Lipid-covered drug particles: combined action of dioctadecyldimethylammonium bromide and amphotericin B or miconazole.
OBJECTIVE
Coverage of antifungal drug particles (miconazole and amphotericin B) with cationic lipid and evaluation of a synergistic action between lipid and drug.


METHODS
Miconazole and amphotericin B were mixed with cationic bilayer fragments (BF) of dioctadecyldimethylammonium bromide (DODAB) at extreme drug to lipid molar proportions (P). Light scattering for particle sizing and zeta-potential analysis evaluated effects of cationic lipid on drug particle size and charge. Colony counts evaluated viability of Candida spp. and Cryptococcus neoformans over a range of P.


RESULTS
BF loading capacity for monomeric amphotericin B is 0.1 mM amphotericin B at 2 mM DODAB (P = 1:20). Above this low P, amphotericin B aggregates in the dispersion. At high P, addition of chaotropic K2HPO4 (0.2-2 mM) converts miconazole or amphotericin B aggregates into negatively charged particles with affinity for cationic lipid, which then surrounds each drug particle with a cationic layer. The combined in vitro action of lipid-covered drug particles against Candida and C. neoformans depends on P and interaction time. DODAB by itself kills C. neoformans and Candida at 2 and 2 to > 250 mg/L minimal fungicidal concentration (MFC). In combination, over the first hour, fungicidal activity is due to DODAB with lipid capsules retarding drug action. At 48 h interaction time and 10(4) cfu/mL, MFC (mg/L) against Candida albicans is reduced from 4 to 1 amphotericin B (at 2 DODAB), and from 8 to 1 miconazole (at 1 DODAB).


CONCLUSIONS
DODAB may be a suitable candidate for use in combination with miconazole for antifungal therapy.
Lincopan
Nilton
N
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo CP 26077, Avenida Lineu Prestes 748-Butantã, CEP 05513-970, São Paulo-SP, Brazil.
Carmona-Ribeiro
Ana M
AM
D000666:Amphotericin B / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D002175:Candida / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004338:Drug Combinations; D008055:Lipids / Q000737:chemistry*; D008825:Miconazole / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010316:Particle Size; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology*; D013501:Surface-Active Agents / Q000737:chemistry / Q000494:pharmacology
D000935:Antifungal Agents; D004338:Drug Combinations; D008055:Lipids; D000644:Quaternary Ammonium Compounds; D013501:Surface-Active Agents; C015831:dimethyldioctadecylammonium; D008825:Miconazole; D000666:Amphotericin B