Oral delivery of sorafenib through spontaneous formation of ionic liquid nanocomplexes

Abstract

Delivery of hydrophobic drugs is a significant challenge due to poor solubility and formulation difficulty. Here, we describe the potential of ionic liquids, in particular choline and geranic acid (CAGE), for oral delivery of a hydrophobic drug, sorafenib (SRF). CAGE provided excellent apparent solubility of SRF tosylate (> 500 mg/mL). Upon oral dosing in rats, CAGE increased peak blood concentrations of SRF by 2.2-fold. The elimination half-life of SRF was also increased by 2-fold and the mean absorption time was extended by 1.6-fold. Furthermore, SRF delivered by CAGE exhibited significantly different biodistribution compared to control formulations. Specifically, accumulation in lungs and kidneys improved 4.4-fold and 6.2-fold, respectively compared to control formulations. Mechanistic studies revealed that SRF-CAGE solution spontaneously formed a self-assembled structure (427 ± 41 nm), which is likely responsible for altered biodistribution in vivo. UPLC-MS studies confirmed the presence of choline-geranate species in blood indicative of micellar/emulsion structures which eventually dissociated into choline and geranic acid molecular species. These studies provide a simple, scalable strategy for oral delivery of hydrophobic drugs.

Introduction

Oral delivery of hydrophobic therapeutic drugs remains a significant challenge because of their low oral bioavailability, which can be attributed to low aqueous solubility, poor intestinal permeability, high level of P-glycoprotein (P-gp) efflux, and pre-systemic metabolism [[1], [2], [3]]. Numerous nanoparticle-based systems, such as nanosuspension, nanoemulsion, solid lipid nanoparticles, and inorganic-based nanoparticles, have been explored to overcome these challenges [[4], [5], [6], [7], [8]]. Although these nanoparticle-based systems offer unique advantages to enhance oral bioavailability, their efficiency has been far from ideal. In addition, tuning of the biodistribution of orally administered drugs while enhancing bioavailability via nanoparticles has rarely been reported [9,10]. Developing more effective and translatable oral drug delivery strategies for poorly soluble therapeutics is a significant unmet need.

Recently, choline and geranic acid-based ionic liquids (ILs) (hereafter referred to as CAGE), a biocompatible IL, has been reported as a promising platform for antimicrobial applications [11,12] and transdermal delivery of large molecules such as insulin [13,14]. In particular, CAGE 1:2 (a composition with choline: geranic acid stoichiometry of 1:2) has shown unique potential for delivering drugs [14]. CAGE has been used to enable oral delivery of insulin, and offer control of glucose levels by improving the intestinal permeability of insulin [15]. Due to their extraordinary solvating ability, ILs can offer a unique strategy to solubilize and/or formulate hydrophobic drugs, ultimately boosting their therapeutic efficacy [[16], [17], [18], [19]]. However, the use of CAGE for oral delivery of small molecules has not yet been demonstrated.

Herein we demonstrate the use of CAGE for oral delivery of a hydrophobic drug sorafenib (SRF). CAGE 1:2 was used in this study considering its superior tissue penetrating ability compared to other CAGE variants [[13], [14], [15]]. SRF, a potent multikinase inhibitor, is currently used to treat advanced renal cell carcinoma (RCC, 2005) and hepatocellular carcinoma (HCC, 2007) [20]. However, it is poorly soluble in water and has low oral bioavailability (8.43%) [21], which greatly restricts its therapeutic efficacy. The recommended daily dose of the current clinically used dosage form (NEXAVAR) is 400 mg (2 × 200 mg tablets) taken twice daily. This high dosing frequency arises largely from low oral bioavailability. This limitation motivates this study. Here we compare the ability of CAGE to orally deliver SRF. Owing to the very low aqueous solubility of SRF [22], SRF tosylate was used in this study for controls (SRF tosylate saline suspension) as well as test formulation (SRF tosylate solution in CAGE, SRF-CAGE) (Fig. 1). Pharmacokinetics and biodistribution of SRF, as well as CAGE components, was assessed using Ultra High Performance Liquid Chromatography with Mass Spectrometry detection (UPLC-MS). The results show that CAGE offers improved absorption as well as altered biodistribution of SRF.