Abstract
Clofazimine (B663) is a highly lipophilic drug used in the treatment of leprosy. The solubility and gastrointestinal membrane permeability ( P app) of B663 in mixed micellar systems were examined. Membrane permeability was determined using a rat gut perfusion model and, in addition, these studies incorporated the hydrophilic marker PEG 4000. The mixed micellar systems studied contained the bile salt, sodium cholate (NaC), in association with different fatty acids including caprylic acid, oleic acid and linoleic acid. At a set concentration of NaC (40 mM) the solubility of B663 increased with increasing concentration of each fatty acid. Relative to NaC, the maximum enhancement in solubility (16-fold) was obtained with the NaC/linoleic acid (40:40 mM) system. An optimum bile salt/fatty acid ratio of 1:1 existed for maximum solubility enhancement. All mixed micellar systems enhanced the absorption of B663 relative to the simple micelle. The P app tended to increase with increasing fatty acid concentration, maximum enhancement being obtained with the NaC/linoleic acid 40:40 mM system. With each mixed micellar system a higher P app was obtained with lower drug loading. The effects of the mixed micellar systems on the absorption of PEG 4000 varied with fatty acid loading. These results have shown that mixed micelles can enhance the absorption of B663 to a greater extent relative to non-micellar and simple micellar systems. Maximum enhancement (> 800-fold) in the rate of B663 absorption was obtained with the NaC/linoleic acid 40:40 mM system. These results offer a possible explanation for the reported enhancement in gastrointestinal absorption of B663 when co-administered with fatty materials.
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