RESUMEN
The main purpose of this work was to optimize the rheological properties of docetaxel (DCT)-loaded thermosensitive liquid suppositories for rectal administration. DCT-loaded liquid suppositories were prepared by a cold method and characterized in terms of physicochemical and viscoelastic properties. Major formulation parameters including poloxamer (P407) and Tween 80 were optimized to adjust the thermogelling and mucoadhesive properties for rectal administration. Notably, the gel strength and mucoadhesive force significantly increased with the increase in these variables. Furthermore, DCT incorporation did not alter the viscoelastic behavior, and the mean particle size of nanomicelles in it was approximately 16 nm with a distinct spherical shape. The formulation existed as liquid at room temperature and transformed into gel at physiological temperature through the reverse gelation phenomenon. Thus, DCT-loaded thermosensitive liquid suppositories [DCT/P407/P188/Tween 80 (0.25/11/15/10 %)] with optimal gel properties were easy to prepare and administer rectally, and might enable the gel to stay in the rectum without getting out from rectum.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/química , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Reología/métodos , Taxoides/administración & dosificación , Taxoides/química , Adhesividad/efectos de los fármacos , Administración Rectal , Animales , Docetaxel , Femenino , Conejos , Supositorios , Temperatura , Viscosidad/efectos de los fármacosRESUMEN
PURPOSE: To investigate the potential of thermosensitive and biadhesive nanomicelles in improving the bioavailability of docetaxel (DCT) and its chemotherapeutic effect. METHOD: DCT-loaded nanomicelles were prepared by emulsufication and characterized in terms of physico-chemical and visco-elastic parameters. The optimzed formulation was evaluated for in vivo localization, pharmacokinetic and anti-tumor efficacy. RESULTS: The hydrodynamic size of DCT-loaded nanomicelles was approximately 13 nm and the nanomicelles exhibited a sufficient gelation strength (9250 mPa·s) and bioadhesive force (2100 dyn/cm²) to be retained in the upper part of rectum. We observed a high rectal bioavailability of 29% DCT compared to that following oral administration in rats, as it successfully evaded the multidrug efflux transporters and hepatic first-pass metabolism. Plasma concentration around â¼50 ng/mL was maintained throughout the study period (12 h) while Taxotere® attained subtherapeutic range within 4 h of drug administration. Results also revealed that the rectally administered DCT-loaded nanomicelles exhibited a significant anti-tumor effect (200 mm³) with a reduced toxicity profile when compared to orally administered DCT (950 mm³). Furthermore, histological study showed that the rectal mucosa was completely intact with no signs of irritation upon treatment with DCT-loaded nanomicelles. CONCLUSIONS: Taken together, our novel thermosensitive and biadhesive nanomicelles demonstrated the ability to improve the bioavailability and chemotherapeutic potential of DCT in vivo. To the best of our knowledge, this is the first report describing the rectal delivery of DCT-loaded nanomicelles.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Micelas , Recto/metabolismo , Taxoides/administración & dosificación , Taxoides/uso terapéutico , Administración Rectal , Animales , Antineoplásicos/farmacocinética , Docetaxel , Sistemas de Liberación de Medicamentos , Femenino , Masculino , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Taxoides/farmacocinéticaRESUMEN
To develop a novel itraconazole-loaded solid dispersion without crystalline change with improved bioavailability, various itraconazole-loaded solid dispersions were prepared with water, polyvinylpyrroline, poloxamer and citric acid. The effect of carriers on aqueous solubility of itraconazole was investigated. Their physicochemical properties were investigated using SEM, DSC, and powder X-ray diffraction. The dissolution, bioavailability in rats and stability of solid dispersions were evaluated. Unlike conventional solid dispersion system, the itraconazole-loaded solid dispersion with relatively rough surface did not change crystalline form of drug. Our DSC and powder X-ray diffraction results suggested that this solid dispersion was formed by attaching hydrophilic carriers to the surface of drug without crystal change, resulting in conversion of the hydrophobic drug to hydrophilic form. The itraconazole-loaded solid dispersion at the weight ratio of itraconazole/polyvinylpyrroline/poloxamer of 10/2/0.5 gave maximum drug solubility of about 20 microg/mL. It did not change the crystalline form of drug for at least 6 months, indicating that it was physically stable. It gave higher AUC, C(max) and T(max) compared to itraconazole powder and similar values to the commercial product, suggesting that it was bioequivalent to commercial product in rats. Thus, it would be useful to deliver a poorly water-soluble itraconazole without crystalline change with improved bioavailability.
Asunto(s)
Antifúngicos/farmacocinética , Portadores de Fármacos/química , Itraconazol/farmacocinética , Animales , Antifúngicos/administración & dosificación , Antifúngicos/química , Área Bajo la Curva , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría , Ácido Cítrico/química , Cristalización , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Interacciones Hidrofóbicas e Hidrofílicas , Itraconazol/administración & dosificación , Itraconazol/química , Masculino , Microscopía Electrónica de Rastreo , Poloxámero/química , Povidona/química , Ratas , Ratas Sprague-Dawley , Solubilidad , Difracción de Rayos XRESUMEN
OBJECTIVES: The aim of this study was to develop a novel itraconazole-loaded gelatin microcapsule without ethanol with enhanced oral bioavailability. METHODS: Various gelatin microcapsules were prepared using a spray-drying technique. Their physicochemical properties, dissolution, characteristics and pharmacokinetics in rats were evaluated and compared with those of a commercial product. KEY FINDINGS: The gelatin microcapsule at a weight ratio for itraconazole/gelatin/citric acid of 1 : 3 : 0.3 was spherical in shape with a smooth surface and inner hole, and gave a maximum drug solubility of about 700 microg/ml. The gelatin microcapsule dramatically increased the initial dissolution rate of itraconazole compared with a commercial product in simulated gastric fluids (pH 1.2). Moreover, at the same dose as the commercial product, it gave significantly higher initial plasma concentrations, C(max) and AUC of itraconazole in rats than did the commercial product, indicating that providing the drug in the gelatin microcapsule caused enhanced absorption in rats. At half dose, it gave similar AUC, C(max) and T(max) values to the commercial product, suggesting that it was bioequivalent to the commercial product in rats. CONCLUSIONS: The itraconazole-loaded gelatin microcapsule without ethanol developed using a spray-drying technique at half the dose of the commercial product can deliver itraconazole in a pattern that allows fast absorption in the initial phase, making it bioequivalent to the commercial product.
Asunto(s)
Cápsulas , Portadores de Fármacos/química , Itraconazol/farmacocinética , Tecnología Farmacéutica/métodos , Administración Oral , Animales , Área Bajo la Curva , Disponibilidad Biológica , Química Farmacéutica/métodos , Ácido Cítrico , Jugo Gástrico , Gelatina , Concentración de Iones de Hidrógeno , Absorción Intestinal , Itraconazol/sangre , Itraconazol/química , Masculino , Ratas , Ratas Sprague-Dawley , SolubilidadRESUMEN
To develop an industrially practical thermosensitive injectable hydrogel that is easy to administer, gels quickly in the body and allows sustained release of the drug, poloxamer-based hydrogels containing piroxicam as a model drug were prepared with poloxamer, sodium hydroxide and sodium chloride using the cold method. Their rheological characterization, dissolution and pharmacokinetics after intramuscular administration to rabbits were evaluated. Among the ingredients tested, sodium hydroxide and piroxicam decreased the viscosity and retarded the gelation time of the injectable gel. However, sodium chloride did the opposite. The thermosensitive injectable gel composed of 2.5% piroxicam, 15% P 407, 17% P 188, 0.01% sodium hydroxide and 1.6% sodium chloride was instantly applied to practical industrial product, since it was easy to administer intramuscularly and gelled quickly in the body. The drug was dissolved out of the hydrogels by Fickian diffusion through the extramicellar aqueous channels of the gel matrix. Sodium chloride barely affected the dissolution mechanism or dissolution rate of the drug from the injectable gels. Furthermore, it maintained the plasma concentrations of drug for 4 days and gave a 150-fold higher AUC compared to piroxicam solution. Thus, it would be practically useful for delivering piroxicam in a pattern that allows sustained release for a long time, leading to better bioavailability.