Oral delivery of sorafenib through spontaneous formation of ionic liquid nanocomplexes
Graphical abstract
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.
Section snippets
Materials
SRF tosylate was purchased from Selleck Chemicals LLC. Megestrol acetate was obtained by VWR International Inc. Geranic acid (technical grade, 85%, Sigma-Aldrich (St. Louis, MO, USA) was purified through repeat crystallization with acetone at −80 °C until colorless. Choline bicarbonate (80%) was purchased from Sigma-Aldrich (St. Louis, MO, USA). Choline-d9 Chloride was obtained from Toronto Research Chemicals INC (Ontario, Canada). Formic acid 99 + %, methanol, acetone, and acetonitrile were
Characterization of CAGE and SRF-CAGE
The successful synthesis of CAGE 1:2 was confirmed with 1H NMR spectroscopy. The NMR spectra were consistent with previous reports for the same material [14]. When SRF tosylate was added to CAGE, the physical appearance of the resultant SRF-CAGE solution after sonication was similar to that of neat CAGE (Fig. S1). SRF tosylate readily dissolved in CAGE. A 500 mg/mL mixture of SRF-CAGE together with SRF powder and neat CAGE were analyzed using FTIR spectra (Fig. S2a) and XRD spectra (Fig. S2b).
Conclusion
CAGE not only dramatically improved the solubility of hydrophobic therapeutic drugs, but also increased and extended drug absorption profiles. CAGE thus provides a platform for drug half-life extension and improved pharmacokinetic and pharmacodynamic properties. Furthermore, CAGE can tune the biodistribution of the therapeutic drugs, thus offering potential means to target these organs. CAGE offers a promising drug delivery platform for improving the oral absorption of water-insoluble drugs and
Acknowledgments
The authors thank Michael Lewandowski for technical assistance, and acknowledge Wyss Institute facilities and support from School of Engineering & Applied Sciences at Harvard University. SM is a shareholder/consultant/board member of Cage Bio, Liquideon LLC and i2O Therapeutics which have licensed patent applications that cover the use of ionic liquids on which SM is an inventor.
Credit statement
YS developed the methodologies. YS, ZZ, YG, DP, AS, ET, JG performed experiments and analyzed data. SM and YS conceptualized the study and wrote the manuscript.
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