Preparation and characterization of insulin-loaded acrylic hydrogels containing absorption enhancers.

The objectives of this study were to prepare insulin-loaded acrylic hydrogel formulations containing various absorption enhancers, to perform in vitro and in vivo characterization of these formulations, and to evaluate the factors which affecting insulin availability on rectal delivery of insulin using this hydrogel system. The acrylic block copolymer of methacrylic acid and methacrylate, Eudispert, was used to make the hydrogel formulations. As absorption enhancers, 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CyD), lauric acid (C12), or the sodium salt of C12 (C12Na), were incorporated into the hydrogels. In an in vitro release test, the release rate of insulin from the hydrogels decreased as the polymer concentration of the hydrogel increased. The addition of C12Na to the hydrogel further increased the insulin release rate, which was greater at higher concentrations of the enhancer. A portion of the C12Na was found to remain bound to the acrylic polymer in dissolution medium. Serum insulin levels were determined at various time points after the administration of insulin solution or insulin-loaded (50 units/kg body weight) Eudispert hydrogels containing 5% (w/w) of C12, C12Na, or DM-beta-CyD to in situ loops in various regions of the rat intestine. The most effective enhancement of insulin release was observed with formulations containing C12Na. The bioavailability of insulin from the hydrogels was lower than that from the insulin solutions. Hydrogel formulations containing 7% or 10% Eudispert remained in the rectum for 5 h after rectal administration. However, the 5% (w/w) C12Na solution stained with Evan's-blue had diffused out and the dye had reached the upper intestinal tract within 2 h. Finally, the rectal administration of insulin-loaded hydrogels, containing 4%, 7%, or 10% (w/w) Eudispert and 5% (w/w) of enhancer (C12, C12Na, or DM-beta-CyD) to normal rats was shown to decrease serum glucose concentrations. The greatest effect was found with insulin-loaded 7% (Eudispert) hydrogel containing C12Na which having cosiderable large insulin release rate and bioadhesive characteristics.

Preparation and characterization of acrylic hydrogels neutralized by basic amino acids.

Basic amino acids were used as neutralizers in the gellation of Eudispert as an acrylic hydrogel. Arginine and lysine successfully neutralized Eudispert, as did sodium hydroxide, and formed hydrogels. A gentle rise of pH was observed as the dosage of the base increased when arginine and lysine were used, in contrast to the sharp rise of pH observed when sodium hydroxide was used. The rank of viscosity of the prepared hydrogels was as follows: lysine > arginine > NaOH. The release rate of model drugs (salicylic acid, theophylline, and bovine insulin) from the prepared hydrogels ranked as follows: NaOH>lysine>arginine, the sustained-release profile being observed with arginine. The rate of diffusion of the model drug from the hydrogel was inversely proportional to the molecular weight of the cationized neutralizer used. It is concluded that the strategy of neutralization of acidic polymers by basic amino acids has advantage with the respect to both the sustained-release characteristics of the gel and the biocompatibility of the basic amino acids themselves.

Relationship between histamine release and leukotrienes production from human basophils derived from atopic dermatitis donors.

Basophils are known to release histamine and to produce leukotrienes (LTs) following both IgE-dependent and -independent stimuli. Although there exist a few reports which examined the relationship between histamine release and LTs production, their conclusions were not always in agreement with each other. In the present study, we examined the relationship between histamine release and LTs production from basophils in the presence or absence of 1 ng/ml of interleukin-3 (IL-3). Normal basophils released a smaller amount of histamine and LTs than atopic determatitis (AD) basophils, when basophils were stimulated with an optimal concentration of anti-IgE antibody. When we examined the relationship of histamine release and LTs production from AD donors induced through Fc epsilon RI, we found a significant exponential correlation between these two mediators (R2 = 0.58 in the absence of IL-3, R2 = 0.83 in the presence of IL-3). Although IL-3 enhanced both histamine release and LTs production from AD donors, the relationship between these two mediators was not affected. In conclusion, there was an exponential correlation between histamine release and LTs production from AD basophils, which was not affected by the pretreatment with IL-3.