RESUMO
After the dosing of an extended-release (ER) formulation, compounds may exist in solutions at various concentrations in the colon because the drugs are released at various speeds from the ER dosage form. The aim of this study was to investigate the relationship between the drug concentration profiles in plasma and the drug doses in the colon. Several drug solutions of different concentrations were directly administered into the ascending colon of dogs using a lubricated endoscope, and the effects of the drug dose on colonic absorption were estimated. As a result, dose-dependency of colonic absorption varied from compound to compound. Although the relative bioavailability of colonic administration of diclofenac, metformin and cevimeline compared to oral administration was similar regardless of the drug doses in the colon, colonic absorption of diltiazem varied according to the doses. From the results of the co-administration of verapamil and fexofenadine, it was clear that diltiazem underwent extensive hepatic and gastrointestinal first-pass metabolism, resulting in a low area under the curves (AUC) at a low drug dose. During the design of oral ER delivery systems, a colonic absorption study of candidate compounds should be carried out at several solutions of different drug concentrations and assessed carefully.
Assuntos
Colo/metabolismo , Preparações de Ação Retardada/farmacocinética , Administração Oral , Animais , Antialérgicos/metabolismo , Antiarrítmicos/metabolismo , Anti-Inflamatórios não Esteroides/análise , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Hipertensivos/análise , Anti-Hipertensivos/sangue , Anti-Hipertensivos/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Preparações de Ação Retardada/análise , Diclofenaco/análise , Diclofenaco/sangue , Diclofenaco/farmacocinética , Diltiazem/análise , Diltiazem/sangue , Diltiazem/farmacocinética , Cães , Relação Dose-Resposta a Droga , Hipoglicemiantes/análise , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Metformina/análise , Metformina/sangue , Metformina/farmacocinética , Agonistas Muscarínicos/análise , Agonistas Muscarínicos/sangue , Agonistas Muscarínicos/farmacocinética , Quinuclidinas/análise , Quinuclidinas/sangue , Quinuclidinas/farmacocinética , Terfenadina/análogos & derivados , Terfenadina/metabolismo , Tiofenos/análise , Tiofenos/sangue , Tiofenos/farmacocinética , Verapamil/metabolismoRESUMO
The purpose of this study was to develop a new method using beagle dogs in order to evaluate the colonic absorption properties of oral extended-release (ER) solid dosage forms. The established method is not only noninvasive and inexpensive but full-sized ER dosage forms are also directly administered to the colons of conscious dogs through the anus with an endoscope and modified bioptome. In the method, it was possible to administer the ER dosage forms into the ascending colon of dogs within 30 s-1 min. The colonic absorption of Voltaren-XR (Diclofenac sodium), Glucophage-XR (metformin), Pacif (morphine hydrochloride), Herbesser-R (diltiazem hydrochloride) and Plendil (felodipine), which are currently on the market, were investigated by this method. The relative bioavailabilities of these ER dosage forms to oral drug solution were 100.3%, 42.5%, 60.6%, 46.3% and 29.8%, respectively. Some of these results reflected the human colonic absorption profiles reported in the literature. This newly developed method could provide researchers with an alternative way to predict the human colon absorption performance of oral ER delivery systems.
Assuntos
Colo/metabolismo , Colonoscopia/métodos , Absorção Intestinal , Preparações Farmacêuticas/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Preparações de Ação Retardada , Cães , Humanos , Masculino , Preparações Farmacêuticas/administração & dosagem , Especificidade da EspécieRESUMO
In general, spectrophotometric methods (inductively coupled plasma or atomic absorption spectrophotometry) are used for the assay of magnesium stearate (Mg-St). In this study, a new rapid, selective assay method was developed for Mg-St in pharmaceutical formulations. The method was based on isocratic reverse-phase liquid chromatography using a mobile phase of acetonitrile-water (80:20, v/v) after precolumn derivatization with 2-nitrophenyl hydrazine for sensitive UV detection. Margaric acid was used as an internal standard and the substances were detectable at 230 nm or 400 nm. Using a short (2 cm) HPLC column reduced the analytical time to 5 min. Validation of the newly developed method was performed in accordance with the International Conference on Harmonization guidelines. The linearity range for Mg-St was 0.00-0.04 mg/ml (as the concentration of injected sample solution) and their correlation factor was 0.9998. The determination and detection limits for Mg-St were 6 microg and 2 microg, respectively. The proposed method was successfully applied to the determination of trace amounts of Mg-St in commercially available tablets with a high recovery percentage, good accuracy, and precision.