Foram produzidos comprimidos de liberação prolongada de teofilina baseados em matrizes hidrofílicas de misturas de hidroxipropilmetilcelulose e etilcelulose e polietilenoglicol. O planejamento estatístico de mistura Design Expert® foi empregado na seleção da composição do sistema de controle da liberação e, numa segunda fase, para otimização das formulações de comprimidos. Foram produzidas 26 formulações por compressão direta e as características físico-químicas dos comprimidos como peso médio, friabilidade, dureza e teor de fármaco foram determinadas. A porcentagem de teofilina liberada foi avaliada conforme o método da Farmacopéia Americana 30 ed. (2007), para cápsulas de liberação prolongada (Teste 10 - pá), por um período de 8 horas. Conforme as farmacopéicas os comprimidos produzidos apresentaram características físico-químicas de acordo com as especificações, com exceção das formulações 2 e 3, para o teste de friabilidade, cujos valores foram superiores. Entretanto, quanto ao ensaio de dissolução, a formulação 13, constituída por 30% de etilcelulose, atendeu aos valores preconizados para liberação prolongada de teofilina. As respostas obtidas dos experimentos foram introduzidas no programa Design Expert® que gerou superfícies de respostas nas quais foi possível avaliar a influência da composição nos parâmetros friabilidade e porcentagem de teofilina liberada na dissolução. Dessa forma, foi possível obter 3 formulações com etilcelulose (13,50% a 15,90%), metilcelulose tipo E4MCR (6,90% a 8,10%) e metilcelulose tipo K4MPRCR (0,30% a 0,60%), com as características desejadas empregando o planejamento estatístico de mistura, com o número mínimo de experimentos sem a necessidade de estudar todas as possíveis combinações experimentais, abreviando o trabalho com ganho de tempo. Os resultados encontrados para friabilidade e dissolução nas formulações otimizadas foram próximos dos previstos pela análise de regressão e dentro dos valores especificados na Farmacopéia Americana 30 ed. 2007. / Controlled release dosage forms of theophylline were prepared with hidrophyllic matrix using polymers as hydroxy-methyl-cellulose, hydroxy-ethyl-cellulose and polyethylenglycol. The program Design Expert® was used to select polymers composition and at the second moment, to optimized tablets formulations. It was obtained 26 formulations by direct compression that physical-chemical characteristics of tablets as weight deviation, friability, hardness and drug dosage were performed. Dissolution rate of these tablets were controlled by United States Pharmacopeia 30 ed. Test for theophylline extended-release capsules (test 10 - paddle) corresponding to 8 hours of experiment. The evaluation indicates that tablets produced were in accordance with Brazilian Pharmacopoeia 4 ed., and United States Pharmacopoeia 30 ed., except for formulations 2 and 3 that the values for friability were low. And about dissolution rate of these tablets only formulation 13 applied to preconized value for dissolution method for theophylline extendedrelease capsules. Design Expert® was fed with the results obtained from experiments that showed surface result after that it were possible to analyze the influence of the composition of components on the friability and dissolution rate of theophylline parameters. Considering the specifications, 3 formulations were obtained and were analyzed. The results obtained were close to results predicted for regression analysis and in accordance with Brazilian Pharmacopoeia 4 ed., and United States Pharmacopoeia 30 ed. The proposed experimental Design Expert® program strategy should allow a rapid evaluation and identification of the parameters important in determining the drug release rate from matrix tablets, providing a powerful support for their rational selection during preformulation studies and thus shortening the time necessary for the development of effective dosage forms with the desired drug release behavior.

174 f. / Submitted by Ana Hilda Fonseca (anahilda@ufba.br) on 2013-08-20T15:49:02Z No. of bitstreams: 1 Tese de doutorado - Ingrid - VERSÃO FINAL - UFBA.pdf: 5563445 bytes, checksum: 8345d9745885c1103c219247c69338fc (MD5) / Approved for entry into archive by Ana Hilda Fonseca(anahilda@ufba.br) on 2013-08-20T15:51:20Z (GMT) No. of bitstreams: 1 Tese de doutorado - Ingrid - VERSÃO FINAL - UFBA.pdf: 5563445 bytes, checksum: 8345d9745885c1103c219247c69338fc (MD5) / Made available in DSpace on 2013-08-20T15:51:20Z (GMT). No. of bitstreams: 1 Tese de doutorado - Ingrid - VERSÃO FINAL - UFBA.pdf: 5563445 bytes, checksum: 8345d9745885c1103c219247c69338fc (MD5) Previous issue date: 2012 / O rincoforol (2-metil-5(E)hepteno-4-ol) é o maior constituinte do feromônio de agregação do macho do Rhynchophorus palmarum L. (Coleoptera: Curculionidade), um besouro que ataca diversas espécies de palmeiras e é o principal vetor do nematódeo Bursaphelenchus cocophylus, agente causador da doença do anel vermelho.No Brasil, esse besouro ataca principalmente o coqueiro e o dendezeiro, culturas de grande relevância econômica para o país. Esse feromônio vem sendo utilizado em iscas do tipo eppendorf com um orifício na tampa para controlar a população do besouro. Esse dispositivo facilita a liberação lenta quando comparada à evaporação direta do estado líquido. No entanto, a validade dessas iscas depende da velocidade de evaporação do rincoforol através do dispositivo, que libera quantidade excessiva do feromônio. Com o objetivo de prolongar o tempo de liberação do rincoforol, diferentes zeólitos foram sintetizados, caracterizados e avaliados em relação à sua utilização como adsorvente para o rincoforol. Para isso, a influência de variáveis como: estrutura do zeólito, razão Si/Al, natureza do cátion de compensação, dimensão de poros e acidez foi verificada para o processo de adsorção. Devido à falta de informações referente à estabilidade do rincoforol, foi realizado um estudo termogravimétrico sobre seu comportamento térmico. Estudos de recuperação demonstraram que houve interação entre o rincoforol e os zeólitos ZSM-5 e MCM-22 nas diferentes razões Si/Al, resultando na degradação do feromônio, inviabilizando seu uso como suporte para liberação prolongada. Os materiais silicalita-1, zeólito Y e zeólito L apresentaram bons resultados de recuperação e a liberação do rincoforol a partir desses materiais foi medida em uma termobalança em condição isotérmica. Resultados promissores foram observados quando a velocidade de liberação obtida a partir dos zeólitos foi comparada com o rincoforol comercial. Assim, os estudos realizados nesse trabalho permitiu selecionar zeólitos com grande potencial comercial como dispositivo liberador do rincoforol por um período prolongado. / Salvador

Submitted by RANIELLE DE OLIVEIRA SILVA null (ranielleborges@yahoo.com.br) on 2016-06-14T16:20:17Z No. of bitstreams: 1 DissertaçãoMestrado_Ranielle_Silva 2.pdf: 11995453 bytes, checksum: abf2ac6021bf67009b8af99fe28a0026 (MD5) / Approved for entry into archive by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2016-06-16T14:40:09Z (GMT) No. of bitstreams: 1 silva_ro_me_araiq_par.pdf: 1314893 bytes, checksum: 9254863d01a93bf48fa2f06ae37a9209 (MD5) / Made available in DSpace on 2016-06-16T14:40:09Z (GMT). No. of bitstreams: 1 silva_ro_me_araiq_par.pdf: 1314893 bytes, checksum: 9254863d01a93bf48fa2f06ae37a9209 (MD5) Previous issue date: 2016-05-09 / Híbridos Siloxano-PPO obtidos pela síntese sol-gel foram utilizados como matrizes carreadoras do fármaco cloridrato de propranolol com interesse de se aumentar a disponibilidade do fármaco em meio aquoso. Foram preparados amostras contendo teores de 5 e 30% do fármaco. A eficiência na formação da rede híbrida foi confirmada por análises FTIR, RMN e SAXS. A cinética de liberação mostrou que ela ocorre de forma prolongada (superior a 1200 h) com regimes intermitentes de aceleração e desaceleração da taxa de liberação. Foram aplicados ajustes matemáticos a cada regime utilizando a equação de Korsmayer-Peppas que demonstraram que a saída do fármaco ocorre por diferentes mecanismos. Observou-se que o acesso da água na amostra durante a liberação não é homogêneo, mas sim gradual da superfície ao centro. Devido a esses fenômenos as caracterizações foram feitas em diferentes regiões da amostra (periferia e centro) e em diferentes períodos da liberação, visando acompanhar a difusão da água para o interior da amostra e a cinética de saída do fármaco. As análises estruturais de DRX e as térmicas por TGA e DSC mostraram que o fármaco é incorporado na matriz híbrida na forma solubilizada e na forma cristalina. As medias realizadas em função do tempo mostraram que a velocidade de saída do fármaco e de entrada da água na matriz híbrida é maior na superfície em relação ao volume, confirmando o acesso gradual da água. Essas análises indicam a correlação entre as fases cristalina do fármaco com os primeiros regimes e da parte solubilizada com a liberação mais lenta. As medidas de DSC mostraram que o acesso da água em regiões mais internas da amostra resultaram no comportamento de confinamento da água, indicado pelo fenômeno de super congelamento. Foi detectado por medias de SAXS a existência de espalhadores secundários presentes em todas as amostras, inclusive nas matrizes híbridas sem a adição de fármaco, que foram atribuídos a agregados formados por domínios com maior densidade de nanopartículas de sílica. A evolução no tamanho desses agregados foi correlacionada aos regimes de liberação. Conclui-se, que a cinética de liberação tem uma forte dependência da evolução da matriz híbrida causadas por mudanças estruturais favorecidas pela mobilidade da cadeia polimérica e pela interação do fármaco com a água. / Siloxane-PPO hybrids obtained by sol-gel synthesis have been used as drug delivery systems for propranolol hydrochloride with the intent to increase the drug availability in the aqueous medium. Samples with 5% and 30% of drug have been prepared. The efficiency related to the formation of the hybrid network has been confirmed by means of FTIR, RMN and SAXS analyses. The drug delivery kinetics showed that it occurs in a prolonged form (more that 1200h) with increasing and decreasing intermediate release rates. The Korsmayer-Peppas equation has been used for each release rate with mathematical adjustments that displayed how the drug release occurred through different mechanisms. It has been observed that the water intake inside the sample during the drug release was not homogeneous but gradual, from the surface to the centre. Due to these phenomena, the characterizations have been carried out in different regions of the samples (exterior and interior) and at different drug delivery periods, aiming at accompanying the water diffusion to the sample centre and the drug release kinetics. The XRD structural analyses and the thermal analyses by means of TGA and DSC showed that the drug is incorporated in the hybrid matrix in a solubilized form and in a crystalline form. The tests done as function of time displayed that the drug release velocity and water intake inside the hybrid matrix is greater at the surface in relation to its volume, confirming the gradual access of water. These analyses point to the correlation between the drug crystalline phase with the first release regimes and between the solubilized form with the slower release. The DSC tests showed that the water intake inside more internal regions of the sample resulted in the water confinement, demonstrated by the super-cooling phenomenon. By means of SAXS, the existence in all the samples, including those without drug, of secondary scatterings has been observed and these have been attributed to aggregates formed by domains with a higher silica nanoparticle density. The size evolution of these aggregates has been correlated to the drug release regimes. It has been concluded that the drug release kinetics has a strong dependence with the hybrid matrix evolution caused by structural changes facilitated by polymer chain mobility and by drug/water interaction.

Foram produzidos comprimidos de liberação prolongada de teofilina baseados em matrizes hidrofílicas de misturas de hidroxipropilmetilcelulose e etilcelulose e polietilenoglicol. O planejamento estatístico de mistura Design Expert® foi empregado na seleção da composição do sistema de controle da liberação e, numa segunda fase, para otimização das formulações de comprimidos. Foram produzidas 26 formulações por compressão direta e as características físico-químicas dos comprimidos como peso médio, friabilidade, dureza e teor de fármaco foram determinadas. A porcentagem de teofilina liberada foi avaliada conforme o método da Farmacopéia Americana 30 ed. (2007), para cápsulas de liberação prolongada (Teste 10 - pá), por um período de 8 horas. Conforme as farmacopéicas os comprimidos produzidos apresentaram características físico-químicas de acordo com as especificações, com exceção das formulações 2 e 3, para o teste de friabilidade, cujos valores foram superiores. Entretanto, quanto ao ensaio de dissolução, a formulação 13, constituída por 30% de etilcelulose, atendeu aos valores preconizados para liberação prolongada de teofilina. As respostas obtidas dos experimentos foram introduzidas no programa Design Expert® que gerou superfícies de respostas nas quais foi possível avaliar a influência da composição nos parâmetros friabilidade e porcentagem de teofilina liberada na dissolução. Dessa forma, foi possível obter 3 formulações com etilcelulose (13,50% a 15,90%), metilcelulose tipo E4MCR (6,90% a 8,10%) e metilcelulose tipo K4MPRCR (0,30% a 0,60%), com as características desejadas empregando o planejamento estatístico de mistura, com o número mínimo de experimentos sem a necessidade de estudar todas as possíveis combinações experimentais, abreviando o trabalho com ganho de tempo. Os resultados encontrados para friabilidade e dissolução nas formulações otimizadas foram próximos dos previstos pela análise de regressão e dentro dos valores especificados na Farmacopéia Americana 30 ed. 2007. / Controlled release dosage forms of theophylline were prepared with hidrophyllic matrix using polymers as hydroxy-methyl-cellulose, hydroxy-ethyl-cellulose and polyethylenglycol. The program Design Expert® was used to select polymers composition and at the second moment, to optimized tablets formulations. It was obtained 26 formulations by direct compression that physical-chemical characteristics of tablets as weight deviation, friability, hardness and drug dosage were performed. Dissolution rate of these tablets were controlled by United States Pharmacopeia 30 ed. Test for theophylline extended-release capsules (test 10 - paddle) corresponding to 8 hours of experiment. The evaluation indicates that tablets produced were in accordance with Brazilian Pharmacopoeia 4 ed., and United States Pharmacopoeia 30 ed., except for formulations 2 and 3 that the values for friability were low. And about dissolution rate of these tablets only formulation 13 applied to preconized value for dissolution method for theophylline extendedrelease capsules. Design Expert® was fed with the results obtained from experiments that showed surface result after that it were possible to analyze the influence of the composition of components on the friability and dissolution rate of theophylline parameters. Considering the specifications, 3 formulations were obtained and were analyzed. The results obtained were close to results predicted for regression analysis and in accordance with Brazilian Pharmacopoeia 4 ed., and United States Pharmacopoeia 30 ed. The proposed experimental Design Expert® program strategy should allow a rapid evaluation and identification of the parameters important in determining the drug release rate from matrix tablets, providing a powerful support for their rational selection during preformulation studies and thus shortening the time necessary for the development of effective dosage forms with the desired drug release behavior.

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Technology Consultant: doc. RNDr. Milan Dittrich, CSc. Student: Marie Křivková Title of Thesis: Modification of parameters of nanoparticles prepared from aliphatic hydroxyacids polyesters Polyesters of aliphatic α-hydroxyacids are mentioned in the theoretical part. A significant part of it is mostly devoted to the polyester PLGA. Physicochemical properties, the process of biodegradation and biodistribution are described there. Subsequently, some examples of PLGA utilization in pharmacy and medicine are mentioned. The theoretical part deals also with the method of diffusion used for nanoparticles preparation, which was used in the experimental part, and the principles of size and surface charge measurements of these nanoparticles. The crucial part of this master thesis is based upon an experiment. It is focused on various approaches to the formulation of nanoparticles out of aliphatic polyester carriers with variable molecular constitution. Polymer PLGA with linear molecule and polymers containing PLGA branched on tripentaerythritol and polyacrylic acid were used. Using the diffusion method, nanoparticles were prepared out of these carriers. The outer water-based phase was modified by use of cetrimide of different...

L’une des principales problématiques du développement de produits biologiques, comme les probiotiques, réside dans l’impact du processus de fabrication sur la souche d’intérêt. Le maintien de l’activité thérapeutique est d’un intérêt capital pour obtenir l’effet bénéfique et, des travaux ont également optimisé les propriétés de la souche Lcr35® au travers du procédé de fabrication. Ainsi, toutes les étapes de fabrication du produit sont autant d’étapes qui peuvent modifier les caractéristiques de la souche bactérienne. La compression a été reconnue comme étant une étape qui permet d’éliminer les contaminations bactériennes et a également été décrite comme néfaste pour la viabilité d’une souche probiotique. Ces données constituent donc un a priori négatif au développement de probiotiques comprimés.Inversement, cette forme galénique est reconnue pour améliorer la demi-Vie des produits et améliorer la stabilité des bactéries dans un milieu gastrique. Cependant, aucune étude complète des propriétés d’une souche probiotique, après compression, n’a été effectuée. Or, afin d’établir un dossier d’AMM, toutes ces propriétés se doivent d’être vérifiées sur le produit final.Les travaux présentés se sont donc attachés à étudier les principales propriétés de la souche Lcr35® après compression. Tout d’abord, la perte de viabilité initiale en fonction de la pression de compression a été évaluée expérimentalement et une loi de décroissance d’ordre 1 est proposée. Un tel modèle permet ainsi d’anticiper la perte de viabilité selon la formulation et les conditions de compression. D’autre part, le profil génétique ainsi que le profil d’expression des gènes de la souche Lcr35® ont été étudiés après compression. Ni l’un ni l’autre n’a été modifié par le stress mécanique généré par la compression. De même, les propriétés d’inhibition du pathogène vaginal C. albicans ainsi que la résistance à pH acide de la souche sont maintenues. La résistance au pH gastrique est même améliorée par une protection mécanique vis-À-Vis du milieu.Selon les données de stabilité (ICH Q1A), la viabilité de la souche Lcr35® n’est pas non plus affectée par la compression. Les données de stabilité ont fait l’objet d’une modélisation par l’équation d’Arrhenius permettant d’obtenir un modèle fiable de prédiction de la stabilité, à partir des données en conditions accélérées (40°C).Dans une approche QbD de développement des produits pharmaceutiques, ces données serviront de base de comparaison pour la caractérisation de formulations en développement où des éléments tels que le milieu de culture, la souche ou la forme galénique peuvent être modifiés.Cette caractérisation globale de la souche Lcr35®, après compression, a permis d’infirmer l’a priori négatif sur la compression des bactéries. Ces travaux ont permis de comprendre, de caractériser et de modéliser les aspects liés à la compression des probiotiques. Ils constituent un prérequis primordial au développement d’un nouveau produit sous la forme d’un comprimé. Suite à une étape de développement complémentaire, ils ont d’ailleurs permis d’aboutir au premier produit commercialisé sous la forme d’un comprimé à libération prolongée, par la société Probionov : Gynophilus® LP.Ces données sur la compression élargissent la connaissance fondamentale de l’effet des procédés pharmaceutiques sur les propriétés des probiotiques et ouvrent de manière considérable leur champ de développement. Cette forme est un atout considérable en termes de stabilité mais surtout, elle fait intervenir de nombreuses perspectives de développement : gastro-Résistants, effervescents, multicouches, etc. Par l’intermédiaire de cette technologie, une administration plus ciblée de la souche par exemple dans les parties distales de l’intestin pourra être envisagée pour optimiser le bénéfice thérapeutique des souches probiotiques. Le but final étant de pouvoir diminuer la posologie des traitements tout en améliorant l’observance et le confort des patients. / One of the main issues in the development of biological products, such as probiotics, is the impact of the manufacturing process on the strain of interest. Maintaining therapeutic activity is of great interest for the expected beneficial effect and work has even optimized the properties of the Lcr35® strain through the manufacturing process. Therefore, all process stages leading to the final product are steps that can alter the characteristics of the bacterial strain.Compression is recognized in some publications as being a step which eliminates bacterial contaminations present for example in the excipients. For the development of new probiotic products, compression has also been described as negative for bacterial viability. These data are therefore a negative a priori on development of probiotic products in the tablet form. Conversely, this dosage form is known to improve the half-Life of products and improve the stability of bacteria in gastric environment. However, no comprehensive study of the properties of a probiotic strain after compression was done. Nevertheless, to establish a marketing authorization, all the properties of the strain must be checked on the final product.This work has proposed a review of the main properties of the Lcr35® strain after compression. First of all, the initial loss of viability as a function of compression pressure was studied experimentally and was modeled by a first order law. It allows us to anticipate the loss of viability of a strain depending on the formulation and compression conditions. Furthermore, the genetic profile and the profile of gene expression have not been changed due to the compression step. We also noticed that the inhibition properties of the pathogen C. albicans growth and acid resistance of the strain are maintained. Resistance to gastric pH is also enhanced by a phenomenon of mechanical protection against the environment.According to the data of stability under ICH conditions, the viability of the compressed Lcr35® strain is not affected by the compression. Stability data have therefore been modeled by the Arrhenius equation to obtain a reliable model for predicting the stability data from accelerated conditions (40°C). In a QbD approach to pharmaceutical development, these data serve as a basis of comparison for the characterization of developing formulations where parameters such as the culture environment, the drying method, the strain or the galenic form can be changed. This global characterization of Lcr35® strain after compression has set aside the negative a priori against the compression of bacteria. This work helped to understand, characterize and model aspects linked to probiotics compression. They are an essential prerequisite for the development of a new probiotic product in the form of a tablet. Following a further development step, they also helped to lead to the first product in the tablet form, marketed by the company Probionov : Gynophilus® LP (vaginal administration). These compression data considerably broaden the field of development of probiotics. Indeed, this form is a considerable advantage in terms of stability but more importantly, the tablet form involves many development opportunities: gastro-Resistant, effervescent, multi-Layered tablets, etc. Through this technology, a more targeted administration of the strain such as up to the colon may be considered to maximize the therapeutic benefit of the probiotic strains. The ultimate goal is to be able to decrease the dosage of treatment while improving observance of the treatment and the patient comfort.

Prolonged-release (PR) fampridine is the only approved medication to improve walking in multiple sclerosis (MS), having been shown to produce a clinically meaningful improvement in walking ability in the subset of MS patients with Expanded Disability Status Scale 4–7. Recent responder subgroup analyses in the phase III ENHANCE study show a large effect size in terms of an increase of 20.58 points on the patient-reported 12-item MS Walking Scale in the 43% of patients classified as responders to PR-fampridine, corresponding to a standardized response mean of 1.68. Use of PR-fampridine in clinical practice varies across Europe, depending partly on whether it is reimbursed. A group of European MS experts met in June 2017 to discuss their experience with using PR-fampridine, including their views on the patient population for treatment, assessment of treatment response, re-testing and retreatment, and stopping criteria. This article summarizes the experts’ opinions on how PRfampridine can be used in real-world clinical practice to optimize the benefits to people with MS with impaired walking ability.

Bakgrund: LARO i Sverige är omgärdat av strikta regler. Läkemedlen som används, däribland buprenorfin, intas dagligen övervakat av sjuksköterska de tre första månaderna och vidare till dess att patienten bedöms kunna ta läkemedlet på egen hand. Sedan 2018 finns buprenorfin som depotinjektion veckovis eller månadsvis, vilket innebär en ny omvårdnadssituation. Syfte: Att utforska sjuksköterskans perspektiv på införandet av buprenorfin som depotinjektion i LARO. Metod: Tolv semistrukturerade intervjuer av sjuksköterskor med erfarenhet av depotinjektioner buprenorfin i LARO. Resultat: Införandet av depotinjektioner innebar ett fokusskifte i behandling och omvårdnad med bland annat minskad kontroll och ökad tillit mellan sjuksköterska och patient. Behandlingen med depotinjektioner ansågs kunna öppna för ökad egenmakt för patienterna. LARO-enheternas organisatoriska förutsättningar påverkade hur de tagit sig an den nya behandlingsformen. Kunskap och samsyn efterfrågades. Slutsats: Depotinjektioner buprenorfin kan öppna upp för nya sätt att främja egenmakt i LARO. Det finns ett behov av forskning på området. / Background: Opioid substitution treatment in Sweden is strictly regulated. Medications like Buprenorphine are taken daily supervised by a nurse during the initial three months and thereafter until the patient is assessed to be trusted with self-administration. Prolonged-release injectable Buprenorphine has beenavailable since 2018 for weekly or monthly use. This has implications for nursing care and practices. Purpose: To explore the nurse’s perspective on introducing prolonged-release injectable buprenorphine in opioid substitution treatment. Method: Twelve semi-structured interviews were conducted with nurses experienced in treatment with prolonged-release injectable buprenorphine. Results: The introduction of injection treatment entailed a shift in focus regarding restrains, trust and patient empowerment. The care units’ approaches to the new treatment differed and was influenced by organisational conditions. Nurses requested more knowledge and consensus about the new treatment. Conclusion:Prolonged-release injectable formulations may enable new approaches to patientempowerment in opioid substitution treatment. Research in this field is required.