Highly increasing solubility of clofazimine, an extremely water-insoluble basic drug, in lipid-based SEDDS using digestion products of long-chain lipids

Abstract

Clofazimine (CFZ) is a highly effective antibiotic against leprosy and drug-resistant tuberculosis and is on the WHO List of Essential Drugs. However, no CFZ product with optimal bioavailability is available worldwide. The manufacturer withdrew its only marketed product, presumably due to poor and erratic bioavailability because of extremely low aqueous solubility in the gastrointestinal pH range. We developed a self-emulsifying drug delivery system (SEDDS) using a lipid digestion product (LDP) containing glyceryl monooleate and oleic acid at ∼1:2 molar ratio to increase drug solubility and ensure rapid dispersion into microemulsion. While solubilities of CFZ in glyceryl monooleate, glyceryl trioleate, and two common surfactants (Tween 80 and Kolliphor EL) were comparatively low (<15 mg/g), oleic acid provided a very high solubility of ∼500 mg/g. Because of the presence of oleic acid, the clofazimine solubility in SEDDS containing a 50:50 w/w mixture of LDP and surfactants increased to 130 mg/g. Two formulations having 50 or 100 mg CFZ in one gram of SEDDS were developed. They dispersed rapidly and almost completely in simulated intestinal fluid and in the USP pH 6.8 phosphate buffer containing 3 mM sodium taurocholate. There was some precipitation of CFZ as the HCl salt at low gastric pH during dispersion testing, but the effect could be avoided using enteric-coated capsules. Thus, an enteric-coated lipid-based formulation for CFZ with as high as 100 mg/g drug loading was developed, providing complete drug release and producing microemulsions under intestinal pH conditions.