Development and characterization of anti-inflammatory activity of curcumin-loaded biodegradable microspheres with potential use in intestinal inflammatory disorders.

This research addresses the development and in vitro evaluation of a microparticulate system intended for intestine-targeted delivery of curcumin (CRM), a natural polyphenol with anti-inflammatory properties. Microspheres (Ms) based on zein (ZN) and Gantrez® AN119 (PVMMA) were prepared by spray-drying and coated with a pH-sensitive polymer (Eudragit® FS30D). An experimental design was performed to optimize the microparticulate formulation. A detailed characterization of systems was carried out by SEM, DSC, FTIR, particle size, ζ potential measurements and in vitro CRM release. The optimized formulation was evaluated in LPS-stimulated RAW 264.7 macrophages to investigate its anti-inflammatory activity. FTIR and DSC studies suggest a predominant presence of α-helix structure for ZN when formulated and also, a strong interaction between components. The stabilization of α-helix by PVMMA or CRM would take place by hydrogen bonds. Although the encapsulation efficiency was high (89%) for ZN/PVMMA Ms, the coating process with Eudragit® led to an EE decrease of 62%. Coating of Ms was found to retain a 20% of drug within 6h of release, although a strong initial burst release was observed. Cells viability and apoptosis were not affected when cells were co-incubated with coated Ms with CRM. The exposure of unstimulated cells to Ms did not show any effect on NO and PGE2 production. However, a reduction in NO and PGE2 production was obtained when CRM-loaded Ms were co-incubated with stimulated macrophages. Further, this inhibition was significantly higher compared to the decrease obtained when Ms with pure CRM were used in culture, which suggested a synergistic effect of CRM and Ms. Finally, CRM-loaded Ms caused a significant inhibition of analysed pro-inflammatory cytokines (TNFα, IL-1ß, NOS2, COX-2) in macrophages stimulated with LPS. All these results confirm the advantageous features of ZN/PVMMA microspheres as a serious alternative for delivering CRM to reduce the inflammatory activity at intestinal regions affected by inflammatory bowel diseases.

Pharmacokinetic model of florfenicol in turbot (Scophthalmus maximus): establishment of optimal dosage and administration in medicated feed.

The pharmacokinetics of florfenicol (FF) in turbot (Scophthalmus maximus) was studied after single intravenous (10 mg kg-1 ) and oral (100 mg kg-1 ) administration. The plasma concentration-time data of florfenicol were described by an open one-compartment model. The elimination half-life (t1/2 ) was estimated to be 21.0 h, and the total body clearance, Cl, was determined as 0.028 L kg h-1 . The apparent volume distribution (Vd ) was calculated to be 0.86 L kg-1 and the mean residence time (MRTiv ) was 30.2 h. Following oral administration, the maximum plasma concentration (Cmax ) of 55.4 µg mL-1 was reached at 12 h (Tmax ). The absorption constant (ka ) was 0.158 h-1 . The bioavailability was estimated to be 57.1%. The low bioavailability observed at higher doses was explained by the saturation of the mechanisms of absorption. The drug absorption process was limited by its inherent low solubility, which limited the amount of available FF absorbed in the gastrointestinal tract. Based on the pharmacokinetic data, an optimal dosing schedule for FF administration is hereby provided. Based on the minimum inhibitory concentration found for susceptible strains of Aeromonas salmonicida, oral FF administration of first, an initial dose of 30 mg FF kg-1 , followed by 6 maintenance doses at 18 mg kg-1 /daily could be effective against furunculosis in turbot.

[Analysis of ocular toxicity of fluconazole and voriconazole eyedrops using HET-CAM]. / Análisis de la toxicidad ocular de los colirios de voriconazoly fluconazol con HET-CAM.

PURPOSE: The objective of the study is to provide toxicological information through the HET-CAM test of Fluconazole and Voriconazole eye drops prepared commonly in Pharmacy Services for the treatment of fungal keratitis. METHOD: Experimental Study. The ocular toxicity of topical voriconazole 10 mg/ml and fluconazole 2 mg/ml were evaluated by the hen's egg test (HET) on the chorioallantoic membrane (CAM). The effects on blood vessels were based on its behavior during 300 seconds and processes that may occur at each time, then we calculated the irritation index (is, irritation score). RESULTS AND CONCLUSIONS: Both eye drops, voriconazol and fluconazole have been proven to be safe, since the IS that we obtained was zero for both samples and did not present significant signs of irritation. Therefore, these eyedrops are considered suitable for ocular use from a toxicological point of view.

OBJETIVO: El objetivo del estudio es aportar información toxicológica mediante el ensayo HET-CAM, de los colirios de Fluconazol y Voriconazol elaborados de manera habitual en los Servicios de Farmacia para el tratamiento de las queratitis fúngicas. MÉTODOS: Estudio experimental en el que se ensaya la potencial toxicidad ocular del colirio de voriconazol 10 mg/ml y fluconazol 2 mg/ml mediante el método Hen s Egg Test-Chorioallantoic Membrane (HET-CAM). Los resultados se fundamentan en la observación de los posibles procesos dañinos que pudiesen ocurrir en los vasos sanguíneos de la membrana corioalantoidea del embrión de pollo durante un tiempo de contacto de 300 segundos, calculándose posteriormente el índice de irritación (IS, Irritation Score). RESULTADOS Y CONCLUSIONES: Se obtienen IS nulos para ambas muestras, no mostrando por tanto indicios de irritación aguda apreciables, considerándose por tanto aptos para su utilización desde el punto de vista toxicológico.

Use of 1H NMR STD, waterLOGSY, and Langmuir monolayer techniques for characterization of drug-zein protein complexes.

Zein is a protein based natural biopolymer containing a large amount of nonpolar amino acids, which has shown the ability to form aggregates and entrap solutes, such as drugs and amino acids to form stable protein-drug complexes. In this work, π-A isotherm, NMR, and Dynamic light scattering were used to detect the formation of protein aggregates and the affinity between zein and two different drugs: tetracycline and indomethacin. An effective interaction of zein and the two drugs was evidenced by means of liquid NMR reinforced by means of changes in the surface pressure by π-A isotherm. The effective interactions zein/drugs under air/water interface were evidenced as a change in the surface pressure of the π-A isotherm of zein in the presence of drug solutions. The presence of tetracycline in the subphase decreased the area occupied by the monolayer at the expanded region until pressures of 12 mN/m were the areas became similar, but indomethacin produces an increment of the area in both expanded and collapsed region. The feasible methodology employed, focused in the functionality of the protein-drug interaction, can be very promising in the drug delivery field.

Hydration and N-acetyl-l-cysteine alter the microstructure of human nail and bovine hoof: implications for drug delivery.

This work aimed to (a) characterize the microstructure and porosity of human nail and bovine hoof by mercury intrusion porosimetry and SEM image analysis, (b) study the effects of hydration and of N-acetyl-l-cysteine treatment on the microstructure of both membranes, and (c) determine whether the microstructural modifications were associated with changes in drug penetration measured by standard diffusion studies. Bovine hoof surface is more porous than nail surface although there were no differences between the mean surface pore sizes. Hydration and N-acetyl-l-cysteine increased the roughness and apparent surface porosity, and the porosity determined by mercury intrusion porosimetry of both membranes. Pore-Cor™ was used to generate tridimensional structures having percolation characteristics comparable to nail and hooves. The modeled structures were horizontally banded having an inner less-porous area which disappeared upon treatment. Treatment increased the predicted permeability of the simulated structures. Triamcinolone permeation increased significantly for hooves treated N-acetyl-l-cysteine, i.e., the membranes for which microstructural and permeability changes were the largest. Thus, microstructural changes determined via mercury intrusion porosimetry and subsequently modeled by Pore-Cor™ were related to drug diffusion. Further refinement of the technique will allow fast screening of penetration enhancers to be used in ungual drug delivery.

Cyclodextrins: more than pharmaceutical excipients.

Cyclodextrins are pharmaceutical excipients used to enhance the solubility, stability, safety and bioavailability of drugs. Recent findings have shown them to display adjuvant activity in vaccine therapy and prophylactic and therapeutic activity in the treatment of several host-pathogen infections. This article focuses on their activity and mechanism of action.

Starch-dextrin mixtures as base excipients for extrusion-spheronization pellets.

Extrusion-spheronization pellets are generally produced with microcrystalline cellulose (MCC) as the principal excipient, giving rise to particles of very high quality. A number of alternative excipients have been proposed and evaluated, mostly other cellulose derivatives (e.g. different grades of Avicel), or mixtures of MCCs and other excipients. In the present study, we evaluated the possible use of starch+agglutinant mixtures as principal excipients for extrusion-spheronization pellets, with the aim of producing pellets with more suitable properties for certain types of release. We first characterized the different excipients in terms of morphometry and basic physical properties. Subsequently, torque-rheometry was used to characterize the rheology of wetted masses of the different excipients and excipient mixtures, with the aim of determining optimal amount of wetting agent (water). We also evaluated the water absorption and water retention capacities of each excipient. In view of the results obtained, we produced pellets with the different starch+agglutinant mixtures (but without drug), and used image analysis to characterize pellet morphology. Our results show that some of the mixtures-notably starch (corn starch or wheat starch)+20% white dextrin-gave high-quality pellets with good size and shape distributions. In addition, the properties of the different materials tested suggest that it may be possible to obtain pellets with very different properties.

Anticryptosporidial activity of furan derivative G1 and its inclusion complex with beta-cyclodextrin.

The capacity of beta-cyclodextrin (betaCD) to form a complex with a new furanic derivative, G1, was investigated. Interactions of the drug and betaCD in solution and in the solid state were studied using phase solubility techniques, thermal methods, X-ray, and IR spectroscopy. Preparation of a kneaded mix of G1/betaCD increased both the aqueous solubility and the dissolution rate of the furan derivative. The anticryptosporidial efficacies of the drug and of the inclusion complex were evaluated using a suckling murine model. Oral administration of G1 considerably decreased the intensity of the infection, but betaCD showed similar anticryptosporidial activity to that of the betaCD-G1 complex and higher activity than G1 alone.

Chitosan and chondroitin microspheres for oral-administration controlled release of metoclopramide.

This study investigated the usefulness of chitosan and chondroitin sulphate microspheres for controlled release of metoclopramide hydrochloride in oral administration. Microspheres were prepared by spray drying of aqueous polymer dispersions containing the drug and different amounts of formaldehyde as cross-linker. Drug release kinetics were investigated in vitro in media of different pH. Chondroitin sulphate microspheres scarcely retarded drug release, regardless of cross-linker concentration and medium pH, and were thus not further characterized. Chitosan microspheres prepared with more than 15% formaldehyde (w/w with respect to polymer) showed good control release (more than 8 h), and release rates were little affected by medium pH. Release from chitosan microspheres prepared with 20% formaldehyde was independent of pH, suggesting that this may be the most appropriate formulation. The size distribution of the chitosan microparticles was clearly bimodal, with the smaller-diameter subpopulation corresponding to microsphere fragments and other particles. Electron microscopy showed the chitosan microspheres to be almost-spherical, though with shallow invaginations. The kinetics of drug release from chitosan microspheres were best fitted by models originally developed for systems in which release rate is largely governed by rate of diffusion through the matrix.

Formulation of triamcinolone acetonide pellets suitable for coating and colon targeting.

Spherical pellets containing 5% of triamcinolone acetonide (TA) were formed by extrusion/spheronization following formulation with microcrystalline cellulose (MCC) and/or a hydrophilic excipient (lactose, sodium carboxymethylcellulose or beta-cyclodextrin, beta-CD). Their suitability for coating, with a view to colonic drug delivery, was assessed in terms of their size, sphericity and dissolution test response. Best results were afforded by 5:90:5 MCC-beta-CD-TA pellets obtained by complexation of TA with beta-CD prior to addition of MCC, extrusion and spheronization.

Kinetics of anhydride formation in xerogels of poly(acrylic acid).

The aim of this work was to study the cross-linkage of xerogels made of Carbopol of different molecular weight (polymers deriving from polyacrylic acid), and the influence exerted by different percentages of beta-cyclodextrin upon the cross-linkage percentage. Xerogels were obtained by high-pressure compression and cross-linking was studied by measuring the weight loss of different formulations over a temperature range of 70 to 190 degrees C. Kinetics of anhydride formation were found to follow a second-order mechanism with an activation energy of approximately 25 kcal mol-1.