Salts, solvents, formulations and transdermal agents

Abstract

An ionic liquid according to the present invention has a structure represented by general formula (1). In general formula (1), R represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkenyl group, and at least one ethylene group included in the alkenyl group may be replaced with a vinylene group. X+ represents a phospholipid having a cationic group.

Description

[Technical Field]

[0001] The present invention provides salt , solvents, formulations and transdermal absorption agents. [Background technology]

[0002] Ionic liquids, which are liquids composed solely of ions, have been attracting attention in recent years. Ionic liquids are salts that exist as liquids over a wide temperature range. They have low melting points, high solubility, low volatility, and flame retardancy. Therefore, they are expected to be applied in a variety of fields, including electrochemical devices, separation and extraction solvents, reaction solvents, tribology, and biotechnology. In particular, in the biotechnology field, active research is being conducted on the use of ionic liquids as enzyme reaction solvents, drug delivery, and protein refolding.

[0003] As such ionic liquids, Patent Document 1 proposes an ionic liquid using a phosphonium-type cation (phosphonium-type ionic liquid), and Patent Document 2 proposes an ionic liquid using an organic amine compound as the cation. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Publication No. 2020-15688 [Patent Document 2] International Publication No. 2009 / 066457 Summary of the Invention [Problem to be solved by the invention]

[0005] Among the above ionic liquids, phosphonium-type ionic liquids are highly irritating, and ionic liquids using organic amine compounds are highly toxic. Therefore, both of these ionic liquids have presented challenges in their application to bio-related fields. Therefore, the use of amino acids as cations has been investigated in an effort to develop ionic liquids with low toxicity. However, using amino acids as cations makes the ionic liquid hydrophilic, resulting in low solubility in organic solvents and hydrophobic drugs, which significantly limits their applications. Thus, conventional ionic liquids do not achieve both low toxicity and solubility, making them ineffective in bio-related fields.

[0006] The present invention has been made in view of the above circumstances, and provides a compound having low toxicity, excellent biocompatibility, and high solubility in both hydrophilic and hydrophobic substances. salt The purpose is to provide the following. [Means for solving the problem]

[0007] As a result of intensive research to solve the above problems, the present inventors have discovered that a phospholipid having a cationic group can be obtained by combining a fatty acid and a phospholipid having a cationic group. salt By forming the compound, it has low toxicity and exhibits high solubility in both hydrophilic and hydrophobic substances. salt was found to be realized.

[0008] According to the first aspect of the present invention salt has a structure represented by the following general formula (1): death, It has a melting point of 100°C or less and is in a liquid state. do. [ka] In general formula (1), R represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkenyl group, and at least one of the ethylene groups constituting the alkenyl group may be replaced with a vinylene group. + represents a phospholipid having a cationic group.]

[0009] In this case, X in the general formula (1) + is a glycerophospholipid having a cationic group; This may also be the case.

[0010] In addition, X in the general formula (1) + has a structure represented by the following general formula (2): This may also be the case. [ka] [In general formula (2), R 1 represents an alkyl group substituted with a cationic group, and R 2 represents a hydrogen atom or a substituted or unsubstituted alkyl group, and R 3 represents a substituted or unsubstituted alkyl group.]

[0011] In addition, R in the general formula (2) 3 is an alkyl group substituted with an alkylcarbonyloxy group; This may also be the case.

[0012] In addition, R in the general formula (2) 3 is an alkyl group substituted with two or more alkylcarbonyloxy groups; This may also be the case.

[0013] In addition, R in the general formula (2) 2 is a substituted or unsubstituted alkyl group; This may also be the case.

[0014] Also, the cationic group is a quaternary ammonium group. This may also be the case.

[0015] In addition, X in the general formula (1) + is a derivative of phosphatidylcholine, This may also be the case.

[0016] In addition, the number of carbon atoms in R in the general formula (1) is 8 to 22. This may also be the case.

[0017] In addition, when R in the general formula (1) has an unsaturated bond, This may also be the case.

[0018] In addition, R in the general formula (1) has a polyene structure. This may also be the case.

[0019] In addition, R in the general formula (1) is a group consisting of only carbon atoms and hydrogen atoms. This may also be the case.

[0020] Moreover, the first aspect of the present invention salt teeth, is hydrophobic, This may also be the case.

[0021] Moreover, the first aspect of the present invention salt teeth, Having a structure represented by the following formula: This may also be the case. [ka] [In the formula, R represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkenyl group, and at least one ethylene group constituting the alkenyl group may be replaced with a vinylene group.]

[0022] The solvent according to the second aspect of the present invention is The first aspect of the present invention salt Includes:

[0023] The formulation according to the third aspect of the present invention comprises: The first aspect of the present invention salt Includes:

[0024] The transdermal absorption preparation according to the fourth aspect of the present invention comprises: The first aspect of the present invention salt Includes:

[0025] The transdermal absorption preparation according to the fourth aspect of the present invention comprises: further comprising a sorbitan fatty acid ester, This may also be the case.

[0026] The sorbitan fatty acid ester is Sorbitan monolaurate, This may also be the case.

[0027] In addition, R-COO in the general formula (1) - is a carboxylate ion formed by dissociating a hydrogen ion from the carboxy group of linoleic acid. This may also be the case. [Effects of the Invention]

[0028] The present invention salt has low toxicity, excellent biocompatibility, and exhibits high solubility in both hydrophilic and hydrophobic substances. [Brief explanation of the drawings]

[0029] [Figure 1] FIG. 1 shows NMR spectra of ionic liquids 1 to 3 synthesized in the examples. [Figure 2] FIG. 1 shows the particle size distribution measured by dynamic light scattering (DLS) for a liquid sample prepared by mixing ionic liquid 1 and isopropyl myristate (IPM). [Figure 3] FIG. 1 shows the particle size distribution measured by DLS for a liquid sample prepared by mixing ionic liquid 1 and water. [Figure 4] FIG. 1 shows the cell viability of epidermal tissue treated with sample solutions containing ionic liquids 1 to 3 or various reagents. [Figure 5] (A) shows the particle size distribution of Example 1 measured by DLS, (B) shows an image of Example 1 taken by transmission electron microscopy (TEM), and (C) shows an image of Example 1 taken by confocal laser scanning microscopy (CLSM). [Figure 6] (A) is a diagram showing the particle size distribution of Example 2 measured by DLS, (B) is a diagram showing an image of Example 2 taken by TEM, and (C) is a diagram showing an image of Example 2 taken by CLSM. [Figure 7] (A) is a diagram showing the particle size distribution of Example 3 measured by DLS, (B) is a diagram showing an image of Example 3 taken by TEM, and (C) is a diagram showing an image of Example 3 taken by CLSM. [Figure 8] FIG. 1 shows particle size distributions of droplets in Examples 1 to 3 measured by CLSM. [Figure 9] (A) A diagram showing the particle size distribution of Example 1 on day 90 measured by DLS. (B) A diagram showing the particle size distribution of Example 2 on day 90 measured by DLS. (C) A diagram showing the particle size distribution of Example 3 on day 90 measured by DLS. [Figure 10] (A) A diagram showing the amount of leuprorelin acetate (LA) contained in Example 1, as measured by high-pressure liquid chromatography (HPLC). (B) A diagram showing the amount of LA contained in Example 2, as measured by HPLC. (C) A diagram showing the amount of LA contained in Example 3, as measured by HPLC. [Figure 11] 1(A) shows the encapsulation rates of LA in Examples 1 to 3. FIG. 1(B) shows the maximum amount of LA supported in samples containing ionic liquids 1, 2, and 4. [Figure 12] FIG. 1 shows the time course of LA concentration in the receiver phase in a skin permeation test. [Figure 13] FIG. 1 shows the amount of transdermal and topical LA after 36 hours in a skin penetration test. [Figure 14] FIG. 1 shows plasma LA concentrations in an in vivo pharmacokinetic study. [Figure 15] FIG. 1 shows the cell viability of epidermal tissue treated with a formulation containing ionic liquid 1. [Figure 16] FIG. 1 shows the change over time in body weight of mice to which a formulation containing ionic liquid 1 was administered transdermally. [Figure 17]FIG. 1 shows an image of the stratum corneum of a mouse to which a formulation containing ionic liquid 1 was administered transdermally. DETAILED DESCRIPTION OF THE INVENTION

[0030] Hereinafter, embodiments of the present invention will be described in detail. The following description of the constituent elements may be based on representative embodiments and specific examples, but the present invention is not limited to such embodiments. In this specification, a numerical range expressed using "to" means a range including the numerical values ​​before and after "to" as the lower and upper limits. In addition, the isotopes of hydrogen atoms present in the molecules of the compounds used in the present invention are not particularly limited, and for example, when all the hydrogen atoms in the molecule are 1 H, or part or all of 2 It may also be H (deuterium D).

[0031] <Ionic liquid> The ionic liquid according to this embodiment has a structure represented by the following general formula (1).

[0032] [ka]

[0033] In general formula (1), R represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkenyl group, and at least one ethylene group constituting the alkenyl group may be substituted with a vinylene group.

[0034] The alkyl group for R may be linear, branched, or cyclic. The alkyl group for R preferably has 8 to 22 carbon atoms, more preferably 12 to 22. Examples of the alkyl group for R include linear alkyl groups such as dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, henicosyl, and docosyl, as well as branched alkyl groups and cyclic alkyl groups. Substituents that may be substituted on the alkyl group include an amino group, a benzyl group, and a halogen atom (e.g., a fluorine atom). These substituents may be further substituted with a substituent. When the alkyl group is substituted with a substituent, the total number of carbon atoms in the alkyl group and the substituent is preferably 8 to 22, more preferably 12 to 22.

[0035] The alkenyl group in R may be either linear or branched. The alkenyl group in R preferably has 8 to 22 carbon atoms, more preferably 12 to 22. Examples of the alkenyl group in R include linear alkenyl groups such as dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, icosenyl, henicosenyl, and docosenyl, as well as branched alkenyl groups thereof. Substituents that may be substituted on the alkenyl group include amino, benzyl, and halogen atoms (e.g., fluorine atoms). These substituents may be further substituted with a substituent. When the alkenyl group is substituted with a substituent, the total number of carbon atoms in the alkenyl group and the substituent is preferably 8 to 22, more preferably 12 to 22. Furthermore, at least one ethylene group of the alkenyl group in R may be substituted with a vinylene group to form a polyene structure. The number of double bonds in the polyene structure is preferably 2 to 6, more preferably 2 to 4. The positions of the double bonds are not particularly limited, but it is preferable that the double bonds are spaced apart by at least two single bonds.

[0036] Among these, R is preferably a group having an unsaturated bond, and more preferably a substituted or unsubstituted alkenyl group or a group having a substituted or unsubstituted polyene structure. Furthermore, the alkyl group, alkenyl group, and group having a polyene structure in R may be substituted with a substituent, but even in this case, R is preferably composed of only carbon atoms and hydrogen atoms. In other words, when the alkyl group, alkenyl group, and polyene structure are substituted with a substituent, the substituent is preferably also composed of only carbon atoms and hydrogen atoms.

[0037] R-COO - For example, carboxylate ions, in which a hydrogen ion dissociates from the carboxy group of a fatty acid, or derivatives thereof can be used. The fatty acids that generate carboxylate ions may be saturated or unsaturated. Examples of saturated fatty acids include myristic acid (C14:0), palmitic acid (C16:0), stearic acid (C18:0), and lauric acid (C12:0). Examples of unsaturated fatty acids include oleic acid (C18:1), linoleic acid (C18:2), α-linolenic acid (C18:3), γ-linolenic acid (C18:3), arachidonic acid (C20:4), eicosapentaenoic acid (C20:5), docosahexaenoic acid (C22:6), and erucic acid (C22:1). The numbers in parentheses indicate the number of carbon atoms and the number of double bonds in each fatty acid. For example, the (C18:2) in linoleic acid indicates that it has 18 carbon atoms and two double bonds.

[0038] In general formula (1), X + represents a phospholipid having a cationic group. Here, "phospholipid" refers to a lipid containing a phosphate ester structure, and "cationic group" refers to a substituent group that is positively charged. X +is preferably a glycerophospholipid having a cationic group, and more preferably a phosphatidylcholine derivative. Here, the phosphatidylcholine derivative refers to a compound having a glycerol backbone, substituted or unsubstituted alkanoyl groups bonded to the 1st and 2nd positions of the glycerol backbone, a phosphate ester group (-P(O)(OH)O-) bonded to the 3rd position of the glycerol backbone, and a choline residue bonded to the phosphate ester group. In this phosphatidylcholine derivative, at least one ethylene group of the alkanoyl group may be replaced with a vinylene group, and the hydrogen atom of the hydroxyl group of the phosphate ester group may be substituted with a substituted or unsubstituted alkyl group.

[0039] Also, X + is preferably a phospholipid having a structure represented by the following general formula (2), and more preferably a glycerophospholipid having a structure represented by the following general formula (2).

[0040] [ka]

[0041] In general formula (2), R 1 represents an alkyl group substituted with a cationic group, and R 2 represents a hydrogen atom or a substituted or unsubstituted alkyl group, and R 3 represents a substituted or unsubstituted alkyl group.

[0042] R 1 The alkyl group in R may be linear, branched, or cyclic. 1 The alkyl group in the formula (I) preferably has 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6 carbon atoms. For example, R 1 Examples of the alkyl group in R include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group. 1 The alkyl group in the formula (I) is preferably an ethyl group.

[0043] R 1 The cationic group in the formula (3) is preferably an ammonium group represented by the following general formula (3).

[0044] [ka]

[0045] In general formula (3), R 4 represents a hydrogen atom or a substituted or unsubstituted alkyl group, and * represents the bonding position to the alkyl group. 4 may be the same or different. 4 There is no particular limitation on the number of substituted or unsubstituted alkyl groups among R 4 may all be hydrogen atoms or substituted or unsubstituted alkyl groups, or one or two of them may be hydrogen atoms and the remaining may be substituted or unsubstituted alkyl groups.

[0046] R 4 The alkyl group in R may be linear, branched, or cyclic. 4 The alkyl group in the formula (I) preferably has 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6 carbon atoms. For example, R 4 Examples of the alkyl group in R include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group. 4 The alkyl group in is preferably a methyl group. Examples of substituents that can be substituted on the alkyl group include a benzyl group and a halogen atom (e.g., a fluorine atom). These substituents may be further substituted with a substituent.

[0047] R 1 The cationic group in is preferably a quaternary ammonium group, and is preferably a quaternary ammonium group (R 4is more preferably an ammonium group in which all of the alkyl groups are substituted or unsubstituted alkyl groups. Although there are no particular limitations on the substitution position of the cationic group in the alkyl group, it is preferred that the hydrogen atom bonded to the carbon atom at the terminal of the alkyl group is substituted with the cationic group.

[0048] In general formula (2), R 2 represents a hydrogen atom or a substituted or unsubstituted alkyl group. 2 is preferably a substituted or unsubstituted alkyl group. 2 The alkyl group in R may be linear, branched, or cyclic. 2 The alkyl group in the formula (I) preferably has 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6 carbon atoms. For example, R 2 Examples of the alkyl group in R include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group. 2 The alkyl group in is preferably an ethyl group. Examples of substituents that can be substituted on the alkyl group include a benzyl group and a halogen atom (e.g., a fluorine atom). These substituents may be further substituted with a substituent.

[0049] In general formula (2), R 3 represents a substituted or unsubstituted alkyl group. 3 The alkyl group in R may be linear, branched, or cyclic. 3 The alkyl group in the formula (I) preferably has 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6 carbon atoms. For example, R 3 Examples of the alkyl group in R include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group. 3 The alkyl group in is preferably an n-propyl group. Examples of substituents that can be substituted on the alkyl group include an alkylcarbonyloxy group, a benzyl group, and a halogen atom (e.g., a fluorine atom). These substituents may be further substituted with a substituent.

[0050] R 3 A preferred example of R is an alkyl group substituted with an alkylcarbonyloxy group. 3 is an alkyl group substituted with two or more alkylcarbonyloxy groups, wherein the two or more alkylcarbonyloxy groups may be the same or different, but are preferably the same.

[0051] The number of alkylcarbonyloxy groups substituted in the alkyl group is preferably 2 to 8, more preferably 2 to 4, and most preferably 2. The substitution positions of the alkylcarbonyloxy groups in the alkyl group are not particularly limited, but R 3 When the alkyl group as the main chain is an n-propyl group, the hydrogen atom bonded to the terminal carbon atom and the hydrogen atom bonded to the carbon atom adjacent thereto are replaced with alkylcarbonyloxy groups, which corresponds to a glycerophospholipid and is a particularly preferred phospholipid.

[0052] For the explanation, preferred range, and specific examples of the alkyl group in the alkylcarbonyloxy group, reference can be made to the explanation, preferred range, and specific examples of the alkyl group in R above.

[0053] Preferred examples of ionic liquid compounds having a structure represented by general formula (1) are given below. However, the ionic liquid according to the present embodiment should not be construed as being limited by these specific examples. In the following formula, R-COO - represents R-COO in general formula (1). - Specific examples thereof include carboxylate ions of linoleic acid, oleic acid, acetic acid, and stearic acid.

[0054] [ka]

[0055] [Characteristics of ionic liquids] Next, preferable properties of the ionic liquid according to this embodiment will be described. (hydrophobic) The ionic liquid according to this embodiment is preferably hydrophobic, where "hydrophobic" means that it dissolves in the IPM at a concentration of 0.1% by weight or more.

[0056] The ionic liquid according to the present embodiment preferably dissolves in the IPM at 0.1 wt % or more (i.e., hydrophobicity), more preferably at 5 wt % or more, and even more preferably at 20 wt % or more. Here, "the ionic liquid dissolves in the IPM" includes not only the ionic liquid dissolving in the IPM as a homogeneous system, but also the ionic liquid dissolving in the IPM as a reversed micelle. The formation of reversed micelles in the IPM can be confirmed by observing a peak in the particle size distribution measured by DLS.

[0057] The ionic liquid according to the present embodiment has a structure represented by general formula (1), and R and X + Because the ionic liquids contain alkyl or alkenyl groups, they can be easily made hydrophobic. Hydrophobic ionic liquids exhibit high compatibility with hydrophobic solvents, oily bases, and hydrophobic drugs, making them easily mixable with these substances. In addition, ionic liquids have high permeability through the permeation barrier of the stratum corneum, allowing for easy transdermal absorption. Therefore, hydrophobic ionic liquids are particularly useful in transdermal drug delivery systems (DDS).

[0058] (micelle or liposome forming ability) The ionic liquid according to the present embodiment is hydrophobic. When the ionic liquid is mixed with water at a concentration of, for example, up to 20%, and the particle size distribution of the resulting liquid mixture is measured by DLS, a peak preferably appears, preferably in the range of 0.01 to 1 μm. The peak in the particle size distribution indicates that the ionic liquid has formed micelles or liposomes with the particle size in the liquid mixture and dissolved therein. Such ionic liquids exhibit high compatibility and dissolve in hydrophobic solvents, and form micelles or liposomes in hydrophilic solvents and disperse uniformly (micelle dissolution), thereby achieving good solubility in both hydrophobic and hydrophilic solvents. Furthermore, the micelles or liposomes can be used for various purposes. For example, ionic liquids that have formed micelles or liposomes can be suitably used as carriers for drug delivery systems by encapsulating various molecules therein.

[0059] (Melting Point) The ionic liquid according to the present embodiment preferably has a melting point of 100°C or less, more preferably 60°C or less, and even more preferably 40°C or less. Here, the melting point is determined by differential scanning calorimetry. Ionic liquids with melting points in the above range remain in a liquid state over a wide temperature range, and can therefore be suitably used as solvents.

[0060] <Solvent> The solvent according to the present embodiment includes the ionic liquid according to the present embodiment. The ionic liquid contained in the solvent according to the present embodiment may be composed of only one type of compound represented by general formula (1), or may contain two or more types. Furthermore, the solvent according to the present embodiment may be composed only of the ionic liquid according to the present embodiment, or may contain other solvents. The other solvents are not particularly limited and can be appropriately selected from known solvents.

[0061] The ionic liquid according to the present embodiment has a structure represented by general formula (1), and R and X +The ionic liquid according to the present embodiment contains an alkyl or alkenyl group, making it highly compatible with hydrophobic substances. Furthermore, the carboxylate ion and cationic group make it behave like a surfactant toward hydrophilic substances. Therefore, the ionic liquid according to the present embodiment can be combined with a hydrophobic or hydrophilic solvent and mixed uniformly, and can dissolve both hydrophobic and hydrophilic solutes. For example, while many pharmacologically active substances are generally poorly soluble, the use of the ionic liquid according to the present embodiment as a solvent makes it possible to dissolve even such poorly soluble pharmacologically active substances. The use of this ionic liquid makes it possible to realize a solvent that exhibits high solubility regardless of the solvent and solute used. Furthermore, it is possible to realize formulations and transdermal absorption agents with excellent biocompatibility.

[0062] <Formulation> The formulation according to the present embodiment contains the ionic liquid according to the present embodiment. The ionic liquid contained in the formulation according to the present embodiment may be one or more of the compounds represented by general formula (1). Furthermore, the formulation according to the present embodiment may contain, in addition to the ionic liquid according to the present embodiment, ingredients commonly used in formulations, such as active ingredients, additives, excipients, and bases. Furthermore, the form of the formulation according to the present embodiment is not particularly limited, and may be any of an oral medication, an external medication, an injection, and the like.

[0063] The ionic liquid according to the present embodiment is a combination of an anion having a basic skeleton of a fatty acid and a cation having a basic skeleton of a phospholipid, and both basic skeletons are bio-related substances, so that the ionic liquid according to the present embodiment has low toxicity and high biocompatibility. + The ionic liquid according to the present embodiment has the advantages of an ionic liquid and can be easily prepared as a safe formulation.

[0064] <Transdermal absorption agent> The transdermal absorption agent according to the present embodiment contains the ionic liquid according to the present embodiment. The ionic liquid contained in the transdermal absorption agent according to the present embodiment may be one type or two or more types of compounds represented by general formula (1).

[0065] The ionic liquid according to the present embodiment is low in toxicity, highly biocompatible, and hydrophobic due to the inclusion of alkyl or alkenyl groups and lipid structures in the molecule, allowing it to permeate the stratum corneum of the skin. Therefore, the ionic liquid according to the present embodiment has the advantages of an ionic liquid, is safe, and can realize a transdermal absorption agent that exhibits good transdermal absorbability.

[0066] The dosage form of the transdermal absorption agent is not particularly limited, and may be any dosage form, such as a liquid (lotion, spray, etc.), ointment, cream, gel, emulsion, or patch. The transdermal absorption agent may contain an active ingredient and a base in addition to the ionic liquid of the present embodiment. The base may be appropriately selected from bases typically used in transdermal absorption agents. The transdermal absorption agent may also contain additives, such as stabilizers, preservatives, solubilizers, emulsifiers, suspending agents, pH adjusters, and antioxidants, which are used in pharmaceuticals such as topical preparations, quasi-drugs, and cosmetics, as needed.

[0067] The transdermal absorption agent may further contain a co-surfactant in addition to the ionic liquid that functions like a surfactant. The co-surfactant is, for example, a sorbitan fatty acid ester. Examples of the sorbitan fatty acid ester include sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, and sorbitan monopalmitate. The sorbitan fatty acid ester is preferably sorbitan monolaurate (span-20).

[0068] The content of the co-surfactant in the transdermal absorption formulation is appropriately set, for example, 1 to 10% by mass (w / v), 2 to 8% by mass (w / v), 3 to 7% by mass (w / v), 4 to 6% by mass (w / v), and preferably 5% by mass. The content of the ionic liquid in the transdermal absorption formulation is appropriately set, for example, 1 to 10% by mass (w / v), 2 to 8% by mass (w / v), 3 to 7% by mass (w / v), 4 to 6% by mass (w / v), and preferably 5% by mass. The mass ratio of the ionic liquid to the co-surfactant in the transdermal absorption formulation may be, for example, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 0.6:1, 0.7:1, 0.8:1, or 0.9:1, and is preferably 1:1.

[0069] When the ionic liquid is contained in a transdermal absorption agent, it is preferable that R—COO - is a carboxylate ion formed when a hydrogen ion dissociates from the carboxy group of linoleic acid. [Example]

[0070] The features of the present invention will be explained in more detail below with reference to examples and comparative examples. The materials, amounts used, ratios, treatment details, treatment procedures, etc. shown in the following examples can be changed as appropriate without departing from the spirit of the present invention. Therefore, the scope of the present invention should not be interpreted as being limited by the specific examples shown below. Melting point measurements were performed using a differential thermal / thermogravimetric simultaneous analyzer (TG / DTA 7300, manufactured by Hitachi High-Technologies Corporation), and DLS measurements were performed using a Zetasizer (Nano series, manufactured by Malvern Panalytical, Malvern-UK).

[0071] [1] Synthesis of ionic liquids (Synthesis Example 1) Synthesis of ionic liquid 1 [ka]

[0072] 1,2-Dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC), ethyl trifluoromethanesulfonate (ETFM) (1 molar equivalent), and ultra-dehydrated chloroform were placed in a container and stirred overnight at 45°C under a nitrogen atmosphere. The reaction solution was dried overnight under a nitrogen atmosphere in the dark to obtain Intermediate 1 (1,2-Dimyristoyl-sn-glycero-3-ethylphosphatidylcholine (EDMPC) trifluoromethanesulfonate).

[0073] [ka]

[0074] Intermediate 1 was dissolved in chloroform, and then 0.2N hydrochloric acid was added to cause a phase separation reaction, yielding a lower layer containing Intermediate 2 (EDMPC chloride) and an upper layer (aqueous phase) containing trifluoromethanesulfonic acid. The upper layer was removed, and the lower layer was washed with Milli-Q water to remove unreacted hydrochloric acid. Chloroform and excess water were then removed using an evaporator and a refrigerated dryer, yielding Intermediate 2.

[0075] [ka]

[0076] Linoleic acid (1 molar equivalent) and chloroform (ultra-dehydrated) were added to intermediate 2, and the mixture was stirred overnight at 45°C under a dry nitrogen atmosphere in the dark to yield the desired ionic liquid 1. The NMR spectrum of the resulting ionic liquid 1 is shown in Figure 1.

[0077] (Synthesis Examples 2 and 3) Synthesis of ionic liquids 2, 3, and 4 Ionic liquid 2 containing a carboxylate ion of oleic acid, ionic liquid 3 containing a carboxylate ion of acetic acid, and ionic liquid 4 containing a carboxylate ion of stearic acid were synthesized in the same manner as in Synthesis Example 1, except that oleic acid, acetic acid, or stearic acid was used instead of linoleic acid. The NMR spectra of the resulting ionic liquids 2 and 3 are shown in Figure 1.

[0078] [2] Evaluation The melting points, DLS measurements, and solubility and toxicity of the synthesized ionic liquids 1 to 3 were measured. In the following, ionic liquid 1 will be referred to as [EDMPC][Lin], ionic liquid 2 as [EDMPC][Ole], ionic liquid 3 as [EDMPC][Act], and ionic liquid 4 as [EDMPC][Ste].

[0079] (Melt point measurement) The melting points were measured by differential scanning calorimetry and were found to be 14.8°C for ionic liquid 1, 34.5°C for ionic liquid 2, and 47.5°C for ionic liquid 3, all of which were low melting points below 50°C.

[0080] (DLS measurement) Two liquid samples were prepared by mixing each ionic liquid with either IPM or water at a 5 wt% concentration, and the particle size distributions of each were measured by DLS. Figure 2 shows the particle size distribution of ionic liquid 1 in IPM, and Figure 3 shows its distribution in water. As shown in Figures 2 and 3, peaks were observed at specific particle sizes in both the IPM and water samples. Similar peaks were also observed in the particle size distributions of other ionic liquids. The observation of peaks in the water sample indicates that ionic liquids 1–3 are hydrophobic and behave like surfactants in water, forming micelles and dispersing uniformly (micelle dissolution). The presence of peaks in the IPM particle size distribution also suggests the possibility that ionic liquids 1–3 may form reverse micelles in hydrophobic solvents.

[0081] (Evaluation of solubility) The solubility of ionic liquids in various solvents was evaluated at room temperature. Specifically, ionic liquids 1 to 3 were placed in glass tubes together with the solvents, and mixed by stirring for 1 to 2 minutes using a vortex mixer. The weight ratio of ionic liquids 1 to 3 to the solvent was 50:50. The solubility and transparency of the resulting liquids (liquid samples) were visually observed and evaluated according to the following criteria. The results are shown in Table 1. 〇: The ionic liquid is uniformly dissolved and the liquid sample is highly transparent. △: The ionic liquid is dissolved uniformly, but the liquid sample is cloudy. ×: The ionic liquid and the solvent separate, and the ionic liquid does not dissolve in the solvent. For comparison, the same evaluation was also carried out on intermediate 2 ([EDMPC][Cl]).

[0082] [Table 1]

[0083] As shown in Table 1, intermediate 2, which has a chloride ion as the anion, was soluble in IPM and isopropyl alcohol, but not in water-containing solvents (water, phosphate-buffered saline) or nonpolar solvents (n-hexane, cyclohexane, heptane, and toluene). On the other hand, ionic liquids 1–3, which used fatty acid carboxylate ions as the anion, all exhibited high solubility in various solvents. The cloudiness of the liquid samples using water and phosphate-buffered saline is likely due to the formation of micelles in these solvents. This indicates that combining a fatty acid carboxylate ion with a cationic phospholipid improves solubility in both aqueous and nonpolar solvents, resulting in high solubility in both nonpolar and polar solvents, and in both hydrophobic and hydrophilic solvents.

[0084] (Cytotoxicity test) Cytotoxicity tests were performed on artificial human epidermis (Japan Tissue Engineering: LabCyte EPI-MODEL 12 cells) using the MTT cell viability assay. The MTT cell viability assay measures cell viability by converting yellow MTT (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide) to blue formazan via intracellular mitochondrial dehydrogenase. Higher formazan production (higher absorbance at 570 nm) indicates higher cell viability.

[0085] Specifically, sample solutions were prepared by dissolving ionic liquids 1 to 3 in IPM, where the concentrations of the ionic liquids in each sample solution were 5 wt%, 10 wt%, 20 wt%, 50 wt%, or 100 wt%.

[0086] Separately, a 24-well plate containing assay medium (500 μL) was prepared, and a culture cup for human epidermal cells was placed in each well. This 24-well plate was then incubated for 24 hours at 37°C in a humidified atmosphere of 5% CO2. Then, 25 μL of sample solution and 25 μL of phosphate-buffered saline (PBS) as a control were added to each culture cup, and the plates were incubated for 24 hours at 37°C in a humidified atmosphere of 5% CO2. After incubation, the sample solution was removed from each culture cup, and the tissue surface in the cup was washed 15 times with Dulbecco's phosphate-buffered saline. Next, 500 μL of 0.5 mg / mL MTT assay medium was added to each culture cup, and the plates were incubated for 3 hours at 37°C in a 5% CO2 atmosphere. After incubation, the epidermal tissue was removed from the culture cup and transferred to a microtube containing 2-propanol (300 μL). The tissue was then left for 48 hours in the dark at room temperature to extract the formazan colored in the epidermal tissue into 2-propanol. 100 μL of this tissue extract and 2-propanol (blank) were added to each well of a 96-well ELISA plate, and the absorbance was measured at 650 nm and 570 nm, respectively. The cell viability was calculated using the following formula:

[0087] Cell viability (%) = [A (sample solution) / A (PBS)] x 100 In the formula, A (sample solution) represents the absorbance at 570 nm of the tissue extract treated with each sample solution, and A (PBS) represents the absorbance at 570 nm of the tissue extract treated with phosphate buffered saline.

[0088] The test was performed three times as described above, and the average cell viability and standard deviation (SD) were calculated. The results are shown in Figure 4. In Figure 4, the abbreviations and ionic liquids listed along the horizontal axis indicate the type of reagent used to treat the epidermal tissue or the ionic liquid contained in the sample solution. Additionally, [Choline][Ole], emim Tf2SA, and SDS are comparative examples. [Choline][Ole] represents an ionic liquid of choline and oleic acid, emim Tf2SA represents a commercially available ionic liquid (1-ethyl-3-methylimidazolium bis(trifluoroethylsulfonyl)amide), and SDS represents sodium lauryl sulfate (anionic surfactant).

[0089] As shown in Figure 4, ionic liquids 1 to 3 achieved high cell viability even when used at a concentration of 20 wt%, demonstrating that they pose no toxicity problems. Furthermore, cell viability at 100% concentration was also measured for ionic liquids 1 and 2, and in this case, a much higher cell viability was obtained than with 20% SDS. These results demonstrate that ionic liquids combining phospholipids with cationic groups and carboxylate ions of fatty acids have extremely low toxicity.

[0090] The application of ionic liquids 1, 2, and 4 to transdermal absorption formulations for the delivery of LA through the skin was investigated as follows. Statistical analysis was performed using Dugnet's multiple comparison method, two-way analysis of variance using Prism 6 (GraphPad Software), and Tukey's test. Statistical significance was expressed as *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, and *****p<0.00001.

[0091] (Sample preparation) Two mL of a 3.0 mg / mL LA aqueous solution and 4 mL of a 12.5 mg / mL cyclohexane solution of ionic liquid 1, ionic liquid 2, or ionic liquid 4 were homogenized at 26,000 rpm for 2 minutes using a homogenizer (POLYTRON, high-speed homogenizer, PT2500E). The resulting solution was lyophilized to remove water and cyclohexane, yielding a powdered ionic liquid-peptide complex. The ionic liquid-peptide complex was stirred in 1 mL of IPM solution containing 5% Span-20 for 12 hours to yield an ionic liquid / oil nanodispersion system (IL / O-ND).

[0092] (IL / O-ND Characterization) The particle size, polydispersity index (PDI), and peak intensity of Examples 1, 2, and 3 were evaluated by DLS. The particle size was determined as the average of 10 measurements for each sample. The particle size and shape were analyzed by TEM. For TEM, 2 μL of sample was placed on a carbon-copper film TEM grid and incubated for 2 minutes to allow the sample to be absorbed into the film. The IPM was washed with cyclohexane and incubated for another 2 minutes. The deposited complex was stained with a 2% uranyl acetate solution. Images of the sample were then observed at 120 kV using a TEM-2010 (JEOL). Morphological analysis of the diameter and shape of the droplets of the sample was performed in bright field by CLSM using an LSM700 (Carl Zeiss). Images were captured at a resolution of 63×3.

[0093] Figures 5(A), 6(A), and 7(A) show the DLS results for Examples 1, 2, and 3, respectively. The particle diameters of the droplets for Examples 1, 2, and 3 were 251 nm, 220 nm, and 265 nm, respectively. Figures 5(B), 6(B), and 7(B) show TEM images of Examples 1, 2, and 3, respectively. In the TEM images, slight deformation was observed in the particles for Examples 1 to 3. Figures 5(C), 6(C), and 7(C) show CLSM images of Examples 1, 2, and 3, respectively. In the CLSM images, Examples 1 to 3 formed uniform particles, and the particles were freely dispersed by forming nanoparticles. The particle diameters, PDIs, and peak intensities measured by DLS are shown in Table 2. Figure 8 shows the diameters of the droplets for Examples 1 to 3 measured by CLSM. The particle diameters measured by CLSM ranged from 200 to 300 nm, supporting the DLS results.

[0094] [Table 2]

[0095] (Evaluation of IL / O-ND stability) The physicochemical stability of LA in IL / O-ND was evaluated by measuring particle size and quantifying LA over 90 days using DLS and HPLC for samples stored at low (-4°C), room (25°C), and high (37°C) temperatures. Regarding particle size, droplet size was measured by DLS as described above.

[0096] For HPLC evaluation, the linear correlation curve of LA obtained using a dilution solution (25% acetonitrile aqueous solution containing 1% TFA) with concentrations of 0.01 to 0.1 μg / mL was considered. Test samples were prepared by centrifuging a dilution solution with a LA concentration of 0.1 μg / mL at 10,000 rpm for 30 minutes. HPLC measurements were performed using an HPLC system (JASCO Corporation). The mobile phase was a solution containing 0.0087 M ammonium phosphate monobasic and acetonitrile in a volume ratio of 77:23, adjusted to pH 6.5 with HaOH / HCl. Chromatographic separation was performed at 30 °C using an Inert Sustain ODS column (150 × 4.6 mm, 5 μm, GL Sciences). 100 μL of the injected test sample was separated at 220 nm with a mobile phase flow rate of 1.0 mL / min.

[0097] According to the DLS results, the particle sizes of Examples 1, 2, and 3 remained constant (200-300 nm) at room temperature for at least 90 days, but tended to decrease by 50-60 nm at high temperatures and increase by 700-1000 nm at low temperatures. Figures 9(A), (B), and (C) show the particle sizes of Examples 1, 2, and 3, respectively, after 90 days.

[0098] Figures 10(A), (B), and (C) show the amounts of LA measured by HPLC in Examples 1, 2, and 3. The amount of LA tended to decrease slightly at low temperatures, but this was not a significant change. It remained stable at any temperature, with almost no change.

[0099] (Evaluation of the amount of LA encapsulated in IL / O-ND) The IL / O-ND solution containing LA was centrifuged at 10,000 rpm for 30 minutes to obtain the supernatant. The amount of LA encapsulated in the IL / O-ND was evaluated by measuring the concentration of unencapsulated LA leaked into the supernatant by HPLC. The concentration of unencapsulated LA leaked into the supernatant was determined based on a calibration curve created from a standard LA solution, and the encapsulation rate of LA in the IL / O-ND was calculated. An IPM containing 3 mg / mL LA and 5% span-20 was used as Comparative Example 1, and an IPM containing 3 mg / mL LA and 5% ionic liquid 1 was used as Comparative Example 2.

[0100] (Evaluation of maximum capacity of LA in IL / O-ND) To evaluate the maximum loading capacity of LA on IL / O-ND, an excess amount of LA was added to an IPM containing 5% ionic liquid 1, 2, or 4 and 5% span-20, and the mixture was continuously stirred. LA that was not loaded on the IL / O-ND was removed by centrifugation. The LA concentration in the sample was measured by HPLC. An IPM containing 5% span-20 was used as Comparative Example 3, and an IPM containing 5% ionic liquid 1 was used as Comparative Example 4.

[0101] Figure 11(A) shows the LA loading rate in Examples 1 to 3. The addition of ionic liquid 1, 2, or 4 and a cosurfactant to the IPM significantly increased the LA loading rate in nanoparticles. Figure 11(B) shows the maximum LA loading in samples containing ionic liquid 1, 2, or 4. Ionic liquids 1, 2, and 4 significantly increased the LA loading rate in nanoparticles.

[0102] (Skin penetration test) A skin permeation test was carried out for the compositions shown in Table 3 using a Franz diffusion cell in which mouse skin was placed. Comparative Example 5 contained diethylene glycol monoethyl ether (DGME), a chemical permeation enhancer, as a surfactant. A fragment (2 × 2 cm) of mouse skin (Hos-HR-1, Hoshino Laboratory Animal Breeding Center) was placed in a Franz diffusion cell whose receiver chamber was filled with 5 mL of HEPES buffer (HEPES salt dissolved in Milli-Q at a concentration of 31 M and adjusted to pH 7.4 with NaOH and HCl solutions).2 250 μL of the composition was added to the shaved mouse skin area to be used as the donor compartment, and the system was maintained at 32.5°C using a circulating water bath, and the receiver phase was stirred by rotating a stir bar via magnetic force.

[0103] At 1, 3, 6, 9, 24, and 36 hours, 300 μL of the composition was added to the donor compartment, while 300 μL of the vehicle was aspirated to replace the receiver phase. Transdermal (passed through the skin) and topical (intradermal) LA were quantified by HPLC. For quantification of intradermal LA, the donor compartment was unfixed after 36 hours, and the skin surface was washed multiple times with 20% ethanol solution. The skin was cut into 16 pieces and stirred in a diluent for 12 hours to extract LA. The extracted solution was diluted 10-100 times, and the LA concentration was measured by HPLC.

[0104] [Table 3]

[0105] As shown in Figure 12, the LA concentration in the receiver phase was highest after 24 hours and gradually decreased, except for Example 1. Example 1 showed an increased LA concentration even after 36 hours. Figure 13 shows the transdermal and topical LA amounts after 36 hours. Example 1 allowed the greatest amount of LA to penetrate the skin and be transported transdermally.

[0106] Skin permeation kinetic parameters were evaluated by lag time and least squares method. Transdermal flux (J) and permeation coefficient (Kp) were calculated based on Kp = J / Cd, where Cd is the concentration of LA in the donor formulation (μg / mL). Lag time (t L ) is calculated from the intercept on the X-axis, and the diffusion coefficient (D) is calculated as D = I 2 / 6t L The skin partition coefficient (K skin ) to K skin The skin permeation kinetic parameters were calculated from the formula: = (J × I) / (D × Cd).

[0107] [Table 4]

[0108] (Effect of IL / O-ND on the stratum corneum of the skin) Frozen pig skin (YMPC, Hoshino Laboratory Animal Breeding Center) was thawed at room temperature, and the dried skin was heated at 60°C for 60–120 seconds to remove the epidermal layer. The collected epidermal sheets were then immersed in a 0.25% trypsin and 1 mM ethylenediaminetetraacetic acid (EDTA) solution with the stratum corneum facing up at room temperature for 24 hours. The isolated stratum corneum was washed with water and allowed to dry for another 24 hours. The stratum corneum slices were immersed in the test samples (IPM, ionic liquids 1, 2, 4, Tween-80, DGME, or PBS) in a glass tube for 30 minutes at room temperature. The stratum corneum sheets were washed with 20% ethanol and allowed to dry for 1 hour. The stratum corneum sheets were analyzed by Fourier transform infrared (FTIR) spectroscopy. Untreated stratum corneum was used as a control.

[0109] The lipid matrix organization (lamellar structure of cholesterol, fatty acids, and ceramides) and the keratinous protein structure of the stratum corneum are the main barriers to transdermal DDS, affecting the rate of drug diffusion into the deeper layers of the skin. The FTIR spectrum of the stratum corneum shows a peak at 2825–2975 cm -1 The lipid stretching region at 1475–1725 cm -1 The effect of IL / O-ND on the skin layer is shown in Table 5. In the spectrum, the absorption of the amide structure or keratin protein was observed at 1550 cm for amide-I;-C=O. -1 and amide-II; NH-C=O at 1650 cm -1 The shift of 2845 cm -1 and 2923 cm -1The CH2 symmetric and CH2 asymmetric vibrational stretching of lipids in carbohydrates is directly related to the molecular diffusion of drugs through the skin. The deformability of the α-helical colloidal and β-sheet structures of keratinous proteins is enhanced, leading to improved drug penetration. These shifts are enhanced in ionic liquids due to the lipid-soluble cations and fatty acid anions of the ionic liquids.

[0110] The unsaturated double bond carbon of linoleic acid (C18:2) in ionic liquid 1 significantly promotes the deformation of hydrogen bonds in the stratum corneum. These shifts are related to the gauche / trans structure that characterizes the lipid organization of the stratum corneum and suggest a decrease in lipid barrier function. The largest CH2 symmetric and CH2 asymmetric shifts in ionic liquid 1 indicate that ionic liquid 1 efficiently impairs barrier function and is suitable for transdermal DDS.

[0111] [Table 5]

[0112] (Effect on pharmacokinetics of IL / O-ND) A pharmacokinetic study of IL / O-ND was conducted in BALB / C mice (female, 6 weeks old, 20±2 g, Kyudo Co., Ltd.) randomly divided into six groups of five mice per group. The hair on the backs of the mice was removed, and two days later, 300 μL of the formulation shown in Table 6 (90 μg LA / mouse) was administered to clean skin using a 1 cm × 1 cm patch. Mice subcutaneously injected with 300 μL of PBS containing 90 μg LA served as positive controls. Approximately 200 μL of retroorbital blood was collected from the eyes of the mice after the designated time intervals. Blood was also collected from the injected groups after the designated time intervals. Serum was obtained by centrifuging the blood samples at 10,000 rpm for 20 minutes. Plasma LA concentrations were determined by enzyme-linked immunosorbent assay (ELISA) as follows.

[0113] 100 μL of plasma was vortexed with 100 μL of 4% phosphoric acid and applied to a WCX-SPE column. The WCX-SPE column was washed with 200 μL of 5% ammonium hydroxide followed by 20% acetonitrile, and LA was eluted with 100 μL of acetonitrile / water (75 / 25) containing 1% TFA. The eluted LA was evaporated in a microevaporator and eluted in 100 μL of water. It was then assayed by ELISA according to the protocol of the LHRH (Leuprolide) ELISA kit (A18102, BMA Biomedicals, Peninsula Laboratories). The LA concentration in plasma was determined by measuring the absorbance of the sample at 450 nm.

[0114] Figure 14 shows the change in plasma LA concentration over time. Table 6 shows the pharmacokinetic parameters. Transdermal administration of LA was better than injection. With administration by injection, the plasma LA concentration increased significantly 30 minutes after administration and decreased after 4 hours. On the other hand, with transdermal administration, particularly with administration by Example 1, the plasma LA concentration gradually increased up to 36 hours after administration. Example 1 was shown to be suitable for transdermal DDS using a patch.

[0115] [Table 6]

[0116] (Biocompatibility evaluation) The MTT cell viability assay was performed as described above for the formulations shown in Table 7. In Table 7, e-TFSA represents 1-dodecyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, and e-TF2N represents 1-dodecyl-3-methylimidazolium bis(trifluoroethylsulfonyl)imide.

[0117] Furthermore, the biocompatibility of each formulation was evaluated in vivo using female BALB / C mice (Kyudo Co., Ltd.). 300 μL of the formulation was administered via a patch three times, five days apart. The patch remained on the skin for 24 hours after each administration. Body weight was measured every other day until the final day, and at the end of the experiment, skin samples were collected for histological analysis. For histological sample preparation and staining, the skin was exposed to water and 50% 2-propanol, then frozen at -30°C in 4% formaldehyde solution for 2–3 hours. Approximately 20 μm-thick sections were obtained from the skin and fixed on slides. The sections were washed with acetone, ethanol, and water. After removing unwanted residue, the sections were stained with hematoxylin solution for 6 hours, washed with water, and then stained with eosin solution for an additional 20–30 minutes. After washing with water and dehydrating with ethanol, the sections were covered with glass and observed under a color microscope (BZ-9000, Keyence Corporation).

[0118] [Table 7]

[0119] Figure 15 shows the cell viability. The cell viability of Example 1, as well as Comparative Examples 6, 8, and 9, was close to 100%. On the other hand, the cell viability of Comparative Examples 5, 10, 11, and 12 was 59%, 53%, 18%, and 6%, respectively. This result demonstrated the in vitro biocompatibility of Example 1.

[0120] Figure 16 shows the body weights of the mice, measured every other day. There was no significant change in body weight until the 15th day in either case, but in Comparative Example 11, the mouse died after the first administration, and the skin darkened and was destroyed. Figure 17 shows the stratum corneum photographed at 20x magnification using a fluorescence microscope. No damage was observed in the stratum corneum of the untreated, Example 1, Comparative Examples 6, and 9. Slight damage was observed in Comparative Examples 5 and 10, and damage was observed in both layers of the skin in Comparative Examples 11 and 12. From the above, it was demonstrated that Example 1 is highly biocompatible and safe in vivo, making it useful for pharmaceutical preparations, particularly transdermal absorption agents.

[0121] The present invention allows various embodiments and modifications without departing from the broad spirit and scope of the present invention. Furthermore, the above-described embodiments are intended to explain the present invention and do not limit the scope of the present invention. That is, the scope of the present invention is defined by the claims, not the embodiments. Various modifications made within the scope of the claims and the meaning of the invention equivalent thereto are considered to be within the scope of the present invention.

[0122] This application is based on Japanese Patent Application No. 2020-056457, filed on March 26, 2020. The entire specification, claims, and drawings of Japanese Patent Application No. 2020-056457 are incorporated herein by reference. [Industrial Applicability]

[0123] The present invention salt has low toxicity, excellent biocompatibility, and exhibits high solubility in both hydrophilic and hydrophobic substances, and can therefore be safely used in various fields, including bio-related fields. Therefore, the present invention has high industrial applicability.

Claims

1. It has a structure represented by the following general formula (1): A salt that has a melting point of 100°C or less and exists in a liquid state. 【Chemistry 1】 [In general formula (1), R represents a substituted or unsubstituted linear alkyl group or a substituted or unsubstituted linear alkenyl group, at least one ethylene group constituting the linear alkenyl group may be replaced with a vinylene group, the linear alkyl group has 8 to 22 carbon atoms, and the linear alkenyl group has 8 to 22 carbon atoms; X ＋ represents a phospholipid having a cationic group, and has a structure represented by the following general formula (2). 【Chemistry 2】 {In general formula (2), R 1 represents a linear alkyl group having 1 to 6 carbon atoms substituted with the cationic group, the cationic group being a quaternary ammonium group, R 2 represents a hydrogen atom or a substituted or unsubstituted linear alkyl group having 1 to 6 carbon atoms, and R 3 represents an alkyl group having 1 to 6 carbon atoms substituted with two alkylcarbonyloxy groups, the alkyl group in the alkylcarbonyloxy group being a linear alkyl group having 8 to 22 carbon atoms.}

2. X in the general formula (1) ＋ The salt of claim 1 , wherein is a glycerophospholipid having a cationic group.

3. The salt according to claim 1, wherein R 1 is a methyl group, an ethyl group, or an n-propyl group substituted with a cationic group, and R 2 is a hydrogen atom, a methyl group, an ethyl group, or an n-propyl group.

4. The salt according to claim 1, wherein R 1 is a methyl group, an ethyl group, or an n-propyl group substituted with the cationic group.

5. The salt according to claim 1, wherein R 2 is a substituted or unsubstituted methyl group, ethyl group, or n-propyl group.

6. The salt according to claim 1, wherein R 3 is an n-propyl group substituted with the alkylcarbonyloxy group.

7. R 1 is a methyl group, an ethyl group, or an n-propyl group substituted with the cationic group; R 2 is a substituted or unsubstituted methyl group, ethyl group, or n-propyl group; R 3 is an n-propyl group substituted with the alkylcarbonyloxy group; The salt according to any one of claims 1 to 6.

8. X in the general formula (1) ＋ 3. The salt of claim 2, wherein is a derivative of phosphatidylcholine.

9. The salt according to claim 1, wherein the linear alkyl group for R has 12 to 22 carbon atoms, and the linear alkyl group in the alkylcarbonyloxy group for R 3 has 12 to 22 carbon atoms.

10. The salt according to any one of claims 1 to 9, wherein R in the general formula (1) has an unsaturated bond.

11. The salt according to claim 10, wherein R in the general formula (1) has a polyene structure.

12. The salt according to any one of claims 1 to 11, wherein R in the general formula (1) is a group consisting of only carbon atoms and hydrogen atoms.

13. The salt according to any one of claims 1 to 12, which is hydrophobic.

14. 14. The salt of claim 13 having a structure represented by the formula: 【Transformation 3】 [In the formula, R represents a substituted or unsubstituted linear alkyl group or a substituted or unsubstituted linear alkenyl group, at least one ethylene group constituting the linear alkenyl group may be replaced with a vinylene group, the linear alkyl group has 8 to 22 carbon atoms, and the linear alkenyl group has 8 to 22 carbon atoms.]

15. A solvent comprising the salt according to any one of claims 1 to 14.

16. A formulation comprising the salt of any one of claims 1 to 14.

17. A transdermal absorption agent comprising the salt according to any one of claims 1 to 14.

18. further comprising a sorbitan fatty acid ester, The transdermal absorption agent according to claim 17.

19. The sorbitan fatty acid ester is Sorbitan monolaurate, The transdermal absorption agent according to claim 18.

20. R—COO in the general formula (1) － is a carboxylate ion formed by dissociating a hydrogen ion from the carboxy group of linoleic acid. The transdermal absorption preparation according to any one of claims 17 to 19.

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