RESUMO
INTRODUCCION: El tratamiento de la tuberculosis requiere de la administración conjunta de rifampicina (RIF) e isoniacida (ISO). RIF se descompone en medio ácido al producto 3-FRSV, que en presencia de ISO forma IH. La liberación secuencial de RIF en estómago e ISO en intestino podría llevar a un incremento en la estabilidad de RIF. En una etapa previa RIF e ISO se asociaron a los polielectrolitos carboximetilcelulosa (CMC) y ácido algínico (AA), respectivamente, para obtener los materiales portadores CMC-RIF y AA-ISO que permiten la liberación inmediata de RIF y sostenida ISO. Los mismos pueden ser comprimidos para formar matrices hidrofílicas polielectrolico-fármaco (MHPF).OBJETIVO: Evaluar el impacto de la liberación secuencial de RIF e ISO en la estabilidad de RIF en condiciones simulando el contenido gástrico.METODOS: Los estudios de liberación desde las MHPF MCM-RIF + AA-ISO se realizaron en fluido gástrico simulado, utilizando referencia soluciones de RIF o RIF + ISO y la matric CMC-RIF en las mismas condiciones. La evaluación se realizó durante 2 hs, a 37ºC utilizando el aparato 2. La cuantificación se realizó mediante un método de HPLC indicativo de estabilidad, que permitió identificar ambos fármacos y sus productos de degradación.RESULTADOS: La MHPF CMC-RIF presenta muy rápida velocidad de disolución. La combinación de las MHPF CMC-RIF y AA-ISO permite la liberación selectiva e inmediata de RIF en medio ácido, con mínimos niveles concominantes de ISO, permitiendo una reducción en la formación de IH. Este producto de descomposición ha sido asociado con incremento en los eventos hepatotóxicos asociados a la combinación de RIF e ISO. Sin embargo, CMC acelera la degradación de RIF a 3-FRSV.CONCLUSIONES: La liberación secuencial de RIF e ISO permite reducir la formación de IH y es una estrategia adecuada para el desarrollo de comprimidos bi-capa. La optimización de la estabilidad requiere la adecuación de la capa de liberación inmediata de RIF.
INTRODUCTION: Tuberculosis treatment requires the administration of a combination of rifampicin (RIF) and isoniazid (ISO). In acidic media RIF decomposes to 3-FRSV, which in the presence of ISO forms IH. The sequential release of RIF in the stomach and ISO in the intestine could lead to an increase in RIF stability. In a previous work RIF and ISO were associated to the polyelectrolytes carboxymethylcellulose (CMC) and alginic acid (AA) to obtain carrier material CMC-RIF and AA-ISO that allow immediate release of RIF sustained of ISO. These materials can be compressed to form swellable drug polyelectrolyte matrices (SDPM).OBJECTIVE: To evaluate the impact of the sequential release of RIF and ISO in the stability of RIF in conditions simulating gastric contents.METHODS: Release studies were carried out from SDPM CMC-RIF + AA-ISO in simulated gastric fluid using as references RIF or RIF + ISO solutions under the same conditions. Samples were taken for 2 hs at 37ºC, using apparatus 2. The presence of both drugs and degradation products was analyzed by a stability indicating HPLC techinique.RESULTS: The SDPM CMC-RIF presented very fast release rate. The combination of SDPM CMC-RIF and AA-ISO permits selective and immediate release of RIF in acidic media, with minumum levels of ISO, with noticeable reduction of IH formation. This product has been associated with an increased frequency in hepatotoxic events associated with RIF and ISO combination. However, CMC accelerated degradation of RIF to 3-FRSV.CONCLUSIONS: Sequential release of RIF and ISO allowed a reduction in the formation of IH and seemed to be a suitable strategy for the development of bilayer tablets. Stability optimization should include adapting the immediate release layer of RIF.
Assuntos
Antituberculosos , Rifampina , Sistemas de Liberação de Medicamentos , Tuberculose , Argentina , Saúde PúblicaRESUMO
INTRODUCCION: El tratamiento de la tuberculosis requiere de la administración conjunta de rifampicina (RIF) e isoniacida (ISO). RIF se descompone en medio ácido al producto 3-FRSV, que en presencia de ISO forma IH. La liberación secuencial de RIF en estómago e ISO en intestino podría llevar a un incremento en la estabilidad de RIF. En una etapa previa RIF e ISO se asociaron a los polielectrolitos carboximetilcelulosa (CMC) y ácido algínico (AA), respectivamente, para obtener los materiales portadores CMC-RIF y AA-ISO que permiten la liberación inmediata de RIF y sostenida ISO. Los mismos pueden ser comprimidos para formar matrices hidrofílicas polielectrolico-fármaco (MHPF).OBJETIVO: Evaluar el impacto de la liberación secuencial de RIF e ISO en la estabilidad de RIF en condiciones simulando el contenido gástrico.METODOS: Los estudios de liberación desde las MHPF MCM-RIF + AA-ISO se realizaron en fluido gástrico simulado, utilizando referencia soluciones de RIF o RIF + ISO y la matric CMC-RIF en las mismas condiciones. La evaluación se realizó durante 2 hs, a 37ºC utilizando el aparato 2. La cuantificación se realizó mediante un método de HPLC indicativo de estabilidad, que permitió identificar ambos fármacos y sus productos de degradación.RESULTADOS: La MHPF CMC-RIF presenta muy rápida velocidad de disolución. La combinación de las MHPF CMC-RIF y AA-ISO permite la liberación selectiva e inmediata de RIF en medio ácido, con mínimos niveles concominantes de ISO, permitiendo una reducción en la formación de IH. Este producto de descomposición ha sido asociado con incremento en los eventos hepatotóxicos asociados a la combinación de RIF e ISO. Sin embargo, CMC acelera la degradación de RIF a 3-FRSV.CONCLUSIONES: La liberación secuencial de RIF e ISO permite reducir la formación de IH y es una estrategia adecuada para el desarrollo de comprimidos bi-capa. La optimización de la estabilidad requiere la adecuación de la capa de liberación inmediata de RIF.
INTRODUCTION: Tuberculosis treatment requires the administration of a combination of rifampicin (RIF) and isoniazid (ISO). In acidic media RIF decomposes to 3-FRSV, which in the presence of ISO forms IH. The sequential release of RIF in the stomach and ISO in the intestine could lead to an increase in RIF stability. In a previous work RIF and ISO were associated to the polyelectrolytes carboxymethylcellulose (CMC) and alginic acid (AA) to obtain carrier material CMC-RIF and AA-ISO that allow immediate release of RIF sustained of ISO. These materials can be compressed to form swellable drug polyelectrolyte matrices (SDPM).OBJECTIVE: To evaluate the impact of the sequential release of RIF and ISO in the stability of RIF in conditions simulating gastric contents.METHODS: Release studies were carried out from SDPM CMC-RIF + AA-ISO in simulated gastric fluid using as references RIF or RIF + ISO solutions under the same conditions. Samples were taken for 2 hs at 37ºC, using apparatus 2. The presence of both drugs and degradation products was analyzed by a stability indicating HPLC techinique.RESULTS: The SDPM CMC-RIF presented very fast release rate. The combination of SDPM CMC-RIF and AA-ISO permits selective and immediate release of RIF in acidic media, with minumum levels of ISO, with noticeable reduction of IH formation. This product has been associated with an increased frequency in hepatotoxic events associated with RIF and ISO combination. However, CMC accelerated degradation of RIF to 3-FRSV.CONCLUSIONS: Sequential release of RIF and ISO allowed a reduction in the formation of IH and seemed to be a suitable strategy for the development of bilayer tablets. Stability optimization should include adapting the immediate release layer of RIF.
Assuntos
Tuberculose , Sistemas de Liberação de Medicamentos , Rifampina , Antituberculosos , Argentina , Saúde PúblicaRESUMO
The hydrochlorides of the 1:3 aluminum:norfloxacin and aluminum:ciprofloxacin complexes were characterized according to the Biopharmaceutics Classification System (BCS) premises in comparison with their parent compounds. The pH-solubility profiles of the complexes were experimentally determined at 25 and 37 degrees C in the range of pH 1-8 and compared to that of uncomplexed norfloxacin and ciprofloxacin. Both complexes are clearly more soluble than the antibiotics themselves, even at the lowest solubility pHs. The increase in solubility was ascribed to the species controlling solubility, which were analyzed in the solid phases at equilibrium at selected pHs. Additionally, permeability was set as low, based on data reported in the scientific literature regarding oral bioavailability, intestinal and cell cultures permeabilities and also considering the influence of stoichiometric amounts of aluminum. The complexes fulfill the BCS criterion to be classified as class 3 compounds (high solubility/low permeability). Instead, the active pharmaceutical ingredients (APIs) currently used in solid dosage forms, norfloxacin and ciprofloxacin hydrochloride, proved to be BCS class 4 (low solubility/low permeability). The solubility improvement turns the complexes as potential biowaiver candidates from the scientific point of view and may be a good way for developing more dose-efficient formulations. An immediate release tablet showing very rapid dissolution was obtained. Its dissolution profile was compared to that of the commercial ciprofloxacin hydrochloride tablets allowing to dissolution of the complete dose at a critical pH such as 6.8.
Assuntos
Biofarmácia , Ciprofloxacina/química , Norfloxacino/química , Ciprofloxacina/análogos & derivados , Ciprofloxacina/classificação , Composição de Medicamentos , Excipientes/química , Norfloxacino/análogos & derivados , Norfloxacino/classificação , Permeabilidade , Solubilidade , ComprimidosRESUMO
A set of new aluminium complexes of norfloxacin (NOR) and ciprofloxacin (CIP) that show an improvement in their pharmaceutical properties were studied using solution and solid-state nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy. The complexes synthesized with two different methods were compared. One of these methods will allow formulation of the compounds at production scale. High-resolution (13)C spectra were obtained with the cross-polarization and magic angle spinning (CP-MAS) experiment. These spectra were assigned by comparing them with the solution data of the pure drug and by using a quaternary carbon edition technique. The carbon relaxation times in the rotating frame, T(1rhoC), were measured for all the complexes. A two-exponential decay evidences that the complexes are nonhomogeneous. The short T(1rhoC) values are in the range 320-1100 micros and the long values in the range 1.8-7 ms. (27)Al MAS NMR spectra revealed an octahedral coordination between the aluminium ion and oxygens of the pure drug, supporting a 3:1 ligand:metal stoichiometry in both CIP and NOR complexes. The stretching and deformation modes of carboxylic acid and carboxylate and keto groups were analyzed by IR. This technique shows that the same modes are present in the aluminium complexes obtained by the two methods and that the coordination of the fluoroquinolone to aluminium occurs through the 4-keto and 3-carboxylic groups.