Lance M R, Washington C, Davis S S
Department of Pharmaceutical Sciences, University of Nottingham, University Park, UK.
J Antimicrob Chemother. 1995 Jul;36(1):119-28. doi: 10.1093/jac/36.1.119.
This paper investigates the relationship between the in-vitro toxicity of amphotericin B/triglyceride emulsion formulations, and their phospholipid composition and method of manufacture. Emulsion toxicity, as measured by the erythrocyte potassium leakage assay, was found to be dependent on the transition temperature of the phospholipid emulsifier, and the thermal history of the emulsion. Emulsions made using unsaturated phospholipids showed a low toxicity irrespective of the method of manufacture. Emulsions made using phospholipids with phase transition temperatures above the maximum process temperature displayed a toxicity comparable to the deoxycholate-solubilized formulation. This toxicity was significantly reduced when such formulations were heated to a temperature above the phase transition temperature for the phospholipid. We interpret these data as demonstrating that the amphotericin molecule must be inserted fully into the phospholipid emulsifier in order to produce a low toxicity emulsion, and that this insertion is critically dependent on the composition of the emulsifier and its phase transition properties.
本文研究了两性霉素B/甘油三酯乳剂配方的体外毒性与其磷脂组成及制备方法之间的关系。通过红细胞钾泄漏试验测定的乳剂毒性，被发现取决于磷脂乳化剂的转变温度以及乳剂的热历史。使用不饱和磷脂制成的乳剂，无论制备方法如何，毒性都较低。使用相变温度高于最高加工温度的磷脂制成的乳剂，其毒性与脱氧胆酸盐增溶配方相当。当将此类配方加热到高于磷脂相变温度的温度时，这种毒性会显著降低。我们将这些数据解释为表明两性霉素分子必须完全插入磷脂乳化剂中才能产生低毒性乳剂，并且这种插入关键取决于乳化剂的组成及其相变特性。
