Using mixtures of linoleic acid, a long-chain polyunsaturated fatty acid, and its monoglyceride in lipid-based formulations to increase drug loading and enhance aqueous microemulsification

Abstract

Although lipid-based formulations (LBFs) of self-emulsifying drug delivery systems (SEDDS) have been used for poorly water-soluble drugs, they have many limitations, the first being the low solubility of drugs in lipids, which limits drug loading in formulations, and the second being inadequate dispersion of formulations in the aqueous fluids of the human gastrointestinal tract (GIT). Large amounts of organic cosolvents and surfactants, up to 90% of the formulation, have been used to overcome these limitations. We previously demonstrated that the situation could be improved by using lipid digestion products (LDP), which consist of a 2:1 M ratio of long-chain fatty acids and monoglycerides, rather than lipids (triglycerides) themselves. The drug solubility and, therefore, drug loading in the formulations increased greatly in the presence of a long-chain fatty acid in the LDP. However, only one acid, oleic acid (OA), and its monoglyceride were used in those studies. To demonstrate the versatility of the approach, a different LDP, another acid, linoleic acid (LA), and its monoglyceride, glyceryl monolinoleate (GML), were used at a 2:1 M ratio in the present study, with clofazimine (CFZ) as the model. Although both OA and LA are C-18 fatty acids, the latter has two double bonds instead of one, which affects its physicochemical properties, such as pKa and molecular packing. Therefore, in addition to drug solubility, any additional effects of the extra double bond on LBFs were investigated. LA showed a high CFZ solubility of 480 mg/g, comparable to OA, and performed better in LBFs, with the developed formulation (100 mg/g) dispersing as microemulsions at intestinal pH, with particle sizes <250 nm, much smaller than the 400 nm observed for OA. High drug solubility and a smaller microemulsion particle size could increase in vivo drug release and absorption.