Degradação forçada e análise fatorial para caracterização da estabilidade de formulações líquidas de carbocisteína / Forced Degradation and Factorial Analysis of Stability of Liquid Formulations containing Carbocisteine

Este estudo teve como objetivo avaliar a estabilidade de xaropes contendo carbocisteína, submetidos à degradação forçada, utilizando Desenho Experimental Fatorial (DEF). Os fatores avaliados foram pH (5,0; 6,5; 8,0), presença ou ausência de EDTA dissódico e metabissulfito de sódio (0,1%). Para o estudo de degradação forçada, as formulações foram submetidas a estresse térmico (50 °C e 75% UR) e oxidação com peróxido de hidrogênio a 3%. Posteriormente, as formulações foram analisadas quanto ao pH, propriedades organolépticas e teor de fármaco por CLAE-UV, nos tempos 0, 15 e 35 dias. Os resultados mostraram que as formulações submetidas à degradação forçada sofreram uma diminuição no teor do fármaco, enquanto que o pH se manteve relativamente estável. Em relação a cor, apenas as formulações que não possuíam antioxidantes mostraram-se mais escuras. A análise dos resultados do DEF mostrou interação significativa (p<0,05) para os fatores pH/metabissulfito e EDTA/metabissulfito. As formulações contendo metabissulfito em pH 5,0 apresentaram maior degradação e as formulações com metabissulfito sem EDTA também não foram eficientes para impedir a degradação da carbocisteína.

The aim of this study was to use Factorial Design (FD) to assess the stability of carbocisteine syrups subjected to forced degradation. The factors assessed were pH (5.0; 6.5; 8.0), presence or absence of disodium EDTA and sodium metabisulfite (0.1%). For the study of forced degradation, the formulations were subjected to thermal stress (50°C and 75% RH) and oxidation with 3% hydrogen peroxide. The formulations were analyzed for pH, organoleptic properties and drug content by HPLC-UV, at 0, 15 and 35 days. The results showed that the formulations exposed to forced degradation suffered a fall in drug content, while the pH remained relatively stable. Regarding the color, only the formulations without antioxidant exhibited a darker coloration. The results of FD revealed significant interactions (p<0.05) for pH/metabisulfite and EDTA / metabisulfite. Formulations containing metabisulfite at pH 5.0 showed the greatest degradation and those with metabisulfite and without EDTA were also not effective in preventing the degradation of carbocisteine.

Tratamiento de intoxicaciones por compuestos hepatotóxicos: uso de la N-acetilcisteína y las carboximetilcisteína: [revisión] / Treatment of intoxications by hepatotoxic compounds: use of N-acetylcystein and S-carboxymetylcystein: [review]

La N-acetilcisteina (NAC) es un fármaco con propiedades antidóticas útiles en la intoxicación por compuestos hepatotóxicos, como paraquat, acetaminofen y fósforo inorgánico. No se encuentra fácilmente disponible en Venezuela a pesar que la frecuencia y severidad de este tipo de intoxicación son significativas. Se discuten ciertas características fármacocinéticas y fármacodinámicas de la NAC y de la S-carboximetilcisteina (SCMC), presente en el mercado farmacéutico venezolano. Además se presenta una revisión de las experiencias clínicas y experimentales con la SCMC en intoxicaciones por compuestos hepatototóxicos.

N-acetylcysteine (NAC) is a drug with antidotal properties useful in poisoning by hepatotoxic compounds such as paraquat, acetaminophen and inorganic phosphorus. Although the frequency and severity of this type of poisoning are significant, NAC is not readily available in Venezuela. Certain pharmacokinetic and pharmacodynamic characteristics of NAC and S-carboxymetylcisteine (SCMC), available in venezuelan pharmaceutical market are discussed. In addition, a review of the clinical and experimental experiences with SCMC in poisoning for hepatotoxic compounds is presented.

Determinação do prazo de validade do medicamento carbocisteína xarope através do método de Arrhenius / Determination of carbocysteine syrup shelf life by Arrhenius method

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.

Thirty-five cases of S-carboxymethylcysteine use in paraquat poisoning.

The herbicide paraquat is associated with a high mortality rate. It produces multiorgan damage through the induction of acute oxidative stress, by generation of reactive oxygen species that cause oxidative damage to biomolecules. In addition to general supportive measures, the management of paraquat poisoning includes gastric washing, forced diuresis, haemodialysis and the use of antioxidants, such as N-acetylcysteine. However, this drug is rather unavailable in Venezuela and S-carboxymethylcysteine has been used. We report 35 patients with mild to severe paraquat poisoning, which beside standard supportive treatment received 1500 mg S-carboxymethylcysteine, up to 2-3 w. The mortality rate was 22.86% (8 deaths/35 cases) and was related to the severity of paraquat poisoning (as assessed by urine dithionite tests). We conclude that S-carboxymethylcysteine is a reliable alternative in managing patients with paraquat poisoning.

Prolonged survival after experimental paraquat intoxication: role of alternative antioxidants.

Since paraquat poisoning causes multiorgan damage through the generation of several redox products, the usual therapy includes antioxidative drugs, such as N-acetylcysteine. We investigated whether selected antioxidative drugs can improve survival from acute paraquat toxicity. Forty-eight male 2-3-mo-old Wistar rats were divided into 4 groups receiving paraquat dichloride in a single injection (11 mg/kg bw ip) I h before the administration of normal saline (control ip), S-carboxymethylcysteine (600 mg/kg bw po), propofol (100 mg/kg bw ip) or trimetazidine (10 mg/kg bw po). Animals were observed for 7 d. The median survival time in the control group was 3 d whereas it was 4 (p = 0.15), 4.5 (p < 0.05) or 5 (p < 0.05) d for the trimetazidine, S-carboxymethylcysteine or propofol-treated groups, respectively.

Carbocisteína más ampicilina en el manejo de padecimientos bronquiales de origen bacteriano agudo / Carbocystein plus ampicillin in the management of bronchial diseases of acute bacterial origin

Se estudió el efecto de la asociación ampicilina más el agente mucolítico carbocisteína en comparación al tratamiento exclusivo con ampicilina, en 80 pacientes adultos con infecciones bacterianas n complicadas de las vías respiratorias inferiores. Además de los parámetros de la clínica respiratoria, se valoró el efecto de la asociación mediante cultivo, antibiograma, viscosimetría e histopatología de la secreción bronquial y se cuantificó la concentración del antibiótico en dicha secreción obtenida de la expectoración. Los cuarenta pacientes tratados con la asociación de fármacos tuvieron una remisión más rápida y altamente significativa a nivel estadístico sobre los parámetros de la clínica respiratoria relacionados con la hipersecreción bronquial y estasis mucosa. Asimismo se registró una mayor concentración del antibiótico en la secreción bronquial de los pacientes que adicionalmente recibieron carbocisteína. Lo anterior se vió reflejado en un menor tiempo en la desaparición del agente patógeno y la recuperación del estado general del paciente. La tolerancia a la combinación antibiótico-mucolítico fue excelente