Helicobacter pylori (H. pylori) is implicated in the etiology of duodenal and gastric ulcer diseases and gastric cancer in severe cases.1) Many studies have been demonstrated that H. pylori eradication treatment is indicated in all patients with active or recurrent peptic ulceration. Oral triple-therapy schedules using a proton inhibitor or an H 2 -antagonist in combination of two antibiotics such as clarithromycin, metronidazole, amoxicillin and tetracycline have been proved to be highly effective in the treatment of H. pylori. However, such the triple therapy sometimes results in failure of the H. pylori therapy because of poor compliance with the treatment regimen, with the development of antibiotic resistance and with drug-drug interaction, etc.2,3) Therefore, it is desired to develop new strategies of H. pylori therapy, including the development of new drugs and multiple-combinations, etc.4-Methylbenzyl-4Ј-[trans-4-(guanidinomethyl)cyclohexylcarbonyloxy]biphenyl-4-carboxlylate monohydrochloride (TG44, Fig. 4 for the chemical structure) is a newly synthesized H. pylori eradicating agent with high selectivity to H. pylori, compared with other gram-negative and gram-positive bacteria.4) The structure of TG44 is closely related to an antiulcer agent, benexate, which is formulated in the form of b-CyD complex and on market as a trade name of Ulgut or Lonmiel, although the pharmacological indication is different between them. Because benezate is commercially available as a b-CyD complex, we used b-CyD as a solubilizing agent for TG44, among various CyDs and their derivatives. The H. pylori eradicating activity of TG44 was markedly enhanced when it was orally administered in the form of bCyD complex, compared with TG44 alone, which will be reported elsewhere. The enhanced antimicrobial activity of TG44/b-CyD complex may be ascribed to improved dissolving properties of the b-CyD complex, but the detailed mechanism is not yet fully elucidated. This study dealt with the inclusion complexation of TG44 with b-CyD in water and in solid state, to gain insight into the high in-vivo H. pylori eradicating activity of TG44/b-CyD complex.
ExperimentalMaterials TG44 and b-CyD were supplied by Nagase ChemteX Corporation (Osaka, Japan) and Nihon Shokuhin Kako Co., Ltd. (Tokyo, Japan), respectively. All other chemicals and solvents were of analytical reagent grade, and deionized distilled water was used throughout the study.Solubility Measurements Solubility studies were carried out according to the method of Higuchi and Connors.5) The screw-capped vials containing TG44 in excess amounts (0.3 g/50 ml) in aqueous CyD solutions at various concentrations (2ϫ10Ϫ3 M) were stirred for 24 h at 25°C. The suspension was filtered through a syringe with a membrane-filter, and the filtrate was adequately diluted and analyzed for TG44 using high-performance liquid chromatography (HPLC) under the following conditions: a Shimadzu Class LC-10A HPLC system, (Kyoto, Japan), a column of CERI L-column ODS 5 mm (Tokyo, Japan), a mobile phase of phosp...