Title of Invention: Pharmaceutical Compositions Containing Temperature-Responsive Ionic Liquids
Technical field
[0001]
　The present invention relates to a pharmaceutical composition comprising a temperature responsive ionic liquid.
Background technology
[0002]
　Oral administration, intravenous administration, transdermal administration and the like are known as administration routes of pharmaceutical products, and have been appropriately developed according to the physical properties and characteristics of the active ingredient.
[0003]
　In particular, transdermal administration facilitates the administration of patients who have difficulty swallowing, such as elderly patients and patients with dementia, avoids side effects caused by the increase in blood concentration of drugs by oral or injection, and also by diet. In recent years, technological development for improving drug permeability has progressed because it has the advantage of improving patient's drug compliance, such as being less susceptible to the effects and making it easier for patients who are busy and tend to have disordered eating habits to obtain stable drug effects. I'm out. However, in general, water-soluble drugs and drugs with a large molecular weight have low skin permeability because they are blocked by the stratum corneum of the skin, which has a high barrier function, and their transdermal absorbability is extremely low. Therefore, they are orally or intravenously administered. In comparison with this, there is a problem that the administered drug is not sufficiently utilized in the living body. Therefore, there is a technical problem that the drugs applicable to transdermal administration are limited.
[0004]
　So far, as a technique for improving the skin permeability of a drug by transdermal administration, various methods such as addition of a transdermal absorption promoter as a pharmaceutical prescription and iontophoresis, microneedle, etc. as an administration technique have been performed. Has been developed. However, the optimal transdermal absorption promoter differs depending on the drug, so that it is not versatile, and some drugs are incompatible with the transdermal absorption promoter and may require another compatibilizer. On the other hand, the above-mentioned administration technique has problems that it causes pain at the time of administration and, in principle, there is a risk of infectious disease by giving a certain amount of damage to the skin.
[0005]
　In recent years, the percutaneous absorption technique using an ionic liquid has been attracting attention as a technique for improving the compatibility with a drug and the drug solubility, which are the problems of conventional transdermal absorption promoters, and for expecting a transdermal absorption promoting effect. .. Since ionic liquids have innumerable combinations of cations and anions, they have the advantage of having a high degree of freedom in designing their physical properties.
[0006]
　For example, Patent Document 1 discloses a technique for improving the transdermal absorbability of a basic drug such as lidocaine or an acidic drug such as etodolac by using a fatty acid-based ionic liquid.
[0007]
　Patent Document 2 discloses a technique for improving the solubility of taxol by using 1-butyl-3-methyl-1H-imidazolium bromide, which is an imidazolium-based ionic liquid, for the purpose of improving the bioavailability of a drug. ..
[0008]
　On the other hand, in Patent Document 3, for the purpose of improving the skin permeability of a water-soluble drug, a basic functional group-containing compound having a molecular weight of 50 to 120 and a melting point of 50 to 350 ° C. such as choline and guanidine, and LogP Disclosed is a transdermal absorption enhancer containing an isomorphic salt with an acidic functional group-containing compound having a value of -4 to 7.3.
prior art literature
Licensed Literature
[0009]
Patent Document 1: International Publication No. 2009/06467
Patent Document 2: Japanese Patent Application Laid-Open No. 2007-022942
Patent Document 3: International Publication No. 2016/068336
Outline of the invention
Problems to be solved by the invention
[0010]
　However, the drugs to which the technique of Patent Document 1 can be applied are limited to drugs showing acidity or drugs showing basicity, and are not versatile.
[0011]
　Patent Document 2 only describes the effect of 1-butyl-3-methyl-1H-imidazolium bromide on improving the solubility of taxol, which is a sparingly soluble medicinal ingredient, and relates to the skin permeability of the drug. There is no description or suggestion, and there is no disclosure or suggestion of a temperature-responsive ionic liquid. Furthermore, since the ionic liquid used is water-soluble, the effect of disturbing the barrier of the stratum corneum, which is lipophilic, is weak, and it is presumed that the effect is insufficient.
[0012]
　In Patent Document 3, specific data are disclosed in Examples as basic functional group-containing compounds only for choline, histamine, guanidine, and imidazole, and the transdermal absorption promoter and the ionic liquid are used. There is no disclosure of the relationship, much less a temperature-responsive ionic liquid.
[0013]
　Therefore, an object of the present invention is to provide a pharmaceutical composition having improved permeability of a drug on the skin, mucous membranes and the like.
Means to solve problems
[0014]
　As a result of diligent studies to solve the above problems, it was found that the permeability of a drug in the skin, mucous membranes and the like can be improved by using a temperature-responsive ionic liquid, and the present invention has been completed.
[0015]
　That is, the present invention includes the following [1] to [9].
[1] A pharmaceutical composition comprising a drug and a temperature-responsive ionic liquid.
[2] The pharmaceutical composition according to [1], wherein the anion of the temperature-responsive ionic liquid contains at least one selected from the group consisting of aromatic carboxylate ions and aromatic sulfonate ions.
[3] The pharmaceutical composition according to [1] or [2], wherein the anion of the temperature-responsive ionic liquid is an anion represented by the following formula (I) and / or general formula (II).
[Chemical formula 1]

[In formula (II), R 1 represents a hydrogen atom or an acyl group, and R 2 represents an alkyl group, a halogen atom or a sulfo group which may be substituted with a halogen atom. [4 ]
The pharmaceutical composition according to any one of [1] to [3], wherein the temperature-responsive ionic liquid has a lower limit critical solution temperature.
[5] The pharmaceutical composition according to [4], wherein the lower limit critical solution temperature is 40 ° C. or lower.
[6] The pharmaceutical composition according to any one of [1] to [5], wherein the cation of the temperature-responsive ionic liquid is a tetraalkylammonium ion or a tetraalkylphosphonium ion.
[7] The pharmaceutical composition according to any one of [1] to [6], which is an external preparation.
[8] A temperature-responsive ionic liquid having an anion represented by the following general formula (II).
[Chemical 2]

[In formula (II), R 1 represents a hydrogen atom or an acyl group, and R 2 represents an alkyl group, a halogen atom or a sulfo group which may be substituted with a halogen atom. ]
[9] The temperature-responsive ionic liquid according to [8], which has a lower limit critical solution temperature.
The invention's effect
[0016]
　According to the present invention, since it is possible to provide a pharmaceutical composition having excellent drug permeability, it can be applied to various dosage forms.
Embodiment for carrying out the invention
[0017]
　The present invention will be described in detail below.
[0018]
　The pharmaceutical composition of the present invention is characterized by containing a drug as an active ingredient and a temperature-responsive ionic liquid.
[0019]
　The temperature-responsive ionic liquid is composed of a cation and an anion, and is not particularly limited as long as it exhibits temperature responsiveness. The melting point of the temperature-responsive ionic liquid is not particularly limited.
[0020]
　Here, the temperature responsiveness refers to a property in which the shape and / or the property changes in response to a temperature (heat) change, for example, a volume change such as expansion and contraction, and a lower critical solution temperature (Lower Critical Solution Temperature). : LCST) and the upper critical solution temperature (Upper Critical Solution Temperature: UCST) and other hydrophobic changes, and these temperature-responsive ionic liquids are called temperature-responsive ionic liquids.
[0021]
　In the above pharmaceutical composition, the temperature-responsive ionic liquid preferably has a lower limit critical solution temperature (LCST). The lower limit critical solution temperature is a temperature-responsive ionic liquid in which the hydrophobicity of the temperature-responsive ionic liquid rapidly increases at a certain temperature when the temperature is raised from a low temperature to a high temperature. It means the temperature of time. At this time, when the temperature-responsive ionic liquid contains water, it does not matter whether the temperature-responsive ionic liquid is compatible with water on the lower temperature side than the lower limit critical solution temperature. This is an ionic liquid that is phase-separated from water on the lower temperature side than the lower limit critical solution temperature because the temperature-responsive ionic liquid has the property of containing a certain amount of water even on the lower temperature side than the lower limit critical solution temperature. However, this is because the hydrophobicity of the temperature-responsive ionic liquid rapidly increases when heated to the lower limit critical solution temperature or higher.
[0022]
　Whether or not it is a temperature-responsive ionic liquid having a lower limit critical solution temperature (hereinafter, also referred to as LCST type temperature-responsive ionic liquid) is determined when the absorbance at the wavelength in the visible light region is measured while gradually increasing the temperature. It can be confirmed by observing the phenomenon that white turbidity occurs due to an increase in hydrophobicity at a certain temperature and the absorbance sharply increases. The specific procedure is as follows. First, a mixed solution of ionic liquid and water is prepared, and the layer state at room temperature is observed. Next, the mixed solution is placed in a refrigerator at 4 ° C., stirred well, and then allowed to stand for 1 hour, and then the state is observed. Here, when the layer state of the mixed liquid of the ionic liquid and water at room temperature is the same as that of the layer state at 4 ° C., the temperature is raised at 0.5 ° C./min in the range of 20 ° C. to 95 ° C. By measuring the change in absorbance at 450 nm, it can be confirmed whether the measured ionic liquid is an LCST type temperature-responsive ionic liquid. Further, the lower limit critical solution temperature can be obtained by analyzing the obtained data of the change in absorbance by the differential method of the Tm (nucleic acid melting temperature) analysis program. On the other hand, if the layered state of the ionic liquid and water mixture at room temperature is different from the layered state at 4 ° C, the temperature is raised at 0.5 ° C / min in the range of 5 ° C to 40 ° C. By measuring the change in absorbance at 450 nm, it can be confirmed whether the measured ionic liquid is an LCST type temperature-responsive ionic liquid. The reason why a temperature-responsive ionic liquid having a lower limit critical solution temperature is preferable is as follows, but the present invention is not particularly limited to the following description. A temperature-responsive ionic liquid having a lower critical solution temperature can efficiently dissolve both water-soluble drugs and fat-soluble drugs at temperatures lower than the lower critical solution temperature due to the amphoteric nature of the temperature-responsive ionic liquid. can. On the other hand, above the lower limit critical solution temperature, the hydrophobicity of the temperature-responsive ionic liquid becomes stronger, so that the affinity between the highly lipophilic stratum corneum or mucous membrane and the temperature-responsive ionic liquid increases, and the temperature responsiveness increases. Ionic liquids act efficiently on the stratum corneum and mucous membranes. In addition, local changes in hydrophobicity cause drug concentration gradients in the pharmaceutical composition and between the pharmaceutical composition and the stratum corneum. Occurs. As a result of these, the drug can easily move in the base of the pharmaceutical composition, the drug can easily slip through the barrier of the stratum corneum and the mucous membrane, and the permeability of the drug can be improved.
[0023]
　In one embodiment, the normal temperature of humans is around 37 ° C., and it can be expected that the ionic liquid exhibits temperature responsiveness in an environment where the drug is administered, so that the permeability of the drug can be efficiently increased. The lower limit critical solution temperature of the temperature-responsive ionic liquid may be 40 ° C. or lower, for example, 35 ° C. or lower, 30 ° C. or lower, 25 ° C. or lower, or 20 ° C. or lower. The lower limit is not particularly limited, and is, for example, 5 ° C. or higher, 10 ° C. or higher, and 15 ° C. or higher. The upper limit and the lower limit can be combined arbitrarily. For example, the lower limit critical solution temperature of a temperature-responsive ionic liquid is 5 ° C or higher and 40 ° C or lower, 5 ° C or higher and 30 ° C or lower, 5 ° C or higher and 25 ° C or lower, 5 ° C or higher and 20 ° C or lower, 10 ° C or higher and 40 ° C or lower, 10 ° C. or higher and 30 ° C. or lower, 10 ° C. or higher and 25 ° C. or lower, 15 ° C. or higher and 40 ° C. or lower, and 15 ° C. or higher and 30 ° C. or lower.
[0024]
　Whether or not it is a temperature-responsive ionic liquid having an upper limit critical solution temperature (hereinafter, also referred to as UCST type temperature-responsive ionic liquid) is determined when the absorbance of the wavelength in the visible light region is measured while gradually increasing the temperature. It can be confirmed by observing the phenomenon that the absorbance sharply decreases as it becomes transparent due to the increase in hydrophilicity at a certain temperature. Specifically, it can be confirmed whether or not it is a UCST type temperature responsive ionic liquid by measuring the change in absorbance by the same method as the above-mentioned method for confirming the LCST type temperature responsive ionic liquid. Further, the upper limit critical solution temperature can be obtained by analyzing the obtained data of the change in absorbance by the differential method of the Tm (nucleic acid melting temperature) analysis program.
[0025]
　As the temperature-responsive ionic liquid, any combination of cations and anions can be selected as long as it is a combination exhibiting temperature responsiveness. For example, both can be combined in equimolar amounts.
[0026]
　Examples of the cations constituting the temperature-responsive ionic liquid include those having a nitrogen atom as an ionic center, those having a phosphorus atom as an ionic center, those having a sulfur atom as an ionic center, and those having a nitrogen atom and a sulfur atom as ionic centers. Examples include those having and, but the present invention is not limited to these.
[0027]
　Examples of the cation centered on the nitrogen atom include imidazolium ion, ammonium ion, pyridinium ion, quinolinium ion, pyrrolidinium ion, piperidinium ion, piperazinium ion, morpholinium ion, pyridadinium ion, and the like. Pyrimidinium ion, pyrazinium ion, pyrazolium ion, thiazolium ion, oxazolium ion, triazolium ion, guanidium ion, 4-aza-1-azonia-bicyclo- [2,2,2] octanium ion And so on. Further, these cations may have a substituent represented by an alkyl group at any position, and the number of substituents may be plural.
[0028]
　As the cation centered on the nitrogen atom, imidazolium ion, ammonium ion, pyridinium ion, pyrrolidinium ion or piperidinium ion is preferable.
[0029]
　Specific examples of the imidazolium ion include 1-methylimidazolium ion, 1-ethylimidazolium ion, 1-propyl imidazolium ion, 1-butyl imidazolium ion, 1-butyl-3-methylimidazolium ion, 1-. Ethyl-3-methylimidazolium ion, 1-allyl-3-methylimidazolium ion, 1,3-diallylimidazolium ion, 1-benzyl-3-methylimidazolium ion, 1-methyl-3-octylimidazolium ion , 1-ethyl-2,3-dimethylimidazolium ion, 1-butyl-2,3-dimethylimidazolium ion, 1,2-dimethyl-3-propylimidazolium ion, 1-cyanopropyl-3-methylimidazolium ion Ions, 1,3-biscyanomethylimidazolium ion, 1,3-bis (3-cyanopropyl) imidazolium ion, 1- (2-hydroxyethyl) -3-methylimidazolium ion, 1-methoxyethyl-3 -Methyl imidazolium ion, 1- [2- (2-methoxyethoxy) -ethyl] -3-methyl imidazolium ion, 1,3-diethoxy imidazolium ion, 1,3-dimethoxy imidazolium ion, 1,3 -Dihydroxyimidazolium ion, 1-methyl-3- (3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctylimidazolium ion, 1-methyl -3-[(Triethoxysilyl) propyl] imidazolium ion and the like can be mentioned.
[0030]
　Specific examples of the ammonium ion include tetraalkylammonium ions such as tetramethylammonium ion, tetraethylammonium ion, tetrapropylammonium ion, tetrabutylammonium ion, tetrahexylammonium ion, and trihexyltetradecylammonium ion, (2-hydroxy). Ethyl) trimethylammonium ion, N, N-diethyl-N- (2-methoxyethyl) -N-methylammonium ion, tris (2-hydroxyethyl) methylammonium ion, trimethyl (1H, 1H, 2H, 2H-heptadeca) Fluorodecyl) ammonium ion, trimethyl- (4-vinylbenzyl) ammonium ion, tributyl- (4-vinylbenzyl) ammonium ion, 2- (methacryloyloxy) ethyltrimethylammonium ion, benzyldimethyl (octyl) ammonium ion, N, N -Dimethyl-N- (2-phenoxyethyl) -1-dodecylammonium ion and the like can be mentioned.
[0031]
　Specific examples of the pyridinium ion include 1-ethylpyridinium ion, 1-butylpyridinium ion, 1- (3-hydroxypropyl) pyridinium ion, 1-ethyl-3-methylpyridinium ion, 1-butyl-3-methylpyridinium ion. , 1-butyl-4-methylpyridinium ion, 1- (3-cyanopropyl) pyridinium ion and the like.
[0032]
　Specific examples of the pyrrolidinium ion include 1-methyl-1-propylpyrrolidinium ion, 1-butyl-1-methylpyrrolidinium ion, 1- (2-hydroxyethyl) -1-methylpyrrolidinium ion, 1-ethyl. -1-Methylpyrrolidinium ion and the like can be mentioned.
[0033]
　Specific examples of the piperidinium ion include 1-methyl-1-propylpiperidinium ion, 1-butyl-1-methylpiperidinium ion, 1- (2-hydroxyethyl) -1-methylpiperidinium ion, and 1-ethyl. -1-Methylpiperidinium ion and the like can be mentioned.
[0034]
　A cation centered on a phosphorus atom is generally called a phosphonium ion, and specifically, tetrapropylphosphonium ion, tetrabutylphosphonium ion, tetrahexylphosphonium ion, trihexyltetradecylphosphonium ion, and triphenylmethylphosphonium. Tetraalkylphosphonium ions such as ions, triisobutylmethylphosphonium ions, triethylmethylphosphonium ions, tributylmethylphosphonium ions, tributylhexadecylphosphonium ions, (2-cyanoethyl) triethylphosphonium ions, (3-chloropropyl) trioctylphosphonium ions, Examples thereof include tributyl (4-vinylbenzyl) phosphonium ion, 3- (triphenylphosphonio) propan-1-sulfonic acid ion and the like.
[0035]
　A cation centered on a sulfur atom is generally called a sulfonium ion, and specific examples thereof include triethylsulfonium ion, tributylsulfonium ion, 1-ethyltetrahydrothiophenium ion, 1-butyltetrahydrothiophenium ion and the like. Be done.
[0036]
　From the viewpoint of having an appropriate fat solubility and achieving both temperature responsiveness and drug solubility, preferred embodiments of the cation constituting the temperature responsive ionic liquid include ammonium ion and phosphonium ion, and more preferably. Examples thereof include tetraalkylammonium ion and tetraalkylphosphonium ion. In one embodiment, tetraalkylammonium ions (eg, tetrabutylammonium ion, tetrapentylammonium ion, tetrahexylammonium ion, tetraheptylammonium ion, tetra) having a total carbon number of 13 or more and 35 or less of the four alkyl groups. Octylammonium ion, trioctylmethylammonium ion,) or tetraalkylphosphonium ion (eg, tetrabutylphosphonium ion, tetrapentylphosphonium ion, tetraoctylphosphonium ion, tributylhexylphosphonium ion, tributylheptylphosphonium ion, tributyloctylphosphonium ion, tributyl Dodecylphosphonium ion, tributyltridecylphosphonium ion, tributylpentadecylphosphonium ion, tributylhexadecylphosphonium ion, trihexyltetradecylphosphonium ion) can be mentioned. In a tetraalkylammonium ion or a tetraalkylphosphonium ion, the four alkyl groups may be the same or different. In the tetraalkylammonium ion or the tetraalkylphosphonium ion, the value of CRogP indicating the hydrophobicity of the cation is preferably larger than −1.0.
[0037]
　Examples of the anion constituting the temperature-responsive ion liquid include halide ion, imide-based ion such as bis (trifluoromethylsulfonyl) imide, carboxylate ion, sulfonic acid ion, phosphate ion, phosphonate ion, and phosphinic acid. Examples thereof include, but are not limited to, ions and amino acid ions. Further, these anions may have a substituent typified by an alkyl group or an aryl group at any position, and the number of substituents may be plural.
[0038]
　The anion constituting the temperature-responsive ionic liquid preferably contains at least one selected from the group consisting of aromatic carboxylate ions and aromatic sulfonate ions.
[0039]
　Examples of aromatic carboxylate ions include substituted or unsubstituted benzoic acid ions, for example, benzoic acid substituted with optionally substituted alkyl groups such as benzoic acid ion, toluic acid ion or trifluoromethylbenzoic acid ion. Halogenated benzoic acid ions such as acid ion, fluorobenzoic acid ion, chlorobenzoic acid ion, bromobenzoic acid ion or iodine benzoic acid ion, acylated benzoic acid ion such as formylbenzoic acid ion or acetylbenzoic acid ion, hydroxybenzoic acid Alkylated benzoic acid ion or sulfobenzoic acid ion such as ion, aminobenzoic acid ion, methoxybenzoic acid ion, or substituted or unsubstituted polycyclic aromatic carboxylic acid ion, for example, naphthalene carboxylic acid ion or anthracene carboxylic acid ion. And so on. As long as the combination is a temperature-responsive ionic liquid, the position of the substituent on the aromatic carboxylate ion may be any position, and the number and types of the substituents are not particularly limited. When the substituent contains a hydroxy group, an amino group, or the like, the hydroxy group, the amino group, or the like may be further substituted with an acyl group or the like.
[0040]
　Examples of aromatic sulfonate ions include substituted or unsubstituted benzene sulfonic acid ions, for example, optionally substituted alkyl such as benzene sulfonic acid ion, toluene sulfonic acid ion, xylene sulfonic acid ion or trichloromethyl sulfonic acid ion. Halogenized benzene sulfonic acid ion such as benzene sulfonic acid ion, fluorobenzene sulfonic acid ion, chlorobenzene sulfonic acid ion, bromobenzene sulfonic acid ion or iodobenzene sulfonic acid ion substituted with a group, hydroxybenzene sulfonic acid ion, aminobenzene sulfonate. Examples thereof include alkylated benzenesulfonic acid ion such as acid ion or methoxybenzenesulfonic acid ion. As long as the combination is a temperature-responsive ionic liquid, the position of the substituent on the aromatic sulfonate ion may be any position, and the number and types of the substituents are not particularly limited. When the substituent includes a hydroxy group, an amino group, or the like, the hydroxy group, the amino group, or the like may be further substituted with an acyl group or the like.
[0041]
　Preferred examples of anions constituting the temperature-responsive ionic liquid include salicylic acid or salicylic acid derivative-derived anions. Here, examples of the salicylic acid derivative include a compound having a substituent on the benzene ring of salicylic acid and a compound having a substituent on the phenolic hydroxyl group. In one embodiment, the anion constituting the temperature-responsive ionic liquid is, for example, an anion represented by the following formula (I) and / or general formula (II).
[Chemical 3]

[0042]
　In formula (II), R 1 is a hydrogen atom or an acyl group. Here, examples of the acyl group include an acetyl group.
[0043]
　In formula (II), R 2 is an alkyl group, a halogen atom or a sulfo group which may be substituted with a halogen atom. Here, examples of the alkyl group which may be substituted with a halogen atom include a methyl group, an ethyl group, a propyl group, a butyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group and a 2-fluoroethyl group. However, it is not limited to these. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The position of R 2 may be any position.
[0044]
　本発明の医薬組成物に用いられる温度応答性イオン液体としては、例えば、アンモニウムイオン（例えば、テトラアルキルアンモニウムイオン）と芳香族カルボキシレートイオン（例えば、サリチル酸又はサリチル酸誘導体由来のアニオン）とを含む温度応答性イオン液体、アンモニウムイオン（例えば、テトラアルキルアンモニウムイオン）と芳香族スルホネートイオンとを含む温度応答性イオン液体、ホスホニウムイオン（例えば、テトラアルキルホスホニウムイオン）と芳香族カルボキシレートイオン（例えば、サリチル酸又はサリチル酸誘導体由来のアニオン）とを含む温度応答性イオン液体、ホスホニウムイオン（例えば、テトラアルキルホスホニウムイオン）と芳香族スルホネートイオンとを含む温度応答性イオン液体が挙げられる。より具体的には、温度応答性イオン液体としては、テトラブチルアンモニウム＝サリチレート、テトラブチルアンモニウム＝４－（トリフルオロメチル）サリチレート、テトラブチルホスホニウム＝サリチレート、テトラブチルホスホニウム＝４－（トリフルオロメチル）サリチレート、テトラブチルホスホニウム＝アセチルサリチレート、テトラブチルホスホニウム＝５－ブロモサリチレート、テトラブチルホスホニウム＝４－クロロサリチレート、テトラブチルホスホニウム＝５－クロロサリチレート、テトラブチルホスホニウム＝５－ヨードサリチレート、テトラブチルホスホニウム＝３－メチルサリチレート、テトラブチルホスホニウム＝４－メチルサリチレート、テトラブチルホスホニウム＝３－カルボキシ－４－ヒドロキシベンゼンスルホネート、テトラブチルホスホニウム＝ｐ－トルエンスルホネート、テトラブチルホスホニウム＝ｍ－キシレン－４－スルホネート、テトラブチルホスホニウム＝４－クロロベンゼンスルホネート、テトラブチルホスホニウム＝４－ヒドロキシベンゼンスルホネート、テトラブチルホスホニウム＝４－アミノトルエン－３－スルホネート等が挙げられる。
[0045]
　Further, the temperature-responsive ionic liquid used in the pharmaceutical composition of the present invention includes not only an ionic liquid that exhibits temperature responsiveness when used alone, but also an ionic liquid that exhibits temperature responsiveness when two or more types are used in combination. Also included are combinations and temperature-responsive ionic liquids containing two or more cations and / or anions. At that time, if the final ionic liquid exhibits temperature responsiveness, an ionic liquid that does not exhibit temperature responsiveness by itself and a temperature responsive ionic liquid may be combined.
[0046]
　For example, tetrabutylphosphonium = 4-aminosalicylate, which is an ionic liquid, does not show temperature responsiveness by itself, but by mixing an equal molar amount with tetrabutylphosphonium = salicylate, the mixed ionic liquid becomes temperature responsive. Will be shown. Further, the lower limit critical solution temperature can be controlled to an arbitrary value by appropriately changing the mixing ratio of both.
[0047]
　Further, in a method of mixing two or more kinds of temperature-responsive ionic liquids at an arbitrary ratio, or when synthesizing a temperature-responsive ionic liquid, one kind of cation and two or more kinds of anions, two or more kinds of cations and one. The lower limit critical solution temperature can also be controlled to an arbitrary value by a method using two or more kinds of cations and two or more kinds of anions. For example, by mixing the two in an arbitrary ratio so that the total of salicylic acid: 4- (trifluoromethyl) salicylic acid is 1 mol with respect to 1 mol of tetrabutylphosphonium hydroxide, the temperature containing two kinds of anions is contained. Responsive ionic liquids can be obtained.
[0048]
　The temperature-responsive ionic liquid can be purchased as a commercial product or synthesized according to a general ionic liquid synthesis method. For example, to give a production example in which the temperature-responsive ionic liquid is an ammonium salt, the ammonium salt obtained by reacting an amine with an alkyl halide compound or the like is subjected to anion exchange using a metal salt for purification. There are methods such as a method of obtaining the desired ammonium salt by performing treatment (anion exchange method) and a method of obtaining the desired ammonium salt by directly reacting an amine with an acid (neutralization method). It is not limited to these. Even when the temperature-responsive ionic liquid is a phosphonium salt, it can be synthesized by using either the above-mentioned anion exchange method or the neutralization method. In the case of the neutralization method, the desired phosphonium salt can be obtained by directly reacting the phosphonium hydroxide with the acid to neutralize it.
[0049]
　The drug used in the pharmaceutical composition of the present invention is not particularly limited, and can be appropriately selected and used from known drugs (active ingredients).
[0050]
　Urinary dysfunction agents such as nin, antiepileptic agents such as nitrazepam and meprobamate, Parkinson's disease therapeutic agents such as rotigotin, lopinilol, chlorzoxazone and repodopa, antipsychotic agents such as bronanserin, dementia therapeutic agents such as donepezil and rivastigmin, and nicotine. Examples thereof include, but are not limited to, quitting aids such as vitamins and prostaglandins. Further, these drugs may be pharmacologically acceptable salts or solvates thereof. Here, examples of the pharmacologically acceptable salt include a salt with an inorganic acid and a salt with an organic acid. Examples of the salt with the inorganic acid include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide or phosphate, and examples of the salt with the organic acid include oxalate. , Malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, ascorbate , Glutarate, Mandelate, Phtrate, Methansulfonate, Ethansulfonate, benzenesulfonate, p-toluenesulfonate, Kamfersulfonate, Asparagate, Glutamate or silicate or silicic acid Salt is mentioned. Examples of the solvate include hydrates.
[0051]
　The molecular weight of the drug is not particularly limited, but is, for example, 100 to 1000, 150 to 600, 150 to 500, 150 to 400, 150 to 350.
[0052]
　The pharmaceutical composition of the present invention can improve the solubility of a drug by containing a temperature-responsive ionic liquid, and can improve the permeability of the drug not only to the epidermis but also to the mucous membrane, and thus can be administered orally. And commonly known routes of administration such as nasal administration, intravenous administration, transpulmonary administration or parenteral administration such as transdermal administration can be used.
[0053]
　Dosage forms for oral administration of the pharmaceutical composition of the present invention include, for example, tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules and microcapsules). , Syrups, emulsions or suspensions.
[0054]
　Preparation of an orally-administered preparation can be carried out according to a known production method generally used in the pharmaceutical field, and excipients, binders, lubricants, disintegrants, etc. commonly used in the pharmaceutical field. It can be produced by appropriately containing a pharmacologically acceptable additive such as a sweetener, a surfactant, a suspending agent and / or an emulsifier.
[0055]
　Dosage forms for parenteral administration of the pharmaceutical composition of the present invention include, for example, nasal preparations, eye drops, injections, injections, infusions, external preparations or suppositories. Since the pharmaceutical composition of the present invention has an effect of promoting permeation into the keratin, an external preparation which is a non-invasive administration method is preferable.
[0056]
　As the external preparation, any conventionally used dosage form such as ointment, cream, gel, gel cream, lotion, spray, poultice, tape, reservoir type patch and the like can be used.
[0057]
　The preparation of the above-mentioned external preparation can be carried out according to a known production method generally used in the pharmaceutical field, and is produced by appropriately containing a pharmacologically acceptable additive generally used in the pharmaceutical field. can do. Hereinafter, typical dosage forms such as paps and tapes will be described, but the present invention is not limited thereto.
[0058]
　For the preparation of the poultice, for example, a water-soluble polymer or a polyhydric alcohol can be used as a pharmacologically acceptable additive.
[0059]
　Here, examples of the water-soluble polymer include gelatin, casein, purulan, dextran, sodium alginate, soluble starch, carboxystarn, dextrin, carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, and polyethylene oxide. , Polyacrylic acid, polyacrylamide, sodium polyacrylate, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl ether, methoxyethylene maleic anhydride copolymer, isobutylene anhydrous maleic acid copolymer, N-vinylacetamide or N-vinylacetamide. Acrylic acid and / or acrylate copolymers and the like can be mentioned.
[0060]
　Examples of the polyhydric alcohol include polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, 1.3-butylene glycol, 1.4-butylene glycol, isobutylene glycol, glycerin, diglycerin and sorbitol.
[0061]
　For the preparation of the tape preparation, for example, a tacky base or a tackifier can be used as a pharmacologically acceptable additive.
[0062]
　Here, the adhesive base can be appropriately selected from known ones in consideration of skin safety, medicinal component release property, adhesion to the skin, etc., for example, acrylic adhesive, rubber adhesive, silicone. Examples include system adhesives.
[0063]
　Examples of the acrylic pressure-sensitive adhesive include homopolymers or copolymers of (meth) acrylic acid alkyl esters, copolymers of the above (meth) acrylic acid alkyl esters and other functional monomers, and the like. ..
[0064]
　Examples of the rubber-based pressure-sensitive adhesive include natural rubber, synthetic isoprene rubber, polyisoprene, polyvinyl ether, polyurethane, polyisoprene, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer, and styrene-isoprene-styrene block. Examples include polymers.
[0065]
　Examples of the silicone-based pressure-sensitive adhesive include polyorganosiloxane and polydimethylsiloxane.
[0066]
　Examples of the tackifier include rosin and hydrogenated, hydrogenated, polymerized, and esterified rosin derivatives, terpene resins such as α-pinene and β-pinene, terpene-phenolic resins, and aliphatics. Examples thereof include aromatic, alicyclic, and copolymerized petroleum resins, alkyl-phenyl resins, and xylene resins.
[0067]
　The content of the temperature-responsive ionic liquid contained in the pharmaceutical composition of the present invention is not particularly limited, but preferably contains an amount capable of improving the solubility of the drug, for example, 1 weight with respect to the weight of the drug. % To 1,000,000% by weight is preferable. When the content of the temperature-responsive ionic liquid exceeds 10% by weight based on the weight of the pharmaceutical composition, the temperature-responsive ionic liquid should be an internal solution such as a soft capsule or a porous body as appropriate. Responsive ionic liquids can be powdered into pharmaceutical compositions.
[0068]
　The present invention provides a temperature-responsive ionic liquid that can be used in the pharmaceutical composition of the present invention.
[0069]
　In one embodiment, a temperature-responsive ionic liquid having an anion represented by the following general formula (II) can be mentioned.
[Changing 4]

[0070]
　In formula (II), R 1 is a hydrogen atom or an acyl group, and R 2 is an alkyl group, a halogen atom or a sulfo group which may be substituted with a halogen atom.
[0071]
　As the anion represented by the above general formula (II), one type may be used, or two or more types may be contained.
[0072]
　In one embodiment, as an example of a temperature-responsive ionic liquid, an anion represented by the above general formula (II) and an ammonium ion (for example, tetrabutylammonium ion) or a phosphonium ion (for example, tetraalkylphosphonium ion) are used. Examples include, but are not limited to, temperature-responsive ionic liquids having. More specifically, tetrabutylammonium = 4- (trifluoromethyl) salicylate, tetrabutylphosphonium = 4- (trifluoromethyl) salicylate, tetrabutylphosphonium = acetylsalicylate, tetrabutylphosphonium = 5-bromosalichi Rate, tetrabutylphosphonium = 4-chlorosalicylate, tetrabutylphosphonium = 5-chlorosalicylate, tetrabutylphosphonium = 5-iodosalicylate, tetrabutylphosphonium = 3-methylsalicylate, tetrabutylphosphonium = Examples thereof include 4-methylsalicylate and tetrabutylphosphonium = 3-carboxy-4-hydroxybenzenesulfonate.
[0073]
　Further, as long as it is a temperature-responsive ionic liquid having an anion represented by the above general formula (II), two or more types of anions may be used. For example, two kinds of components that become anions represented by the above general formula (II) may be used for synthesis, or two kinds of temperature-responsive ionic liquids having an anions represented by the above general formula (II) may be used. The above may be mixed. Specific examples thereof include, but are not limited to, tetrabutylammonium = salicylate 4- (trifluoromethyl) salicylate, tetrabutylphosphonium = salicylate 4- (trifluoromethyl) salicylate and the like. Further, a temperature-responsive ionic liquid obtained by mixing tetrabutylphosphonium = 3-methylsalicylate and tetrabutylphosphonium = 4-aminosalicylate, or tetrabutylphosphonium = 4-methylsalicylate and tetrabutylphosphonium. = A temperature-responsive ionic liquid obtained by mixing a temperature-responsive ionic liquid and a non-temperature-responsive ionic liquid, such as an ionic liquid obtained by mixing 4-aminosalicylate, is also included.
[0074]
　The temperature-responsive ionic liquid preferably has a lower critical solution temperature. In one embodiment, the lower limit critical solution temperature of the temperature responsive ionic liquid may be 40 ° C. or lower, for example, 35 ° C. or lower, 25 ° C. or lower, or 20 ° C. or lower. The lower limit is not particularly limited, and is, for example, 5 ° C. or higher, 10 ° C. or higher, and 15 ° C. or higher. The upper limit and the lower limit can be combined arbitrarily. For example, the lower limit critical solution temperature of a temperature-responsive ionic liquid is 5 ° C or higher and 40 ° C or lower, 5 ° C or higher and 30 ° C or lower, 5 ° C or higher and 25 ° C or lower, 5 ° C or higher and 20 ° C or lower, 10 ° C or higher and 40 ° C or lower, 10 ° C. or higher and 30 ° C. or lower, 10 ° C. or higher and 25 ° C. or lower, 15 ° C. or higher and 40 ° C. or lower, and 15 ° C. or higher and 30 ° C. or lower.
[0075]
　The temperature-responsive ionic liquid can improve the solubility of the drug and can improve the permeability of the drug not only to the epidermis but also to the mucous membrane. It can be used as an agent.
Example
[0076]
　Hereinafter, the present invention will be described in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto.
[0077]
　Commercially available compounds were used for the compounds used in the synthesis of the compounds of the synthesis example and the reference example, for which the synthesis method was not described. % Shows mol / mol% for yield,% by volume for solvents used in column chromatography and high performance liquid chromatography, and% by weight for others unless otherwise specified. The solvent name shown in the NMR data indicates the solvent used for the measurement. The 400 MHz NMR spectrum was measured using a JNM-ECS400 type nuclear magnetic resonance apparatus manufactured by JEOL Ltd. The chemical shift is expressed in δ (unit: ppm) with reference to tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruple line), and m (, respectively. Multiple lines), br (wide) or a combination thereof. When protons such as hydroxyl groups and amino groups have very gentle peaks, they are not described. The IR spectrum was measured by the ATR method using FT / IR-6800 manufactured by JASCO Corporation. The molecular weight is LC-MS / MS (LC: Nexera 20A / 30A manufactured by Shimadzu Corporation, MS / MS: QTRAP-5500 (cation detection) manufactured by SIEX, LC: ACUQUITY UPLC I-Class manufactured by Waters, MS / MS: Cy The permeation amount of various drugs was measured using API-5000 (anion detection) manufactured by X Co., Ltd. LC-MS / MS (LC: Nexera 20A / 30A manufactured by Shimadzu Corporation, MS / MS: QTRAP-5500 manufactured by Sci-X Co., Ltd.). ) Was measured. Unless otherwise specified, commercially available reagents were used in the reaction without purification.
[0078]
(Synthesis Example 1) Synthesis of tetrabutylphosphonium = 4- (trifluoromethyl) salicylate:
[C5]

　Tetrabutylphosphonium hydroxyd 40% aqueous solution 6.91 g (10 mmol) and 4- (trifluoromethyl) salicylic acid 2.06 g Each (10 mmol) was weighed and placed in a glass vial. Stir at room temperature for 2 hours, confirm that 4- (trifluoromethyl) salicylate is completely dissolved, and terminate the reaction to terminate the reaction with tetrabutylphosphonium = 4- (trifluoromethyl) salicylate and water. A mixed solution (hereinafter referred to as a sample of Synthesis Example 1) was quantitatively obtained. The sample of Synthesis Example 1 was used in Example 1, Example 2, Example 4, and Example 5 described later.
　A part of the obtained sample of Synthesis Example 1 was taken, dichloromethane was added, and an ionic liquid was extracted. Then, the organic layer was dried over anhydrous magnesium sulfate and then concentrated to obtain tetrabutylphosphonium = 4- (trifluoromethyl) salicylate (hereinafter, the compound of Synthesis Example 1) which is a pale yellow liquid. The measurement results of 1 H-NMR, FT-IR and MS of the obtained compound of Synthesis Example 1 are as follows, and it was confirmed that the desired ionic liquid was obtained.
　 1 1 H-NMR (CDCl 3 ) δ: 8.01 (1H, d, J = 8.0Hz), 7.06 (1H, s), 6.94 (1H, d, J = 8.0Hz), 2 .26-2.18 (8H, m), 1.51-1.44 (16H, m), 0.94 (12H, t, J = 8.0Hz).
　FT-IR: 3390cm -1(OH stretch), 1592cm -1 (C=O stretch)
　MS: [M] + = 259, [M-H] - = 205
[0079]
(Synthesis Example 2) Synthesis of tetrabutylphosphonium = 5-bromosalicylate:
[Chemical formula 6]

　Weighing 6.91 g (10 mmol) of a 40% aqueous solution of tetrabutylphosphonium hydroxide and 2.17 g (10 mmol) of 5-bromosalicylic acid, respectively. Then, it was placed in a glass vial. Stir at room temperature for 2 hours, confirm that 5-bromosalicylic acid is completely dissolved, and terminate the reaction. By terminating the reaction, a mixed solution of tetrabutylphosphonium = 5-bromosalicylate and water (hereinafter referred to as “synthesis”) The sample of Example 2) was obtained quantitatively. The sample of Synthesis Example 2 was used in Example 1 described later.
　A part of the obtained sample of Synthesis Example 2 was taken, dichloromethane was added, and an ionic liquid was extracted. Then, the organic layer was dried over anhydrous magnesium sulfate and then concentrated to obtain a pale yellow liquid, tetrabutylphosphonium = 5-bromosalicylate (hereinafter, the compound of Synthesis Example 2). The measurement results of 1 H-NMR, FT-IR and MS of the obtained compound of Synthesis Example 2 are as follows, and it was confirmed that the desired ionic liquid was obtained.
　 1 1 H-NMR (CDCl 3 ) δ: 8.01 (1H, dd, J = 2.9, 1.3Hz), 7.28 (1H, dd, J = 8.3, 2.9Hz), 6. 72 (1H, dd, J = 8.3,1.3Hz), 2.23-2.16 (8H, m), 1.51-1.43 (16H, m), 0.94 (12H, t) , J = 7.8Hz).
　FT-IR: 3398cm -1 (OH expansion and contraction), 1577cm -1(C=O expansion)
　MS: [M] + = 259, [M-H] - = 217
[0080]
(Synthesis Example 3) Synthesis of tetrabutylphosphonium = 3-methylsalicylate:
[Chemical formula 7]

　Weighing 6.91 g (10 mmol) of a 40% aqueous solution of tetrabutylphosphonium hydroxide and 1.52 g (10 mmol) of 3-methylsalicylic acid, respectively. Then, it was placed in a glass vial. Stir at room temperature for 2 hours, confirm that 3-methylsalicylic acid is completely dissolved, and terminate the reaction. By terminating the reaction, a mixed solution of tetrabutylphosphonium = 3-methylsalicylate and water (hereinafter referred to as “synthesis”) (Sample 3) was obtained quantitatively. The sample of Synthesis Example 3 was used in Example 1 described later.
　A part of the obtained sample of Synthesis Example 3 was taken, dichloromethane was added, and an ionic liquid was extracted. Then, the organic layer was dried over anhydrous magnesium sulfate and then concentrated to obtain a pale yellow liquid, tetrabutylphosphonium = 3-methylsalicylate (hereinafter, the compound of Synthesis Example 3). The measurement results of 1 H-NMR, FT-IR and MS of the obtained compound of Synthesis Example 3 are as follows, and it was confirmed that the desired ionic liquid was obtained.
　 1 1 H-NMR (CDCl 3 ) δ: 7.77 (1H, d, J = 7.7Hz), 7.09 (1H, d, J = 7.7Hz), 6.61 (1H, t, J = 7.7Hz), 2.23 (3H, s) 2.22-2.13 (8H, m), 1.53-1.36 (16H, m), 0.93 (12H, t, J = 8) .0Hz).
FT-IR: 3398cm -1 (OH expansion and contraction), 1577cm -1(C=O expansion)
　MS: [M] + = 259, [M-H] - = 151
[0081]
(Synthesis Example 4) Synthesis of tetrabutylphosphonium = 4-methylsalicylate:
[Chemical formula 8]

　Weighing 6.91 g (10 mmol) of a 40% aqueous solution of tetrabutylphosphonium hydroxide and 1.52 g (10 mmol) of 4-methylsalicylic acid, respectively. Then, it was placed in a glass vial. Stir at room temperature for 2 hours, confirm that 4-methylsalicylic acid is completely dissolved, and terminate the reaction. By terminating the reaction, a mixed solution of tetrabutylphosphonium = 4-methylsalicylate and water (hereinafter referred to as “synthesis”) The sample of Example 4) was obtained quantitatively. The sample of Synthesis Example 4 was used in Example 1 described later.
　A part of the obtained sample of Synthesis Example 4 was taken, dichloromethane was added, and an ionic liquid was extracted. Then, the organic layer was dried over anhydrous magnesium sulfate and then concentrated to obtain a pale yellow liquid, tetrabutylphosphonium = 4-methylsalicylate (hereinafter, the compound of Synthesis Example 4). The measurement results of 1 H-NMR, FT-IR and MS of the obtained compound of Synthesis Example 4 are as follows, and it was confirmed that the desired ionic liquid was obtained.
　 1 1 H-NMR (CDCl 3 ) δ: 7.78 (1H, d, J = 7.8Hz), 6.63 (1H, d, J = 1.5Hz), 6.53 (1H, dd, J = 7.8, 1.5Hz), 2.45 (1H, br), 2.27 (3H, s), 2.23-2.14 (8H, m), 1.51-1.39 (16H, m), 0.94 (12H, t, J = 7.4Hz).
　FT-IR: 3398 cm -1 (OH expansion and contraction), 1581 cm -1 (C=O expansion)
　MS: [M] + = 259, [M-H] - = 151
[0082]
(Synthesis Example 5) Synthesis of tetrabutylphosphonium = 4-chlorosalicylate:
[Chemical No. 9]

　Weighing 6.91 g (10 mmol) of a 40% aqueous solution of tetrabutylphosphonium hydroxide and 1.73 g (10 mmol) of 4-chlorosalicylic acid, respectively. Then, it was placed in a glass vial. Stir at room temperature for 2 hours, confirm that 4-chlorosalicylic acid is completely dissolved, and terminate the reaction. By terminating the reaction, a mixed solution of tetrabutylphosphonium = 4-chlorosalicylate and water (hereinafter referred to as “synthesis”) Example 5 sample) was obtained quantitatively. The sample of Synthesis Example 5 was used in Example 1 described later.
　A part of the obtained sample of Synthesis Example 5 was taken, dichloromethane was added, and an ionic liquid was extracted. Then, the organic layer was dried over anhydrous magnesium sulfate and then concentrated to obtain tetrabutylphosphonium = 4-chlorosalicylate (hereinafter, the compound of Synthesis Example 5) which is an orange liquid. The measurement results of 1 H-NMR, FT-IR and MS of the obtained compound of Synthesis Example 5 are as follows, and it was confirmed that the desired ionic liquid was obtained.
　 1 1 H-NMR (CDCl 3 ) δ: 7.83 (1H, d, J = 8.0Hz), 6.82 (1H, d, J = 2.5Hz), 6.53 (1H, dd, J = 8.0, 2.5Hz), 2.24-2.16 (8H, m), 1.51-1.41 (16H, m), 0.95 (12H, t, J = 7.2Hz).
　FT-IR: 3394cm -1 (OH expansion and contraction), 1574cm -1(C=O expansion)
　MS: [M] + = 259, [M-H] - = 171
[0083]
(Synthesis Example 6) Synthesis of tetrabutylphosphonium = 5-chlorosalicylate:
[Chemical formula 10]

　Weighing 6.91 g (10 mmol) of a 40% aqueous solution of tetrabutylphosphonium hydroxide and 1.73 g (10 mmol) of 5-chlorosalicylic acid, respectively. Then, it was placed in a glass vial. Stir at room temperature for 2 hours, confirm that 5-chlorosalicylic acid is completely dissolved, and terminate the reaction. By terminating the reaction, a mixed solution of tetrabutylphosphonium = 5-chlorosalicylate and water (hereinafter referred to as “synthesis”) Example 6 sample) was obtained quantitatively. The sample of Synthesis Example 6 was used in Example 1 described later.
　Dichloromethane was added to a part of the obtained sample of Synthesis Example 6 to extract an organic layer. Then, the organic layer was dried over anhydrous magnesium sulfate and then concentrated to obtain a pale yellow liquid, tetrabutylphosphonium = 5-chlorosalicylate (hereinafter, the compound of Synthesis Example 6). The measurement results of 1 H-NMR, FT-IR and MS of the obtained compound of Synthesis Example 6 are as follows, and it was confirmed that the desired ionic liquid was obtained.
　 1 1 H-NMR (CDCl 3 ) δ: 7.87 (1H, d, J = 3.6Hz), 7.15 (1H, dd, J = 9.0, 3.6Hz), 6.76 (1H, 1H, d, J = 9.0Hz), 2.27-2.16 (8H, m) 1.53-1.41 (16H, m), 0.94 (12H, t, J = 7.6Hz).
　FT-IR: 3394 cm -1 (OH expansion and contraction), 1577 cm -1(C=O expansion)
　MS: [M] + = 259, [M-H] - = 171
[0084]
(Synthesis Example 7) Synthesis of tetrabutylphosphonium = 5-iodosalicylate:
[Chemical formula 11]

　Weighing 6.91 g (10 mmol) of a 40% aqueous solution of tetrabutylphosphonium hydroxide and 2.64 g (10 mmol) of 5-iodosalicylic acid, respectively. Then, it was placed in a glass vial. Stir at room temperature for 2 hours, confirm that 5-iodosalicylic acid is completely dissolved, and terminate the reaction. By terminating the reaction, a mixed solution of tetrabutylphosphonium = 5-iodosalicylate and water (hereinafter, synthesis). (Sample 7) was obtained quantitatively. The sample of Synthesis Example 7 was used in Example 1 described later.
　Dichloromethane was added to a part of the obtained sample of Synthesis Example 7 to extract an organic layer. Then, the organic layer was dried over anhydrous magnesium sulfate and then concentrated to obtain a pale yellow liquid, tetrabutylphosphonium = 5-iodosalicylate (hereinafter, the compound of Synthesis Example 7). The measurement results of 1 H-NMR, FT-IR and MS of the obtained compound of Synthesis Example 7 are as follows, and it was confirmed that the desired ionic liquid was obtained.
　 1 1 H-NMR (CDCl 3 ) δ: 8.19 (1H, d, J = 3.5Hz), 7.45 (1H, dd, J = 8.5,3.5Hz), 6.62 (1H, d, J = 8.5Hz), 2.40 (1H, br), 2.24-2.14 (8H, m), 1.55-1.40 (16H, m), 0.95 (12H, t, J = 7.9 Hz).
　FT-IR: 3394cm -1 (OH expansion and contraction), 1574cm -1(C=O expansion)
　MS: [M] + = 259, [M-H] - = 263
[0085]
(Synthesis Example 8) Synthesis of tetrabutylphosphonium = 3-carboxy-4-hydroxybenzenesulfonate:
[Chemical formula 12]

　Tetrabutylphosphonium hydroxyd 40% aqueous solution 6.91 g (10 mmol) and 5-sulfosalicylic acid dihydrate 2. Each of 54 g (10 mmol) was weighed and placed in a glass vial. Stir at room temperature for 2 hours, confirm that 5-sulfosalicylic acid dihydrate is completely dissolved, and terminate the reaction to complete the reaction with tetrabutylphosphonium = 3-carboxy-4-hydroxybenzenesulfonate and water. (Hereinafter, a sample of Synthesis Example 8) was quantitatively obtained. The sample of Synthesis Example 8 was used in Example 1 described later.
　Dichloromethane was added to a part of the obtained sample of Synthesis Example 8 to extract an organic layer. Then, the organic layer was dried over anhydrous magnesium sulfate and then concentrated to obtain a pale yellow liquid, tetrabutylphosphonium = 3-carboxy-4-hydroxybenzenesulfonate (hereinafter, the compound of Synthesis Example 8). The measurement results of 1 H-NMR and FT-IR of the obtained compound of Synthesis Example 8 are as follows, and it was confirmed that the desired ionic liquid was obtained.
　 1 1 H-NMR (CDCl 3 ) δ: 8.49 (1H, d, J = 2.8Hz), 7.96 (1H, dd, J = 8.1,2.8Hz), 6.89 (1H, d, J = 8.1Hz), 2.23-1.16 (8H, m), 1.51-1.38 (16H, m), 0.89 (12H, t, J = 7.6Hz).
　FT-IR: 3440cm -1(OH stretch), 1600cm -1 (C=O stretch)
[0086]
(Synthesis Example 9) Synthesis of tetrabutylphosphonium = salicylate:
[Chemical formula 13]

　Chem. Commun. According to the method described in 10248-10250 (2013), 6.91 g (10 mmol) of a 40% aqueous solution of tetrabutylphosphonium hydroxide and 1.38 g (10 mmol) of salicylic acid were weighed and placed in a glass vial. Stir at room temperature for 2 hours, confirm that salicylic acid is completely dissolved, and terminate the reaction to quantitatively prepare a mixed solution of tetrabutylphosphonium = salicylate and water (hereinafter, sample of Synthesis Example 9). Got to. The sample of Synthesis Example 9 was used as the sample of Examples 1 to 6 described later.

The scope of the claims
[Request item 1]
　A pharmaceutical composition comprising a drug and a temperature responsive ionic liquid.
[Request item 2]
　The pharmaceutical composition according to claim 1, wherein the anion of the temperature-responsive ionic liquid contains at least one selected from the group consisting of aromatic carboxylate ions and aromatic sulfonate ions.
[Request Item 3]
　The pharmaceutical composition according to claim 1 or 2, wherein the anion of the temperature-responsive ionic liquid is an anion represented by the following formula (I) and / or general formula (II).
[Chemical formula 1]

[In formula (II), R 1 represents a hydrogen atom or an acyl group, and R 2 represents an alkyl group, a halogen atom or a sulfo group which may be substituted with a halogen atom. ]
[Request Item 4]
　The pharmaceutical composition according to any one of claims 1 to 3, wherein the temperature-responsive ionic liquid has a lower limit critical solution temperature.
[Request Item 5]
　The pharmaceutical composition according to claim 4, wherein the lower limit critical solution temperature is 40 ° C. or lower.
[Request Item 6]
　The pharmaceutical composition according to any one of claims 1 to 5, wherein the cation of the temperature-responsive ionic liquid is a tetraalkylammonium ion or a tetraalkylphosphonium ion.
[Request Item 7]
　The pharmaceutical composition according to any one of claims 1 to 6, which is an external preparation.
[Request Item 8]
　A temperature-responsive ionic liquid having an anion represented by the following general formula (II).
[Chemical formula 2]

[In formula (II), R 1 represents a hydrogen atom or an acyl group, and R 2 represents an alkyl group, a halogen atom or a sulfo group which may be substituted with a halogen atom. ]
[Request Item 9]
　The temperature-responsive ionic liquid of claim 8, which has a lower critical solution temperature.