Development of an Injectable Formulation for the Novel Lipid A Analog E5531 Using a ?pH-jump Method'

Development of an Injectable Formulation for the Novel Lipid A Analog E5531 Using a ?pH-jump Method'
(Received June 28, 2004)
(Accepted August 19, 2004)
Yasuyuki ASAI1
YAKUGAKU ZASSHI
Vol. 124 (2004) , No. 12 965-972
1) Formulation Research Laboratory, Kawashima, Eisai Co., Ltd.
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?C (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/l NaOH in the pH-jump method, and the addition of Ca2+ to the solution. The membrane fluidity was correlated with the pharmacokinetics in rats.

Key words? lipid A analog; injectable formulation; pH-jump method; membrane fluidity; pharmacokinetics

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