[Novel formulations of a liver protection drug glycyrrhizin].

In Japan, glycyrrhizin injections have been used as a therapeutic drug for allergy inflammation since 1948 and for chronic hepatitis since 1979. A 20 ml injection of glycyrrhizin contains 53 mg of monoammonium glycyrrhizinate (40 mg as glycyrrhizin acid), 400 mg of glycine, and 20 mg of L-cysteine. Patients receiving glycyrrhizin injections two or three times per week are forced to accept a decline in quality of life. Because administering glycyrrhizin by injection has some disadvantages, many researchers have systematically searched for novel glycyrrhizin formulations that can be administered through oral, rectal, intranasal, and subcutaneous routes. There are two problems, however, in developing new formulations: (1) glycyrrhizin has low membrane permeability and is thus poorly absorbed, and (2) highly concentrated glycyrrhizin readily forms gels in aqueous solutions. Here, we describe the utility of glycyrrhizin formulations prepared in safe solubility agents and absorption-enhancing agents, as assessed in animal experiments. We also discuss pharmaceutical issues in developing various glycyrrhizin formulations. In the near future, convenient pharmaceutical preparations of glycyrrhizin will be developed for chronic hepatitis patients who require glycyrrhizin therapy.

Adsorption of bile acid by chitosan salts prepared with cinnamic acid and analogue compounds.

A chitosan (CS) powder treated with cinnamic acid and an analogue compound (CN) was prepared as CS-CN. Using it, bile acid adsorption by CS-CN and the release of CN were investigated in vitro. When CS-CN was soaked in a taurocholate solution, it released CN and simultaneously adsorbed the bile acid. For CS-CN prepared with cinnamic acid, the amount of CN released was 0.286 +/- 0.001 mmol/g CS-CN; the amount of taurocholate adsorbed was 0.284 +/- 0.003 mmol/g CS-CN. These two functions were recognized on alginate or pectin gel beads containing CS-CN. The amount of released CN was altered extensively by the species of CN used for gel-bead preparation. Results suggest that CS-CN is a candidate for complementary medicine to prevent lifestyle-related diseases.

Clove oil prevents glycyrrhizin gel formation in aqueous solution.

One persistent problem with using therapeutic concentrations of glycyrrhizin (GZ) is that, at these high concentrations, it forms a gel in an aqueous solution. We previously solved this problem by dissolving GZ in a highly concentrated phosphate buffer. Unfortunately, the resulting GZ solution has a hyperosmotic pressure that renders it unsuitable for use in patients. The aim of this study was to prepare a highly concentrated GZ solution having an osmotic pressure ratio of 1 and a pH of 7.4. By adding small amounts of oil and using a 100 mM phosphate buffer, we achieved an emulsified GZ solution that is stable at room temperature and has a physiological osmotic pressure and pH. When clove oil was used as an emulsifier, the gel formation temperature of GZ solution decreased appreciably compared to that of GZ solution without clove oil. Using scanning electron microscopy (SEM), we examined the detailed characteristics of GZ gels prepared from solutions with or without clove oil. SEM of cross sections of GZ gels revealed an irregular structure in gels prepared with clove oil, indicating that clove oil prevented the formation of the intermolecular GZ networks typically characterized by gels derived from pure GZ solutions.

Membrane permeability and antipyrine absorption in a rat model of ischemic colitis.

The aim of this study was to determine whether the duration of ischemia affects antipyrine absorption in the large intestine. This was carried out in a rat model of ischemic colitis in which ischemia and associated inflammation was induced by marginal vessel ligation. Blood flow was disrupted by positioning an o-ring around the distal rectum and ligating the marginal vessel at two locations in the hind-gut ligament artery region. Ligation was performed for 1, 2, 3, and 5h. We assessed large intestine damage by measuring key indicators of inflammation, myeloperoxidase (MPO) activity and thiobarbituric acid reactant substrates (TBARS) in the mucosa and by histological staining with hematoxylin-eosin stain. Antipyrine membrane permeability was assessed in Ussing-type diffusion chambers, and related pharmacokinetics were calculated from antipyrine plasma concentration measurements following colon administration of the drug. Vessel ligation caused some sloughing of epithelial cells and elevated the MPO and TBARS levels. Prolonged ligation failed to affect the apparent permeability coefficient (P(app)) of antipyrine. Prolonged ligation, however, gradually increased plasma antipyrine concentrations to near control levels. This increase was paralleled by increases in the absorption rate constant AUC and antipyrine bioavailability. Taken together, these results suggest that the absorption kinetics of antipyrine may depend on blood flow changes in the large intestine that occur with inflammation.

Drug release properties of a gel bead prepared with pectin and hydrolysate.

A calcium-induced pectin gel bead (PB) containing pectin hydrolysate was prepared, and the drug release profiles and degradation properties of the PB were investigated in aqueous media. The stiff PB swelled in physiological saline and its drug release rate decreased with exposure to increasing concentrations of CaCl2 during preparation. And erosion of the PB was not observed in physiological saline. However, the PB did disintegrate in phosphate buffer (pH 6.8) and the rate of disintegration depended on the calcium chloride concentration used to prepare the PB. In addition, the drug release rate of the PB in buffer solution decreased as the rate of gel erosion declined. Consequently, it appears that the PB gel matrix is an effective medium by which to control the release of drug within the gastrointestinal tract.

Derivation of hydroxamic acid from pectin and its applications in colorimetric determination.

A hydroxamic acid (HX) derivative of pectin was prepared, and its potential application to simple colorimetric determination of polysaccharides was investigated. The coupling reaction between pectin and hydroxylamine (HA) progresses in the presence of 1-cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate (CMEC). The calibration curve for pectin showed good agreement and the lower limit of detection was 0.5 mg. This is a very simple and rapid determination method, which does not require tedious pre-treatment, for polysaccharides containing carboxyl groups.

Functions of a chitosan-orotic acid salt in the gastrointestinal tract.

A chitosan (CS)-orotic acid salt (CS-OT) was prepared, and the release of orotic acid (OT) from CS-OT as well as the adsorption of bile acids by CS-OT was investigated in vitro. The amount of OT released from CS-OT was about 2-2.7 micromol/mg CS-OT and this changed depending on the species of CS. CS-OT also adsorbed bile acids and the amount increased incrementally according to the number of amino group contained in CS. Furthermore, CS-OT was given to rats as feed in order to investigate the influence on serum cholesterol levels. A decrease in serum cholesterol levels was observed in the group, which was fed a diet containing CS-OT or CS for 1-2 weeks, but no differences in body weight changes were recognized. Therefore, CS-OT may be applied to treating hyperlipidemia.