Transformation of Poorly Water-Soluble Drugs into Lipophilic Ionic Liquids Enhances Oral Drug Exposure from Lipid Based Formulations

Abstract

Absorption after oral administration is a requirement for almost all drug products but is a challenge for drugs with intrinsically low water solubility. Here, the weakly basic, poorly water-soluble drugs (PWSDs) itraconazole, cinnarizine, and halofantrine were converted into lipophilic ionic liquids to facilitate incorporation into lipid-based formulations and integration into lipid absorption pathways. Ionic liquids were formed via metathesis reactions of the hydrochloride salt of the PWSDs with a range of lipophilic counterions. The resultant active pharmaceutical ingredient-ionic liquids (API-ILs) were liquids or low melting point solids and either completely miscible or highly soluble in lipid based, self-emulsifying drug delivery systems (SEDDS) comprising mixtures of long or medium chain glycerides, surfactants such as Kolliphor-EL and cosolvents such as ethanol. They also readily incorporated into the colloids formed in intestinal fluids during lipid digestion. Itraconazole docusate or cinnarizine decylsulfate API-ILs were subsequently dissolved in long chain lipid SEDDS at high concentration, administered to rats and in vivo exposure assessed. The data were compared to control formulations based on the same SEDDS formulations containing the same concentrations of drug as the free base, but in this case as a suspension (since the solubility of the free base in the SEDDS was much lower than the API-ILs). For itraconazole, comparison was also made to a physical mixture of itraconazole free base and sodium docusate in the same SEDDS formulation. For both drugs plasma exposure was significantly higher for the API-IL containing formulations (2-fold for cinnarizine and 20-fold for itraconazole), when compared to the suspension formulations (or the physical mixture in the case of itraconazole) at the same dose. The liquid SEDDS formulations, made possible by the use of the API-ILs, also provide advantages in dose uniformity, capsule filling, and stability compared to similar suspension formulations. The data suggest that the formation of lipophilic ionic liquids provides a means of increasing dissolved-drug loading in lipid based formulations and thereby promoting the exposure of poorly water-soluble drugs after oral administration.

Ionic Liquid Forms of the Antimalarial Lumefantrine in Combination with LFCS Type IIIB Lipid-Based Formulations Preferentially Increase Lipid Solubility, In Vitro Solubilization Behavior and In Vivo Exposure

“…In general, lumefantrine solubility was higher in the medium-chain formulations than in the long-chain formulations, and solubility was higher in the more polar formulations such as the Type IIIB and Type IV formulation. This is consistent with previous work, with both non-IL drugs and ILs [32,35]. Isolation of lumefantrine as the dodecyl sulfate IL resulted in increases in solubility in the Type IIIB and Type IV formulations, but did not result in significant advantages in lipid solubility in the others.…”

“…Type I formulations require digestion and are composed of only oils. Type II formulations contain lipids and water-insoluble surfactants and self-emulsify on contact with the GI fluids (i.e., self-emulsifying drug delivery systems (SEDDS)) [30][31][32]. Type III formulations are self-microemulsifying drug delivery systems (SMEDDS) or self-nanoemulsifying drug delivery systems (SNEDDS) and are sub-classified into Type IIIA and Type IIIB.…”

“…A potential limitation of the utility of LBFs is low drug loading in the formulation such that the therapeutic drug dose cannot be solubilized in a volume of lipid that can be filled into one or two capsules [6]. The use of ionic liquid forms of drugs can increase drug loading in LBFs [6,[32][33][34], but whether solubilization is maintained at these higher drug loads as the formulation is dispersed and digested is not well understood. Similarly, the relationship between formulation type and composition and the fate of an API-IL during formulation digestion has not been widely explored.…”

Ionic Liquids Treated within the Grand Canonical Adaptive Resolution Molecular Dynamics Technique

“…By chemical modification of the polar or apolar components or charge of the ions, numerous ILs with a range of physicochemical properties such as viscosity, catalytic activity, or solvation can be generated. We now have task specific ionic liquids that can be applied for a range of designated applications [4,5]: ionic liquids as drugs [6,7], as batteries and super-capacitors for solving energy demands of the environment [8][9][10][11], to capture greenhouse gases, to dissolve proteins [12,13] and cellulose [14,15].…”

Probing spatial locality in ionic liquids with the grand canonical adaptive resolution molecular dynamics technique

“…We show that even for sub-regions whose radius corresponds to the size of a few molecules, spatial properties are reasonably reproduced thus suggesting a higher degree of spatial locality, a hypothesis put forward also by other researchers and that seems to play an important role for the characterization of fundamental properties of a large class of ionic liquids. can be employed for a range of designated applications 4,5 : ionic liquids as drugs 6,7 , as batteries and super-capacitors for solving energy demands of the environment [8][9][10][11] , to capture greenhouse gases, to dissolve proteins 12, 13 and cellulose 14,15 .…”