Development of an Injectable Formulation for the Novel Lipid A Analog E5531 Using a`pH-jump Method'
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In order to design an injectable formulation of E5531, a novel synthetic disaccharide analog of novel lipid A, for the treatment of septic shock, a`pH-jump method' was developed. In this method, E5531 was dispersed in 0.003 mol/l NaOH (pH 11.0, above pKa2) at 50℃ (above phase transition temperature) and then mixed with a buffer to neutralize the pH to 7.3. E5531 was dispersed as particles, and the size was approximately 20 nm. The structure of the particles was vesicular. After dispersal, the solution was sterilized using a filter, filled aseptically into vials, and lyophilized. The size of the particles did not change before and after lyophilization. The relationship between the physicochemical properties of the particles and the pharmacokinetics in rats after intravenous administration was investigated. The membrane fluidity of the particles was affected by the dispersal methods, the dispersal time in 0.003 mol/1 NaOH in the pH-jump method, and the addition of Ca2+ to the solution. The membrane fluidity was correlated with the pharmacokinetics in rats. INTRODUCTION Lipid A is a component of bacterial lipopolysaccharide (LPS), which is present in the major amphiphilic constituents of the leaflet of Gram-negative bacteria. Lipid A is a potent biologically active site and induces prostaglandins, and cytokines such as interferon, interleukin and tumor necrosis factor (TNF) in mammalian cells such as macrophages and lymphocytes. This compound also induces undesirable toxic effects, such as fever and the Schwartzmann bleeding reaction. Many attempts have been made to synthesize low toxic lipid A analogs. Christ and others have indicated that E5531 (Fig.1), a novel synthetic disaccharide analog of lipid A, has low toxicity and retains some of the biological activities of lipid A such as the reduction of TNF production. This compound has been found to be a specific LPS antagonist in an LPS-binding assay, and is an inhibitor of LPS-induced TNF production in monocytes/macrophages, so it is expected that E5531 will be useful for the treatment of septic shock.
- 公益社団法人日本薬学会の論文
- 2004-12-01
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