RESUMO
The purpose of this study is to compare the bioavailability of two itraconazole (CAS 84625-61-6) capsule formulations. An open, randomized, two-period crossover study with a 7-day washout interval was conduced in 32 healthy volunteers. The plasma samples were obtained up to 96 h after drug administration. A sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of itraconazole in human plasma. Itraconazole and ketoconazole (internal standard) were extracted from the plasma by liquid-liquid extraction using diethylether : dichloromethane (70 : 30) as extraction solvent and separated on a C8 analytical column (150 mm x 4.6 mm I.D.) maintained at 40 degrees C. The elution was performed by a constant flow rate of 1.2 mL/min and the mobile phase consisted of acetonitrile and acetic acid 0.1% (85 :15 v/v). The mass spectrometer equipped with an electrospray source in positive mode, was set up in multiple reaction monitoring, to detect parent --> production 705.0 392.0 (itraconazole) and 531.0 --> 81.70 (ketoconazole). The chromatographic separation was obtained within 3.5 min and was linear in the concentration range of 5 to 600 ng/mL. Bioequivalence between the products was determined by calculating 90% confidence intervals for the ratio of C(max) (95.02%-109.48%), AUC(0-t) (81.41%-107.77%) and AUC(0-inf) (80.85%-106.86%). These values for the test and reference products are within the 80-125% interval, proposed by FDA and EMEA. It was concluded that the proposed method was successfully applied to a pharmacokinetic study in healthy human volunteers, and results showed that the two itraconazole formulations are bioequivalent in their rate and extent of absorption.
Assuntos
Antifúngicos/farmacocinética , Itraconazol/farmacocinética , Adolescente , Adulto , Antifúngicos/administração & dosagem , Área Sob a Curva , Disponibilidade Biológica , Cápsulas , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Método Duplo-Cego , Feminino , Interações Alimento-Droga , Humanos , Itraconazol/administração & dosagem , Masculino , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Equivalência Terapêutica , Adulto JovemRESUMO
A fast, sensitive, and specific liquid chromatographic/tandem mass spectrometric method was developed and validated for determination of tetracycline in human plasma. Tetracycline and oxytetracycline [internal standard (IS)] were extracted from the plasma by protein precipitation. The mobile phase consisted of acetonitrile-formic acid 0.1% (48 + 52, v/v), run at a flow rate of 1 ml/min (split 1:5). Detection was performed by positive electrospray ionization in multiple reaction monitoring mode, monitoring the transitions 444.8 > 410.0 and 461.0 > 426.0 for tetracycline and IS, respectively. The analysis was performed in 3.5 min and the method was linear in the plasma concentration range of 50-6000 ng/mL. The mean extraction recoveries for tetracycline and IS from plasma were 92.14 and 94.04%, respectively. Method validation investigated parameters such as the linearity, precision, accuracy, specificity, and stability, giving results within the acceptable range. The proposed method was successfully applied for determination of tetracycline in human plasma samples to support bioequivalence studies.
Assuntos
Antibacterianos/sangue , Tetraciclina/sangue , Adolescente , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Área Sob a Curva , Calibragem , Cromatografia Líquida , Estabilidade de Medicamentos , Feminino , Congelamento , Humanos , Masculino , Controle de Qualidade , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Tetraciclina/administração & dosagem , Tetraciclina/farmacocinética , Equivalência TerapêuticaRESUMO
A carbocisteína é um agente mucolítico utilizado como adjuvante no tratamento de infecções do trato respiratório. A qualidade, segurança e eficácia do medicamento durante o seu prazo de validade são responsabilidades da indústria farmacêutica. A validade pode ser determinada através de estudos de estabilidade acelerados, nos quais fatores extrínsecos provocam a degradação do produto. De acordo com Arrhenius, existe uma relação entre temperatura e cinética química. Desta forma, amostras do produto foram expostas a condições drásticas: 40, 50, 60 e 70 ºC. O método de doseamento do xarope de carbocisteína foi validado podendo ser aplicado nas avaliações de rotina do controle de qualidade e no estudo de estabilidade deste produto. O prazo de validade proposto para o xarope de carbocisteína, calculado através da equação de Arrhenius, para a temperatura de 25 ºC foi de 240,9 dias. No entanto, foi observada diferença entre o prazo proposto e a validade usualmente praticada para este produto. Este estudo, ainda, demonstrou a presença de picos endógenos, que precisam ser melhor estudados a fim de se confirmar a presença de produtos de degradação.
Carbocysteine is a mucolytic agent in adjunctive therapy of respiratory tract infections. The pharmaceutical industry is responsible for quality, safety and efficiency of the product during its shelf life. Shelf life can be determinated through an accelerated stability study where the degradation of the drug is managed with the extrinsic factors. According to Arrhenius, there is a relationship between temperature and chemical kinetic, so, the samples were exposed to drastic conditions at 40, 50, 60 and 70 ºC. The syrup assay method has been validated and it may be applied to analysis of carbocysteine syrup in routine quality control and stability studies. Through Arrhenius equation the proposed shelf life of carbocysteine syrup was 240.9 days when the dosage form is stored in appropriated conditions, 25 ºC. However difference was found between the proposed shelf life and the usual shelf life of this drug. In addition, this study has showed the presence of endogenous peaks that must be better evaluated to confirm or not the presence of degradation products.