{"paper_id":"873bf933-076e-4a3c-84ae-e7a89f1d8396","body_text":"ChemComm RSCPublishing \nCOMMUNICATION \nThis journal is © The Royal Society of Chemistry 2012  J. Name ., 2012, 00 , 1 -3 | 1 \nCite this: DOI: 10.1039/x0xx00000x \nReceived 00th January 2012, \nAccepted 00th January 2012 \nDOI: 10.1039/x0xx00000x \nwww.rsc.org/ \nIonic Liquids Provide Unique Opportunities for Oral \nDrug Delivery:  Structure Optimization and In Vivo \nEvidence of Utility \nHywel D. Williams,a Yasemin Sahbaz,b Leigh Ford,b Tri-Hung Nguyen,a Peter J. \nScammells*b and Christopher J. H. Porter*a \n \nIonic liquids (ILs) have been exploited to improve the \nabsorption of poorly water -soluble drugs. Custom -made ILs \nsolubilized very high  quantities of the poorly water -soluble \ndrugs, danazol and itraconazole , and maintained drug \nsolubilization under simulated intestinal conditions. A danazol-\ncontaining self-emulsifying IL formulation gave rise to 4.3 -fold \nhigher exposure than the crystalline drug and prolonged \nexposure compared with a lipid formulation . \nIonic liquids (ILs) have generated considerable interest  in fields as \nbroad as catalysis,1 extraction,2 energy storage3 and CO2 capture.4 The \nunique solvent properties of ILs are perhaps most well described5 and \nform the basis of the use of ILs as potentially ‘green’ solvents in \nchemical synthesis .6 Solubility properties are also a critical design \nfeature of optimized drug delivery vehicles, and an area in which ILs \nmight be expected to provide particular advantage. Although a \nnumber of interesting studies have demonstrated the capacity of ILs \nto dissolve active pharmaceutical ingredients, 7 in vivo application of \nILs as enhanced oral drug delivery vectors has not been described. We \ndescribe here customized ILs to provide remarkable (20 -500 fold) \nincreases in drug solubility in oral formulations, and show for the first \ntime that this provides a means to enhance and prolong absorption of \ndrugs with intrinsically low solubility in water. \n Poorly water-soluble drugs are a challenge in drug delivery since \ntraditional formulations (tablets, capsules etc.) typically fail to provide \nfor useful drug exposure after oral administration .8 This reflects the \nfact that in almost all cases, drugs must be molecularly dispersed in \naqueous solution in the gastro -intestinal (GI) fluids for absorption to \noccur. For poorly  water-soluble drugs, dissolution is usually \nsufficiently slow that drug absorption is restricted. A common \nmechanism by which the absorption of such drugs can be enhanced is \nto pre-dissolve the drug in a non-aqueous vehicle, usually a lipid, and \nto ‘piggy-back’ into lipid digestion/absorption pathways. In this way \ndrug solubili zation is maintained by partition into the lipidic \nmicrodomains (micelles, vesicles etc.) that are produced by lipid \ndigestion.9 Notable examples of lipid -based formulations that hav e \nachieved commercial success include Neoral ®, Agenerase ® and \nNorvir SEC®. A limitation of this technology, however, is low drug \nsolubility in most lipid vehicles. This reduces the prospective dose \nthat can be administered. To address this technological limitation, we \nshow here that ILs have the potential to provide a large increase in \nsolvent capacity for model poorly water -soluble drugs when \ncompared to commonly used lipidic excipients and also to promote \nand sustain drug absorption after oral administration. \n Our init ial series of ILs were based on a nicotinic acid and its \nmetabolite, trigonelline (N-methylnictonic acid). Nicotinic acid is a \ndietary component with low toxicity, while trigonelline is the second \nmost abundant alkaloid in roasted coffee beans and is found in a range \nof plants and in some animals .10,11 Nicotinic acid/trigonelline based \nILs also show good biodegradability .12  Water-immiscible ILs were \ntargeted since, like lipids, water -immiscible ILs were expected to \nretain solvent properties on mixing with the GI fluids. Accordingly, \nnicotinic acid-based cations were paired in the first in stance with the \nhydrophobic bis (trifluoromethylsulfonyl)imide ([NTf 2]) anion \n(Scheme 1). \n \nScheme 1. Preparation of nicotinicate ester ILs (where R = butyl, hexyl, \noctyl and R’ = methyl, butyl, hexyl, octyl). \n \n To probe the solvent properties of the ILs, danazol was initially \nused as a model drug. Danazol has low aqueous solubility \n(~1µg.ml-1)13 and this limits exposure after oral administration .14 \nSimilar to many poorly water -soluble drugs, danazol has low \nsolubility in lipids (< 5 -10 mg.g-1 in triglycerides),15 precluding the \nuse of lipid based formulations as a means to enhance oral \nbioavailability. Danazol therefore provides an excellent example of a \nLiNTf2\nR'X\nN\nCOOR\nN\nCOOR\nR X\nN\nCOOR\nR'\nAgN(CN)2\nN\nCOOR\nR' N(CN)2\nNTf2\n\nCOMMUNICATION ChemComm \n2 | J. Name ., 2012, 00 , 1 -3 This journal is © The Royal Society of Chemistry 2012  \ndrug for which lipid formulations may be beneficial, but where low \nsolubility in commonly used excipients limits utility. 3 -\nButoxycarbonyl-1-methylpyridinium triflimide (Figure 1A), was \ninitially evalu ated following extensive study in previous work .12a \nIncreasing the alkyl chain length of the pyridinium  cation led to \nincreases in danazol solubility, likely as a result of increases in \nhydrophobic van der Waals (dispersive) solute -solvent interactions \nthat promote solute dissolution.16  \n \nFig. 1 A: A: Fine tuning the IL cation structure to optimize danazol \nsolubility. [hhcpy][NTf2] (shaded grey) was selected for further study. B: \nSolubility of danazol, itraconazole and fenofibrate in IL comprising the \n[hhcpy]+ cation and triflimide [NTf 2]¯ or dicyanamide [N(CN) 2]¯ anions \nin comparison to solubility in soybean oil (SBO).   Values in A are \nexpressed as means (n = 3), and in B, as means (n = 3) ±1 SD.  \n \n The highest solubility was achieved using a 1 -hexyl-3-\nhexyloxycarbonylpyridinium cation ([hhcpy] +) (shaded in Fig.  1A). \nThe [NTf 2] anion was subsequently substituted for the more \nhydrophilic dicyanamide [N(CN)2] anion to explore the possibility of \nattaining higher solvent capacity using a more polar anion. Using the \n[hhcpy] cation and [N(CN) 2] anion, danazol solubility increased 3.6 -\nfold from 26.3 mg.g -1 to over 95 mg.g -1 (Fig. 1B). This represents a \n20-fold increase in solubility over soybean oil, and a level of solvency \nthat exceeds that provided by many widely used co -solvents such as \nethanol and PEG. The solvent properties of [hhcpy][NTf 2] and \n[hhcpy][N(CN)2] were also evaluated for itraconazole (another drug \nshowing poor water and lipid solubility16) and itraconazole solubility \nwas >100 -fold and ~500 -fold higher, respectively, than that of \nsoybean oil in these ILs  (although absolute solubility was somewhat \nlower than danazol). The solvation benefit provided by ILs appears to \nbe highest for drugs that exhibit poorer solvation in traditional lipids \n(e.g. danazol, itraconazole), since the ILs showed little solvent benefit \nover soybean oil for a more lipophilic drug, fenofibrate, where lipid \nsolubility was already high.  \n Further studies were subsequently conducted to identify more \namphiphilic ILs with improved miscibility properties with a range of \nlipid-based drug delivery systems. These ‘2 nd generation’ ILs were \nbased on a 3 -methylpyridinium core that is structurally similar to \nnicotinic acid, but allows for simpler synthesis and more facile scale-\nup for in vivo  evaluation. A series of derivatives of the 3 -\nmethylpyridinium cation were synthesized, and the data obtained for \nthe 1 -octyl-3-methylpyridinium cation ([C 8mpy]+) (Scheme 2) are \ndescribed in detail here. Alkyl sulfate anions were explored since the \nhydrogen bond acceptor sites on the sulfate moiety were expected to \ncomplement the hydrogen bond donor site on danazol , and the long \nalkyl chain was expected to increase the potential for favorable van \nder Waals interactions between the IL and non-polar drugs, and limit \nthe water-miscibility of the IL (since IL miscibility with water was \nexpected to increase the risk of d rug precipitation on dispersion in \nvivo). Alkyl sulfate anions therefore possessed the combined qualities \nof [N(CN)2] (i.e. hydrogen bonding) and  [NTf2] (i.e. hydrophobicity) \nanions. The melting temperature of the ILs containing longer chain \nanions [C10SO4]¯ and [C 18SO4]¯ were higher than the 1 st generation \nILs, and as such, it was not possible to accurately measure drug \nsolubility at room temperature. However, danazol solubility in the \n[C6SO4]¯ derivative, which was liquid at 37 °C, was high (88.9 mg.g -\n1) and similar to that of the 1st generation ILs containing [N(CN)2]¯. \n \n \nScheme 2. Preparation of 1 -methyl-3-octylpyridinum alkyl sulfate ILs \n(abbreviated as [C8mpy][CnSO4]). R = hexyl, decyl, octadecyl ( details \nof the synthesis method are in the supporting information). \n \n [hhcpy][[NTf2] and [hhcpy][[N(CN) 2] from the 1 st generation \nseries and [C8mpy][C10SO4] and [C 8mpy][C18SO4] from the 2 nd \ngeneration ILs were progressed into in vitro  studies to ass ess their \npotential as components of oral drug delivery systems. ILs were \nincorporated into formulations modeled on contemporary lipid \nformulations that emulsify spontaneously on contact with the GI \nfluids (so called self-emulsifying drug delivery systems or SEDDS) \nand improve the oral bioavailability of many poorly water -soluble \ndrugs.17 Formulations (described in Table S1, Supporting \nInformation) were loaded with danazol, and the respective \nsolubilization properties assessed after dispersion in simulated gastric \nand intestinal fluids. With the exception of SEDDS N(CN)2 (the \ndispersion of which resulted in drug crystallization), the other IL -\nSEDDS were highly effective in maintaining danazol in a solubilized \nform in vitro. Danazol absorption in rats was therefore assessed after \nadministration of SEDDS based on ILs comprising [hhcpy][[NTf 2] \nand [C8mpy][C10SO4] and [C 8mpy][C18SO4]  (SEDDSNTf2, \nSEDDSC10SO4, SEDDS C18SO4). A ‘gold standard’ lipid -based \nformulation (SEDDS lipid) was also explored as was a crystalline \ndanazol suspension. The plasma concentration profiles for danazol \nafter administration of each formulation are shown in Figure 2A and \ntotal danazol  exposure (the area under the plasma concentration \ncurves) in Figure 2B (see Supporting Information, Table S2 for all \npharmacokinetic results). The SEDDS lipid resulted in danazol \nexposure of 498.3 ± 149.8 ng.h.mL-1 over 8 h, whereas the suspension \nprovided only a fraction (<25%) of this exposure, highlighting the \nbenefit of administering a poorly water -soluble drug in a lipid \nformulation. Danazol plasma concentrations after administration of \nSEDDSNTf2, and SEDDS C10SO4, were also low despite these \nformulations containing drug in the pre-dissolved form. The exposure \nobtained for SEDDS C18SO4, however, was much improved, and \nconsistent with that of the SEDDS lipid but with noteworthy evidence \nof sustained plasma concentrations and the prospect of controlled drug \nrelease and absorption. \nN N\nC8H17\nC8H17Br\nBr\nROSO3NH4\nROSO3\nN\nC8H17\n0\n50\n100\n0\n50\n100\n150\n0\n25\n50\n\nJournal Name COMMUNICATION \nThis journal is © The Royal Society of Chemistry 2012  J. Name ., 2012, 00 , 1 -3 | 3 \n Digestion of SEDDS lipid in the intestine allows the incorporated \ndrug to ‘piggyback’ the lipid absorption pathway resulting in transfer \nof digested lipids (and drug) into intestinal mixed -micelles for \nefficient transport to the intestinal wall.8 In contrast, IL-based SEDDS \nare not digested. Poor drug absorption from these formulations is \ntherefore likely attributable to inefficient transfer to the intestinal wall \nof the relatively large colloidal droplets formed by dispersion of the \nIL formulations in the GI fluids. The improved absorption of danazol \nfrom SEDDS C18SO4 suggests that this IL system allowed for more \neffective interaction with endogenous bile salt micelles resulting in \nthe generation of highly dispersed species with improved access to the \nabsorptive surface. Interestingly, the structure of this IL -based \nmicellar species appears to be sufficiently different to that of lipid-bile \nsalt mixed-micelles to allow for controlled drug release, and therefore, \nsustained drug absorption. Segments of gastric and intestinal mucosa \nfrom SEDDSlipid and SEDDSC18SO4 administered rats were isolated \n24 h post-dose for histological analysis (see Supporting Information, \nFig. S1 & S2). The results show that SEDDS lipid did not cause any \ndetectable histological injury. In half of the animals administered \nSEDDSC18SO4, no histological damage was evident, however in two \nanimals there was some evidence of submucosal inflammation in the \nnon-glandular region of the stomach, suggesting the possibility o f \nsome local irritancy. \n \nFig. 2 Ionic liquids enhance and sustain drug absorption . A. Danazol \nplasma concentrations after oral administration of 25 mg.kg - 1 danazol \nto rats in IL- or lipid-containing SEDDS or as a suspension formulation. \nMean (n ≥ 4) ± SEM. B: Total danazol exposure (AUC) over 8 h. Mean \n(n ≥ 4) ± SEM.  statistically significant (p < 0.05) relative to the \nsuspension. Total exposure of danazol after a dministration in the \nSEDDSC18CO4 IL formulation was similar to that of the ‘gold standard’ \nSEDDS lipid formulation, but with pronounced evidence of sustained \nplasma concentrations.  \n \n In summary, custom -made ILs have been synthesized that show \ngreat promise as improved drug delivery vehicles for poorly water -\nsoluble drugs. IL -based SEDDS have many potential advantages \nincluding high drug loading capacity, facile dispersion in GI fluids, \ninsensitivity to GI digestive processes and in some cases the ability to \nincrease and extend drug absorption profiles. The flexibility of the IL \nsynthetic platform provides particular attraction and subsequent \nstudies will explore the potential for individually tailored drug \ndelivery systems for drugs with widely differing, b ut problematic, \nphysicochemical properties. \n This work was partially funded by the ARC Centre of Excellence \nfor Free Radical Chemistry and Biotechnology. The authors also \nacknowledge Dr Mette Anby and Miss Orlagh  Feeney for assistance \nduring mass spectrometry analysis of rat plasma samples and Prof. \nRob Singer for helpful discussions. \n \nNotes and references \na Drug Delivery, Disposition and Dynamics  and b Medicinal Chemistry, \nMonash Institute of Pharmaceutical Scien ces, Monash University, 381 \nRoyal Parade, Parkville, Victoria 3052, Australia . \nElectronic Supplementary Information (ESI) available: Experimental \nmethods, ionic liquid synthesis, Tables S1-S2 Figures S1-S4.  \n \n1 (a) N. V. Plechkova, K. R. Seddon, Chem. Soc. 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