Memoria para optar al título profesional de Químico Farmacéutico / Las formas farmacéuticas de liberación controlada son una gran alternativa para modificar ciertos parámetros biofarmacéuticos y farmacocinéticos de muchos fármacos, como por ejemplo, la velocidad y/o el sitio de liberación desde la forma farmacéutica, la biodisponibilidad, la duración del efecto, entre otros. Además desde el punto vista clínico, se puede lograr una mejor eficacia en el cumplimiento de los tratamientos lo que se traduce en un mayor beneficio para los pacientes. En la actualidad, existe una gran variedad de este tipo de formulaciones, entre las cuales se encuentran las matrices monolíticas. Dependiendo del tipo de material que la conforma, una matriz se puede clasificar en: hidrofílica, inerte y lipídica. Las matrices lipídicas pueden ser una buena alternativa para fármacos poco solubles en medio acuoso y entre sus ventajas se encuentran el control potencial sobre la velocidad de liberación y sitio de cesión del fármaco, ser bien toleradas en el tracto gastrointestinal y proteger al fármaco de las condiciones del medio de disolución si así lo requiere. Entre los excipientes disponibles para la elaboración de estas matrices están los productos de la línea Gelucire®, que corresponden a mezclas de mono-, di- y triglicéridos con ésteres de polietilenglicol (PEG). Éstos se identifican por medio de dos números, el primero corresponde al punto de fusión y el segundo al balance hidrófilo-lipófilo (BHL). Existe una gama de Gelucires, dada por la variedad de mezclas de mono, di y triglicéridos, y mono y diésteres de PEG; entre estos productos se encuentra el Gelucire®50/13, el cual es utilizado en la elaboración de formas farmacéuticas de liberación controlada. El fármaco seleccionado para ser incorporado en la matriz lipídica a base de Gelucire®50/13 fue el albendazol, que se caracteriza por ser un fármaco poco soluble en agua, lo que limita su biodisponibilidad a pesar de presentar una buena permeabilidad, por lo que corresponde a la Clase II (baja solubilidad y alta permeabilidad) según el Sistema de Clasificación Biofarmacéutica (BSC). El principal objetivo de este estudio fue evaluar el efecto de la incorporación de un excipiente dispersante, Labrafil® M1944 CS, sobre la liberación de albendazol desde una matriz a base de Gelucire®50/13. Para ello se elaboraron matrices de Gelucire®50/13 con albendazol y Aerosil®200 en cantidades constantes y con Labrafil® M1944 CS en porcentajes crecientes. Se realizaron perfiles de liberación del fármaco desde las matrices diseñadas utilizando el aparato 2 de la USP 30 a 50 rpm, 37ºC en 900 mL y como medio de disolución HCl 0,1N (pH 1,2) y un buffer fosfato de pH 6,8. Para las matrices encapsuladas, se utilizó buffer fosfato de pH 6,8 como medio de disolución. Los porcentajes de albendazol liberados a las ocho horas desde las matrices a base de Gelucire® 50/13 (F0) y Gelucire® 50/13-Labrafil® M 1944 CS (F1, F2 y F3) fueron de 36,19 ± 0,75%, 44,58 ± 0,91%, 58,01 ± 1,77% y 96,57 ± 1,46, respectivamente. La matriz Gelucire® 50/13-Labrafil® M 1944 CS (F4) a las dos horas, alcanzó rápidamente una liberación de 99,48 ± 0,78%. Para las matrices encapsuladas, los porcentajes de albendazol liberados a las ocho horas desde las matrices lipídicas FA, FB, FC y FD fueron de 29,04 ± 1,05%, 40,06 ± 0,41%, 52,99 ± 1,5% y 97,91 ± 0,98; respectivamente. La matriz FE, a las cinco horas, alcanzó rápidamente una liberación de 97,67 ± 1,12%. Los resultados obtenidos muestran que la adición de Labrafil® M1944 CS en la matriz lipídica en cantidades crecientes incrementó la liberación de albendazol. El estudio de los mecanismos de liberación indicó que en el caso de las matrices sometidas a dos medios de disolución, los perfiles de liberación se ajustaron a una cinética de primer orden y presentaron un mecanismo de liberación combinado de difusión y erosión. Para el caso de las matrices encapsuladas, los perfiles se ajustaron a ambos modelos cinéticos, orden cero y uno, presentando además un mecanismo combinado de difusión y erosión. Finalmente, se elaboró una matriz encapsulada que fue recubierta con un polímero entérico, obteniendo una liberación retardada por dos horas y posteriormente, un perfil de liberación similar al de referencia. / The controlled release dosage forms are a great choice to modify certain biopharmaceutical and pharmacokinetic parameters of a lot of drugs, for instance, the rate and/or the place of release from its pharmaceutical form, bioavailability, how much time the effect is going to last, and others. Besides a clinical point of view, you can get more efficiency in fulfilling the treatments, which translates into a major benefit to the patients. Currently, there’s a huge variety of this kind of formulations, in which the monolithic matrix systems are found. Depending on the material that it’s built of, a matrix can be classified in: hydrophilic, inert, and lipidic. The lipidic matrix can be a good choice to poor soluble drugs in a watery environment, and some of the advantages are the potential control of the rate and place for the release of the drug, being well tolerated by the gastrointestinal tract and protecting the drug from the conditions of the dissolution medium if it’s required. Among the excipients available for the elaboration of these matrix systems, is the product line Gelucire®. These products correspond to mixtures of mono, di and triglycerides with fatty acid esters of polyethylene glycol (PEG). These are identified by two numbers: The first one corresponding to the melting point, and the second one corresponding to hydrophile–lipophile balance (HLB). There’s a wide range of Gelucire®, which have been formed by different mixtures of mono, di and triglycerides, and mono and PEG diesters; among these products is the Gelucire 50/13, which is used in the elaboration of the controlled release dosage forms. The selected drug to be incorporated in the lipidic matrix based on the Gelucire 50/13, was the albendazole, which is known for being poorly soluble in water, which limits its bioavailability in spite of having a good permeability, which corresponds to Class II (low solubility and high permeability), according to the biopharmaceutical classification systems (BSC). The main target of this study was to evaluate the effect of the incorporation of a dispersing excipient, Labrafil® M1944 CS, over the release of albendazole from a Gelucire®50/13 based matrix. To reach this goal, matrix systems of Gelucire®50/13 with albendazole, using constant quantities of Aerosil®200, and also using growing percentages of Labrafil® M1944 were elaborated. The release profiles of the drug were made from the designed matrix systems, using USP Apparatus 2 to 40 rpm, 39°C in 900 mL, and as a dissolution medium HCI 0,1N (pH 1,2) and a phosphate buffer of pH 6,8. For the encapsulated matrix systems, a phosphate buffer of pH 6,8 was used, as a dissolution medium. The percentages of albendazole released after 8 hours from the matrix systems based on Gelucire® 50/13 (F0) and Gelucire® 50/13-Labrafil® M 1944 CS (F1, F2 y F3) were of 36.19 ± 0.75%, 44.58 ± 0.91%, 58.01 ± 1,77% y 96,57 ± 1,46, respectively. The Gelucire® 50/13-Labrafil® M 1944 CS (F4) matrix, after two hours, reached a release of de 99,48 ± 0,78% very rapidly. As for the encapsulated matrix systems, the percentages of albendazole released after eight hours from the lipidic matrix systems FA, FB, FC and FD were of 29,04 ± 1,05%, 40,06 ± 0,41%, 52,99 ± 1,5% y 97,91 ± 0,98; respectively. The FE matrix, after five hours, reached a release of 97,67 ± 1,12% very rapidly. The results show that, adding Labrafil® M1944 CS into the matrix in growing quantities increases the release of albendazole. The study of the release mechanisms showed that, when it comes to the matrix systems under two dissolution mediums, the release profiles adjusted their selves to a first order kinetic and presented a combined release mechanism of diffusion and erosion. When it comes to the encapsulated matrix systems, the profiles were adjusted to both kinetic models, zero and one order, and, presented a combined mechanism of diffusion and erosion. Finally, an encapsulated matrix was elaborated, which was coated by a enteric polymer, getting a delayed release of two hours, and then, a release profile very similar to the one in reference.

LIMA, Renata Monteiro. Interação Albendazol-Praziquantel em voluntários sadios : disposição cinética, metabolismo enantiosseletividade. 2008. 105 f. Dissertação (Mestrado em Ciências Farmacêuticas) - Universidade Federal do Ceará. Faculdade de Farmácia, Odontologia e Enfermagem, Fortaleza, 2008. / Submitted by denise santos (denise.santos@ufc.br) on 2013-01-03T16:44:09Z No. of bitstreams: 1 2008_dis_rmlima.pdf: 1940739 bytes, checksum: 944253f74189c0999d66a889b32bdf0d (MD5) / Approved for entry into archive by Erika Fernandes(erikaleitefernandes@gmail.com) on 2013-01-23T11:38:37Z (GMT) No. of bitstreams: 1 2008_dis_rmlima.pdf: 1940739 bytes, checksum: 944253f74189c0999d66a889b32bdf0d (MD5) / Made available in DSpace on 2013-01-23T11:38:37Z (GMT). No. of bitstreams: 1 2008_dis_rmlima.pdf: 1940739 bytes, checksum: 944253f74189c0999d66a889b32bdf0d (MD5) Previous issue date: 2008 / The praziquantel (PZQ), a chiral drug available as racemic, and the albendazole (ABZ), a drug biotransformed into active metabolic chiral suphoxide of abendazol (ASOX), have been used in the treatment of human neurocysticercosis. The study covers the examination / search of the kinetic disposition, the metabolism, and the enantioselectiveness in the ABZ-PZQ association in healthy volunteers. The crossed and random study was developed in three phases (n=9), in which some volunteers started by PHASE 1 (400 mg of ABZ), others by PHASE 2 (1500mg of PZQ), and others by PHASE 3 (400 mg of ABZ + 1500mg of PZQ). The period of washout was of a minimum of 15 days (PHASE 1 followed by PHASE 2 and PHASE 1 followed by PHASE 3) or of 7 days (PHASE 2 followed by one of the other Phases). The serial blood samples were collected in a period of 0-48 hours. The ABZ metabolics were analised by HPLC with detection by fluorescence and the PZQ enantiomers and the trans-4-hydroxypraziquantel (4-OHPZQ) were analised by LC-MS-MS. The pharmacokinetic patterns were determined with the help of the WinNonlin program. The test of Wilcoxon (p≤0.05) was used to evaluate the enantiomer ratios of plasma concentrations of ASOX, PZQ and 4-OHPZQ. The data are shown as medians. The kinetic disposition of the PZQ, 4-OHPZQ and ASOX is enantioselective in the monotherapy situation; the ratios of AUC are of 2.97 to (+)-(S)-PZQ / (-)-(R)-PZQ, 0.78 to (+)-(S)-4-OHPZQ / (-)-(R)-4-OHPZQ, and 7.08 to (+)-ASOX / (-)-PZQ. The administration of the PZQ results in the increase of the plasma concentrations of the (+)-ASOX in 264% (AUC 980.42 vs 2591.80ng.h./ml), of the (-)-ASOX in 358% (139.59 vs 500.28ng.h./ml), and of the sulphona of albendazole in 187% (170.85 vs 319.50ng.h./ml), suggesting the PZQ as an inhibiting factor of the intestinal Pgp. The administration of the ABZ does not change/ alter the kinetic disposition of the (+)-(S)-PZQ, and of the metabolic (-)-(R)-4-OHPZQ and (+)-(S)-4-OHPZQ, but it results in the increase of the plasma concentrations of the (-)-(R)-PZQ in 64.77% (AUC 518.02 vs 853.57ng.h./ml ), suggesting enantioselective inhibition of the metabolism of the ASOX. The data allow us to suggest the possibility of increase of therapeutic efficacy in the ABZ-PZQ interaction; although, other studies are necessary to evaluate the safety of the interaction. / O praziquantel (PZQ), um fármaco quiral disponível como racemato, e o albendazol (ABZ), um fármaco biotransformado ao metabólito ativo quiral sulfóxido de abendazol (ASOX), tem sido empregados no tratamento da neurocisticercose humana. O estudo abrange a investigação da disposição cinética, metabolismo e enantiosseletividade na associação ABZ - PZQ em voluntários sadios. O estudo cruzado e aleatório foi desenvolvido em três fases (n=9), sendo que alguns voluntários iniciaram pela FASE 1 (400mg de ABZ), outros pela FASE 2 (1500mg de PZQ) e outros pela FASE 3 (400mg de ABZ + 1500mg de PZQ). O período de washout foi de no mínimo 15 dias (FASE 1 seguida da FASE 2 e FASE 1 seguida da FASE 3) ou 7 dias (FASE 2 seguida de uma das outras FASES). As amostras seriadas de sangue foram coletadas no período de 0-48h. Os metabólitos do ABZ foram analisados por HPLC com detecção por fluorescência e os enantiômeros do PZQ e do trans-4-hidroxipraziquantel (4-OHPZQ) foram analisados por LC-MS-MS. Os parâmetros farmacocinéticos foram determinados com auxílio do programa WinNonlin. O teste de Wilcoxon (p≤0.05) foi empregado para avaliar as razões enantioméricas de concentrações plasmáticas do ASOX, PZQ e 4-OHPZQ. Os dados estão expressos como medianas. A disposição cinética do PZQ, 4-OHPZQ e do ASOX é enantiosseletiva na situação de monoterapia; as razões de AUC são de 2,97 para (+)-(S)-PZQ /(-)-(R)-PZQ, 0,78 para (+)-(S)-4OHPZQ /(-)-(R)-4-OHPZQ e 7,08 para (+)-ASOX/(-)-ASOX. A administração de PZQ resulta em aumento das concentrações plasmáticas do (+)-ASOX em 264% (AUC 980,42 vs 2591,80 ng.h/ml), do (-)-ASOX em 358% (139,59 vs 500,28 ng.h./ml) e do sulfona de albendazol em 187% (170,85 vs 319,50ng.h./ml) sugerindo o PZQ como inibidor da Pgp intestinal. A administração de ABZ não altera a disposição cinética do (+)-(S)-PZQ e dos metabólitos (-)-(R)-4-OHPZQ e (+)-(S)-4OHPZQ, mas resulta em aumento das concentrações plasmáticas do (-)-(R)-PZQ em 64,77% (AUC 518,02 vs 853,57ng.h/ml) sugerindo inibição enantiosseletiva do metabolismo do ASOX. Os dados permitem sugerir a possibilidade de aumento da eficácia terapêutica na interação ABZ-PZQ, embora outros estudos sejam necessários para avaliar a segurança da interação.

Memoria para optar al título de Químico Farmacéutico / El objetivo de este estudio fue evaluar el efecto de un agente dispersante, (Labrafil®M2125 CS) y una dispersión sólida, sobre la liberación de albendazol desde sistemas matriciales lipídicos. Para esto se realizaron formulaciones con Gelucire® 50/13 y albendazol (F0) y formulaciones de Gelucire® 50/13 y albendazol con porcentajes crecientes de Labrafil®M2125 CS de 1%, 2%, 3% y 5% p/p (F1, F2, F3 y F4), y además comprimidos matriciales de Gelucire® 50/13 y albendazol (Fa) y de dispersión albendazol:PVP-Gelucire® 50/13 (Fb). Los perfiles de liberación del albendazol desde las matrices diseñadas se realizaron utilizando el aparato 2 de la USP 30 a 50 rpm, 37ºC en 900 mL y como medio de disolución HCl 0,1N (pH 1,2) y un buffer fosfato de pH 6,8 durante 8 horas. Los perfiles de liberación obtenidos desde matrices lipídicas a base de Gelucire® 50/13 (F0) fueron de 47,06±0,34 y para las matrices Gelucire® 50/13-Labrafil® M 2125 CS (F1, F2, F3, F4) fueron de 49,23±0,39%; 62,43±0,26%; 68,23±0,26% y 72,91 ±0,68%, respectivamente. El estudio de los mecanismos de liberación indicó que el modelo cinético que presentaron las matrices lipídicas en todas sus formulaciones se ajustó a una cinética de orden cero y el mecanismo de liberación del fármaco se realizó principalmente por erosión de matriz. El porcentaje de albendazol liberado al término de las 8 horas desde la comprimidos matriciales de Gelucire® 50/13 fue de 66,24±0,39% y para los comprimidos que usaron la dispersión sólida del principio activo fue de 87,99±0,52%. El modelo cinético que presentaron los comprimidos matriciales en las dos formulaciones se ajustó a una cinética de orden uno. El modelo de liberación para Fa se acerca al modelo de difusión, mientras que Fb el un mecanismo de liberación no está muy definido, pudiendo ocurrir en forma simultánea, difusión y erosión.

El objetivo principal del trabajo presentado fue analizar el comportamiento farmacologico de un antihelmíntico de la familia de los benzimidazoles, el albendazol sulfóxido (ABZSO) y de sus enantiómeros, evaluando su capacidad para atravesar la barrera placentária y causar embriotoxicidad y malformaciones congénitas. Para ello se estudió la cinética metabólica en fluido ruminal, utilizando un modelo de fermentadores de doble flujo, y la cinética plasmática en ovejas. Posteriormente se analizó el paso placentario de los enantiómeros de ABZSO en ovejas y las concentraciones embrionarias en ratas. Las muestras colectadas en estos procesos se analizaron mediante una técnica de HPLC (High Performance Liquid Chromatography) para cuantificar la presencia de netobimin (NTB), albendazol (ABZ), ABZSO y sus enantiómeros y el metabolito albendazol sulfona (ABZSO2). El estudio de las malformaciones externas se llevó a cabo por observación directa, mientras que las malformaciones esqueléticas se analizaron mediante tinción con rojo de alizarina S y posterior transparentación de los tejidos blandos. En los fluidos ruminales se observó un predominio de los procesos de reducción de NTB a ABZ y de ABZSO a ABZ en comparación con los procesos de oxidación de ABZ a ABZSO y de éste a ABZSO2. Por otra parte, no fueron observados procesos enantioselectivos en el metabolismo de los enantiómeros de ABZSO. En el plasma de las ovejas se observó un predominio del (+)-ABZSO, mientras que en la rata los dos enantiómeros presentaron un perfil cinético semejante, sugiriendo la existencia de diferencias entre especies. En estos estudios no se observaron diferencias relacionadas con el sexo y la gestación en el perfil farmacocinético de los enantiómeros de ABZSO en ovejas. También se ha observado que los dos enantiómeros tienen capacidad de atravesar la barrera placentaria de las ratas y de las ovejas en elevadas concentraciones y que la placenta de la oveja impedía en cierto grado el paso de estas moléculas hacia el feto. Asimismo se observó un elevado poder embriotóxico y alta capacidad teratógena del ABZSO cuando se administró la forma racémica. Cuando se administraron los enantiómeros por separado se pudo observar que los dos son buenos substratos de la sulfonación y que siguen un perfil cinético similar. Asimismo no se ha observado una reracemización, indicando este hecho una gran estabilidad de los enantiómeros de ABZSO y una baja capacidad reductora en los fluidos gastrointestinales de la rata. / The main objective of this work was to analyse the pharmacological behaviour of a benzimidazole anthelmintic compound, albendazole sulphoxide (ABZSO) and its enantiomers, evaluating their ability to pass through the placental barrier and to produce developmental toxicity. The ruminal fluid kinetics of these compounds in artificial rumens, and the plasma kinetics in sheep was performed. The placental transfer and the embryo concentration of the ABZSO enantiomers were also studied in sheep and rats respectively. All the collected samples were analysed by HPLC (High Performance Liquid Chromatography) in order to determine netobimin (NTB), albendazole (ABZ), albendazole sulfoxide (ABZSO) and its enantiomers, and the metabolite sulfone (ABZSO2) concentration. The study of external abnormalities was performed by direct observation, whereas the skeletal malformation analysis was done using red alizarin S before transparentation of the smooth tissue. The reductive reations of the ruminal flora from NTB to ABZ and from ABZSO to ABZ were higher than the oxidation from ABZ to ABZSO and from ABZSO to ABZSO2. In other hand, no differences concerning the production or consumption of ABZSO enantiomers by the ruminal flora were observed, indicating that the ruminal bacteria metabolism was not enantioselective. In the sheep plasma there was a predominance of (+)-ABZSO, whereas in the rat plasma, both enantiomers showed similar kinetics profile, suggesting the existence of differences in ABZSO enantiomers plasma concentrations species. In our studies no pharmacokinetic differences of ABZSO enantiomers related to sex and pregnancy were observed in sheep. Both ABZSO enantiomers show the ability to pass through the placental barrier of rats and sheep, and that the sheep placenta impaired these compounds to reach the foetus. The ABZSO caused embrionary and teratogenic effects when administered in racemic form indicating that these effects were due to the presence of both enantiomers. When the enantiomers were administered separately, both enantiomers showed to be good substrates of sulfonation, and also to have a similar kinetic profile. Also, no reracemisation was observed after both enantiomers administration, indicating the high stability of ABZSO enantiomers, and the low reductive capacity of rat gastrointestinal fluid.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia, Florianópolis, 2011 / Made available in DSpace on 2012-10-26T01:09:53Z (GMT). No. of bitstreams: 1 294507.pdf: 934211 bytes, checksum: 882e97259e79d7f3cd3b6d02d11e374f (MD5) / O estudo de bioequivalência garante a intercambiabilidade entre o medicamento referência e o genérico. Várias metodologias têm sido desenvolvidas para fornecer previsões farmacocinéticas em humanos. Entre elas, os ensaios em ratos podem ser uma ferramenta útil para predizer a bioequivalência de produtos farmacêuticos. Neste trabalho os fármacos hidroclorotiazida e albendazol foram submetidos a testes de bioequivalência farmacêutica em ratos e seus dados comparados a dados clínicos, a fim de verificar o potencial preditivo do modelo animal. As formulações foram administradas por via oral a ratos Wistar. Coletas seriadas de sangue em períodos determinados foram realizadas na veia caudal. A quantificação das amostras foi realizada por Cromatografia Líquida de Ultra Performance acoplada à Espectrometria de Massas (CLUP-EM/EM). Os resultados dos ensaios clínicos de bioequivalência dos produtos foram cedidos pelo laboratório Biocinese e as análises estatísticas foram realizadas comparando-se os resultados de humanos e animais para os parâmetros farmacocinéticos ASC0-t, ASC0-?, Cmáx, Tmáx e T1/2. De maneira geral, os dados farmacocinéticos obtidos em ratos seguiram o mesmo comportamento dos dados obtidos em seres humanos, sendo que o desempenho do fármaco em animais foi capaz de predizer os dados em humanos para albendazol, fármaco da classe IV (baixa permeabilidade/ baixa solubilidade) na formulação suspensão. Assim, o estabelecimento de um modelo animal para predição de bioequivalência pode contribuir para melhorar a qualidade durante o desenvolvimento de formulações, possibilitando, para os produtos que apresentem a mesma biodisponibilidade do produto referência, um custo menor e também um tempo menor no estudo de sua bioequivalência.

Even though the international combat against Neglected Tropical Diseases such as schistosomiasis or soil-transmitted helminthiases depends on reliable therapeutics, anthelminthic pharmacovigilance has been neglected on many national African drug markets. Therefore, quality and composition of 88 different batches of Albendazole, Mebendazole and Praziquantel locally collected from randomly selected facilities in Western Burkina Faso, Southeast Côte d’Ivoire, Southwest Ghana and Northwest Tanzania were analysed. Visual examination of both packaging and samples was performed according to the WHO ‘Be Aware’ tool. Products were then screened with the GPHF Minilab, consisting of tests of mass uniformity, disintegration times and thin-layer chromatography (TLC). Confirmatory tests were performed according to international pharmacopoeiae, applying assays for dissolution profiles and high-performance liquid chromatography (HPLC). Despite minor irregularities, appearance of the products did not hint at falsified medicines. However, 19.6 % of the brands collected in Ghana and Tanzania were not officially licensed for sale. Mass uniformity was confirmed in 53 out of 58 brands of tablets. 41 out of 56 products passed disintegration times; 10 out of the 15 failing products did not disintegrate at all. TLC results did not reveal any falsifications or pronounced dosing errors. HPLC findings confirmed the TLC results despite shifted specification limits: ten of the 83 tested batches contained less than 90 %, none more than 110 % label claim. However, no more than 46.3 % (31 / 67) of the tablet batches assayed passed the respective criteria for dissolution. In the four study countries, no falsified anthelminthic medicine was encountered. The active pharmaceutical ingredient was not found to either exceed or distinctively fall below specification limits. Galenic characteristics as most critical criteria however, especially dissolution profiles, revealed substantial deficits. / Obwohl der internationale Kampf gegen vernachlässigte Tropenkrankheiten wie Schistosomiasis oder Geohelminthosen von zuverlässigen Therapeutika abhängt, wurde die Pharmakovigilanz von Antihelminthika auf vielen nationalen afrikanischen Arzneimittelmärkten vernachlässigt. Daher wurden Qualität und Zusammensetzung von 88 verschiedenen Chargen von Albendazol, Mebendazol und Praziquantel, die vor Ort in zufällig ausgewählten pharmazeutischen Einrichtungen im Nordwesten Tansanias, im Westen Burkina Fasos, im Südosten der Elfenbeinküste und im Südwesten Ghanas bezogen wurden, analysiert. Die äußerliche Untersuchung von Verpackungen und Proben erfolgte gemäß der "Be Aware" WHO-Checkliste. Anschließend wurden die Präparate mit dem GPHF-Minilab untersucht, welches die Masseneinheitlichkeit, den Tablettenzerfall sowie den enthaltenen Wirkstoff orientierend über Dünnschichtchromatographien (TLCs) bewertete. Die Bestätigungstests erfolgten gemäß den internationalen Arzneimittelbüchern mittels Wirkstofffreisetzung und Hochleistungsflüssigkeitschromatographie (HPLC). Trotz kleinerer Unregelmäßigkeiten deutete das Aussehen der Präparate nicht auf gefälschte Arzneimittel hin. Allerdings waren 19,6 % der in Ghana und Tansania akquirierten Produkte nicht offiziell für den Verkauf zugelassen. Die Einheitlichkeit der (Tabletten-)Masse wurde für 53 von 58 Produkte bestätigt. 41 von 56 Produkten bestanden das Kriterium der Tablettenzerfallszeiten; zehn der defizienten 15 Produkte hingegen zerfielen überhaupt nicht. Die TLCs konnten keine Fälschungen oder ausgeprägte Fehldosierung demaskieren. Die HPLC-Befunde bestätigten die TLC-Ergebnisse trotz verschobener Spezifikationsgrenzen: zehn der 83 untersuchten Chargen enthielten weniger als 90 %, keine mehr als 110 % des angegebenen Wirkstoffes. Allerdings erfüllten nicht mehr als 46,3 % (31 / 67) der untersuchten Tabletten-Chargen die jeweiligen Kriterien der Wirkstofffreisetzung. In den vier Untersuchungsländern wurde kein gefälschtes Anthelminthikum gefunden. Beim aktiven Wirkstoff wurden weder Über- noch deutliche Unterschreitungen der Spezifikationsgrenzen festgestellt. Die galenischen Eigenschaften jedoch, insbesondere die Wirkstofffreisetzung, imponierten mit relevanten Defiziten als kritischstes Merkmal.

As parasitoses causadas por helmintos constituem um grave problema sanitário, tanto para os seres humanos quanto para os animais, além de gerar grandes prejuízos econômicos. O sulfóxido de albendazol é um fármaco anti-helmíntico de amplo espectro, largamente utilizado na medicina veterinária, veiculado pelas vias oral e parenteral, mediante a utilização de formas farmacêuticas convencionais. Apresenta biodisponibilidade baixa e irregular em função de sua pouca solubilidade nos fluidos biológicos. Para a manutenção da concentração plasmática e completa eliminação dos parasitos, são necessárias administrações reiteradas, ocasionando transtornos decorrentes do manejo freqüente dos animais e do aumento do custo da terapia. O presente trabalho teve como objetivo desenvolver e caracterizar um sistema microparticulado para liberação sustentada de sulfóxido de albendazol, de modo que este pudesse permanecer no organismo dos animais pelo tempo suficiente para a completa eliminação dos parasitos após uma única administração. Os sistemas foram obtidos a utilizando as técnicas de spray-drying e emulsificação / evaporação de solvente, tendo sido utilizados os polímeros Eudragit RS 30 D® e Eudragit RS PO®, respectivamente. As micropartículas obtidas foram caracterizadas com relação ao tamanho, à morfologia e à eficiência de encapsulação. Através da técnica de emulsificação / evaporação de solvente, foram obtidas partículas com diâmetro médio inferior a 300nm, estreita faixa de distribuição de tamanho e eficiência de encapsulação de aproximadamente 60%. Os resultados do estudo in vitro do perfil de liberação do fármaco a partir das micropartículas obtidas mostraram que, apesar de o sistema desenvolvido não ter sido capaz de sustentar a liberação do fármaco, o mesmo promoveu um aumento significativo da solubilidade do sulfóxido de albendazol em pH 7,4, fato este que pode contribuir para o aumento da biodisponibilidade do mesmo após administração parenteral. / The helminthosis are a serious sanitary problem, as for the men than for the animals, besides the great economic lacks. Albendazole sulphoxide is an antihelminthic drug with broad spectrum of action, widely used at veterinarian medicine, throw oral and parentereal vies, in conventional pharmaceutical dosages. It has low and irregular bioavailability due its low solubility in the biological fluids. For the maintenance of the plasmatic concentration and complete elimination of the parasites, it is required several administrations, creating many troubles due the frequent handling of the animals and increase in the costs of the therapy. The present work had as objective to develop and characterize microparticles for sustained release of albendazole sulphoxide, in order that the drug could be for a longer time in the animals organisms and the parasites could be eliminated after just one administration. The referred microparticles were obtained from the spray-drying and emulsification / evaporation of solvent techniques, using the polymers Eudragit RS 30 D® and Eudragit RS PO®, respectively. The obtained systems were characterized considering size, morphology and encapsulation efficiency. Using the emulsification / evaporation of solvent technique, it was prepared microparticles with medium diameter under 300nm, narrow range of size distribution and encapsulation efficiency of about 60%. The results of the in vitro release profile study of the drug from the prepared microparticles showed that besides the developed system was not be able to sustain the drug delivery, it was able to improve significantly the solubility of albendazole sulphoxide at pH 7.4, what can be useful to improve its parenteral bioavailability.

O presente trabalho teve como objetivo desenvolver metodologia para avaliação da dissolução intrínseca (DI) de amostras de albendazol (ABZ) e mebendazol (MBZ), empregando-se o método de disco rotativo. Inicialmente foi realizada a caracterização físico-química dos fármacos, empregando-se os ensaios de termogravimetria (TG), calorimetria exploratória diferencial (DSC), difratometria de raios X (DRX), microscopia eletrônica de varredura (MEV), densidade verdadeira, área superficial e tamanho de partícula, para sete amostras de ABZ e oito de MBZ. Com as análises de DRX e DSC foi possível verificar a presença dos polimorfos I e II, além de outras estruturas cristalinas nas amostras de ABZ. Em relação ao MBZ foi possível identificar os polimorfos A, C e a mistura destes polimorfos. Mediante o ensaio de solubilidade, verificou-se que as amostras que possuem o polimorfo C foram as mais solúveis nos meios de HCl 0,1N e suco gástrico. Finalmente, desenvolveu-se a metodologia para a avaliação da DI de ABZ e MBZ. Para avaliar o impacto das condições de ensaio na DI, escolheu-se uma amostra de ambos fármacos, que foi submetida a diferentes ensaios conforme delineamento experimental ortogonal de Taguchi do tipo L9(34). Verificou-se que tanto para o ABZ quanto para o MBZ, a variável que apresentou maior impacto na velocidade de dissolução intrínseca (VDI) foi o meio de dissolução. Dessa maneira, selecionaram-se as condições para a realização dos ensaios comparativos entre as amostras (diferentes fornecedores). Observou-se que as amostras que apresentam o polimorfo II (ABZ) e o C (MBZ) são aquelas que mostraram maiores valores de VDI. As condições empregadas para o estudo da VDI das amostras dos fármacos permitiram evidenciar diferenças entre os polimorfos demonstrando que a técnica de dissolução intrínseca é viável na caracterização das formas polimórficas de ABZ e MBZ. / The purpose of this study was to develop a methodology for evaluating the intrinsic dissolution (ID) of samples of albendazole (ABZ) and mebendazole (MBZ), employing the rotating disk method. Initially, a physicochemical characterization of seven samples of ABZ and eight samples of MBZ was carried out through thermogravimetric tests (TG), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM), as well as evaluations of true density, surface area and particle size. With the XRD and DSC analyses, it was possible to ascertain the presence of polymorphs I and II, as well as other crystalline structures in the ABZ samples. With regards to MBZ, it was possible to identify polymorphs A and C, as well as a mixture of these polymorphs. With the execution of a solubility test, it was ascertained that the samples with polymorph C were the most soluble in the HCl 0.1N and gastric acid media. Finally, a methodology for the evaluation of the ID of ABZ and MBZ was developed. In order to evaluate the impact of the test conditions on ID, samples of both drugs were chosen, which were then subjected to different tests, according to the L9 (34) Taguchi experimental orthogonal array. It was ascertained that for both ABZ and MBZ, the variable with the greatest impact on the intrinsic dissolution rate (IDR) was the dissolution medium. Accordingly, the conditions for the execution of comparative tests between the samples were selected (different suppliers). It was observed that the samples that presented the polymorph II (ABZ) and C (MBZ) were also those that presented the greatest IDR values. The conditions employed for the IDR study of the drug samples enabled differences between the polymorphs to be ascertained, thus demonstrating that the intrinsic dissolution technique is viable for the characterization of polymorphic forms of ABZ and MBZ.

O presente trabalho teve como objetivo desenvolver metodologia para avaliação da dissolução intrínseca (DI) de amostras de albendazol (ABZ) e mebendazol (MBZ), empregando-se o método de disco rotativo. Inicialmente foi realizada a caracterização físico-química dos fármacos, empregando-se os ensaios de termogravimetria (TG), calorimetria exploratória diferencial (DSC), difratometria de raios X (DRX), microscopia eletrônica de varredura (MEV), densidade verdadeira, área superficial e tamanho de partícula, para sete amostras de ABZ e oito de MBZ. Com as análises de DRX e DSC foi possível verificar a presença dos polimorfos I e II, além de outras estruturas cristalinas nas amostras de ABZ. Em relação ao MBZ foi possível identificar os polimorfos A, C e a mistura destes polimorfos. Mediante o ensaio de solubilidade, verificou-se que as amostras que possuem o polimorfo C foram as mais solúveis nos meios de HCl 0,1N e suco gástrico. Finalmente, desenvolveu-se a metodologia para a avaliação da DI de ABZ e MBZ. Para avaliar o impacto das condições de ensaio na DI, escolheu-se uma amostra de ambos fármacos, que foi submetida a diferentes ensaios conforme delineamento experimental ortogonal de Taguchi do tipo L9(34). Verificou-se que tanto para o ABZ quanto para o MBZ, a variável que apresentou maior impacto na velocidade de dissolução intrínseca (VDI) foi o meio de dissolução. Dessa maneira, selecionaram-se as condições para a realização dos ensaios comparativos entre as amostras (diferentes fornecedores). Observou-se que as amostras que apresentam o polimorfo II (ABZ) e o C (MBZ) são aquelas que mostraram maiores valores de VDI. As condições empregadas para o estudo da VDI das amostras dos fármacos permitiram evidenciar diferenças entre os polimorfos demonstrando que a técnica de dissolução intrínseca é viável na caracterização das formas polimórficas de ABZ e MBZ. / The purpose of this study was to develop a methodology for evaluating the intrinsic dissolution (ID) of samples of albendazole (ABZ) and mebendazole (MBZ), employing the rotating disk method. Initially, a physicochemical characterization of seven samples of ABZ and eight samples of MBZ was carried out through thermogravimetric tests (TG), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM), as well as evaluations of true density, surface area and particle size. With the XRD and DSC analyses, it was possible to ascertain the presence of polymorphs I and II, as well as other crystalline structures in the ABZ samples. With regards to MBZ, it was possible to identify polymorphs A and C, as well as a mixture of these polymorphs. With the execution of a solubility test, it was ascertained that the samples with polymorph C were the most soluble in the HCl 0.1N and gastric acid media. Finally, a methodology for the evaluation of the ID of ABZ and MBZ was developed. In order to evaluate the impact of the test conditions on ID, samples of both drugs were chosen, which were then subjected to different tests, according to the L9 (34) Taguchi experimental orthogonal array. It was ascertained that for both ABZ and MBZ, the variable with the greatest impact on the intrinsic dissolution rate (IDR) was the dissolution medium. Accordingly, the conditions for the execution of comparative tests between the samples were selected (different suppliers). It was observed that the samples that presented the polymorph II (ABZ) and C (MBZ) were also those that presented the greatest IDR values. The conditions employed for the IDR study of the drug samples enabled differences between the polymorphs to be ascertained, thus demonstrating that the intrinsic dissolution technique is viable for the characterization of polymorphic forms of ABZ and MBZ.

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Andrea Krejzová Supervisor: PharmDr. Ivan Vokřál, Ph.D. Title of diploma thesis: Effect of albendazole on the activity of selected enzymes in tapeworm Hymenolepis diminuta The efficacy of anthelmintics used to treat diseases caused by helminths is not always sufficient, and in some cases, we are directly facing resistance to these drugs. Helminths, including tapeworms, are able to defend against the toxic effect of anthelmintics using several mechanisms. Xenobiotic metabolizing enzymes and transport proteins belong to these mechanisms. When xenobiotic metabolizing enzymes are induced, the efficacy of therapy may be significantly reduced. The effect of xenobiotic metabolizing enzymes on the drug resistance development has been already described in number of helminths. In tapeworms this information is still missing. Main aim of this study was to determine effect of drug albendazole on the activity of selected xenobiotic metabolizing enzymes in rat tapeworm (Hymenolepis diminuta). Tapeworms were incubated with albendazole (1 μM and 10 μM) for 24 hours. Then activities of selected enzymes in cytosol-like, microsome-like and mitochondria-like fractions were determined. This study is focused on...