RESUMEN
Novel lipid-polymer composite microspheres (LP-MS) were prepared by combining pH-sensitive polymer Eudragit S100 with solid lipid Compritol 888 ATO for colonic delivery of 10-hydroxycamptothecin (HCPT), and pH-dependent controlled drug release has been achieved. The colon-specific biodistribution and uptake by the mucosal tissue were examined using coumarin-6-marked LP-MS. It is proved that good in vitro-in vivo relationship has been achieved, with more drugs being delivered to colon and a higher drug level was maintained for a long period. Moreover, in vivo bioavailability of LP-MS was evaluated with conventional enteric microspheres (enteric MS) as reference. After administration of LP-MS, systemic absorption of HCPT was greatly reduced, with area under the curve from 0 to 24h (AUC0-24 h , 2.186 ± 0.27) being significantly lower than that of enteric MS group (6.352 ± 0.696). In conclusion, the novel pH-sensitive LP-MS has potential for colon-specific drug delivery.
Asunto(s)
Resinas Acrílicas/química , Antineoplásicos Fitogénicos/administración & dosificación , Camptotecina/análogos & derivados , Colon/metabolismo , Preparaciones de Acción Retardada/química , Ácidos Grasos/química , Resinas Acrílicas/metabolismo , Animales , Antineoplásicos Fitogénicos/farmacocinética , Camptotecina/administración & dosificación , Camptotecina/farmacocinética , Sistemas de Liberación de Medicamentos , Ácidos Grasos/metabolismo , Concentración de Iones de Hidrógeno , Microesferas , RatasRESUMEN
Lipid-polymer composite microspheres (LP-MS) for colon-specific drug delivery were prepared using an ultrasonic spray freeze-drying technique. These microspheres, which consist of the pH-sensitive polymer Eudragit S100 and the non-polar lipid Compritol 888 ATO, were characterized by morphological and physicochemical properties. It was found that the LP-MS have a spherical lipid porous matrix with a smooth pH-sensitive polymer film on both internal and external surfaces, and the insoluble drug 10-hydroxycamptothecin was dispersed in an amorphous state in the carrier. Morphological changes of microparticles under different pH conditions were observed by confocal laser scanning microscopy, which showed that the lipid matrix in LP-MS restricted the swelling property of the polymer at pH 6.8. In drug release studies, less than 15% of the drug was released below pH 6.8, whereas more than 30% was released with a sustained-release model at pH 7.4. The LP-MS could provide a promising vehicle for colon drug delivery.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Camptotecina/análogos & derivados , Colon/metabolismo , Sistemas de Liberación de Medicamentos , Ácidos Grasos/química , Liofilización/métodos , Ácidos Polimetacrílicos/química , Camptotecina/administración & dosificación , Excipientes/química , Humanos , Microesferas , Neoplasias/tratamiento farmacológico , Tamaño de la Partícula , Solubilidad , Ultrasonido/métodosRESUMEN
In this study, an examination of the potential effect of lipids on the first-pass metabolism of anethol trithione (ATT) was investigated. ATT is metabolized rapidly and extensively in liver into 4-hydroxy-anethole trithione (ATX), which was confirmed using the rat intestinal perfusion with the mesenteric cannulation model. Male Sprague-Dawley rats were orally administered of the lipid-based formulations (prepared by medium chain triglycerides (MCT)), the cyclodextrin formulation and the suspension formulation, respectively. For 6.75 mg/kg groups, ATX/ATT area under the plasma concentration-time curve (AUC) ratio decreased by 87% and 76% after administration of the MCT-based formulations and the cyclodextrin formulation, when compared with the suspension formulation (p < 0.05), respectively; for 2.25 mg/kg groups, it decreased by 53% in the MCT group when compared with the cyclodextrin group (p < 0.05). The saturation of pre-system metabolism of ATT was observed after administration of the MCT-based formulations and the cyclodextrin formulation, likely as a result of enhanced absorption and therefore presentation of higher drug concentrations to liver, when compared with the suspension formulation. A trend toward lower systemic metabolite to parent ratios was evident after administration of the lipid formulations, when compared with the cyclodextrin formulation; however, this was not statistically significant. Further studies on the potential for lipids to inhibit hepatic metabolism are therefore warranted.
Asunto(s)
Anetol Tritiona/farmacocinética , Metabolismo de los Lípidos , Anetol Tritiona/sangre , Animales , Área Bajo la Curva , Mucosa Intestinal/metabolismo , Masculino , Modelos Biológicos , Ratas , Ratas Sprague-DawleyRESUMEN
AIM: To develop a novel vehicle based on cubosomes as an ophthalmic drug delivery system for flurbiprofen (FB) to reduce ocular irritancy and improve bioavailability. METHODS: FB-loaded cubosomes were prepared using hot and high-pressure homogenization. Cubosomes were then characterized by particle size, zeta potential, encapsulation efficiency, particle morphology, inner cubic structure and in vitro release. Corneal permeation was evaluated using modified Franz-type cells. Ocular irritation was then evaluated using both the Draize method and histological examination. The ocular pharmacokinetics of FB was determined using microdialysis. RESULTS: The particle size of each cubosome formulation was about 150 nm. A bicontinuous cubic phase of cubic P-type was determined using cryo-transmission electron microscopy (cryo-TEM) observation and small angle X-ray scattering (SAXS) analysis. In vitro corneal permeation study revealed that FB formulated in cubosomes exhibited 2.5-fold (F1) and 2.0-fold (F2) increase in P(app) compared with FB PBS. In the ocular irritation test, irritation scores for each group were less than 2, indicating that all formulations exhibited excellent ocular tolerance. Histological examination revealed that neither the structure nor the integrity of the cornea was visibly affected after incubation with FB cubosomes. The AUC of FB administered as FB cubosome F2 was 486.36+/-38.93 ng.mL(-1).min.microg(-1), which was significantly higher than that of FB Na eye drops (P<0.01). Compared with FB Na eye drops, the T(max) of FB cubosome F2 was about 1.6-fold higher and the MRT was also significantly longer (P<0.001). CONCLUSION: This novel low-irritant vehicle based on cubosomes might be a promising system for effective ocular drug delivery.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Córnea/metabolismo , Sistemas de Liberación de Medicamentos , Flurbiprofeno/administración & dosificación , Administración Tópica , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/toxicidad , Área Bajo la Curva , Disponibilidad Biológica , Flurbiprofeno/farmacocinética , Flurbiprofeno/toxicidad , Masculino , Microdiálisis , Microscopía Electrónica de Transmisión/métodos , Soluciones Oftálmicas , Tamaño de la Partícula , Permeabilidad , ConejosRESUMEN
This study was conducted to investigate the relationship between the carbon chain length/double bonds of alkyl esters and their inhibitory potency/mechanism on carboxylesterases (CESs). CESs activity was evaluated by inhibition of adefovir dipivoxil (ADV) metabolism in rat intestinal homogenates. Furthermore, the inhibitory effect of BNPP and ethyl (E)-hex-2-enoate (C8:1) on drug absorption was evaluated in situ intestinal perfusion model. The results showed that the rank order of the inhibitory potency on CESs was C10:0 > C8:0 > C6:0 > C4:0 > C12:0, C8:1 > C8:0, C6:1 > C6:0, while the esters (C14:0, C13:1, C16:0, C18:0, C17:1, C20:0) were found to have no inhibitory effect at investigated concentrations. However, the unsaturated esters (C20:1, C20:2, C20:3) displayed the inhibitory effect on CESs. Moreover, the double reciprocal plots indicated that alky esters inhibited the CESs in competitive and mixed competitive ways which were reversible. In addition, the result of most effective CESs inhibitor C8:1 from in situ experiment showed that C8:1 can inhibit the CESs-mediated intestinal metabolism and improve the drug absorption. And the inhibition had no time-dependent effect, compared with that of BNPP groups. The study suggested that alkyl esters can be served as effective and reversible CESs inhibitors, besides that their inhibitory potency/mechanism can be affected by their carbon chain length/double bonds.
Asunto(s)
Hidrolasas de Éster Carboxílico/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Ácidos Grasos Insaturados/farmacología , Intestinos/enzimología , Animales , Caproatos/química , Caproatos/metabolismo , Hidrolasas de Éster Carboxílico/metabolismo , Inhibidores Enzimáticos/química , Ácidos Grasos no Esterificados/farmacología , Mucosa Intestinal/metabolismo , RatasRESUMEN
AIM: To improve the oral absorption of adefovir dipivoxil (ADV) by employing MCT and the esterase inhibitor ethyl oleate (EO) as a complex oil phase in emulsion. METHODS: EO was used as the esterase inhibitor, and its inhibitory effect on esterase activity was assessed in rat intestinal homogenates. ADV emulsions with or without EO were prepared. The emulsions' protective effect against intestinal metabolism was evaluated in rat luminal contents, ex vivo, as well as in vivo. RESULTS: The IC(50) of EO in intestinal mucosal homogenates was 2.2 mg/mL. The emulsions exhibited significant protective effects in rat luminal contents compared to a simple suspension (98.7%, 96.3%, 95.7% vs 74.7%, P<0.01). The permeability calculated from the emulsion containing EO was significantly different (11.4 x 10(-6) vs 7.4/8.0 x 10(-6), P<0.05) from the simple suspension or the emulsion without EO in an ex vivo assay. A bioavailability study in vivo revealed that emulsions containing both EO and MCT as a complex oil phase demonstrated 1.6- and 1.5-fold enhancements in area under the curve (AUC(0-12)) values (5358 vs 3386/3618, P<0.05), respectively, when compared with emulsions containing EO or MCT as a single oil phase. CONCLUSION: Heterotic lipid formulations (emulsions) with an esterase inhibitor (ie, EO) may be useful in protecting ester prodrugs from intestinal metabolism and increasing their oral bioavailability.
Asunto(s)
Adenina/análogos & derivados , Antivirales/farmacocinética , Ácidos Oléicos/química , Organofosfonatos/farmacocinética , Triglicéridos/química , Adenina/administración & dosificación , Adenina/farmacocinética , Administración Oral , Animales , Antivirales/administración & dosificación , Área Bajo la Curva , Disponibilidad Biológica , Emulsiones , Inhibidores Enzimáticos/química , Esterasas/antagonistas & inhibidores , Concentración 50 Inhibidora , Absorción Intestinal , Mucosa Intestinal/metabolismo , Masculino , Organofosfonatos/administración & dosificación , Ratas , Ratas Sprague-DawleyRESUMEN
The aim of the study is to prepare flurbiprofen axetil nanoemulsion-in situ gel system (FBA/NE-ISG) and observe its ocular pharmacokinetics, rheological behavior, TEM images, irritation and cornea retention. Production of nanoemulsion was based on high-speed shear and homogenization process, and then mixed with gellan gum to prepare FBA/NE-ISG. Rheological study showed that FBA/NE-ISG possesses strong gelation capacity and its viscosity and elastic modulus increases by 2 Pa*s and 5 Pa respectively when mixed with artificial tear at the ratio of 40 : 7. TEM images suggested no significant changes in particle morphology of the pre and post gelation. Good ocular compatibility of FBA/NE-ISG was testified by the irritation test based on histological examination. In vivo fluorescence imaging system was applied to investigate the characteristics of cornea retention, and the results indicated that the nanoemulsion-in situ gel (NE-ISG) prolonged the cornea retention time significantly since K(NE-ISG) (0.008 5 min(-1) was much lower compared with flurbiprofen sodium eye drops (FB-Na, 0.03% w/v) of which the K(Eye drops) was 0.105 2 min(-1), indicated that the cornea retention time of NE-ISG was prolonged significantly. Pharmacokinetics of FBA/NE-ISG in rabbit aqueous humor was studied by cornea puncture, the MRT (12.3 h) and AUC(0-12h) (126.8 microg x min x mL(-1)) of FBA/NE-ISG was 2.7 and 2.9 times higher than that of the flurbiprofen sodium eye drops respectively, which meant that the ocular bioavailability was improved greatly by the novel preparation. Therefore, FBA/NE-ISG can enhance the ocular bioavailability by prolonging drug corneal retention significantly. What's more, encapsulated by emulsion droplets prodrug flurbiprofen (FBA) instead of flurbiprofen (FB) can reduce the ocular irritation.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Humor Acuoso/metabolismo , Córnea/efectos de los fármacos , Flurbiprofeno/análogos & derivados , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Disponibilidad Biológica , Córnea/citología , Emulsiones , Femenino , Flurbiprofeno/administración & dosificación , Flurbiprofeno/efectos adversos , Flurbiprofeno/farmacocinética , Geles , Masculino , Nanopartículas , Soluciones Oftálmicas , Conejos , Reología , ViscosidadRESUMEN
AIM: To investigate the effect of breast cancer resistance protein (BCRP) inhibitors and pharmaceutical excipients on reducing the biliary excretion of camptothecins (CPT), ameliorating delayed-type diarrhea and intestinal mucosa damage induced by CPT. METHODS: The cumulative biliary excretion of irinotecan (CPT-11) and hydroxycamptothecin (HCPT) with or without BCRP inhibitors and excipients was investigated in rats. The gastrointestinal toxicity, assessed as the diarrheal score, body weight change and microscopic pathological damage was also determined in rats. RESULTS: Breast cancer resistance protein (BCRP) exhibited important effects on the biliary excretion of CPT. Coadministration of BCRP inhibitors such as GF120918 and cyclosporin A reduced the biliary excretion of CPT-11 and HCPT. Pharmaceutical excipients such as Pluronic F68 and PEG 2000 stearate also showed inhibitory effects on BCRP and similarly reduced CPT biliary excretion. The observed gastrointestinal toxicity was ameliorated by coadministration of BCRP inhibitors and excipients compared with injection of CPT-11 and HCPT alone. CONCLUSION: The use of excipients as inhibitors of BCRP is safe and relatively non-toxic, and may lead to important pharmacotherapeutic benefits by decreasing the gastrointestinal toxicity of CPT.
Asunto(s)
Antineoplásicos Fitogénicos/toxicidad , Neoplasias de la Mama/metabolismo , Camptotecina/análogos & derivados , Camptotecina/toxicidad , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/prevención & control , Proteínas de Neoplasias/antagonistas & inhibidores , Animales , Antineoplásicos Fitogénicos/antagonistas & inhibidores , Biotransformación , Camptotecina/antagonistas & inhibidores , Diarrea/inducido químicamente , Diarrea/prevención & control , Excipientes , Enfermedades Gastrointestinales/patología , Mucosa Intestinal/patología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The aim was to prepare a novel ocular cationic microemulsion-in situ gel (CM-ISG) system with vitamin A palmitate (VAP) as model drug, and investigate the corneal retention behavior and corneal irritation of the system. VAP/CM was prepared by a process based on supply of energy, and the before-and-after gelation rheology of VAP/CM-ISG was investigated. In vitro VAP release and gel dissolution of both VAP/CM-ISG and Oculotect Gel was determined. And in vitro corneal retention behavior of both formulations was evaluated by captive bubble technique. Ocular irritation test was carried out based on the Draize method. Images of TEM showed that homogenous VAP/CM was made, and no significant differences of particle size were found between the VAP/CM and VAP/CM in Poloxamer 407 gel. Rheology study illustrated that VAP/CM reduced the phase transition temperature of Poloxamer 407 gel by 1.5 degrees C, and the elastic modulus increased about 15.7 times. The in vitro release and gel dissolution profile of both formulations exhibited the characteristics of zero order kinetics. Comparing with Oculotect Gel, desorption kinetics study of VAP/CM-ISG exhibited longer corneal retention time and smaller contact angle. Irritation test showed a good ocular compatibility of VAP/CM-ISG. Therefore, VAP/CM-ISG combined both advantages of the cationic microemulsion and in situ gel system, provided better wettability and longer ocular retention time. It might be a promising ocular drug delivery system.
Asunto(s)
Córnea/metabolismo , Sistemas de Liberación de Medicamentos , Vitamina A/análogos & derivados , Animales , Córnea/efectos de los fármacos , Preparaciones de Acción Retardada , Diterpenos , Portadores de Fármacos , Emulsiones , Soluciones Oftálmicas , Poloxámero/química , Conejos , Distribución Aleatoria , Ésteres de Retinilo , Viscosidad , Vitamina A/administración & dosificación , Vitamina A/farmacocinética , Vitamina A/toxicidadRESUMEN
Hydroxycamptothecin (HCPT) loaded PEG modified nanostructured lipid carriers (HCPT-PEG-NLC) and nanostructured lipid carriers (HCPT-NLC) were prepared by melt emulsification and homogenization method. The morphology, particle size and encapsulation efficiency of them were investigated. HCPT concentrations in plasma, heart, liver, spleen, lung, kidney and ovary were determined after iv of HCPT injection, HCPT-PEG-NLC and HCPT-NLC in mice. The targeting indexes of HCPT-PEG-NLC and HCPT-NLC were calculated. The transmission electron microscope imaging showed that HCPT-PEG-NLC and HCPT-NLC exhibited a spherical shape. The particle sizes of them were (88.6 +/- 22.5) and (127.2 +/- 43.4) nm. The encapsulation efficiency were (90.51 +/- 3.29)% and (84.37 +/- 2.81)%, respectively. After iv injection into the tail vein of mice, HCPT plasma concentrations of HCPT-PEG-NLC and HCPT-NLC were higher than that of HCPT injection at each sampling time. They also showed longer elimination time in every tissue. HCPT-NLC accumulated in endothelial system (RES), Re and Ce of it in liver and spleen were significantly higher than HCPT-PEG-NLC. HPCT-PEG-NLC prolonged circulation time and increased bioavailability of HCPT. MRT and AUC0-24 h of it were 19.80 and 17.02 times higher than those of HCPT injection. It also significantly reduced phagocytosis of RES, and showed lung targeting effect (Re and Ce were 14.51 and 41.35). To summarize, HCPT-PEG-NLC could prolong the circulation time of HCPT in vivo, and had the lung targeting effect. It was a promising carrier to increase therapeutic effect of HCPT in treating lung cancer.
Asunto(s)
Camptotecina/análogos & derivados , Sistemas de Liberación de Medicamentos , Lípidos/química , Polietilenglicoles/química , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/sangre , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacocinética , Disponibilidad Biológica , Camptotecina/administración & dosificación , Camptotecina/sangre , Camptotecina/química , Camptotecina/farmacocinética , Preparaciones de Acción Retardada , Estabilidad de Medicamentos , Femenino , Pulmón/metabolismo , Ratones , Sistema Mononuclear Fagocítico/fisiología , Nanopartículas , Tamaño de la Partícula , Fagocitosis/efectos de los fármacos , Distribución TisularRESUMEN
To screen a new poorly water-soluble antischistosomal drug QH917 self-microemulsifying drug delivery system which has steady release in vitro and absorption in situ separately. The formulation was optimized using central composite design-response surface methodology. Independent variables were oil content (%) and the weight ratio of surfactant and cosurfactant (Km), while response variables were self-microemulsifying time (t), mean particle size (PS) and polydispersity index (PI). The effects of ionic strength, food, pH, rotation speed and medium volume on drug release of the optimized formulation were evaluated under conditions simulating in vivo physiological situations. The absorption of the optimized formulation was studied using in situ intestinal permeability technique of rats. The optimized formulation was as follows: the content of media chain triglyceride (MCT) was 30%-34% (w/w); and the weight ratio of surfactant polyoxyl 40 hydrogenated castor oil (Cremophor RH40) and co-surfactant ethanol was 4.8-5.2. Release of QH917 from the optimized formulation was nearly unaffected by ionic strength, food, pH, rotation speed and medium volume. There was no marked difference of the absorption rate between rats with and without ligated bile duct in rat intestinal permeability technique. Inter-individual variability in absorption of the optimized formulation was negligible. Central composite design-response surface methodology is an efficient approach for optimizing formulations of self-microemulsifying drug delivery system; drug release in vitro and absorption behavior in situ of the optimized formulation is steady.
Asunto(s)
Artemisininas/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Absorción Intestinal , Esquistosomicidas/administración & dosificación , Animales , Artemisininas/farmacocinética , Emulsiones , Masculino , Tamaño de la Partícula , Distribución Aleatoria , Ratas , Ratas Wistar , Esquistosomicidas/farmacocinética , Solubilidad , Tensoactivos/química , Triglicéridos/químicaRESUMEN
We have shown previously that Fas activation results in a partial reduction of phorbol 12-myristate 13-acetate (PMA)-stimulated neutrophil adhesion to endothelial cells. The reduction in adhesion precedes early membrane markers of apoptosis and is not associated with any loss of membrane integrity. Rather, Fas activation reduces the PMA-stimulated expression and aggregation of beta2 integrins responsible for endothelial adhesion. A possible signaling mechanism for Fas effects on adhesion is the localization of protein kinase C delta (PKCdelta). Western blot and immunofluorescence studies indicated that 1 h of Fas activation is required to reduce PMA-stimulated translocation of PKCdelta to the membrane and adhesion. Rottlerin, a PKCdelta inhibitor, also reduced PMA-induced PKCdelta translocation and adhesion. In contrast, Gö6976, an inhibitor of conventional PKC isotypes, did not affect PMA-stimulated PKCdelta translocation or reduce adhesion. There was no additive effect of Fas activation and rottlerin on reducing adhesion, suggesting that both agents were using a common pathway.