Biomedical subjects

Susumu Kawashima

Publications and source records attributed to Susumu Kawashima.

At least 19 recordsLinked to original sources

PubMed2006

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.

Adsorption↗

PubMed2005

Sustained insulin release with biodegradation of chitosan gel beads prepared by copper ions.

Chitosan (CS) gel beads were prepared with chelated copper (II) ions as a vehicle for the delivery of peptide and protein drugs. Insulin, which is a model of peptide and protein drugs, was scarcely released from the CS gel beads in vitro, presumably due to the nature of interactions occurring between insulin, CS and the copper (II) ions. The efficacy of insulin released from the CS gel beads was confirmed by implantation into diabetic mice. A consistent reduction in blood glucose level was observed in vivo due to insulin release as the CS gel beads were degraded. Control over insulin release was achieved by altering the properties of the CS. Thus, CS gel beads are promising as a biocompatible and biodegradable vehicle by which peptide and protein drugs can be delivered.

Animals↗

PubMed2005

Current status of quality in Japanese clinical trials.

The changes in the quality of Japanese clinical trials were evaluated by comparing the results of Good Clinical Practice (GCP) audits conducted from April 1997 to March 2000 (fiscal year (FY) 1997-1999) with those from April 2001 to March 2002 (FY2001). During both of the periods inspections were undertaken by the Organization for Pharmaceutical Safety and Research (OPSR). The audit findings in the former period were based on the audits that covered 331 hospitals and 775 trials conducted under the old GCP guideline. The audits in the latter period targeted 147 hospitals and 238 trials conducted under the old or new GCP guideline. The total number of deficiencies detected by GCP audits in the former three-year period (FY 1997-1999) was 1529, and the corresponding number in the latter single year (FY 2001) was 912. Two remarkable changes in OPSR's findings were observed between FY 1997-1999 and FY 2001 as follows; the proportion of protocol deviations increased from 14.7% (225/1529) to 53.1% (484/912), while the proportion of errors in case report forms (CRFs) decreased from 43.6% (666/1529) to 15.4% (140/912). The new GCP guideline sets very high standards for a hospital's qualification: to have sufficient equipment and hospital resources, to have capacity for promptly responding to urgent trial-related problems, to have an IRB, and to have appropriate staff including clinical research coordinators (CRCs) assigned to the clinical trial. Our results suggest that the impact of the regulatory changes of applicable standard is large for a hospital's qualification for conducting clinical trials in Japan.

Clinical Protocols↗

PubMed2005

The controlled release of insulin-mimetic metal ions by the multifunction of chitosan.

Vanadium, which is an insulin-mimetic metal ion, was efficiently adsorbed on chitosan (CS). The adsorption of vanadium on CS was affected by the vanadium/CS ratio and the initial concentration of vanadium in preparative medium under constant pH condition. The vanadium-CS complex was able to control vanadium release. Moreover, a consistent control of vanadium release was achieved by incorporation of the vanadium-CS complex into a CS gel. After implantation of the CS gel retaining the vanadium-CS complex into diabetic mice, insulin-mimetic efficacy was confirmed by observation of a steady reduction in blood glucose levels. The sustained vanadium release also contributed to minimization of the side-effects. Thus, CS gel retaining the vanadium-CS complex appears promising as a vehicle for vanadium with long-term action and a low toxicity leading to its clinical use.

Adsorption↗

PubMed2004

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.

Animals↗

PubMed2004

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.

Calcium Chloride↗

PubMed2004

Properties of an alginate gel bead containing a chitosan-drug salt.

A calcium-induced alginate gel bead (Alg-CS) containing chitosan (CS) and 2-(4-chlorophenoxy)-2-methylpropionic acid (CMP) was prepared. We then investigated (a) CMP release from Alg-CS, and (b) uptake of bile acid into the Alg-CS, within the gastrointestinal tract. Dried Alg-CS gradually swelled in taurocholate solution, while releasing CMP and taking up bile acid. The amount of bile acid taken up into the Alg-CS increased incrementally according to the degree of deacetylation of CS. Furthermore, the molecular weight of CS also affected the properties of the Alg-CS. An approximately linear relationship was observed between CMP release and bile acid uptake of Alg-CS.

Acetylation↗

PubMed2004

Adsorption of bile acid by chitosan-orotic acid salt and its application as an oral preparation.

The orotic acid (OT) salt of chitosan (CS), CS-OT, and that of a CS derivative, CP, were prepared, and the adsorption of primary or secondary bile acid was investigated. Calcium-induced alginate gel beads (Alg-Ca) containing CS-OT were also prepared and autoclaved, and the possibility of these beads to act as a vehicle for oral administration to prevent hyperlipidemia was investigated. When taurocholate (TCA) and glycocholate (GCA) were present together in the medium, CS-OT adsorbed identical amounts of both bile acids. This trend was seen in all CPs, although the capacity to adsorb bile acid was affected by the number and/or structure of the amino groups in the CP. On the other hand, taurodeoxycholate, a secondary bile acid was preferentially adsorbed over TCA and GCA. Alg-Ca containing CS-OT took up bile acids in a similar manner as CS-OT irrespective of the water content of the gel matrix. As all elements can be taken as a food, Alg-Ca containing CS-OT could serve as a useful dietary agent for the prevention of hyperlipidemia, which is a lifestyle-related disease.

Administration, Oral↗

PubMed2004

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.

Chromatography, High Pressure Liquid↗

PubMed2004

Properties of calcium-induced gel beads prepared with alginate and hydrolysates.

Calcium-induced alginate gel beads (Alg-Ca) containing alginate hydrolysate, such as the guluronic acid block (GB), was prepared and the drug release profiles were investigated under simulated gastrointestinal conditions. The addition of GB to Alg-Ca altered its rheological properties. A model drug (hydrocortisone) was incorporated at 78% of its theoretical yield within the dried Alg-Ca containing 5% GB and it was gradually released from the beads in JP XIV 1st medium for disintegration test (pH 1.2), while it was rapidly released with disintegration of the gel matrix in JP XIV 2nd medium (pH 6.8). In contrast, for Alg-Ca containing GB and chitosan, disintegration was not observed in these media and the drug release rate was markedly different. These results demonstrate that the release profiles of drugs incorporated into Alg-Ca can be controlled by adding these polysaccharides.

Alginates↗

PubMed2003

Retention and release behavior of insulin in chitosan gel beads.

Chitosan (CS) gel beads were prepared in a 10% (w/v) aqueous amino acid solution (pH 9.0) as a vehicle for delivering peptide and protein drugs. CS gel beads with a weight-average molecular weight of (16-280) x 10(4) were employed in this study. Preparation of the CS gel beads was affected by properties such as molecular weight and degree of deacetylation. Insulin, which is commonly used to assess protein drug delivery, was retained in the CS gel beads. Drug release from the CS gel beads was governed by diffusion of drug from the gel matrix. Sustained release of insulin from the CS gel beads was observed, despite the fact that insulin is a comparatively water-soluble drug. because insulin formed a complex with CS. Modification of the CS gel matrix by chondroitin sulfate inhibited release of insulin from the gel beads. CS gel beads were implanted into air pouches prepared subcutaneously on the dorsal surface of diabetic mice in order to investigate the efficacy of insulin retained in the CS beads. Blood glucose levels were found to be reduced after implantation of CS gel beads retaining insulin. CS gel beads may possibly improve the stability and control of insulin release. These observations indicate that CS beads are a promising biocompatible and biodegradable vehicle for peptide and protein delivery.

Chitin↗

PubMed2003

Preparation of floating alginate gel beads for drug delivery to the gastric mucosa.

Alginate gel beads containing ethylcellulose (ALECs) were prepared and investigated with regard to buoyancy, in vitro and in vivo drug release profiles, and drug targeting specificity in the gastric mucosa. When the ethylcellulose (EC) content of ALECs containing metronidazole (MZ) was higher than 3%, the beads floated in all test solutions with a specific gravity of approx. 1.01. ALECs containing 5% EC released MZ gradually and floated throughout the experimental period in simulated gastric juice (pH 1.2), and all of the drug had been released after 90 min. When we orally administered ALECs to guinea pigs, about 85% of the incorporated MZ was released at 1 h. The MZ concentration of the gastric mucosa after administration of ALECs was greater than that observed with administration of MZ solution, despite lower serum concentrations. Furthermore, the similar data were obtained for ALECs with 7% EC. These results suggest that ALECs may become a practical vehicle for delivering drugs to the gastric mucosa.

Administration, Oral↗

PubMed2003

Preparation and rectal absorption of highly concentrated glycyrrhizin solution.

We developed a simple method for preparing a highly concentrated solution of glycyrrhizin monoammonium salt (GZ) at low viscosity with no surfactants nor organic solvents and investigated the absorption profile after rectal administration to rats. GZ (200 mg/ml) was dissolved in phosphate buffered solution, pH 7.0; over 350 mM concentration was maintained for the aqueous solution without gel-formation. When glycerin was used as a non-aqueous formulation, GZ did not form gel. Apparent permeability coefficients of GZ obtained from 350 mM phosphate buffered solution (pH 7.0) and glycerin solution through rat rectal mucosa estimated by in vitro parallel diffusion chamber technique were 0.686 x 10(-6) and 0.379 x 10(-6) cm/s, respectively. On the other hand, the area under plasma concentration-time curves of GZ in 400 mM phosphate buffer (pH 7.0) and glycerin formulations after rectal administration to the rat were significantly higher than that in polyethylene glycol 400/propylene glycol (55 : 5) formulation. Maximum plasma concentrations of these formulations were dependent on the apparent permeability coefficients of GZ. Increased absorption observed by phosphate buffered formulation accompanied no pronounced histological damage in mucosa. These results demonstrate that addition of a highly concentrated phosphate salts is effective not only for lowering the viscosity of a highly concentration of GZ solution, but also for improving the mucosal GZ absorption.

Administration, Rectal↗

PubMed2003

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.

Adjuvants, Pharmaceutic↗

PubMed2003

Effects of natural polysaccharide addition on drug release from calcium-induced alginate gel beads.

Calcium-induced alginate gel beads (Alg-Ca) containing various polysaccharides, including an alginate hydrolysate, were prepared and the drug release profiles were investigated. Hydrocortisone (HC) was gradually released from Alg-Ca into the mimic gastric fluid, while in intestinal fluid, it was quickly released with the dissolution of Alg-Ca. However, with Alg-Ca containing 5% chitin (CT), dissolution of Alg-Ca was not observed, and release of HC showed apparent zero-order kinetics. Furthermore, addition of the alginate hydrolysate altered the HC-release profile for Alg-Ca.

Alginates↗

PubMed2003

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.

Colorimetry↗

PubMed2002

Behavior of alginate gel beads containing chitosan salt prepared with water-soluble vitamins.

Alginate gel beads were prepared which contained weak acid salts of chitosan (Alg-CS) and water-soluble vitamins (e.g. ascorbic acid (AS)) and the behavior of the beads, uptake of bile acids was investigated in vitro. The Alg-CS beads rapidly took up bile acid and this phenomenon was observed for both hydrogel beads and dried beads. About 120 micromol of taurocholic acid was taken up into Alg-CS (1 g) prepared with orotic acid. Dried Alg-CS is the granule which can be made easily, and keeps the ability of CS salt, and all elements can be taken as a food. Therefore, Alg-CS could serve as a useful dietary agent for the prevention of hyperlipidemia.

Alginates↗

PubMed2002

In vitro and in situ evidence for the contribution of Labrasol and Gelucire 44/14 on transport of cephalexin and cefoperazone by rat intestine.

In vitro and in situ intestinal transport of beta-lactam antibiotics in the presence of two novel pharmaceutical excipients, caprylocaproyl and lauroyl macrogolglycerides (Labrasol and Gelucire 44/14), is described. The objective was to compare the effects of both macrogolglycerides on the intestinal transport of cephalexin, a substrate of oligopeptide transporters, and cefoperazone, a non-substrate of them. The in vitro transport studies were performed using a sheet of rat jejunum mounted in Ussing-type diffusion chambers. The in situ studies used an isolated internal loop model in the rat. Labrasol and Gelucire 44/14 were used as the excipients at low concentrations (0.01-0.5%, w/v). The membrane permeability of both drugs was compared by apparent permeability coefficients (P(app)) determined from changes in the amount of permeation vs. time in in vitro studies and by apparent absorptive clearance (CL(app)) determined from changes in the steady state drug concentration of perfusate in in situ studies. The P(app) value of cephalexin increased with an increase in the concentration of Labrasol (0.05-0.5%) compared to the value without Labrasol. The enhancing effect of Labrasol on cephalexin transport was similarly observed in in situ studies, and when 0.5% Labrasol was used in the presence of glycyl-L-leucine or L-alanyl-L-alanine, 60 or 46% enhancement of the active transport of cephalexin by Labrasol was obtained. On the other hand, Gelucire 44/14 did not affect the P(app) and CL(app) of either drug. The different effects of the excipients on cephalexin transport were thought to be due to the influences of size parameters such as a polydispersity index and particle size, and the change in the short-circuit current of jejunum by the addition of the excipient.

Animals↗