title: Improvement of dissolution properties of a new Helicobacter pylori eradicating agent (TG44) by inclusion complexation with beta-cyclodextrin.
abstract: The interaction of a newly developed Helicobacter pylori eradicating agent (TG44, 4-methylbenzyl-4'-[trans-4-(guanidinomethyl)cyclohexylcarbonyloxy]biphenyl-4-carboxlylate monohydrochloride) with beta-cyclodextrin (beta-CyD) in aqueous solution and in solid state was studied to gain insight into the high in-vivo H. pylori eradicating activity of TG44/beta-CyD complex. The interaction was studied by the solubility method, spectroscopic methods, powder X-ray diffractometry and differential scanning colorimetry (DSC). TG44 gave A(L)-type phase solubility diagram with beta-CyD in water, showing a linear increase in solubility of the drug up to 8 mM beta-CyD concentration. The solubility of TG44 (0.04 mM in water at 25 degrees C) increased about 70-folds at 8 mM beta-CyD. Ultraviolet, circular dichroism, fluorescence and (1)H-nuclear magnetic resonance spectroscopic studies indicated that TG44 forms the inclusion complex with beta-CyD in a 1:1 stoichiometry and the biphenyl moiety of TG44 is preferably included in the beta-CyD cavity in water. The Giordano plot made by monitoring changes in the fusion enthalpy of TG44 (about 184 degrees C) suggested that TG44 forms the 1:1 complex with beta-CyD in the solid state. The TG44/beta-CyD solid complex in a 1:1 stoichiometry was prepared by the grinding and spray-drying methods and confirmed by powder X-ray diffractometry and DSC that the complex is in an amorphous state. The initial dissolution rate of TG44/beta-CyD complex was significantly faster than those of the drug alone and the physical mixture of both components, maintaining higher supersaturated concentrations of the drug for a long time. The results suggested that the higher eradicating activity of TG44/beta-CyD complex to Helicobacter pylori, compared with that of the drug alone, is attributable at least partly to the faster dissolving property of the complex and its ability to maintain the supersaturated state of the drug in the gastric fluid.
authors.affiliation: Nagase ChemteX Corporation, Kobe Product Development Center, Hyogo, Japan.
authors.forename: Kinsei
authors.initials: K
authors.lastname: Anzai
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Mizoguchi
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yanagi
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Hirayama
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
authors.forename: Kaneto
authors.initials: K
authors.lastname: Uekama
mesh_terms: D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology; D002152:Calorimetry, Differential Scanning; D002942:Circular Dichroism; D006146:Guanidines / Q000737:chemistry* / Q000494:pharmacology; D016480:Helicobacter pylori / Q000187:drug effects; D019906:Nuclear Magnetic Resonance, Biomolecular; D012995:Solubility; D013696:Temperature; D013997:Time Factors; D014867:Water / Q000737:chemistry*; D014961:X-Ray Diffraction; D047392:beta-Cyclodextrins / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C510407:4-methylbenzyl 4'-(4-(guanidinomethyl)cyclohexylcarbonyloxy)biphenyl-4-carboxylate; D001565:Benzoates; D006146:Guanidines; D047392:beta-Cyclodextrins; D014867:Water