Ionic liquids provide unique opportunities for oral drug delivery: Structure optimization and in vivo evidence of utility

Article abstract of DOI:10.1039/c3cc48650h

Ionic liquids (ILs) have been exploited to improve the absorption of poorly water-soluble drugs. Custom-made ILs solubilized very high quantities of the poorly water-soluble drugs, danazol and itraconazole, and maintained drug solubilization under simulated gastro-intestinal conditions. A danazol-containing self-emulsifying IL formulation gave rise to 4.3-fold higher exposure than the crystalline drug and prolonged exposure compared with a lipid formulation.

Full text of DOI:10.1039/c3cc48650h

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Ionic liquids provide unique opportunities for oral
drug delivery: structure optimization and in vivo
evidence of utility†
Cite this: Chem. Commun., 2014,
50, 1688
Received 13th November 2013,
Accepted 16th December 2013
Hywel D. Williams,a Yasemin Sahbaz,b Leigh Ford,b Tri-Hung Nguyen,a
Peter J. Scammells*b and Christopher J. H. Porter*a
DOI: 10.1039/c3cc48650h
www.rsc.org/chemcomm
Ionic liquids (ILs) have been exploited to improve the absorption of and to ‘piggy-back’ into lipid digestion/absorption pathways. In
poorly water-soluble drugs. Custom-made ILs solubilized very high this way drug solubilization is maintained by the lipidic micro-
quantities of the poorly water-soluble drugs, danazol and itraconazole, domains (micelles, vesicles etc.) that are produced by lipid
and maintained drug solubilization under simulated gastro-intestinal digestion.9 Notable examples of lipid-based formulations that have
conditions. A danazol-containing self-emulsifying IL formulation gave achieved commercial success include Neorals, Agenerases and
rise to 4.3-fold higher exposure than the crystalline drug and prolonged Norvir SECs. A potential limitation of this technology, however, is
exposure compared with a lipid formulation.
low drug solubility in most lipid vehicles. This reduces the prospec-
tive dose that can be administered. To address this issue, we show
Ionic liquids (ILs) have generated considerable interest in fields as here that ILs have the potential to provide a large increase in solvent
broad as catalysis,1 extraction,2 energy storage3 and CO2 capture.4 The capacity for model poorly water-soluble drugs when compared to
unique solvent properties of ILs are perhaps most well described5 and commonly used lipidic excipients and also to promote and sustain
form the basis of the use of ILs as potentially ‘green’ solvents in drug absorption after oral administration.
chemical synthesis.6 Solubility properties are also a critical design
Our initial series of ILs were based on nicotinic acid and its
feature of optimized drug delivery vehicles, and an area in which metabolite, trigonelline (N-methylnicotinic acid). Nicotinic acid is a
ILs might be expected to provide particular advantage. Although a dietary component with low toxicity, while trigonelline is the second
number of interesting studies have demonstrated the capacity of ILs most abundant alkaloid in roasted coffee beans and is found in a range
to dissolve active pharmaceutical ingredients,7 in vivo application of of plants and in some animals.10,11 Nicotinic acid/trigonelline based ILs
ILs as enhanced oral drug delivery vectors has not been described. We also show good biodegradability.12 Water-immiscible ILs were targeted
describe here customized ILs to provide remarkable (20–500 fold) since, like lipids, water-immiscible ILs were expected to retain solvent
increases in drug solubility in oral formulations, and show for the first properties on mixing with the GI fluids. Accordingly, nicotinic acid-
time that this provides a means to enhance and prolong absorption of based cations were paired in the first instance with the hydrophobic
drugs with intrinsically low solubility in water.
bis(trifluoromethylsulfonyl)imide ([NTf2]) anion (Scheme 1).
Poorly water-soluble drugs are a challenge in drug delivery since
To probe the solvent properties of the ILs, danazol was initially
traditional formulations (tablets, capsules etc.) typically fail to provide used as a model drug. Danazol has low aqueous solubility
for useful drug exposure after oral administration.8 This reflects the (B1 mg mLꢀ1 13 and this limits exposure after oral administration.14
)
fact that in almost all cases, drugs must be molecularly dispersed Similar to many poorly water-soluble drugs, danazol has low
in aqueous solution in the gastro-intestinal (GI) fluids for absorption
to occur. For poorly water-soluble drugs, dissolution is usually suffici-
ently slow that drug absorption is restricted. A common mechanism
by which the absorption of such drugs can be enhanced is to
pre-dissolve the drug in a non-aqueous vehicle, usually a lipid,
a Drug Delivery, Disposition and Dynamics, Monash University, 381 Royal Parade,
Parkville, Victoria 3052, Australia. E-mail: chris.porter@monash.edu
b Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences,
Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
E-mail: peter.scammells@monash.edu
† Electronic supplementary information (ESI) available: Experimental methods,
Scheme 1 Preparation of nicotinicate ester ILs (where R = butyl, hexyl,
octyl and R0 = methyl, butyl, hexyl, octyl).
ionic liquid synthesis, Tables S1 and S2, Fig. S1–S4. See DOI: 10.1039/c3cc48650h
1688 | Chem. Commun., 2014, 50, 1688--1690
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solubility in lipids (o5–10 mg gꢀ1 in triglycerides),15 precluding the
use of lipid based formulations as a means to enhance oral
bioavailability. Danazol therefore provides an excellent example of
a drug for which lipid formulations may be beneficial, but where low
solubility in commonly used excipients limits utility. 3-Butoxy- Scheme 2 Preparation of 1-methyl-3-octylpyridinum alkyl sulfate ILs
(abbreviated as [C8mbpy][CnSO4]). R = hexyl, decyl, octadecyl (details of
carbonyl-1-methylpyridinium triflimide (Fig. 1A), was initially
the synthesis method are in the ESI†).
evaluated following extensive study in previous work.12a Increasing
the alkyl chain length of the pyridinium cation led to increases in
danazol solubility, likely as a result of increases in hydrophobic provided by ILs appears to be highest for drugs that exhibit poorer
van der Waals (dispersive) solute–solvent interactions that solvation in traditional lipids (e.g. danazol, itraconazole), since the ILs
promote solute dissolution.16
showed little solvent benefit over soybean oil for a more lipophilic
The highest solubility was achieved using a 1-hexyl-3-hexyloxy- drug, fenofibrate, where lipid solubility was already high.
carbonylpyridinium cation ([hhcpy]+) (shaded in Fig. 1A). The [NTf2]
Further studies were subsequently conducted to identify more
anion was subsequently substituted for the more hydrophilic dicya- amphiphilic ILs with improved miscibility properties with a range
namide [N(CN)2] anion to explore the possibility of attaining higher of lipid-based drug delivery systems. These ‘2nd generation’ ILs
solvent capacity using a more polar anion. Using the [hhcpy] cation were based on a 3-methylpyridinium core that is structurally
and [N(CN)2] anion, danazol solubility increased 3.6-fold from similar to nicotinic acid, but allows for simpler synthesis and more
26.3 mg gꢀ1 to over 95 mg gꢀ1 (Fig. 1B). This represents a 20-fold facile scale-up for in vivo evaluation. A series of derivatives of the
increase in solubility over soybean oil, and a level of solvency that 3-methylpyridinium cation were synthesized, and the data obtained
exceeds that provided by many widely used co-solvents such as for the 1-octyl-3-methylpyridinium cation ([C8mbpy]+) (Scheme 2) are
ethanol and PEG. The solvent properties of [hhcpy][NTf2] and described in detail here. Alkyl sulfate anions were explored since the
[hhcpy][N(CN)2] were also evaluated for itraconazole (another drug hydrogen bond acceptor sites on the sulfate moiety were expected to
showing poor water and lipid solubility16) and itraconazole solubility complement the hydrogen bond donor site on danazol, and the long
was >100-fold and B500-fold higher, respectively, than that of alkyl chain was expected to increase the potential for favorable van der
soybean oil (a common lipid excipient) in these ILs (although absolute Waals interactions between the IL and non-polar drugs, and limit the
solubility was somewhat lower than danazol). The solvation benefit water-miscibility of the IL (since IL miscibility with water was expected
to increase the risk of drug precipitation on dispersion in vivo). Alkyl
sulfate anions therefore possessed the combined qualities of [N(CN)2]
(i.e. hydrogen bonding) and [NTf2] (i.e. hydrophobicity) anions. The
melting temperature of the ILs containing longer chain anions
[C10SO4]ꢀ and [C18SO4]ꢀ were higher than the 1st generation ILs,
and as such, it was not possible to accurately measure drug solubility
at room temperature. However, danazol solubility in the [C6SO4]ꢀ
derivative, which was liquid at 37 1C, was high (88.9 mg gꢀ1) and
similar to that of the 1st generation ILs containing [N(CN)2]ꢀ.
[hhcpy][NTf2] and [hhcpy][N(CN)2] from the 1st generation series
and [C8mbpy][C10SO4] and [C8mbpy][C18SO4] from the 2nd generation
ILs were progressed into in vitro studies to assess their potential as
components of oral drug delivery systems. ILs were incorporated into
formulations modeled on contemporary lipid formulations that
emulsify spontaneously on contact with the GI fluids (so called self-
emulsifying drug delivery systems or SEDDS) and improve the oral
bioavailability of many poorly water-soluble drugs.17 Formulations
(described in Table S1, ESI†) were loaded with danazol, and the
respective solubilization properties assessed after dispersion in simu-
lated gastric and intestinal fluids. With the exception of SEDDSN(CN)
2
(the dispersion of which resulted in drug crystallization), the
other IL-SEDDS were highly effective in maintaining danazol in a
solubilized form in vitro. Danazol absorption in rats was therefore
assessed after administration of SEDDS based on ILs comprising
[hhcpy][NTf2] and [C8mbpy][C10SO4] and [C8mbpy][C18SO4] (SEDDSNTf
,
2
Fig. 1 (A) Fine tuning the IL cation structure to optimize danazol solubility.
[hhcpy][NTf2] (shaded grey) was selected for further study. (B) Solubility of
danazol, itraconazole and fenofibrate in IL comprising the [hhcpy]+ cation
and triflimide [NTf2]ꢀ or dicyanamide [N(CN)2]ꢀ anions in comparison to
solubility in soybean oil (SBO). Values in (A) are expressed as means (n = 3),
and in (B), as means (n = 3) ꢁ1 SD.
SEDDSC SO , SEDDSC SO ). A ‘gold standard’ lipid-based formulation
10
4
18
4
(SEDDSlipid) was also explored as was a crystalline danazol suspension.
The plasma concentration profiles for danazol after administration
of each formulation are shown in Fig. 2A and total danazol exposure
(the area under the plasma concentration curves) in Fig. 2B
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was some evidence of submucosal inflammation in the non-
glandular region of the stomach, suggesting the possibility of
some local irritancy.
In summary, custom-made ILs have been synthesized that show
great promise as improved drug delivery vehicles for poorly water-
soluble drugs. IL-based SEDDS have many potential advantages
including high drug loading capacity, facile dispersion in GI fluids,
insensitivity to GI digestive processes and in some cases the ability to
increase and extend drug absorption profiles. The flexibility of the IL
synthetic platform provides particular attraction and subsequent
studies will explore the potential for individually tailored drug
delivery systems for drugs with widely differing, but problematic,
physicochemical properties.
This work was partially funded by the ARC Centre of
Excellence for Free Radical Chemistry and Biotechnology. The
authors also acknowledge Dr Mette Anby and Miss Orlagh Feeney
for assistance during mass spectrometry analysis of rat plasma
samples and Prof. Rob Singer for helpful discussions.
Fig. 2 Ionic liquids enhance and sustain drug absorption. (A) Danazol
plasma concentrations after oral administration of 25 mg kgꢀ1 danazol to
rats in IL- or lipid-containing SEDDS or as a suspension formulation. Mean
(n Z 4) ꢁ SEM. (B) Total danazol exposure (AUC) over 8 h. Mean (n Z 4) ꢁ
SEM. % statistically significant (p o 0.05) relative to the suspension. Total
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exposure of danazol after administration in the SEDDSC
IL formula-
CO
18
4
tion was similar to that of the ‘gold standard’ SEDDS lipid formulation, but
with pronounced evidence of sustained plasma concentrations.
(see ESI,† Table S2 for all pharmacokinetic results). The SEDDSlipid
resulted in danazol exposure of 498.3 ꢁ 149.8 ng h mLꢀ1 over 8 h,
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exposure, highlighting the benefit of administering a poorly water-
soluble drug in a lipid formulation. Danazol plasma concentrations
after administration of SEDDSNTf , and SEDDSC SO , were also low
2
10
4
despite these formulations containing drug in the pre-dissolved form.
The exposure obtained for SEDDSC SO , however, was much
18
4
improved, and consistent with that of the SEDDSlipid but with
noteworthy evidence of sustained plasma concentrations and the
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of digested lipids (and drug) into intestinal mixed-micelles for
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are not digested. Poor drug absorption from these formulations is
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from SEDDSC SO suggests that this IL system allowed for more
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histological injury. In half of the animals administered SEDDSC SO
,
18
4
no histological damage was evident, however in two animals there
1690 | Chem. Commun., 2014, 50, 1688--1690
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