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A dissolução de um fármaco a partir de uma forma farmacêutica (FF) sólida oral é um pré-requisito para que o mesmo seja absorvido pelo organismo e cumpra seus efeitos terapêuticos. O ensaio de dissolução de medicamentos permite avaliar a quantidade de princípio ativo que é liberado a partir de sua FF, mimetizando in vitro o processo que ocorre no trato gastrointestinal (TGI). O DDDPlus® é o único programa de computador dedicado exclusivamente a simular ensaios de dissolução. O objetivo deste trabalho foi avaliar a capacidade do programa de computador DDDPlus® em fornecer perfis de dissolução in silico de comprimidos matriciais contendo metformina semelhantes aos perfis de dissolução in vitro e avaliar a possibilidade de substituir a comparação de perfis de dissolução in vitro de diferentes formulações de comprimidos matriciais contendo metformina pela comparação de perfis de dissolução in silico fornecidos pelo DDDPlus®.Para tanto, um planejamento estatístico foi realizado para obtenção de perfis de dissolução, variando a velocidade das pás e o uso do sinker. Os perfis de dissolução de 3 formulações teste (T1, T2 e T3) de comprimidos de liberação modificada por matriz polimérica contendo metformina foram comparadas pelos métodos de eficiência de dissolução (ED), tempo médio de dissolução (TMD), fator de diferença (f2) e fator de semelhança (f1). Os resultados indicaram o uso do sinker como fator determinante para a ED e TMD. Assim, o método que utilizava o sinker e a velocidade das pás de 50RPM foi utilizado para avaliar 4 produtos comercializados no Brasil. No DDDPlus® os ensaios de dissolução in vitro das formulações T1, T2 e T3 foram otimizadas para a obtenção das constantes de calibração (CC), as CC foram utilizadas para simular os ensaios de dissolução de T1, T2 e T3 em velocidades de 25 e 50RPM. Os perfis de dissolução simulados foram comparados aos perfis observados, resultando em valores de R2. Valores de R2 acima de 0,90 foram obtidos para todas as simulações realizadas utilizando CC de ensaios in vitro que utilizaram sinker, indicando o potencial do programa em auxiliar o desenvolvimento de novas formulações. Valores de R2 abaixo de 0,70 foram obtidos após a simulação de ensaios utilizando CC de ensaios in vitro que não utilizavam o sinker, indicando que o programa de computador não previu a adesão do comprimido ao fundo da cuba de dissolução durante o ensaio. Os perfis de dissolução simulados das formulações T1, T2 e T3 foram comparadas por f1 e f2 com os perfis de dissolução dos produtos do mercado. Tais comparações concluíram que o software não é indicado como substituto dos ensaios in vitro quando se almeja comparar perfis de dissolução. / Dissolution of a drug from an oral solid pharmaceutical form (FF) is a prerequisite for it to be absorbed by the body and to fulfill its therapeutic effects. in vitroDrug dissolution assay allows the amount of active principle released from a FF and mimics the in vivo the process that occurs in the gastrointestinal tract (TGI). DDDPlus® is the only computer program dedicated exclusively to simulating dissolution testing. The objective of this work was to evaluate the ability of DDDPlus® software to provide in silico dissolution profiles of matrix tablets containing metformin similar to in vitro dissolution profiles and to evaluate the possibility of replacing in vitro dissolution profiles comparison of different formulations of matrix tablets containing metformin for a comparison of in silico dissolution profiles provided by DDDPlus®. For this purpose, a statistical design was used, varying agitation speed and the use of sinker to obtain dissolution profiles for 3 test formulations (T1, T2 and T3) of polymer matrix-modified release tablets containing metformin. Dissolution profiles were compared by means of dissolution efficiency (ED), mean dissolution time (TMD), difference factor (f2) and similarity factor (f1). The results indicated the use of sinker as a determinant factor for ED and TMD. Thus, the method that used sinker and agitation speed of 50RPM was used to evaluate 4 products commercialized in Brazil. in vitro dissolution tests of the T1, T2 and T3 formulations were optimized using In DDDPlus® to obtain the calibration constants (CC), which were used to simulate dissolution profiles of T1, T2 and T3 at speeds of 25 and 50RPM. in silico dissolution profiles were compared to in vitro dissolution profiles, resulting in R2 values. R2 values above 0.90 were obtained for all simulations performed using CC from in vitro assays using sinker, indicating the potential of the program to assist the development of new formulations. R2 values below 0.70 were obtained after the simulation of assays using CC from in vitro assays that did not use the sinker, indicating that the computer program did not predict adhesion of the tablet to the bottom of the dissolution cell during the assay. The simulated dissolution profiles of the T1, T2 and T3 formulations were compared by f1 and f2 with the dissolution profiles of the market products. Such comparisons concluded that the software is not indicated as a substitute for in vitro assays when comparing dissolution profiles is desired.

A dissolução de um fármaco a partir de uma forma farmacêutica (FF) sólida oral é um pré-requisito para que o mesmo seja absorvido pelo organismo e cumpra seus efeitos terapêuticos. O ensaio de dissolução de medicamentos permite avaliar a quantidade de princípio ativo que é liberado a partir de sua FF, mimetizando in vitro o processo que ocorre no trato gastrointestinal (TGI). O DDDPlus® é o único programa de computador dedicado exclusivamente a simular ensaios de dissolução. O objetivo deste trabalho foi avaliar a capacidade do programa de computador DDDPlus® em fornecer perfis de dissolução in silico de comprimidos matriciais contendo metformina semelhantes aos perfis de dissolução in vitro e avaliar a possibilidade de substituir a comparação de perfis de dissolução in vitro de diferentes formulações de comprimidos matriciais contendo metformina pela comparação de perfis de dissolução in silico fornecidos pelo DDDPlus®.Para tanto, um planejamento estatístico foi realizado para obtenção de perfis de dissolução, variando a velocidade das pás e o uso do sinker. Os perfis de dissolução de 3 formulações teste (T1, T2 e T3) de comprimidos de liberação modificada por matriz polimérica contendo metformina foram comparadas pelos métodos de eficiência de dissolução (ED), tempo médio de dissolução (TMD), fator de diferença (f2) e fator de semelhança (f1). Os resultados indicaram o uso do sinker como fator determinante para a ED e TMD. Assim, o método que utilizava o sinker e a velocidade das pás de 50RPM foi utilizado para avaliar 4 produtos comercializados no Brasil. No DDDPlus® os ensaios de dissolução in vitro das formulações T1, T2 e T3 foram otimizadas para a obtenção das constantes de calibração (CC), as CC foram utilizadas para simular os ensaios de dissolução de T1, T2 e T3 em velocidades de 25 e 50RPM. Os perfis de dissolução simulados foram comparados aos perfis observados, resultando em valores de R2. Valores de R2 acima de 0,90 foram obtidos para todas as simulações realizadas utilizando CC de ensaios in vitro que utilizaram sinker, indicando o potencial do programa em auxiliar o desenvolvimento de novas formulações. Valores de R2 abaixo de 0,70 foram obtidos após a simulação de ensaios utilizando CC de ensaios in vitro que não utilizavam o sinker, indicando que o programa de computador não previu a adesão do comprimido ao fundo da cuba de dissolução durante o ensaio. Os perfis de dissolução simulados das formulações T1, T2 e T3 foram comparadas por f1 e f2 com os perfis de dissolução dos produtos do mercado. Tais comparações concluíram que o software não é indicado como substituto dos ensaios in vitro quando se almeja comparar perfis de dissolução. / Dissolution of a drug from an oral solid pharmaceutical form (FF) is a prerequisite for it to be absorbed by the body and to fulfill its therapeutic effects. in vitroDrug dissolution assay allows the amount of active principle released from a FF and mimics the in vivo the process that occurs in the gastrointestinal tract (TGI). DDDPlus® is the only computer program dedicated exclusively to simulating dissolution testing. The objective of this work was to evaluate the ability of DDDPlus® software to provide in silico dissolution profiles of matrix tablets containing metformin similar to in vitro dissolution profiles and to evaluate the possibility of replacing in vitro dissolution profiles comparison of different formulations of matrix tablets containing metformin for a comparison of in silico dissolution profiles provided by DDDPlus®. For this purpose, a statistical design was used, varying agitation speed and the use of sinker to obtain dissolution profiles for 3 test formulations (T1, T2 and T3) of polymer matrix-modified release tablets containing metformin. Dissolution profiles were compared by means of dissolution efficiency (ED), mean dissolution time (TMD), difference factor (f2) and similarity factor (f1). The results indicated the use of sinker as a determinant factor for ED and TMD. Thus, the method that used sinker and agitation speed of 50RPM was used to evaluate 4 products commercialized in Brazil. in vitro dissolution tests of the T1, T2 and T3 formulations were optimized using In DDDPlus® to obtain the calibration constants (CC), which were used to simulate dissolution profiles of T1, T2 and T3 at speeds of 25 and 50RPM. in silico dissolution profiles were compared to in vitro dissolution profiles, resulting in R2 values. R2 values above 0.90 were obtained for all simulations performed using CC from in vitro assays using sinker, indicating the potential of the program to assist the development of new formulations. R2 values below 0.70 were obtained after the simulation of assays using CC from in vitro assays that did not use the sinker, indicating that the computer program did not predict adhesion of the tablet to the bottom of the dissolution cell during the assay. The simulated dissolution profiles of the T1, T2 and T3 formulations were compared by f1 and f2 with the dissolution profiles of the market products. Such comparisons concluded that the software is not indicated as a substitute for in vitro assays when comparing dissolution profiles is desired.

Submitted by José Sidnaldo Pinsetta Junior (j.pinsetta@gmail.com) on 2018-09-10T13:07:04Z No. of bitstreams: 1 Dissertação José Sidnaldo final - repositorio.pdf: 4492049 bytes, checksum: 4ab3eb4e73554043616e04c8821af820 (MD5) / Approved for entry into archive by Neli Silvia Pereira null (nelisps@fcav.unesp.br) on 2018-09-10T18:26:39Z (GMT) No. of bitstreams: 1 pinsettajunior_js_me_jabo.pdf: 4492049 bytes, checksum: 4ab3eb4e73554043616e04c8821af820 (MD5) / Made available in DSpace on 2018-09-10T18:26:39Z (GMT). No. of bitstreams: 1 pinsettajunior_js_me_jabo.pdf: 4492049 bytes, checksum: 4ab3eb4e73554043616e04c8821af820 (MD5) Previous issue date: 2018-07-12 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A berinjela é uma olerícola de grande importância em diversos países e seu consumo tem aumentado no Brasil devido às características nutricionais para a alimentação humana. No entanto, esse vegetal apresenta limitações de comercialização como produto minimamente processado devido ao rápido escurecimento enzimático após o corte. O objetivo deste trabalho foi estudar os efeitos do recobrimento comestível a base de hidroxipropilmetilcelulose (HPMC) combinado, ou não, com agentes antiescurecimento sobre a qualidade de berinjelas minimamente processadas (BMP). Foram utilizadas berinjelas da cv Nápoli higienizadas e processadas em cubos, com posterior aplicação os recobrimentos por aspersão. Na primeira etapa foram testadas três formulações de HPMC + Cera de Abelha (CA) nas concentrações de 20, 40 e 60%. No segundo experimento testou-se o efeito do HPMC associado ao ácido cítrico (0,5; 1 e 1,5 %) e no terceiro experimento, ao ácido ascórbico (0,5; 1 e 1,5 %). As BPM foram acondicionadas em embalagens de PET (Polietileno tereftalato) e armazenadas em expositores refrigerados a 5°C. As análises foram realizadas a cada 3 dias até 12 dias, determinando-se a perda acumulada de massa fresca, firmeza, índice de brancura, composição gasosa do interior da embalagem, determinação de acetaldeído e etanol, compostos fenólicos totais, atividade das enzimas polifenoloxidase (PPO), peroxidase (POD) e fenilalanina amônia-liase (PAL), e contagem microbiana (microrganismos aeróbios mesófilos, coliformes totais e E. coli). O recobrimento com HPMC+40% de cera de abelha reduziu a atividade de enzimas responsáveis pelo escurecimento e a adição de 0,5% de ácido cítrico ou 1% de ácido ascórbico ao recobrimento levou a uma menor síntese de compostos fenólicos e menor atividade enzimática. / The eggplant is a vegetable of great importance in many countries and it has an increasing consumption in Brazil thanks to nutritional benefits for human health. Nevertheless, it presents limitations to commercialization due to fast enzymatic browning after cutting. The aim of this Project was to study the effects of an edible coating Hydroxypropyl methylcellulose (HPMC) based in association, or not, with food aditives on the quality of fresh-cut eggplant (FCE). Eggplants cv. "Napoli" were sanitised and processed in cubes of 2,5 x 2,5 x 2,5 cm and later sprayed with the coatings. In the first step, three HPMC and Beewax (BW), 20, 40 and 60% emulsions were tested. In the second experiment, the effect of HPMC+40% BW associated with citric acid (0,5; 1 e 1,5 %) were assessed and in a third experiment, in association with ascorbic acid (0,5; 1 e 1,5 %). The FCE was packed in PET trays and stored at 5°C. Analysis were carried out each 3 days until 12 days. It was assessed the accumulated loss of fresh matter, firmness, whiteness index, atmosphere inside packaging, acetaldehyde and ethanol determination, total phenols, enzyme activity of polyphenol oxidase (PPO), peroxidase (POD), phenylalanine ammonia-lyase (PAL) and microbiology counting (total mesophilic aerobic count, total coliforms and E. coli). The coating with HPMC+40% BW reduced the activity of enzymes responsible for browning and the addition of 0,5% of citric acid or 1% of ascorbic acid to the coating led to a lower synthesis of phenolic compounds and to lower enzymatic activity. / FAPESP: 2016/23600-1

Tesis por compendio / [ES] La criopreservación de semen de peces es una técnica que puede aumentar la eficiencia de la reproducción en cautiverio de especies de peces de agua dulce y marinas. A lo largo de las últimas décadas, se han establecido protocolos para criopreservación de semen de diversas especies de peces. Sin embargo, el foco principal de los pescadores ha sido en tener éxito en el congelamiento y descongelamiento de los espermatozoides, no llevando en cuenta el período en que los gametos se quedan expuestos a la solución crioprotectora en un momento previo a la fertilización. Esta exposición de los espermatozoides a las soluciones crioprotectoras después del descongelamiento puede ser perjudicial a la calidad de los gametos, ya que pueden ser tóxicos. La mayoría de los protocolos establecidos utilizan recipientes de plástico ultrarresistentes para almacenar el semen durante el proceso de criopreservación. Estos recipientes normalmente no se reutilizan, generando residuos altamente contaminantes al medio ambiente. Así, el objetivo principal de la tesis fue crear y probar métodos de bajo costo que potencialicen el uso de los espermatozoides descongelados de peces y torne el proceso de criopreservación de semen menos contaminante al medio ambiente. Los experimentos de los capítulos 1 y 2 se llevaron a cabo en Brasil. Utilizamos el jundiá gris Rhamdia quelen, especie considerada modelo experimental para peces nativos de América del Sur. En el capítulo 1, probamos el uso de la dilución de semen descongelado para disminuir la toxicidad de la solución crioprotectora. La técnica se utiliza comúnmente en protocolos de criopreservación de semen de mamíferos, pero nunca antes se había aplicado al semen descongelado de peces suramericanos. Muestras de semen descongelado de R. quelen se diluyeron en un diluyente salino (NaCl al 1,1% - 325 mOsm kg-1; pH 7,6). Después, observamos que los espermatozoides de muestras diluidas mostraron mayores velocidades, rectitud, progresión y frecuencia de batido flagelar que las muestras no diluidas. La dilución del semen descongelado también proporcionó mayores tasas de fertilización y eclosión que el grupo no diluido. De esta manera, la dilución de semen descongelado de R. quelen resultó ser una metodología sencilla, económica y eficiente que debe incluirse en el protocolo de criopreservación del semen de la especie. En los capítulos 2 y 3 desarrollamos y probamos la metodología para el uso de cápsulas de gelatina biodegradables (colágeno) y cápsulas de hipromelosa biodegradables (HPMC) como recipiente alternativo al uso de pajuelas de plástico en la criopreservación de semen de peces. En el segundo capítulo observamos que las cápsulas biodegradables mantuvieron los parámetros cinéticos y la capacidad reproductiva del esperma de R. quelen así como las pajuelas de plástico.Los procedimientos experimentales del capítulo 3 se llevaron a cabo en España. En este capítulo aplicamos la metodología desarrollada en el capítulo 2 para la criopreservación del semen de anguila europea Anguilla anguilla, dorada Sparus aurata y lubina Dicentrarchus labrax. En estas tres especies, las cápsulas biodegradables conservaron los parámetros cinéticos y la integridad de la membrana de los espermatozoides, así como las pajuelas de plástico. Además, observamos que el daño al ADN en muestras de semen de anguila europea y lubina europea criopreservadas en cápsulas y pajuelas no difirió. Sin embargo, las muestras de semen de dorada mostraron mayor daño en el ADN que las criopreservadas en pajuelas. Aunque, el nivel de daño que observamos en las muestras almacenadas en las cápsulas se considera bajo, por lo que pueden no comprometer el desarrollo embrionario. Evaluamos los resultados y concluimos que las cápsulas de gelatina biodegradables y las cápsulas de HPMC biodegradables pueden utilizarse como recipientes alternativos al uso de pajuelas de plástico para la criopreservación de semen de las cuatro especies de peces. / [CA] La criopreservació de l'esperma de peixos és una tècnica que pot augmentar l'eficiència de la reproducció en captivitat d'espècies de peixos d'aigua dolça i marins. Al llarg de les dècades passades, s'han establert protocols per a la criopreservació de l'esperma de diverses espècies de peixos. No obstant això, el focus principal dels pescadors ha estat tenir èxit en la congelació i descongelació dels espermatozoides, sense tenir en compte el temps en què els gamets queden exposats a la solució crioprotectora abans de la fecundació. Aquesta exposició dels espermatozoides a les solucions crioprotectores després de la descongelació pot ser perjudicial per a la qualitat dels gàmetes, ja que poden ser tòxics. La majoria dels protocols establerts utilitzen recipients de plàstic ultrarresistents per emmagatzemar l'esperma durant el procés de criopreservació. Aquests recipients normalment no es reutilitzen, generant residus altament contaminants per al medi ambient. Així, l'objectiu principal de la tesi va ser criar i provar mètodes de baix cost que potenciïn l'ús dels espermatozoides descongelats de peixos i facin que el procés de criopreservació de l'esperma sigui menys contaminant per al medi ambient. Els experiments dels capítols 1 i 2 es van dur a terme a Brasil. Vam utilitzar el jundia gris Rhamdia quelen, una espècie considerada com a model experimental per a peixos natius d'Amèrica del Sud. En el capítol 1, vam provar l'ús de la dilució de l'esperma descongelat per reduir la toxicitat de la solució crioprotectora. Aquesta tècnica s'utilitza comúment en protocols de criopreservació de l'esperma de mamífers, però mai abans s'havia aplicat a l'esperma descongelat de peixos sud-americans. Mostres d'esperma descongelat de R. quelen es van diluir en un diluent salí (NaCl al 1,1% - 325 mOsm kg-1; pH 7,6). Després, vam observar que els espermatozoides de mostres diluïdes mostraven majors velocitats, rectitud, progressió i freqüència de batuda flagel·lar que les mostres no diluïdes. La dilució de l'esperma descongelat també va proporcionar majors taxes de fecundació i eclosió que el grup no diluït. D'aquesta manera, la dilució de l'esperma descongelat de R. quelen va resultar ser una metodologia senzilla, econòmica i eficient que ha d'incloure's en el protocol de criopreservació de l'esperma de l'espècie. En els capítols 2 i 3 vam desenvolupar i provar la metodologia per a l'ús de càpsules de gelatina biodegradables (col·lagen) i càpsules d'hipromelosa biodegradables (HPMC) com a recipient alternatiu a l'ús de canuts de plàstic en la criopreservació de l'esperma de peixos. En el segon capítol vam observar que les càpsules biodegradables mantenien els paràmetres cinètics i la capacitat reproductiva de l'esperma de R. quelen així com els canuts de plàstic. Els procediments experimentals del capítol 3 es van dur a terme a Espanya. En aquest capítol vam aplicar la metodologia desenvolupada al capítol 2 per a la criopreservació de l'esperma d'anguila europea Anguilla anguilla, daurada Sparus aurata i llobarro Dicentrarchus labrax. En aquestes tres espècies, les càpsules biodegradables van conservar els paràmetres cinètics i la integritat de la membrana dels espermatozoides, així com els canuts de plàstic. A més, vam observar que el dany a l'ADN en mostres d'esperma d'anguila europea i llobarro europeu criopreservades en càpsules i canuts no es va diferir. No obstant això, les mostres d'esperma de daurada van mostrar més dany a l'ADN que les criopreservades en canuts. Tot i això, el nivell de dany que vam observar a les mostres emmagatzemades en càpsules es considera baix, pel que poden no comprometre el desenvolupament embrionari. Vam avaluar els resultats i vam concloure que les càpsules de gelatina biodegradables i les càpsules d'HPMC biodegradables es poden utilitzar com a recipients alternatius a l'ús de canuts de plàstic per a la criopreservació de l'esperma de les quatre espècies de peixos. / [EN] Fish sperm cryopreservation is a technique that can increase the reproduction in captive efficiency of freshwater and marine fishes.Over the last few decades, protocols for sperm cryopreservation from many fishes have been established. However, the researchers' main focus was successfully freezing and thawing sperm, neglecting the period in which the gametes remain in contact with the cryoprotective solution until fertilization. Exposure of sperm to cryoprotectant solutions after thawing can be harmful to the quality of the gametes since they can be toxic. The majority of the established protocols use ultra-resistant plastic containers to store sperm during the cryopreservation process. These containers usually are not reused, generating highly polluting waste for the environment. Furthermore, in some countries, the containers usually used are sold by a few industries, which makes acquisition difficult and increases the product's price. Thus, the main objective of the thesis was to create and test low-cost methodologies that enhance the use of fish post-thaw sperm and make the sperm cryopreservation process more environmentally friendly. The experiments in the Chapters 1 and 2 were developed in Brazil. We used the South American silver catfish Rhamdia quelen, a species considered an experimental model for native South American fishes. In Chapter 1, we tested the use of post-thawing dilution to reduce the toxicity of the cryoprotectant solution. This technique is commonly used in mammalian sperm cryopreservation protocols but has never before been applied to post-thaw sperm of South American fishes. South American silver catfish post-thaw sperm samples were diluted in a saline extender (1.1% NaCl - 325 mOsm kg-1; pH 7.6). The post-thaw sperm diluted samples showed higher velocities, straightness, progression, and flagellar beat frequency than the cells of undiluted samples (control). The post-thawing dilution also provided higher fertilization and hatching rates than the control group. Thus, the post-thawing sperm dilution proved to be a simple, cheap, and efficient methodology that should be included in the silver catfish sperm cryopreservation protocol. In Chapters 2 and 3, we developed, tested, and described the methodology for using biodegradable gelatin (collagen) and hypromellose (HPMC) capsules as an alternative container to plastic straws in the fish sperm cryopreservation. In the second chapter, we observed that the biodegradable capsules maintained the kinetic parameters and reproductive capacity of South American silver catfish sperm just as effectively as plastic straws. The experimental procedures in Chapter 3 were carried out in Spain. We apply the methodology developed in Chapter 2 to the cryopreservation of sperm from European eel Anguilla anguilla, gilthead seabream Sparus aurata, and European sea bass Dicentrarchus labrax. In these three species, biodegradable capsules preserved the sperm kinetic parameters and membrane integrity just as effectively plastic straws. We observed that DNA damage in European eel and European sea bass sperm samples cryopreserved in capsules and straws did not differ. On the other hand, gilthead seabream sperm samples showed higher DNA damage than those cryopreserved in straws. However, the damage level observed in samples stored in capsules is considered low, thus, may not compromise embryonic development. We observed the results and concluded that biodegradable gelatin and HPMC capsules could be used as alternative containers to plastic straws for sperm cryopreservation from the tfour aquaculture fishes. / This study was supported by MICINN with funding from European Union NextGenerationEU (PRTR-C17.I1) and by Generalitat Valenciana (THINKINAZUL/2021/012;THINKINAZUL/2021/024;THINKINAZUL/2021/042) including the contract of FF-G.WAG-L has a Margarita Salas postdoctoral contract (RD 289/2021. UAB) by the Spanish Ministry of Universities. LF has a PhD contract from Generalitat Valenciana (GRISOLIAP/2020/063). TSF (141717/2019-0 and 200285/2021-1) and MPS (200452/2022-3) have fellowships from Brazilian National Council for Scientific and Technological Development (CNPq). / De Souza França, T. (2024). Development and Application of Low-Cost and Environment-Friendly Techniques for Fish Sperm Cryopreservation [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/204486 / Compendio

A comprehensive review of the nasal route of administration, in particular the nasal drug delivery system has been presented. The physicochemical properties, mode of action and pharmacology of H1-receptor antagonists, in particular cyclizine HCl, have been highlighted. The techniques for the assessment of toxicity (in-vitro ciliary beat frequency (CBF) studies for human nasal explants and morphology studies of the rat nasal mucosa), synthesis of cyclizine lactate, solubility studies of both cyclizine HCI and cyclizine lactate, viscosity determination of the gel formulated and assessment of the deposition and distribution of the hydroxypropylmethyl cellulose (HPMC) dispersions within the human nasal cavity model were conducted. In this study, preliminary studies on the toxicity of the various formulation components (excipients and active ingredient) were carried out. Results from these studies indicated that for both the excipients and the drug, pH significantly affects the ciliary motility hence all ciliary beat frequency determinations were conducted at nasal pH. Furthermore, effects of the various concentrations (0.0625%(w/v), 0.125%(w/v), 0.25%(w/v), 0.5%(w/v) and l%(w/v)) of the excipients on ciliary motility were investigated. Transmission electron microscopy (TEM) studies proved useful in evaluating the integrity and changes in the surface morphology of the rat nasal mucosa post treatment with the various excipients (carboxymethyl cellulose, hydroxypropylmethyl cellulose, trimethyl chitosan 36.3% DQ, Carbopol P934 and polysorbate-80) at varying concentrations. Of the excipients investigated, hydroxypropylmethyl cellulose (HPMC) showed ciliofriendliness since there was no apparent ultra structural damage, although a slight decrease in ciliary beat frequency (CBF) was observed at the highest viscosity. Moreover, hydroxypropylmethyl cellulose (HPMC) is said to be a bioadhesive excipient, which would therefore confer its bioadhesive properties to the intranasal preparation to enhance the retention time between the absorbing mucosa and the drug and hence increase nasal drug absorption. This excipient was therefore selected as the ideal for use in the formulation of the intranasal preparation. The aqueous solubility of a drug plays an important role in nasal administration since it is required that the drug component be applied in a limited volume of about 200pl. To enhance the aqueous solubility of the sparingly water-soluble cyclizine HCl, a lactate salt was synthesised and characterised. This compound was found to be highly soluble in water. The intranasal preparation was therefore manufactured using the lactate form of cyclizine. A single blind study was conducted to determine and compare the pharmacokinetic parameters for both Valoid oral tablets containing 100mg cyclizine HCl (reference drug) and cyclizine lactate intranasal preparation 125mglml (study drug). The results obtained indicated a significant improvement in the bioavailability of cyclizine. For oral administration Cmax = 200.79ng/ml at tmax = 5.57h and for the intranasal preparation Cmax = 5354.22ng/ml at tmax = 1.59h. A 19.2-fold increase in drug bioavailability was observed after intranasal administration (AUCin = 122860.70ng/ml/h) compared with oral administration (AUCpo = 5943.48ng/ml/h). This enhanced bioavailability through nasal administration indicated that enhanced nasal drug absorption and hence increased bioavailability not only depends on the favourable anatomical and physiological characteristics of the nasal mucosa but possibly on the inherent physico-chemical characteristics of the drug molecule and the formulation components. Thus chemical modification of the sparingly water-soluble cyclizine HCl to the highly water-soluble cyclizine lactate facilitated the dissolution of more solute in a limited volume of solvent. This new feature therefore may have impacted positively to the transport of cyclizine across the nasal mucosa. Furthermore, the hydroxypropylmethyl cellulose (HPMC), component of the formulation, could have conferred its mucoadhesive properties to the preparation. Perhaps it increased the retention time of the dosage form within the nasal passages through bond formation with the nasal mucosa thereby increasing the contact time between the absorbing mucosa and the dosage form. This interaction between the mucoadhesive and the nasal mucosa may have resulted in the modification of tissue permeability (possibly transient opening of the tight junctions) and eventual increase in the drug penetration/absorption. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2004.

Hydrophilic polymers in a swellable matrix tablet hydrate quickly to form a hydrogel layer on the exterior of the dosage once in contact with water or biologic fluid. The resultant hydrogel serves as a barrier to regulate water permeation into the matrix and drug diffusion from the preparation. It is therefore important to understand how the polymer is hydrated and what mechanism exists between hydrogel formation and drug dissolution from a swellable matrix tablet. In this thesis, a TA texture analyzer was utilized to monitor and characterize matrix swelling properties during dissolution process. Multiple regression models were employed to analyze the quantitative relationship between drug dissolution or hydrogel thickness and major formulation factors (polymer ratio, drug solubility). Modified release matrix tablets were prepared using four APIs with a range of aqueous solubility, i.e., acetaminophen (ACE), chlorpheniramine (CHL), ibuprofen (IBU), and pseudoephedrine hydrochloride (PSE). Two hydrophilic polymers, polyethylene oxide (PEO) and hydroxypropyl methylcellulose (HPMC) were selected and tested as primary matrix polymers for the formulations. It was found from the experiments that multiple regression model was capable of estimating drug dissolution for both PEO and HPMC matrix preparations. Based on major formulation factors the regression models provide satisfactory prediction of drug release, which could further aid in formulation development and optimization.

A comprehensive review of the nasal route of administration, in particular the nasal drug delivery system has been presented. The physicochemical properties, mode of action and pharmacology of H1-receptor antagonists, in particular cyclizine HCl, have been highlighted. The techniques for the assessment of toxicity (in-vitro ciliary beat frequency (CBF) studies for human nasal explants and morphology studies of the rat nasal mucosa), synthesis of cyclizine lactate, solubility studies of both cyclizine HCI and cyclizine lactate, viscosity determination of the gel formulated and assessment of the deposition and distribution of the hydroxypropylmethyl cellulose (HPMC) dispersions within the human nasal cavity model were conducted. In this study, preliminary studies on the toxicity of the various formulation components (excipients and active ingredient) were carried out. Results from these studies indicated that for both the excipients and the drug, pH significantly affects the ciliary motility hence all ciliary beat frequency determinations were conducted at nasal pH. Furthermore, effects of the various concentrations (0.0625%(w/v), 0.125%(w/v), 0.25%(w/v), 0.5%(w/v) and l%(w/v)) of the excipients on ciliary motility were investigated. Transmission electron microscopy (TEM) studies proved useful in evaluating the integrity and changes in the surface morphology of the rat nasal mucosa post treatment with the various excipients (carboxymethyl cellulose, hydroxypropylmethyl cellulose, trimethyl chitosan 36.3% DQ, Carbopol P934 and polysorbate-80) at varying concentrations. Of the excipients investigated, hydroxypropylmethyl cellulose (HPMC) showed ciliofriendliness since there was no apparent ultra structural damage, although a slight decrease in ciliary beat frequency (CBF) was observed at the highest viscosity. Moreover, hydroxypropylmethyl cellulose (HPMC) is said to be a bioadhesive excipient, which would therefore confer its bioadhesive properties to the intranasal preparation to enhance the retention time between the absorbing mucosa and the drug and hence increase nasal drug absorption. This excipient was therefore selected as the ideal for use in the formulation of the intranasal preparation. The aqueous solubility of a drug plays an important role in nasal administration since it is required that the drug component be applied in a limited volume of about 200pl. To enhance the aqueous solubility of the sparingly water-soluble cyclizine HCl, a lactate salt was synthesised and characterised. This compound was found to be highly soluble in water. The intranasal preparation was therefore manufactured using the lactate form of cyclizine. A single blind study was conducted to determine and compare the pharmacokinetic parameters for both Valoid oral tablets containing 100mg cyclizine HCl (reference drug) and cyclizine lactate intranasal preparation 125mglml (study drug). The results obtained indicated a significant improvement in the bioavailability of cyclizine. For oral administration Cmax = 200.79ng/ml at tmax = 5.57h and for the intranasal preparation Cmax = 5354.22ng/ml at tmax = 1.59h. A 19.2-fold increase in drug bioavailability was observed after intranasal administration (AUCin = 122860.70ng/ml/h) compared with oral administration (AUCpo = 5943.48ng/ml/h). This enhanced bioavailability through nasal administration indicated that enhanced nasal drug absorption and hence increased bioavailability not only depends on the favourable anatomical and physiological characteristics of the nasal mucosa but possibly on the inherent physico-chemical characteristics of the drug molecule and the formulation components. Thus chemical modification of the sparingly water-soluble cyclizine HCl to the highly water-soluble cyclizine lactate facilitated the dissolution of more solute in a limited volume of solvent. This new feature therefore may have impacted positively to the transport of cyclizine across the nasal mucosa. Furthermore, the hydroxypropylmethyl cellulose (HPMC), component of the formulation, could have conferred its mucoadhesive properties to the preparation. Perhaps it increased the retention time of the dosage form within the nasal passages through bond formation with the nasal mucosa thereby increasing the contact time between the absorbing mucosa and the dosage form. This interaction between the mucoadhesive and the nasal mucosa may have resulted in the modification of tissue permeability (possibly transient opening of the tight junctions) and eventual increase in the drug penetration/absorption. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2004.

Hydrophilic polymers in a swellable matrix tablet hydrate quickly to form a hydrogel layer on the exterior of the dosage once in contact with water or biologic fluid. The resultant hydrogel serves as a barrier to regulate water permeation into the matrix and drug diffusion from the preparation. It is therefore important to understand how the polymer is hydrated and what mechanism exists between hydrogel formation and drug dissolution from a swellable matrix tablet. In this thesis, a TA texture analyzer was utilized to monitor and characterize matrix swelling properties during dissolution process. Multiple regression models were employed to analyze the quantitative relationship between drug dissolution or hydrogel thickness and major formulation factors (polymer ratio, drug solubility). Modified release matrix tablets were prepared using four APIs with a range of aqueous solubility, i.e., acetaminophen (ACE), chlorpheniramine (CHL), ibuprofen (IBU), and pseudoephedrine hydrochloride (PSE). Two hydrophilic polymers, polyethylene oxide (PEO) and hydroxypropyl methylcellulose (HPMC) were selected and tested as primary matrix polymers for the formulations. It was found from the experiments that multiple regression model was capable of estimating drug dissolution for both PEO and HPMC matrix preparations. Based on major formulation factors the regression models provide satisfactory prediction of drug release, which could further aid in formulation development and optimization.

Submitted by José Sidnaldo Pinsetta Junior (j.pinsetta@gmail.com) on 2018-07-25T00:08:38Z No. of bitstreams: 1 Dissertação José Sidnaldo Pinsetta Junior - versão final.pdf: 4463450 bytes, checksum: 1f7984d7f6b9905aa1c1ff1247d39508 (MD5) / Approved for entry into archive by Karina Gimenes Fernandes null (karinagi@fcav.unesp.br) on 2018-07-25T10:45:12Z (GMT) No. of bitstreams: 1 pinsettajunior_js_me_jabo.pdf: 4201809 bytes, checksum: b644c7389d5dfd07f09c8a0bc7398586 (MD5) / Made available in DSpace on 2018-07-25T10:45:12Z (GMT). No. of bitstreams: 1 pinsettajunior_js_me_jabo.pdf: 4201809 bytes, checksum: b644c7389d5dfd07f09c8a0bc7398586 (MD5) Previous issue date: 2018-07-12 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A berinjela é uma olerícola de grande importância em diversos países e seu consumo tem aumentado no Brasil devido às características nutricionais para a alimentação humana. No entanto, esse vegetal apresenta limitações de comercialização como produto minimamente processado devido ao rápido escurecimento enzimático após o corte. O objetivo deste trabalho foi estudar os efeitos do recobrimento comestível a base de hidroxipropilmetilcelulose (HPMC) combinado, ou não, com agentes antiescurecimento sobre a qualidade de berinjelas minimamente processadas (BMP). Foram utilizadas berinjelas da cv Nápoli higienizadas e processadas em cubos, com posterior aplicação os recobrimentos por aspersão. Na primeira etapa foram testadas três formulações de HPMC + Cera de Abelha (CA) nas concentrações de 20, 40 e 60%. No segundo experimento testou-se o efeito do HPMC associado ao ácido cítrico (0,5; 1 e 1,5 %) e no terceiro experimento, ao ácido ascórbico (0,5; 1 e 1,5 %). As BPM foram acondicionadas em embalagens de PET (Polietileno tereftalato) e armazenadas em expositores refrigerados a 5°C. As análises foram realizadas a cada 3 dias até 12 dias, determinando-se a perda acumulada de massa fresca, firmeza, índice de brancura, composição gasosa do interior da embalagem, determinação de acetaldeído e etanol, compostos fenólicos totais, atividade das enzimas polifenoloxidase (PPO), peroxidase (POD) e fenilalanina amônia-liase (PAL), e contagem microbiana (microrganismos aeróbios mesófilos, coliformes totais e E. coli). O recobrimento com HPMC+40% de cera de abelha reduziu a atividade de enzimas responsáveis pelo escurecimento e a adição de 0,5% de ácido cítrico ou 1% de ácido ascórbico ao recobrimento levou a uma menor síntese de compostos fenólicos e menor atividade enzimática. / The eggplant is a vegetable of great importance in many countries and it has an increasing consumption in Brazil thanks to nutritional benefits for human health. Nevertheless, it presents limitations to commercialization due to fast enzymatic browning after cutting. The aim of this Project was to study the effects of an edible coating Hydroxypropyl methylcellulose (HPMC) based in association, or not, with food aditives on the quality of fresh-cut eggplant (FCE). Eggplants cv. "Napoli" were sanitised and processed in cubes of 2,5 x 2,5 x 2,5 cm and later sprayed with the coatings. In the first step, three HPMC and Beewax (BW), 20, 40 and 60% emulsions were tested. In the second experiment, the effect of HPMC+40% BW associated with citric acid (0,5; 1 e 1,5 %) were assessed and in a third experiment, in association with ascorbic acid (0,5; 1 e 1,5 %). The FCE was packed in PET trays and stored at 5°C. Analysis were carried out each 3 days until 12 days. It was assessed the accumulated loss of fresh matter, firmness, whiteness index, atmosphere inside packaging, acetaldehyde and ethanol determination, total phenols, enzyme activity of polyphenol oxidase (PPO), peroxidase (POD), phenylalanine ammonia-lyase (PAL) and microbiology counting (total mesophilic aerobic count, total coliforms and E. coli). The coating with HPMC+40% BW reduced the activity of enzymes responsible for browning and the addition of 0,5% of citric acid or 1% of ascorbic acid to the coating led to a lower synthesis of phenolic compounds and to lower enzymatic activity. / FAPESP: 2016/23600-1