REDUCTION OF PAIN ON INTRAVENOUS-INFUSION WITH BILE-SALT FORMULATIONS FOR A MACROLIDE ANTIBIOTIC

Macrolide antibiotics are well-known to cause pain on intravenous injection. The studies reported here indicate the feasibility of using bile salts, especially bile salt-phospholipid mixed micelle systems. to reduce the pain on injection of clarithromycin (6-O-methyl erythromycin). Sodium glycodeoxycholate was identified as the bile salt which was most effective in forming physically stable formulations of clarithromycin and in reducing the pain on injection, as shown by two animal models, the mouse scratch test and the rat paw lick test. Clarithromycin-bile salt formulations generally caused hemolysis, but this could be reduced by HSA and, especially, phospholipids. A formulation composed of clarithromycin lactobionate/glycodeoxycholate/egg phosphatides (1:3:2 molar ratio) was identified as a formulation which is chemically and physically stable, reduces the pain by at least 50% according to the animal models, has comparable efficacy to clarithromycin lactobionate in a mouse protection test, and had toxicity in rats which was less than that of clarithromycin lactobionate. The results suggest the potential of using mixed micelle systems in the formulation of macrolides and other drugs which are painful on intravenous administration.