Solvent for poorly water-soluble substances, and zwitterion

Abstract

Provided are a poorly water-soluble substance solubilizer capable of dissolving various poorly water-soluble substances, and zwitterions contained in the poorly water-soluble substance solubilizer. 【Solution means】A poorly water-soluble substance solubilizer containing at least one selected from the group consisting of zwitterions represented by any one of formula (1), formula (2), and formula (3). In formula (1), A 10 is -COO - , -SO3 - , -OP=O(H)O - , -OP=O(CH3)O - and -OP=O(O(alkyl group))O - is an anion selected from the group consisting of, R 11 is an alkyl group having 1 to 6 carbon atoms, and R 12 is an alkylene group having 6 to 9 carbon atoms. In formula (2), A 20 and R 21 are the same as A 10 and R 11 respectively, and R 24 is the same as R 21 , and R 22 is an alkylene group having 6 to 9 carbon atoms. In formula (3), A 30 , R 31 , and R 32 are the same as A 10 , R 11 , and R 12 respectively. [Chemical formula 1] TIFF2026082421000046.tif33170

Description

[Technical Field]

[0001] The present invention relates to a solvent for poorly water-soluble substances containing a zwitterion, and to a zwitterion. [Background technology]

[0002] Traditionally, when dissolving poorly water-soluble substances such as pharmaceuticals (hereinafter referred to as "poorly water-soluble substances"), dimethyl sulfoxide (DMSO) is often used as the solvent. However, some poorly water-soluble substances do not dissolve in DMSO, and there are also concerns about cytotoxicity caused by DMSO.

[0003] As a solvent that can replace conventional DMSO, Patent Document 1 discloses a zwitterion that has low toxicity to various cells such as human cells and can be used as a culture medium additive or a solvent for poorly soluble substances. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] Japanese Patent Publication No. 2018-191623 [Overview of the project] [Problems that the invention aims to solve]

[0005] However, because the properties of poorly water-soluble substances vary widely, there is room for improvement in solvents for these substances.

[0006] The present invention has been made in view of the above circumstances, and aims to provide a solvent for poorly water-soluble substances that can dissolve various poorly water-soluble substances, and a zwitterion contained in the solvent for poorly water-soluble substances. [Means for solving the problem]

[0007] The present invention includes the following embodiments. A solubilizer for poorly water-soluble substances, comprising at least one selected from the group consisting of zwitterions represented by any one of the following general formula (1), the following general formula (2), and the following general formula (3).

[0008] [Chemical formula]

[0009] [In the formula, A 10 is an anion selected from the group consisting of -COO - , -SO3 - , -OP=O(H)O - , -OP=O(CH3)O - and -OP=O(OR 13 )O - . R 11 is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. R 12 is an alkylene group having 6 to 9 carbon atoms. R 13 is an alkyl group.]

[0010] [Chemical formula]

[0011] [In the formula, A 20 is an anion selected from the group consisting of -COO - , -SO3 - , -OP=O(H)O - , -OP=O(CH3)O - and -OP=O(OR 23 )O - . R 21 is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. R 22 is an alkylene group having 3 to 9 carbon atoms. R 23 is an alkyl group. R 24This is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms.

[0012] [ka]

[0013] [In the formula, A 30 -COO - , -SO3 - -OP=O(H)O - -OP=O(CH3)O - and -OP=O(OR 33 )O - It is an anion selected from the group consisting of R. 31 This is an alkyl group having 1 to 6 carbon atoms, and may have at least one atom selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. 32 This is an alkylene group with 3 to 9 carbon atoms. 33 It is an alkyl group.

[0014] [2] The dissolving agent for poorly water-soluble substances according to [1], wherein the zwitterion represented by the general formula (1) is a zwitterion represented by the following general formula (1').

[0015] [ka]

[0016] [In the formula, R 11 ' is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. 12 ' is an alkylene group with 6 to 9 carbon atoms.

[0017] [3] The dissolving agent for poorly water-soluble substances according to [1], wherein the zwitterion represented by the general formula (2) is a zwitterion represented by the following general formula (2').

[0018] [ka]

[0019] [In the formula, R 21 ' is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. 22 ' is an alkylene group with 3 to 9 carbon atoms. 24 ' is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms.

[0020] [4] The dissolving agent for poorly water-soluble substances according to [1], wherein the zwitterion represented by the general formula (3) is a zwitterion represented by the following general formula (3').

[0021] [ka]

[0022] [In the formula, R 31 ' is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. 32 ' is an alkylene group with 3 to 9 carbon atoms.

[0023] [5] Containing the zwitterion represented by the general formula (1), The poorly water-soluble substance solvent according to any one of [1] to [4], wherein the poorly water-soluble substance is a steroid compound. [6] The poorly water-soluble substance solvent according to any one of [1] to [4], wherein the poorly water-soluble substance is a polypeptide. [7] The poorly water-soluble substance solvent according to any one of [1] to [4], wherein the poorly water-soluble substance is zoledronic acid monohydrate. [8] A solvent for poorly water-soluble substances according to any one of [1] to [4], wherein the molecular weight of the poorly water-soluble substance is 200 or more and 10,000 or less.

[0024] [9] A zwitterion represented by any of the following general formulas (1), (2), or (3).

[0025] [ka] [In the formula, A 10 -COO - , -SO3 - -OP=O(H)O - -OP=O(CH3)O - and -OP=O(OR 13 )O - It is an anion selected from the group consisting of R. 11 This is an alkyl group having 1 to 6 carbon atoms, and may have at least one atom selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. 12 This is an alkylene group with 6 to 9 carbon atoms. 13 It is an alkyl group.

[0026] [ka]

[0027] [In the formula, A 20 -COO - , -SO3 - -OP=O(H)O - -OP=O(CH3)O - and -OP=O(OR 23 )O - It is an anion selected from the group consisting of R. 21This is an alkyl group having 1 to 6 carbon atoms, and may have at least one atom selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. 22 This is an alkylene group with 3 to 9 carbon atoms. 23 R is an alkyl group. 24 This refers to an alkyl group having 1 to 6 carbon atoms.

[0028] [ka]

[0029] [In the formula, A 30 -COO - , -SO3 - -OP=O(H)O - -OP=O(CH3)O - and -OP=O(OR 33 )O - It is an anion selected from the group consisting of R. 31 This is an alkyl group having 1 to 6 carbon atoms, and may have at least one atom selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. 32 This is an alkylene group with 3 to 9 carbon atoms. 33 It is an alkyl group.

[0030]

[10] The zwitterion according to [9], wherein the zwitterion represented by any of the general formulas (1), (2), and (3) is a zwitterion represented by any of the following formulas C1imC6C, C1imC7C, C1imC9C, C1C1imC3C, C1C1imC5C, and C1morC3C.

[0031] [ka] [Effects of the Invention]

[0032] The dissolving agent for poorly water-soluble substances according to the present invention contains a specific zwitterion. This zwitterion is an imidarium cation or morpholinium cation whose cation moiety has a specific side chain, and the number of carbon atoms between the cation moiety and the anion moiety is within a specific range. By having the above configuration, the hydrophobicity of the side chain of the cation moiety and the hydrophobicity between the cation moiety and the anion moiety are improved. Therefore, the dissolving agent for poorly water-soluble substances according to the present invention can dissolve various poorly water-soluble substances, including substances that could not be dissolved by conventional zwitterions. In other words, according to the present invention, it is possible to provide a dissolving agent for poorly water-soluble substances that can dissolve various poorly water-soluble substances, and a zwitterion contained in said dissolving agent for poorly water-soluble substances. [Brief explanation of the drawing]

[0033] [Figure 1] This is the 1H NMR spectrum of the zwitterion C1imC6C obtained in Synthesis Example 1. [Figure 2] This is the 1H NMR spectrum of the zwitterion C1imC7C obtained in synthesis example 2. [Figure 3] This is the 1H NMR spectrum of the zwitterion C1imC9C obtained in Synthesis Example 3. [Figure 4] This is the 1H NMR spectrum of the zwitterion C1C1imC3C obtained in synthesis example 4. [Figure 5] This is the 1H NMR spectrum of the zwitterion C1C1imC5C obtained in synthesis example 5. [Figure 6] This is the 1H NMR spectrum of the zwitterion C1morC3C obtained in synthesis example 6. [Figure 7A] This graph shows the time course of OD600 when Kluyveromyces marxianus, a lactose-fermenting yeast, was cultured in 0.25 mol / L zwitterion-containing YPD medium in Test Example 2. [Figure 7B]This graph shows the relative OD600 of Cluiveromyces marcyanas after being cultured for 8 hours in 0.25 mol / L zwitterion-containing YPD medium in Test Example 2 (with the OD600 after 8 hours of culture in YPD medium without zwitterions (YPD in the figure) set to 1.0). [Modes for carrying out the invention]

[0034] <Soluble agent for poorly water-soluble substances> The solvent for poorly water-soluble substances in this embodiment includes at least one selected from the group consisting of zwitterions represented by any one of general formulas (1), (2), and (3).

[0035] • Zwitterion represented by general formula (1) The zwitterion represented by general formula (1) (hereinafter also referred to as "zwitterion (1)") is represented by the following general formula (1).

[0036] [ka]

[0037] [In the formula, A 10 -COO - , -SO3 - -OP=O(H)O - -OP=O(CH3)O - and -OP=O(OR 13 )O - It is an anion selected from the group consisting of R. 11 This is an alkyl group having 1 to 6 carbon atoms, and may have at least one atom selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. 12 This is an alkylene group with 6 to 9 carbon atoms. 13 It is an alkyl group.

[0038] In the above general formula (1), A 10 As for, -COO - -OP=O(H)O -, -OP=O(CH3)O - and -OP=O(OR 13 )O - may be an anion selected from the group consisting of -COO - , -SO3 - , -OP=O(CH3)O - and -OP=O(OR 13 )O - may be an anion selected from the group consisting of -COO - , -SO3 - , -OP=O(H)O - , and -OP=O(OR 13 )O - may be an anion selected from the group consisting of -COO - , -SO3 - , -OP=O(H)O - , and -OP=O(CH3)O - from the group consisting of may be an anion. Among them, A 10 as, -COO - is preferred. R 11 as may be an alkyl group having 1 to 6 carbon atoms, or an alkyl group having at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms of the alkyl group. Among them, R 11 as is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, CH3OCH2CH2- or CH3OCH2CH2OCH2CH2-, more preferably a methyl group, an ethyl group, an iso-propyl group or a n-propyl group, still more preferably a methyl group or an ethyl group, and particularly preferably a methyl group. R 12 as is preferably a linear or branched alkylene group having 6 to 9 carbon atoms, more preferably a n-hexylene group, a n-heptylene group, a n-octylene group, or a n-nonylene group, still more preferably a n-hexylene group, a n-heptylene group, or a n-nonylene group. R 13While not particularly limited, linear or branched alkyl groups are preferred, linear or branched alkyl groups having 1 to 6 carbon atoms are more preferred, and methyl, ethyl, n-propyl, or iso-propyl groups are even more preferred.

[0039] A good example of a zwitterion (1) is the zwitterion represented by the following general formula (1') (hereinafter also referred to as "zwitterion (1')").

[0040] [ka] [In the formula, R 11 ' is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. 12 ' is an alkylene group with 6 to 9 carbon atoms.

[0041] In the above general formula (1'), R 11 ' may be an alkyl group having 1 to 6 carbon atoms, and the alkyl group may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms. Among them, R 11 The ' group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, CH3OCH2CH2- or CH3OCH2CH2OCH2CH2-, more preferably a methyl group, an ethyl group, an n-propyl group, or an iso-propyl group, even more preferably a methyl group or an ethyl group, and particularly preferably a methyl group. R 12 As for the group, linear or branched alkylene groups having 6 to 9 carbon atoms are preferred, more preferably n-hexylene, n-heptylene, n-octylene, or n-nonylene groups, and even more preferably n-hexylene, n-heptylene, or n-nonylene groups.

[0042] As for the above zwitterion (1'), from the viewpoint of being able to dissolve poorly water-soluble substances better, R 11' is a methyl group, an ethyl group, an n-propyl group, or an iso-propyl group, and R 12 A zwitterion in which ' is an n-hexylene group, an n-heptylene group, an n-octylene group, or an n-nonylene group is preferred. More preferably R 11 ' is a methyl group, R 12 The zwitterion is one in which ' is an n-hexylene group, an n-heptylene group, an n-octylene group, or an n-nonylene group. More preferably, it is a zwitterion represented by the following formula C1imC6C, C1imC7C, or C1imC9C.

[0043] [ka]

[0044] Examples of poorly water-soluble substances that can be dissolved by the zwitterion (1) in this embodiment include the poorly water-soluble substances described below. Among these, steroid compounds, polypeptides, or medium-molecular-weight compounds with a molecular weight of 250 to 1000 are preferred, and estriol, β-estradiol, progesterone, stanolone, insulin, zoledronic acid monohydrate, or paclitaxel are more preferred. Preferred poorly water-soluble substances that can be dissolved by the zwitterion represented by the above formula C1imC6C include insulin, zoledronic acid monohydrate, or paclitaxel. Preferred poorly water-soluble substances that can be dissolved by the zwitterion represented by the above formula C1imC7C include estriol, progesterone, insulin, zoledronic acid monohydrate, or paclitaxel. Preferred poorly water-soluble substances that can be dissolved by the zwitterion represented by the above formula C1imC9C include estriol, β-estradiol, progesterone, stanolone, insulin, zoledronic acid monohydrate, or paclitaxel.

[0045] • Zwitterion represented by general formula (2) The zwitterion represented by general formula (2) (hereinafter also referred to as "zwitterion (2)") is represented by the following general formula (2).

[0046] [ka]

[0047] [In the formula, A 20 -COO - , -SO3 - -OP=O(H)O - -OP=O(CH3)O - and -OP=O(OR 23 )O - It is an anion selected from the group consisting of R. 21 This is an alkyl group having 1 to 6 carbon atoms, and may have at least one atom selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. 22 This is an alkylene group with 3 to 9 carbon atoms. 23 R is an alkyl group. 24 This is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms.

[0048] In the above general formula (2), A 20 As for A above, 10 Similar examples include A. 20 As for, -COO - It is preferable. R 21 This may be an alkyl group having 1 to 6 carbon atoms, and may also be an alkyl group having at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms of the alkyl group. In particular, R 21The C1-C6 alkyl group is preferably a linear or branched C1-C6 alkyl group, CH3OCH2CH2- or CH3OCH2CH2OCH2CH2-, more preferably a methyl group, ethyl group, n-propyl group, or iso-propyl group, even more preferably a methyl group or ethyl group, and particularly preferably a methyl group. R 22 Preferably, the alkylene group is linear or branched and has 3 to 9 carbon atoms; more preferably, n-propylene, n-butylene, n-pentylene, n-hexylene, n-heptylene, n-octylene, or n-nonylene; even more preferably, n-propylene, n-butylene, n-pentylene, n-hexylene, or n-heptylene; particularly preferably, n-propylene, n-butylene, or n-pentylene; and most preferably, n-propylene or n-pentylene. R 23 While not particularly limited, linear or branched alkyl groups are preferred, linear or branched alkyl groups having 1 to 6 carbon atoms are more preferred, and methyl, ethyl, n-propyl, or iso-propyl groups are even more preferred. R 24 The C1-C6 alkyl group is preferably a linear or branched C1-C6 alkyl group, CH3OCH2CH2- or CH3OCH2CH2OCH2CH2-, more preferably a methyl group, ethyl group, iso-propyl group, or n-propyl group, even more preferably a methyl group or ethyl group, and particularly preferably a methyl group.

[0049] A good example of a zwitterion (2) is the zwitterion represented by the following general formula (2') (hereinafter also referred to as "zwitterion (2')").

[0050] [ka] [In the formula, R 21 ' is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. 22' is an alkylene group with 3 to 9 carbon atoms. 24 ' is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms.

[0051] In the above general formula (2'), R 21 ' may be an alkyl group having 1 to 6 carbon atoms, and may be an alkyl group having at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms of the alkyl group. In particular, R 21 The ' group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, CH3OCH2CH2- or CH3OCH2CH2OCH2CH2-, more preferably a methyl group, an ethyl group, an n-propyl group, or an iso-propyl group, even more preferably a methyl group or an ethyl group, and particularly preferably a methyl group. R 22 As for the group, linear or branched alkylene groups having 3 to 9 carbon atoms are preferred, more preferably n-propylene, n-butylene, n-pentylene, n-hexylene, n-heptylene, n-octylene, or n-nonylene groups, even more preferably n-propylene, n-butylene, n-pentylene, n-hexylene, or n-heptylene groups, particularly preferably n-propylene, n-butylene, or n-pentylene groups, and most preferably n-propylene or n-pentylene groups. R 24 The ' group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, CH3OCH2CH2- or CH3OCH2CH2OCH2CH2-, more preferably a methyl group, an ethyl group, an iso-propyl group, or an n-propyl group, even more preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

[0052] The above zwitterion (2') is R 21 ' is a methyl group, an ethyl group, an iso-propyl group, or an n-propyl group, R 22' is an n-propylene group, n-butylene group, n-pentylene group, n-hexylene group, n-heptylene group, n-octylene group, or n-nonylene group, and R 24 A zwitterion is preferred in which ' is a methyl group, an ethyl group, an n-propyl group, or an iso-propyl group. More preferably, R 21 ' is a methyl group or an ethyl group, R 22 ' is an n-propylene group, an n-butylene group, an n-pentylene group, an n-hexylene group, or an n-heptylene group, and R 24 ' is a zwitterion in which is a methyl group or an ethyl group. More preferably, R 21 ' is a methyl group, R 22 ' is an n-propylene group, an n-butylene group, or an n-pentylene group, and R 24 The zwitterion is a methyl group. Particularly preferred is a zwitterion represented by the following formula C1C1imC3C or C1C1imC5C.

[0053] [ka]

[0054] In particular, from the viewpoint of lower toxicity to cells, the zwitterion (2') is preferably represented by the above formula C1C1imC3C or C1C1imC5C. Alternatively, from the viewpoint of being able to dissolve poorly water-soluble substances more effectively, the zwitterion (2') is more preferably represented by the formula C1C1imC3C or the formula C1C1imC5C. Alternatively, from the viewpoint of being able to dissolve poorly water-soluble substances more effectively and having lower cytotoxicity, the zwitterion (2') is more preferably represented by the above formula C1C1imC3C or C1C1imC5C.

[0055] Examples of poorly water-soluble substances that can be dissolved by the zwitterion (2) in this embodiment include the poorly water-soluble substances described later. Among these, steroid compounds, polypeptides, or medium-molecular-weight compounds with a molecular weight of 250 to 1000 are preferred, and erythromycin, insulin, or zoledronic acid monohydrate are more preferred. Preferred poorly water-soluble substances that can be dissolved by the zwitterion represented by the above formula C1C1imC3C are insulin or zoledronic acid monohydrate. Preferred poorly water-soluble substances that can be dissolved by the zwitterion represented by the above formula C1C1imC5C are erythromycin or zoledronic acid monohydrate.

[0056] • Zwitterion represented by general formula (3) The zwitterion represented by general formula (3) (hereinafter also referred to as "zwitterion (3)") is represented by the following general formula (3).

[0057] [ka]

[0058] [In the formula, A 30 -COO - , -SO3 - -OP=O(H)O - -OP=O(CH3)O - and -OP=O(OR 33 )O - It is an anion selected from the group consisting of R. 31 This is an alkyl group having 1 to 6 carbon atoms, and may have at least one atom selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. 32 This is an alkylene group with 3 to 9 carbon atoms. 33 It is an alkyl group.

[0059] In the above general formula (3), A 30 As for A above, 10 Similar examples include A. 30As for, -COO - It is preferable. R 31 This may be an alkyl group having 1 to 6 carbon atoms, and may also be an alkyl group having at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms of the alkyl group. In particular, R 31 The group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, CH3OCH2CH2-, or CH3OCH2CH2OCH2CH2-, more preferably a methyl group, an ethyl group, an iso-propyl group, or an n-propyl group, even more preferably a methyl group or an ethyl group, and particularly preferably a methyl group. R 32 Preferably, the alkylene group is linear or branched and has 3 to 9 carbon atoms; more preferably, n-propylene, n-butylene, n-pentylene, n-hexylene, n-heptylene, n-octylene, or n-nonylene; even more preferably, n-propylene, n-butylene, n-pentylene, n-hexylene, or n-heptylene; even more preferably, n-propylene, n-butylene, or n-pentylene; particularly preferably, n-propylene or n-butylene; and most preferably, n-propylene. R 33 While not particularly limited, linear or branched alkyl groups are preferred, linear or branched alkyl groups having 1 to 6 carbon atoms are more preferred, and methyl, ethyl, n-propyl, or iso-propyl groups are even more preferred.

[0060] A good example of a zwitterion (3) is the zwitterion represented by the following general formula (3') (hereinafter also referred to as "zwitterion (3')"). [ka] [In the formula, R 31 ' is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. 32 ' is an alkylene group with 3 to 9 carbon atoms.

[0061] In the above general formula (3'), R 31 ' may be an alkyl group having 1 to 6 carbon atoms, and may be an alkyl group having at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms of the alkyl group. In particular, R 31 The ' group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, CH3OCH2CH2-, or CH3OCH2CH2OCH2CH2-, more preferably a methyl group, an ethyl group, an isopropyl group, or an n-propyl group, even more preferably a methyl group or an ethyl group, and particularly preferably a methyl group. R 32 As for the group, linear or branched alkylene groups having 3 to 9 carbon atoms are preferred, more preferably n-propylene, n-butylene, n-pentylene, n-hexylene, n-heptylene, n-octylene, or n-nonylene groups, even more preferably n-propylene, n-butylene, n-pentylene, n-hexylene, or n-heptylene groups, even more preferably n-propylene, n-butylene, or n-pentylene groups, particularly preferably n-propylene or n-butylene groups, and most preferably n-propylene.

[0062] As for the above zwitterion (3'), from the viewpoint of being able to dissolve poorly water-soluble substances better, R 31 ' is a methyl group, an ethyl group, an isopropyl group, or an n-propyl group, and R 32 A zwitterion is preferred in which ' is an n-propylene group, an n-butylene group, an n-pentylene group, an n-hexylene group, an n-heptylene group, an n-octylene group, or an n-nonylene group. More preferably, R 31 ' is a methyl group or an ethyl group, and R 32 ' is a zwitterion in which ' is an n-propylene group, an n-butylene group, an n-pentylene group, an n-hexylene group, or an n-heptylene group. More preferably, R 31 ' is a methyl group, and R 32The zwitterion is one in which ' is an n-propylene group, an n-butylene group, or an n-pentylene group. Particularly preferred is a zwitterion represented by the following formula C1morC3C.

[0063] [ka]

[0064] Examples of poorly water-soluble substances that can be dissolved by the zwitterion (3) in this embodiment include the poorly water-soluble substances described later. Among these, steroid compounds, polypeptides, or medium-molecular-weight compounds with a molecular weight of 250 to 1000 are preferred, and insulin or zoledronic acid monohydrate are more preferred. Preferred poorly water-soluble substances that can be dissolved by the zwitterion represented by the above formula C1morC3C are insulin or zoledronic acid monohydrate.

[0065] (Manufacturing method) The zwitterions (1) to (3) in the poorly water-soluble substance solvent of this embodiment can each be synthesized by the following methods. The zwitterion (1) can be synthesized, for example, by refluxing 1-alkylimidazole and an anionic reagent (e.g., ethyl bromoalkylate) in acetonitrile, mixing it with an anion exchange resin, and then removing the solvent under reduced pressure. The zwitterion (2) can be synthesized by the same method as the zwitterion (1), except, for example, that 1,2-alkylimidazole is used instead of 1-alkylimidazole. The zwitterion (3) can be synthesized by the same method as the zwitterion (1), except, for example, that 4-alkylmorpholine is used instead of 1-alkylimidazole. The zwitterions (1) to (3) in the embodiment of the poorly water-soluble substance solvent can, in more specific examples, be synthesized using the synthesis method described in the examples below. The solvent for poorly water-soluble substances of this embodiment can be manufactured by mixing the above zwitterions (1) to (3) with other components as appropriate.

[0066] In the poorly water-soluble substance solvent of this embodiment, the lower limit of the content of zwitterions (1) to (3) is preferably 20% by mass or more, more preferably 25% by mass or more, even more preferably 30% by mass or more, and particularly preferably 50% by mass or more. The upper limit of the content of zwitterions (1) to (3) is preferably 100% by mass or less, more preferably 99% by mass or less, even more preferably 95% by mass or less, and particularly preferably 90% by mass or less. Furthermore, the above lower and upper limits for the content of zwitterions (1) to (3) can be combined arbitrarily. For example, 20% to 100% by mass, 25% to 99% by mass, 30% to 95% by mass, 50% to 90% by mass, 25% to 90% by mass, and 50% to 100% by mass or more.

[0067] The solvent for poorly water-soluble substances in this embodiment may be appropriately adjusted in terms of the types of zwitterions (1) to (3) and the composition ratio of zwitterions (1) to (3).

[0068] (Other ingredients) The poorly water-soluble substance solvent of this embodiment may contain other components besides the zwitterions (1) to (3). Examples of other components include solvents (excluding those corresponding to the zwitterions (1) to (3)), thickeners, preservatives, isotonic agents, buffers, pH adjusters, excipients, preservatives, cryoprotectants, colorants, and surfactants.

[0069] The solvent for poorly water-soluble substances in this embodiment may use zwitterions (1) to (3) individually, but water, physiological saline, phosphate-buffered saline (PBS), DMSO, glycerol, methanol, ethanol, etc., or combinations thereof may be used as the solvent.

[0070] (Dosage form) The poorly water-soluble substance dissolving agent of this embodiment can be manufactured by mixing zwitterions (1) to (3) with other components as appropriate. The dosage form of the poorly water-soluble substance dissolving agent may include, but is not limited to, liquids, tablets, powders, granules, etc.

[0071] (poorly water-soluble substances) The poorly water-soluble substances that the poorly water-soluble substance dissolving agent of this embodiment can dissolve are not particularly limited as long as they have the property of being only slightly soluble in water, but substances with a solubility of 1% by mass or less in water at 25°C are preferred, more preferably 0.5% by mass or less, and even more preferably 0.1% by mass or less.

[0072] The molecular weight of the above poorly water-soluble substance is not particularly limited as long as it has the property of being only slightly soluble in water, but it is generally known that solubility decreases as the molecular weight increases. The molecular weight of the above poorly water-soluble substance is preferably 200 to 100,000,000, more preferably 200 to 50,000,000, even more preferably 200 to 10,000,000, even more preferably 200 to 1,000,000, even more preferably 200 to 100,000, particularly preferably 200 to 10,000, and most preferably 250 to 6,500.

[0073] Examples of poorly water-soluble substances include active ingredients (including candidate substances that may become active ingredients) of pharmaceuticals, veterinary drugs, quasi-drugs, cosmetics, and pesticides, as well as food additives, biologically derived substances, and plant-derived substances. These may include low-molecular-weight substances (e.g., steroid compounds (compounds with a steroid skeleton)), oligomers (oligopeptides, polypeptides, polysaccharides, DNA, and RNA, etc.), and high-molecular-weight substances.

[0074] Poorly water-soluble drugs include those described as "slightly soluble," "poorly soluble," "very poorly soluble," and "almost insoluble" in the 18th edition of the Japanese Pharmacopoeia. Poorly water-soluble drugs include hormones, antitumor agents, antibiotics, antihyperlipidemic agents, antibacterial agents, allergy treatments, antihypertensive agents, arteriosclerosis treatments, blood circulation promoters, fat-soluble vitamins, diabetes treatments, antiandrogens, cardiac stimulants, antiarrhythmics, anti-inflammatory agents, hypnotics and sedatives, tranquilizers, antiepileptics, antidepressants, gastrointestinal disease treatments, diuretics, local anesthetics, anticoagulants, antihistamines, antimuscarinic agents, antimycobacterial agents, immunosuppressants, and anti-methicillin agents. Examples include sedatives, antivirals, anxiety-relieving sedatives, astringents, β-adrenergic receptor blockers, myocardial inotropic agents, contrast agents, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopamine agonists, lipid regulators, muscle relaxants, parasympathetic agonists, thyroid calcitonin, prostaglandins, radiopharmaceuticals, sex hormones, stimulants, appetite suppressants, sympathetic agonists, thyroid agents, vasodilators, isoflavones, and xanthenes.

[0075] As for hormone preparations, insulin, dexamethasone, dexamethasone acetate, betamethasone, betamethasone valerate, betamethasone dipropionate, beclomethasone propylonate, prednisolone, prednisolone valerate, prednisolone acetate, methylprednisolone, methylprednisolone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone propionate acetate, amcinonide, triamcinolone, triamcinolone acetonide, fluocinolone acetonide, estriol, fluocinonide, hexestrol, methimazole, estriol propionate, clobetazone acetate, clobetasol propionate, testosterone, propionate Examples include testosterone ionate, testosterone enanthate, fluoxymesterone, stanolone, dromostanolone propionate, β-estradiol, estradiol benzoate, estradiol propionate, estradiol valerate, ethinylestradiol, mestranol, estriol acetate benzoate, fluorometholone, fludroxycortide, diflucortone valerate, halcinonide, progesterone, hydroxyprogesterone caproate, pregnanediol, medroxyprogesterone acetate, dimethisterone, norethisterone, allylestrenol, gestorone caproate, and oxendrone.

[0076] Examples of antitumor agents include paclitaxel, zoledronic acid monohydrate, methotrexate, taxol, doxorubicin hydrochloride, bleomycin hydrochloride, tamoxifen, cisplatin, carboplatin, cyclosporine, HER2 inhibitors, melphalan, dacarbazine, carmofur, enocitabine, etoposide, 5-fluorouracil, mitoxantrone, mesna, dimesna, aminoglutethimide, acroline, cyclophosphamide, lomustine, carmustine, cyclophosphamide, busulfan, para-aminosalicylic acid, mercaptopurine, tegaflu, azathioprine, vinblastine sulfate, mitomycin C, L-asparakinase, and ubenimex.

[0077] Examples of antibiotics include streptomycin, chloramphenicol, gentamicin, tetracycline, penicillin, amikacin, dibekacin, bacitracin, cephalexin, nystatin, erythromycin, fradiomycin sulfate, cefmetazole, and tolnaftate.

[0078] Examples of antihyperlipidemia agents include cholestyramine, niceritrol, clinofibrate, clofibrate, fenofibrate, bezafibrate, soysterol, tocopherol nicotinate, nicomole, probucol, simvastatin, colestimide, and elastase.

[0079] Examples of antibacterial agents include erythromycin, chloramphenicol, rokitamycin, roxithromycin, cefatolidine, ofloxacin, ciprofloxacin hydrochloride, tosufloxacin tosylate, norfloxacin, lomefloxacin hydrochloride, pazufloxacin, cefpodoxime proxetil, midecamycin acetate, josamycin propionate, and fosfomycin or its salts.

[0080] Examples of agents used to treat allergic diseases include ebastine, mequitazine, methoxyphenamine, clemastine fumarate, cyproheptadine hydrochloride, fexofenadine hydrochloride, diphenhydramine, metodilamine, and cremisole.

[0081] Examples of antihypertensive agents include nicardipine hydrochloride, delapril hydrochloride, barnidipine hydrochloride, efonidipine hydrochloride, benidipine hydrochloride, alacepril, captopril, cilnidipine, felodipine, amlodipine besylate, nisoldipine, manidipine hydrochloride, nitrendipine, nilvadipine, trandolapril, valsartan, candesartan cilexetil, urapidil, carvedilol, prazosin hydrochloride, bunazosin hydrochloride, doxazosin mesylate, reserpine, methyldopa, guanabenz acetate, deserupidine, meptame, and meptamate.

[0082] Examples of agents used to treat arteriosclerosis include elastase, clofibrate, symfibrate, soysterol, and nicomole.

[0083] Examples of blood circulation promoters include tocopherol acetate, tocopherol nicotinate, benzyl nicotinate, caffeine, trazoline, verapamil, cyclandelate, and acetylcholine.

[0084] Examples of fat-soluble vitamins include vitamin A, vitamin D, vitamin E, and vitamin K.

[0085] Examples of diabetes medications include gliclazide, tolbutamide, glibenclamide, troglitazone, epalrestat, buformin, and metformin.

[0086] Examples of antiandrogenic agents include gestolone caproate, osapron acetate, flutamide, oxendrone, allylestrenol, chlormadinone acetate, and bicalutamide.

[0087] Examples of cardiac stimulants include digoxin, digotoxin, and cobidecarenone.

[0088] Examples of antiarrhythmic drugs include lidocaine, bopindolol malonate, arotinolol hydrochloride, atenolol, pindolol, nadolol, propafenone hydrochloride, amiodarone hydrochloride, disopyramide, and carteolol hydrochloride.

[0089] Anti-inflammatory agents include glycyrrhetinic acid, dipotassium glycyrrhizinate, aspirin, aluminum aspirin, ibuprofen, ketoprofen, licyrrhetinic acid, salicylic acid, acetaminophen, methyl salicylate, glycol salicylate, aminopyrine, phenacetin, mefenamic acid, flufenamic acid, aluminum flufenamic acid, tolfenamic acid, acemetacin, indomethacin, alclofenac, diclofenac, ibuprofen piconol, oxyfen butazone, phenyl butazone, ketophenyl butazone, clofezone, tiaramide hydrochloride, diclofenac sodium, sulindac, naproxen, febufen, flurbiprofen, fenprofen, and bufe Examples include Xasamac, mepirizole, perisoxal citrate, Graphenin, Bucolome, pentazocine, methiadic acid, protidic acid, pranoprofen, fenoprofen calcium, piroxicam, feprazon, fentiazac, bendazac, dimethylisopropylazulene, bufexamac, Bucolome, benzidamine, tiaramide, tinoridine, ethenzamide, tenoxicam, chlortenoxicam, clidanac, naproxen, glycyrrhizin, azulene, camphor, thymol, l-menthol, sazapyrine, alclofuenac, diclofenac, suprofen, loxoprofen, diflunisal, tiaprofenoic acid, oxaprozin, and felbinac.

[0090] Examples of hypnotic sedatives include barbital, amobarbital, amobarbital sodium, phenobarbital, phenobarbital sodium, secobarbital sodium, pentobarbital calcium, hexobarbital, triclophos, bromovalerylurea, glutethimid, methacarone, perlapine, nitrazepam, estazolam, flurazepam hydrochloride, flunitrazepam, and estazolam.

[0091] Examples of tranquilizers include diazepam, lorazepam, and oxazolam.

[0092] Examples of antiepileptic drugs include phenytoin, carbamazepine, phenobarbital, primidone, phenasemide, ethylphenasemide, etotoin, fen succimide, nitrazeban, and clonazeban.

[0093] Examples of antidepressants include phenelzine, imiplanin, and noxyptyline.

[0094] Examples of drugs used to treat gastrointestinal diseases include famotidine, sucralfate, aldioxa, irsoglazine maleate, metoclopramide, cimetidine, omeprazole, lansoprazole, emprostil, gefarnate, teprenone, sulpiride, trepibutone, and oxethazaine.

[0095] Examples of diuretics include spironolactone, chlorthalidone, polythiazide, triamterene, hydrochlorothiazide, and furosemide.

[0096] Examples of local anesthetics include ethyl aminobenzoate, procaine hydrochloride, lidocaine, lidocaine hydrochloride, dipcaine hydrochloride, tetracaine hydrochloride, benzyl alcohol, tacaine, bezocaine, pramoxin hydrochloride, catacaine hydrochloride, butanicaine hydrochloride, pipelocaine hydrochloride, and chlorobutanol.

[0097] Examples of anticoagulants include coumarin and heparin.

[0098] Examples of antiviral agents include acyclovir, nevirapine, zidovudine, zanamivir, oseltamivir, and favipiravir.

[0099] Examples of isoflavones include ononine, daidzein, biochanin A, glycitein, daidzin, glycitin, and genistin. Isoflavones may be aglycones or glycosides.

[0100] Examples of poorly water-soluble substances used as quasi-drugs or cosmetics include dl-α-tocopherol acetate, α-tocopherol (vitamin E), methyl cinnamate, ethyl cinnamate, hexyl laurate, trichlorocarbanilide, triazine, benzophenone, triazole, eugenol, isoeugenol, ethyl methylphenylglycidate, geranyl acetate, piperonal, cinnamyl acetate, decyl oleate, terpenyl acetate, anilide, cinnamide, sulfonated benzimidazole, carotene, piroctone olamine, minoxidil, phytosteside, tocopherol nicotinate, ethinylestradiol, polyporsterone, and ecdysteroids.

[0101] As pesticides, any poorly water-soluble active pesticide component that has insecticidal, fungicidal, herbicidal, and plant growth regulating effects can be applied. For example, poorly water-soluble insecticides include abamectin, acrinatrin, amitraz, azadirachtin, azamethiphos, azinophosmethyl, azocyclotin, methiocarb, thiodicarb, trimetacarb, etofenprox, ethylthiometon, methoxychlor, chlorpyrifosmethyl, chlorfensone, chlorfluazuron, tebufenpyrad, bensultap, bifenthrin, bromopropylate, buprofezin, carbaryl, chlorfenapyr, clofentezene, coumaphos, diazinon, cycloprothrin, cyfluthrin, β-cyfluthrin, cypermethrin, α-cypermethrin, θ-cypermethrin, deltamethrin, diafenthiuron, dicofol, diflubenzuron, and cal It can dissolve bosulfan, endosulfan, esfenvalerate, ethoxazol, phenazaquin, fenbutane oxide, phenoxycarb, fenpyroximate, fipronil, fluazuron, flucycloxuron, flufenoxuron, flubendiamide, fenthion, halofenozide, hexaflumuron, hexythiazox, hydramethylnon, metaflumizone, lufenuron, milbemectin, novaron, pentachlorophenol, pyridaben, rotenone, sulfuramide, tebufenozide, tebupyrimphos, teflubenzuron, tetrachlorvinphos, tetradiphon, benfuracarb, tolfenpyrad, triflumulon, tralomethrin, and flatiocarb, among others.

[0102] In addition, bactericidal substances that are poorly water-soluble include bromconazole, carpropamide, diclofen, metconazole, hexaconazole, fentin, mancozeb, maneb, diclomedin, azoxystrobin, isoprothiolane, venalaxyl, benomyl, vitertanol, captafoll, captan, carbendazim, quinomethionate, chlorothalonil, clozolinate, cyprodinil, diclofluanide, dichloran, diclosimate, diethofencarb, dimethomorph, diniconazole, dithianone, thiadinil, epoxyconazole, famoxadone, phenalimol, fenbuconazole, fenflam, fenpiclonil, fluazinam, fludioxonil, fluoro Examples include Mid, fluquinconazole, flusulfamide, flutolanil, holpet, hexachlorobenzene, imibenconazole, ipoconazole, iprodione, kresoximmethyl, mepanipyrim, mepronil, methylam, nickelbis(dimethyldithiocarbamate), nualimol, oxycopper, oxolinic acid, pencyclon, phthalide, procymidone, propineb, quintozen, sulfur, tebuconazole, tecrophthalam, technazen, tifluzamide, thiophenate-methyl, thyram, tolclophosmethyl, triadimephon, tolfluanide, triadimenol, triazoxide, trifoline, triticonazole, vinclozoline, zineb, and zillam.

[0103] Poorly water-soluble herbicides include bromobutide, acronifen, clomethoxyfen, lactofen, promethrin, propazine, azaphenidine, tenylchlor, bifenox, sulfentrazone, pyraflufen ethyl, flumicrolacpentyl, flumioxazine, atrazine, indanophan, bensulfuron methyl, benzofenap, bromophenoxime, chlorbromulon, chlorimulon ethyl, chlornitrofen, chlorotoluron, chlortaldimethyl, clomeprop, dimuron, desmedifam, diclobenyl, diflufenican, dimeflon, dinitramine, diuron, etamethosulfuron methyl, triaziflame, phenoxapropyl ethyl, and flamp. Examples include Ropmethyl, Flazasulfuron, Flumezulam, Fluthiasetmethyl, Flupoxam, Flulidone, Flulutamon, Oxadiclomefone, Isoproturone, Isoxaben, Isoxapyrhop, Renasil, Linuron, Mefenacet, Metabenzthiazulon, Metobenzulon, Naproanilide, Nevron, Norflurazone, Oryzalin, Oxadiazone, Oxyfluorphene, Fenmedifam, Prodiamine, Propyzamide, Pyrazolinate, Pyrazosulfuron ethyl, Pyributicarb, Quinclorac, Quizaropop ethyl, Limusulfuron, Sideuron, Simazine, Terbutyrazine, Terbutrin, Thiazopyr, Tracoxidim, and Trietadine.

[0104] Examples of poorly water-soluble plant growth regulators include cyclanilide, flumetraline, 6-benzylaminopurine, forchlorfenuron, inabenfide, 2-(1-naphthyl)acetamide, paclobutrazol, N-phenylphthalamidic acid, tidiazuron, and uniconazole.

[0105] Furthermore, examples of poorly water-soluble substances used as food additives include glycyrrhizin, L-ascorbic acid stearate, benzoic acid, isoeugenol, ergocalciferol (vitamin D2), eugenol, butyl parahydroxybenzoate, isopropyl parahydroxybenzoate, β-carotene, citronellyl formate, cholecalciferol (vitamin D3), propyl gallate, folic acid, lecithin, cinnamyl acetate, phenethyl acetate, ethyl cinnamate, dibutylhydroxytoluene, allyl hexanoate, methyl β-methyl ketone, riboflavin butyrate, and dl-α-tocopherol.

[0106] Examples of poorly water-soluble plant-derived substances include xylan, lignin, chondroitin sulfate, and glucomannan.

[0107] Examples of poorly water-soluble polypeptides (proteins) include insulin, collagen, casein, albumin, elastin, and silk protein.

[0108] Examples of poorly water-soluble polysaccharides include chitin and chitosan.

[0109] (How to use) By using the poorly water-soluble substance dissolving agent of this embodiment, a poorly water-soluble substance can be dissolved in the dissolving agent, and then the resulting solution can be added to an aqueous solvent to improve the solubility of the poorly water-soluble substance dissolving agent in the aqueous solvent. Examples of aqueous solvents include, but are not limited to, water, physiological saline, and phosphate-buffered saline (PBS).

[0110] When dissolving poorly water-soluble substances in a solvent for poorly water-soluble substances, the liquid temperature of the solvent is preferably in the range of 0 to 150°C, more preferably 10°C to 100°C, and even more preferably 25°C to 100°C, from the viewpoint of making the poorly water-soluble substances easier to dissolve.

[0111] <Zwitterion> The zwitterions of this embodiment are the same as the zwitterions (1) to (3) in the above-mentioned <solvent for poorly water-soluble substances>. In particular, zwitterions represented by any of the above formulas C1imC6C, C1imC7C, C1imC9C, C1C1imC3C, C1C1imC5C, and C1morC3C are preferred. [Examples]

[0112] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0113] <Synthesis of zwitterions> [Synthesis Example 1: Zwitterion C1imC6C] 20 mmol of 1-methylimidazole was mixed with 250 mL of acetone, then mixed with 20 mmol of ethyl-7-bromoheptanoate and refluxed at 60°C for 16 hours. After washing with diethyl ether, the mixture was mixed with an anion exchange resin, filtered, and the solvent was removed under reduced pressure to obtain the zwitterion C1imC6C.

[0114] The structure of the obtained zwitterion C1imC6C was identified from the NMR spectrum measurement results shown in Figure 1.

[0115] [ka]

[0116] [Synthesis Example 2: Zwitterion C1imC7C] The zwitterion C1imC7C was synthesized in the same manner as described in Synthesis Example 1 above, except that ethyl-8-bromooctanoate was used instead of ethyl-7-bromoheptanoate.

[0117] The structure of the obtained zwitterion C1imC7C was identified from the NMR spectrum measurement results shown in Figure 2.

[0118] [ka]

[0119] [Synthesis Example 3: Zwitterion C1imC9C] The zwitterion C1imC9C was synthesized in the same manner as described in Synthesis Example 1 above, except that ethyl-10-bromodecanoate was used instead of ethyl-7-bromoheptanoate.

[0120] The structure of the obtained zwitterion C1imC9C was identified from the NMR spectrum measurement results shown in Figure 3.

[0121] [ka] [Synthesis Example 4: Zwitterion C1C1imC3C] The zwitterion C1C1imC3C was synthesized in the same manner as described in Synthesis Example 1 above, except that 1,2-dimethylimidazole was used instead of 1-methylimidazole and ethyl-4-bromobutyrate was used instead of ethyl-7-bromoheptanoate.

[0122] The structure of the obtained zwitterion C1C1imC3C was identified from the NMR spectrum measurement results shown in Figure 4.

[0123] [ka]

[0124] [Synthesis Example 5: Zwitterion C1C1imC5C] The zwitterion C1C1imC5C was synthesized in the same manner as described in Synthesis Example 4 above, except that ethyl-6-bromohexanoate was used instead of ethyl-4-bromobutyrate.

[0125] The structure of the obtained zwitterion C1C1imC5C was identified from the NMR spectrum measurement results shown in Figure 5.

[0126] [ka]

[0127] [Synthesis Example 6: Zwitterion C1morC3C] The zwitterion C1morC3C was synthesized in the same manner as described in Synthesis Example 4 above, except that 4-methylmorpholine was used instead of 1,2-dimethylimidazole.

[0128] The structure of the obtained zwitterion C1morC3C was identified from the NMR spectrum measurement results shown in Figure 6.

[0129] [ka]

[0130] <Test Example 1: Solubility Test of Poorly Water-Soluble Substances> Solubility tests of poorly water-soluble substances were conducted using the poorly water-soluble substance dissolving agent of this embodiment.

[0131] (Soluble agent for poorly water-soluble substances) Of the zwitterions synthesized in the above-mentioned <Synthesis of Zwitterions>, C1imC6C, C1imC7C, C1C1imC9C, C1C1imC3C, C1C1imC5C, and C1morC3C were used as examples. As shown in Tables 1 to 9 below, each zwitterion was mixed with water to obtain a zwitterion concentration of 25% by mass or 50% by mass to prepare a solvent for poorly water-soluble substances. In addition, the zwitterion OE2imC3C and DMSO were used as reference examples. The zwitterion OE2imC3C was mixed with water to a zwitterion concentration of 25% by mass.

[0132] [ka]

[0133] (poorly water-soluble substances) As poorly water-soluble substances, we used estriol (CAS number: 50-27-1), testosterone (CAS number: 58-22-0), paclitaxel (CAS number: 33069-62-4), erythromycin (CAS number: 114-07-8), progesterone (CAS number: 57-83-0), β-estradiol (CAS number: 50-28-2), stanolone (CAS number: 521-18-6), zoledronic acid monohydrate (CAS number: 165800-06-6), and insulin (CAS number: 11061-68-0).

[0134] The above-mentioned poorly water-soluble substances were added to the above-mentioned solvent for poorly water-soluble substances (solution temperature: 30°C or 80°C) at the concentrations shown in Tables 1 to 9 below. After stirring overnight, visual observation was performed, and the solubility of the poorly water-soluble substances was evaluated according to the following evaluation criteria (A to D). A rating of A or B indicated better solubility of the poorly water-soluble substances. A: Poorly water-soluble substances are dissolved, and no insoluble substances are detected. B: Although the poorly water-soluble substances are almost completely dissolved, some insoluble matter is observed (possibly dust, solvent-derived components, or undissolved residue of the poorly water-soluble substances). C: The poorly water-soluble substance is partially dissolved, or the amount of insoluble matter is significantly reduced compared to immediately after addition. D: Poorly water-soluble substances are not dissolved, or the amount of insoluble matter has not decreased compared to immediately after addition.

[0135] The results of the solubility test are shown in Tables 1-9 below. In Tables 1-9, %(w / v) represents mass-volume percentage concentration, and wt% represents mass percentage concentration.

[0136] [Table 1]

[0137] [Table 2]

[0138] [Table 3]

[0139] [Table 4]

[0140] [Table 5]

[0141] [Table 6]

[0142] [Table 7]

[0143] [Table 8]

[0144] [Table 9]

[0145] As shown in Tables 1-9, it has become clear that the poorly water-soluble substance dissolving agent of this embodiment can dissolve various types of poorly water-soluble substances.

[0146] <Test Example 2: Cytotoxicity Test> The cytotoxicity of the zwitterions in the poorly water-soluble substance solvent of this embodiment was evaluated using the lactose-fermenting yeast Kluyveromyces marxianus.

[0147] (Soluble agent for poorly water-soluble substances) Of the zwitterions synthesized in the above <Synthesis of Zwitterions> section, C1C1imC3C and C1C1imC5C were used. Furthermore, as reference examples, the zwitterion OE2imC3C and 1-ethyl-3-methylimidazolium acetate (IL) were used. IL is generally known as an ionic liquid with high cytotoxicity.

[0148] Each zwitterion or IL was added to YPD medium to achieve a zwitterion concentration or IL concentration of 0.25 mol / L. Then, Kluiveromyces marcyanas was added to OD. 600 The bacteria were inoculated into YPD medium so that the OD ratio was 0.2. Then, they were incubated at 50°C for 8 hours, and the OD ratio of the culture medium was measured. 600 The OD was measured over time. 600 This was used as an indicator of the yeast concentration. The results are shown in Figures 7A and 7B. In Figures 7A and 7B, "YPD" refers to the OD of the culture medium when the yeast was inoculated into YPD medium without the addition of zwitterions. 600 The results are shown below.

[0149] As shown in Figures 7A and 7B, the zwitterion in the poorly water-soluble substance solvent of this embodiment was found to have a level of toxicity to cells that is comparable to that of DMSO. [Industrial applicability]

[0150] According to the present invention, it is possible to provide a solvent for poorly water-soluble substances that can dissolve various poorly water-soluble substances, and a zwitterion contained in the solvent for poorly water-soluble substances.

Claims

1. A solvent for poorly water-soluble substances, comprising at least one selected from the group consisting of zwitterions represented by any of the following general formulas (1), (2), and (3). 【Chemistry 1】 [wherein, A １０ is -COO － , -SO ３ － , -OP=O(H)O － , -OP=O(CH ３ )O － and -OP=O(OR １３ )O － is an anion selected from the group consisting of. R １１ is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. R １２ is an alkylene group having 6 to 9 carbon atoms. R １３ is an alkyl group.] 【Chemistry 2】 [In the formula, A ２０ -COO － , -SO ３ － , -OP=O(H)O － -OP=O(CH ３ ) O － and -OP = O(OR ２３ ) O － It is an anion selected from the group consisting of R. ２１ R is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. ２２ This is an alkylene group having 3 to 9 carbon atoms. ２３ R is an alkyl group. ２４ This is an alkyl group having 1 to 6 carbon atoms. 【Transformation 3】 [In the formula, A ３０ -COO － , -SO ３ － , -OP=O(H)O － -OP=O(CH ３ ) O － and -OP = O(OR ３３ ) O － It is an anion selected from the group consisting of R. ３１ R is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. ３２ This is an alkylene group having 3 to 9 carbon atoms. ３３ It is an alkyl group.

2. The dissolving agent for poorly water-soluble substances according to claim 1, wherein the zwitterion represented by the general formula (1) is a zwitterion represented by the following general formula (1'). 【Chemistry 4】 [In the formula, R １１ ' is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. １２ ' is an alkylene group having 6 to 9 carbon atoms.

3. The dissolving agent for poorly water-soluble substances according to claim 1, wherein the zwitterion represented by the general formula (2) is the zwitterion represented by the following general formula (2'). 【Transformation 5】 [In the formula, R ２１ ' is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. ２２ ' is an alkylene group having 3 to 9 carbon atoms. ２４ ' is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms.

4. The dissolving agent for poorly water-soluble substances according to claim 1, wherein the zwitterion represented by the general formula (3) is the zwitterion represented by the following general formula (3'). 【Transformation 6】 [In the formula, R ３１ ' is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. ３２ ' is an alkylene group having 3 to 9 carbon atoms.

5. The zwitterion is represented by the general formula (1) above, The poorly water-soluble substance dissolving agent according to claim 1, wherein the poorly water-soluble substance is a steroid compound.

6. The poorly water-soluble substance dissolving agent according to any one of claims 1 to 4, wherein the poorly water-soluble substance is a polypeptide.

7. The dissolving agent for poorly water-soluble substances according to any one of claims 1 to 4, wherein the poorly water-soluble substance is zoledronic acid monohydrate.

8. The poorly water-soluble substance dissolving agent according to any one of claims 1 to 4, wherein the molecular weight of the poorly water-soluble substance is 200 or more and 10,000 or less.

9. A zwitterion represented by any of the following general formulas (1), (2), or (3). 【Transformation 7】 [In the formula, A １０ -COO － , -SO ３ － , -OP=O(H)O － -OP=O(CH ３ ) O － and -OP = O(OR １３ ) O － It is an anion selected from the group consisting of R. １１ R is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. １２ This is an alkylene group with 6 to 9 carbon atoms. １３ It is an alkyl group. 【Transformation 8】 [In the formula, A ２０ -COO － , -SO ３ － , -OP=O(H)O － -OP=O(CH ３ ) O － and -OP = O(OR ２３ ) O － It is an anion selected from the group consisting of R. ２１ R is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. ２２ This is an alkylene group having 3 to 9 carbon atoms. ２３ R is an alkyl group. ２４ This is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. 【Chemistry 9】 [In the formula, A ３０ -COO － , -SO ３ － , -OP=O(H)O － -OP=O(CH ３ ) O － and -OP = O(OR ３３ ) O － It is an anion selected from the group consisting of R. ３１ R is an alkyl group having 1 to 6 carbon atoms, and may have at least one selected from the group consisting of -O-, -NH-, and -S- between the carbon atoms forming the alkyl group having 1 to 6 carbon atoms. ３２ This is an alkylene group having 3 to 9 carbon atoms. ３３ It is an alkyl group.

10. The zwitterion represented by any one of the general formula (1), the general formula (2), and the general formula (3) is the following formula C １ imC ６ C, the following formula C １ imC ７ C, the following formula C １ imC ９ C, the following formula C １ C １ imC ３ C, the following formula C １ C １ imC ５ C, and the following formula C １ morC ３ C, and the zwitterion according to claim 9, which is a zwitterion represented by any one of them. 【Chemistry 10】

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