutico desejado para o fármaco. Para sua produção, é indispensável a manutenção da integridade do revestimento daquelas unidades. Uma estratégia para o alcance deste objetivo envolve a utilização de grânulos inertes deformantes, comprimidos em conjunto com os grânulos revestidos, que atuam como um sistema de amortecimento das forças de compressão. Neste trabalho investigou-se a produção de grânulos deformantes através de dois métodos de granulação por via úmida, avaliando a influência de adjuvantes sobre as características dos produtos obtidos. Empregando a técnica de extrusão/esferonização obtiveram-se grânulos com propriedades de fluxo, empacotamento e resistência mecânica aceitáveis. O efeito dos adjuvantes sobre as etapas tecnológicas foi estudado por meio de um planejamento fatorial. Testaram-se duas variedades de celulose microcristalina, os desintegrantes croscarmelose sódica e crospovidona e soluções aglutinantes aquosas e hidroetanólicas de povidona. Para o desenvolvimento dos comprimidos utilizaram-se, como modelo, grânulos revestidos gastro-resistentes contendo omeprazol. A influência da composição dos grânulos deformantes sobre a liodisponibilidade do fármaco dos comprimidos foi avaliada através de análise fatorial 23. Os grânulos deformantes protegeram o revestimento polimérico dos pellets com diferentes intensidades. / Monolythic particulate systems containing the active constituents as coated pellets became great interest due to the improvement of safety and bioavailability. The use of such units as components of tablets shows as main advantages the divisibility of the pharmaceutical dosage form without loosing the desired biopharmaceutical profile of the drug. Consequently for the tablet production, the integrity of the polymeric film must be attained. A strategic option involves the utilization of inert soft pellets, which could be compressed together with the film coated pellets, absorbing the compaction forces. In this work the production of soft pellets was investigated using two wet granulation methods and evaluating the influence of formulation adjuvants on the pellets properties. The extrusion/spheronization technique yielded pellets with acceptable flow, packing and mechanical characteristics. The influence of the adjuvants on the technological steps was carried out through a statistical designed experiment. Microcrystalline cellulose from two producers, the disintegrants sodium croscarmellose and crospovidone, and aqueous and hydroethanolic dispersions of povidone, as binder, were tested. For the tablets development omeprazol gastroresistant film coated pellets were used as model. Aiming at the study of the influence of the soft pellets composition on drug lyoavailability was performed a 23 factorial experiment. The soft pellets protected at different intensities the polymeric coating of the gastroresistant pellets.

Submitted by Cássia Santos (cassia.bcufg@gmail.com) on 2015-01-30T10:47:22Z No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Dissertação - Rodrigo Gomes de Alencar - 2014.pdf: 13066901 bytes, checksum: 15e26e7a3dde863c6267ef54f83385be (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2015-01-30T12:58:45Z (GMT) No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Dissertação - Rodrigo Gomes de Alencar - 2014.pdf: 13066901 bytes, checksum: 15e26e7a3dde863c6267ef54f83385be (MD5) / Made available in DSpace on 2015-01-30T12:58:45Z (GMT). No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Dissertação - Rodrigo Gomes de Alencar - 2014.pdf: 13066901 bytes, checksum: 15e26e7a3dde863c6267ef54f83385be (MD5) Previous issue date: 2014-04-25 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Ketoprofen is a nonsteroidal anti-inflammatory drug used for the treatment of mild to moderate pain in chronic inflammatory conditions. Due to its superior potency ketoprofen can be used in the treatment of inflammatory bowel disease (IBD). The treatment of IBD becomes safer and more effective when the drug is incorporated into colon-specific drug delivery systems. Pellets are multiparticulate solid dosage forms extensively investigated as colon-specific drug delivery systems. Pellets can be introduced into capsules or compressed into tablets. The industrial production of tablets containing pellets has several advantages when compared to the production of capsules. However, the compression of the pellets should not affect the release of the drug and the tablets should quickly disintegrate following administration. Therefore, the aim of this study was to develop tablets containing ketoprofen coated pellets for colon-specific drug release. For this, pellets were produced by extrusion and spheronization technique containing 40% (w / w) ketoprofen. Ketoprofen pellets obtained were coated with two different pH - dependent polymers derived from methacrylic acid (Opadry ® k 94 or Eudragit ® FS 30D) with weight gains of 10 or 20% (w / w). The coated pellets were then compressed under different pellets’ amounts and different compression forces. An extra- granular mixture of lactose and microcrystalline cellulose was used as compression aid. The in vitro release of ketoprofen from the systems obtained was evaluated in Bio Dis ® apparatus. The morphological and physical properties of pellets and tablets were assessed. The Eudragit ® FS 30 D coated pellets with weight gains of 10 or 20% showed higher efficiency of colon-specific delivery (94 %), however, the drug was released slowly and incompletely in conditions mimicking the pH of the colonic region. After compression of the pellets, the efficiency of colon – specific drug delivery was lowered after compression (between 20% and 61%, depending on the formulation). The lowest decrease of colon specific efficiency was observed in formulations containing lower amount of pellets, which also produced disintegrating matrices with potential for use in the topical treatment of IBD. / O cetoprofeno é um antiinflamatório não esteroidal usado para o tratamento de dores leves a moderadas, em condições inflamatórias crônicas. Devido a sua elevada potência antiinflamatória, o cetoprofeno pode ser aproveitado no tratamento das doenças inflamatórias intestinais (DII). O tratamento das DII se torna mais seguro e eficaz quando o fármaco é incorporado em sistemas de liberação cólon-específica. Pellets são formas farmacêuticas multiparticuladas bastante investigadas como sistemas de liberação cólon-específica. Após sua produção, os pellets podem ser inseridos em cápsulas ou comprimidos. A produção industrial de comprimidos contendo pellets apresenta inúmeras vantagens quando comparada ao processo de enchimento de cápsulas. No entanto, a compressão dos pellets não deve afetar as características de liberação do fármaco e os comprimidos formados devem se desintegrar rapidamente. Dessa forma, o objetivo deste trabalho foi desenvolver comprimidos contendo pellets revestidos para liberação cólon-específica de cetoprofeno. Para tanto, foram produzidos pellets contendo 40% (p/p) de cetoprofeno e celulose microcristalina pela técnica de extrusão e esferonização. Os pellets de cetoprofeno obtidos foram revestidos com dois diferentes polímeros pH-dependentes, ambos derivados do ácido metacrílico (Opadry ® 94 k ou Eudragit ® FS 30) com ganhos de massa 10 ou 20% (p/p). Os pellets revestidos foram então comprimidos com diferentes cargas de pellets e submetidos a diferentes forças de compressão, utilizando como adjuvante extra-pellets uma mistura granulada de lactose e celulose microcristalina. A liberação in vitro do cetoprofeno a partir das formas farmacêuticas obtidas foi avaliada em dissolutor Bio Dis aparato III. As caracterizações morfológicas e físicas dos pellets e comprimidos foram conduzidas. Os pellets obtidos por revestimento com Eudragit ® FS 30 D, com ganhos de massa de 10 ou 20%, mostraram elevada eficiência de liberação cólon-específica in vitro (até 94%), no entanto, o fármaco foi liberado de forma lenta e incompleta em meio com pH similar ao encontrado na região colônica. Após a compressão dos pellets, os valores de eficiência de liberação cólon-específica sofreram reduções entre 20% e 61%. A menor diminuição da eficiência de liberação cólon-específica foi observada nas formulações contendo a menor carga de pellets, as quais deram origem à matrizes desintegráveis com potencial para utilização no tratamento tópico das DII.