RESUMEN
A sensitive and selective LC-MS/MS method was developed and validated for the quantitation of a novel Gαi2 inhibitor, GT-14, in rat plasma using a SCIEX 6500+ triple QUAD LC-MS system equipped with an ExionLC UHPLC unit. GT-14 (m/z 265.2 â 134.1) and griseofulvin (Internal Standard, IS) (m/z 353.1 â 285.1) were detected in a positive mode by electrospray ionization (ESI) using multiple reaction monitoring (MRM). The assay was linear in the concentration range of 0.78-1000â¯ng/mL in rat plasma. Both accuracy and precision values were within the acceptance criteria of ±15 %, as established by FDA guidance. The matrix effect was negligible from plasma, with signal percentages of 98.5-106.9 %. The mean recovery was 104.5 %, indicating complete extraction of GT-14 from plasma. GT-14 was found to be stable under different experimental conditions. The validated method was successfully applied to evaluate plasma protein binding and in vivo pharmacokinetics of GT-14 in rats.
Asunto(s)
Griseofulvina , Animales , Masculino , Ratas , Griseofulvina/farmacocinética , Griseofulvina/sangre , Cromatografía Líquida con Espectrometría de Masas , Unión Proteica , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masas en Tándem/métodosRESUMEN
Production of submicron particles (0.1-1 µm) has been identified by the pharmaceutical industry as a key technology to enhance the bioavailability of poorly water-soluble drugs. However, nanosuspensions derived from commonly applied wet milling suffer from long-term stability issues, making further downstream processing necessary. In previous works, the formulation as a long-term stable solid crystalline suspension (SCS) was introduced, for which the crystalline drug is ground in a (molten) hydrophilic carrier matrix. The model formulation of the antimycotic Griseofulvin and the sugar alcohol Xylitol was reused for comparative purposes. Due to process limitations regarding the degree of comminution, the present work demonstrates the application of fine grinding in the framework of SCS manufacturing. A custom-built mill with annular gap geometry successfully yielded particles in the targeted submicron range. A process optimization study lead to improved energy utilization during grinding, which reduced the necessary grinding time and, thereby, the thermal exposition of the drug. Investigation of solid-state properties of the SCS, via differential scanning calorimetry and x-ray powder diffraction, showed no alteration even for extended grinding times. In dissolution experiments, the melt-milled SCS outperformed its predecessors, although mostly agglomerates were found by SEM imaging in the solidified product. In conclusion, melt milling is a valuable tool to overcome low aqueous solubility.
Asunto(s)
Composición de Medicamentos/métodos , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría , Química Farmacéutica , Composición de Medicamentos/instrumentación , Liberación de Fármacos , Estabilidad de Medicamentos , Griseofulvina/química , Griseofulvina/farmacocinética , Tamaño de la Partícula , Solubilidad , Suspensiones , Agua/química , Difracción de Rayos X , Xilitol/química , Xilitol/farmacocinéticaRESUMEN
Griseofulvin is a commonly used antifungal agent which is administered per oral (p.o.). The oral administration route, however, shows rather low bioavailability. The aim of this study was to improve the bioavailability and to evaluate and interpret the pharmacokinetic profiles after subcutaneous (s.c.) administration of crystalline griseofulvin nano- and microsuspensions. Both formulations were injected at 5 and 500 µmol/kg to rats. For the lower concentration, the profiles were similar after s.c. injection but extended as compared to p.o. administration. For the higher concentration, injection of microsuspension resulted in a maintained plateau whereas the nanosuspension resulted in an obvious peak exposure followed by extended elimination. Both suspensions showed improved exposure with dose. The differences in peak exposures between nano- and microparticles, at the high dose, were mainly ascribed to differences in dissolution rate, experimentally determined in vitro, using spectroscopic methods. The extended appearance in the circulation may depend on the physicochemical properties of the compound and the physiological conditions at the injection site. The bioavailability was improved for both formulations compared with an orally administered nanosuspension, suggesting the s.c. route to be a preferred administration option for compounds with low oral bioavailability regarding both overall exposure and extended efficacy.
Asunto(s)
Composición de Medicamentos/métodos , Griseofulvina/farmacocinética , Nanopartículas/administración & dosificación , Administración Oral , Animales , Antifúngicos/administración & dosificación , Disponibilidad Biológica , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Evaluación Preclínica de Medicamentos , Liberación de Fármacos , Griseofulvina/administración & dosificación , Inyecciones Subcutáneas , Masculino , Modelos Animales , Tamaño de la Partícula , Ratas , Solubilidad , SuspensionesRESUMEN
The objective of the study was to evaluate the pharmacokinetic profile after different subcutaneous (s.c.) administrations of nano- and microparticle suspensions of griseofulvin to mice. The solubility of the compound was determined as approximately 40⯵M, at 37⯰C, independent of particle size, stabilizer mixtures investigated and solvent used for measurement. The present in vivo studies demonstrated non-linear absorption kinetics (in peak concentration, Cmax) for griseofulvin up to 50â¯mg/kg after s.c. administration of nanocrystals and microsuspensions but linear increase in area under the curve (AUC) at all occasions investigated. Cmax was higher for smaller particles administered. Both investigated suspensions, at 10 and 50â¯mg/kg, showed significantly sustained plasma profiles compared to i.v. and p.o. administration. Administering 10 and 50â¯mg/kg of griseofulvin nanocrystals as 10â¯mL/kg, instead of 2.5â¯mL/kg, improved Cmax but AUC was unchanged. The present study showed that the bioavailability of griseofulvin, administered as nano- and microparticles, increased significantly after s.c. administration (60-100%) compared with p.o. dosing (17%). The drug is currently orally administered and clearly exposed to a significant first pass metabolism, i.e. an ideal candidate for an alternative administration route, like s.c. injection.
Asunto(s)
Antifúngicos/administración & dosificación , Griseofulvina/administración & dosificación , Nanopartículas/administración & dosificación , Administración Oral , Animales , Antifúngicos/farmacocinética , Disponibilidad Biológica , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Femenino , Griseofulvina/farmacocinética , Inyecciones Subcutáneas , Ratones Endogámicos C57BL , Tamaño de la PartículaRESUMEN
Thylakoid-rich spinach extract is being used as dietary weight-loss supplements in Japan. A recent rat study has suggested that intake of thylakoid-rich spinach extract with dietary oil inhibits dietary fat absorption via binding to bile acids, which promotes excretion of bile acids in feces. While, we confirmed that a serving size of thylakoid-rich spinach extract contains a large amount of calcium (130 mg/5 g). Therefore, using rats, we evaluated whether one-time ingestion of thylakoid-rich spinach extract affects the gastrointestinal absorption of water-insoluble drugs, such as griseofulvin (GF) and indomethacin (IM), or ciprofloxacin (CPFX) that chelate with polyvalent metal cations. Pretreatment of the rats with thylakoid-rich spinach extract (100 or 300 mg/kg) for 15 min prior to oral administration of GF (50 mg/kg) or IM (10 mg/kg) did not significantly alter the pharmacokinetic properties of either drug. Meanwhile, co-administration of thylakoid-rich spinach extract (500 mg/kg) and CPFX (20 mg/kg) significantly reduced the peak plasma concentration and the area under the plasma concentration-time curve of CPFX to 25 and 40%, respectively in rats. In vitro studies demonstrated that when a mixture of thylakoid-rich spinach extract and CPFX was centrifuged, there was a significant reduction in the supernatant concentration of CPFX relative to the control. When the experiment was repeated in the presence of ethylenediaminetetraacetic acid, the concentration of CPFX was unchanged. These results suggest that the intake of thylakoid-rich spinach extract may reduce the absorption of drugs that form a chelate with polyvalent metal cations, such as CPFX.
Asunto(s)
Interacciones Alimento-Droga/fisiología , Griseofulvina/farmacocinética , Indometacina/farmacocinética , Extractos Vegetales/metabolismo , Spinacia oleracea , Tilacoides/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Absorción Gastrointestinal/efectos de los fármacos , Absorción Gastrointestinal/fisiología , Masculino , Extractos Vegetales/aislamiento & purificación , Ratas , Ratas WistarRESUMEN
Griseofulvin (1) is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Comprehensive SAR studies have led to the identification of 2'-benzyloxy griseofulvin 2, a more potent analogue with low micromolar anticancer potency in vitro. Analogue 2 was also shown to retard tumor growth through inhibition of centrosomal clustering in murine xenograft models of colon cancer and multiple myeloma. However, similar to griseofulvin, compound 2 exhibited poor metabolic stability and aqueous solubility. In order to improve the poor pharmacokinetic properties, 11 griseofulvin analogues were synthesized and evaluated for biological activity and physiological stabilities including SGF, plasma, and metabolic stability. Finally, the most promising compounds were investigated in respect to thermodynamic solubility and formulation studies. The 2'-benzylamine analogue 10 proved to be the most promising compound with low µM in vitro anticancer potency, a 200-fold increase in PBS solubility over compound 2, and with improved metabolic stability. Furthermore, this analogue proved compatible with formulations suitable for both oral and intravenous administration. Finally, 2'-benzylamine analogue 10 was confirmed to induce G2/M cell cycle arrest in vitro.
Asunto(s)
Antineoplásicos/química , Griseofulvina/farmacocinética , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Estabilidad de Medicamentos , Griseofulvina/administración & dosificación , Griseofulvina/síntesis química , Humanos , Ratones , Solubilidad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This work investigates whether the solubility of poorly soluble compounds can be improved by using mesoporous magnesium carbonate (MMC) as the drug delivery system. A solvent evaporation method was used to load structurally diverse model drugs (celecoxib, cinnarizine and griseofulvin) into the pores of MMC. The drug-loaded carrier system was then characterized in terms of porosity, crystallinity, and release profiles by a variety of experimental techniques, including X-ray diffraction, nitrogen adsorption analysis, differential scanning calorimetry, infrared spectroscopy, UV absorption spectroscopy, and thermogravimetric analysis. All three drugs were in a non-crystalline state after loading into the pores of MMC. The concentrations of the drugs in solution over time (a measure of the release rates from loaded MMC) were higher than the corresponding concentrations (dissolution rates) of equal amounts of the crystalline drugs. The release rates were five (celecoxib), three (cinnarizine) and two times (griseofulvin) higher than the dissolution rates of their crystalline counterparts. Supersaturation release profiles were also observed; the areas under the concentration-time curves (0-240min) were 25- (celecoxib), 5- (cinnarizine) and 2-fold (griseofulvin) greater than those of the crystalline drugs. Hence, MMC shows promise as a general drug delivery vehicle for increasing the bioavailability of compounds with dissolution rate- or solubility-limited absorption.
Asunto(s)
Celecoxib/química , Cinarizina/química , Portadores de Fármacos/química , Griseofulvina/química , Magnesio/química , Algoritmos , Rastreo Diferencial de Calorimetría , Celecoxib/farmacocinética , Cinarizina/farmacocinética , Portadores de Fármacos/farmacocinética , Liberación de Fármacos , Griseofulvina/farmacocinética , Porosidad , Solubilidad , Difracción de Rayos XRESUMEN
The aim of this study is to assess pullulan as a novel steric stabilizer during the wet-stirred media milling (WSMM) of griseofulvin, a model poorly water-soluble drug, and as a film-former in the preparation of strip films via casting-drying the wet-milled drug suspensions for dissolution and bioavailability enhancement. To this end, pullulan films, with xanthan gum (XG) as thickening agent and glycerin as plasticizer, were loaded with griseofulvin nanoparticles prepared by WSMM using pullulan in combination with sodium dodecyl sulfate (SDS) as an ionic stabilizer. The effects of drug loading and milling time on the particle size and suspension stability were investigated, as well as XG concentration and casting thickness on film properties and dissolution rate. The nanosuspensions prepared with pullulan-SDS combination were relatively stable over 7 days; hence, this combination was used for the film preparation. All pullulan-based strip films exhibited excellent content uniformity (most <3% RSD) despite containing only 0.3-1.3 mg drug, which was ensured by the use of precursor suspensions with >5000 cP viscosity. USP IV dissolution tests revealed fast/immediate drug release (t80 < 30 min) from films <120 µm thick. Thinner films, films with lower XG loading, or smaller drug particles led to faster drug dissolution, while drug loading had no discernible effect. Overall, these results suggest that pullulan may serve as an acceptable stabilizer for media milling in combination with surfactant as well as a fast-dissolving film former for the fast release of poorly water-soluble drug nanoparticles.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Glucanos/química , Griseofulvina/administración & dosificación , Griseofulvina/farmacocinética , Nanopartículas/administración & dosificación , Tecnología Farmacéutica/métodos , Disponibilidad Biológica , Composición de Medicamentos , Griseofulvina/química , Nanopartículas/química , Tamaño de la Partícula , Polisacáridos Bacterianos/química , Solubilidad , Propiedades de Superficie , Tecnología Farmacéutica/instrumentación , Resistencia a la Tracción , ViscosidadRESUMEN
Like other GLP-1 receptor agonists used for treatment of type 2 diabetes, liraglutide delays gastric emptying. In this clinical absorption study, the primary objective was to investigate the effect of liraglutide (at steady state) on the rate and/or extent of gastrointestinal (GI) absorption of concomitantly orally taken drugs from three classes of the Biopharmaceutics Classification System (BCS). To provide a general prediction on liraglutide drug-drug absorption interaction, single-dose pharmacokinetics of drugs representing BCS classes II (low solubility-high permeability; atorvastatin 40 mg and griseofulvin 500 mg), III (high solubility-low permeability; lisinopril 20 mg), and IV (low solubility-low permeability; digoxin 1 mg) were studied in healthy subjects at steady state of liraglutide 1.8 mg, or placebo, in a two-period crossover design. With liraglutide, the oral drugs atorvastatin, lisinopril, and digoxin showed delayed tmax (by ≤2 h) and did not meet the criterion for bioequivalence for Cmax (reduced Cmax by 27-38%); griseofulvin had similar tmax and 37% increased Cmax. Although the prespecified bioequivalence criterion was not met by all drugs, the overall plasma exposure (AUC) of griseofulvin, atorvastatin, lisinopril, and digoxin only exhibited minor changes and was not considered to be of clinical relevance.
Asunto(s)
Biofarmacia/clasificación , Interacciones Farmacológicas , Absorción Gastrointestinal , Liraglutida/farmacología , Administración Oral , Adolescente , Adulto , Antifúngicos/administración & dosificación , Antifúngicos/farmacocinética , Antihipertensivos/administración & dosificación , Antihipertensivos/farmacocinética , Atorvastatina/administración & dosificación , Atorvastatina/farmacocinética , Cardiotónicos/administración & dosificación , Cardiotónicos/farmacocinética , Simulación por Computador , Estudios Cruzados , Digoxina/administración & dosificación , Digoxina/farmacocinética , Método Doble Ciego , Femenino , Vaciamiento Gástrico , Griseofulvina/administración & dosificación , Griseofulvina/farmacocinética , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Hipoglucemiantes/farmacología , Lisinopril/administración & dosificación , Lisinopril/farmacocinética , Masculino , Persona de Mediana Edad , Equivalencia Terapéutica , Distribución Tisular , Adulto JovenRESUMEN
The oral bioavailability of a poorly water-soluble drug is often inadequate for the desired therapeutic effect. The bioavailability can be improved by enhancing the physicochemical properties of the drug (e.g., dissolution rate, permeation across the gastrointestinal tract). Other approach include shielding the drug from the gastric metabolism and targeted drug release to obtain optimal drug absorption. In this study, a poorly water-soluble model drug, griseofulvin, was encapsulated as disordered solid dispersions into Eudragit L 100-55 enteric polymer micromatrix particles, which were produced by electrospraying. Similar micromatrix particles were also produced with griseofulvin-loaded thermally oxidized mesoporous silicon (TOPSi) nanoparticles dispersed to the polymer micromatrices. The in vitro drug dissolution at pH 1.2 and 6.8, and permeation at pH 7.4 across Caco-2/HT29 cell monolayers from the micromatrix particles, were investigated. The micromatrix particles were found to be gastro-resistant, while at pH 6.8 the griseofulvin was released very rapidly in a fast-dissolving form. Compared to free griseofulvin, the permeability of encapsulated griseofulvin across the intestinal cell monolayers was greatly improved, particularly for the TOPSi-doped micromatrix particles. The griseofulvin solid dispersions were stable during storage for 6 months at accelerated conditions. Overall, the method developed here could prove to be a useful oral drug delivery solution for improving the bioavailability of poorly water-soluble or otherwise problematic drugs.
Asunto(s)
Griseofulvina/química , Polímeros/química , Resinas Acrílicas/química , Disponibilidad Biológica , Células CACO-2 , Línea Celular Tumoral , Portadores de Fármacos/química , Griseofulvina/farmacocinética , Células HT29 , Humanos , Absorción Intestinal/efectos de los fármacos , Nanopartículas/química , Permeabilidad , Silicio/química , Solubilidad , Tecnología Farmacéutica/métodos , Agua/químicaRESUMEN
Antecedentes: Los dermatofitos son un grupo de hongos queratinolíticos que producen infecciones denominadas dermatofitosis o tiñas. En Chile, los dermatofitos aislados con mayor frecuencia son Trichophyton rubrumy Trichophyton mentagrophytes en la población adulta, y Microsporum canis en niños prepúberes. Para el tratamiento de estas micosis se emplean antifúngicos tópicos y orales como la griseofulvina, antifúngicos azólicos como el clotrimazol, el itraconazol o el fluconazol, alilaminas como la terbinafina, y nuevas moléculas antifúngicas. Objetivos: Evaluar la sensibilidad in vitro de los dermatofitos frente a cinco antifúngicos y establecer posibles cambios respecto a estudios anteriores. Métodos: Se estudiaron 62 dermatofitos obtenidos de muestras clínicas (marzo-junio de 2010). Se utilizó el método de microdilución en caldo (M38-A2). Resultados: El rango de CMI para el fluconazol fue de 0,25-1 μg/ml; 0,03-0,06 μg/ml para el clotrimazol, la terbinafina y el itraconazol, y 0,015-0,03 μg/ml para la griseofulvina frente a T. rubrum y T. mentagrophytes. Excepto para le fluconazol, no se encontraron diferencias estadísticas significativas en los rangos de sensibilidad antifúngica. Conclusiones: Los valores de CMI para el fluconazol fueron los más altos (0,25-1 μg/ml) de todas las sustancias ensayadas, habiendo diferencias estadísticamente significativas entre este y el resto de antifúngicos. No hubo cepas resistentes a los antifúngicos analizados, y tampoco se encontraron cambios en el perfil de sensibilidad antifúngica in vitro en relación con estudios anteriores realizados en Chile (AU)
Background: Dermatophytes are a group of keratinophilic fungi able to produce dermatophytosis or tinea infections. In Chile, Trichophyton rubrum and Trichophyton mentagrophytes are the ones most commonly isolated in adults, while Microsporum canis is found among children. Treatment of these infections is usually with topical or oral antifungals, such as griseofulvin or azole derivatives (clotrimazole, itraconazole, fluconazole), allylamines (terbinafine) or new drugs that are available. Aims: Evaluation of the in vitro susceptibility of dermatophytes to five antifungal agents and the comparison of the susceptibility pattern with that of previous years. Methods: Sixty-two clinical isolates of dermatophyte fungi were studied (March-June 2010). The CLSI M38-A2 micromethod was used. Results: Fluconazole MIC values for T. rubrum and T. mentagrophytes varied between 0.25 and 1 μg/ml; MIC range to clotrimazole, terbinafine and itraconazole was 0.03-0.06 μg/ml, and MIC values for griseofulvin were 0.015-0.03 μg/ml. No statistically significant differences were found between susceptibility patterns, except for fluconazole. Conclusions: Fluconazole was less active in comparison with other drugs tested (0.25-1 μg/ml). None of the isolates were resistant to any of the drugs, and no changes in the susceptibility pattern were observed when comparing the results with data previously reported concerning dermatophytes in Chile (AU)
Asunto(s)
Humanos , Trichophyton/patogenicidad , Arthrodermataceae/patogenicidad , Antifúngicos/farmacocinética , Técnicas In Vitro/métodos , Pruebas de Sensibilidad Microbiana , Fluconazol/farmacocinética , Combinación Trimetoprim y Sulfametoxazol/farmacocinética , Griseofulvina/farmacocinética , Itraconazol/farmacocinéticaRESUMEN
In this study, we reported the application of Povacoat®, a hydrophilic polyvinylalcohol copolymer, as a dispersion stabilizer of nanoparticles of poorly water-soluble compounds. In addition, the influence of aggregation of the nanoparticles on their solubility and oral absorption was studied. Griseofulvin (GF) was used as a model compound with poor water solubility and was milled to nanoparticles by wet bead milling. The dispersion stability of GF milled with Povacoat® or the generally used polymers (polyvinylalcohol, hydroxypropylcellulose SSL, and polyvinylpyrrolidone K30) was compared. Milled GF suspended in Povacoat® aqueous solution with D-mannitol, added to improve the disintegration rate of freeze-dried GF, exhibited high dispersion stability without aggregation (D90 = ca. 0.220 µm), whereas milled GF suspended in aqueous solutions of the other polymers aggregated (D90 > 5 µm). Milled GF with Povacoat® showed improved aqueous solubility and bioavailability compared with the other polymers. The aggregation of nanoparticles had significant impact on the solubility and bioavailability of GF. Povacoat® also prevented the aggregation of the various milled poorly water-soluble compounds (hydrochlorothiazide and tolbutamide, etc.) more effectively than the other polymers. These results showed that Povacoat® could have wide applicability to the development of nanoformulations of poorly water-soluble compounds.
Asunto(s)
Excipientes/química , Griseofulvina/química , Nanopartículas , Polimetil Metacrilato/química , Alcohol Polivinílico/química , Administración Oral , Animales , Disponibilidad Biológica , Celulosa/análogos & derivados , Celulosa/química , Química Farmacéutica , Cristalización , Estabilidad de Medicamentos , Liofilización , Griseofulvina/administración & dosificación , Griseofulvina/farmacocinética , Interacciones Hidrofóbicas e Hidrofílicas , Cinética , Masculino , Manitol/química , Nanotecnología , Alcohol Polivinílico/análogos & derivados , Povidona/química , Ratas Sprague-Dawley , Solubilidad , Tecnología Farmacéutica/métodosRESUMEN
After the great commercial success of sub-3 µm superficially porous particles, vendors are now also starting to commercialize 5 µm superficially porous particles, as an alternative to their fully porous counterparts which are routinely used in pharmaceutical analysis. In this study, the performance of 5 µm superficially porous particles was compared to that of fully porous 5 µm particles in terms of efficiency, separation performance and loadability on a conventional HPLC instrument. Van Deemter and kinetic plots were first used to evaluate the efficiency and performance of both particle types using alkylphenones as a test mixture. The van Deemter and kinetic plots showed that the superficially porous particles provide a superior kinetic performance compared to the fully porous particles over the entire relevant range of separation conditions, when both support types were evaluated at the same operating pressure. The same observations were made both for isocratic and gradient analysis. The superior performance was further demonstrated for the separation of a pharmaceutical compound (griseofulvin) and its impurities, where a gain in analysis time of around 2 could be obtained using the superficially porous particles. Finally, both particle types were evaluated in terms of loadability by plotting the resolution of the active pharmaceutical ingredient and its closest impurity as a function of the signal-to-noise ratio obtained for the smallest impurity. It was demonstrated that the superficially porous particles show better separation performance for griseofulvin and its impurities without significantly compromising sensitivity due to loadability issues in comparison with their fully porous counterparts. Moreover these columns can be used on conventional equipment without modifications to obtain a significant improvement in analysis time.
Asunto(s)
Contaminación de Medicamentos , Griseofulvina/análisis , Griseofulvina/farmacocinética , Tamaño de la Partícula , Cromatografía Líquida de Alta Presión/métodos , Cinética , PorosidadRESUMEN
PURPOSE: This study aimed to develop a novel approach for predicting the oral absorption of low-solubility drugs by considering regional differences in solubility and permeability within the gastrointestinal (GI) tract. METHODS: Simulated GI fluids were prepared to reflect rat in vivo bile acid and phospholipid concentrations in the upper and lower small intestine. The saturated solubility and permeability of griseofulvin (GF) and albendazole (AZ), a drug with low aqueous solubility, were measured using these simulated fluids, and fraction absorbed (Fa) at time t after oral administration was calculated. RESULTS: The saturated solubility of GF and AZ, a drug with low aqueous solubility, differed considerably between the simulated GI fluids. Large regional differences in drugs concentration were also observed following oral administration in vivo. The predicted Fa values using solubility and permeability data of the simulated GI fluid were found to correspond closely to the in vivo data. CONCLUSION: These results indicated the importance of evaluating regional differences in drug solubility and permeability in order to predict oral absorption of low-solubility drugs accurately. The new methodology developed in the present study could be useful for new oral drug development.
Asunto(s)
Permeabilidad de la Membrana Celular , Tracto Gastrointestinal/metabolismo , Absorción Intestinal , Administración Intravenosa , Administración Oral , Albendazol/farmacocinética , Animales , Líquidos Corporales/metabolismo , Griseofulvina/farmacocinética , Ratas , SolubilidadRESUMEN
It is well known that large differences exist in the bioavailability of orally administered drugs between species. Dissolution is the first step in the oral absorption of solid drugs. In this study, we measured the in vivo luminal concentrations of griseofulvin (GF) and albendazole (AZ), Biopharmaceutics Classification System (BCS) class II drugs, and the GF fraction absorbed (Fa) in rats. Then, we compared the GF Fa in rat with that in other species reported previously to evaluate differences in drug dissolution and oral absorption. The Fa of GF has been reported to decrease from 80% to 40% with an increase in the oral dose in dogs and humans, because the rate-limiting step for absorption shifts from dissolution to solubility. However, such non-linearity was not observed in rats that were administered doses in the same ranges as those in humans, and the Fa values in rats were higher than those in dogs or humans. The in vivo luminal concentration of GF after oral administration in rats was much higher than the saturated solubility of GF in fasted-state simulated dog (FaSSIF(dog)) or human intestinal fluid (FaSSIF(human)). Furthermore, oral administration of AZ showed similar tendencies of interspecies differences in dissolution and oral absorption.
Asunto(s)
Albendazol/farmacocinética , Griseofulvina/farmacocinética , Absorción , Administración Oral , Albendazol/administración & dosificación , Animales , Líquidos Corporales/química , Perros , Tracto Gastrointestinal/metabolismo , Griseofulvina/administración & dosificación , Humanos , Absorción Intestinal , Masculino , Ratas , Solubilidad , Especificidad de la EspecieRESUMEN
Griseofulvin-loaded solid lipid nanoparticles (SLNs) were prepared by hot microemulsion technique and optimized for type and concentration of lipid and surfactant. The optimized SLN composition was characterized in terms of particle shape and size, drug entrapment efficiency, pH, stability, spreadability, ex-vivo skin permeation, dermatokinetics, skin sensitivity, in vitro antifungal assay and in vivo antifungal activity against Microsporum canis using guinea pig model for dermatophytosis. The cumulative amount of drug permeated through excised mice skin from SLNs was more than 5-folds as compared to permeation from conventional cream base. Fluorescent microscopy revealed presence of nanoparticles in the skin layers suggesting the penetration of nanoparticles into the skin owing to their nano-size and thence a controlled drug release. A complete mycological and clinical cure was observed in M. canis infected guinea pigs after twice daily application of SLN gel containing griseofulvin for 8 days. Also, the formulation was observed to be non-sensitizing, histopathologically safe, and SLN gel was stable at 5 +/- 3 degrees C, 25 +/- 2 degrees C and 40 +/- 2 degrees C for a period of six months. It can be concluded from our study that SLNs provide a good skin permeation effect and may be a promising carrier for topical delivery of griseofulvin.
Asunto(s)
Griseofulvina/farmacología , Lípidos/química , Nanopartículas/química , Piel/efectos de los fármacos , Administración Cutánea , Animales , Antifúngicos/farmacología , Rastreo Diferencial de Calorimetría , Química Farmacéutica , Hongos/efectos de los fármacos , Griseofulvina/farmacocinética , Griseofulvina/uso terapéutico , Cobayas , Técnicas In Vitro , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Microscopía Fluorescente , Micosis/tratamiento farmacológico , Micosis/microbiología , Micosis/patología , Nanopartículas/ultraestructura , Tamaño de la Partícula , Permeabilidad/efectos de los fármacos , Rodamina 123/metabolismo , Piel/microbiología , Piel/patología , Absorción Cutánea/efectos de los fármacos , SolubilidadRESUMEN
Drug polymer-based amorphous solid dispersions (ASD) are widely used in the pharmaceutical industry to improve bioavailability for poorly water-soluble compounds. Spray-drying is the most common process involved in the manufacturing of ASD material. However, spray-drying involves a high investment of material quantity and time. Lower investment manufacturing processes such as fast evaporation and freeze-drying (lyophilization) have been developed to manufacture ASD at the bench level. The general belief is that the overall performance of ASD material is thermodynamically driven and should be independent of the manufacturing process. However, no formal comparison has been made to assess the in vivo performance of material generated by different processes. This study compares the in vitro and in vivo properties of ASD material generated by fast evaporation, lyophilization, and spray-drying methods using griseofulvin as a model compound and hydroxypropyl methylcellulose acetate succinate as the polymer matrix. Our data suggest that despite minor differences in the formulation release properties and stability of the ASD materials, the overall exposure is comparable between the three manufacturing processes under the conditions examined. These results suggest that fast evaporation and lyophilization may be suitable to generate ASD material for oral evaluation. However, caution should be exercised since the general applicability of the present findings will need to be further evaluated.
Asunto(s)
Griseofulvina/química , Metilcelulosa/análogos & derivados , Tecnología Farmacéutica/métodos , Administración Oral , Animales , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría , Química Farmacéutica , Cristalografía por Rayos X , Composición de Medicamentos , Estabilidad de Medicamentos , Liofilización , Griseofulvina/administración & dosificación , Griseofulvina/farmacocinética , Espectroscopía de Resonancia Magnética , Masculino , Metilcelulosa/química , Difracción de Polvo , Ratas , Ratas Sprague-Dawley , Solubilidad , TermogravimetríaRESUMEN
PURPOSE: To introduce guidelines in selecting the particle size distribution (n(0), cm(-1)) that will guarantee optimal oral absorption for drugs with low solubility. METHODS: Unlike other multi-compartmental models the gastrointestinal tract is modeled as a continuous tube with spatially varying properties. The transport through the intestinal lumen is described using the dispersion model. The model accounts for the dissolution of poly-dispersed powders. RESULTS: The model was used to examine the sensitivity of the absorption on permeability (P) and water solubility (C(s)) following administration in different log-normal powders. The absorption exhibits inverse sigmoidal dependence on the mean particle size (r(m), µm) regardless of the administrated dose or drug properties. Thus, there is an optimal r(m) that maximizes the benefit-cost ratio of the formulation; finer particles do not improve the absorption while coarser particles decrease it. Using the model we find that the optimal r(m) depends mainly on the drug C(s) and on the geometrical standard deviation (gSTD). CONCLUSIONS: The results of this work provide the formulator with guidelines to select both r(m) and gSTD that guarantee optimal absorption.
Asunto(s)
Tracto Gastrointestinal/metabolismo , Modelos Químicos , Preparaciones Farmacéuticas/química , Agua/química , Administración Oral , Química Farmacéutica/métodos , Griseofulvina/química , Griseofulvina/farmacocinética , Absorción Intestinal , Cinética , Tamaño de la Partícula , Permeabilidad , Farmacocinética , SolubilidadRESUMEN
PURPOSE: To investigate the use of nano self-assemblies formed by polyallylamine (PAA) modified with 5 or 10% mole fluorenylmethoxy carbonyl (Fmoc(5)/(10)), dimethylamino-1-naphthalenesulfonyl (Dansyl(5)/(10)) and 5% mole cholesteryl group (Ch(5)) for oral hydrophobic drug delivery. METHODS: Propofol, griseofulvin and prednisolone were loaded into amphiphilic PAAs. Particle size and morphology of drug-loaded self-assemblies were determined using photon correlation spectroscopy and transmission electron microscopy. Solubilising capacity, in vitro drug release and formulation stability were analysed by HPLC, and in vitro biocompatibility studies (haemolysis and cytotoxicity) were carried out on bovine erythrocytes and Caco-2 cells, respectively. Dansyl(10) and Ch(5) griseofulvin formulations were administered intra-gastrically to rats, and drug plasma levels were analysed by HPLC. RESULTS: Drug-encapsulated self-assemblies typically have hydrodynamic size of 300-400 nm. Dansyl(10) exhibited universal drug solubiliser property and had significantly improved prednisolone, griseofulvin and propofol solubility by 145, 557 and 224-fold, respectively. Fmoc polymers resulted in modest drug solubility improvement. These polymers were non-haemolytic, did not enhance cytotoxicity compared to unmodified PAA, and demonstrated significant increase in griseofulvin plasma concentration compared to griseofulvin in water after oral administration. CONCLUSIONS: Ch(5) and Dansyl(10) showed promising potential as nano-carriers for oral hydrophobic drug delivery.
Asunto(s)
Antiinflamatorios/administración & dosificación , Portadores de Fármacos/química , Griseofulvina/administración & dosificación , Hipnóticos y Sedantes/administración & dosificación , Poliaminas/química , Prednisolona/administración & dosificación , Propofol/administración & dosificación , Administración Oral , Animales , Antiinflamatorios/farmacocinética , Células CACO-2 , Bovinos , Supervivencia Celular , Colestenos/química , Colestenos/toxicidad , Compuestos de Dansilo/química , Compuestos de Dansilo/toxicidad , Portadores de Fármacos/toxicidad , Fluorenos/química , Fluorenos/toxicidad , Griseofulvina/farmacocinética , Hemólisis/efectos de los fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Hipnóticos y Sedantes/farmacocinética , Masculino , Poliaminas/toxicidad , Prednisolona/farmacocinética , Propofol/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
As 95% of all prescriptions are for orally administered drugs, the issue of oral absorption is central to the development of pharmaceuticals. Oral absorption is limited by a high molecular weight (>500 Da), a high log P value (>2.0) and low gastrointestinal permeability. We have designed a triple action nanomedicine from a chitosan amphiphile: quaternary ammonium palmitoyl glycol chitosan (GCPQ), which significantly enhances the oral absorption of hydrophobic drugs (e.g., griseofulvin and cyclosporin A) and, to a lesser extent, the absorption of hydrophilic drugs (e.g., ranitidine). The griseofulvin and cyclosporin A C(max) was increased 6- and 5-fold respectively with this new nanomedicine. Hydrophobic drug absorption is facilitated by the nanomedicine: (a) increasing the dissolution rate of hydrophobic molecules, (b) adhering to and penetrating the mucus layer and thus enabling intimate contact between the drug and the gastrointestinal epithelium absorptive cells, and (c) enhancing the transcellular transport of hydrophobic compounds. Although the C(max) of ranitidine was enhanced by 80% with the nanomedicine, there was no appreciable opening of tight junctions by the polymer particles.