Design, characterization and in vitro evaluation of 5-aminosalicylic acid loaded N-succinyl-chitosan microparticles for colon specific delivery.

The objective of this study was to prepare NS-chitosan microparticles for the delivery of 5-aminosalicylic acid (5-ASA) to the colon. Microparticles can spread out over a large area of colon allowing a more effective local efficacy of 5-ASA. N-Succinyl-chitosan was chosen as carrier system because of its excellent pharmaceutical properties in colon drug targeting such as poor solubility in acid environment, biocompatibility, mucoadhesive properties, and low toxicity. It was prepared by introducing succinic group into chitosan N-terminals of the glucosamine units. 5-ASA loaded NS-chitosan microparticles were prepared using spray-drying. As a control, a matrix obtained by freeze-drying technique was also prepared and tested. Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC) and X-ray diffraction studies show the 5-ASA/NS-chitosan electrostatic interactions in both the systems. Mean size of the microparticles was around 5 µm, zeta potential value of both systems was always negative. Scanning electron microscopy (SEM) images show an acceptable spherical non porous structure of microparticles. In vitro swelling and drug release studies were in accordance with the polymer properties, showing the highest swelling ratio and drug release at pH=7.4 (colonic pH) where microparticles were able to deliver more than 90% of 5-ASA during 24h experiments. Rheological studies are in accordance with the swelling and release studies.

N-Succinyl-chitosan systems for 5-aminosalicylic acid colon delivery: in vivo study with TNBS-induced colitis model in rats.

5-Aminosalicylic acid (5-ASA) loaded N-Succinyl-chitosan (SucCH) microparticle and freeze-dried system were prepared as potential delivery systems to the colon. Physicochemical characterization and in vitro release and swelling studies were previously assessed and showed that the two formulations appeared to be good candidates to deliver the drug to the colon. In this work the effectiveness of these two systems in the treatment of inflammatory bowel disease was evaluated. In vitro mucoadhesive studies showed excellent mucoadhesive properties of both the systems to the inflamed colonic mucosa. Experimental colitis was induced by rectal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into male Wistar rats. Colon/body weight ratio, clinical activity score system, myeloperoxidase activity and histological evaluation were determined as inflammatory indices. The two formulations were compared with drug suspension and SucCH suspension. The results showed that the loading of 5-ASA into SucCH polymer markedly improved efficacy in the healing of induced colitis in rats.

Chitosomes as drug delivery systems for C-phycocyanin: preparation and characterization.

The aim of this work was to investigate chitosomes, i.e. liposomes coated by a polyelectrolyte complex between chitosan (CH) and xantan gum (XG), as potential delivery system for oral administration of the protein C-phycocyanin. To this purpose several CH-XG-microcomplexes were prepared in aqueous lactic acid at different chitosan-xanthan gum percent ratios and rheological properties of the microcomplexes were studied to analyse the contribution of chitosan and xanthan gum in the reaction of microcomplexation. After establishing the best microcomplexes, chitosomes were prepared by coating C-phycocyanin loaded liposomes with the CH-XG hydrogels using spray-drying or freeze-drying. The chitosomes were characterized in terms of morphology, size distribution, zeta potential, swelling properties, drug release, and mucoadhesive properties. Rheological studies showed the influence of xanthan gum in the microcomplex properties. Moreover, obtained results demonstrated the effects of formulation and process variables on particle size, drug content, swelling, drug release, and especially on the mucoadhesiveness of C-PC chitosomes of CH-XG. In particular, chitosomes prepared by spray-drying technique using CH-XG in 0.5/8.0 (w/w) ratio showed a regular surface and a drug release characteristic for a Fickian diffusion of the active ingredient. The in vitro mucoadhesive study revealed that the spray-drying method is advantageous to prepare C-phycocyanin loaded chitosomes with excellent mucoadhesive properties for colonic drug delivery.

Estabilidad en suero fisiológico del busulfán intravenoso en un envase de poliolefinas / Stability in serum of intravenous busulfan in a polyolefin pack

Introducción: Aunque se ha utilizado por vía oral, la variabilidad en su absorción y el riesgo de que se produzcan vómitos, ha impulsado la utilización intravenosa de busulfán. En el presente trabajo se estudiará la estabilidad de 60 mg de busulfán, en volúmenes fijos de 250 ml (0,24 mg/ml) y 500 ml (0,12 mg/ml) de suero fisiológico y diferentes condiciones de conservación, en un nuevo envase de plástico, de lámina construida de poliolefina/poliamida. Material y métodos: Se empleó la cromatografía líquida de alta eficacia con detección ultravioleta para determinar las concentraciones de busulfán derivatizado con dietilditiocarbamatotrihidrato sódico. La estabilidad se evaluó, para ambas concentraciones, tanto en nevera como a temperatura ambiente, mediante el t90 de cada ensayo. Resultados: El porcentaje de concentración remanente de busulfán a las 24 h siempre fue inferior al 90%. A 25 ºC y concentración de 0,24 mg/ml el t90 fue de 8,4 h; a 4 ºC y concentración de 0,24 mg/ml fue de 16,7 h; a 25 ºC y concentración de 0,12 mg/ml fue de 12 h, y a 4 ºC y concentración de 0,12 mg/ml fue de 11,5 h. Conclusiones: El presente estudio demuestra que el busulfán a una concentración de 0,24 mg/ml en suero fisiológico será estable en las bolsas ensayadas durante un período de almacenamiento de 12 h en nevera más las 2 h de administración del fármaco (AU)

Introduction: Although it has been used orally, the variability in its absorption and the risk of causing vomiting has lead to a push towards the intravenous use of bulsulfan. This study looks at the stability of 60 mg of busulfan, in fixed volumes of 250 mL (0.24 mg/mL) and 500 mL (0.12 mg/mL) of serum and different conservation conditions, in a new plastic pack made from polyolefin/polyamide laminates. Material and methods: High-efficiency liquid chromatography with ultraviolet detection was used to determine the concentration of busulfan derivate with sodium diethyldithiocarbamatetrihydrate. Stability was assessed for both concentrations; refrigerated and at room temperature, using the t90 of each sample. Results: The percentage of the remaining busulfan concentration at 24 h was always less than 90%. At 25 oC and 0.24 mg/mL concentration, the t90 was 8.4 h; at 4 oC and a concentration of 0.24 mg/mL it was 16.7 h; at 25 oC and a concentration of 0.12 mg/mL it was 12 h and at 4 oC and a concentration of 0.12 mg/mL it was 11.5 h. Conclusions: This study show that busulfan in a concentration of 0.24 mg/mL in serum is stable in the bags tested during a refrigerated storage period of 12 h plus two additional hours of administration of the drug (AU)

[Stability in serum of intravenous busulfan in a polyolefin pack]. / Estabilidad en suero fisiológico del busulfán intravenoso en un envase de poliolefinas.

INTRODUCTION: Although it has been used orally, the variability in its absorption and the risk of causing vomiting has lead to a push towards the intravenous use of bulsulfan. This study looks at the stability of 60 mg of busulfan, in fixed volumes of 250 mL (0.24 mg/mL) and 500 mL (0.12 mg/mL) of serum and different conservation conditions, in a new plastic pack made from polyolefin/polyamide laminates. MATERIAL AND METHODS: High-efficiency liquid chromatography with ultraviolet detection was used to determine the concentration of busulfan derivate with sodium diethyldithiocarbamatetrihydrate. Stability was assessed for both concentrations; refrigerated and at room temperature, using the t(90) of each sample. RESULTS: The percentage of the remaining busulfan concentration at 24 h was always less than 90%. At 25 degrees C and 0.24 mg/mL concentration, the t90 was 8.4 h; at 4 degrees C and a concentration of 0.24 mg/mL it was 16.7 h; at 25 degrees C and a concentration of 0.12 mg/mL it was 12 h and at 4 degrees C and a concentration of 0.12 mg/mL it was 11.5 h. CONCLUSIONS: This study show that busulfan in a concentration of 0.24 mg/mL in serum is stable in the bags tested during a refrigerated storage period of 12 h plus two additional hours of administration of the drug.

Acyclovir delivery matrices based on poly(ethylene glycol)/chitosan semi-interpenetrating networks.

Chitosan matrix systems have been studied as potential vehicles for the prolonged release of acyclovir (ACV). The influence of chitosan concentration (from 0.83% to 1.67%) on viscoelastic properties of formulations with and without glyoxal was analyzed. For chitosan-poly(ethylene glycol) 400 formulations loss modulus (G'') are greater than storage modulus (G'). This corresponds to the characteristic behavior of nonstructured systems. When glyoxal was added to the chitosan-poly(ethylene glycol) 400 formulations, gelled matrix was obtained (i.e., G' is higher than G''), except for the lowest chitosan concentration. ACV release rates for the both types of systems, with and without glyoxal, were also determined. The ACV diffusion coefficient values from matrices are less than for the respective formulation without glyoxal and it was found to depend on the crosslink density within the matrices. Viscoelastic parameters, dynamic moduli (G', G''), and complex viscosity (eta*), were correlated with the ACV diffusion coefficients (D). The complex viscosity (eta*) could be used as a parameter of predictive value for the release rate of drugs.

Enhancing effect of alpha-hydroxyacids on "in vitro" permeation across the human skin of compounds with different lipophilicity.

The percutaneous penetration-enhancing effects of glycolic acid, lactic acid and sodium lauryl sulphate through the human epidermis was investigated using 5-fluorouracil as a hydrophilic model permeant and three compounds belonging to the phenylalcohols: 2-phenyl-ethanol, 4-phenyl-butanol and 5-phenyl-pentanol. The lipophilicity values of the compounds ranged from log Poct -0.95 to 2.89. The effect of the enhancer concentration was also studied. Skin pretreatment with aqueous solutions of the three enhancers did not increase the permeability coefficient of the most lipophilic compound (log Poct = 2.89). For the other compounds assayed, the increase in the permeability coefficients depended on the concentration used in skin pretreatment, and on the lipophilicity of the compounds tested-and was always greater for the most hydrophilic compound (5-fluorouracil), for which lactic acid exerted a greater enhancer effect than glycolic acid or sodium lauryl sulphate. Primary irritation testing of the three enhancers was also carried out at the two concentrations used in skin pretreatment for diffusional experiments (1% and 5%, w/w). The least irritant capacity corresponded to lactic acid; consequently, this alpha-hydroxyacid could be proposed as a percutaneous penetration enhancer for hydrophilic molecules that are of interest for transdermal administration.

Influencia del propilenglicol sobre las propiedades bioadhesivas de un hidrogel de Carbopol 971-P / No disponible

Se ha estudiado el comportamiento bioadhesivode un gel de Carbopol 971-P, en presenciade diferentes concentraciones de propilenglicol(10%, 30%, 50%, 70%, m/m). A partir delas curvas fuerza-desplazamiento se han calculadola fuerza máxima y el trabajo de adhesión.El estudio comparativo de los valores mediosdel trabajo de adhesión indica que noexisten diferencias significativas (P<0,05) entreel hidrogel de Carbopol 971-P sin propilenglicol(control) y los hidrogeles adicionados depropilenglicol a las concentraciones más elevadas(10 y 30%, respectivamente). Se concluyeque, cuando se pretende utilizar Carbopol971-P en preparaciones adhesivas para la administraciónde fármacos de baja hidrosolubilidad,es posible incrementar la concentraciónde fármaco disuelto en el sistema bioadhesivo,mediante la incorporación de propilenglicol enconcentraciones de hasta un 30% (m/m), sinque se modifique significativamente su capacidadbioadhesiva

The influence of different concentrations ofpropylene glycol (10%, 30%, 50%, 70%, w/w)on the properties of bioadhesion of Carbopol971-P gels has been analyzed. From force-deformationcurves, the peak force and the tensilework have been calculated. The comparativestudy of the mean values of tensile work indicatethat no significant differences (P<0.05) existamong the Carbopol 971-P hydrogels withoutpropylene glycol (control) and with propyleneglycol for the lowest concentrations (10 and30%, respectively). Therefore, it seems possibleto use Carbopol 971-P hydrogels addedwith propylene glycol until a concentration of30% (w/w), in order to increase drug solubility,without significant modification of its capacityof bioadhesion

In vitro percutaneous penetration of acyclovir from solvent systems and Carbopol 971-P hydrogels: influence of propylene glycol.

The mechanism underlying propylene glycol (PG) effects on acyclovir (ACV) penetration through human epidermis were studied. Solvent systems and Carbopol gels containing increasing percentage of PG (from 0% to 70%, w/w) were used. Viscosity studies of both vehicles were carried out to characterise the influence of rheological behaviour. In solvent systems skin permeation values of ACV increase as the concentration of PG increase yielding a maximum enhancement ratio (ER = 10) for 70% PG. The release rate of ACV from gels was determined. Higuchi's model was used to estimate the apparent diffusion coefficient of the drug. These values show a decrease as the content of PG in the vehicle increases; this effect could be attributed to the increase of the viscosity in the diffusional pathway. When gels are used skin permeation values of ACV were smaller than those of the solvent systems. This could be attributed to the network structure created by the polymer that increases the length of the diffusional pathway. The maximum ER (= 6.8) was for Carbopol gel containing 50% PG. Therefore, these gels can be considered candidates for further research to confirm their usefulness as delivery systems for ACV topical formulations.

Importancia de los sistemas lipídicos nonoparticulares (SLN) en preparados dermatológicos / Importance of the lipidics nonoparticulars systems in dermatological preparations

Los sistemas lipídicos nanoparticulares (SLN) representan una excelente alternativa a los diferentes sistemas transportadores de ingredientes activos de tamaño coloidal: microemulsiones, liposomas y micro- y nanopartículas poliméricas. Los SLN se han utilizado tanto en el campo farmacéutico como en el cosmético. Las ventajas que proporcionan cuando se utilizan para la administración tópica de principios activos, son evidentes: protección de compuestos lábiles frente a la degradación química, control de la liberación de ingredientes activos, desarrollo de un efecto oclusivo y un efecto barrera frente a las radiaciones ultravioleta. No obstante, presentan algunos incovenientes como su capacidad de carga limitada y la posible liberación súbita "efecto burst" del principio activo durante el período de almacenamiento. En esta revisión se analiza la composición, el método de elaboración por homogeneización de presión elevada, los mecanismos implicados en la liberación y las aplicaciones de estos sistemas en el campo de los preparados dermatológicos (AU)

An in vitro percutaneous absorption study of non-ionic compounds across human skin.

Generally, the mechanisms of percutaneous absorption are studied from correlations between representative penetration parameters (permeability coefficients) and variables accounting for lipophilicity or other related physicochemical properties. The present study was developed on the basis of the in vitro permeability coefficients through human skin, 280 microns in thickness, of a non-ionic homologous series of compounds (phenylalkanols). The corresponding penetration/lipophilicity correlations were compared with those found for a basic homologous series (4-n-alkylanilines) through a membrane of similar characteristics. The in vitro behaviour of both series of compounds may be regarded as similar. Differences were only observed in the permeability coefficients of those elements which in both series exhibited lipophilicity values above that considered optimum, as predicted by the selected biophysical penetration model. Consequently, it appears that the removal of the thick dermal tissue leads to increased permeation rates for the more lipophilic compounds and suggests that the dermis acts as an aqueous matrix.

A comparative "in vitro" study of permeability with different synthetic and biological membranes.

Permeability coefficients of seven compounds belonging to a true homologous series (4-alkylanilines) through several different synthetic and biological membranes were assayed in a two-chamber diffusion cell. Permeability-lipophilicity relationships for the experimental data were established and compared in order to ascertain whether the behaviour of these membranes was similar to that of the human skin. In all cases, the best fit for the permeation-lipophilicity correlation was provided by the bilinear model. It was demonstrated that this type of correlation, when a dimethylpolysiloxane membrane is used, is due to the existence of a supplementary stagnant aqueous layer adjacent to the membrane in the receptor compartment. This is clear from the fact that when Polysorbate 80 is added to the receptor solution, the effect of this layer is abolished. In these conditions, hyperbolic equation gives, consequently, the best fit for penetration-lipophilicity correlation. On the basis of the data obtained with rat skin and Polysorbate 80 in the receptor solution, it can be concluded that for biological membranes the bilinear model obtained is due to their heterogeneous nature. The optimum lipophilicity value for penetration according to the bilinear model was not the same for all the membranes assayed. Human and rat skin were qualitatively similar in behaviour.