Characterization of liposomes and an emulsion containing mitomycin C or lipophilic mitomycin C prodrugs

• Published in: Journal of pharmaceutical sciences Vol. 75; no. 12; p. 1166
• Main Authors: Sasaki, H, Kakutani, T, Hashida, M, Sezaki, H
• Format: Journal Article
• Language: English
• Published: United States 01.12.1986
• Subjects: Chemical Phenomena; Chemistry; Dosage Forms; Emulsions; Liposomes - administration & dosage; Mitomycin; Mitomycins - administration & dosage; Oils; Perylene; Phosphatidylcholines; Water
• ISSN: 0022-3549
• DOI: 10.1002/jps.2600751210

The characteristics of liposomes and an oil-water emulsion containing either mitomycin C (MMC) or its lipophilic prodrugs were investigated. Prodrugs were incorporated into liposomes and oil droplets of an oil-water emulsion, and this incorporation was dependent on the lipid content of the liposomes and droplets. A good correlation was observed between the calculated lipid:water partition ratios and partition coefficients in chloroform:water. The prodrugs were rapidly distributed between the lipid and aqueous phases when they were injected into the dispersion medium of empty liposomes and an oil-water emulsion, or when the formulations incorporating prodrugs were diluted with water. Addition of prodrugs to liposomes containing perylene resulted in a decrease of fluorescence. Based on these findings, prodrugs were concluded to be incorporated into lipidic dispersion formulations based on their partitioning behavior. N1a-[(Nonyloxy)carbonyl]MMC (7) showed the highest incorporation into lipidic formulations, while prodrugs with moderate lipophilicities were rapidly released from lipid particles. Liposomes incorporating 7 maintained their multilamellar vesicular form as shown by electron microscopy and by examining their entrapping capacity for water soluble marker dyes. The release of prodrug 7 from both formulations was slow in a buffer solution, but considerable release and conversion to the parent drug were observed when rat plasma was added to the same system. These results suggest that the stability of MMC could be improved by incorporation into lipidic formulations and that a suitable release rate in vivo could be accomplished by use of a prodrug.