Ionic liquids for drug delivery

Abstract

To provide a method comprising administering to a subject a composition comprising an ionic liquid that exhibits uptake kinetics of an active compound that does not exhibit toxic side effects and / or does not act as an irritant at the time of delivery, and to provide a composition comprising an ionic liquid.SOLUTION: Provided is a method of administering at least one active compound, comprising administering the active compound in combination with at least one ionic liquid comprising: a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0; and a cation comprising a quaternary ammonium.SELECTED DRAWING: Figure 7

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62 / 828,539, filed April 3, 2019, the contents of which are incorporated by reference herein in their entirety.

[0002] Sequence Listing This application contains a Sequence Listing, which has been submitted electronically in ASCII format and is incorporated by reference herein in its entirety. The ASCII copy created on March 24, 2020 has the file name 002806-094500WOPT_SL.txt and is 2,891 bytes in size.

[0003] Technical Field The technology described herein relates to ionic liquids for the stabilization and delivery of active compounds. [Background technology]

[0004] background The uptake of many active compounds, for example pharmacologic active compounds, can be improved by delivering the compound in a solvent.However, such approaches are often inappropriate for in vivo use, since most of these solvents exhibit toxic side effects and / or act as irritants at the time of delivery.These toxic and irritating effects are serious enough to suppress any increase in the uptake or performance of active compounds. Summary of the Invention

[0005] overview As shown herein, the inventors have identified features of ionic liquids that provide surprisingly superior uptake kinetics of active compounds, and thus, described herein are compositions and methods related to these unexpectedly highly effective ionic liquids (ILs).

[0006] In one aspect of any embodiment, described herein is a method of administering at least one active compound, comprising administering the active compound in combination with at least one ionic liquid (IL) comprising i) a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0; and ii) a cation comprising a quaternary ammonium. In one aspect of any embodiment, described herein is a combination of at least one active compound with at least one ionic liquid (IL) comprising i) a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0; and ii) a cation comprising a quaternary ammonium for use in a drug delivery method.

[0007] In one aspect of any embodiment, described herein is a method of reducing weight / weight gain or treating obesity, diabetes, ulcers, cancer, or fibrosis in a subject in need thereof, comprising administering to the subject a composition comprising at least one ionic liquid comprising i) a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0; and ii) a cation comprising a quaternary ammonium. In one aspect of any embodiment, described herein is a composition comprising at least one ionic liquid comprising i) a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0; and ii) a cation comprising a quaternary ammonium for use in a method of reducing weight / weight gain or treating obesity, diabetes, ulcers, cancer, or fibrosis in a subject in need thereof. In some embodiments, the subject is not administered a therapeutic agent or active compound other than the at least one ionic liquid, and / or the composition does not comprise a therapeutic agent or active compound other than the at least one ionic liquid. In some embodiments, the subject is administered a therapeutic agent or active compound other than at least one ionic liquid (e.g., in the same formulation as the at least one IL or in a separate formulation) and / or the composition further comprises at least one therapeutic agent or active compound other than the at least one ionic liquid.

[0008] In one aspect, provided herein is a composition comprising at least one ionic liquid comprising i) a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0; and ii) a cation comprising a quaternary ammonium. In some embodiments, the composition further comprises a therapeutic agent or active compound in combination with the at least one ionic liquid.

[0009] In some embodiments of any aspect, the anion has a pKa of at least 4.5. In some embodiments of any aspect, the anion has a pKa of at least 5.0. In some embodiments of any aspect, the anion has a LogP of at least 2.0. In some embodiments of any aspect, the anion has a LogP of at least 2.5. In some embodiments of any aspect, the anion has a LogP of at least 2.75.

[0010] In some embodiments of any aspect, the anion comprises a carbon chain backbone of at least 8 carbons. In some embodiments of any aspect, the anion is an alkene. In some embodiments of any aspect, the anion is geranic acid, octanoic acid, or citronellic acid.

[0011] In some embodiments of any aspect, the cation has a molar mass equal to or greater than choline. In some embodiments of any aspect, the cation has a molar mass greater than choline. In some embodiments of any aspect, the quaternary ammonium is NR4 + and at least one R group comprises a hydroxy group. In some embodiments of any aspect, the quaternary ammonium has the structure NR4 + and only one R group contains a hydroxy group. In some embodiments of any aspect, the cation is C1, C6, or C7.

[0012] In some embodiments of any aspect, the cation is selected from choline, C1, C6, and C7, and the anion is citronellic acid. In some embodiments of any aspect, the cation is C1, and the anion is citronellic acid. In some embodiments of any aspect, the cation is selected from C1, C6, and C7, and the anion is geranic acid. In some embodiments of any aspect, the ionic liquid is choline:citronellic acid, C1:geranic acid, or C1:citronellic acid. In some embodiments of any aspect, the ionic liquid is not CAGE.

[0013] In some embodiments of any aspect, the ionic liquid has fewer than 20, fewer than 10, or fewer than 5 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY).

[0014] In some embodiments of any aspect, the administration is transdermal. In some embodiments of any aspect, the administration is transdermal, mucosal, oral, subcutaneous, intradermal, parenteral, intratumoral, or intravenous. In some embodiments of any aspect, the composition or combination is formulated for transdermal administration. In some embodiments of any aspect, the composition or combination is formulated for transdermal, mucosal, oral, subcutaneous, intradermal, parenteral, intratumoral, or intravenous administration. In some embodiments of any aspect, the mucosa is nasal, oral, or vaginal mucosa.

[0015] In some embodiments of any aspect, the ionic liquid is at a concentration of at least 0.1% w / v. In some embodiments of any aspect, the ionic liquid is at a concentration of about 10 to about 70% w / v. In some embodiments of any aspect, the ionic liquid is at a concentration of about 30 to about 50% w / v. In some embodiments of any aspect, the ionic liquid is at a concentration of about 30 to about 40% w / v. In some embodiments of any aspect, the ionic liquid comprises a ratio of cations to anions of about 2:1 to about 1:10. In some embodiments of any aspect, the ionic liquid comprises a ratio of cations to anions of about 1:1 to about 1:4. In some embodiments of any aspect, the ionic liquid comprises a ratio of cations to anions of about 1:2. In some embodiments of any aspect, the ionic liquid has a cation:anion ratio of less than 1:1. In some embodiments of any aspect, the ionic liquid has a cation:anion ratio that includes an excess of anion.

[0016] In some embodiments of any aspect, the active compound is hydrophobic. In some embodiments of any aspect, the active compound is hydrophilic. In some embodiments of any aspect, the active compound comprises a polypeptide. In some embodiments of any aspect, the active compound has a molecular weight greater than 450. In some embodiments of any aspect, the active compound has a molecular weight greater than 500. In some embodiments of any aspect, the active compound comprises an antibody or antibody reagent. In some embodiments of any aspect, the active compound comprises insulin, acarbose, ruxolitinib, or a GLP-1 polypeptide or a mimetic or analog thereof.

[0017] In some embodiments of any aspect, the combination and / or composition is administered once. In some embodiments of any aspect, the combination and / or composition is administered in multiple doses. In some embodiments of any aspect, the active compound and / or composition is provided in a dosage of 1-20 mg / kg.

[0018] In some embodiments of any aspect, the active compound and the ionic liquid are further combined with at least one non-ionic surfactant. In some embodiments of any aspect, the combination and / or composition further comprises an additional pharma- ceutically acceptable carrier. In some embodiments of any aspect, the administration is oral, and the combination and / or composition is provided in a degradable capsule. In some embodiments of any aspect, the combination is an admixture. In some embodiments of any aspect, the combination and / or composition is provided in one or more nanoparticles. In some embodiments of any aspect, the combination is provided in the form of one or more nanoparticles comprising the active compound, and the nanoparticles are in solution or suspension in the composition comprising the ionic liquid. [Brief description of the drawings]

[0019] [Figure 1] Figure 1A shows the chemical structures of choline and geranic acid, and Figure 1B shows a CAGE prepared by salt metathesis of choline bicarbonate and geranic acid in a molar ratio of 1:2. [Diagram 2] Figure 2 shows the two drugs evaluated in this study: acarbose and ruxolitinib. Acarbose was used as a model hydrophilic drug (MW: 646, LogP: -6.8) and ruxolitinib was used as a model hydrophobic drug (MW: 306 and LogP: 2.9). [Diagram 3] Figure 3 shows the amount of acarbose or ruxolitinib delivered into and across the skin after topical application from various CAGE compositions. Both drugs were dissolved in CAGE at a concentration of 1 mg / ml (N=3, error bars are SEM). [Figure 4] Figure 4 shows the anions used as substitutes for geranic acid. The anions were selected to cover a range of molecular weights, pKa and LogP values. [Diagram 5] 5A-5D show the relationship between the overall transport rank of the anion surrogates and (FIG. 5A) the molecular weight, (FIG. 5B) the pKa, (FIG. 5C) the LogP, and (FIG. 5D) the number of carbons in the anion. [Figure 6] Figures 6A-6B show the NOESY spectra of (Figure 6A) choline:citronellic acid and (Figure 6B) choline:glutaric acid. Circled cross peaks indicate portions of the molecule within 5 nm of each other. The number of cross peaks indicates significant differences between the ILs tested. [Figure 7] Figure 7 shows the correlation between transport ranking and the number of NOSEY cross-correlation peaks. NOSEY data for choline:citronellic acid and choline:glutaric acid are from Figures 6A-6B. NOSEY data for other ILs are shown in the SI. Transport rankings and abbreviations are shown in Table 2. [Figure 8] FIG. 8 shows a series of quaternary ammonium salts that were synthesized as cationic replacements for choline. [Figure 9] FIG. 9A shows the transport of ruxolitinib (1 mg / ml) by ionic liquids into different parts of the skin over a 24 hour period (LR, horizontal stripes are C1:citronellic acid, diagonal stripes are C1:geranic acid, solid fill is CAGE, dots are choline:citronellic acid). E is epidermis, D is dermis, A is acceptor fluid. Error bars are SEM (n=3). FIG. 9B shows the 2D NOESY spectrum of C1:citronellic acid showing one cross peak (circle). [Figure 10] FIG. 10 shows the transport of ruxolitinib (1 mg / ml) into different parts of the skin over a 24 hour period by PBS (white columns, not detected) and ionic liquid (2:1 shown as diagonal stripes, 1:1 as solid, 1:2 as horizontal stripes, and 1:4 as dots). E is the epidermis, D is the dermis, and A is the acceptor fluid. Error bars are the mean SE. Note that pure methanol is used to extract ruxolitinib from the skin, but this also extracts significant SC lipids, dwarfing the drug peak seen by HPLC. Therefore, the SC data was excluded from the ruxolitinib analysis. [Figure 11]FIG. 11 shows the transport of acarbose (1 mg / ml) into different parts of the skin over a 24 hour period by PBS (white columns, not detected) and CAGE ionic liquids (2:1 shown as diagonal stripes, 1:1 as solid, 1:2 as horizontal stripes, and 1:4 as dots). SC is the stratum corneum, E is the epidermis, D is the dermis, and A is the acceptor fluid. Error bars are the SE of the mean. [Figure 12] FIG. 12 shows the transport of acarbose by ionic liquids to different parts of the skin over a 24 hour period (LR, solid is CAGE, dots are choline citronellate, downward diagonal lines are choline hexanoate, wavy lines are choline decanoate, horizontal lines are choline salicylate, texture is choline glutarate, confetti is choline glycolate, upward diagonal lines are choline octenoate, and grid is choline octanoate). SC is stratum corneum, E is epidermis, D is dermis, A is acceptor fluid. Error bars are SE of the mean. [Figure 13] FIG. 13 shows the transport of ruxolitinib (1 mg / ml) by ionic liquids to different parts of the skin over a 24 hour period (LR, solid is CAGE, horizontal lines are choline salicylate, texture is choline glutarate, confetti is choline glycolate, dots are choline citronellate, downward diagonal lines are choline hexanoate, wavy lines are choline decanoate, upward diagonal lines are choline octenoate, and grid is choline octanoate). E is epidermis, D is dermis, and A is acceptor fluid. Error bars are SE of the mean. [Figure 14] FIG. 14 shows the 2D NOESY spectrum of choline octenate (1:2). [Figure 15] FIG. 15 shows the 2D NOESY spectrum of choline octanoate (1:2). [Figure 16] FIG. 16 shows the 2D NOESY spectrum of choline decanoate (1:2). [Figure 17] FIG. 17 shows the 2D NOESY spectrum of choline salicylate (1:2). [Figure 18] FIG. 18 shows the 2D NOESY spectrum of choline glycolate (1:2). [Figure 19] FIG. 19 shows the 2D NOESY spectrum of choline hexanoate (1:2). [Figure 20] Figure 20 shows the 2D NOESY spectrum of choline geranate (CAGE, 1:2) (from Tanner et al., 2018). [Figure 21] FIG. 21 shows the 2D NOESY spectrum of choline substitute 1 and geranic acid (1:2). [Figure 22] Figure 22 shows the intestinal administration of insulin and the indicated ionic liquids. Insulin was mixed with the ionic liquid and administered to the intestine. Blood glucose and plasma insulin concentrations were measured. "C-" used in the legend to Figure 22 refers to choline as the cation in the ionic liquid. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Detailed Description The data provided herein show that the anion of an ionic liquid (IL) exerts a major influence on whether an active agent is transported across a biological barrier (e.g., an epithelial layer such as the dermis). Anions with high hydrophobicity and high mass provide improved drug delivery properties than anions with low hydrophobicity and low mass. When selecting a cation to pair with an anion, the main concern is that the cation not be too closely associated with the anion, which would cause the anion to be retained on the first side of the biological barrier.

[0021] Thus, in one aspect of any embodiment, described herein is an ionic liquid comprising: i) a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and / or a LogP of at least 1.0; and ii) a cation comprising a quaternary ammonium. In one aspect of any embodiment, described herein is an active compound in combination with at least one ionic liquid, the ionic liquid comprising: i) a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and / or a LogP of at least 1.0; and ii) a cation comprising a quaternary ammonium. Thus, in one aspect of any embodiment, described herein is a method of administering at least one active compound, comprising administering the active compound in combination with at least one ionic liquid, the ionic liquid comprising: i) a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and / or a LogP of at least 1.0; and ii) a cation comprising a quaternary ammonium.

[0022] The term "ionic liquid (IL)" as used herein refers to an organic salt or mixture of organic salts that are in a liquid state at room temperature. This class of solvents has been shown to be useful in a variety of fields, including industrial processing, catalysis, pharmaceuticals, and electrochemistry. Ionic liquids include at least one anion component and at least one cation component. Ionic liquids can include additional hydrogen bond donors (i.e., any molecule that can provide an -OH or -NH group), examples include, but are not limited to, alcohols, fatty acids, and amines. The at least one anion component and the at least one cation component can be present in any molar ratio. Exemplary molar ratios (cation:anion) include, but are not limited to, 1:1, 1:2, 2:1, 1:3, 3:1, 2:3, 3:2, and ranges between these ratios. For further discussion of ionic liquids, see, e.g., Hough, et al., "The third evolution of ionic liquids: active pharmaceutical ingredients", New Journal of Chemistry, 31:1429 (2007) and Xu, et al., "Ionic Liquids: Ion Mobilities, Glass Temperatures, and Fragilities", Journal of Physical Chemistry B, 107(25):6170-6178 (2003), each of which is incorporated by reference in its entirety. In some embodiments of any aspect, the ionic liquid or solvent exists as a liquid below 100° C. In some embodiments of any aspect, the ionic liquid or solvent exists as a liquid at room temperature.

[0023] As described herein, anions with high hydrophobicity and high mass provide improved drug delivery properties over anions with low hydrophobicity and low mass. In some embodiments of any aspect, the anion of the IL described herein is hydrophobic. In some embodiments of any aspect, the anion of the IL described herein comprises a carboxylate.

[0024] In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least 4.0, e.g., 4.0 or more. In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least 4.5, e.g., 4.5 or more. In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least 5.0, e.g., 5.0 or more. In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least about 4.0, e.g., about 4.0 or more. In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least about 4.5, e.g., about 4.5 or more. In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least about 5.0, e.g., about 5.0 or more.

[0025] In some embodiments of any aspect, the anion has a pKa of at least 4.895. In some embodiments of any aspect, the anion has a pKa of 4.5 to 5.5. In some embodiments of any aspect, the anion has a pKa of 4.895 to 5.19.

[0026] In some embodiments of any aspect, the anion has a pKa of at least about 4.895. In some embodiments of any aspect, the anion has a pKa of about 4.5 to about 5.5. In some embodiments of any aspect, the anion has a pKa of about 4.895 to about 5.19.

[0027] Hydrophobicity may be assessed by analysis of logP. "LogP" refers to the logarithm of P (the partition coefficient). P is a measure of how well a substance partitions between lipids (oils) and water. P itself is a constant. It is defined as the ratio of the concentration of a compound in the aqueous phase to the concentration of the compound in the immiscible solvent, as a neutral molecule. Partition coefficient, P = [organic] / [aqueous], where [ ] = concentration Log P=log 10 (Partition coefficient) = log10 P In practice, LogP values ​​will vary depending on the measurement conditions and the choice of partitioning solvent. A LogP value of 1 means that the concentration of the compound is 10 times higher in the organic phase than in the aqueous phase. An increase in logP value of 1 indicates a 10-fold increase in the compound concentration in the organic phase compared to the aqueous phase.

[0028] In some embodiments of any aspect, the anion of the IL described herein has a LogP of at least 1.0, e.g., 1.0 or more. In some embodiments of any aspect, the anion of the IL described herein has a LogP of at least 2.0, e.g., 2.0 or more. In some embodiments of any aspect, the anion of the IL described herein has a LogP of at least 2.5, e.g., 2.5 or more. In some embodiments of any aspect, the anion of the IL described herein has a LogP of at least 2.75, e.g., 2.75 or more. In some embodiments of any aspect, the anion of the IL described herein has a LogP of at least about 1.0, e.g., about 1.0 or more. In some embodiments of any aspect, the anion of the IL described herein has a LogP of at least about 2.0, e.g., about 2.0 or more. In some embodiments of any aspect, the anion of the IL described herein has a LogP of at least about 2.5, e.g., about 2.5 or more. In some embodiments of any aspect, the anion of an IL described herein has a LogP of at least about 2.75, such as about 2.75 or greater.

[0029] In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least 4.0 and a LogP of at least 1.0. In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least 4.0 and a LogP of at least 2.0. In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least 4.0 and a LogP of at least 2.5. In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least 4.0 and a LogP of at least 2.75.

[0030] In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least 4.5 and a LogP of at least 1.0. In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least 4.5 and a LogP of at least 2.0. In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least 4.5 and a LogP of at least 2.5. In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least 4.5 and a LogP of at least 2.75.

[0031] In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least 5.0 and a LogP of at least 1.0. In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least 5.0 and a LogP of at least 2.0. In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least 5.0 and a LogP of at least 2.5. In some embodiments of any aspect, the anion of the IL described herein has a pKa of at least 5.0 and a LogP of at least 2.75.

[0032] In some embodiments of any aspect, the anion has a LogP of at least 2.75. In some embodiments of any aspect, the anion has a LogP of at least 2.8. In some embodiments of any aspect, the anion has a LogP of 2.5 to 3.5. In some embodiments of any aspect, the anion has a LogP of 2.8 to 3.01.

[0033] In some embodiments of any aspect, the anion has a LogP of at least about 2.75. In some embodiments of any aspect, the anion has a LogP of at least about 2.8. In some embodiments of any aspect, the anion has a LogP of about 2.5 to about 3.5. In some embodiments of any aspect, the anion has a LogP of about 2.8 to about 3.01.

[0034] In some embodiments of any aspect, the carboxylic acid comprises a carbon backbone chain having 8 carbons and has a Log P of 2.8 or greater and a pKa between 4.8 and 5.2. In some embodiments of any aspect, the carboxylic acid has a Log P of 2.9 or greater and a pKa between 4.8 and 5.1.

[0035] The pKa and LogP values ​​of anions are known in the art and / or can be calculated by those skilled in the art. For example, PubChem and SpiderChem provide these values ​​for various anions, and chemical manufacturers typically provide them as part of their product catalog listings. The pKa and LogP values ​​of exemplary anions are provided in Table 5 herein.

[0036] In some embodiments of any aspect, the carboxylic acid comprises a carbon chain of at least 6 carbons. In some embodiments of any aspect, the carboxylic acid comprises a carbon chain of at least 7 carbons. In some embodiments of any aspect, the carboxylic acid comprises a carbon chain of at least 8 carbons. In some embodiments of any aspect, the carboxylic acid comprises a carbon chain of at least 9 carbons. In some embodiments of any aspect, the carboxylic acid comprises a carbon chain of at least 10 carbons. In some embodiments of any aspect, the carboxylic acid comprises a carbon chain of at least 11 carbons.

[0037] In some embodiments of any aspect, the anion is an alkane. In some embodiments of any aspect, the anion is an alkene. In some embodiments of any aspect, the anion comprises a single carboxyl group. In some embodiments of any aspect, the carbon chain of the carboxylic acid comprises one or more substituents. In some embodiments of any aspect, the carbon chain backbone of the carboxylic acid comprises one or more substituents, where each substituent comprises at least one carbon atom. In some embodiments of any aspect, the carbon chain backbone of the carboxylic acid comprises one or more substituents, where at least one substituent comprises a methyl group. In some embodiments of any aspect, the carbon chain backbone of the carboxylic acid comprises two substituents, where each substituent comprises at least one carbon atom. In some embodiments of any aspect, the carbon chain backbone of the carboxylic acid comprises two substituents, where one substituent comprises a methyl group. In some embodiments of any aspect, the carbon chain backbone of the carboxylic acid comprises two substituents, where each substituent comprises a methyl group.

[0038] In some embodiments of any aspect, the anion is an unsubstituted alkane. In some embodiments of any aspect, the anion is an unsubstituted alkene. In some embodiments of any aspect, the carbon chain backbone of the carboxylic acid comprises one or more substituents. In some embodiments of any aspect, the carbon chain of the carboxylic acid comprises one or more substituents, where each substituent comprises at least one carbon atom. In some embodiments of any aspect, the carbon chain of the carboxylic acid comprises one or more substituents, where each substituent is an alkyl, aryl, heteroalkyl, heteroaryl, alkane, or alkene. In some embodiments of any aspect, the carbon chain of the carboxylic acid comprises one or more substituents, where each substituent is an unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroalkyl, unsubstituted heteroaryl, unsubstituted alkane, or unsubstituted alkene.

[0039] In some embodiments of any aspect, the carboxylic acid comprises a carbon backbone chain having 8 carbons, is optionally a monoalkene, and optionally has two substituents. In some embodiments of any aspect, at least one of the substituents is a methyl group. In some embodiments of any aspect, both substituents are methyl groups. In some embodiments of any aspect, the carboxylic acid is selected from the group consisting of: octanoic acid; 2-octenoic acid; 3-octenoic acid; 4-octenoic acid; 5-octenoic acid; 6-octenoic acid; 7-octenoic acid; 2,2-dimethyloctanoic acid; 2,3-dimethyloctanoic acid; 2,4-dimethyloctanoic acid; 2,5-dimethyloctanoic acid; 2,6-dimethyloctanoic acid; 2,7-dimethyloctanoic acid; 3,3-dimethyloctanoic acid; 3,4-dimethyloctanoic acid; 3,5-dimethyloctanoic acid. dimethyloctanoic acid;3,6-dimethyloctanoic acid;3,7-dimethyloctanoic acid;4,4-dimethyloctanoic acid;4,5-dimethyloctanoic acid;4,6-dimethyloctanoic acid;4,7-dimethyloctanoic acid;5,5-dimethyloctanoic acid;5,6-dimethyloctanoic acid;5,7-dimethyloctanoic acid;6,6-dimethyloctanoic acid;6,7-dimethyloctanoic acid;7,7-dimethyloctanoic acid;2,3-dimethyl-2-octenoic acid;2,4-dimethyl-2-octenoic acid;2, 5-Dimethyl-2-octenoic acid;2,6-Dimethyl-2-octenoic acid;2,7-Dimethyl-2-octenoic acid;3,4-Dimethyl-2-octenoic acid;3,5-Dimethyl-2-octenoic acid;3,6-Dimethyl-2-octenoic acid;3,7-Dimethyl-2-octenoic acid;4,4-Dimethyl-2-octenoic acid;4,5-Dimethyl-2-octenoic acid;4,6-Dimethyl-2-octenoic acid;4,7-Dimethyl-2-octenoic acid;5,5-Dimethyl-2-octenoic acid;5,6-Dimethyl- 2-Octenoic acid;5,7-dimethyl-2-octenoic acid;6,6-dimethyl-2-octenoic acid;6,7-dimethyl-2-octenoic acid, 7,7-dimethyl-2-octenoic acid;2,2-dimethyl-3-octenoic acid;2,3-dimethyl-3-octenoic acid;2,4-dimethyl-3-octenoic acid;2,5-dimethyl-3-octenoic acid;2,6-dimethyl-3-octenoic acid;2,7-dimethyl-3-octenoic acid;3,4-dimethyl-3-octenoic acid;3,5-dimethyl-3-octenoic acid;3,6-Dimethyl-3-octenoic acid;3,7-Dimethyl-3-octenoic acid;4,5-Dimethyl-3-octenoic acid;4,6-Dimethyl-3-octenoic acid;4,7-Dimethyl-3-octenoic acid;5,5-Dimethyl-3-octenoic acid;5,6-Dimethyl-3-octenoic acid;5,7-Dimethyl-3-octenoic acid;6,6-Dimethyl-3-octenoic acid;6,7-Dimethyl-3-octenoic acid;7,7-Dimethyl-3-octenoic acid;2,2-Dimethyl-4-octenoic acid;2,3-Dimethyl-4-octenoic acid;2,4-Dimethyl-4-octenoic acid;2,5-Dimethyl -4-Octenoic acid;2,6-dimethyl-4-octenoic acid;2,7-dimethyl-4-octenoic acid;3,3-dimethyl-4-octenoic acid;3,4-dimethyl-4-octenoic acid;3,5-dimethyl-4-octenoic acid;3,6-dimethyl-4-octenoic acid;3,7-dimethyl-4-octenoic acid;4,5-dimethyl-4-octenoic acid;4,6-dimethyl-4-octenoic acid;4,7-dimethyl-4-octenoic acid;5,6-dimethyl-4-octenoic acid;5,7-dimethyl-4-octenoic acid;6,6-dimethyl-4-octenoic acid;6,7-dimethyl-4-octenoic acid; 7,7-Dimethyl-4-octenoic acid;2,2-Dimethyl-5-octenoic acid;2,3-Dimethyl-5-octenoic acid;2,4-Dimethyl-5-octenoic acid;2,5-Dimethyl-5-octenoic acid;2,6-Dimethyl-5-octenoic acid;2,7-Dimethyl-5-octenoic acid;3,3-Dimethyl-5-octenoic acid;3,4-Dimethyl-5-octenoic acid;3,5-Dimethyl-5-octenoic acid;3,6-Dimethyl-5-octenoic acid;3,7-Dimethyl-5-octenoic acid;4,4-Dimethyl-5-octenoic acid;4,5-Dimethyl-5-octenoic acid;4,6-Dimethyl -5-Octenoic acid;4,7-dimethyl-5-octenoic acid;5,6-dimethyl-5-octenoic acid;5,7-dimethyl-5-octenoic acid;6,7-dimethyl-5-octenoic acid;7,7-dimethyl-5-octenoic acid;2,2-dimethyl-6-octenoic acid;2,3-dimethyl-6-octenoic acid;2,4-dimethyl-6-octenoic acid;2,5-dimethyl-6-octenoic acid;2,6-dimethyl-6-octenoic acid;2,7-dimethyl-6-octenoic acid;3,3-dimethyl-6-octenoic acid;3,4-dimethyl-6-octenoic acid;3,5-dimethyl-6-octenoic acid;3,6-Dimethyl-6-octenoic acid;3,7-Dimethyl-6-octenoic acid (citranelic acid);4,4-Dimethyl-6-octenoic acid;4,5-Dimethyl-6-octenoic acid;4,6-Dimethyl-6-octenoic acid;4,7-Dimethyl-6-octenoic acid;5,5-Dimethyl-6-octenoic acid;5,6-Dimethyl-6-octenoic acid;5,7-Dimethyl-6-octenoic acid;6,7-Dimethyl-6-octenoic acid;2,2-Dimethyl-7-octenoic acid;2,3-Dimethyl-7-octenoic acid;2,4-Dimethyl-7-octenoic acid;2,5-Dimethyl-7-octenoic acid;2,6-Dimethyl-7-octenoic acid; 2,7-Dimethyl-7-octenoic acid; 4,4-Dimethyl-7-octenoic acid; 3,4-Dimethyl-7-octenoic acid; 3,5-Dimethyl-7-octenoic acid; 3,6-Dimethyl-7-octenoic acid; 3,7-Dimethyl-7-octenoic acid; 4,4-Dimethyl-7-octenoic acid; 4,5-Dimethyl-7-octenoic acid; 4,6-Dimethyl-7-octenoic acid; 4,7-Dimethyl-7-octenoic acid; 5,5-Dimethyl-7-octenoic acid; 5,6-Dimethyl-7-octenoic acid; 5,7-Dimethyl-7-octenoic acid; 6,6-Dimethyl-7-octenoic acid; 6,7-Dimethyl-7-octenoic acid; and its isomers. In some embodiments of any aspect, the carboxylic acid is selected from the group consisting of: octanoic acid; 2-octenoic acid; 3-octenoic acid; 4-octenoic acid; 5-octenoic acid; 6-octenoic acid; 7-octenoic acid; 2,2-dimethyloctanoic acid; 2,4-dimethyloctanoic acid; 2,5-dimethyloctanoic acid; 2,6-dimethyloctanoic acid; 2,7-dimethyloctanoic acid; 3,3-dimethyloctanoic acid; 3,5-dimethyloctanoic acid; 3,6-dimethyloctanoic acid; 3,7-dimethyloctanoic acid; 4,4-dimethyloctanoic acid. tanoic acid;4,5-dimethyloctanoic acid;4,6-dimethyloctanoic acid;5,5-dimethyloctanoic acid;5,6-dimethyloctanoic acid;5,7-dimethyloctanoic acid;6,6-dimethyloctanoic acid;7,7-dimethyloctanoic acid;3,7-dimethyl-2-octenoic acid;3,7-dimethyl-3-octenoic acid;3,7-dimethyl-4-octenoic acid;2,7-dimethyl-6-octenoic acid;3,7-dimethyl-6-octenoic acid (citranelic acid);2,2-dimethyl-7-octenoic acid;2,3-dimethyl-7-octenoic acid;and isomers thereof. In some embodiments of any aspect, the carboxylic acid is selected from the group consisting of citranelic acid, octanoic acid, 2-octenoic acid, and isomers thereof. In some embodiments of any aspect, the carboxylic acid is selected from the group consisting of citranelic acid, octanoic acid, or trans-2-octenoic acid. In some embodiments of any aspect, octenoic acid as used herein (e.g., Table 5) refers to trans-2-octenoic acid;

[0040] In some embodiments of any aspect, the carboxylic acid comprises a carbon backbone chain having 8 carbons, and is optionally a monoalkene. In some embodiments of any aspect, the carbon backbone chain of the carboxylic acid is unsubstituted. In some embodiments of any aspect, the carboxylic acid is selected from the group consisting of octanoic acid, 2-octenoic acid, 3-octenoic acid, 4-octenoic acid, 5-octenoic acid, 6-octenoic acid, 7-octenoic acid, and isomers thereof. In some alternatives, the carboxylic acid is octanoic acid or trans-2-octenoic acid (octenoic acid).

[0041] Exemplary, non-limiting anions are provided in Table 5 below.

[0042] (Table 5) TIFF2025069232000002.tif213164

[0043] In some embodiments of any aspect, the anion is selected from Table 5. In some embodiments of any aspect, the anion is selected from Group 1 of Table 5. In some embodiments of any aspect, the anion is selected from Group 2 of Table 5. In some embodiments of any aspect, the anion is selected from Group 3 of Table 5. In some embodiments of any aspect, the anion is selected from Group 4 of Table 5. In some embodiments of any aspect, the anion is selected from Group 5 of Table 5. In some embodiments of any aspect, the anion is selected from Group 6 of Table 5. In some embodiments of any aspect, the anion is selected from Group 7 of Table 5. In some embodiments of any aspect, the anion is selected from Group 8 of Table 5. In some embodiments of any aspect, the anion is selected from Groups 1-2 of Table 5. In some embodiments of any aspect, the anion is selected from Groups 1-3 of Table 5. In some embodiments of any aspect, the anion is selected from Groups 1-4 of Table 5. In some embodiments of any aspect, the anion is selected from Groups 1-5 of Table 5. In some embodiments of any aspect, the anion is selected from Groups 1-6 of Table 5. In some embodiments of any aspect, the anion is selected from Groups 1-7 of Table 5. In some embodiments of any aspect, the anion is selected from Group 9 of Table 5. In some embodiments of any aspect, the anion is selected from Group 10 of Table 5. In some embodiments of any aspect, the anion is selected from Groups 9-10 of Table 5.

[0044] In some embodiments of any aspect, the anion is geranic acid, octanoic acid, and / or citronellic acid. In some embodiments of any aspect, the anion is geranic acid. In some embodiments of any aspect, the anion is octanoic acid. In some embodiments of any aspect, the anion is citronellic acid. In some embodiments of any aspect, the anion comprises an 8-carbon backbone carbon chain. In some embodiments of any aspect, the anion is geranic acid, octenic acid, octanoic acid, or citronellic acid. In some embodiments of any aspect, the anion is octenic acid, octanoic acid, or citronellic acid.

[0045] As described herein, when selecting a cation to pair with an anion, the main concern is that the cation not be too closely associated with the anion, which would cause the anion to be retained on the first side of the biological barrier. Choline and its derivatives have been shown to be particularly suitable as IL cations for the types of anions described herein. Thus, the cations of the ILs described herein can be cations that contain quaternary ammonium. Quaternary ammonions have the structure NR4 + where each R is independently an alkyl or aryl group.

[0046] In some embodiments of any aspect, the cation has a molar mass equal to or greater than choline, for example, equal to or greater than 104.1708 g / mol. In some embodiments of any aspect, the cation has a molar mass greater than choline, for example, equal to or greater than 104.1708 g / mol.

[0047] In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises an alkyl, alkane, alkene, or aryl. In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises an alkyl, alkane, or alkene. In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises an alkane or alkene. In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises a carbon chain of 10 carbon atoms or less in length, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 30 carbon atoms or less in length. In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises a carbon chain of 12 carbon atoms or less in length. In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises a carbon chain of 15 carbon atoms or less in length. In some embodiments of any aspect, each R group of the quaternary ammonium independently includes a carbon chain no greater than 20 carbon atoms in length.

[0048] In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises a carbon chain of 10 carbon atoms or less, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 30 carbon atoms or less. In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises a carbon chain of 12 carbon atoms or less. In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises a carbon chain of 15 carbon atoms or less. In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises a carbon chain of 20 carbon atoms or less.

[0049] In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises an alkyl group of 10 carbon atoms or less, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 30 carbon atoms or less. In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises an alkyl group of 12 carbon atoms or less. In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises an alkyl group of 15 carbon atoms or less. In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises an alkyl group of 20 carbon atoms or less.

[0050] In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises an alkane, an alkene, an aryl, a heteroaryl, an alkyl, or a heteroalkyl. In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises an unsubstituted alkane, an unsubstituted alkene, an unsubstituted aryl, an unsubstituted heteroaryl, an unsubstituted alkyl, or an unsubstituted heteroalkyl. In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises an unsubstituted alkane. In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises an unsubstituted alkane. In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises an unsubstituted alkene. In some embodiments of any aspect, each R group of the quaternary ammonium independently comprises one or more substituents.

[0051] In some embodiments of any aspect, at least one R group of the quaternary ammonium includes a hydroxy group. In some embodiments of any aspect, one R group of the quaternary ammonium includes a hydroxy group. In some embodiments of any aspect, only one R group of the quaternary ammonium includes a hydroxy group.

[0052] Exemplary, non-limiting cations can include choline and any of the cations designated C1-C7 as defined by the following structure: TIFF2025069232000003.tif113128

[0053] Further non-limiting examples of cations include: 1-(hydroxymethyl)-1-methylpyrrolidin-1-ium 1-(2-hydroxyethyl)-1-methylpyrrolidin-1-ium 1-Ethyl-1-(3-hydroxypropyl)pyrrolidin-1-ium 1-(3-hydroxypropyl)-1-methylpyrrolidin-1-ium 1-(4-hydroxybutyl)-1-methylpyrrolidin-1-ium 1-Ethyl-1-(4-hydroxybutyl)pyrrolidin-1-ium 1-(4-hydroxybutyl)-1-propylpyrrolidin-1-ium 1-(5-hydroxypentyl)-1-propylpyrrolidin-1-ium 1-Ethyl-1-(5-hydroxypentyl)pyrrolidin-1-ium 1-(5-hydroxypentyl)-1-methylpyrrolidin-1-ium 1-(hydroxymethyl)-1-methylpiperidin-1-ium 1-(2-hydroxyethyl)-1-methylpiperidin-1-ium 1-Ethyl-1-(2-hydroxyethyl)piperidin-1-ium 1-Ethyl-1-(3-hydroxypropyl)piperidin-1-ium 1-(3-hydroxypropyl)-1-propylpiperidin-1-ium 1-(3-hydroxypropyl)-1-methylpiperidin-1-ium 1-(4-hydroxybutyl)-1-methylpiperidin-1-ium 1-Ethyl-1-(4-hydroxybutyl)piperidin-1-ium 1-(4-hydroxybutyl)-1-propylpiperidin-1-ium 1-Butyl-1-(5-hydroxypentyl)piperidin-1-ium 1-(5-hydroxypentyl)-1-propylpiperidin-1-ium 1-Ethyl-1-(5-hydroxypentyl)piperidin-1-ium 1-(5-hydroxypentyl)-1-methylpiperidin-1-ium 3-Ethyl-1-methyl-1H-imidazol-3-ium 1-Methyl-3-propyl-1H-imidazol-3-ium 3-Butyl-1-methyl-1H-imidazol-3-ium 1-Methyl-3-pentyl-1H-imidazol-3-ium 1,2-Dimethyl-3-pentyl-1H-imidazol-3-ium 3-Butyl-1,2-dimethyl-1H-imidazol-3-ium 1,2-Dimethyl-3-propyl-1H-imidazol-3-ium 3-(hydroxymethyl)-1,2-dimethyl-1H-imidazol-3-ium 3-(2-hydroxyethyl)-1,2-dimethyl-1H-imidazol-3-ium 3-(3-hydroxypropyl)-1,2-dimethyl-1H-imidazol-3-ium 3-(4-hydroxybutyl)-1,2-dimethyl-1H-imidazol-3-ium 3-(5-hydroxypentyl)-1,2-dimethyl-1H-imidazol-3-ium 3-(5-hydroxypentyl)-1-methyl-1H-imidazol-3-ium 3-(4-hydroxybutyl)-1-methyl-1H-imidazol-3-ium 3-(3-hydroxypropyl)-1-methyl-1H-imidazol-3-ium 3-(2-hydroxyethyl)-1-methyl-1H-imidazol-3-ium 3-(Hydroxymethyl)-1,2,4,5-tetramethyl-1H-imidazol-3-ium 3-(2-hydroxyethyl)-1,2,4,5-tetramethyl-1H-imidazol-3-ium 3-(3-hydroxypropyl)-1,2,4,5-tetramethyl-1H-imidazol-3-ium 3-(4-hydroxybutyl)-1,2,4,5-tetramethyl-1H-imidazol-3-ium 3-(5-hydroxypentyl)-1,2,4,5-tetramethyl-1H-imidazol-3-ium 1-(5-hydroxypentyl)pyridin-1-ium 1-(4-hydroxybutyl)pyridin-1-ium 1-(3-hydroxypropyl)pyridin-1-ium 1-(2-hydroxyethyl)pyridin-1-ium 1-(Hydroxymethyl)pyridin-1-ium 1-Hydroxypyridin-1-ium (Hydroxymethyl)trimethylphosphonium Triethyl(hydroxymethyl)phosphonium Triethyl(2-hydroxyethyl)phosphonium (2-hydroxyethyl)tripropylphosphonium (3-Hydroxypropyl)tripropylphosphonium Tributyl(3-hydroxypropyl)phosphonium (3-Hydroxypropyl)tripentylphosphonium (4-Hydroxybutyl)tripentylphosphonium (5-Hydroxypentyl)tripentylphosphonium

[0054] In some embodiments of any aspect, the cation is choline, C1, C6, and / or C7. In some embodiments of any aspect, the cation is C1, C6, and / or C7.

[0055] In some embodiments of any aspect, the cation is selected from choline, C1, C6, and / or C7, and the anion is citronellic acid. In some embodiments of any aspect, the cation is choline and the anion is citronellic acid. In some embodiments of any aspect, the cation is C1 and the anion is citronellic acid. In some embodiments of any aspect, the cation is C6 and the anion is citronellic acid. In some embodiments of any aspect, the cation is C7 and the anion is citronellic acid.

[0056] In some embodiments of any aspect, the cation is selected from C1, C6, and / or C7 and the anion is geranic acid. In some embodiments of any aspect, the cation is C1 and the anion is geranic acid. In some embodiments of any aspect, the cation is C6 and the anion is geranic acid. In some embodiments of any aspect, the cation is C7 and the anion is geranic acid.

[0057] In some embodiments of any aspect, the cation is selected from choline, C1, C6, and / or C7, and the anion is octanoic acid. In some embodiments of any aspect, the cation is choline and the anion is octanoic acid. In some embodiments of any aspect, the cation is C1 and the anion is octanoic acid. In some embodiments of any aspect, the cation is C6 and the anion is octanoic acid. In some embodiments of any aspect, the cation is C7 and the anion is octanoic acid.

[0058] In some embodiments of any aspect, the cation is selected from choline, C1, C6, and C7, and the anion is selected from citronellic acid, octanoic acid, and octenoic acid. In some embodiments of any aspect, the cation is choline, and the anion is selected from citronellic acid, octanoic acid, and octenoic acid. In some embodiments of any aspect, the ionic liquid is choline:citronellic acid, choline:octanoic acid, or choline:octenoic acid.

[0059] In some embodiments of any aspect, the octenoic acid is 2-octenoic acid.

[0060] Non-limiting exemplary combinations of cations and anions are provided in Table 6 below.

[0061] (Table 6) TIFF2025069232000004.tif180152

[0062] In some embodiments of any aspect, the ionic liquid is not CAGE (Choline And GEranate). In some embodiments of any aspect, the cation of the ionic liquid is not choline. In some embodiments of any aspect, the anion of the ionic liquid is not geranate or geranic acid.

[0063] As shown herein, the number of cross peaks measured by nuclear Overhauser effect spectroscopy (NOESY) for a given IL correlates with its performance in drug delivery, with fewer cross peaks indicating better drug delivery performance. Essentially, the number of cross peaks indicates intramolecular interactions between ions mediated by protons. That is, each in-phase peak (same color as the 1D diagonal line) indicates that the molecules are within 5 nm of each other as an average throughout the liquid. In some embodiments of any aspect, the method described herein further comprises measuring the number of cross peaks of one or more ILs by NOESY. In some embodiments of any aspect, the ionic liquids described herein have less than 20 cross peaks as measured by nuclear Overhauser effect spectroscopy (NOESY), e.g., less than 20, less than 15, less than 10, less than 9, less than 8, less than 7, less than 6, or less than 5 cross peaks. In some embodiments of any aspect, the ionic liquids described herein have less than 10 cross peaks as measured by nuclear Overhauser effect spectroscopy (NOESY). In some embodiments of any aspect, the ionic liquids described herein have fewer than 5 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY). Methods for performing NOESY are known in the art and are described in the Examples herein.

[0064] In one aspect of any embodiment, provided herein is a method for designing, selecting, and / or identifying an ionic liquid. The ionic liquid can be designed, selected, and / or identified for administration, administration by a specific route (e.g., transdermal, mucosal, oral, subcutaneous, intradermal, parenteral, intratumoral, or intravenous), and / or delivery or administration of one or more active compounds. As described herein, an ionic liquid is most favorable for administration, administration by a specific route (e.g., transdermal, mucosal, oral, subcutaneous, intradermal, parenteral, intratumoral, or intravenous), and / or delivery or administration of one or more active compounds when the ionic interaction of the cation and anion is reduced. Thus, a pair of cations and anions that minimizes ionic interaction can be selected. For example, a pair can be selected to minimize the interaction below a threshold provided herein, minimize the interaction below a reference level, and / or provide the most minimized cation and anion of any pair combination of cations and anions from a pool or cations and anions.

[0065] Thus, in one aspect of any embodiment, provided herein is a method for designing and / or identifying an ionic liquid comprising two ions, one ion being a cation and the other anion, comprising the steps of: In the first option: a. selecting one of the two ions of the ionic liquid; and b. selecting the other ion to minimize ion-ion interactions; In the second option: a. selecting a cation; and b. selecting the anion to minimize ionic interactions; or In the third option: a. selecting an anion; and b. Selecting cations to minimize ionic interactions.

[0066] In one aspect of any embodiment, provided herein is a method for designing and / or identifying an ionic liquid comprising two ions, one ion being a cation and the other anion, from a pool of candidate cations and a pool of candidate anions, the method comprising the steps of: In the first option: a. selecting one of two ions of the ionic liquid from a pool of candidate ions; and b. selecting from the other pool of candidate ions an ion that best minimizes ion-ion interactions with the ion selected in step a; In the second option: a. selecting a cation from a pool of candidate cations; b. selecting from the pool of candidate anions the anion that best minimizes ionic interactions with the cation selected in step a; or In the third option: a. selecting a cation from a pool of candidate anions; b. selecting from the pool of candidate cations the anion that best minimizes ionic interactions with the anion selected in step a.

[0067] In some embodiments of any aspect, an ionic liquid with minimal ion-ion interactions has fewer than 20 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY), e.g., fewer than 20, fewer than 15, fewer than 10, fewer than 9, fewer than 8, fewer than 7, fewer than 6, or fewer than 5 cross peaks. In some embodiments of any aspect, an ionic liquid with minimal ion-ion interactions has fewer than 10 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY). In some embodiments of any aspect, an ionic liquid with minimal ion-ion interactions has fewer than 5 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY).

[0068] In some embodiments of any aspect, the IL is at a concentration of at least 0.01% w / v. In some embodiments of any aspect, the IL is at a concentration of at least 0.05% w / v. In some embodiments of any aspect, the IL is at a concentration of at least 0.1% w / v. In some embodiments of any aspect, the IL is at a concentration of at least 0.2% w / v, at least 0.3% w / v, at least 0.4% w / v, at least 0.5% w / v, at least 1% w / v or more. In some embodiments of any aspect, the IL is at a concentration of about 0.01% w / v to about 1% w / v. In some embodiments of any aspect, the IL is at a concentration of 0.01% w / v to 1% w / v. In some embodiments of any aspect, the IL is at a concentration of about 0.05% w / v to about 0.5% w / v. In some embodiments of any aspect, the IL is at a concentration of 0.05% w / v to 0.5% w / v.

[0069] In some embodiments of any aspect, the IL is at a concentration of at least 25% w / w. In some embodiments of any aspect, the IL is at a concentration of at least 25% w / w in water. In some embodiments of any aspect, the IL is at a concentration of at least 25% w / w in saline or a physiologically compatible buffer.

[0070] In some embodiments of any aspect, the IL is at a concentration of about 5% w / w to about 75% w / w. In some embodiments of any aspect, the IL is at a concentration of 5% w / w to 75% w / w. In some embodiments of any aspect, the IL is at a concentration of about 5% w / w to about 75% w / w in water, saline, or a physiologically compatible buffer. In some embodiments of any aspect, the IL is at a concentration of 5% w / w to 75% w / w in water, saline, or a physiologically compatible buffer.

[0071] In some embodiments of any aspect, the IL is at a concentration of at least about 0.1% w / w. In some embodiments of any aspect, the IL is at a concentration of at least 0.1% w / w. In some embodiments of any aspect, the IL is at a concentration of about 10% w / w to about 70% w / w. In some embodiments of any aspect, the IL is at a concentration of 10% w / w to 70% w / w. In some embodiments of any aspect, the IL is at a concentration of about 30% w / w to about 50% w / w. In some embodiments of any aspect, the IL is at a concentration of 30% w / w to 40% w / w. In some embodiments of any aspect, the IL is at a concentration of about 30% w / w to about 50% w / w. In some embodiments of any aspect, the IL is at a concentration of 30% w / w to 40% w / w.

[0072] In some embodiments of any aspect, the % w / w concentration of the IL is the % w / w concentration in water, saline, or a physiologically compatible buffer.

[0073] In some embodiments of any aspect, the IL is 100% w / w or 100% w / v.

[0074] In some embodiments, the IL is an anhydrous salt, e.g., an ionic liquid that is not diluted or dissolved in water. In some embodiments, the IL is provided as an aqueous solution.

[0075] In some embodiments of any aspect, the IL is at a concentration of at least 25% w / w and has a cation:anion ratio of at least 1:3. In some embodiments of any aspect, the IL is at a concentration of at least 25% w / w in water and has a cation:anion ratio of at least 1:3. In some embodiments of any aspect, the IL is at a concentration of at least 25% w / w and has a cation:anion ratio of 1:3 or 1:4. In some embodiments of any aspect, the IL is at a concentration of at least 25% w / w in water and has a cation:anion ratio of 1:3 or 1:4. In some embodiments of any aspect, the IL is a gel, or a shear-thinning Newtonian gel.

[0076] In some embodiments of any aspect, the IL has a cation:anion ratio of about 10:1 to about 1:10. In some embodiments of any aspect, the IL has a cation:anion ratio of 10:1 to 1:10. In some embodiments of any aspect, the IL has a cation:anion ratio of about 5:1 to about 1:5. In some embodiments of any aspect, the IL has a cation:anion ratio of 5:1 to 1:5. In some embodiments of any aspect, the IL has a cation:anion ratio of about 2:1 to about 1:4. In some embodiments of any aspect, the IL has a cation:anion ratio of 2:1 to 1:4. In some embodiments of any aspect, the IL has a cation:anion ratio of about 2:1 to about 1:10. In some embodiments of any aspect, the IL has a cation:anion ratio of 2:1 to 1:10. In some embodiments of any aspect, the IL has a cation:anion ratio where there is a greater amount of anion, for example, a ratio less than 1:1. In some embodiments of any aspect, the IL has a cation:anion ratio such that there is an excess of anions. In some embodiments of any aspect, the IL has a cation:anion ratio of about 1:1 to about 1:10. In some embodiments of any aspect, the IL has a cation:anion ratio of 1:1 to 1:10. In some embodiments of any aspect, the IL has a cation:anion ratio of about 1:1 to about 1:4. In some embodiments of any aspect, the IL has a cation:anion ratio of 1:1 to 1:4. In some embodiments of any aspect, the IL has a cation:anion ratio of about 1:1 to about 1:3. In some embodiments of any aspect, the IL has a cation:anion ratio of 1:1 to 1:3. In some embodiments of any aspect, the IL has a cation:anion ratio of about 1:1 to about 1:2. In some embodiments of any aspect, the IL has a cation:anion ratio of 1:1 to 1:2. In some embodiments of any aspect, the IL has a ratio of cations:anions of about 1:1, 1:2, 1:3, or 1:4. In some embodiments of any aspect, the IL has a ratio of cations:anions of 1:1, 1:2, 1:3, or 1:4.Without wishing to be bound by theory, compositions having a higher amount of anions relative to cations exhibit greater hydrophobicity.

[0077] In some embodiments of any aspect, e.g., when one or more nucleic acid molecules are provided in combination with an IL, the ratio of cations:anions is greater than 1:1, e.g., greater than 1:2, from about 1:2 to about 1:4, or from 1:2 to 1:4.

[0078] In some embodiments of any aspect, the IL is at a concentration of at least 20 mM. In some embodiments of any aspect, the IL is at a concentration of at least about 20 mM. In some embodiments of any aspect, the IL is at a concentration of at least 25 mM. In some embodiments of any aspect, the IL is at a concentration of at least about 25 mM. In some embodiments of any aspect, the IL is at a concentration of at least 50 mM. In some embodiments of any aspect, the IL is at a concentration of at least about 50 mM. In some embodiments of any aspect, the IL is at a concentration of at least 100 mM, 500 mM, 1 M, 2 M, 3 M or more. In some embodiments of any aspect, the IL is at a concentration of at least about 100 mM, 500 mM, 1 M, 2 M, 3 M or more.

[0079] In some embodiments of any aspect, the IL is at a concentration of about 50 mM to about 4 M. In some embodiments of any aspect, the IL is at a concentration of 50 mM to 4 M. In some embodiments of any aspect, the IL is at a concentration of about 500 mM to about 4 M. In some embodiments of any aspect, the IL is at a concentration of 500 mM to 4 M. In some embodiments of any aspect, the IL is at a concentration of about 1 M to about 4 M. In some embodiments of any aspect, the IL is at a concentration of 1 M to 4 M. In some embodiments of any aspect, the IL is at a concentration of about 2 M to about 4 M. In some embodiments of any aspect, the IL is at a concentration of 2 M to 4 M.

[0080] In some embodiments of any aspect, the IL concentration in the composition or formulation is about 0.1 mM to 20 mM. In some embodiments of any aspect, the IL concentration in the composition or formulation is about 0.5 mM to 20 mM, 0.5 mM to 18 mM, 0.5 mM to 16 mM, 0.5 mM to 14 mM, 0.5 mM to 12 mM, 0.5 mM to 10 mM, 0.5 mM to 8 mM, 1 mM to 20 mM, 1 mM to 18 mM, 1 mM to 16 mM, 1mM~14mM, 1mM~12mM, 1mM~10mM, 1mM~8mM, 2mM~20mM, 2mM~18mM, 2mM~16mM, 2mM~14m M, 2mM~12mM, 2mM~10mM, 2mM~8mM, 4mM~20mM, 4mM~18mM, 4mM~16mM, 4mM~12mM, 4mM~1 0mM, 4mM~8mM, 6mM~20mM, 6mM~18mM, 6mM~14mM, 6mM~12mM, 6mM~10mM, 6mM~8mM, 8mM ~20mM, 8mM~18mM, 8mM~16mM, 8mM~14mM, 8mM~12mM, 8mM~10mM, 10mM~20mM, 10mM~18m M, 10 mM to 16 mM, 10 mM to 14 mM, 10 mM to 12 mM, 12 mM to 20 mM, 12 mM to 18 mM, 12 mM to 16 mM, 12 mM to 14 mM, 14 mM to 20 mM, 14 mM to 18 mM, 14 mM to 16 mM, 16 mM to 20 mM, 16 mM to 18 mM, or 18 mM to 20 mM. In some embodiments of any aspect, the IL concentration in the composition or formulation is about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, or about 20 mM.

[0081] It is specifically contemplated that the compositions or combinations described herein may include one, two, three, or more of any of the types of components described herein. For example, the compositions may include a mixture, solution, combination, or emulsion of multiple different ionic liquids, and / or a mixture, solution, combination, or emulsion of multiple different non-ionic surfactants, and / or a mixture, solution, combination, or emulsion of multiple different active compounds.

[0082] As used herein, "in combination with" refers to two or more substances present in the same formulation, in any molecular or physical arrangement, e.g., in an admixture, solution, mixture, suspension, colloid, emulsion. The formulation may be a homogenous or heterogenous mixture. In some embodiments of either aspect, the active compound may be contained with the IL in a solution, mixture, admixture, suspension, etc., by a superstructure, e.g., a nanoparticle, liposome, vector, cell, scaffold, etc.

[0083] As used herein, an "active compound" or "active agent" is any agent that has an effect on a target cell or target organism. The terms "compound" and "agent" refer to any entity that is not normally present or does not exist at the level administered and / or provided to a cell, tissue, or subject. The agent can be selected from a group including: chemicals; small organic or inorganic molecules; signaling molecules; nucleic acid sequences; nucleic acid analogs; proteins; peptides; enzymes; aptamers; peptidomimetics, peptide derivatives, peptide analogs, antibodies; intrabodies; biopolymers, extracts made from biological materials such as bacterial, plant, fungal, or animal cells or tissues; natural or synthetic compositions or functional fragments thereof. In some embodiments, the agent is any chemical, entity, or moiety, including but not limited to synthetic and natural non-proteinaceous entities. The agent can be known to have the desired activity and / or properties or can be selected from a library of diverse compounds. Non-limiting examples of active compounds contemplated for use in the methods described herein include small molecules, polypeptides, nucleic acids, chemotherapeutic / chemotherapeutic compounds, antibodies, antibody reagents, vaccines, GLP-1 polypeptides or mimetics / analogs thereof, insulin, acarbose, or ruxolitinib.

[0084] As described herein, the nucleic acid molecule can be a vector, an expression vector, an inhibitory nucleic acid, an aptamer, a template molecule or cassette (e.g., for gene editing), or a targeting molecule (e.g., for CRISPR-Cas technology), or any other nucleic acid molecule that is desired to be delivered to a cell.The nucleic acid molecule can be RNA, DNA, or synthetic or modified versions thereof.

[0085] In one aspect of any of the aspects, described herein is a method of delivering a nucleic acid molecule to a cell, comprising contacting the cell with a nucleic acid molecule combined with an IL as described herein. In some embodiments of any of the aspects, the cell is a cell in a subject, and the contacting step comprises administering the nucleic acid molecule combined with an IL to the subject. In some embodiments of any of the aspects, the cell is in vitro, in vivo, or ex vivo. In some embodiments of any of the aspects, the cell is a eukaryotic organism. In some embodiments of any of the aspects, the cell is a mammalian cell. In some embodiments of any of the aspects, the cell is an epithelial cell, such as an intestinal epithelial cell.

[0086] As used herein, the term "small molecule" refers to a chemical agent that may include, but is not limited to, peptides, peptidomimetics, amino acids, amino acid analogs, polynucleotides, polynucleotide analogs, aptamers, nucleotides, nucleotide analogs, organic or inorganic compounds having a molecular weight of less than about 10,000 grams per mole (i.e., including heteroorganic and organometallic compounds), organic or inorganic compounds having a molecular weight of less than about 5,000 grams per mole, organic or inorganic compounds having a molecular weight of less than about 1,000 grams per mole, organic or inorganic compounds having a molecular weight of less than about 500 grams per mole, as well as salts, esters, and other pharma- ceutically acceptable forms of such compounds.

[0087] In some embodiments of any aspect, active compound can be a therapeutic compound or drug, for example, an agent or compound that is therapeutically effective in treating at least one disease state in a subject.Therapeutic compounds for various diseases are known in the art, for example, see the database available on the World Wide Web at drugs.com or the catalog of FDA-approved compounds available on the World Wide Web at catalog.data.gov / dataset / drugsfda-database, each of which is incorporated herein by reference in its entirety.

[0088] As used herein, the term "chemotherapeutic agent" refers to any chemical or biological agent that has therapeutic utility in the treatment of diseases characterized by abnormal cell proliferation. Such diseases include tumors, neoplasms, and cancers, as well as diseases characterized by hyperplastic proliferation. These agents may function to inhibit cellular activities that cancer cells depend on for continued proliferation. In some aspects of all embodiments, the chemotherapeutic agent is a cell cycle inhibitor or a cytostatic agent. Categories of chemotherapeutic agents useful in the methods of the present invention include alkylating / alkaloid agents, antimetabolites, hormones or hormone analogs, and a wide variety of antitumor drugs. Most of these agents are directly or indirectly toxic to cancer cells. In one embodiment, the chemotherapeutic agent is a radioactive molecule.

[0089] In some embodiments of either aspect, the active compound is a hydrophobic molecule, such as estradiol, testosterone, corticosterone, paclitaxel, doxorubicin, cisplatin, and / or camptothecin. In some embodiments of either aspect, the active compound is a hydrophilic molecule.

[0090] In some embodiments of any aspect, the active compound is an antibody or antibody reagent. The term "antibody reagent" as used herein refers to a polypeptide that contains at least one immunoglobulin variable domain or immunoglobulin variable domain sequence and specifically binds to a given antigen. An antibody reagent may include an antibody or a polypeptide that contains an antigen-binding domain of an antibody. In some embodiments, an antibody reagent may include a monoclonal antibody or a polypeptide that contains an antigen-binding domain of a monoclonal antibody. For example, an antibody may include a heavy (H) chain variable region (abbreviated herein as VH) and a light (L) chain variable region (abbreviated herein as VL). In another example, an antibody includes two heavy (H) chain variable regions and two light (L) chain variable regions. The term "antibody reagent" encompasses antigen-binding fragments of antibodies (e.g., single chain antibodies, Fab and sFab fragments, F(ab')2, Fd fragments, Fv fragments, scFv, and domain antibody (dAb) fragments as well as complete antibodies.

[0091] In some embodiments of any aspect, the active compound has a molecular weight greater than about 450. In some embodiments of any aspect, the active compound has a molecular weight greater than about 500. In some embodiments of any aspect, the active compound has a molecular weight greater than 450, e.g., greater than 450, greater than 500, greater than 550, greater than 600, greater than 1000, or more. In some embodiments of any aspect, the active compound is polar.

[0092] In some embodiments of any aspect, the compositions or combinations described herein comprising at least one IL and optionally an active compound can be formulated as oral, subcutaneous, intravenous, intradermal, or parenteral formulations. In some embodiments of any aspect, the oral formulation can be a degradable capsule that contains a composition comprising at least one IL and optionally an active compound.

[0093] In some embodiments of any aspect, described herein is a composition comprising at least one IL and at least one active compound described herein. In some embodiments of any aspect, described herein is a composition consisting essentially of at least one IL and at least one active compound described herein. In some embodiments of any aspect, described herein is a composition consisting of at least one IL and at least one active compound described herein. In some embodiments of any aspect, a composition comprising at least one IL and at least one active compound described herein is administered as monotherapy, e.g., no other treatment for the condition is administered to the subject.

[0094] In one aspect of any embodiment, described herein is a pharmaceutical composition comprising at least one active compound in combination with at least one IL described herein. In some embodiments, the pharmaceutical composition comprises at least one IL and one or more active compounds described herein. In some embodiments, the pharmaceutical composition consists essentially of at least one IL and one or more active compounds described herein. In some embodiments, the pharmaceutical composition consists of at least one IL and one or more active compounds described herein. In some embodiments, the pharmaceutical composition consists essentially of an aqueous solution of at least one IL and one or more active compounds described herein. In some embodiments, the pharmaceutical composition consists of an aqueous solution of at least one IL and one or more active compounds described herein.

[0095] The compositions, formulations, and combinations described herein can include at least one IL described herein, e.g., one IL, two ILs, three ILs, or more. In some embodiments of any aspect, the compositions, formulations, or combinations described herein can include at least one IL described herein and CAGE (choline and geranate).

[0096] In some embodiments of any aspect, the at least one active compound and the at least one ionic liquid are further combined with at least one nonionic surfactant. As used herein, "nonionic surfactant" refers to a surfactant that lacks a net ionic charge and does not visibly separate in aqueous media. The properties of nonionic surfactants depend largely on the ratio of hydrophilic and hydrophobic groups in the molecule. Hydrophilic groups include oxyethylene groups (--OCH2 CH2--) and hydroxy groups. By varying the number of these groups in hydrophobic molecules such as fatty acids, a range of substances can be obtained from strongly hydrophobic and water-insoluble compounds such as glyceryl monostearate to strongly hydrophilic and water-soluble compounds such as macrogol. Between these two extreme types are those with a more evenly balanced ratio of hydrophilic and hydrophobic groups, such as macrogol esters and ethers and sorbitan derivatives. Suitable non-ionic surfactants can be found in Martindale, The Extra Pharmacopoeia, 28th Edition, 1982, The Pharmaceutical Press, London, Great Britain, pp. 370 to 379.Non-limiting examples of non-ionic surfactants include polysorbates, Tween™, block copolymers of ethylene oxide and propylene oxide, glycol and glyceryl esters of fatty acids and their derivatives, polyoxyethylene esters of fatty acids (macrogol esters), polyoxyethylene ethers of fatty acids and their derivatives (macrogol ethers), polyvinyl alcohol, and sorbitan esters, sorbitan monoesters, ethers made from fatty alcohols and polyethylene glycols, polyoxyethylene-polypropylene glycols, alkyl polyglycosides, cetomacrogol 1000, cetostearyl alcohol, cetyl alcohol, cocamide DEA, cocamide MEA, decyl glucoside, decyl polyglucose, glycerol monostearate, IGEPAL, and the like. Examples of suitable surfactants include CA-630, isoceteth-20, lauryl glucoside, maltoside, monolaurin, mycosubtilin, nonidet P-40, nonoxynol-9, nonoxynol, NP-40, octaethylene glycol monododecyl ether, N-octyl β-D-thioglucopyranoside, octyl glucoside, oleyl alcohol, PEG-10 sunflower glyceride, pentaethylene glycol monododecyl ether, polidocanol, poloxamer, poloxamer 407, polyethoxylated tallow amine, polyglycerol polyricinoleate, sorbitan, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, stearyl alcohol, surfactin, Triton X-100, and the like. In some embodiments of any aspect, the at least one nonionic surfactant has a neutral hydrophilic head group.

[0097] As used herein, "polysorbate" refers to surfactants derived from ethoxylated sorbitan (a derivative of sorbitol) esterified with fatty acids. Common trade names for polysorbates include Scattics™, Alkest™, Canarcel™, and Tween™. Exemplary polysorbates include polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), and polysorbate 80 (polyoxyethylene (20) sorbitan monooleate).

[0098] In some embodiments of any aspect, the at least one non-ionic surfactant (e.g., at least one polysorbate) is present at a concentration of about 0.1% to about 50% w / v. In some embodiments of any aspect, the at least one non-ionic surfactant (e.g., at least one polysorbate) is present at a concentration of 0.1% to 50% w / v. In some embodiments of any aspect, the at least one non-ionic surfactant (e.g., at least one polysorbate) is present at a concentration of about 1% to about 5% w / v. In some embodiments of any aspect, the at least one non-ionic surfactant (e.g., at least one polysorbate) is present at a concentration of 1% to 5% w / v. In some embodiments of any aspect, the at least one non-ionic surfactant (e.g., at least one polysorbate) is present at a concentration of about 3% to about 10% w / v. In some embodiments of any aspect, the at least one non-ionic surfactant (e.g., at least one polysorbate) is present at a concentration of 3% to 10% w / v. In some embodiments of any aspect, the at least one non-ionic surfactant (e.g., at least one polysorbate) is present at a concentration of less than about 5% w / v. In some embodiments of any aspect, the at least one non-ionic surfactant (e.g., at least one polysorbate) is present at a concentration of less than 5% w / v.

[0099] In some embodiments of any aspect, the combination of at least one active compound and at least one IL described herein is provided in one or more nanoparticles. In some embodiments of any aspect, the combination of at least one active compound and at least one IL described herein comprises nanoparticles comprising the active compound, and the nanoparticles are in solution or suspension in a composition comprising at least one IL described herein.

[0100] In some embodiments of any aspect, the compositions described herein, such as those comprising at least one IL and an active compound, may further comprise a pharma- ceutically acceptable carrier. As used herein, the terms "pharmacologically acceptable," "physiologically tolerated," and grammatical variations thereof, are used interchangeably when referring to compositions, carriers, diluents, and reagents, and denote that the material can be administered to or on a mammal without producing undesirable physiological effects, such as nausea, dizziness, stomach upset, and the like. A pharma- ceutically acceptable carrier does not promote the mounting of an immune response against an agent with which it is admixed, unless so desired. The preparation of pharmacological compositions that include active ingredients dissolved or dispersed therein is well understood in the art and need not be limited based on formulation. Typically, such compositions are prepared to be injectable, either as liquid solutions or suspensions, but may also be prepared in solid forms suitable for dissolution or suspension in liquid prior to use. The preparation may also be emulsified or presented as a liposomal composition. The active ingredient can be mixed with excipients that are pharma- ceutically acceptable and compatible with the active ingredient, in an amount appropriate for use in the therapeutic methods described herein. Suitable excipients include, for example, water, saline, dextrose, glycerol, ethanol, and the like, and combinations thereof. In addition, if desired, the composition can contain minor amounts of auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like, which enhance the effectiveness of the active ingredient. The therapeutic compositions of the present disclosure can contain pharma-ceutically acceptable salts of the components therein. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids, such as, for example, hydrochloric or phosphoric acid, or organic acids, such as acetic, tartaric, mandelic, and the like (formed with the free amino groups of the polypeptide). Salts formed with free carboxyl groups can also be derived from inorganic bases, such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxide, and organic bases, such as isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, procaine, and the like. Physiologically tolerable carriers are well known in the art.Exemplary liquid carriers are sterile aqueous solutions that contain no materials in addition to the active ingredient and water, or buffers such as sodium phosphate, physiological saline, or both, e.g., phosphate-buffered saline, at physiological pH values. Additionally, aqueous carriers can contain multiple buffer salts and salts such as sodium and potassium chloride, dextrose, polyethylene glycol, and other solutes. Liquid compositions can also contain liquid phases in addition to and to the exclusion of water. Examples of such additional liquid phases are glycerin, vegetable oils such as cottonseed oil, and water-oil emulsions. The amount of active agent used in the methods described herein that is effective in treating a particular disorder or condition depends on the nature of the disorder or condition and can be determined by standard clinical techniques. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field of technology. For example, a parenteral composition suitable for administration by injection is prepared by dissolving 1.5% by weight of the active ingredient in 0.9% sodium chloride solution.

[0101] The term "carrier" in the context of pharmaceutical carriers refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. If desired, the composition can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, and the like. The compositions may be formulated as suppositories, using traditional binders and carriers such as triglycerides. Oral formulations may include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed. (Mack Publishing Co., 1990). The formulation should suit the mode of administration.

[0102] Pharmaceutically acceptable carriers and diluents include saline, aqueous buffer solutions, solvents and / or dispersion media. The use of such carriers and diluents is well known in the art. Some non-limiting examples of materials that can serve as pharma-ceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, methylcellulose, ethylcellulose, microcrystalline cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricants such as magnesium stearate, sodium lauryl sulfate, and talc; (8) excipients such as cocoa butter and suppository wax; (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil. (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol (PEG); (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffer solutions; (21) polyesters, polycarbonates, and / or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids; (23) serum components, such as serum albumin, HDL, and LDL; (22) C2-C3 fatty acids, such as ethanol. 12 alcohol; and (23) other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, coloring agents, release agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants may also be present in the formulation. The terms "excipient", "carrier", "pharmaceutical acceptable carrier" and the like are used interchangeably herein. In some embodiments, the carrier inhibits the degradation of the active compound. The term "pharmaceutical acceptable carrier" excludes tissue culture medium.

[0103] In some embodiments of any aspect, the compositions described herein, e.g., compositions comprising at least one IL and an active compound described herein, can be formulated as oral, subcutaneous, intravenous, intradermal, or parenteral formulations. In some embodiments of any aspect, the oral formulation can be a degradable capsule that contains the compositions described herein, e.g., compositions comprising at least one IL and an active compound described herein.

[0104] In some embodiments of any aspect described herein, the biological activity of the active compound is improved or stabilized compared to the activity in the absence of at least one IL. In some embodiments of any aspect described herein, the permeability of the active compound through the skin is greatly enhanced compared to a control in the absence of at least one IL.

[0105] In one aspect of any embodiment, described herein is a method of administering at least an active compound to a subject using a catheter coated with at least one IL described herein. In one aspect of any embodiment, described herein is a method of withdrawing bodily fluids by placing a catheter coated with at least one IL described herein within the body.

[0106] In one aspect of any embodiment, the composition or combination described herein is for administration or delivery of at least one active compound, for example, for the treatment of disease.In one aspect of any embodiment, described herein is a method of administering at least one active compound, comprising administering the active compound in combination with at least one IL described herein.In one aspect of any embodiment, described herein is a method of treating disease by administering at least one active compound, comprising administering the active compound in combination with at least one IL described herein.

[0107] In some embodiments, the methods described herein relate to treating a subject who has or has been diagnosed with a condition with a composition described herein, for example, comprising at least one IL and an active compound. A subject who has a condition, for example, diabetes, can be identified by a physician using current diabetes diagnostic methods. Symptoms and / or complications of diabetes that characterize these conditions and aid in diagnosis are well known in the art and include, but are not limited to, weight loss, slow healing, polyuria, polydipsia, polyphagiam headache, itchy skin, and fatigue. For example, tests that can help diagnose diabetes include, but are not limited to, blood tests (e.g., fasting glucose levels). A family history of diabetes, or exposure to risk factors for diabetes (e.g., being overweight) can also help determine whether a subject may have diabetes or make a diagnosis of diabetes.

[0108] The compositions and methods described herein can be administered to a subject having or diagnosed as having a condition described herein. In some embodiments, the methods described herein include administering to a subject an effective amount of a composition described herein, e.g., a composition comprising at least one IL and an active compound described herein, to reduce the symptoms of a condition described herein. As used herein, "reducing symptoms" refers to improving any marker or symptom associated with the condition. Compared to an equivalent untreated control, such reduction is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, 99% or more, as measured by any standard technique. Various means for administering the compositions described herein to a subject are known to those skilled in the art. Such methods include, but are not limited to, oral, parenteral, intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, dermal, injection, or intratumoral administration. Administration can be local or systemic.

[0109] In some embodiments of any aspect, the administration is transdermal. In some embodiments of any aspect, the administration is transdermal, to a mucosa (e.g., nasal, oral, or vaginal mucosa), oral, subcutaneous, intradermal, parenteral, intratumoral, or intravenous.

[0110] Oral administration may include providing a liquid such as, but not limited to, a tablet (including but not limited to, scored or coated tablets), a pill, a caplet, a capsule, a chewable tablet, a powder packet, a cachet, a troche, a wafer, an aerosol spray, or a syrup, elixir, solution or suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil emulsion. Oral formulations may include separate dosage forms such as, but not limited to, a tablet (including but not limited to, scored or coated tablets), a pill, a caplet, a capsule, a chewable tablet, a powder packet, a cachet, a troche, a wafer, an aerosol spray, or a liquid such as, but not limited to, a syrup, elixir, solution or suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil emulsion. Such compositions include a predetermined amount of an ionic liquid as described herein and at least one active compound and may be prepared by methods of formulation well known to those of skill in the art. See generally, Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams, and Wilkins, Philadelphia PA. (2005).

[0111] In one aspect of any embodiment, described herein is a method of delivery of at least one active compound by subcutaneous, intradermal, or intravenous administration, comprising administering the active compound in combination with at least one IL described herein. In some embodiments of any aspect, subcutaneous, intradermal, or intravenous administration includes administration via injection, catheter, port, etc.

[0112] In one aspect of any embodiment, described herein is a method for parenteral delivery of at least one active compound, comprising parenterally administering the active compound in combination with at least one IL described herein. In some embodiments, parenteral administration includes delivery to a tumor, e.g., a cancer tumor. In some embodiments of any aspect, the composition or combination described herein can be in a parenteral dosage form. Because administration of a parenteral dosage form typically bypasses the patient's natural defense against contaminants, the parenteral dosage form is preferably sterile or sterilizable before administration to a patient. Examples of parenteral dosage forms include, but are not limited to, injectable solutions, dry formulations that can be dissolved or suspended in a pharma- ceutically acceptable vehicle for injection, injectable suspensions, and emulsions. In addition, controlled release parenteral dosage forms can be prepared for administration to a patient, including, but not limited to, DUROS®-type dosage forms and dose-dumping.

[0113] Suitable vehicles that can be used to provide parenteral dosage forms of compositions containing the ionic liquids described herein in combination with at least one active compound disclosed within the scope are well known to those skilled in the art. Examples include, but are not limited to: sterile water; water for injection, USP; saline; glucose solution; aqueous vehicles, such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer's; water-miscible vehicles, such as, but not limited to, ethyl alcohol, polyethylene glycol, and propylene glycol; and non-aqueous vehicles, such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. Compounds that modify or alter the solubility of ingredients in the compositions disclosed herein can also be incorporated into the parenteral dosage forms of the present disclosure, including normal and controlled release parenteral dosage forms.

[0114] Conventional dosage forms generally provide for rapid or immediate drug release from the formulation. Depending on the pharmacology and pharmacokinetics of the drug, the use of conventional dosage forms may lead to wide variations in drug concentrations in the patient's blood and other tissues. These variations may affect several parameters, such as frequency of administration, onset of action, duration of effectiveness, maintenance of therapeutic blood levels, toxicity, side effects, etc. As previously described herein, compositions comprising ionic liquids as described herein in combination with at least one active compound may eliminate certain reasons for using controlled release formulations, however, it is contemplated herein that the methods and compositions may be utilized in controlled release formulations in some embodiments. For example, controlled release formulations may be used to control the onset of action, duration of action, plasma levels within a therapeutic window, and peak blood levels of the drug. In particular, controlled or sustained release dosage forms or formulations may be used to ensure maximum efficacy of the drug is achieved while minimizing potential side effects and safety concerns that may arise from both underdosing (i.e., below the minimum therapeutic level) of the drug as well as exceeding toxic levels of the drug. In some embodiments, compositions comprising ionic liquids as described herein in combination with at least one active compound may be administered in sustained release formulations.

[0115] Controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled release counterparts. Ideally, the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum amount of drug substance being used to cure or control a medical condition in a minimal amount of time. Advantages of controlled release formulations include: 1) extended activity of the drug; 2) reduced frequency of administration; 3) improved patient compliance; 4) less total drug use; 5) reduced local or systemic side effects; 6) minimized drug accumulation; 7) reduced fluctuations in blood levels; 8) improved efficacy of treatment; 9) reduced synergy or loss of drug activity; and 10) improved rate of control of a disease or medical condition. Kim, Cherng-ju, Controlled Release Dosage Form Design, 2 (Technomic Publishing, Lancaster, Pa.: 2000).

[0116] Most controlled release formulations are designed to initially release an amount of drug (active ingredient) that immediately produces the desired therapeutic effect, and then slowly and continuously release other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug being metabolized and excreted from the body. Controlled release of active ingredients can be stimulated by a variety of conditions, including but not limited to pH, ionic strength, osmolality, temperature, enzymes, water, and other physiological conditions or compounds.

[0117] Various known controlled or sustained release dosage forms, formulations and devices can be adapted for use with the salts and compositions of the present disclosure.Examples include, but are not limited to, those described in U.S. Patent No. 3,845,770; U.S. Patent No. 3,916,899; U.S. Patent No. 3,536,809; U.S. Patent No. 3,598,123; U.S. Patent No. 4,008,719; U.S. Patent No. 5,674,533; U.S. Patent No. 5,059,595; U.S. Patent No. 5,591,767; U.S. Patent No. 5,120,548; U.S. Patent No. 5,073,543; U.S. Patent No. 5,639,476; U.S. Patent No. 5,354,556; U.S. Patent No. 5,733,566; and U.S. Patent No. 6,365,185 B1, each of which is incorporated herein by reference. These dosage forms can be used to provide sustained or controlled release of one or more active ingredients using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems (such as OROS® (Alza Corporation, Mountain View, Calif. USA)), or combinations thereof to provide desired release profiles at various rates.

[0118] The term "effective amount" as used herein refers to the amount of the composition necessary to alleviate at least one or more symptoms of a disease or disorder, and relates to a sufficient amount of a pharmacological composition to produce a desired effect. Thus, the term "therapeutically effective amount" refers to an amount of the composition sufficient to produce a particular effect when administered to a typical subject. Effective amount as used herein also includes, in various contexts, an amount sufficient to delay the onset of a disease symptom, modify the course of a disease symptom (e.g., but not limited to, delay the progression of a disease symptom), or reverse a disease symptom. Thus, it is generally not feasible to specify an exact "effective amount". However, for any given case, one of ordinary skill in the art can determine a suitable "effective amount" using only routine experimentation.

[0119] Effective doses, toxicity, and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). Dosages can vary depending on the dosage form used and the route of administration utilized. The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Compositions and methods that exhibit large therapeutic indices are preferred. Therapeutically effective doses can be estimated initially from cell culture assays. Doses can also be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of active compound that achieves half-maximal inhibition of symptoms) determined in cell culture or suitable animal models. Levels in plasma can be measured, for example, by high performance liquid chromatography. The effect of any particular dosage can be monitored by suitable bioassays, such as blood glucose assays, among others. Dosages can be determined by a physician and can be adjusted as necessary to accommodate observed therapeutic effects.

[0120] As used herein, "diabetes" refers to diabetes mellitus, a metabolic disease characterized by a deficiency or absence of insulin secretion by the pancreas. As used throughout the specification, unless otherwise specified herein, "diabetes" includes type 1, type 2, type 3, and type 4 diabetes. The onset of diabetes is usually due to a combination of genetic and environmental causes, resulting in abnormally high blood glucose levels (hyperglycemia). The two most common forms of diabetes are due to either a decline in the production of insulin (in type 1) or a decline in the body's response to insulin (in type 2 and gestational). Both lead to hyperglycemia, which primarily causes the acute signs of diabetes: excessive urine production, resulting in compensatory thirst and increased water intake, blurred vision, unexplained weight loss, lethargy, and changes in energy metabolism. Diabetes can cause many complications. Acute complications (hypoglycemia, ketoacidosis, or nonketotic hyperosmolar coma) can occur if the disease is not properly controlled. Serious long-term complications (i.e., chronic side effects) include cardiovascular disease (double risk), chronic renal failure, retinal damage (which can lead to blindness), nerve damage (which can be of several types), and microvascular damage that can cause impotence and poor wound healing. Poor wound healing, especially on the feet, can lead to gangrene and possibly amputation. In some embodiments, the diabetes can be type 2 diabetes. Type 2 diabetes (non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes) is a metabolic disorder that is primarily characterized by insulin resistance (the body's reduced response to insulin), relative insulin deficiency, and hyperglycemia. In some embodiments, the subject can be pre-diabetic, which can be characterized as having, for example, elevated fasting blood glucose or elevated postprandial blood glucose.

[0121] Glucagon-like peptide-1 (GLP-1) is an incretin derived from the transcript of the proglucagon gene that is known to reduce food intake and hunger in humans and contributes to glucose homeostasis. GLP-1 mimetics are currently used to treat type 2 diabetes. Recent clinical trials have shown that these treatments not only improve glucose homeostasis but also successfully induce weight loss. As used herein, "GLP-1 polypeptide" refers to the various pre- and propeptides and cleavage products of GLP-1, such as GLP-1(1-37) (SEQ ID NO: 2), GLP-1(7-36) (SEQ ID NO: 3), and GLP-1(7-37) (SEQ ID NO: 4) in humans. In some embodiments, the GLP-1 polypeptide can be GLP-1(7-36) and / or GLP-1(7-37) or related polypeptides derived from species other than human. GLP-1 polypeptide sequences are known in the art for many species, such as human GLP-1 (NCBI Gene ID: 2641) polypeptide (e.g., NCBI Ref Seq: NP_002045.1; SEQ ID NO: 1) and SEQ ID NOs: 2-4. In some embodiments, pre- or pro-peptides of GLP-1, such as glucagon preproprotein (e.g., SEQ ID NO: 1), can be used in the methods or compositions described herein. Naturally occurring alleles or variants of any of the polypeptides described herein are also specifically contemplated for use in the methods and compositions described herein. TIFF2025069232000005.tif66149

[0122] A variety of GLP-1 mimetics are known in the art and are used to treat diabetes.GLP-1 mimetics (or analogues) can include exendin-4 (Heloderma lizard polypeptide with homology to human GLP-1) and its derivatives, modified GLP-1 analogues to be DPP-IV resistant, or human GLP-1 polypeptides conjugated with various additional agents, for example to extend half-life.GLP-1 mimetics / analogues can include, for example, exenatide, lixisenatide, dulaglutide, semaglutide, albiglutide, LY2189265, liraglutide, and taspoglutide. Examples of such molecules and further discussion of their production and activity can be found in the art, for example, in Gupta. Indian J. Endocrinol Metab 17:413-421 (2013); Garber. Diabetes Treatments 41:S279-S284 (2018); U.S. Patent Publication No. US 2009 / 0181912; and International Patent Publication No. WO 2011 / 080103, each of which is incorporated by reference herein in its entirety.

[0123] In some embodiments of either aspect, the active compound can be a chemotherapeutic agent or an agent effective in treating cancer. As used herein, the term "cancer" generally refers to a class of diseases or conditions in which abnormal cells divide uncontrollably and may invade nearby tissues. Cancer cells may also spread to other parts of the body through the blood and lymphatic system. There are several main types of cancer. Epithelial malignancies are cancers that develop in tissues that line or cover the skin or internal organs. Non-epithelial malignancies are cancers that develop in bone, cartilage, fat, muscle, blood vessels, or other connective or supporting tissues. Leukemia is a cancer that develops in blood-forming tissues, such as bone marrow, causing the production and entry of large numbers of abnormal blood cells into the blood. Lymphoma and multiple myeloma are cancers that develop in cells of the immune system. Central nervous system cancers are cancers that develop in tissues of the brain and spinal cord.

[0124] In some embodiments of either aspect, the cancer is a primary cancer. In some embodiments of either aspect, the cancer is a malignant cancer. As used herein, the term "malignant" refers to a cancer in which tumor cell populations exhibit one or more of uncontrolled proliferation (i.e., division beyond normal limits), invasion (i.e., invasion and destruction of adjacent tissues), and metastasis (i.e., spread to other parts of the body via lymph or blood). As used herein, the term "metastasizing" refers to the spread of cancer from one part of the body to another. A tumor formed by spread cells is called a "metastatic tumor" or "metastatic cancer." A metastatic tumor contains cells that resemble cells in the original (primary) tumor. As used herein, the term "benign" or "non-malignant" refers to a tumor that may grow larger but does not spread to other parts of the body. Benign tumors are self-limited and do not usually invade or metastasize.

[0125] "Cancer cell" or "tumor cell" refers to an individual cell of a cancerous growth or tissue. A tumor generally refers to a swelling or lesion formed by abnormal proliferation of cells, which may be benign, premalignant, or malignant. Most cancer cells form tumors, but some, such as leukemia, do not necessarily form tumors. For tumor-forming cancer cells, the terms cancer (cell) and tumor (cell) are used interchangeably.

[0126] As used herein, the term "neoplasm" refers to any new and abnormal growth of tissue, e.g., an abnormal tissue mass whose growth is in excess of and uncoordinated with the growth of normal tissue. Thus, a neoplasm can be a benign, premalignant, or malignant neoplasm.

[0127] A subject with cancer or tumor is a subject with objectively measurable cancer cells present in the subject's body.This definition includes malignant and actively growing cancers, as well as potentially dormant tumors or micrometastases.Cancer that migrates from its original location and disseminates to other vital organs can ultimately lead to the death of the subject through the functional deterioration of the affected organ.

[0128] Examples of cancer include: carcinoma, lymphoma, blastoma, non-cancerous carcinoma, leukemia, basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and CNS cancer; breast cancer; cancer of the peritoneum; cervical cancer; choriocarcinoma; colon and rectal cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; head and neck cancer; gastric cancer (including gastrointestinal cancer); glioblastoma (GBM); liver cancer; hepatocellular carcinoma; intraepithelial neoplasia; kidney or renal cancer; Laryngeal cancer; leukemia; liver cancer; lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous cell carcinoma of the lung); lymphoma, including Hodgkin's lymphoma and non-Hodgkin's lymphoma; melanoma; myeloma; neuroblastoma; oral cancer (e.g., lip, tongue, mouth, and throat); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; respiratory system cancer; salivary gland cancer; sarcoma; skin cancer; squamous cell carcinoma; gastric cancer; seminal follicular cancer; thyroid cancer; uterine or endometrial cancer; urinary system cancer; vulvar cancer; other epithelial and non-epithelial malignancies; and B-cell lymphomas (low-grade / follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate-grade / follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small noncleaved cell NHL; bulky mass disease NHL) ; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal blood vessel proliferation associated with nevus syndrome, edema (such as associated with brain tumors), and Meigs syndrome.

[0129] A "cancer cell" is a cancerous, precancerous, or transformed cell, either in vivo, ex vivo, or in tissue culture, that has a spontaneous or induced phenotypic change that does not necessarily involve the incorporation of new genetic material. Transformation can result from infection with a transforming virus and incorporation of new genomic nucleic acid, or from incorporation of exogenous nucleic acid, but also from spontaneous or subsequent exposure to carcinogens, which mutate endogenous genes. Transformation / cancer is associated with morphological changes, cellular immortalization, aberrant growth control, foci formation, anchorage independence, malignancy, loss of contact inhibition and density restriction of growth, growth factor or serum independence, tumor-specific markers, invasiveness or metastasis, and tumor growth in a suitable animal host, e.g., nude mice.

[0130] In some embodiments of any aspect, a composition described herein, e.g., a composition comprising at least one IL described herein in combination with at least one active compound, is administered as a monotherapy, e.g., in the absence of another treatment for the condition.

[0131] In some embodiments of any of the aspects, the methods described herein may further include administering a second agent and / or treatment to the subject, either in a composition described herein, e.g., a composition that includes at least one IL described herein in combination with at least one active compound, or as a separate formulation, e.g., as part of a combination therapy. For example, non-limiting examples of second agents and / or treatments for cancer treatment include radiation therapy, surgery, gemcitabine, cisplatin, paclitaxel, carboplatin, bortezomib, AMG479, vorinostat, rituximab, temozolomide, rapamycin, ABT-737, PI-103; alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelanamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelanamine; acetogenins (particularly bullatacin and bullatacinone); camptothecin (including the synthetic analog topotecan); ostatin; kallistatin; CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogs); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosurea such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine;Enediyne antibiotics (e.g., antibiotics such as the calicheamicins, particularly calicheamicin gamma 1I and calicheamicin omega 11 (see, e.g., Agnew, Chem. Intl. Ed. Engl., 33: 183-186 (1994)); dynemicins, including dynemicin A; bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomycins, actinomycins, autramycins, azaserine, bleomycins, cactinomycins, carabicins, caminomycins, carzinophilins, chromomycinis, dactinomycins, daunorubicins, Detrubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potofilomycin, puromycin, keramycin , lodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxif Pyrimidine analogues such as uridine, enocitabine, and floxuridine;androgens such as calsterone, dromostanol propionate, epithiostanol, mepitiostane, and testolactone;antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane;folate supplements such as floric acid;aceglatone;aldophosphamide glycosides;aminolevulinic acid;eniluracil;amsacrine;bestrabulin;bisantrene;edatraxate;defofamine;demecolcine;diazicon;Elformitin; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidynin; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitraelin; pentostatin; phenamet; pirarubicin; rosoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triazicon; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidin); urethane; vindesine; dacarbazine; manomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids such as TAXOL® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France);Chlorambucil;GEMZAR® gemcitabine;6-thioguanine;Mercaptopurine;Methotrexate;Platinum analogues such as cisplatin, oxaliplatin, and carboplatin;Vinblastine;Platinum;Etoposide (VP-16);Ifosfamide;Mitoxantrone;Vincristine;NAVELBINE.RTM.Vinorelbine;Novantrone;Teniposide;Edatrexate;Daunomycin;Aminopterin;Xeloda;Ibandronate;Irinotecan (Camptosar, CPT-11) (including treatment regimens with irinotecan, including 5-FU and leucovorin);Topoisomerase inhibitors RFS 2000;Difluoromethylornithine (DMFO);Retinoids such as retinoic acid;Capecitabine;Combretastatins;Leucovorin (LV); oxaliplatin, including oxaliplatin treatment regimen (FOLFOX); lapatinib (Tykerb.RTM.); PKC-alpha inhibitors that reduce cell proliferation, Raf inhibitors, H-Ras inhibitors, EGFR inhibitors (e.g., erlotinib (Tarceva®)) and VEGF-A inhibitors, as well as pharmacologic acceptable salts, acids, or derivatives of any of the above. Additionally, the method of treatment may further include the use of radiation or radiotherapy. Additionally, the method of treatment may further include the use of surgical treatment.;

[0132] Due to the excellent transdermal drug delivery properties of the ILs described herein, the compositions and combinations described herein are suitable for use with active compounds effective in treating skin diseases and alopecia, such as alopecia areata. Active compounds suitable for treating alopecia can include, for example, corticosteroids (e.g., clobetasol or fluocinonide), minoxidil, elocon (mometasone), irritants (e.g., anthralin or topical coal tar), and cyclosporine.

[0133] In certain embodiments, an effective dose of a composition described herein, e.g., a composition comprising at least one IL described herein in combination with at least one active compound, can be administered to a patient once. In certain embodiments, an effective dose of a composition described herein, e.g., a composition comprising at least one IL described herein in combination with at least one active compound, can be administered to a patient repeatedly. For systemic administration, a subject can be administered a therapeutic amount of a composition described herein, e.g., a composition comprising at least one IL described herein in combination with at least one active compound, e.g., 0.1 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, or more. In some embodiments of any aspect, at least one active compound is present in the combination at a dose of about 1.0 to 20.0 mg / kg. In some embodiments of any aspect, at least one active compound is present in the combination at a dose of 1.0 to 20.0 mg / kg.

[0134] In some embodiments, the active compound is insulin, and the concentration or dosage of insulin can be about 1 U / kg to about 20 U / kg. In some embodiments, the active compound is insulin, and the concentration or dosage of insulin can be 1 U / kg to 20 U / kg. In some embodiments, the active compound is insulin, and the concentration or dosage of insulin can be less than 20 U / kg. In some embodiments, the active compound is insulin, and the concentration or dosage of insulin can be about 2 U / kg to about 10 U / kg. In some embodiments, the active compound is insulin, and the concentration or dosage of insulin can be 2 U / kg to 10 U / kg. In some embodiments, the active compound is insulin, and the concentration or dosage of insulin can be about 2 U / kg to about 5 U / kg. In some embodiments, the active compound is insulin, and the concentration or dosage of insulin can be 2 U / kg to 5 U / kg. In some embodiments, the active compound is insulin, and the concentration or dosage of insulin can be about 5 U / kg to about 10 U / kg. In some embodiments, the active compound is insulin, and the concentration or dosage of insulin can be 5 U / kg to 10 U / kg. In some embodiments, the active compound is insulin, and the concentration or dosage of insulin can be 2 U / kg, 5 U / kg, or 10 U / kg.

[0135] In one aspect of any embodiment, described herein is a method of treating a disease in a subject in need thereof by administering to the subject an active compound in combination with at least one IL described herein by injection into the diseased tissue. In some embodiments, the diseased tissue is a tissue that contains diseased cells. In some embodiments, the diseased tissue is a tissue that exhibits symptoms of a disease. Non-limiting examples of suitable diseased tissues include tumor tissue, fat tissue, adipose tissue, and the like. In some embodiments of any aspect, the disease is a disease caused by tissue proliferation, e.g., unwanted, abnormal, or pathological tissue proliferation. A disease caused by tissue proliferation can be any disease caused or characterized by a rate of tissue proliferation, a location of tissue proliferation, or a pattern / structure of tissue proliferation that differs from that normal for that type of tissue in a healthy subject. Non-limiting examples of such diseases are tumors, cancer, adipose / obesity, and / or hyperplasia. In some embodiments of any aspect, such a disease is a tumor, cancer, adipose / obesity, and / or hyperplasia.

[0136] Enzyme inhibitors are treatment options for several conditions, including diabetes, for example, insulin degrading enzyme inhibitors, ACE inhibitors, and alapha-glucosidase inhibitors have all been explored as therapeutic approaches. Thus, safe and effective enzyme inhibitors are of interest in the treatment of several conditions. Without wishing to be bound by theory, it is contemplated herein that the ILs described herein may exhibit enzyme inhibitory activity. Thus, in some embodiments of any aspect, described herein is a method of treating diabetes, ulcers, cancer, or fibrosis in a subject in need thereof, comprising administering to the subject a composition comprising at least one IL described herein. In some embodiments, the composition does not comprise an additional therapeutically active agent.

[0137] Fibrotic conditions benefit from the production and / or maintenance of extracellular matrix by reducing the accumulation of scar tissue in favor of extracellular matrix. As used herein, "fibrosis" refers to the formation of fibrous tissue as a repair or reaction process, rather than as a normal component of an organ or tissue. Fibrosis is characterized by the accumulation of fibroblasts and the deposition of collagen in excess of normal deposition in any particular tissue. Fibrosis can occur as a result of inflammation, irritation, or healing. A subject in need of treatment for a fibrotic condition is any subject who has, has been diagnosed as, or is at risk of having a fibrotic condition. Non-limiting examples of fibrotic conditions include pulmonary fibrosis; scarring; skin scarring; trauma; wounds; chronic wounds (e.g., in diabetic patients), corneal defects; corneal ulcers; corneal wounds; diabetic ulcers; ulcers; sepsis; arthritis; idiopathic pulmonary fibrosis; cystic fibrosis; liver cirrhosis; endomyocardial fibrosis; mediastinal fibrosis; myelofibrosis; retroperitoneal fibrosis; progressive massive fibrosis; nephrogenic systemic fibrosis; Crohn's disease; keloids; scleroderma; systemic sclerosis; arthrofibrosis; adhesive capsulitis; pulmonary fibrosis; liver fibrosis; renal These include, but are not limited to, fibrosis; cardiac fibrosis; vascular fibrosis; skin fibrosis; ocular fibrosis; myelofibrosis; asthma; sarcoidosis; COPD; emphysema; schistosomiasis; cholangitis; diabetic nephropathy; lupus nephritis; aterial restenosis after angioplasty; atherosclerosis; burn scars; hypertrophic scars; nephrogenic fibrosing dermatosis; post-cataract surgery; proliferative vitreoretinopathy; Peyronie's disease; Dupuytren's contracture; dermatomyositis; and graft versus host disease.

[0138] As used herein, "ulcer" refers to the breakage or destruction of body membrane.In some embodiments, ulcer can be caused by inflammation and / or necrosis of affected tissue.Ulcer can be skin ulcer (e.g. bedsore, diabetic ulcer, ulcerative dermatitis, etc.), corneal ulcer, oral ulcer, digestive ulcer, venous ulcer, stress ulcer, or ulcerative colitis.

[0139] In some embodiments, after the initial treatment regimen, treatment can be performed less frequently.For example, after 3 months of treatment every other week, treatment can be repeated once a month for 6 months or a year or more.Treatment according to the methods described herein can reduce the level of markers or symptoms of a condition by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% or more.

[0140] The dosage of the compositions described herein can be determined by a physician and may be adjusted accordingly to the observed therapeutic effect. With regard to duration and frequency of treatment, a skilled clinician will typically monitor the subject to determine when the treatment provides therapeutic benefit and to determine whether to increase or decrease the dosage, increase or decrease the frequency of administration, discontinue treatment, resume treatment, or make other changes to the treatment plan. The dosing schedule may vary from once a week to daily, depending on several clinical factors, such as the subject's sensitivity to the active compound. The desired dose or amount of the active agent may be administered once, or may be divided into partial doses, e.g., 2-4 partial doses, and administered over a period of time, e.g., at appropriate intervals throughout the day, or on other suitable schedules. In some embodiments, administration may be chronic, e.g., in one or more doses and / or treatments daily for a period of weeks or months. Examples of dosing and / or treatment schedules are daily, twice daily, three times daily, or four or more times daily administration for a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or more. The compositions described herein, e.g., compositions comprising at least one IL in combination with at least one active compound, can be administered over a period of time, e.g., over a period of 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 25 minutes.

[0141] The dosage range for administering the compositions described herein by the methods described herein depends, for example, on the form of active compound, its potency, and the degree to which it is desired to reduce the symptoms, markers, or indicators of the conditions described herein, for example, the percentage of reduction desired for symptoms or markers.The dosage should not be so high as to cause adverse side effects.In general, dosage varies according to the age, condition, and sex of the patient, and can be determined by those skilled in the art.In the case of any complication, dosage can also be adjusted by individual physicians.

[0142] For example, the effectiveness of the compositions described herein in treating the conditions described herein or for inducing the responses described herein can be determined by a skilled clinician. However, a treatment is considered to be "effective treatment" if one or more of the signs or symptoms of the conditions described herein are modified in a beneficial manner, other clinically recognized symptoms are improved or even ameliorated, or a desired response is induced, for example, at least 10% after treatment by the methods described herein, as the term "effective treatment" is used herein. Efficacy can be evaluated, for example, by measuring markers, indicators, symptoms, and / or incidence of the condition treated by the methods described herein, or any other suitable measurable parameters. Efficacy can also be measured by the lack of deterioration of the individual as assessed by hospitalization, or the lack of need for medical intervention (i.e., the progression of the disease is halted). Methods for measuring these indicators are known to those skilled in the art and / or described herein. Treatment includes any treatment of disease in an individual or animal (some non-limiting examples include humans or animals) and includes: (1) inhibiting the disease, e.g., preventing the worsening of symptoms (e.g., pain or inflammation); or (2) reducing the severity of the disease, e.g., causing regression of symptoms. An effective amount for treating a disease means an amount that, when administered to a subject in need thereof, is sufficient to provide effective treatment, as the term effective treatment is defined herein, for that disease. The effectiveness of an agent can be determined by assessing physical indicators of the condition or desired response. It is well within the capabilities of a person skilled in the art to monitor the effectiveness of administration and / or treatment by measuring any one of such parameters, or any combination of parameters. Efficacy can be evaluated in animal models of conditions described herein, e.g., treating diabetes or cancer. When using experimental animal models, the effectiveness of treatment is demonstrated when a statistically significant change in the marker is observed.

[0143] Provided herein are in vitro and animal model assays that allow the evaluation of a given dose of the compositions described herein, for example, compositions that comprise at least one IL in combination with at least one active compound.As a non-limiting example, the effect of a dose of a composition that comprises at least one IL in combination with insulin can be evaluated by using the models described in the examples herein.

[0144] The incidence of obesity is rising, and existing treatments such as dietary therapy are notoriously poor in long-term success. Additional treatments and strategies to reduce obesity or reduce the rate of weight gain are crucial to address both obesity itself and the number of conditions caused or exacerbated by excess weight. Without wishing to be bound by theory, it is contemplated herein that the ILs described herein may reduce the uptake of hydrophobic / lipophilic molecules in the intestine. Thus, provided herein are methods of treating obesity and / or reducing weight / weight gain by administering at least one IL described herein to a subject in need thereof. In some embodiments of any aspect, the subject treated by the method of the invention is a subject who does not have or has not been diagnosed as having diabetes. In some embodiments of any aspect, the subject treated by the method of the invention is a subject who has not been administered insulin. In some embodiments of any aspect, the composition comprising at least one IL does not comprise insulin. In some embodiments of any aspect, the composition comprising at least one IL does not comprise another pharma- ceutically active ingredient and / or another agent that has a therapeutic effect in the treatment of diabetes.

[0145] In some embodiments of any aspect, the active compound is therapeutically effective in treating obesity. In some embodiments of any aspect, the active compound is therapeutically effective in treating diseases associated with obesity. In some embodiments of any aspect, the active compound is therapeutically effective in treating diseases caused by obesity. In some embodiments of any aspect, the active compound is therapeutically effective in treating diseases that cause obesity. In some embodiments of any aspect, the active compound is therapeutically effective in treating metabolic syndrome.

[0146] In some embodiments of any aspect, the subject to whom the composition comprising at least one IL described herein, e.g., in combination with an active compound, is administered is a subject who has, has been diagnosed as having, obesity, excess weight, or is in need of treatment of obesity, excess weight, or prevention of weight gain. In some embodiments, the subject is overweight. The methods described herein include methods of treating obesity, reducing weight gain, preventing weight gain, promoting weight loss, and the like. Such methods can, for example, promote metabolic health and prepare the patient for surgical interventions pursued for aesthetic reasons and / or contraindicated for patients with high BMI or weight. In some embodiments, for example, weight loss can be medically necessary and / or medically indicated, e.g., when the subject is overweight and / or obese. In some embodiments, weight loss can be cosmetic, e.g., when the subject desires to lose weight, regardless of whether weight loss is medically necessary and / or medically indicated.

[0147] The term "obesity" refers to excess fat in the body. Obesity can be determined by any measure accepted and utilized by those skilled in the art. Currently, an accepted measure of obesity is the Body Mass Index (BMI), which is a measure of body weight in kilograms relative to the square of height in meters. Generally, for adults over 20 years of age, a BMI between about 18.5 and 24.9 is considered normal, a BMI between about 25.0 and 29.9 is considered overweight, a BMI of about 30.0 or greater is considered obese, and a BMI of about 40 or greater is considered morbidly obese. (See, e.g., Gallagher et al. (2000) Am J Clin Nutr 72:694-701.) These BMI ranges are based on the effect of body weight on increased risk of disease. Some common conditions associated with high BMI and obesity include cardiovascular disease, high blood pressure (i.e., hypertension), osteoarthritis, cancer, and diabetes. Although BMI correlates with body fat, the relationship between BMI and actual body fat varies with age and gender. For example, for the same BMI, women are more likely to have a higher body fat percentage than men.Furthermore, the BMI thresholds that distinguish between normal, overweight, and obesity may vary, for example, by age, sex, ethnicity, health, and body type, among other factors.In some embodiments, obese subjects are at least about 25 kg / m before undergoing the treatment described herein. 2 In some embodiments, a subject with obesity has a body mass index of at least about 30 kg / m prior to the treatment described herein. 2 The subject may have a body mass index of

[0148] In some embodiments of any aspect, the subject to whom the composition comprising at least one IL described herein, for example in combination with at least one active compound, is administered is a subject who has, has been diagnosed as having, or needs treatment for metabolic disorder or metabolic syndrome. The term "metabolic disorder" refers to any disorder associated with or exacerbated by impaired or altered glucose regulation or glycemic control, such as, for example, insulin resistance. Such disorders include, but are not limited to, obesity; excess adipose tissue; diabetes; fatty liver disease; nonalcoholic fatty liver disease; metabolic syndrome; dyslipidemia; hypertension; hyperglycemia; and cardiovascular disease. "Metabolic syndrome" is distinct from metabolic disorder and refers to a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. Several definitions of metabolic syndrome have been established, for example, by the American Heart Association and the International Diabetes Foundation. By way of example only, the WHO defines metabolic syndrome as the presence of any one of diabetes mellitus, impaired glucose tolerance, impaired fasting glucose or insulin resistance, and two of the following: blood pressure 140 / 90 mmHg or higher, dyslipidemia, central obesity, and microalbuminuria.In some embodiments, the metabolic disorder can be selected from the group consisting of: obesity; excess adipose tissue; diabetes; and cardiovascular disease.

[0149] The uptake of many active compounds, for example pharmacologic active compounds, can be improved by delivering the compound in a solvent.However, such approaches are often inappropriate for in vivo use, since most of such solvents exhibit toxic side effects and / or act as irritants at the time of delivery.Described herein are methods and compositions that can provide improved delivery kinetics and low toxicity.

[0150] For convenience, the meanings of some terms and phrases used in the specification, examples, and the appended claims are provided below. Unless otherwise stated or implied from the context, the following terms and phrases include the meanings provided below. Since the scope of the present invention is limited only by the claims, this definition is provided to help explain certain embodiments and is not intended to limit the claimed invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided herein shall prevail.

[0151] For convenience, the present specification collects here certain terms used in the specification, examples, and appended claims.

[0152] Carboxylic acids are carbonyl-bearing functional groups having the formula RCOOH, where R is aliphatic, heteroaliphatic, alkyl, or heteroalkyl.

[0153] As used herein, the term "alkyl" refers to a straight or branched, saturated aliphatic radical having a chain of carbon atoms. The term "alkyl" includes cycloalkyl or cyclic alkyl. x Alkyl and C x ~C y Alkyl is typically used where X and Y indicate the number of carbon atoms in the chain. For example, C1-C6 alkyl includes alkyls having a chain of 1 to 6 carbons (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, etc.). Alkyl represented with another radical (such as, for example, arylalkyl) means a straight or branched, saturated alkyl divalent radical having the indicated number of atoms, or if no atoms are shown, a bond is represented, such as, for example, (C6-C 10)Aryl(C0-C3)alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, and the like. The alkyl backbone can optionally be interrupted by one or more heteroatoms such as N, O, or S. Examples of alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, and n-octyl radicals.

[0154] In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), more preferably 20 or fewer carbon atoms. Similarly, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, more preferably 5, 6 or 7 carbons in the ring structure. The term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter of which refers to an alkyl moiety having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.

[0155] Unless the carbon number is otherwise specified, "lower alkyl" as used herein means an alkyl group as defined above, but having from 1 to 10 carbons in its backbone structure, more preferably from 1 to 6 carbon atoms. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyl. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0156] Substituents of substituted alkyls can include halogen, hydroxy, nitro, thiol, amino, azide, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyl and sulfonates), and silyl groups, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, and the like.

[0157] As used herein, the term "alkenyl" refers to an unsaturated straight-chain, branched-chain, or cyclic hydrocarbon radical having at least one carbon-carbon double bond. x Alkenyl and C x ~C y Alkenyl is typically used, where X and Y indicate the number of carbon atoms in the chain. For example, C2-C6 alkenyl includes alkenyls having a chain of 1-6 carbons and at least one double bond, such as vinyl, allyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, 1-hexenyl, 3-hexenyl, 3-hexenyl, etc. Alkenyl represented with another radical (such as arylalkenyl) refers to a straight or branched, alkenyl divalent radical having the indicated number of atoms. The backbone of an alkenyl can optionally be inserted with one or more heteroatoms, such as N, O, or S.

[0158] As used herein, the term "alkynyl" refers to an unsaturated hydrocarbon radical having at least one carbon-carbon triple bond. x Alkynyl and C x ~C yAlkynyl is typically used, where X and Y indicate the number of carbon atoms in the chain. For example, C2-C6 alkynyl includes alkynyls having a chain of 1-6 carbons and at least one triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, isopentynyl, 1,3-hexa-diyn-yl, n-hexynyl, 3-pentynyl, 1-hexen-3-ynyl, and the like. Alkynyl represented with another radical (such as arylalkynyl) refers to a straight or branched, alkynyl divalent radical having the indicated number of atoms. The backbone of the alkynyl can optionally be inserted with one or more heteroatoms, such as N, O, or S.

[0159] The term "halogen" or "halo" as used herein refers to an atom selected from fluorine, chlorine, bromine and iodine. The term "halogen radioisotope" or "haloisotope" refers to a radioactive nuclide of an atom selected from fluorine, chlorine, bromine and iodine. "Halogen-substituted moiety" or "halo-substituted moiety" as an isolated group or part of a larger group refers to an aliphatic, alicyclic, or aromatic moiety as described herein, substituted with one or more "halo" atoms, as such terms are defined in this application. For example, halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, etc. (e.g., halo-substituted (C1-C3) alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl (-CF3), 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, etc.).

[0160] The term "cyclyl" or "cycloalkyl" refers to saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, e.g., 3 to 8 carbons, and e.g., 3 to 6 carbons. x Cyclyl and C x ~C yCyclyl is typically used, where X and Y indicate the number of carbon atoms in the ring system. Cycloalkyl groups can be further optionally substituted, for example, with 1, 2, 3, or 4 substituents. Examples of cyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, cycloheptyl, cyclooctyl, bicyclo[2.2.2]octyl, adamantan-l-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, and the like.

[0161] The term "heterocyclyl" refers to a non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms in the case of a monocyclic ring, 1-6 heteroatoms in the case of a bicyclic ring, or 1-9 heteroatoms in the case of a tricyclic ring, the heteroatoms being selected from O, N, or S (e.g., having carbon atoms and 1-3, 1-6, or 1-9 N, O, or S heteroatoms in the case of a monocyclic ring, a bicyclic ring, or a tricyclic ring, respectively). x Heterocyclyl and C x ~C y Heterocyclyl is typically used, where X and Y indicate the number of carbon atoms in the ring system.In some embodiments, 1, 2 or 3 hydrogen atoms of each ring can be replaced by a substituent.Exemplary heterocyclyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,4-diazaperhydroepynyl, 1,3-dioxanyl, 1,4-dioxanyl, etc.

[0162] The terms "bicyclic" and "tricyclic" refer to polycyclic ring assemblies that are fused, bridged, or linked by single bonds. As used herein, the term "fused ring" refers to a ring that is bonded to another ring to form a compound having a bicyclic structure, with ring atoms common to both rings directly bonded to each other. Non-exclusive examples of common fused rings include decalin, naphthalene, anthracene, phenanthrene, indole, furan, benzofuran, quinoline, and the like. Compounds with fused ring systems can be saturated, partially saturated, cyclyl, heterocyclyl, aromatic, heteroaromatic, and the like.

[0163] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic fused aromatic ring system. x Aryl and C x ~C yAryl is typically used where X and Y indicate the number of carbon atoms in the ring system. Exemplary aryl groups include pyridinyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrazolyl, pyridazinyl, pyrazinyl, triazinyl, tetrazolyl, indolyl, benzyl, phenyl, naphthyl, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3 b]Tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, Examples of the aryl group include, but are not limited to, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, and xanthenyl. In some embodiments, 1, 2, 3, or 4 hydrogen atoms of each ring may be replaced by a substituent.

[0164] The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered fused bicyclic, or 11-14 membered fused tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 N, O, or S heteroatoms, respectively, in the case of monocyclic, bicyclic, or tricyclic ring systems). x Heteroaryl and C x ~C yHeteroaryl is typically used, where X and Y indicate the number of carbon atoms in the ring system. Heteroaryl includes benzo[b]furan, benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine, indolizine, imidazo[l,2a]pyridine, quinoline, isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzamide, ... benzothiazole, imidazo[l,5-a]pyridine, pyrazolo[1,5-a]pyridine, imidazo[l,2-a]pyrimidine, imidazo[l,2-c]pyrimidine, imidazo[l,5-a]pyrimidine, imidazo[l,5-c]pyrimidine, pyrrolo[2,3-b]pyridine, pyrrolo[2,3cj]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-d]pyrim ... pyrazine, pyrazolo[1,5-a]pyridine, pyrrolo[l,2-b]pyridazine, pyrrolo[l,2-c]pyrimidine, pyrrolo[l,2-a]pyrimidine, pyrrolo[l,2-a]pyrazine, triazo[l,5-a]pyridine, pteridine, purine, carbazole, acridine, phenazine, phenothiazene, phenoxazine, l,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, pyrido[l,2-a]indole, 2(lH) -pyridinone, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, Venn diagram thiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3b] Tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octaphenyl, ... hydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxepanyl, oxetanyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, Piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydrofuranyl, Some exemplary heteroaryl groups include, but are not limited to, those derived from pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, pyridazinyl, pyrazinyl, quinolinyl, indolyl, thiazolyl, naphthyridinyl, 2-amino-4-oxo-3,Examples include, but are not limited to, 4-dihydropyridin-6-yl, tetrahydroisoquinolinyl, and the like. In some embodiments, 1, 2, 3, or 4 hydrogen atoms of each ring may be replaced by a substituent.

[0165] The term "substituted," as used herein, refers to the independent replacement of one or more hydrogen atoms on a substituted moiety with a substituent independently selected from, but not limited to, alkyl, alkenyl, heterocycloalkyl, alkoxy, aryloxy, hydroxy, amino, amido, alkylamino, arylamino, cyano, halo, mercapto, nitro, carbonyl, acyl, aryl, and heteroaryl groups.

[0166] The term "substituted" as used herein refers to the independent replacement of one or more (typically 1, 2, 3, 4, or 5) hydrogen atoms on a substituted moiety with a substituent independently selected from the group of substituents listed below or otherwise specified in the definition of "substituent." In general, a non-hydrogen substituent may be any substituent that may be bonded to an atom of a given moiety that is specified to be substituted. Examples of the substituents include acyl, acylamino, acyloxy, aldehyde, alicyclic, aliphatic, alkanesulfonamido, alkanesulfonyl, alkaryl, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylcarbanoyl, alkylene, alkylidene, alkylthio, alkynyl, amide, amido, amino, amino, aminoalkyl, aralkyl, aralkylsulfonamido, arenesulfonamido, arenesulfonyl, aromatic, aryl, arylamino, arylcarbanoyl, aryloxy, azido, carbamoyl, carbonyl, carbonyls (including ketone, carboxy, carboxylate), CF3, cyano( CN), cycloalkyl, cycloalkylene, ester, ether, haloalkyl, halogen, halogen, heteroaryl, heterocyclyl, hydroxy, hydroxy, hydroxyalkyl, imino, iminoketone, ketone, mercapto, nitro, oxaalkyl, oxo, oxoalkyl, phosphoryl (including phosphonate and phosphinate), silyl groups, sulfonamide, sulfonyl (including sulfate, sulfamoyl, and sulfonate), thiol, and ureido moieties, each of which may be substituted or unsubstituted. In some cases, two substituents, together with the carbons to which they are attached, may also form a ring.

[0167] The aryl and heteroaryl may be optionally substituted at one or more positions with one or more substituents, such as halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, and the like.

[0168] The term "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Thus, the substituent of an alkyl that makes it an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl. An aroxy may be represented by -O-aryl or O-heteroaryl, where aryl and heteroaryl are as defined below. The alkoxy and aroxy groups may be substituted as previously described for alkyl.

[0169] The term "aralkyl," as used herein, refers to an alkyl group substituted with an aryl group (eg, an aromatic or heteroaromatic group).

[0170] The term "alkylthio" as used herein refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In preferred embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, and -S-alkynyl. Representative alkylthio groups include methylthio, ethylthio, and the like. The term "alkylthio" also encompasses cycloalkyl groups, alkene and cycloalkene groups, and alkyne groups. "Arylthio" refers to an aryl or heteroaryl group.

[0171] The term "sulfinyl" refers to the radical -SO-. It is noted that the sulfinyl radical can be further substituted with a variety of substituents to form different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, sulfoxides, and the like.

[0172] The term "sulfonyl" refers to the radical -SO2-. It is noted that the sulfonyl radical can be further substituted with a variety of substituents to form different sulfonyl groups including sulfonic acid (-SO3H), sulfonamides, sulfonate esters, sulfones, and the like.

[0173] The term "thiocarbonyl" refers to the radical -C(S)-. It is noted that the thiocarbonyl radical can be further substituted with a variety of substituents to form different thiocarbonyl groups including thioacids, thioamides, thioesters, thioketones, and the like.

[0174] The term "amino" as used herein means -NH2. The term "alkylamino" means a nitrogen moiety having at least one straight or branched unsaturated aliphatic, cyclyl, or heterocyclyl radical attached to the nitrogen. For example, representative amino groups include -NH2, -NHCH3, -N(CH3)2, -NH(C1-C 10 Alkyl), -N(C1-C 10The term "alkylamino" includes "alkenylamino", "alkynylamino", "cyclylamino", and "heterocyclylamino". The term "arylamino" refers to a nitrogen moiety having at least one aryl radical attached to the nitrogen. For example, -NHaryl, and -N(aryl)2. The term "heteroarylamino" refers to a nitrogen moiety having at least one heteroaryl radical attached to the nitrogen. For example, -NHheteroaryl, and -N(heteroaryl)2. Optionally, the two substituents can form a ring together with the nitrogen. Unless otherwise specified, compounds described herein that contain an amino moiety can include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tertbutoxycarbonyl, benzyloxycarbonyl, and the like.

[0175] The term "aminoalkyl" refers to alkyl, alkenyl, and alkynyl as defined above, except that one or more substituted or unsubstituted nitrogen atoms (-N-) are positioned between the carbon atoms of the alkyl, alkenyl, or alkynyl. For example, (C2-C6)aminoalkyl refers to a chain containing from 2 to 6 carbon and one or more nitrogen atoms positioned between the carbon atoms.

[0176] The term "alkoxyalkoxy" means -O-(alkyl)-O-(alkyl), such as -OCH2CHOCH3 and the like. The term "alkoxycarbonyl" means -C(O)O-(alkyl), such as -C(=O)OCH3, -C(=O)OCH2CH3 and the like. The term "alkoxyalkyl" means -(alkyl)-O-(alkyl), such as -CHOCH3, -CHOCH2CH3 and the like. The term "aryloxy" means -O-(aryl), such as -O-phenyl, -O-pyridinyl and the like. The term "arylalkyl" means -(alkyl)-(aryl), such as benzyl (i.e. -CH2phenyl), -CH2-pyrindinyl and the like. The term "arylalkyloxy" means -O-(alkyl)-(aryl), such as -O-benzyl, -O-CH2-pyridinyl and the like. The term "cycloalkyloxy" means -O-(cycloalkyl), such as -O-cyclohexyl and the like. The term "cycloalkylalkyloxy" means -O-(alkyl)-(cycloalkyl, e.g., -OCHcyclohexyl, etc. The term "aminoalkoxy" means -O-(alkyl)-NH, e.g., -OCHNH, -OCHCHNH, etc. The term "mono- or dialkylamino" means -NH(alkyl) or -N(alkyl)(alkyl), respectively, e.g., -NHCH, -N(CH). The term "mono- or dialkylaminoalkoxy" means -O-(alkyl)-NH(alkyl) or -O-(alkyl)-N(alkyl)(alkyl), respectively. The term "arylamino" means -NH(aryl), such as -NH-phenyl, -NH-pyridinyl, and the like. The term "arylalkylamino" means -NH-(alkyl)-(aryl), such as -NH-benzyl, -NHCH2-pyridinyl, and the like. The term "alkylamino" means -NH(alkyl), such as -NHCH3, -NHCH2CH3, and the like. The term "cycloalkylamino" means -NH-(cycloalkyl), such as -NH-cyclohexyl, and the like.The term "cycloalkylalkylamino" refers to -NH-(alkyl)-(cycloalkyl), such as -NHCH2-cyclohexyl.

[0177] It should be noted that with respect to all definitions provided herein, the definitions should be interpreted as open-ended in the sense that they may include additional substituents other than those specified. Thus, C1 alkyl indicates that there is one carbon atom, but does not indicate what the substituents on the carbon atom are. Thus, C1 alkyl includes methyl (i.e., -CH3) as well as CR a R b R c where R a , R b , and R c may each independently be hydrogen or any other substituent where the atom alpha to the carbon is a heteroatom or cyano. Thus, CF3, CH2OH and CH2CN are all C1 alkyls.

[0178] Unless otherwise stated, structures depicted herein are meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of a hydrogen atom by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon atom with a C-enriched carbon are within the scope of this invention.

[0179] The term "isomers" as used herein refers to compounds that have the same molecular formula but different structures. Isomers that differ only in configuration and / or conformation are called "stereoisomers." The term "isomer" is also used to refer to enantiomers.

[0180] The term "enantiomer" is used to describe one of a pair of molecular isomers that are mirror images of each other and are non-superimposable. Other terms used to designate or refer to enantiomers include "stereoisomers" (due to different arrangements or stereochemistry around the chiral center; all enantiomers are stereoisomers, but not all stereoisomers are enantiomers) or "enantiomers" (due to the optical activity of the pure enantiomers, which is the ability of different pure enantiomers to rotate plane polarized light in different directions). Enantiomers generally have the same physical properties, such as melting points and boiling points, and also have the same spectroscopic properties. Enantiomers can differ from each other with respect to their interaction with plane polarized light and with respect to biological activity.

[0181] The terms "racemic mixture," "racemic compound," or "racemate" refer to a mixture of two enantiomers of a compound. An ideal racemic mixture is one that contains a 50:50 mixture of both enantiomers of a compound, such that the optical rotation of the (+) enantiomer cancels out the optical rotation of the (-) enantiomer.

[0182] The term "resolving" or "resolution" when used in reference to a racemic mixture refers to the separation of a racemate into its two mirror image forms (i.e., (+) and (-); or (R) and (S) forms). The term can also refer to the enantioselective conversion of a racemate into a single isomeric product.

[0183] The term "enantiomeric excess" or "ee" refers to a reaction product in which one enantiomer is produced in excess of the other, expressed as a molar or weight or volume ratio F (+) and F (-) (F (+) and F (-) The enantiomeric excess is defined as a mixture of (+)- and (-)-enantiomers with the composition shown in (1). (+) -F (-) * and the percent enantiomeric excess is 100 × *F (+) -F (-)* According to. The "purity" of an enantiomer is described by its ee or percent ee value (% ee).

[0184] Whether referred to as a "purified enantiomer" or a "pure enantiomer" or a "resolved enantiomer" or an "enantiomeric excess of a compound," the term is intended to indicate that the amount of one enantiomer exceeds the amount of the other. Thus, when referring to an enantiomeric preparation, the percentage (e.g., mole or weight or volume) of the major enantiomer and / or the percent enantiomeric excess of the major enantiomer may be used to determine whether the preparation represents a purified enantiomeric preparation.

[0185] The terms "enantiomeric purity" or "enantiomeric purity" of an isomer refer to a qualitative or quantitative measure of a purified enantiomer; typically, the measurement is expressed in terms of ee or enantiomeric excess.

[0186] The terms "substantially purified enantiomer," "substantially resolved enantiomers," and "substantially purified enantiomeric preparation" are intended to indicate a preparation (e.g., derived from non-optically active starting materials, substrates, or intermediates) that is enriched in one enantiomer over the other, more preferably in which the other enantiomer constitutes less than 20%, more preferably less than 10%, more preferably less than 5%, and even more preferably less than 2% of the enantiomer or enantiomeric preparation.

[0187] The terms "purified enantiomer", "resolved enantiomer" and "purified enantiomer preparation" are intended to indicate a preparation (e.g., derived from non-optically active starting materials, substrates, or intermediates) that is enriched in one enantiomer (e.g., the R-enantiomer) over the other, and more preferably, the other enantiomer (e.g., the S-enantiomer) constitutes less than 30% of the preparation, preferably less than 20%, more preferably less than 10% (e.g., in this particular case, the R-enantiomer is substantially free of the S-enantiomer), more preferably less than 5%, and even more preferably less than 2%. A purified enantiomer may be synthesized substantially free of the other enantiomer, or a purified enantiomer may be synthesized by a stereopreferential procedure followed by a separation step, or a purified enantiomer may be derived from a racemic mixture.

[0188] The term "enantioselectivity", also called enantiomeric ratio, denoted by the symbol "E", refers to the selective ability of an enzyme to produce one enantiomer from a racemic substrate, relative to the other enantiomer in the product racemic mixture; i.e., it is a measure of the enzyme's ability to distinguish between enantiomers. A nonselective reaction has an E of 1, while resolutions with an E of 20 or more are generally considered useful in synthesis or resolution. Enantioselectivity consists in the difference in the rate of conversion between the enantiomers in question. A reaction product is obtained that is enriched in one of the enantiomers; conversely, the remaining substrate is enriched in the other enantiomer. For practical purposes, it is generally desirable to obtain a large excess of one enantiomer. This is achieved by terminating the conversion process at a certain degree of conversion.

[0189] CAGE (choline and geranate) is an ionic liquid that includes the cation choline (see, e.g., Structure I) and the anion geranate or geranic acid (see, e.g., Structures II and III). Preparation of CAGE can be as described, for example, in International Patent Publication WO 2015 / 066647, which is incorporated herein by reference in its entirety, or as described in the Examples herein. TIFF2025069232000006.tif167128

[0190] The terms "reduce", "reduced", "reduction" or "inhibit" are all used herein to mean a statistically significant amount of reduction. In some embodiments, "reduce", "reduction" or "reduce" or "inhibit" generally means a reduction of at least 10% compared to a reference level (e.g., the absence of a given treatment or agent), and may include, for example, a reduction of at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or more. As used herein, "reduce" or "inhibit" does not encompass complete inhibition or reduction compared to a reference level. "Complete inhibition" is 100% inhibition compared to a reference level. The decrease can preferably be down to a level that is accepted as within the normal range for individuals without the given disorder.

[0191] The terms "increased", "increase", "enhance", or "activate" are all used herein to mean a statically significant amount of increase. In some embodiments, the terms "increased", "increase", "enhance", or "activate" can mean an increase of at least 10% compared to a reference level, such as at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or an increase of less than or equal to 100%, or any increase between 10-100% compared to a reference level, or at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold, or any increase between 2-fold and 10-fold or more compared to a reference level. In the context of a marker or condition, an "increase" is a statistically significant increase in such level.

[0192] As used herein, "subject" refers to a human or an animal. Typically, an animal is a vertebrate, such as a primate, a rodent, a livestock animal, or a game animal. Primates include chimpanzees, macaques, such as cynomolgus monkeys, spider monkeys, and rhesus monkeys. Rodents include mice, rats, woodchucks, ferrets, rabbits, and hamsters. Domestic and game animals include cattle, horses, pigs, deer, bison, buffalo, feline species, such as house cats, canine species, such as dogs, foxes, wolves, bird species, such as chickens, emus, ostriches, and fish, such as trout, catfish, and salmon. In some embodiments, the subject is a mammal, such as a primate, such as a human. The terms "individual," "patient," and "subject" are used interchangeably herein.

[0193] Preferably, the subject is a mammal.The mammal can be, but is not limited to, human, non-human primate, mouse, rat, dog, cat, horse, or cow.A non-human mammal can be advantageously used as a subject to represent the animal model of the disease described herein.The subject can be male / male or female / female.

[0194] The subject may be one that has been previously diagnosed with or identified as suffering from a condition that requires treatment or one or more complications associated with such a condition, and may optionally have already been treated for the condition or one or more complications associated with the condition. Alternatively, the subject may not have been previously diagnosed with the condition or one or more complications associated with the condition. For example, the subject may be one that exhibits one or more risk factors for the condition or one or more complications associated with the condition, or one that does not exhibit risk factors.

[0195] A "subject in need" of treatment for a particular condition can be a subject who has the condition, has been diagnosed with the condition, or is at risk for developing the condition.

[0196] As used herein, the terms "protein" and "polypeptide" are used interchangeably herein to refer to a series of amino acid residues connected to each other by peptide bonds between the alpha amino and carboxy groups of adjacent residues. The terms "protein" and "polypeptide" refer to a polymer of amino acids, including modified amino acids (e.g., phosphorylation, glycation, glycosylation, etc.) and amino acid analogs, regardless of their size or function. Although "protein" and "polypeptide" are often used in reference to relatively large polypeptides, while the term "peptide" is often used in reference to small polypeptides, the usage of these terms in the art overlaps. The terms "protein" and "polypeptide" are used interchangeably herein when referring to gene products and fragments thereof. Thus, exemplary polypeptides or proteins include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments and other equivalents, variants, fragments, and analogs of the foregoing.

[0197] In various embodiments described herein, it is further intended to encompass any variant (natural or otherwise), allele, homolog, conservatively modified variant, and / or conservatively substituted variant of the specific polypeptide described.With respect to amino acid sequences, those skilled in the art will recognize that individual substitutions, deletions, or additions to nucleic acid, peptide, polypeptide, or protein sequences that modify a single amino acid or a small percentage of amino acids in the encoded sequence are "conservatively modified variants" where the modification results in the replacement of an amino acid with a chemically similar amino acid and the desired activity of the polypeptide is retained.Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles consistent with the present disclosure.

[0198] A given amino acid can be replaced with a residue having similar physiochemical characteristics, such as replacing one aliphatic residue with another (e.g., Ile, Val, Leu, or Ala with each other), or replacing one polar residue with another (e.g., between Lys and Arg; Glu and Asp; or Gln and Asn). Other such conservative substitutions, such as the substitution of entire regions with similar hydrophobic characteristics, are well known. Polypeptides containing conservative amino acid substitutions can be tested in any one of the assays described herein to confirm that the desired activity, such as the activity and specificity of the native or reference polypeptide, is retained.

[0199] Amino acids can be grouped by similarities in the properties of their side chains (in A.L. Lehninger, in Biochemistry, second ed., pp. 73-75, Worth Publishers, New York (1975)): (1) nonpolar: Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Trp (W), Met (M); (2) uncharged polar: Gly (G), Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N), Gln (Q); (3) acidic: Asp (D), Glu (E); (4) basic: Lys (K), Arg (R), His (H). Alternatively, naturally occurring residues can be divided into groups based on shared side chain properties: (1) hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that affect chain orientation: Gly, Pro; (6) aromatic: Trp, Tyr, Phe. Non-conservative substitutions involve exchanging a member of one of these classes for another. Particular conservative substitutions include, for example, Ala to Gly or Ser; Arg to Lys; Asn to Gln or His; Asp to Glu; Cys to Ser; Gln to Asn; Glu to Asp; Gly to Ala or Pro; His to Asn or Gln; Ile to Leu or Val; Leu to Ile or Val; Lys to Arg, Gln, or Glu; Met to Leu, Tyr, or Ile; Phe to Met, Leu, or Tyr; Ser to Thr; Thr to Ser; Trp to Tyr; Tyr to Trp; and / or Phe to Val, Ile, or Leu.

[0200] In some embodiments, the polypeptides described herein (or nucleic acids encoding such polypeptides) may be functional fragments of one of the amino acid sequences described herein.As used herein, a "functional fragment" is a fragment or section of a peptide that retains at least 50% of the activity of a wild-type reference polypeptide by the assays described herein below.Functional fragments may include conservative substitutions of the sequences disclosed herein.

[0201] In some embodiments, the polypeptides described herein may be variants of the sequences described herein. In some embodiments, the variants are conservatively modified variants. Conservative substitution variants can be obtained, for example, by mutation of native nucleotide sequences. As referred to herein, "variants" are polypeptides that are substantially homologous to native or reference polypeptides, but have amino acid sequences that differ from those of native or reference polypeptides due to one or more deletions, insertions, or substitutions. The DNA sequence encoding the variant polypeptide encompasses sequences that encode variant proteins or fragments thereof that contain one or more nucleotide additions, deletions, or substitutions when compared to native or reference DNA sequences, but retain activity. A wide variety of PCR-based site-directed mutagenesis approaches are known in the art and can be applied by those skilled in the art.

[0202] The variant amino acid or DNA sequence may be at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more, identical to the native or reference sequence. The degree of homology (percent identity) between a native and a variant sequence can be determined by comparing the two sequences, for example, using freely available computer programs widely used for this purpose on the World Wide Web (e.g., BLASTp or BLASTn with default settings).

[0203] In some embodiments of either aspect, the variant may be a polypeptide having at least 90%, at least 95%, at least 98% or more sequence homology to one of the reference sequences provided herein and retaining the wild-type activity, e.g., incretin activity, of the reference sequence. In some embodiments of either aspect, the variant may be a polypeptide having at least 90%, at least 95%, at least 98% or more sequence homology to one of the native reference sequences provided herein and retaining the wild-type activity, e.g., incretin activity, of the reference sequence. In some embodiments of either aspect, the variant may be a native polypeptide having at least 90%, at least 95%, at least 98% or more sequence homology to one of the reference sequences provided herein and retaining the wild-type activity, e.g., incretin activity, of the reference sequence.

[0204] Modification of the native amino acid sequence can be accomplished by any of a number of techniques known to those skilled in the art. Mutations can be introduced at specific loci, for example, by synthesizing oligonucleotides containing the mutated sequence flanked by restriction sites that allow ligation to a fragment of the native sequence. After ligation, the resulting reconstructed sequence encodes an analog with the desired amino acid insertion, substitution, or deletion. Alternatively, oligonucleotide-directed site-specific mutagenesis procedures can be used to provide modified nucleotide sequences with specific codons modified by the required substitution, deletion, or insertion. Techniques for making such modifications are very well established and include, for example, those disclosed in Walder et al. (Gene 42:133, 1986); Bauer et al. (Gene 37:73, 1985); Craik (BioTechniques, January 1985, 12-19); Smith et al. (Genetic Engineering: Principles and Methods, Plenum Press, 1981); and U.S. Patent Nos. 4,518,584 and 4,737,462, which are incorporated herein by reference in their entirety. Any cysteine ​​residue not involved in maintaining the correct conformation of the polypeptide can also be substituted, generally with serine, to improve the oxidative stability of the molecule and prevent aberrant cross-linking. Conversely, cysteine ​​bond(s) can be added to a polypeptide to improve its stability or promote oligomerization.

[0205] As used herein, the term "antibody" refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site that immunospecifically binds to an antigen. The term also refers to antibodies consisting of two immunoglobulin heavy chains and two immunoglobulin light chains, including, for example, immunoglobulin molecules, monoclonal antibodies, chimeric antibodies, CDR-grafted antibodies, humanized antibodies, Fab, Fab', F(ab')2, Fv, disulfide-linked Fv, scFv, single domain antibodies (dAbs), diabodies, multispecific antibodies, dual specific antibodies, anti-idiotypic antibodies, bispecific antibodies, functionally active epitope-binding portions thereof, and / or bifunctional hybrid antibodies, as well as various forms including full-length antibodies and antigen-binding portions thereof. Each heavy chain is composed of a variable region of the heavy chain (abbreviated herein as HCVR or VH) and a constant region of said heavy chain. The heavy chain constant region is composed of three domains, CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as LCVR or VL) and a constant region of said light chain. The light chain constant region is composed of a CL domain. The VH and VL regions may be further divided into hypervariable regions called complementarity determining regions (CDRs) interlaced with conserved regions called framework regions (FRs). Thus, each VH and VL region is composed of three CDRs and four FRs arranged from N-terminus to C-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. This structure is well known to those skilled in the art.

[0206] As used herein, the term "antibody reagent" refers to a polypeptide that contains at least one immunoglobulin variable domain or immunoglobulin variable domain sequence and specifically binds to a given antigen. An antibody reagent may include an antibody or a polypeptide that contains an antigen-binding domain of an antibody. In some embodiments, an antibody reagent may include a monoclonal antibody or a polypeptide that contains an antigen-binding domain of a monoclonal antibody. For example, an antibody may include a heavy (H) chain variable region (abbreviated herein as VH) and a light (L) chain variable region (abbreviated herein as VL). In another example, an antibody includes two heavy (H) chain variable regions and two light (L) chain variable regions. The term "antibody reagent" encompasses antigen-binding fragments of antibodies (e.g., single chain antibodies, Fab and sFab fragments, F(ab')2, Fd fragments, Fv fragments, scFv, and domain antibody (dAb) fragments as well as complete antibodies.

[0207] Antibodies and / or antibody reagents may include immunoglobulin molecules, monoclonal antibodies, chimeric antibodies, CDR-grafted antibodies, humanized antibodies, fully human antibodies, Fab, Fab', F(ab')2, Fv, disulfide-linked Fv, scFv, single domain antibodies, diabodies, multispecific antibodies, dual specific antibodies, anti-idiotypic antibodies, bispecific antibodies, and functionally active epitope-binding portions thereof.

[0208] The term "nanobody" or single domain antibody (sdAb) as used herein refers to antibodies (VHH) that contain small single variable domains of antibodies obtained from camels and dromedaries. Antibody proteins obtained from members of the camel and dromedary families (Camelus baclrianus and Calelus dromaderius), including New World members such as llama species (Lama paccos, lama glama, lama vicugna), have been characterized with respect to size, structural complexity, and antigenicity to human subjects. Certain IgG antibodies from this family of mammals found in nature lack light chains and are therefore structurally distinct from the typical four-chain quaternary structure with two heavy chains and two light chains of antibodies from other animals. See PCT / EP93 / 02214 (WO 94 / 04678 published March 3, 1994; which is incorporated herein by reference in its entirety).

[0209] Regions of camelid antibodies, the small single variable domains identified as VHHs, can be genetically engineered to generate small proteins with high affinity for targets, resulting in low molecular weight antibody-derived proteins known as "camelid nanobodies". See U.S. Patent No. 5,759,808, issued June 2, 1998; see also Stijlemans, B. et al., 2004 J Biol Chem 279: 1256-1261; Dumoulin, M. et al., 2003 Nature 424: 783-788; Pleschberger, M. et al. 2003 Bioconjugate Chem 14: 440-448; Cortez-Retamozo, V. et al. 2002 Int J Cancer 89: 456-62; and Lauwereys, M. et al. 1998 EMBO J. 17: 3512-3520; each of which is incorporated by reference in its entirety. Engineered libraries of camelid antibodies and antibody fragments are commercially available, for example from Ablynx, Ghent, Belgium. As with other antibodies of non-human origin, the amino acid sequences of camelid antibodies can be recombinantly modified to obtain sequences that more closely resemble human sequences, i.e. the nanobodies can be "humanized". Thus, the naturally low antigenicity of camelid antibodies to humans can be further reduced.

[0210] Camelid nanobodies have a molecular weight approximately one-tenth that of human IgG molecules, and the protein has a physical diameter of only a few nanometers. One significance of the small size is that camelid nanobodies are capable of binding to antigenic sites that are functionally invisible to larger antibody proteins, i.e., camelid nanobodies are useful as reagents for detecting antigens obscured using classical immunological techniques, and as potential therapeutic agents. Another significance of the small size is therefore that camelid nanobodies can bind to and inhibit specific sites in grooves or narrow clefts of target proteins, and thus act in a capacity that more closely resembles the function of classical low molecular weight drugs than classical antibodies. The low molecular weight and small size further result in camelid nanobodies that are highly heat resistant, stable to extreme pH and proteolytic digestion, and have low antigenicity. See U.S. Patent Application No. 20040161738, published August 19, 2004; which is incorporated herein by reference in its entirety. These features, combined with low antigenicity to humans, indicate great therapeutic potential.

[0211] As used herein, the term "nucleic acid" or "nucleic acid sequence" refers to any molecule, preferably a polymeric molecule, incorporating units of ribonucleic acid, deoxyribonucleic acid, or analogs thereof. Nucleic acids can be either single-stranded or double-stranded. Single-stranded nucleic acids can be one nucleic acid strand of a denatured double-stranded DNA. Alternatively, they can be single-stranded nucleic acids that are not derived from any double-stranded DNA. In one aspect, the nucleic acid can be DNA. In another aspect, the nucleic acid can be RNA. Suitable DNA can include, for example, cDNA. Suitable RNA can include, for example, mRNA.

[0212] As used herein, "inhibitory nucleic acid" refers to a nucleic acid molecule capable of inhibiting expression of a target, such as double-stranded RNA (dsRNA), inhibitory RNA (iRNA), and the like.

[0213] Double-stranded RNA molecules (dsRNA) have been shown to block gene expression in a highly conserved regulatory mechanism known as RNA interference (RNAi). The inhibitory nucleic acids described herein can be up to 30 nucleotides in length, i.e., 15-30 nucleotides in length, typically 19-24 nucleotides in length, and include an RNA strand (antisense strand) having a region substantially complementary to at least a portion of a targeted mRNA transcript. These iRNAs can be used to allow targeted degradation of the mRNA transcript, resulting in a decrease in the expression and / or activity of the target.

[0214] As used herein, the term "iRNA" refers to an agent that includes RNA (or modified nucleic acid as described herein below) and mediates targeted cleavage of RNA transcripts via the RNA-induced silencing complex (RISC) pathway. In some embodiments of any aspect, the iRNA described herein results in inhibition of target expression and / or activity. In some embodiments of any aspect, contacting a cell with an inhibitor (e.g., iRNA) results in a reduction in target mRNA levels in the cell of at least about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99%, or 100% of the target mRNA levels found in the cell in the absence of iRNA. In some embodiments of either aspect, administration of an inhibitor (e.g., an iRNA) to a subject results in a decrease in target mRNA levels in the subject of at least about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99%, 100%, or less, including the target mRNA levels found in the subject in the absence of the iRNA.

[0215] In some embodiments of either aspect, the iRNA can be a dsRNA. The dsRNA comprises two RNA strands that are sufficiently complementary to hybridize to form a duplex structure under the conditions in which the dsRNA is used. One strand of the dsRNA (the antisense strand) comprises a region of complementarity that is substantially complementary, and generally completely complementary, to the target sequence. The target sequence can be derived from the sequence of the mRNA formed during expression of the target, for example, it can span one or more intron boundaries. The other strand (the sense strand) comprises a region complementary to the antisense strand such that, when combined under appropriate conditions, the two strands hybridize to form a duplex structure. Generally, the duplex structure is between 15-30 base pairs in length, including 15 and 30 base pairs, more generally between 18-25 base pairs in length, including 18 and 25 base pairs, even more generally between 19-24 base pairs in length, including 19 and 24 base pairs, and most generally between 19-21 base pairs in length, including 19 and 21 base pairs. Similarly, the region of complementarity to the target sequence is between 15 and 30 base pairs in length, including 15 and 30 base pairs, more commonly between 18 and 25 base pairs in length, including 18 and 25 base pairs in length, even more commonly between 19 and 24 base pairs in length, including 19 and 24 base pairs in length, and most commonly between 19 and 21 base pairs in length, including 19 and 21 base pairs in nucleotide length. In some embodiments of either aspect, the dsRNA is between 15 and 20 nucleotides in length, including 15 and 20 nucleotides in length, and in other embodiments, the dsRNA is between 25 and 30 nucleotides in length, including 25 and 30 nucleotides in length. As one of skill in the art will recognize, the targeted region of an RNA that is targeted for cleavage is most often a portion of a larger RNA molecule, often an mRNA molecule. Where relevant, a "portion" of an mRNA target is a contiguous sequence of the mRNA target of sufficient length to be a substrate for RNAi-directed cleavage (i.e., cleavage through the RISC pathway). dsRNA with duplexes as short as 9 base pairs can mediate RNAi-directed RNA cleavage under some circumstances. In most cases, the target is at least 15 nucleotides long, preferably 15-30 nucleotides long.

[0216] Exemplary embodiments of types of inhibitory nucleic acids can include, for example, siRNA, shRNA, miRNA, and / or amiRNA, which are well known in the art.

[0217] In some embodiments of either aspect, the RNA of the iRNA, e.g., dsRNA, is chemically modified to enhance stability or other beneficial features. The nucleic acids described herein may be synthesized and / or modified by methods well established in the art, such as those described in "Current protocols in nucleic acid chemistry," Beaucage, SL et al. (Edrs.), John Wiley & Sons, Inc., New York, NY, USA, which is incorporated herein by reference. Modifications include, for example, (a) end modifications, e.g., 5'-end modifications (phosphorylation, conjugation, inverted linkage, etc.), 3'-end modifications (conjugation, DNA nucleotides, inverted linkage, etc.), (b) base modifications, e.g., substitution with stabilizing bases, destabilizing bases, or bases that base-pair with an extended repertoire of partners, removal of bases (abasic nucleotides), or conjugated bases, (c) sugar modifications (e.g., 2'- or 4'-position) or sugar substitutions, and (d) backbone modifications, including modification or substitution of phosphodiester bonds. Specific examples of RNA compounds useful in the embodiments described herein include, but are not limited to, RNA that contains modified backbones or does not contain natural internucleoside bonds. RNA with modified backbones include, among others, those that do not have phosphorus atoms in their backbones. For the purpose of this specification, and as sometimes referred to in the art, modified RNAs that do not have phosphorus atoms in their internucleoside backbones can also be considered as oligonucleosides. In some embodiments of either aspect, modified RNA has phosphorus atoms in its internucleoside backbones.

[0218] Modified RNA backbones may include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkyl phosphotriesters, methyl and other alkyl phosphonates, including 3'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates, including 3'-amino phosphoramidates and aminoalkyl phosphoramidates, thionophosphoramidates, thionoalkyl phosphonates, thionoalkyl phosphotriesters, and boranophosphates with normal 3'-5' linkages, their 2'-5' linked analogs, and those with reverse polarity, where adjacent pairs of nucleoside units are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'.Various salts, mixed salts, and free acid forms are also included. Modified RNA backbones that do not contain phosphorus atoms therein have backbones formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatom or heterocyclic internucleoside linkages. These include morpholino linkages (formed in part from the sugar portion of the nucleoside); siloxane backbones; sulfide, sulfoxide, and sulfone backbones; formacetyl and thioformacetyl backbones; methyleneformacetyl and thioformacetyl backbones; alkene-containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and other mixed N, O, S, and CH2 moieties. These include those having a heteroatom backbone, and oligonucleosides having a heteroatom backbone, and in particular those having -CH2-NH-CH2-, -CH2-N(CH3)-O-CH2- [known as the methylene (methylimino) or MMI backbone], -CH2-ON(CH3)-CH2-, -CH2-N(CH3)-N(CH3)-CH2-, and -N(CH3)-CH2-CH2- [where the native phosphodiester backbone is represented as -OPO-CH2-].

[0219] In other RNA mimics suitable or contemplated for use in iRNA, both the sugar and internucleoside linkages, i.e., backbone, of the nucleotide units are replaced by novel groups. The base units are maintained for hybridization with suitable nucleic acid target compounds. One such oligomeric compound, an RNA mimic that has been shown to have excellent hybridization properties, is called peptide nucleic acid (PNA). In PNA compounds, the sugar backbone of RNA is replaced with an amide-containing backbone, particularly an aminoethylglycine backbone. Nucleobases are retained and are directly or indirectly bound to the aza nitrogen atoms of the amide portion of the backbone.

[0220] The RNA of iRNA can also be modified to include one or more locked nucleic acids (LNAs). Locked nucleic acids are nucleotides with modified ribose moieties, which contain an additional bridge connecting the 2' and 4' carbons. This structure effectively "locks" the ribose in a 3'-endo structure conformation. The addition of locked nucleic acids to siRNA has been shown to increase the stability of siRNA in serum and reduce non-specific effects (Elmen, J. et al., (2005) Nucleic Acids Research 33(1):439-447; Mook, OR. et al., (2007) Mol Canc Ther 6(3):833-843; Grunweller, A. et al., (2003) Nucleic Acids Research 31(12):3185-3193).

[0221] Modified RNAs may also include one or more substituted sugar moieties. The iRNAs, e.g., dsRNAs, described herein, may include one of the following at the 2' position: OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S-, or N-alkynyl; or O-alkyl-O-alkyl, where the alkyl, alkenyl, and alkynyl may be substituted or unsubstituted C1-C10 alkyl or C2-C10 alkenyl and alkynyl. Exemplary suitable modifications are O[(CH2)nO]mCH3, O(CH2).nOCH3, O(CH2)nNH2, O(CH2)nCH3, O(CH2)nONH2, and O(CH2)nON[(CH2)nCH3)]2, where n and m are from 1 to about 10. In some embodiments of either aspect, the dsRNA comprises one of the following at the 2' position: C1-C10 lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH3, OCN, Cl, Br, CN, CF3, OCF3, SOCH3, SO2CH3, ONO2, NO2, N3, NH2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an iRNA, or a group for improving the pharmacodynamic properties of an iRNA, and other substituents with similar properties. In some embodiments of either aspect, the modification comprises 2'-methoxyethoxy (2'-O-CH2CHOCH3, also known as 2'-O-(2-methoxyethyl) or 2'-MOE) (Martin et al., Helv. Chim. Acta, 1995, 78:486-504), i.e., an alkoxy-alkoxy group. Another exemplary modification is the O(CH2)2ON(CH3)2 group, also known as 2'-dimethylaminooxyethoxy, i.e., 2'-DMAOE, as described in the Examples herein below, as well as 2'-dimethylaminoethoxyethoxy (also known in the art as 2'-O-dimethylaminoethoxyethyl or 2'-DMAEOE), i.e., 2'-O-CH2-O-CH2-N(CH2)2, also described in the Examples herein below.

[0222] Other modifications include 2'-methoxy (2'-OCH3), 2'-aminopropoxy (2'-OCH2CH2CH2NH2) and 2'-fluoro (2'-F). Similar modifications can also be made at other positions on the RNA of an iRNA, particularly the 3' position of the sugar on the 3' terminal nucleotide or in a 2'-5' linked dsRNA and the 5' position of the 5' terminal nucleotide. An iRNA can also have sugar mimetics such as a cyclobutyl moiety in place of the pentofuranosyl sugar.

[0223] Inhibitory nucleic acids may also include modifications or substitutions of nucleobases (often referred to in the art simply as "bases"). As used herein, "unmodified" or "natural" nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C), and uracil (U). Modified nucleobases include 5-methylcytosine (5-me-C), 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyluracil and cytosine, 6-azouracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl anal (8-hydroxyl anal). anal) and other 8-substituted adenines and guanines, 5-halo, especially 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, other synthetic and natural nucleobases such as 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-daazaadenine and 3-deazaguanine and 3-deazaadenine. Some of these nucleobases are particularly useful for increasing the binding affinity of the inhibitory nucleic acids featured in the present invention. These include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6, and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil, and 5-propynylcytosine. 5-Methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2°C (Sanghvi, YS, Crooke, ST and Lebleu, B., Eds., dsRNA Research and Applications, CRC Press, Boca Raton, 1993, pp. 276-278) and are an exemplary base substitution, even more particularly when combined with a 2'-O-methoxyethyl sugar modification.

[0224] The preparation of the above-described modified nucleic acids, backbones, and nucleobases is well known in the art.

[0225] Another modification of the inhibitory nucleic acids featured in the invention involves chemically linking to the inhibitory nucleic acid one or more ligands, moieties, or conjugates that enhance the activity, cellular distribution, pharmacokinetic properties, or cellular uptake of the iRNA. Such moieties include cholesterol moieties (Letsinger et al., Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556), cholic acid (Manoharan et al., Biorg. Med. Chem. Let., 1994, 4: 1053-1060), thioethers such as beryl-S-tritylthiol (Manoharan et al., Ann. NY Acad. Sci., 1992, 660:306-309; Manoharan et al., Biorg. Med. Chem. Let., 1993, 3:2765-2770), thiocholesterols (Oberhauser et al., Nucl. Acids Res., 1992, 1: 1053-1060), and thioesters such as beryl-S-tritylthiol (Manoharan et al., Ann. NY Acad. Sci., 1992, 660:306-309; Manoharan et al., Biorg. Med. Chem. Let., 1993, 3:2765-2770). 20:533-538), aliphatic chains such as dodecanediol or undecyl residues (Saison-Behmoaras et al., EMBO J, 1991, 10:1111-1118; Kabanov et al., FEBS Lett., 1990, 259:327-330; Svinarchuk et al., Biochimie, 1993, 75:49-54), phospholipids such as dihexadecyl-rac-glycerol or triethylammonium 1,2-di-O-hexadecyl-rac-glycero-3-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654; Shea et al., Nucl. Acids Res., 1990, 18:3777-3783), polyamine or polyethylene glycol chains (Manoharan et al., Nucleosides & Nucleotides, 1995, 14:969-973), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654), palmityl moieties (Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229-237), or lipid moieties such as octadecylamine or hexylamino-carbonyloxycholesterol moieties (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277:923-937).

[0226] The term "vector" as used herein refers to a nucleic acid construct designed for delivery to a host cell or for transfer between different host cells. As used herein, a vector can be viral or non-viral. The term "vector" encompasses any genetic element that can replicate when associated with the correct control elements and transfer gene sequences into a cell. Vectors can include, but are not limited to, cloning vectors, expression vectors, recombinant vectors, plasmids, phages, transposons, cosmids, chromosomes, viruses, virions, and the like.

[0227] As used herein, the term "expression vector" refers to a vector that directs the expression of an RNA or polypeptide from a sequence linked to a transcriptional regulatory sequence on the vector. The sequence to be expressed is often, but not necessarily, heterologous to the cell. An expression vector may contain additional elements, for example, an expression vector may have two replication systems, thus allowing it to be maintained in two organisms, for example, in human cells for expression, and in a prokaryotic host for cloning and amplification. The term "expression" refers to the cellular processes involved in the production of RNA and proteins, and, optionally, the secretion of proteins, including, for example, but not limited to, transcription, transcription processing, translation, and protein folding, modification, and processing, as applicable. "Expression product" includes RNA transcribed from a gene, and polypeptides obtained by translation of mRNA transcribed from a gene. The term "gene" refers to a nucleic acid sequence that is transcribed (DNA) into RNA in vitro or in vivo when operably linked to suitable regulatory sequences. A gene may or may not include regions preceding and following the coding region, such as 5' untranslated (5' UTR) or "leader" sequences and 3' UTR or "trailer" sequences, as well as intervening sequences (introns) between individual coding segments (exons).

[0228] As used herein, the term "viral vector" refers to a nucleic acid vector construct that contains at least one element of viral origin and has the ability to be packaged into a viral vector particle. A viral vector can contain a nucleic acid encoding a polypeptide as described herein in place of a non-essential viral gene. The vector and / or particle can be utilized to transfer any nucleic acid into cells, either in vitro or in vivo. Many forms of viral vectors are known in the art.

[0229] By "recombinant vector" is meant a vector that comprises a heterologous nucleic acid sequence or "transgene" that can be expressed in vivo. It should be understood that the vector described herein can be combined with other suitable compositions and therapies in some embodiments. In some embodiments, the vector is episomal. The use of suitable episomal vector provides a means to maintain the nucleotide of interest in high copy number outside chromosomal DNA in a subject, thereby eliminating the potential effects of chromosomal integration.

[0230] As used herein, the terms "treat", "treatment", "treating" or "amelioration" refer to therapeutic treatments aimed at reversing, alleviating, improving, inhibiting, slowing, or halting the progression or severity of symptoms associated with a disease or disorder, such as, for example, a condition or disease described herein. The term "treating" includes reducing or alleviating at least one adverse effect or symptom of a condition, disease, or disorder. Treatment is generally "effective" if one or more symptoms or clinical markers are reduced. Alternatively, treatment is "effective" if the progression of the disease is reduced or halted. That is, "treatment" includes not only improvement of symptoms or markers, but also halting or at least slowing the progression or worsening of symptoms compared to that expected in the absence of treatment. Beneficial or desirable clinical results include, but are not limited to, alleviation of one or more symptoms, whether detectable or undetectable, reduction in the extent of the disease, stabilization of the disease state (i.e., not worsening), slowing or delaying the progression of the disease, improvement or palliative of the disease state, remission (whether partial or complete), and / or reduced mortality. The term "treatment" of a disease also includes causing relief of the symptoms or side effects of the disease (including symptomatic treatment).

[0231] As used herein, the term "pharmaceutical composition" refers to an active agent combined with a pharmaceutically acceptable carrier, e.g., a carrier commonly used in the pharmaceutical industry. The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. In some embodiments of any aspect, the pharmaceutically acceptable carrier can be a carrier other than water. In some embodiments of any aspect, the pharmaceutically acceptable carrier can be a cream, emulsion, gel, liposome, nanoparticle, and / or ointment. In some embodiments of any aspect, the pharmaceutically acceptable carrier can be an artificial or engineered carrier, e.g., a carrier in which the active ingredient is not found to occur in nature.

[0232] As used herein, the term "administration" refers to placing a compound as disclosed herein in a subject by a method or route that results in at least partial delivery of the agent at a desired site. Pharmaceutical compositions containing the compounds disclosed herein can be administered by any suitable route that results in an effective treatment in the subject.

[0233] "Contact" as used herein refers to any suitable means for delivering or exposing an agent to at least one cell.Exemplary delivery methods include, but are not limited to, direct delivery into cell culture medium, perfusion, injection, or other delivery methods known to those skilled in the art.In some embodiments, contact includes physical human activity, such as injection; dispensing, mixing, and / or decanting; and / or operating a delivery device or machine.

[0234] The term "effective amount" refers to an amount of a composition sufficient to result in at least some amelioration of symptoms associated with a condition. In one embodiment, "effective amount" refers to an amount of a composition that reduces a marker or symptom of a condition in a subject having a condition.

[0235] The terms "statistically significant" or "significantly" refer to statistical significance, generally meaning a difference greater than two standard deviations (2SD).

[0236] Other than in the working examples, or unless otherwise indicated, all numbers expressing amounts of ingredients or reaction conditions used herein should be understood to be modified in all instances by the term "about." When used in connection with percentages, the term "about" can mean ±1%.

[0237] As used herein, the terms "comprising" or "comprises" are used in reference to methods and compositions essential to the invention and their respective components, although they may include elements not specified, whether essential or not. As used herein, the term "comprising" means that other elements may be present in addition to the defined elements presented. The use of "comprising" indicates inclusion rather than limitation.

[0238] The term "consisting of" refers to the compositions, methods, and each component thereof described herein, and does not include any element not recited in the description of that embodiment.

[0239] As used herein, the term "consisting essentially of" refers to those elements required for a given embodiment. The term allows for the presence of additional elements that do not materially affect the basic and novel or functional characteristics of that embodiment of the invention.

[0240] The term "specific binding" as used herein refers to the chemical interaction between two molecules, compounds, cells and / or particles, in which a first entity binds to a second target entity with greater specificity and affinity than it binds to a third entity that is a non-target.In some embodiments, specific binding refers to the affinity of a first entity to a second target entity, which is at least 10 times, at least 50 times, at least 100 times, at least 500 times, at least 1000 times or more than its affinity to a third non-target entity.A reagent that is specific for a given target is one that exhibits specific binding to that target under the conditions of the assay being used.

[0241] The singular terms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The abbreviation "eg" is derived from the Latin exempli gratia and is used herein to denote a non-limiting example. Thus, the abbreviation "eg" is synonymous with the term "for example."

[0242] Grouping of alternative elements or aspects of the invention disclosed herein should not be construed as limiting. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in and deleted from a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification herein is deemed to include the modified group and fulfills the written description of all Markush groups used in the appended claims.

[0243] Unless otherwise defined herein, scientific and technical terms used in connection with this application shall have the meanings commonly understood by those skilled in the art to which this disclosure belongs. It should be understood that the present invention is not limited to the specific methodology, protocols, and reagents, etc. described herein, and therefore may vary. The terminology used herein is intended only to describe specific embodiments, and is not intended to limit the scope of the present invention, which is defined solely by the claims.Definitions of common terms in immunology and molecular biology can be found in The Merck Manual of Diagnosis and Therapy, l9th Edition, published by Merck Sharp & Dohme Corp., 2011 (ISBN 978-0-911910-19-3);Robert S. Porter et al. (eds.), The Encyclopedia of Molecular Cell Biology and Molecular Medicine, published by Blackwell Science Ltd., 1999-2012 (ISBN 9783527600908);and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8);Immunology by Werner Luttmann, published by Elsevier, 2006;Janeway's Immunobiology, Kenneth Murphy, Allan Mowat, Casey Weaver (eds.), Taylor & Francis Limited, 2014 (ISBN 0815345305, 9780815345305);Lewin's Genes XI, published by Jones & Bartlett Publishers, 2014 (ISBN-1449659055);Michael Richard Green and Joseph Sambrook, Molecular Cloning: A Laboratory Manual, 4. thed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, USA (2012) (ISBN 1936113414);Davis et al., Basic Methods in Molecular Biology, Elsevier Science Publishing, Inc., New York, USA (2012) (ISBN 044460149X);Laboratory Methods in Enzymology: DNA, Jon Lorsch (ed.) Elsevier, 2013 (ISBN 0124199542);Current Protocols in Molecular Biology (CPMB), Frederick M. Ausubel (ed.), John Wiley and Sons, 2014 (ISBN 047150338X, 9780471503385), Current Protocols in Protein Science (CPPS), John E. Coligan (ed.), John Wiley and Sons Sons, Inc. 2005; and Current Protocols in Immunology (CPI) (John E. Coligan, ADA M Kruisbeek, David H Margulies, Ethan M Shevach, Warren Strobe, (eds.) John Wiley and Sons, Inc., 2003 (ISBN 0471142735, 9780471142737), the contents of which are incorporated herein by reference in their entireties.

[0244] Those skilled in the art can readily identify chemotherapeutic agents to use (see, e.g., Physicians' Cancer Chemotherapy Drug Manual 2014, Edward Chu, Vincent T. DeVita Jr., Jones & Bartlett Learning; Principles of Cancer Therapy, Chapter 85 in Harrison's Principles of Internal Medicine, 18th edition; Therapeutic Targeting of Cancer Cells: Era of Molecularly Targeted Agents and Cancer Pharmacology, Chs. 28-29 in Abeloff's Clinical Oncology, 2013 Elsevier; and Fischer DS (ed): The Cancer Chemotherapy Handbook, 4th ed. St. Louis, Mosby-Year Book, 2003).

[0245] Other terms are defined herein within the description of various aspects of the invention.

[0246] All patents and other publications, including references, issued patents, published patent applications, and co-pending patent applications, cited throughout this application are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that may be used in connection with the technology described herein. These publications are provided solely for their disclosure prior to the filing date of this application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by reason of prior invention or for any other reason. All statements as to the date or indication of the contents of these documents are based on the information available to the applicants and do not constitute any admission as to the accuracy of the dates or contents of these documents.

[0247] The description of the aspects of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. Specific aspects and examples of the disclosure are described herein for illustrative purposes, but as one skilled in the relevant art will recognize, various equivalent modifications are possible within the scope of the disclosure. For example, while steps or functions of a method are shown in a given order, in alternative embodiments the functions may be performed in a different order or may be performed substantially simultaneously. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various aspects described herein can be combined to provide further aspects. Aspects of the disclosure can be modified, if necessary, to use compositions, functions, and concepts of the above references and applications to provide still further aspects of the disclosure. Furthermore, in consideration of biological functional equivalence, some changes can be made to protein structure without affecting biological or chemical action in type or amount. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be within the scope of the appended claims.

[0248] Specific elements of any of the foregoing embodiments can be combined with or substituted for elements of other embodiments. Additionally, although advantages associated with certain embodiments of the present disclosure have been described in the context of those embodiments, other embodiments may also exhibit such advantages, and not necessarily all embodiments need to exhibit such advantages to be within the scope of the present disclosure.

[0249] The technology described herein is further illustrated by the following examples, which should not be construed as further limiting in any way.

[0250] Certain aspects of the technology described herein can be defined by any of the following numbered clauses: 1. A method of administering at least one active compound, comprising administering the active compound to a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the active compound to the subject subject in need thereof, a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0; and Quaternary ammonium cations The method comprises administering in combination with at least one ionic liquid comprising: 2. A method of reducing weight / weight gain or treating obesity, diabetes, ulcers, cancer, or fibrosis in a subject in need thereof, comprising: a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0; and Quaternary ammonium cations 20. The method of claim 19, further comprising administering to a subject a composition comprising at least one ionic liquid comprising: 3. The method of paragraph 2, wherein the composition does not contain a therapeutic agent other than the at least one ionic liquid. 4. The method of claim 2, wherein the composition further comprises an active compound other than the at least one ionic liquid. 5. The method of any of the preceding paragraphs, wherein the anion has a pKa of at least 4.5. 6. The method of any of the preceding paragraphs, wherein the anion has a pKa of at least 5.0. 7. The method of any of the preceding clauses, wherein the anion has a LogP of at least 2.0. 8. The method of any of the preceding paragraphs, wherein the anion has a LogP of at least 2.5. 9. The method of any of the preceding paragraphs, wherein the anion has a LogP of at least 2.75. 10. The method of any of the preceding claims, wherein the anion comprises a carbon chain of at least 8 carbons. 11. The method of any of the preceding claims, wherein the anion is an alkene. 12. The method of any of the preceding claims, wherein the anion is geranic acid, octanoic acid, or citronellic acid. 13. The method of any of the preceding claims, wherein the cation has a molar mass equal to or greater than that of choline. 14. Quaternary ammonium is NR4 +and at least one R group comprises a hydroxy group. 15. Quaternary ammonium is NR4 + and where only one R group contains a hydroxy group. 16. The method of any of the preceding claims, wherein the cation is C1, C6, or C7. 17. The method of any of the preceding claims, wherein the cation is selected from choline, C1, C6, and C7, and the anion is citronellic acid. 18. The method of any of the preceding claims, wherein the cation is C1 and the anion is citronellic acid. 19. The method of any of the preceding paragraphs, wherein the cation is selected from C1, C6, and C7, and the anion is geranic acid. 20. The method of any of the preceding claims, wherein the ionic liquid is choline:citronellic acid, C1:geranic acid, or C1:citronellic acid. 21. The method of any of the preceding paragraphs, wherein the ionic liquid is not a CAGE. 22. The method of any of the preceding paragraphs, wherein the ionic liquid has fewer than 20 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY). 23. The method of any of the preceding paragraphs, wherein the ionic liquid has fewer than 10 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY). 24. The method of any of the preceding paragraphs, wherein the ionic liquid has fewer than 5 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY). 25. The method of any of the preceding paragraphs, wherein administration is transdermal. 26. The method of any of the preceding clauses, wherein administration is transdermal, mucosal, oral, subcutaneous, intradermal, parenteral, intratumoral, or intravenous. 27. The method of paragraph 26, wherein the mucosa is nasal mucosa, oral mucosa, or vaginal mucosa. 28. The method of any of the preceding claims, wherein the ionic liquid is at a concentration of at least 0.1% w / v. 29. The method of any of the preceding paragraphs, wherein the ionic liquid is at a concentration of about 10 to about 70% w / v. 30. The method of any of the preceding paragraphs, wherein the ionic liquid is at a concentration of about 30 to about 50% w / v. 31. The method of any of the preceding paragraphs, wherein the ionic liquid is at a concentration of about 30 to about 40% w / v. 32. The method of any of the preceding paragraphs, wherein the ionic liquid comprises a ratio of cations to anions of about 2:1 to about 1:10. 33. The method of any of the preceding paragraphs, wherein the ionic liquid comprises a ratio of cations to anions of about 1:1 to about 1:4. 34. The method of any of the preceding paragraphs, wherein the ionic liquid comprises a ratio of cations to anions of about 1:2. 35. The method of any of the preceding claims, wherein the ionic liquid has a cation:anion ratio of less than 1:1. 36. The method of any of the preceding paragraphs, wherein the active compound is hydrophobic. 37. The method of any of the preceding paragraphs, wherein the active compound is hydrophilic. 38. The method of any of the preceding claims, wherein the active compound comprises a polypeptide. 39. The method of any of the preceding paragraphs, wherein the active compound has a molecular weight greater than 450. 40. The method of any of the preceding paragraphs, wherein the active compound has a molecular weight greater than 500. 41. The method of any of the preceding paragraphs, wherein the active compound comprises an antibody or antibody reagent. 42. The method of any of the preceding clauses, wherein the active compound comprises insulin, acarbose, ruxolitinib, or a GLP-1 polypeptide or a mimetic or analog thereof. 43. The method of any of the preceding clauses, wherein the combination and / or composition is administered once. 44. The method of any of the preceding clauses, wherein the combination and / or composition is administered in multiple doses. 45. The method of any of the preceding paragraphs, wherein the active compound and / or composition is provided at a dosage of 1 to 20 mg / kg. 46. ​​The method of any of the preceding clauses, wherein the active compound and ionic liquid are further in combination with at least one non-ionic surfactant. 47. The method of any of the preceding clauses, wherein the combination and / or composition further comprises an additional pharma- ceutically acceptable carrier. 48. The method of any of the preceding clauses, wherein administration is oral and the combination and / or composition is provided in a degradable capsule. 49. The method of any of the preceding paragraphs, wherein the combination is a mixture. 50. The method of any of the preceding paragraphs, wherein the combination and / or composition is provided in one or more nanoparticles. 51. The method of any of the preceding clauses, wherein the combination is provided in the form of one or more nanoparticles comprising the active compound, the nanoparticles being in solution or suspension in a composition comprising an ionic liquid. 52. A hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0; and Quaternary ammonium cations A composition comprising at least one ionic liquid comprising: 53. The composition of paragraph 52, wherein the anion has a pKa of at least 4.5. 54. The composition of any of paragraphs 52 to 53, wherein the anion has a pKa of at least 5.0. 55. The composition of any of paragraphs 52 to 54, wherein the anion has a LogP of at least 2.0. 56. The composition of any of paragraphs 52 to 55, wherein the anion has a LogP of at least 2.5. 57. The composition of any of paragraphs 52 to 56, wherein the anion has a LogP of at least 2.75. 58. The composition of any of paragraphs 52-57, wherein the anion comprises a carbon chain of at least 8 carbons. 59. The composition of any of paragraphs 52 to 58, wherein the anion is an alkene. 60. The composition of any of paragraphs 52 to 59, wherein the anion is geranic acid, octanoic acid, or citronellic acid. 61. The composition of any of paragraphs 52 to 60, wherein the cation has a molar mass equal to or greater than that of choline. 62. Quaternary ammonium is NR4 +62. The composition of any of items 52 to 61, wherein at least one R group contains a hydroxy group. 63. Quaternary ammonium is NR4 + 63. The composition of any of items 52 to 62, having a structure of: 64. The composition of any of paragraphs 52 to 63, wherein the cation is C1, C6, or C7. 65. The composition of any of paragraphs 52 to 64, wherein the cation is selected from choline, C1, C6, and C7, and the anion is citronellic acid. 66. The composition of any of paragraphs 52 to 65, wherein the cation is C1 and the anion is citronellic acid. 67. The composition of any of paragraphs 52-66, wherein the cation is selected from C1, C6, and C7, and the anion is geranic acid. 68. The composition of any of paragraphs 52 to 67, wherein the ionic liquid is choline:citronellic acid, C1:geranic acid, or C1:citronellic acid. 69. The composition of any of paragraphs 52 to 68, wherein the ionic liquid is not a CAGE. 70. The composition of any of paragraphs 52 to 69, wherein the ionic liquid comprises a ratio of cations to anions of about 2:1 to about 1:10. 71. The composition of any of paragraphs 52 to 70, wherein the ionic liquid comprises a ratio of cations to anions of about 1:1 to about 1:4. 72. The composition of any of paragraphs 52-71, wherein the ionic liquid comprises a ratio of cations to anions of about 1:2. 73. The composition of any of paragraphs 52 to 72, wherein the ionic liquid has a cation:anion ratio of less than 1:1. 74. The composition of any of paragraphs 52 to 73, wherein the ionic liquid has a cation:anion ratio that includes an excess of anion. 75. The composition of any of paragraphs 52 to 74, wherein the ionic liquid has fewer than 20 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY). 76. The composition of any of paragraphs 52 to 75, wherein the ionic liquid has fewer than 10 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY). 77. The composition of any of paragraphs 52 to 76, wherein the ionic liquid has fewer than 5 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY). 78. The composition of any of paragraphs 52 to 77, further comprising at least one active compound in combination with the at least one ionic liquid. 79. The method of paragraph 78, wherein the active compound is hydrophobic. 80. The composition of any of paragraphs 78 to 79, wherein the active compound is hydrophilic. 81. The composition of any of paragraphs 78 to 80, wherein the active compound comprises a polypeptide. 82. The composition of any of paragraphs 78 to 81, wherein the active compound has a molecular weight of greater than 450. 83. The composition of any of paragraphs 78 to 82, wherein the active compound has a molecular weight of greater than 500. 84. The composition of any of paragraphs 78 to 83, wherein the active compound comprises an antibody or antibody reagent. 85. The composition of any of paragraphs 78 to 84, wherein the active compound comprises insulin, acarbose, ruxolitinib, or a GLP-1 polypeptide or a mimetic or analog thereof. 86. The composition of any of paragraphs 52 to 85, wherein the ionic liquid is at a concentration of at least 0.1% w / v. 87. The composition of any of paragraphs 52 to 86, wherein the ionic liquid is at a concentration of about 10 to about 70% w / v. 88. The composition of any of paragraphs 52 to 87, wherein the ionic liquid is at a concentration of about 30 to about 50% w / v. 89. The composition of any of paragraphs 52 to 88, wherein the ionic liquid is at a concentration of about 30 to about 40% w / v. 90. The composition of any of paragraphs 52 to 89, which is formulated for transdermal administration. 91. The composition of any of paragraphs 52 to 90, which is formulated for transdermal, mucosal, oral, subcutaneous, intradermal, parenteral, intratumoral, or intravenous administration. 92. The composition of paragraph 91, wherein the mucosa is nasal mucosa, oral mucosa, or vaginal mucosa. 93. The composition of any of paragraphs 78 to 92, wherein the active compound is provided in a dosage of 1 to 20 mg / kg. 94. The composition of any of paragraphs 52 to 93, further comprising at least one nonionic surfactant. 95. The composition of any of paragraphs 52 to 94, further comprising a pharma- ceutically acceptable carrier. 96. The composition of any one of paragraphs 52 to 95, provided in a degradable capsule. 97. The composition of any one of paragraphs 78 to 96, which is a mixture. 98. The composition of any of paragraphs 52 to 97, provided in one or more nanoparticles. 99. The composition of any of paragraphs 52 to 98, comprising one or more nanoparticles comprising an active compound, the nanoparticles being in solution or suspension in a composition comprising an ionic liquid.

[0251] Certain aspects of the technology described herein can be defined by any of the following numbered clauses: 1. A method of administering at least one active compound, comprising administering the active compound to a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the active compound to the subject subject in need thereof, a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0; and Quaternary ammonium cations The method comprises administering in combination with at least one ionic liquid comprising: 2. A method of reducing weight / weight gain or treating obesity, diabetes, ulcers, cancer, or fibrosis in a subject in need thereof, comprising: a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0; and Quaternary ammonium cations 20. The method of claim 19, further comprising administering to a subject a composition comprising at least one ionic liquid comprising: 3. The method of paragraph 2, wherein the composition does not contain a therapeutic agent other than the at least one ionic liquid. 4. The method of claim 2, wherein the composition further comprises an active compound other than the at least one ionic liquid. 5. The method of any of the preceding paragraphs, wherein the anion has a pKa of at least 4.5. 6. The method of any of the preceding paragraphs, wherein the anion has a pKa of at least 5.0. 7. The method of any of the preceding claims, wherein the anion has a pKa of at least 4.895. 8. The method of any of the preceding paragraphs, wherein the anion has a pKa of 4.5 to 5.5. 9. The method of any of the preceding paragraphs, wherein the anion has a pKa of 4.895 to 5.19. 10. The method of any of the preceding clauses, wherein the anion has a LogP of at least 2.0. 11. The method of any of the preceding paragraphs, wherein the anion has a LogP of at least 2.5. 12. The method of any of the preceding paragraphs, wherein the anion has a LogP of at least 2.75. 13. The method of any of the preceding paragraphs, wherein the anion has a LogP of at least 2.8. 14. The method of any of the preceding paragraphs, wherein the anion has a LogP of 2.5 to 3.5. 15. The method of any of the preceding paragraphs, wherein the anion has a LogP of 2.8 to 3.01. 16. The method of any of the preceding claims, wherein the anion comprises a carbon chain of at least 8 carbons. 17. The method of any of the preceding claims, wherein the anion comprises an eight-carbon backbone carbon chain. 18. The method of any of the preceding claims, wherein the anion is geranic acid, octenic acid, octanoic acid, or citronellic acid. 19. The method of any of the preceding claims, wherein the anion is octenate, octanoate, or citronellate. 20. The method of any of the preceding claims, wherein the anion is an alkene. 21. The method of any of the preceding claims, wherein the anion is geranic acid, octanoic acid, or citronellic acid. 22. The method of any of the preceding claims, wherein the cation has a molar mass equal to or greater than that of choline. 23. Quaternary ammonium is NR4 + and at least one R group comprises a hydroxy group. 24. Quaternary ammonium is NR4 + and where only one R group contains a hydroxy group. 25. The method of any of the preceding claims, wherein the cation is C1, C6, or C7. 26. The method of any of the preceding claims, wherein the cation is selected from choline, C1, C6, and C7, and the anion is citronellic acid. 27. The method of any of the preceding claims, wherein the cation is C1 and the anion is citronellic acid. 28. The method of any of the preceding claims, wherein the cation is selected from C1, C6, and C7, and the anion is geranic acid. 29. The method of any of the preceding claims, wherein the ionic liquid is choline:citronellic acid, C1:geranic acid, or C1:citronellic acid. 30. The method of any of paragraphs 1 to 16, wherein the cation is selected from choline, C1, C6, and C7, and the anion is selected from citronellic acid, octanoic acid, and octenoic acid. 31. The method of any of paragraphs 1 to 16, wherein the cation is choline and the anion is selected from citronellic acid, octanoic acid, and octenoic acid. 32. The method of any one of paragraphs 1 to 16, wherein the ionic liquid is choline:citronellic acid, choline:octanoic acid, or choline:octenoic acid. 33. The method of any of the preceding paragraphs, wherein the ionic liquid is not a CAGE. 34. The method of any of the preceding paragraphs, wherein the ionic liquid has fewer than 20 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY). 35. The method of any of the preceding paragraphs, wherein the ionic liquid has fewer than 10 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY). 36. The method of any of the preceding clauses, wherein the ionic liquid has fewer than 5 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY). 37. The method of any of the preceding paragraphs, wherein administration is transdermal. 38. The method of any of the preceding clauses, wherein administration is transdermal, mucosal, oral, subcutaneous, intradermal, parenteral, intratumoral, or intravenous. 39. The method of paragraph 26, wherein the mucosa is nasal mucosa, oral mucosa, or vaginal mucosa. 40. The method of any of the preceding paragraphs, wherein administration is oral. 41. The method of any of the preceding claims, wherein the ionic liquid is at a concentration of at least 0.1% w / v. 42. The method of any of the preceding claims, wherein the ionic liquid is at a concentration of about 10 to about 70% w / v. 43. The method of any of the preceding claims, wherein the ionic liquid is at a concentration of about 30 to about 50% w / v. 44. The method of any of the preceding paragraphs, wherein the ionic liquid is at a concentration of about 30 to about 40% w / v. 45. The method of any of the preceding paragraphs, wherein the ionic liquid comprises a ratio of cations to anions of about 2:1 to about 1:10. 46. ​​The method of any of the preceding paragraphs, wherein the ionic liquid comprises a ratio of cations to anions of about 1:1 to about 1:4. 47. The method of any of the preceding claims, wherein the ionic liquid comprises a ratio of cations to anions of about 1:2. 48. The method of any of the preceding claims, wherein the ionic liquid has a cation:anion ratio of less than 1:1. 49. The method of any of the preceding paragraphs, wherein the active compound is hydrophobic. 50. The method of any of the preceding paragraphs, wherein the active compound is hydrophilic. 51. The method of any of the preceding claims, wherein the active compound comprises a polypeptide. 52. The method of any of the preceding paragraphs, wherein the active compound has a molecular weight greater than 450. 53. The method of any of the preceding paragraphs, wherein the active compound has a molecular weight greater than 500. 54. The method of any of the preceding paragraphs, wherein the active compound comprises an antibody or antibody reagent. 55. The method of any of the preceding clauses, wherein the active compound comprises insulin, acarbose, ruxolitinib, or a GLP-1 polypeptide or a mimetic or analog thereof. 56. The method of any of the preceding clauses, wherein the combination and / or composition is administered once. 57. The method of any of the preceding clauses, wherein the combination and / or composition is administered in multiple doses. 58. The method of any of the preceding paragraphs, wherein the active compound and / or composition is provided at a dosage of 1 to 20 mg / kg. 59. The method of any of the preceding claims, wherein the active compound and ionic liquid are further in combination with at least one non-ionic surfactant. 60. The method of any of the preceding clauses, wherein the combination and / or composition further comprises an additional pharma- ceutically acceptable carrier. 61. The method of any of the preceding clauses, wherein administration is oral and the combination and / or composition is provided in a degradable capsule. 62. The method of any of the preceding claims, wherein the combination is a mixture. 63. The method of any of the preceding clauses, wherein the combination and / or composition is provided in one or more nanoparticles. 64. The method of any of the preceding clauses, wherein the combination is provided in the form of one or more nanoparticles comprising the active compound, the nanoparticles being in solution or suspension in a composition comprising an ionic liquid. 65. A hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0; and Quaternary ammonium cations A composition comprising at least one ionic liquid comprising: 66. The composition of paragraph 65, wherein the anion has a pKa of at least 4.5. 67. The composition of paragraph 65, wherein the anion has a pKa of at least 4.895. 68. The composition of paragraph 65, wherein the anion has a pKa of 4.5 to 5.5. 69. The composition of paragraph 65, wherein the anion has a pKa of 4.895 to 5.19. 70. The composition of any of paragraphs 65 to 69, wherein the anion has a pKa of at least 5.0. 71. The composition of any of paragraphs 65 to 69, wherein the anion has a LogP of at least 2.0. 72. The composition of any of paragraphs 65 to 69, wherein the anion has a LogP of at least 2.5. 73. The composition of any of paragraphs 65 to 69, wherein the anion has a LogP of at least 2.75. 74. The composition of any of paragraphs 65 to 69, wherein the anion has a LogP of at least 2.8. 75. The composition of any of paragraphs 65 to 69, wherein the anion has a LogP of 2.5 to 3.5. 76. The composition of any of paragraphs 65 to 69, wherein the anion has a LogP of 2.8 to 3.01. 77. The composition of any of paragraphs 65-76, wherein the anion comprises a carbon chain of at least 8 carbons. 78. The composition of any of paragraphs 65-76, wherein the anion comprises an eight-carbon backbone carbon chain. 79. The composition of any of paragraphs 65 to 76, wherein the anion is geranic acid, octenic acid, octanoic acid, or citronellic acid. 80. The composition of any of paragraphs 65 to 76, wherein the anion is octenoic acid, octanoic acid, or citronellic acid. 81. The composition of any of paragraphs 65 to 80, wherein the anion is an alkene. 82. The composition of any of paragraphs 65 to 81, wherein the anion is geranic acid, octanoic acid, or citronellic acid. 83. The composition of any of paragraphs 65 to 82, wherein the cation has a molar mass equal to or greater than that of choline. 84. Quaternary ammonium is NR4 + 84. The composition of any of items 65 to 83, wherein at least one R group contains a hydroxy group. 85. Quaternary ammonium is NR4 +85. The composition of any of items 65 to 84, having a structure of: wherein only one R group contains a hydroxy group. 86. The composition of any of paragraphs 65 to 85, wherein the cation is C1, C6, or C7. 87. The composition of any of paragraphs 65 to 86, wherein the cation is selected from choline, C1, C6, and C7, and the anion is citronellic acid. 88. The composition of any of paragraphs 65 to 87, wherein the cation is C1 and the anion is citronellic acid. 89. The composition of any of paragraphs 65-88, wherein the cation is selected from C1, C6, and C7, and the anion is geranic acid. 90. The composition of any of paragraphs 65 to 89, wherein the ionic liquid is choline:citronellic acid, C1:geranic acid, or C1:citronellic acid. 91. The composition of any of paragraphs 65 to 90, wherein the cation is selected from choline, C1, C6, and C7, and the anion is selected from citronellic acid, octanoic acid, and octenoic acid. 92. The composition of any of paragraphs 65 to 91, wherein the cation is choline and the anion is selected from citronellic acid, octanoic acid, and octenoic acid. 93. The composition of any of paragraphs 65 to 92, wherein the ionic liquid is choline:citronellic acid, choline:octanoic acid, or choline:octenoic acid. 94. The composition of any of paragraphs 65 to 93, wherein the ionic liquid is not a CAGE. 95. The composition of any of paragraphs 65 to 94, wherein the ionic liquid comprises a ratio of cations to anions of about 2:1 to about 1:10. 96. The composition of any of paragraphs 65 to 95, wherein the ionic liquid comprises a ratio of cations to anions of about 1:1 to about 1:4. 97. The composition of any of paragraphs 65 to 96, wherein the ionic liquid comprises a ratio of cations to anions of about 1:2. 98. The composition of any of paragraphs 65 to 97, wherein the ionic liquid has a cation:anion ratio of less than 1:1. 99. The composition of any of paragraphs 65 to 98, wherein the ionic liquid has a cation:anion ratio that includes an excess of anion. 100. The composition of any of paragraphs 65 to 99, wherein the ionic liquid has fewer than 20 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY). 101. Any of the compositions of paragraphs 65 to 100, wherein the ionic liquid has fewer than 10 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY). 102. The composition of any of paragraphs 65 to 101, wherein the ionic liquid has fewer than 5 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY). 103. The composition of any of paragraphs 65 to 102, further comprising at least one active compound in combination with the at least one ionic liquid. 104. The composition of paragraph 103, wherein the active compound is hydrophobic. 105. The composition of any of paragraphs 103 to 104, wherein the active compound is hydrophilic. 106. The composition of any of paragraphs 103 to 105, wherein the active compound comprises a polypeptide. 107. The composition of any of paragraphs 103 to 106, wherein the active compound has a molecular weight greater than 450. 108. The composition of any of paragraphs 103 to 107, wherein the active compound has a molecular weight of greater than 500. 109. The composition of any of paragraphs 103 to 108, wherein the active compound comprises an antibody or antibody reagent. 110. The composition of any of paragraphs 103 to 109, wherein the active compound comprises insulin, acarbose, ruxolitinib, or a GLP-1 polypeptide or a mimetic or analog thereof. 111. The composition of any of paragraphs 65 to 110, wherein the ionic liquid is at a concentration of at least 0.1% w / v. 112. The composition of any of paragraphs 65 to 111, wherein the ionic liquid is at a concentration of about 10 to about 70% w / v. 113. The composition of any of paragraphs 65 to 112, wherein the ionic liquid is at a concentration of about 30 to about 50% w / v. 114. The composition of any of paragraphs 65 to 113, wherein the ionic liquid is at a concentration of about 30 to about 40% w / v. 115. The composition of any of paragraphs 65 to 114, which is formulated for transdermal administration. 116. The composition of any of paragraphs 65 to 115, which is formulated for transdermal, mucosal, oral, subcutaneous, intradermal, parenteral, intratumoral, or intravenous administration. 117. The composition of paragraph 116, wherein the mucosa is nasal mucosa, oral mucosa, or vaginal mucosa. 118. The composition of any of paragraphs 65 to 117, which is formulated for oral administration. 119. The composition of any of paragraphs 103 to 118, providing the active compound at a dosage of 1 to 20 mg / kg. 120. The composition of any of paragraphs 65 to 119, further comprising at least one nonionic surfactant. 121. The composition of any of paragraphs 65 to 120, further comprising a pharma- ceutically acceptable carrier. 122. The composition of any of paragraphs 65 to 121, provided in a degradable capsule. 123. The composition of any one of paragraphs 65 to 122, which is a mixture. 124. The composition of any of paragraphs 65 to 123, provided in one or more nanoparticles. 125. The composition of any of paragraphs 65 to 124, comprising one or more nanoparticles comprising an active compound, the nanoparticles being in solution or suspension in a composition comprising an ionic liquid. 126. A method for designing and / or identifying an ionic liquid comprising two ions, one ion being a cation and the other anion, comprising the steps of: (a) selecting one of the two ions of the ionic liquid; and (b) selecting the other ion so as to minimize ion-ion interactions; 127. A method for designing and / or identifying an ionic liquid comprising two ions, one ion being a cation and the other anion, comprising the steps of: (a) selecting a cation; and (b) selecting the anion to minimize ionic interactions; 128. A method for designing and / or identifying an ionic liquid comprising two ions, one ion being a cation and the other anion, comprising the steps of: (a) selecting an anion; and (b) selecting the cations to minimize ionic interactions; 129. A method for designing and / or identifying an ionic liquid containing two ions, one ion being a cation and the other anion, from a pool of candidate cations and a pool of candidate anions, comprising the steps of: (a) selecting one of two ions of the ionic liquid from a pool of candidate ions; and (b) selecting from the other pool of candidate ions the ion that best minimizes ion-ion interactions with the ion selected in step a. 130. A method for designing and / or identifying an ionic liquid containing two ions, one ion being a cation and the other anion, from a pool of candidate cations and a pool of candidate anions, comprising the steps of: (a) selecting a cation from a pool of candidate cations; (b) selecting from the pool of candidate anions the anion that best minimizes ionic interactions with the cation selected in step a. 131. A method for designing and / or identifying an ionic liquid containing two ions, one ion being a cation and the other anion, from a pool of candidate cations and a pool of candidate anions, comprising the steps of: (a) selecting a cation from a pool of candidate anions; (b) selecting from the pool of candidate cations the anion that best minimizes ionic interactions with the anion selected in step a. 132. The method of any of paragraphs 126 to 131, wherein the ionic liquid is selected or designed for transdermal administration. 133. The method of any of paragraphs 126 to 132, wherein the ionic liquid is selected or designed for transdermal, mucosal, oral, subcutaneous, intradermal, parenteral, intratumoral, or intravenous administration. 134. The method of paragraph 133, wherein the mucosa is nasal mucosa, oral mucosa, or vaginal mucosa. 135. The method of any of paragraphs 126 to 134, wherein the ionic liquid is selected or designed for oral administration. 136. The method of any of paragraphs 126 to 135, wherein the ionic liquid is selected or designed for delivery of an active compound. 137. The method of any of paragraphs 126 to 136, wherein the cation comprises a quaternary ammonium, or the step of selecting a cation comprises selecting a cation comprising a quaternary ammonium; and the anion comprises a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0, or the step of selecting an anion comprises selecting a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0. 138. The method of any of paragraphs 126-137, wherein the anion has a pKa of at least 4.5 or the step of selecting an anion includes selecting an anion having a pKa of at least 4.5. 139. The method of any of paragraphs 126-138, wherein the anion has a pKa of at least 4.895 or the step of selecting an anion includes selecting an anion having a pKa of at least 4.895. 140. The method of any of paragraphs 126-138, wherein the anion has a pKa between 4.5 and 5.5, or the step of selecting an anion includes selecting an anion having a pKa between 4.5 and 5.5. 141. The method of any of paragraphs 126 to 140, wherein the anion has a pKa between 4.895 and 5.19, or the step of selecting an anion includes selecting an anion having a pKa between 4.895 and 5.19. 142. The method of any of paragraphs 126-141, wherein the anion has a pKa of at least 5.0 or the step of selecting an anion includes selecting an anion having a pKa of at least 5.0. 143. The method of any of paragraphs 126-142, wherein the anion has a LogP of at least 2.0 or the step of selecting an anion includes selecting an anion having a LogP of at least 2.0. 144. The method of any of paragraphs 126 to 143, wherein the anion has a LogP of at least 2.5 or the step of selecting an anion includes selecting an anion having a LogP of at least 2.5. 145. The method of any of paragraphs 126-144, wherein the anion has a LogP of at least 2.75 or the step of selecting an anion includes selecting an anion having a LogP of at least 2.75. 146. The method of any of paragraphs 126-145, wherein the anion has a LogP of at least 2.8 or the step of selecting an anion includes selecting an anion having a LogP of at least 2.8. 147. The method of any of paragraphs 126 to 146, wherein the anion has a LogP of 2.5 to 3.5 or the step of selecting an anion includes selecting an anion having a LogP of 2.5 to 3.5. 148. The method of any of paragraphs 126 to 147, wherein the anion has a LogP of 2.8 to 3.01 or the step of selecting an anion includes selecting an anion having a LogP of 2.8 to 3.01. 149. The method of any of paragraphs 126-148, wherein the anion comprises a carbon chain of at least 8 carbons or the step of selecting an anion comprises selecting an anion that comprises a carbon chain of at least 8 carbons. 150. The method of any of paragraphs 126-149, wherein the anion comprises an eight-carbon backbone carbon chain or the step of selecting an anion comprises selecting an anion that comprises an eight-carbon backbone carbon chain. 151. The method of any of paragraphs 126-150, wherein the anion is geranic acid, octenic acid, octanoic acid, or citronellic acid, or the step of selecting an anion includes selecting an anion that is geranic acid, octenic acid, octanoic acid, or citronellic acid. 152. The method of any of paragraphs 126-151, wherein the anion is octenic acid, octanoic acid, or citronellic acid, or the step of selecting an anion includes selecting an anion that is octenic acid, octanoic acid, or citronellic acid. 153. The method of any of paragraphs 126 to 152, wherein the anion is an alkene or the step of selecting an anion includes selecting an anion that is an alkene. 154. The method of any of paragraphs 126-153, wherein the anion is geranic acid, octanoic acid, or citronellic acid, or the step of selecting an anion includes selecting an anion that is geranic acid, octanoic acid, or citronellic acid. 155. The method of any of paragraphs 126 to 154, wherein the cation has a molar mass equal to or greater than that of choline, or the step of selecting a cation includes selecting a cation having a molar mass equal to or greater than that of choline. 156. Quaternary ammonium is NR4 + and at least one R group contains a hydroxy group. 157. Quaternary ammonium is NR4 + and only one R group contains a hydroxy group. 158. The method of any of paragraphs 126-157, wherein the cation is C1, C6, or C7, or the step of selecting a cation includes selecting a cation that is C1, C6, or C7. 159. The method of any of paragraphs 126-158, wherein the cation is selected from choline, C1, C6, and C7, or the step of selecting a cation includes selecting a cation selected from choline, C1, C6, and C7, and the anion is citronellic acid. 160. The method of any of paragraphs 126 to 159, wherein the cation is selected from C1, C6, and C7, or the step of selecting a cation includes selecting a cation selected from C1, C6, and C7, and the anion is geranic acid. 161. The method of any of paragraphs 126 to 160, wherein the cation is choline, C1, C6, or C7, or the step of selecting a cation includes selecting a cation that is choline, C1, C6, or C7, and the step of selecting an anion includes selecting an anion that is citronellic acid, octanoic acid, or octenoic acid. 162. The method of any of paragraphs 126 to 161, wherein the cation is choline and the step of selecting an anion includes selecting an anion that is citronellic acid, octanoic acid, or octenoic acid. 163. Any of the methods of paragraphs 126 to 162, wherein the ionic liquid is not a CAGE. 164. The method of any of paragraphs 126 to 163, wherein the ionic liquid comprises a ratio of cations to anions of about 2:1 to about 1:10. 165. The method of any of paragraphs 126 to 164, wherein the ionic liquid comprises a ratio of cations to anions of about 1:1 to about 1:4. 166. The method of any of paragraphs 126 to 165, wherein the ionic liquid comprises a ratio of cations to anions of about 1:2. 167. The method of any of paragraphs 126 to 166, wherein the ionic liquid has a cation:anion ratio of less than 1:1. 168. The method of any of paragraphs 126 to 167, wherein the ionic liquid has a cation:anion ratio that includes an excess of anion. 169. The method of any of paragraphs 126 to 168, wherein the step of minimizing ion-ion interactions includes minimizing the number of cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY). 170. Any of the methods of paragraphs 126 to 169, wherein cations and anions have fewer than 20 cross peaks when they are measured by nuclear Overhauser effect spectroscopy (NOESY), thereby minimizing ion-ion interactions. 171. Any of the methods of paragraphs 126 to 170, wherein cations and anions have fewer than 10 cross peaks when they are measured by nuclear Overhauser effect spectroscopy (NOESY), thereby minimizing ion-ion interactions. 172. Any of the methods of paragraphs 126 to 171, wherein cations and anions have fewer than five cross peaks when they are measured by nuclear Overhauser effect spectroscopy (NOESY), thereby minimizing ion-ion interactions. 173. The method of any of paragraphs 126 to 172, wherein the active compound is hydrophobic. 174. The method of any of paragraphs 126 to 173, wherein the active compound is hydrophilic. 175. The method of any of paragraphs 126 to 174, wherein the active compound comprises a polypeptide. 176. The method of any of paragraphs 126 to 175, wherein the active compound has a molecular weight of greater than 450. 177. The method of any of paragraphs 126 to 176, wherein the active compound has a molecular weight of greater than 500. 178. The method of any of paragraphs 126 to 177, wherein the active compound comprises an antibody or antibody reagent. 179. The method of any of paragraphs 126 to 178, wherein the active compound comprises insulin, acarbose, ruxolitinib, or a GLP-1 polypeptide or a mimetic or analog thereof. 180. Any of the methods of paragraphs 126 to 179, wherein the ionic liquid has a concentration of at least 0.1% w / v. 181. The method of any of paragraphs 126 to 180, wherein the ionic liquid has a concentration of about 10 to about 70% w / v. 182. The method of any of paragraphs 126 to 181, wherein the ionic liquid has a concentration of about 30 to about 50% w / v. 183. The method of any of paragraphs 126 to 182, wherein the ionic liquid has a concentration of about 30 to about 40% w / v. 184. The method of any of paragraphs 126 to 183, wherein the active compound is provided at a dosage of 1 to 20 mg / kg. 185. The method of any of paragraphs 126 to 184, wherein the ionic liquid is designed or selected for delivery in a degradable capsule. 186. The method of any of paragraphs 126 to 185, wherein the ionic liquid and the active compound are in a mixture. 187. The method of any of paragraphs 126 to 186, wherein the ionic liquid and, optionally, the active compound are selected or designed for delivery in one or more nanoparticles. 188. The method of any of paragraphs 126 to 187, wherein the ionic liquid is in solution or suspension in a composition that includes one or more nanoparticles that include the active compound. EXAMPLES

[0252] Example 1 Choline-based ionic liquids, especially choline and geranic acid (CAGE), have been used to enhance the delivery of several small and large molecules across the skin. However, there is still no detailed study outlining the design principles of ILs for transdermal drug delivery. Using two model drugs, acarbose and ruxolitinib, with different hydrophilicity, and 16 ionic liquids of various cations and anions, we herein investigate the dependence of skin permeation on the chemical properties of ILs. First, the effect of ion stoichiometry on the skin permeation of drugs was evaluated using CAGE as a representative IL, showing that a choline to geranic acid molar ratio of 1:2 in CAGE resulted in the highest delivery. Then, variants of CAGE were prepared with anions with structural similarity to geranic acid and cations with structural similarity to choline. For all variants, the cation to anion ratio was kept constant at 1:2. A range of permeation enhancement effects was observed among the CAGE variants, with some variants outperforming the original CAGE composition. Mechanistic studies revealed that the potency of ILs in enhancing transdermal drug delivery was inversely correlated with ionic interactions, as determined by 2D NMR. Utilizing this understanding, new CAGE variants were designed that provided the highest delivery of ruxolitinib of all ILs tested here. Overall, these studies provide a generalized framework for optimizing ILs that enhance skin permeation.

[0253] Introduction Transdermal drug delivery provides a painless mode of drug administration while simultaneously avoiding first-pass metabolism [1]. However, overcoming the transport barrier of the skin's top layer, the stratum corneum (SC), is a significant challenge [1]. The SC is composed of a tightly packed brick-and-mortar-like structure of keratinocytes surrounded by lipids [2]. Only a few drugs with low mass and high lipophilicity can pass through the SC barrier unaided. In particular, several methods have been designed to enhance skin permeability to drugs, including the use of ultrasound [3, 4], microneedles [5, 6], iontophoresis [7, 8], jet injectors [9, 10], and penetration enhancers [11–13]. Recently, ionic liquids and deep eutectic solvents (hereafter collectively referred to as ionic liquids (ILs) for simplicity) have been found to be very promising for transdermal drug delivery [14–19]. We previously demonstrated that choline and geranic acid-based ILs, termed CAGE (Figure 1), showed efficacy for transdermal delivery of insulin

[20] as well as small molecule antimicrobial agents

[17] .

[0254] The effectiveness of ILs in enhancing skin permeability is expected to depend on their ionic content and composition. However, such knowledge base is not found in the literature at all. One study showed that the effectiveness of CAGE in insulin delivery is strongly dependent on its ionic stoichiometry. This study further showed that CAGE mediates its enhancing effect mainly through SC lipid interactions

[16] . However, there is still no generalized understanding of the role of ionic properties in determining the delivery efficacy of ILs.

[0255] The study presented here is the first systematic study of the role of anionic and cationic properties in IL-mediated transdermal drug delivery. Drugs with different hydrophobicity were used to evaluate the transport capacity of ILs (Figure 2). The first drug, acarbose, is a hydrophilic molecule used to treat type 2 diabetes by inhibiting the enzymes that digest carbohydrates

[27] . It is currently administered orally but has very low bioavailability and a high gastrointestinal side effect profile, thus limiting its application

[28] . The second drug, ruxolitinib, is a hydrophobic Janus Kinase (JAK) inhibitor currently FDA approved as an oral pill for use in myelofibrosis [29, 30]. It also shows promise in the treatment of alopecia, and therefore its topical delivery is of interest [31, 32]. The ILs used in this study were built around the composition of CAGE. Specifically, eight organic acids of varying molecular weight, pKa and hydrophobicity were used as substitutes for geranic acid, and seven organic quaternary amines were used as substitutes for choline. The resulting ILs were characterized by NMR and their ability to deliver ruxolitinib and acarbose was measured in vitro.

[0256] Methods and Materials material Choline bicarbonate, geranic acid, tertiary amines, halogenated alcohols, phosphate-buffered saline (PBS), DO, and deuterated DMSO were obtained from Sigma Aldrich (St. Louis, MO, USA). Commercially available geranic acid (85%, yellow liquid) was purified prior to use by at least five successive freeze-thaw cycles with acetone until the solution was clear. Residual acetone was removed under reduced pressure prior to use. Pig skin (Lampire Biological Laboratories, Pipersville, PA) was kept at -80°C and thawed immediately prior to use.

[0257] method Synthesis of CAGE. CAGE was synthesized with various ionic stoichiometries as previously reported

[17] . Choline bicarbonate and geranic acid were mixed in various molar ratios, including 1:4, 1:2, 1:1, and 2:1, and CAGE was prepared by salt metathesis reaction. Each CAGE composition was characterized by NMR using DMSO-d6 on an Agilent DD2™ 600 MHz spectrometer.

[0258] Synthesis of choline analogues. Seven variants of choline were prepared to evaluate the dependence of transport on cationic properties. The synthesis was designed based on that reported in Ref

[33] . The starting material for all variants was either triethylamine, tripropylamine or tributylamine. In each case, the amine was reacted with the halogenated alcohol in a 1:1 molar ratio by dissolving in toluene (30 mL) and heating in a round-bottom flask at the indicated temperature for 12 h (Table 4). Important information regarding the various reactants, reaction temperatures and the products obtained is given in Table 4. The bulk of the solvent was then removed using a rotary evaporator at 20 mbar and 60 °C for 2 h. The remaining solvent was removed under reduced pressure at 60 °C for 48 h.

[0259] IL of geranic acid with choline substitutes. Similar to the previously reported CAGE synthesis

[34] , the quaternary amine was reacted with recrystallized geranic acid in a 1:2 molar ratio at 40 °C for 12 h. The resulting ionic liquid was then dried at 20 mbar and 60 °C for 2 h using a rotary evaporator. Residual water was removed under reduced pressure at 60 °C for 48 h.

[0260] IL with geranic acid substitutes. Carboxylic acids dissolved in the minimum amount of ultrapure water (or methanol in the case of salicylic acid) required for dissolution (<5 mL) were reacted with choline bicarbonate in a 1:2 molar ratio (choline:carboxylic acid) at 40 °C for 12 h. The resulting ionic liquid was then dried at 20 mbar and 60 °C for 2 h using a rotary evaporator. Residual water was removed under reduced pressure at 60 °C for 48 h.

[0261] NOESY measurements. Samples were prepared by placing the dried IL in an NMR tube with a coaxial insert containing deuterated DMSO. An Agilent DD2™ 600 MHz spectrometer was used. A 90° pulse width of 11.25 was used, the number of increments (ni) was set to 128, and the number of scans was set to 4. Spectra were post-phase corrected.

[0262] Skin permeation studies. Skin permeation studies were performed using pig skin in Franz-type diffusion cells (skin area = 1.7 cm2) as previously described in detail

[35] . 2 ). Briefly, thawed and washed porcine skin was placed in a diffusion cell with the SC facing up. The acceptor portion of the cell was filled with PBS and equipped with a magnetic stir bar. Only cells with measured skin transdermal currents below 12 μA were used in the study and treatments were randomized. 300 μL of drug solution (1 mg / mL) in each IL was placed on top of the skin, completely covering it. The cell was placed on a stirrer plate at 37° C. for 24 hours, at which point the skin was removed and the surface gently washed with PBS. Each skin layer was then separated. The stratum corneum was removed by tape stripping (up to 10 layers), the epidermis was separated from the dermis with a scalpel, and one-third of the dermis (by area) was removed using three 4 mm punches. The tissue was then placed in either methanol (ruxolitinib) or a 50% methanol / PBS mixture (acarbose) and shaken overnight to extract the drug, which was then analyzed by HPLC, as described below.

[0263] HPLC analysis. Analysis of the amount of drug present in each layer was determined by HPLC. In each case, 2×10 -3A calibration curve consisting of 10 samples covering a concentration range of ~1mg / ml was generated. For acarbose, a 250x4.6, 5μm Nucleosil-NH2 column was used. The isocratic mobile phase was acetonitrile:phosphate buffer (1L contained 0.6g KH2PO4 and 0.48g Na2HPO4) (76:24) at 1mL / min, and the UV detector (210nm) showed a peak appearing at 5.2min. For ruxolitinib, an Inertsil ODS C-18 column with 250x4.6mm inner diameter and 5μm particle size was used. An isocratic elution mobile phase of THF:methanol:acetonitrile 10:40:50 (v / v / v) at a flow rate of 1ml / min was used, and the peak at 3.2min was identified as the product peak (detected by UV at 270nm).

[0264] result Dependence of delivery efficacy on ionic stoichiometry. The first study was performed to evaluate the role of ionic stoichiometry in CAGE in determining its ability to deliver acarbose and ruxolitinib. Four variants of CAGE were synthesized with choline:geranic acid ratios of 2:1, 1:1, 1:2, and 1:4. Acarbose and ruxolitinib were dissolved in CAGE at a concentration of 1 mg / ml. Both drugs were completely dissolved in all CAGE variants at this concentration. The delivery of both drugs to the skin showed a strong dependence on the CAGE composition (Figure 3, acarbose (red) and ruxolitinib (blue)). The amounts shown in Figure 3 correspond to those delivered to the dermis and acceptor parts. The detailed distribution of the drugs in the various skin layers is shown in Figures 11 and 12. The highest amount of delivered drug was found in the dermis, followed by the acceptor and the epidermis. No significant transport of either drug was observed from PBS (negative control). Acarbose was soluble in PBS at a concentration of 1 mg / ml, whereas ruxolitinib was only soluble at a concentration of 0.2 mg / ml, and therefore a saturated solution in PBS was used for the donor. In the case of ruxolitinib, a two-fold increase in geranic acid content (2:1 CAGE to 1:2 CAGE) increased the delivery efficacy by approximately four-fold, after which it plateaued. A similar trend was observed in the case of acarbose, confirming that 1:2 CAGE exhibited the highest delivery efficacy for hydrophilic as well as lipophilic drugs. This is consistent with previous studies with insulin, where 1:2 CAGE was the best among the four variants presented

[16] . It should be noted that no significant transport was observed when ruxolitinib or acarbose were solubilized in pure geranic acid or 80% choline bicarbonate / water. Considering that the 1:2 choline:geranic acid ratio provided the greatest delivery regardless of drug hydrophilicity, subsequent variants were prepared with this stoichiometry.

[0265] Dependence of delivery efficacy on anion chemistry. The first set of IL variants was synthesized by replacing geranic acid with other organic acids. Eight alternatives to geranic acid were used (Figure 4). First, the closest variant of geranic acid is citronellic acid, which has one less double bond compared to geranic acid but is otherwise equivalent. Octanoic acid has the same number of carbons in the backbone as geranic acid but lacks the unsaturation and methyl side groups present in geranic acid. Octenoic acid is an unsaturated analog of octanoic acid, providing an opportunity to evaluate the role of unsaturation in the delivery efficacy. Decanoic acid has the same number of total carbons as geranic acid and lacks unsaturation, providing an opportunity to evaluate the role of the total number of carbons in the delivery efficacy. Glutaric acid is the only dicarboxylic acid included in the list, and salicylic acid is the only aromatic acid. Some of the key properties of the anions, including molecular weight, pKa, LogP and number of carbon atoms, are listed in Table 1.

[0266] Ionic liquids for each of these carboxylic acids were synthesized using salt metathesis of choline bicarbonate with the acid, using choline as the counterion in a stoichiometric ratio of choline:acid 1:2. Ruxolitinib and acarbose were dissolved in each IL variant at a concentration of 1 mg / ml. All ILs showed enhanced delivery of acarbose and ruxolitinib to the skin compared to the control (PBS). In general, the majority of the drug was found in the dermis, followed by the epidermis, then the acceptor (Figures 13 and 14). The amount of acarbose and ruxolitinib delivered, especially the amount of drug delivered to the dermis, showed a marked dependence on the IL chemistry (Table 2). In the case of acarbose, geranic acid outperformed the other anions. Hexenoic and glycolic acids were in second and third position, both anions with low Log P. However, it should be noted that glutaric acid, although having a similarly low Log P of 0.05, did not perform as well, suggesting that enhancement is not simply a function of lipophilicity. Interestingly, the same two anions, glutaric acid and hexenoic acid, were also the least effective anions for ruxolitinib delivery. Citronellic acid and octanoic acid were superior to geranic acid for ruxolitinib delivery. The overall ranking of all variants was determined by averaging the rankings for ruxolitinib and acarbose delivery to identify ILs that provide penetration enhancement for a broad range of drugs.

[0267] Geranic acid ranked highest, followed by its close analog, citronellic acid. Smaller anions, including salicylic acid and glutaric acid, were at the lower end of the ranking range. Interestingly, decanoic acid, which has the same number of carbons as geranic acid, ranked very low and was less effective against acarbose as well as ruxolitinib. Octanoic acid, which has the same number of carbons as the geranic acid backbone, performed fairly well, ranking next to geranic acid and citronellic acid. Octenic acid ranked just below octanoic acid, with citronellic acid ranking below geranic acid, indicating that a single unsaturated bond influences delivery efficacy.

[0268] Correlation between delivery efficacy and molecular parameters. We assessed whether the transport rank of anions correlated with their physicochemical parameters, including molecular weight, pKa, LogP, and carbon number (Figure 5A-5D). These parameters were selected because they capture some of the key chemical descriptors. No significant quantitative trends emerged from these plots. However, some qualitative findings were observed. For example, the highest-ranked anions had pKa values ​​above 5 (Figure 5B) and logP values ​​close to 3 (Figure 5C), suggesting that ILs prepared from weakly hydrophobic acids are more effective in enhancing skin permeability. Given the lack of a simple correlation between a single physicochemical property of an acid and its transport efficacy, we explored other possibilities.

[0269] One of the important parameters that must be considered when using an IL is the interactions between its ionic components. Specifically, strong interactions between anions and cations are important for the formation and stability of the IL. However, interactions between IL components and SC lipids are also important in determining their effectiveness in enhancing skin permeability. Given the relevance of interactions between anions and cations, and considering that anion properties alone did not correlate with the measured permeation rankings, we determined whether intra-ionic interactions correlate with the overall permeation rankings. To this goal, we investigated intra-ionic interactions using 2D Nuclear Overhauser Effect Spectroscopy (NOESY)

[36] . This technique reveals spatial interactions between the underlying chemical groups (in this case, anions and cations) by plotting NMR data on two frequency axes, using diagonal peaks and cross peaks, and counting the number of cross peaks (Figure 6A, 6B). Each cross peak represents two groups of protons that are within 5 nm of each other. NOSEY has been used to study the structures of proteins [37, 38], peptides [39, 40] and ionic liquids [36, 41, 42] due to its unique ability to resolve spatial interactions.

[0270] Exemplary NOESY spectra are shown in Figures 6A-6B, with in-phase cross peaks circled, indicating the portion of ions that are within 5 nm of each other. The remaining spectra are presented in SI. The number of measured cross peaks varied over a wide range. For example, 10 peaks were seen for choline:citronellic acid (Figure 6A), whereas 30 peaks were seen for choline:glutaric acid (Figure 6B). The overall transport ranking of the ILs showed a strong correlation with the number of NOSEY cross peaks (Figure 7). Geranic acid and citronellic acid, which have the lowest number of cross peaks, showed the highest transport rankings, whereas glutaric acid and salicylic acid, which have the highest number of cross peaks, showed the lowest transport rankings.

[0271] Cation modification. Next, cation modification was performed by increasing the alkyl head group of choline and lengthening the ethoxy chain. A total of seven cations were synthesized in addition to choline (Figure 8). Ionic liquids for each cation were synthesized using geranic acid as the anion in a ratio of 1:2 (geranic acid:cation) and characterized using NMR. Ruxolitinib and acarbose were dissolved in each IL at a concentration of 1 mg / ml and delivery to the skin was measured. The ability of ILs prepared with various cations to deliver acarbose and ruxolitinib is shown in Table 3. In the case of acarbose, little difference was observed between the cations tested and none of the newly synthesized cations was superior to choline. This is likely a result of the hydrophilicity of acarbose, which may have conferred more hydrophilicity to the ILs since the choline cation is the most hydrophilic cation tested. In the case of ruxolitinib, a significant dependence of transport on the cation was observed. Bulky cations, e.g., C6 and C7, significantly outperformed choline in terms of delivered dose. Many newly synthesized choline substitutes outperformed choline, with C1 ranking first among them. Again, this improved performance correlated with the NOSEY spectrum. Specifically, C1:geranic acid IL showed only three cross peaks compared to eight in the case of choline:geranic acid (Figure 21). It is hypothesized that the bulkiness of the substituents added to C1 reduces the close contact of the cations with geranic acid.

[0272] Simultaneous changes in anion and cation After exploring several anion and cation alternatives and establishing a correlation between transport rankings and NOSEY cross-correlation peaks, we combined two anions and two cations to create a representative IL. The two anions were geranic acid and its best alternative, citronellic acid. The two cations were choline and its best alternative, C1. Four ILs were compared: choline:geranic acid (CAGE), choline:citronellic acid, C1:geranic acid, and C1:citronellic acid. The delivery of ruxolitinib to the skin was measured with all ILs. NOSEY spectra for all ILs were also measured. A significant dependence of ruxolitinib delivery on IL composition was seen (Figure 9A). C1:citronellic acid delivered 117.1 ± 12.7 μg cm measured in the dermis and acceptor after 24 hours. -2 showed the highest delivery of ruxolitinib. In comparison, C1:geranic acid, choline:geranic acid and choline:citronellic acid delivered 89.9±4.6, 68.0±6.1 and 97.8±4.6 μg cm -2 This delivery effect again correlated strongly with the NOSEY cross-correlation peaks, with C1:citronellic acid showing only one peak compared to eight peaks shown by CAGE (FIG. 9B).

[0273] Consideration Ionic liquids have recently shown great promise in facilitating transdermal transport of drugs [14, 43]. In particular, imidazolium

[18] , quaternary ammonium [44, 45], and cyclic onium-based

[43] cations have been investigated ex vivo for their ability to transport small molecules through the intact stratum corneum into the dermis. However, currently, the physical understanding of the factors that result in optimal ILs for transdermal delivery, especially of quaternary ammonium-based ILs, remains limited.

[0274] The studies reported herein present a systematic evaluation of the dependence of transdermal drug delivery on the anionic and cationic properties of choline carboxylate-based ionic liquids. We first evaluated the dependence of transport on ionic stoichiometry using CAGE as an exemplary IL. The results showed that for ruxolitinib as well as acarbose delivery, ILs with excess anion (geranic acid) exhibited higher transport than those with equimolar or more cationic ILs. These conclusions are consistent with those previously reported using insulin

[16] . The results presented here, together with previous studies on insulin, ceftazidime and mannitol, indicate that CAGE can deliver a wide range of molecules (from mannitol with a MW of 180 to insulin with a LogP of about 6000, acarbose with a LogP of -6.8 to ruxolitinib with a LogP of 2.9, as well as a variety of molecule types including sugars, peptides and aromatics). The ability of CAGE to enhance diverse molecules indicates that the primary effect of CAGE is on the SC, thus addressing the primary barrier function.

[0275] Fourier transform infrared spectroscopy (FTIR) studies showed that CAGE affects SC lipids as measured by the reduction of the methylene peak, an indicator of lipid extraction and / or fluidization

[16] . FTIR studies performed in the literature with imidazolium-based ionic liquids are also consistent with our findings of the effect of ionic liquids on lipid-rich SC

[18] . CAGE variants with a higher proportion of geranic acid (>50 mol%) produced a more pronounced effect on SC lipids, which is consistent with the observed trend of molecular flux. Interestingly, there is a clear optimum for the concentration of geranic acid in the formulation, as pure geranic acid did not produce significant skin flux for either drug. This may be due to the high lipophilicity of geranic acid, which, while favoring the solubilization of ruxolitinib, may reduce its partitioning into the skin. Similar adverse effects of formulation lipophilicity on the delivery of lipophilic drugs have been reported previously for other chemicals

[46] . Thus, choline appears to reduce the lipophilicity of the anion alone, allowing partitioning of geranic acid as well as the drug into the skin.

[0276] Several new variants of CAGE were prepared with a fixed cation:anion 1:2 stoichiometry. In one set of variants, the cation was kept the same in the form of choline, but eight carboxylate anions were used. No clear dependence of drug transport was observed on any single anion parameter, including molecular weight, pKa, LogP, and carbon number. Qualitatively, larger hydrophobic anions were ranked above smaller hydrophilic anions. Specifically, the hydrophobic tail of the anion and / or cation plays a key role in fluidizing SC lipids. As choline is very hydrophilic and lacks an aliphatic chain, the anion provides the primary mode of lipid disruption. Gelanic acid and citronellic acid were two of the most hydrophobic anions in this study and emerged as being among the most effective. Decanoic acid was an exception to this trend. Despite having a comparable MW and pKa, as well as a slightly higher LogP, compared to geranic acid, decanoic acid did not perform well. This suggests a strong role of unsaturation in determining delivery efficacy. Literature studies of chemical enhancers have previously pointed to a role for unsaturation in enhancing transdermal flux. Specifically, it was hypothesized that increased unsaturation enhances SC lipid breakdown, possibly due to increased steric constraints provided by unsaturation

[49] .

[0277] Herein, two factors are believed to govern the design of an ideal ionic liquid for transdermal delivery: the potency of the anion and its ability to penetrate the skin. The potency of the anion relates to how effectively it can essentially disrupt lipids in the SC to facilitate drug transport. The ability of the anion to penetrate the skin can affect its ability to contact SC lipids. Extensive intra-ionic interactions can reduce the ability of the anion to penetrate the SC. Fatty acids have shown high efficacy in skin penetration enhancement [50, 51], and the relative ability of fatty acids to penetrate the skin can significantly affect the efficacy of the IL.

[0278] A strong correlation was found between the number of NOSEY cross peaks and the overall permeability ranking. The cross-correlated peaks in the NOSEY spectra showed a wide range, much greater than that measured for any single molecular parameter. The number of peaks varied from one for C1:citronellic acid to 30 for C1:glutaric acid. Essentially, the number of cross peaks indicates intramolecular interactions between ions mediated by protons. That is, each in-phase peak (same color as the 1D diagonal) indicates that the molecules are within 5 nm of each other as an average across the liquid. 2D NMR has previously been used successfully in neat ionic liquids to investigate ion-ion interactions in ILs [36, 41, 42]. Previous NOSEY studies by CAGE have also shown the presence of interactions between choline and geranic acid, indicating that these interactions vary with ion stoichiometry

[16] .

[0279] Without wishing to be bound by theory, it is believed herein that intra-ionic interactions in ILs play a key role in determining skin transport in at least two ways. First, the presence of strong intra-ionic interactions can create supramolecular structures, large in size and / or energetically stable, that reduce their penetration into the SC and the subsequent disruption of SC lipids. Molecular dynamics simulation studies using CAGE showed strong hydrogen bonds between choline and geranic acid

[52] , with the major interactions arising from those between the carboxyl groups of geranic acid and the hydroxyl groups of choline. Notably, since the lipid disrupting effect of ILs is mainly mediated by hydrophobic anions, interactions that favor the solubilization and retention of anions in the formulation will reduce their ability to penetrate the skin and mediate skin penetration. Secondly, ILs that exhibit high levels of interactions between their own ionic components may also strongly interact with solvated drugs, reducing their partitioning into the skin. Regardless of their mechanistic origin, the correlation between transport effect rankings and cross peaks is very significant and is observed not only in the anionic variants of CAGE but also in the combined cation-anion variants. Specifically, C1: citronellic acid, which exhibited the lowest number of clonal peaks (1), exhibited the highest delivery of ruxolitinib.

[0280] The presence of bulky aliphatic groups such as C1 may limit the interaction of its hydroxyl group with the carboxyl group in citronellic acid. In other words, bulky hydrophobic cations and large hydrophobic anions can potentially make excellent ILs for transdermal drug delivery. The studies presented here clearly demonstrate that 2D NMR can be used as a sieve to determine the efficacy of ILs in enhancing skin permeability.

[0281] Among the anions tested here, several have a history of use in humans. Among the best-performing anions other than geranic acid, citronellic acid is used in cosmetic applications as an antidandruff and masking agent. Octanoic acid (caprylic acid) is a commonly used dietary supplement. Modified choline molecules have some history of use in industrial applications, namely catalysis

[33] . C1 has also been used in rat perfusion studies to examine the blood-brain barrier, although no comprehensive toxicity screening has been performed. Encouragingly, choline-based cations have shown acceptably low toxicity, especially compared to imidazolium-based cations

[53] .

[0282] conclusion This study provides a framework for the design and screening of ionic liquids for transdermal drug delivery. Using two model drugs, acarbose and ruxolitinib, as well as 16 ionic liquids, we tested the dependence of transport on ion stoichiometry as well as molecular composition. For CAGE, compositions containing 1:2 choline:geranic acid provided the greatest transport enhancement. Systematic modification of the anions revealed that ILs with the fewest ion-ion interactions were the most successful in transdermal transport, and we believe herein that this is a result of the anions' ability to freely enter the skin. Modification of the cations that further reduced ion-ion interactions also improved delivery efficacy. The most effective cation and anion combination led to a novel IL that provided the highest enhancement of ruxolitinib transport. This study is the first systematic structural examination of ILs in transdermal drug delivery and provides a paradigm for designing new, effective topical formulations.

[0283] Table 1: Molecular properties of the carboxylic acids used to prepare the new ILs. LogP and pKa were determined theoretically as described in the literature

[54] . TIFF2025069232000007.tif44128

[0284] Table 2. Transport of acarbose and ruxolitinib into the dermis and acceptor over 24 hours by a series of ionic liquids with modifying anions (N=3, error bars indicate SEM). TIFF2025069232000008.tif82160

[0285] Table 3. Transport of acarbose and ruxolitinib into the dermis and acceptor over 24 hours by a series of ionic liquids with modifying cations (N=3, error bars indicate SEM). TIFF2025069232000009.tif60156

[0286] Table 4: Reaction conditions for cation precursors TIFF2025069232000010.tif69166

[0287] 1D NMR characterization: TIFF2025069232000011.tif101158TIFF2025069232000012.tif207159TIFF2025069232000013.tif252159TIFF2025069232000014.tif33159

[0288] References TIFF2025069232000015.tif185159TIFF2025069232000016.tif224158TIFF2025069232000017.tif232159TIFF2025069232000018.tif232159

[0289] Example 2 The effectiveness of various ionic liquid compositions for intestinal administration was tested using insulin. Insulin was mixed with the ionic liquids shown in Figure 22 and administered into the intestine. Blood glucose and plasma insulin concentrations were measured. Choline-citronellic acid, choline-octanoic acid, and choline-octenoic acid were particularly effective for intestinal delivery of insulin.

[0290] Sequence information SEQUENCE LISTING <110> PRESIDENT AND FELLOWS OF HARVARD COLLEGE <120> IONIC LIQUIDS FOR DRUG DELIVERY <150> US 62 / 828,539 <151> 2019-04-03 <160> 4 <170> PatentIn version 3.5 <210> 1 <211> 180 <212> PRT <213> Homo sapiens <400> 1 Met Lys Ser Ile Tyr Phe Val Ala Gly Leu Phe Val Met Leu Val Gln 1 5 10 15 Gly Ser Trp Gln Arg Ser Leu Gln Asp Thr Glu Glu Lys Ser Arg Ser 20 25 30 Phe Ser Ala Ser Gln Ala Asp Pro Leu Ser Asp Pro Asp Gln Met Asn 35 40 45 Glu Asp Lys Arg His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys 50 55 60 Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn 65 70 75 80 Thr Lys Arg Asn Arg Asn Asn Ile Ala Lys Arg His Asp Glu Phe Glu 85 90 95 Arg His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu 100 105 110 Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly 115 120 125 Arg Arg Asp Phe Pro Glu Glu Val Ala Ile Val Glu Glu Leu Gly Arg 130 135 140 Arg His Ala Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp 145 150 155 160 Asn Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile 165 170 175 Thr Asp Arg Lys 180 <210> 2 <211> 37 <212> PRT <213> Homo sapiens <400> 2 His Asp Glu Phe Glu Arg His Ala Glu Gly Thr Phe Thr Ser Asp Val 1 5 10 15 Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu 20 25 30 Val Lys Gly Arg Gly 35 <210> 3 <211> 30 <212> PRT <213> Homo sapiens <400> 3 His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg 20 25 30 <210> 4 <211> 31 <212> PRT <213> Homo sapiens <400> 4 His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly 20 25 30

Claims

1. A method of administering at least one active compound, comprising administering the active compound to a subject comprising: a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0; and Quaternary ammonium cations The method comprises administering in combination with at least one ionic liquid comprising:

2. 1. A method of reducing weight / weight gain or treating obesity, diabetes, ulcers, cancer, or fibrosis in a subject in need thereof, comprising: a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0; and Quaternary ammonium cations 20. The method of claim 19, further comprising administering to a subject a composition comprising at least one ionic liquid comprising:

3. 3. The method of claim 2, wherein the composition does not include a therapeutic agent other than the at least one ionic liquid.

4. The method of claim 2 , wherein the composition further comprises an active compound other than the at least one ionic liquid.

5. 2. The method of claim 1, wherein the anion has a pKa of at least 4.

5.

6. 2. The method of claim 1, wherein the anion has a pKa of at least 5.

0.

7. 2. The method of any one of the preceding claims, wherein the anion has a pKa of at least 4.

895.

8. 2. The method of claim 1, wherein the anion has a pKa of 4.5 to 5.

5.

9. 2. The method of claim 1, wherein the anion has a pKa of 4.895 to 5.

19.

10. 10. The method of claim 1, wherein the anion has a LogP of at least 2.

0.

11. 10. The method of any one of the preceding claims, wherein the anion has a LogP of at least 2.

5.

12. 10. The method of any one of the preceding claims, wherein the anion has a LogP of at least 2.

75.

13. 10. The method of any one of the preceding claims, wherein the anion has a LogP of at least 2.

8.

14. 10. The method of any one of the preceding claims, wherein the anion has a LogP of 2.5 to 3.

5.

15. 10. The method of claim 1, wherein the anion has a LogP of 2.8 to 3.

01.

16. 2. The method of claim 1, wherein the anion comprises a carbon chain of at least 8 carbons.

17. 2. The method of claim 1, wherein the anion comprises an eight-carbon backbone carbon chain.

18. 2. The method of claim 1, wherein the anion is geranic acid, octenic acid, octanoic acid, or citronellic acid.

19. 2. The method of claim 1, wherein the anion is octenoic acid, octanoic acid, or citronellic acid.

20. 2. The method of claim 1, wherein the anion is an alkene.

21. 2. The method of claim 1, wherein the anion is geranic acid, octanoic acid, or citronellic acid.

22. 2. The method according to claim 1, wherein the cation has a molar mass equal to or greater than that of choline.

23. Quaternary ammonium is NR 4 + and at least one R group comprises a hydroxy group.

24. Quaternary ammonium is NR 4 + and wherein only one R group comprises a hydroxy group.

25. 2. The method of claim 1, wherein the cation is C1, C6, or C7.

26. 2. The method of claim 1, wherein the cation is selected from choline, C1, C6, and C7, and the anion is citronellic acid.

27. 10. The method of claim 1, wherein the cation is C1 and the anion is citronellic acid.

28. 2. The method of claim 1, wherein the cation is selected from C1, C6, and C7, and the anion is geranic acid.

29. 2. The method of claim 1, wherein the ionic liquid is choline:citronellic acid, C1:geranic acid, or C1:citronellic acid.

30. 17. The method of any one of claims 1 to 16, wherein the cation is selected from choline, C1, C6, and C7, and the anion is selected from citronellic acid, octanoic acid, and octenoic acid.

31. 17. The method of any one of claims 1 to 16, wherein the cation is choline and the anion is selected from citronellic acid, octanoic acid, and octenoic acid.

32. 17. The method of any one of claims 1 to 16, wherein the ionic liquid is choline:citronellic acid, choline:octanoic acid, or choline:octenoic acid.

33. 2. The method of claim 1, wherein the ionic liquid is not a CAGE.

34. 2. The method of claim 1, wherein the ionic liquid has less than 20 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY).

35. 2. The method of claim 1, wherein the ionic liquid has less than 10 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY).

36. 2. The method of claim 1, wherein the ionic liquid has less than 5 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY).

37. 2. The method of any one of the preceding claims, wherein the administration is transdermal.

38. 20. The method of any one of the preceding claims, wherein the administration is transdermal, mucosal, oral, subcutaneous, intradermal, parenteral, intratumoral, or intravenous.

39. 27. The method of claim 26, wherein the mucosa is a nasal mucosa, an oral mucosa, or a vaginal mucosa.

40. 20. The method of any one of the preceding claims, wherein the administration is oral administration.

41. 10. The method of any one of the preceding claims, wherein the ionic liquid is at a concentration of at least 0.1% w / v.

42. 20. The method of any one of the preceding claims, wherein the ionic liquid is at a concentration of about 10 to about 70% w / v.

43. 20. The method of any one of the preceding claims, wherein the ionic liquid is at a concentration of about 30 to about 50% w / v.

44. 20. The method of any one of the preceding claims, wherein the ionic liquid is at a concentration of about 30 to about 40% w / v.

45. 2. The method of claim 1, wherein the ionic liquid comprises a ratio of cations to anions of about 2:1 to about 1:

10.

46. 2. The method of any one of the preceding claims, wherein the ionic liquid comprises a ratio of cations to anions of about 1:1 to about 1:

4.

47. 2. The method of claim 1, wherein the ionic liquid comprises a ratio of cations to anions of about 1:

2.

48. 2. The method of claim 1, wherein the ionic liquid has a cation:anion ratio of less than 1:

1.

49. 2. The method according to any one of the preceding claims, wherein the active compound is hydrophobic.

50. 20. The method according to any one of the preceding claims, wherein the active compound is hydrophilic.

51. The method of any one of the preceding claims, wherein the active compound comprises a polypeptide.

52. 2. The method of claim 1, wherein the active compound has a molecular weight greater than 450.

53. 20. The method of claim 1, wherein the active compound has a molecular weight greater than 500.

54. The method of any one of the preceding claims, wherein the active compound comprises an antibody or an antibody reagent.

55. 20. The method of any one of the preceding claims, wherein the active compound comprises insulin, acarbose, ruxolitinib, or a GLP-1 polypeptide or a mimetic or analog thereof.

56. The method according to any one of the preceding claims, wherein the combination and / or composition is administered once.

57. The method according to any one of the preceding claims, wherein the combination and / or composition is administered in multiple doses.

58. 10. The method of any one of the preceding claims, wherein the active compound and / or composition is provided in a dosage of 1 to 20 mg / kg.

59. 20. The method of claim 1, wherein the active compound and the ionic liquid are further in combination with at least one non-ionic surfactant.

60. 20. The method according to any one of the preceding claims, wherein the combination and / or composition further comprises an additional pharma- ceutically acceptable carrier.

61. 10. The method according to any one of the preceding claims, wherein administration is oral and the combination and / or composition is provided in a degradable capsule.

62. The method of any one of the preceding claims, wherein the combination is a mixture.

63. The method according to any one of the preceding claims, wherein the combination and / or composition is provided in one or more nanoparticles.

64. 20. The method of claim 1, wherein the combination is provided in the form of one or more nanoparticles comprising the active compound, the nanoparticles being in solution or suspension in a composition comprising an ionic liquid.

65. a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0; and Quaternary ammonium cations A composition comprising at least one ionic liquid comprising:

66. 66. The composition of claim 65, wherein the anion has a pKa of at least 4.

5.

67. 66. The composition of claim 65, wherein the anion has a pKa of at least 4.

895.

68. 66. The composition of claim 65, wherein the anion has a pKa between 4.5 and 5.

5.

69. 66. The composition of claim 65, wherein the anion has a pKa between 4.895 and 5.

19.

70. 70. The composition of any one of claims 65-69, wherein the anion has a pKa of at least 5.

0.

71. 70. The composition of any one of claims 65-69, wherein the anion has a LogP of at least 2.

0.

72. 70. The composition of any one of claims 65-69, wherein the anion has a LogP of at least 2.

5.

73. 70. The composition of any one of claims 65-69, wherein the anion has a LogP of at least 2.

75.

74. 70. The composition of any one of claims 65-69, wherein the anion has a LogP of at least 2.

8.

75. 70. The composition of any one of claims 65-69, wherein the anion has a LogP of 2.5 to 3.

5.

76. 70. The composition of any one of claims 65-69, wherein the anion has a LogP of 2.8 to 3.

01.

77. The composition of any one of claims 65-76, wherein the anion comprises a carbon chain of at least 8 carbons.

78. 77. The composition of any one of claims 65-76, wherein the anion comprises an eight-carbon backbone carbon chain.

79. 77. The composition of any one of claims 65-76, wherein the anion is geranic acid, octenic acid, octanoic acid, or citronellic acid.

80. 77. The composition of any one of claims 65-76, wherein the anion is octenoic acid, octanoic acid, or citronellic acid.

81. The composition of any one of claims 65 to 80, wherein the anion is an alkene.

82. The composition of any one of claims 65-81, wherein the anion is geranic acid, octanoic acid, or citronellic acid.

83. The composition of any one of claims 65 to 82, wherein the cation has a molar mass equal to or greater than that of choline.

84. Quaternary ammonium is NR 4 + and at least one R group comprises a hydroxy group.

85. Quaternary ammonium is NR 4 + and wherein only one R group comprises a hydroxy group.

86. The composition of any one of claims 65-85, wherein the cation is C1, C6, or C7.

87. 87. The composition of any one of claims 65-86, wherein the cation is selected from choline, C1, C6, and C7, and the anion is citronellic acid.

88. The composition of any one of claims 65-87, wherein the cation is C1 and the anion is citronellic acid.

89. The composition of any one of claims 65-88, wherein the cation is selected from C1, C6, and C7, and the anion is geranic acid.

90. 90. The composition of any one of claims 65-89, wherein the ionic liquid is choline:citronellic acid, C1:geranic acid, or C1:citronellic acid.

91. 91. The composition of any one of claims 65-90, wherein the cation is selected from choline, C1, C6, and C7, and the anion is selected from citronellic acid, octanoic acid, and octenoic acid.

92. The composition of any one of claims 65-91, wherein the cation is choline and the anion is selected from citronellic acid, octanoic acid, and octenoic acid.

93. 93. The composition of any one of claims 65-92, wherein the ionic liquid is choline:citronellic acid, choline:octanoic acid, or choline:octenoic acid.

94. The composition of any one of claims 65 to 93, wherein the ionic liquid is not a CAGE.

95. 95. The composition of any one of claims 65-94, wherein the ionic liquid comprises a ratio of cations to anions of about 2:1 to about 1:

10.

96. 96. The composition of any one of claims 65-95, wherein the ionic liquid comprises a ratio of cations to anions of about 1:1 to about 1:

4.

97. 97. The composition of any one of claims 65-96, wherein the ionic liquid comprises a ratio of cations to anions of about 1:

2.

98. 98. The composition of any one of claims 65-97, wherein the ionic liquid has a cation:anion ratio of less than 1:

1.

99. 99. The composition of any one of claims 65 to 98, wherein the ionic liquid has a cation:anion ratio that includes an excess of anion.

100. 100. The composition of any one of claims 65-99, wherein the ionic liquid has fewer than 20 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY).

101. 101. The composition of any one of claims 65-100, wherein the ionic liquid has less than 10 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY).

102. 102. The composition of any one of claims 65-101, wherein the ionic liquid has less than 5 cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY).

103. 103. The composition of any one of claims 65-102, further comprising at least one active compound in combination with said at least one ionic liquid.

104. The composition of claim 103, wherein the active compound is hydrophobic.

105. The composition of any one of claims 103 to 104, wherein the active compound is hydrophilic.

106. The composition of any one of claims 103-105, wherein the active compound comprises a polypeptide.

107. The composition of any one of claims 103-106, wherein the active compound has a molecular weight greater than 450.

108. The composition of any one of claims 103-107, wherein the active compound has a molecular weight greater than 500.

109. The composition of any one of claims 103-108, wherein the active compound comprises an antibody or antibody reagent.

110. The composition of any one of claims 103-109, wherein the active compound comprises insulin, acarbose, ruxolitinib, or a GLP-1 polypeptide or a mimetic or analog thereof.

111. The composition of any one of claims 65-110, wherein the ionic liquid is at a concentration of at least 0.1% w / v.

112. The composition of any one of claims 65-111, wherein the ionic liquid is at a concentration of about 10 to about 70% w / v.

113. The composition of any one of claims 65-112, wherein the ionic liquid is at a concentration of about 30 to about 50% w / v.

114. The composition of any one of claims 65-113, wherein the ionic liquid is at a concentration of about 30 to about 40% w / v.

115. The composition of any one of claims 65-114, formulated for transdermal administration.

116. The composition of any one of claims 65-115, formulated for transdermal, mucosal, oral, subcutaneous, intradermal, parenteral, intratumoral, or intravenous administration.

117. 117. The composition of claim 116, wherein the mucosa is a nasal mucosa, an oral mucosa, or a vaginal mucosa.

118. The composition of any one of claims 65-117, formulated for oral administration.

119. The composition of any one of claims 103-118, providing the active compound at a dosage of 1-20 mg / kg.

120. The composition of any one of claims 65-119, further comprising at least one nonionic surfactant.

121. The composition of any one of claims 65 to 120, further comprising a pharma- ceutically acceptable carrier.

122. The composition of any one of claims 65 to 121 provided in a degradable capsule.

123. The composition of any one of claims 65 to 122, which is an admixture.

124. The composition of any one of claims 65-123, provided in one or more nanoparticles.

125. 125. The composition of any one of claims 65-124, comprising one or more nanoparticles comprising an active compound, said nanoparticles being in solution or suspension in a composition comprising an ionic liquid.

126. 1. A method for designing and / or identifying an ionic liquid comprising two ions, one ion being a cation and the other anion, comprising the steps of: (a) selecting one of the two ions of the ionic liquid; and (b) selecting the other ion so as to minimize ion-ion interactions;

127. 1. A method for designing and / or identifying an ionic liquid comprising two ions, one ion being a cation and the other anion, comprising the steps of: (a) selecting a cation; and (b) Selecting the anion to minimize ionic interactions.

128. 1. A method for designing and / or identifying an ionic liquid comprising two ions, one ion being a cation and the other anion, comprising the steps of: (a) selecting an anion; and (b) selecting cations to minimize ionic interactions;

129. 1. A method for designing and / or identifying an ionic liquid comprising two ions, one ion being a cation and the other being an anion, from a pool of candidate cations and a pool of candidate anions, comprising the steps of: (a) selecting one of two ions of an ionic liquid from a pool of candidate ions; and (b) selecting from the other pool of candidate ions the ion that best minimizes ion-ion interactions with the ion selected in step a.

130. 1. A method for designing and / or identifying an ionic liquid comprising two ions, one ion being a cation and the other being an anion, from a pool of candidate cations and a pool of candidate anions, comprising the steps of: (a) selecting a cation from a pool of candidate cations; (b) selecting from the pool of candidate anions the anion that best minimizes ionic interactions with the cation selected in step a.

131. 1. A method for designing and / or identifying an ionic liquid comprising two ions, one ion being a cation and the other being an anion, from a pool of candidate cations and a pool of candidate anions, comprising the steps of: (a) selecting a cation from a pool of candidate anions; (b) selecting from the pool of candidate cations the anion that best minimizes ionic interactions with the anion selected in step a.

132. The method of any one of claims 126-131, wherein the ionic liquid is selected or designed for transdermal administration.

133. 133. The method of any one of claims 126-132, wherein the ionic liquid is selected or designed for transdermal, mucosal, oral, subcutaneous, intradermal, parenteral, intratumoral, or intravenous administration.

134. 134. The method of claim 133, wherein the mucosa is a nasal mucosa, an oral mucosa, or a vaginal mucosa.

135. The method of any one of claims 126-134, wherein the ionic liquid is selected or designed for oral administration.

136. The method of any one of claims 126-135, wherein the ionic liquid is selected or designed for delivery of the active compound.

137. 137. The method of any one of claims 126-136, wherein the cation comprises a quaternary ammonium, or the step of selecting a cation comprises selecting a cation comprising a quaternary ammonium; and the anion comprises a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.0, or the step of selecting an anion comprises selecting a hydrophobic anion comprising a carboxylic acid having a pKa of at least 4.0 and a LogP of at least 1.

0.

138. 138. The method of any one of claims 126-137, wherein the anion has a pKa of at least 4.5, or wherein selecting the anion comprises selecting an anion having a pKa of at least 4.

5.

139. 139. The method of any one of claims 126-138, wherein the anion has a pKa of at least 4.895, or wherein selecting an anion comprises selecting an anion having a pKa of at least 4.

895.

140. 139. The method of any one of claims 126-138, wherein the anion has a pKa between 4.5 and 5.5, or wherein selecting an anion comprises selecting an anion having a pKa between 4.5 and 5.

5.

141. 141. The method of any one of claims 126-140, wherein the anion has a pKa between 4.895 and 5.19, or wherein selecting an anion comprises selecting an anion having a pKa between 4.895 and 5.

19.

142. 142. The method of any one of claims 126-141, wherein the anion has a pKa of at least 5.0, or wherein selecting an anion comprises selecting an anion having a pKa of at least 5.

0.

143. 143. The method of any one of claims 126-142, wherein the anion has a LogP of at least 2.0 or wherein selecting the anion comprises selecting an anion having a LogP of at least 2.

0.

144. 144. The method of any one of claims 126-143, wherein the anion has a LogP of at least 2.5 or wherein selecting the anion comprises selecting an anion having a LogP of at least 2.

5.

145. 145. The method of any one of claims 126-144, wherein the anion has a LogP of at least 2.75 or wherein selecting the anion comprises selecting an anion having a LogP of at least 2.

75.

146. 146. The method of any one of claims 126-145, wherein the anion has a LogP of at least 2.8 or wherein selecting the anion comprises selecting an anion having a LogP of at least 2.

8.

147. 147. The method of any one of claims 126-146, wherein the anion has a LogP of 2.5 to 3.5, or wherein selecting the anion comprises selecting an anion having a LogP of 2.5 to 3.

5.

148. 148. The method of any one of claims 126-147, wherein the anion has a LogP between 2.8 and 3.01, or wherein selecting the anion comprises selecting an anion having a LogP between 2.8 and 3.

01.

149. 149. The method of any one of claims 126-148, wherein the anion comprises a carbon chain of at least 8 carbons or wherein selecting the anion comprises selecting an anion comprising a carbon chain of at least 8 carbons.

150. 150. The method of any one of claims 126-149, wherein the anion comprises an eight-carbon backbone carbon chain or wherein selecting the anion comprises selecting an anion that comprises an eight-carbon backbone carbon chain.

151. 151. The method of any one of claims 126-150, wherein the anion is geranic acid, octenic acid, octanoic acid, or citronellic acid, or wherein the step of selecting an anion comprises selecting an anion that is geranic acid, octenic acid, octanoic acid, or citronellic acid.

152. 152. The method of any one of claims 126-151, wherein the anion is octenic acid, octanoic acid, or citronellic acid, or wherein the step of selecting an anion comprises selecting an anion that is octenic acid, octanoic acid, or citronellic acid.

153. 153. The method of any one of claims 126-152, wherein the anion is an alkene or the step of selecting an anion comprises selecting an anion that is an alkene.

154. 154. The method of any one of claims 126-153, wherein the anion is geranic acid, octanoic acid, or citronellic acid, or wherein the step of selecting an anion comprises selecting an anion that is geranic acid, octanoic acid, or citronellic acid.

155. The method of any one of claims 126-154, wherein the cation has a molar mass equal to or greater than choline, or wherein the step of selecting a cation comprises selecting a cation having a molar mass equal to or greater than choline.

156. Quaternary ammonium is NR 4 + and at least one R group comprises a hydroxy group.

157. Quaternary ammonium is NR 4 + and wherein only one R group comprises a hydroxy group.

158. The method of any one of claims 126-157, wherein the cation is C1, C6, or C7, or wherein selecting a cation comprises selecting a cation that is C1, C6, or C7.

159. The method of any one of claims 126-158, wherein the cation is selected from choline, C1, C6, and C7, or wherein the step of selecting a cation comprises selecting a cation selected from choline, C1, C6, and C7, and the anion is citronellic acid.

160. 160. The method of any one of claims 126-159, wherein the cation is selected from C1, C6, and C7, or wherein the step of selecting a cation comprises selecting a cation selected from C1, C6, and C7, and the anion is geranic acid.

161. 161. The method of any one of claims 126-160, wherein the cation is choline, C1, C6, or C7, or wherein the step of selecting a cation comprises selecting a cation that is choline, C1, C6, or C7, and the step of selecting an anion comprises selecting an anion that is citronellic acid, octanoic acid, or octenoic acid.

162. 162. The method of any one of claims 126-161, wherein the cation is choline and the step of selecting an anion comprises selecting an anion that is citronellic acid, octanoic acid, or octenoic acid.

163. The method of any one of claims 126-162, wherein the ionic liquid is not CAGE.

164. 164. The method of any one of claims 126-163, wherein the ionic liquid comprises a ratio of cations to anions of about 2:1 to about 1:

10.

165. 165. The method of any one of claims 126-164, wherein the ionic liquid comprises a ratio of cations to anions of about 1:1 to about 1:

4.

166. 166. The method of any one of claims 126-165, wherein the ionic liquid comprises a ratio of cations to anions of about 1:

2.

167. 167. The method of any one of claims 126-166, wherein the ionic liquid has a cation:anion ratio of less than 1:

1.

168. 168. The method of any one of claims 126-167, wherein the ionic liquid has a cation:anion ratio that includes an excess of anion.

169. 169. The method of any one of claims 126-168, wherein minimizing ion-ion interactions comprises minimizing the number of cross peaks as measured by Nuclear Overhauser Effect Spectroscopy (NOESY).

170. 170. The method of any one of claims 126-169, wherein cations and anions have less than 20 cross peaks when measured by Nuclear Overhauser Effect Spectroscopy (NOESY), minimizing ionic interactions.

171. The method of any one of claims 126-170, wherein cations and anions have less than 10 cross peaks when measured by Nuclear Overhauser Effect Spectroscopy (NOESY), minimizing ionic interactions.

172. The method of any one of claims 126-171, wherein cations and anions have less than 5 cross peaks when measured by Nuclear Overhauser Effect Spectroscopy (NOESY), thereby minimizing ionic interactions.

173. The method of any one of claims 126-172, wherein the active compound is hydrophobic.

174. The method of any one of claims 126-173, wherein the active compound is hydrophilic.

175. The method of any one of claims 126-174, wherein the active compound comprises a polypeptide.

176. The method of any one of claims 126-175, wherein the active compound has a molecular weight greater than 450.

177. The method of any one of claims 126-176, wherein the active compound has a molecular weight greater than 500.

178. The method of any one of claims 126-177, wherein the active compound comprises an antibody or antibody reagent.

179. The method of any one of claims 126-178, wherein the active compound comprises insulin, acarbose, ruxolitinib, or a GLP-1 polypeptide or a mimetic or analog thereof.

180. 180. The method of any one of claims 126-179, wherein the ionic liquid is at a concentration of at least 0.1% w / v.

181. The method of any one of claims 126-180, wherein the ionic liquid is at a concentration of about 10 to about 70% w / v.

182. The method of any one of claims 126-181, wherein the ionic liquid is at a concentration of about 30 to about 50% w / v.

183. The method of any one of claims 126-182, wherein the ionic liquid is at a concentration of about 30 to about 40% w / v.

184. The method of any one of claims 126-183, wherein the active compound is provided at a dosage of 1-20 mg / kg.

185. The method of any one of claims 126-184, wherein the ionic liquid is designed or selected for delivery in a degradable capsule.

186. The method of any one of claims 126-185, wherein the ionic liquid and the active compound are in admixture.

187. The method of any one of claims 126-186, wherein the ionic liquid and optionally the active compound are selected or designed for delivery in one or more nanoparticles.

188. The method of any one of claims 126-187, wherein the ionic liquid is in solution or suspension in a composition comprising one or more nanoparticles comprising the active compound.

Images