Comparative study of the biopharmaceutical quality of Clonazepam 0.5 mg commercialized in the Peruvian market

Agradecimientos A la Facultad de Medicina de la Universidad Nacional de San Marcos y a la Facultad de Farmacia y Bioquímica de la Universidad Nacional de Trujillo, especialmente a la cátedra de Tecnología Farmacéutica, Biofarmacia y Farmacocinética por el apoyo brindado con el laboratorio y los equipos.Introducción: el Clonazepam pertenece a un grupo de medicamentos llamados benzodiazepinas. Se sabe que estos medicamentos actúan en el cerebro a través del GABA. Es un anticonvulsivante utilizado para varios tipos de ataques, incluyendo ataques miotónicos o atónicos, epilepsia fotosensible, y crisis de ausencia, aunque puede desarrollarse tolerancia. Raras veces es eficaz en ataques tónico-clónicos generalizados o parciales. Método: el presente estudio se realizó para analizar los parámetros comparativos de control de calidad in vitro mediante la evaluación de la variación de peso, friabilidad, dureza, tiempo de desintegración y perfil de disolución entre el medicamento innovador (Rivotril®) y medicamentos multifuente que son comercializados en el mercado peruano. Para realizar el estudio comparativo, se seleccionaron tabletas de Clonazepam 0,5 mg multifuente de diferentes laboratorios comparándolos con el medicamento innovador y se evaluaron las características fisicoquímicas y biofarmacéuticas. Los ensayos farmacopeicos se evaluaron según lo establecido en la USP 42. Resultados: los resultados permitieron establecer que todas las marcas analizadas cumplieron los criterios de aceptación establecidos en la farmacopea para cada principio activo y que el comportamiento biofarmacéutico de ellas era muy similar para ambos tipos de molécula. Conclusiones: se estableció que todas las tabletas multifuente de Clonazepam 0,5 mg incluidos en esta investigación son bioequivalentes con la marca innovadora elegida y, por lo que permite proponer a la comunidad científica la determinación de la equivalencia biofarmacéutica como elemento de apoyo en la toma de decisiones de compra en el servicio farmacéutico

Estudio comparativo de la calidad biofarmacéutica de Clonazepam 0,5 mg comercializados en el mercado peruano

Introduction: Clonazepam belongs to a group of medications called benzodiazepines. It is known that these drugs act in the brain through GABA. It is an anticonvulsant used for various types of attacks, including myotonic or atonic attacks, photosensitive epilepsy, and absence attacks, although tolerance may develop. It is rarely effective in generalized or partial tonic-clonic attacks. Method: the present study was carried out to analyze the comparative parameters of in vitro quality control by evaluating the variation in weight, friability, hardness, disintegration time and dissolution profile between the innovative drug (Rivotril®) and multi-source drugs that are marketed in the Peruvian market. To carry out the comparative study, Clonazepam 0.5 mg multi-source tablets were selected from different laboratories comparing them with the innovative medicine and the physicochemical and biopharmaceutical characteristics were evaluated. Pharmacopoeial trials were evaluated as established in USP 42. Results: the results made it possible to establish that all the brands analyzed met the acceptance criteria established in the pharmacopoeia for each active ingredient and that their biopharmaceutical behavior was very similar for both types of molecule. Conclusions: it was established that all Clonazepam 0.5 mg multi-source tablets included in this research are bioequivalent with the chosen innovative brand and, therefore, allow the determination of biopharmaceutical equivalence as a support element in decision-making to be proposed to the scientific community purchase in the pharmaceutical serviceIntroduction: Clonazepam belongs to a group of medications called benzodiazepines. It is known that these drugs act in the brain through GABA. It is an anticonvulsant used for various types of attacks, including myotonic or atonic attacks, photosensitive epilepsy, and absence attacks, although tolerance may develop. It is rarely effective in generalized or partial tonic-clonic attacks. Method: the present study was carried out to analyze the comparative parameters of in vitro quality control by evaluating the variation in weight, friability, hardness, disintegration time and dissolution profile between the innovative drug (Rivotril®) and multi-source drugs that are marketed in the Peruvian market. To carry out the comparative study, Clonazepam 0.5 mg multi-source tablets were selected from different laboratories comparing them with the innovative medicine and the physicochemical and biopharmaceutical characteristics were evaluated. Pharmacopoeial trials were evaluated as established in USP 42. Results: the results made it possible to establish that all the brands analyzed met the acceptance criteria established in the pharmacopoeia for each active ingredient and that their biopharmaceutical behavior was very similar for both types of molecule. Conclusions: it was established that all Clonazepam 0.5 mg multi-source tablets included in this research are bioequivalent with the chosen innovative brand and, therefore, allow the determination of biopharmaceutical equivalence as a support element in decision-making to be proposed to the scientific community purchase in the pharmaceutical serviceIntroducción: el Clonazepam pertenece a un grupo de medicamentos llamados benzodiazepinas. Se sabe que estos medicamentos actúan en el cerebro a través del GABA. Es un anticonvulsivante utilizado para varios tipos de ataques, incluyendo ataques miotónicos o atónicos, epilepsia fotosensible, y crisis de ausencia, aunque puede desarrollarse tolerancia. Raras veces es eficaz en ataques tónico-clónicos generalizados o parciales. Método: el presente estudio se realizó para analizar los parámetros comparativos de control de calidad in vitro mediante la evaluación de la variación de peso, friabilidad, dureza, tiempo de desintegración y perfil de disolución entre el medicamento innovador (Rivotril®) y medicamentos multifuente que son comercializados en el mercado peruano. Para realizar el estudio comparativo, se seleccionaron tabletas de Clonazepam 0,5 mg multifuente de diferentes laboratorios comparándolos con el medicamento innovador y se evaluaron las características fisicoquímicas y biofarmacéuticas. Los ensayos farmacopeicos se evaluaron según lo establecido en la USP 42. Resultados: los resultados permitieron establecer que todas las marcas analizadas cumplieron los criterios de aceptación establecidos en la farmacopea para cada principio activo y que el comportamiento biofarmacéutico de ellas era muy similar para ambos tipos de molécula. Conclusiones: se estableció que todas las tabletas multifuente de Clonazepam 0,5 mg incluidos en esta investigación son bioequivalentes con la marca innovadora elegida y, por lo que permite proponer a la comunidad científica la determinación de la equivalencia biofarmacéutica como elemento de apoyo en la toma de decisiones de compra en el servicio farmacéutico.

Development of a methodology to evaluate the dissolution profile of atorvastatin calcium tablets 20 mg marketed in Peru, Brazil and Bolivia

O presente estudo teve por finalidade desenvolver uma metodologia de dissolução discriminativa para avaliar comprimidos contendo diferentes polimorfos de atorvastatina cálcica (ATR). Este trabalho é conformado por quatro capítulos, no qual o primeiro apresenta uma breve revisão de literatura sobre as características dos polimorfos da ATR, abordando-se informações mais relevantes sobre o ATR em relação ao polimorfismo e sua influência na biodisponibilidade. No segundo capítulo, apresenta-se a importância da caracterização dos polimorfismos e suas implicações para a ATR. As amostras de ATR foram identificadas por difração raio X e análise térmica e, posteriormente, demonstrou-se as diferenças entre quatro amostras comercializadas no mercado brasileiro relacionadas ao hábito cristalino, tamanho de partícula e solubilidade. No terceiro capítulo, demonstra-se o desenvolvimento do método de dissolução discriminativo para comprimidos contendo duas formas polimórficas da ATR. Para tanto, avaliou-se a solubilidade destas pelo método do equilíbrio e determinou-se as condições experimentais mais adequadas para o ensaio de dissolução por intermédio de planejamento fatorial completo do tipo 23, sendo as variáveis independentes o meio de dissolução, a velocidade de agitação e as formas polimórficas (I e VIII). Os resultados obtidos foram tratados estatisticamente através da análise de variância, dos gráficos de Pareto e de superfície de resposta. Concluiu-se que a velocidade de agitação e o meio de dissolução impactam os resultados, afetando a dissolução das formulações com os polimorfos avaliados. Assim, as condições selecionadas foram: 750 mL de meio água a 65 rpm. Após o desenvolvimento do método, este foi comparado com o da Food and Drug Administration (FDA) para comprimidos de atorvastatina cálcica. Ao final dos ensaios, o método desenvolvido mostrou-se adequado para apontar diferenças entre os polimorfos da ATR. No quarto capítulo, o método desenvolvido foi utilizado para avaliar o perfil de dissolução de comprimidos comercializados em três países sul-americanos: Brasil, Peru e Bolívia. As porcentagens de fármaco dissolvidas e a Eficiência de Dissolução foram as variáveis estudadas e, posteriormente, tratadas estatisticamente através da análise de componentes principais, sendo possível comparar o perfil de dissolução de dessete formulações. Dessa forma, foi possível concluir que cinco formulações avaliadas (BR1, BR2 PE6, BR7 e BO3) possuíam a forma polimórfica VIII, enquanto duas formulações (BR5 e PE2) continham a forma polimórfica I. As demais, possivelmente, apresentam misturas ou outras formas polimórficas.This present study was aimed at developing a discriminative dissolution methodology to evaluate tablets containing different calcium atorvastatin (ATR) polymorphs. This paper consists of four chapters. The first chapter presents a brief literature review of the characteristics of ATR polymorphs, and addresses more relevant information about ATR in relation to polymorphism and its influence on bioavailability. The second chapter presents the importance of the characterization of polymorphs and their implications for ATR. The ATR samples were identified by X-ray diffraction and thermal analysis. Subsequently, the differences among the four samples marketed in the Brazilian market with relation to crystalline habit, particle size and solubility were demonstrated. The third chapter demonstrates the development of the discriminative dissolution method for tablets containing two polymorphic forms of ATR. For this, their solubilities were evaluated by the equilibrium method and the most suitable experimental conditions for the dissolution test were determined by means of complete factorial design of type 23, and the independent variables were the dissolution medium, the stirring speed and polymorphic forms (I and VIII). The results obtained were statistically treated through analysis of variance, Pareto and response surface graphs. It was concluded that the stirring speed and the dissolution medium influenced the results, affecting the dissolution of the formulations with the evaluated polymorphs. Thus, the selected condition was 750 mL of water at 65 rpm. Following the development of the method, it was compared with that of the Food and Drug Administration (FDA) for atorvastatin calcium tablets. At the end of the tests, the developed method was adequate to point out differences between the ATR polymorphs. In the fourth chapter, the developed method was used to evaluate the dissolution profile of tablets marketed in three South American countries: Brazil, Peru and Bolivia. Dissolved drug percentages and Dissolution Efficiency were the studied variables and statistically treated by principal component analysis. Through this method, it was possible to compare the dissolution profile of seventeen formulations. Thus, it was possible to conclude that five formulations evaluated (BR1, BR2, PE6, PE7 e BO3) had the polymorphic form VIII, while two formulations (BR5 e PE2) contained the polymorphic form I. The others possibly have mixtures or other forms polymorphic

Rivaroxaban with or without aspirin in stable cardiovascular disease

BACKGROUND: We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. METHODS: In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months. RESULTS: The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=−4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group. CONCLUSIONS: Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events