Sumihiro Shiraishi

Controlled release of indomethacin by chitosan-polyelectrolyte complex: optimization and in vivo/in vitro evaluation

Abstract Chitosan gel beads containing indomethacin, an acidic drug, were prepared by a polyelectrolyte complexation of sodium tripolyphosphate and chitosan. The effects of the molecular weights of chitosan hydrolysates on the release and absorption rates of indomethacin from gel beads were examined. The release rates of indomethacin decreased with increasing of molecular weight and indomethacin content. A negative correlation was observed between the molecular weight and release rate constant (r = −0.983). The release of indomethacin depended upon the dispersion of the indomethacin solid particles in the beads, as well as the porosity, tortuosity and surface area of the matrix. The plasma concentrations ofindomethacin after oral administration of chitosan gel beads to beagle dogs exhibited the sustained-release pattern. With increasing molecular weight of chitosan, the AUC and Cmax were decreased, while MAT was increased. A good correlation was observed between the molecular weight of chitosan or dissolution rate constant and the MAT or AUC. The results revealed that the chitosan gel beads composed of chitosan hydrolysate, of molecular weight 25 000, might be the best for the sustained-release preparation of indomethacin. It was suggested that the absorption of other drugs could be controlled by the proper selection of chitosan hydrolysate of optimal molecular weight and predicted from in vitro dissolution tests.

Interaction of indomethacin with low molecular weight chitosan, and improvements of some pharmaceutical properties of indomethacin by low molecular weight chitosans

Abstract The interaction of four kinds of low molecular weight chitosans, which were different in molecular weight and degree of deacetylation, were studied in solution and the solid state using an anti-inflammatory drug, indomethacin (IM), as an acidic model molecule. The solubility of IM enhanced with increasing concentration of low molecular weight chitosan, especially C-I which had the lowest molecular weight and least degree of deacetylation. The C-I crystal complex was obtained in a molar ratio of 16:1 (IM: C-I) from aqueous solution. The data suggested that the acetyl group and amino group of chitosan played an important role in the complexation. The IM dissolution rates from kneaded mixtures with low molecular weight chitosans were enhanced in the order of C - I > C - II > C - III > C - IV (molecular weight: C - IV > C - III > C - II > C - I ). The oral absorption rate of IM from C-I kneaded mixture was improved compared with IM alone.

Improvement of Absorption Rate of Indomethacin and Reduction of Stomach Irritation by Alginate Dispersions

Abstract— The dissolution rates of indomethacin from low molecular weight (mol. wt) alginate dispersions were significantly enhanced in comparison with that of indomethacin alone. The dispersion with lower mol. wt alginate exhibited more rapid dissolution rate than that of dispersion with higher mol. wt alginate. These enhanced dissolution rates of indomethacin by alginate may be due to the improvement of wettability and the decrease of crystallinity and crystal size. The absorption rate from alginate dispersions was enhanced in comparison with that from indomethacin alone, and enhanced only the rate of bioavailability in beagle dogs and volunteers. In addition, indomethacin‐induced gastric lesions were reduced by dispersing indomethacin in alginate.

Identification of a Gene Involved in the Synthesis of a Dipeptidyl Peptidase IV Inhibitor in Aspergillus oryzae

ABSTRACT WYK-1 is a dipeptidyl peptidase IV inhibitor produced by Aspergillus oryzae strain AO-1. Because WYK-1 is an isoquinoline derivative consisting of three l-amino acids, we hypothesized that a nonribosomal peptide synthetase was involved in its biosynthesis. We identified 28 nonribosomal peptide synthetase genes in the sequenced genome of A. oryzae RIB40. These genes were also identified in AO-1. Among them, AO090001000009 (wykN) was specifically expressed under WYK-1-producing conditions in AO-1. Therefore, we constructed wykN gene disruptants of AO-1 after nonhomologous recombination was suppressed by RNA interference to promote homologous recombination. Our results demonstrated that the disruptants did not produce WYK-1. Furthermore, the expression patterns of 10 genes downstream of wykN were similar to the expression pattern of wykN under several conditions. Additionally, homology searches revealed that some of these genes were predicted to be involved in WYK-1 biosynthesis. Therefore, we propose that wykN and the 10 genes identified in this study constitute the WYK-1 biosynthetic gene cluster.

Effects of solid-state reaction between paracetamol and cloperastine hydrochloride on the pharmaceutical properties of their preparations

Tablets containing both paracetamol (PM) and cloperastine hydrochloride (CLH) in a combination formulation prepared by standard vertical granulation technology were found to have altered pharmaceutical properties. The hardness and disintegration time of tablets containing both PM and CLH gradually increased during storage, and the cross-screw did not operate smoothly during preparation of the mixed powder. The objective of the present study was to investigate the mechanism of formation of eutectic mixtures consisting of PM and CLH. Binary mixtures of PM and CLH in various proportions were prepared as physical mixtures and analyzed by DSC to study their thermal behavior. Phase diagrams obtained from the endothermic peaks due to melting of physical mixtures of PM and CLH demonstrated the formation of eutectic mixtures with eutectic temperatures of 86.9-110.2 degrees C depending on the ratio of constituents. The formation of the eutectic mixture was studied for a 50:50 mol.% ratio of PM and CLH. PXRD analysis revealed that the eutectic mixture of PM and CLH is structurally different from native PM and CLH. The most probable interaction sites between PM and CLH were demonstrated by DSC analysis of a binary mixture of PM and CLH prepared by melt quenching.

Identification of Furosemide Photodegradation Products in Water–Acetonitrile Mixture

The aim of this study was to identify the chemical structure of the photodegradation products of furosemide in a water-acetonitrile mixture (1 : 1). Furosemide solution was irradiated with a D65 fluorescent lamp and the products were isolated by preparative HPLC. The fractions were evaporated to dryness in vacuo. The purity of the photodegradation products was measured by HPLC. The purity of products 1, 3, and 4 was greater than 90%, whereas that of product 2 was 13%, therefore, photodegradation product 2 was unstable. We identified photodegradation products 1 and 3 as 4-chloro-5-sulfamoylanthranilic acid and 4-hydroxy-N-furfuryl-5-sulfamoylanthranilic acid, respectively, by LC/MS and NMR. Additionally, we assumed that photodegradation product 4 was methyl 2-((furan-2-ylmethyl)amino)-4-hydroxy-3-(methyleneamino)-5-sulfamoylbenzoate by LC/MS and NMR. This showed that furosemide underwent hydrolysis and substitution, and reacted with the acetonitrile under the light of a D65 fluorescent lamp. We were furthermore able to determine the elution times of the photodegradation products of furosemide by applying the Japanese Pharmacopoeia chromatographic method for related substances to the isolated products.

Investigation of Discoloration of Furosemide Tablets in a Light-Shielded Environment

We observed that uncoated furosemide tablets turned yellow in a light-shielded automatic packaging machine and discoloration of the furosemide tablets was heterogeneity and occurred on the surface of the tablets only. The machine was equipped with an internal blower to maintain a constant temperature. Therefore, we investigated the effect of air flow on the discoloration of the furosemide tablets using a blower in a dark environment. The color difference (ΔE) of the furosemide tablets increased linearly as the blowing time increased. We performed structural analysis of the yellow compound in the furosemide tablets by LC-MS and identified the compound as a hydrolysate of furosemide. This suggested that furosemide hydrolysis was accelerated by the air flow. The furosemide tablets were prepared with the most stable furosemide polymorph, form I. X-Ray powder diffractometry and IR spectroscopy showed that during tablet preparation, no crystal transition occurred to an unstable furosemide polymorph. Furthermore, IR spectroscopy showed that the crystal form of furosemide in the yellow portion of the tablets was form I. To elucidate the factors producing the discoloration, we investigated the effect of humidity and atmosphere (air, oxygen, and nitrogen) on the discoloration of the furosemide tablets. The results suggested that the discoloration of the furosemide tablets was accelerated by oxidation, although humidity did not affect the hydrolysis. Therefore, we concluded that the discoloration of the furosemide tablets in the automatic packing machine was caused by acceleration of oxidative degradation by air flow.