Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/62—Quaternary ammonium compounds
  • C07C211/63—Quaternary ammonium compounds having quaternised nitrogen atoms bound to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
  • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
  • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/54—Quaternary phosphonium compounds

Definitions

• the present invention relates to a temperature-responsive ionic liquid, a transdermal absorption enhancer or a transdermal absorption enhancer assistant, and a pharmaceutical composition.
• Known routes of administration for pharmaceuticals include oral administration, intravenous administration, and transdermal administration, and are developed appropriately according to the physical properties and characteristics of the active ingredients.
• Transdermal administration has the advantage of improving patient compliance with medication, as it is easy for elderly patients and those with dementia who have difficulty swallowing to take the medication, it avoids side effects caused by increased blood levels of drugs when administered orally or by injection, and it is less affected by food, making it easier for busy patients who tend to have irregular eating habits to obtain stable drug effects.
• water-soluble drugs and drugs with large molecular weights generally have low skin permeability because they are blocked by the stratum corneum of the skin, which has a high barrier function, and so the drugs that can be administered transdermally are limited.
• transdermal absorption enhancer One of the techniques to improve the skin permeability of drugs when administered transdermally is to add a transdermal absorption enhancer.
• a transdermal absorption enhancer there are issues with this, such as the lack of versatility of transdermal absorption enhancers, as the optimal one varies depending on the drug, and the fact that some drugs are incompatible with transdermal absorption enhancers, making a separate compatibilizer necessary.
• Ionic liquids have the advantage of being able to accommodate countless combinations of cations and anions, allowing for a high degree of freedom in designing their physical properties.
• Patent Document 1 discloses a pharmaceutical composition that improves drug permeability by mixing with a temperature-responsive ionic liquid.
• Patent Document 1 mainly discloses temperature-responsive ionic liquids having salicylate ions with no substituents on the benzene ring, and disclosure of temperature-responsive ionic liquids having salicylate ions with substituents on the benzene ring is limited.
• Patent Document 1 merely discloses that temperature-responsive ionic liquids having salicylate ions with substituents on the benzene ring, such as 4-(trifluoromethyl)salicylate ion, improve the permeability of certain drugs.
• the present invention aims to provide a temperature-responsive ionic liquid that improves the permeability of various drugs through the skin, mucous membranes, etc. by introducing more suitable substituents into the benzene ring of the salicylate ion.
• the present invention provides a temperature-responsive ionic liquid comprising an anion represented by the following general formula (I) and a cation:
• R 1 represents a hydrogen atom or an acyl group
• R 2 represents an aryl group, an alkoxy group or a fluorine atom.
• R 1 represents a hydrogen atom or an acyl group
• R 2 represents an aryl group, an alkoxy group, or a fluorine atom.
• a transdermal absorption enhancer or a transdermal absorption enhancer auxiliary comprising the temperature responsive ionic liquid according to any one of (1) to (7).
• the percutaneous absorption enhancer or percutaneous absorption enhancer auxiliary according to (8) which is for enhancing or auxiliary for enhancing percutaneous absorption of a basic drug or a salt thereof.
• a solubilizer comprising the temperature responsive ionic liquid according to any one of (1) to (7).
• (12) A pharmaceutical composition comprising the temperature responsive ionic liquid according to any one of (1) to (7) above and a drug.
• the basic drug or a salt thereof is selected from the group consisting of skeletal muscle relaxants, antiepileptic drugs, therapeutic drugs for Parkinson's disease, antipsychotic drugs, therapeutic drugs for dementia, therapeutic drugs for attention deficit hyperactivity disorders, Janus kinase inhibitors, and therapeutic drugs for migraine.
• the present invention also provides a temperature-responsive ionic liquid comprising an anion represented by the following general formula (II):
• R 1 represents a hydrogen atom or an acyl group
• R 2 represents an aryl group, an alkoxy group, or a fluorine atom.
• R 1 represents a hydrogen atom or an acyl group
• R 2 represents an alkoxy group or a fluorine atom.
• the temperature responsive ionic liquid according to (16) or (17) above which has a lower critical solution temperature.
• the present invention can improve the permeability of various drugs.
• the temperature responsive ionic liquid of the present invention is characterized by containing an anion represented by the following general formula (I) and a cation.
• R 1 represents a hydrogen atom or an acyl group
• R 2 represents an aryl group, an alkoxy group, or a fluorine atom.
• a temperature-responsive ionic liquid is an ionic liquid composed of a cation and an anion, and exhibits temperature responsiveness. There are no particular limitations on the melting point of the temperature-responsive ionic liquid.
• temperature responsiveness refers to the property of changing shape and/or properties in response to a change in temperature (heat).
• examples of the temperature responsiveness of ionic liquids include volumetric changes such as expansion and contraction, and changes in hydrophobicity such as the lower critical solution temperature (LCST) and upper critical solution temperature (UCST).
• the temperature-responsive ionic liquid of the present invention preferably has an LCST in order to enhance the permeability of drugs.
• the LCST refers to the temperature beyond which the hydrophobicity of the temperature-responsive ionic liquid increases and its solubility in water decreases when the temperature of the temperature-responsive ionic liquid is increased. In this case, if the temperature-responsive ionic liquid contains water, it does not matter whether the temperature-responsive ionic liquid is compatible with water at a temperature lower than the LCST.
• the temperature-responsive ionic liquid has the property of containing a certain amount of water even at a temperature lower than the LCST, and therefore even an ionic liquid that is phase-separated from water at a temperature lower than the LCST will exhibit behavior in which the hydrophobicity of the temperature-responsive ionic liquid increases when heated to above the LCST.
• temperature-responsive ionic liquid of LCST type Whether a temperature-responsive ionic liquid has an LCST (hereinafter also referred to as "temperature-responsive ionic liquid of LCST type") can be confirmed by measuring the absorbance of wavelengths in the visible light region while gradually increasing the temperature, and by checking whether or not the phenomenon of cloudiness due to increased hydrophobicity occurs at a certain temperature and the absorbance increases.
• the specific procedure is as follows. First, a mixture of ionic liquid and water is prepared, mixed well, and then the solution is placed in a measurement cell. After leaving the solution at 4°C until it becomes transparent, the temperature is raised from 4°C to 95°C at a rate of 0.5°C/min.
• the change in absorbance at 450 nm is measured, and it can be confirmed whether the measured ionic liquid is a temperature-responsive ionic liquid of LCST type.
• the LCST value can be obtained by analyzing the obtained data on the absorbance change using the differential method of a Tm (nucleic acid melting temperature) analysis program.
• the LCST of the temperature-responsive ionic liquid is preferably 40°C or lower, more preferably 35°C or lower, and even more preferably 30°C or lower.
• the lower limit is preferably 5°C or higher, more preferably 10°C or higher, and even more preferably 15°C or higher. The upper and lower limits can be combined in any way.
• a liquid is a temperature-responsive ionic liquid having UCST (hereinafter also referred to as "UCST-type temperature-responsive ionic liquid”) can be confirmed by measuring the absorbance of wavelengths in the visible light region while gradually increasing the temperature, and observing whether or not at a certain temperature the solution becomes transparent due to increased hydrophilicity and the absorbance decreases.
• a liquid is a UCST-type temperature-responsive ionic liquid
• the UCST value can be determined by analyzing the obtained data on the change in absorbance using the differential method of a Tm (nucleic acid melting temperature) analysis program.
• the temperature-responsive ionic liquid of the present invention can be a combination of an anion represented by the above general formula (I) and any cation selected from the above, as long as the combination shows temperature responsiveness.
• the two can be combined in equimolar amounts.
• the liquid may contain two or more types of cations.
• examples of the acyl group include an acetyl group
• examples of the aryl group include a phenyl group, a naphthyl group, a phenanthryl group, or an anthracenyl group.
• the aryl group may be substituted, and the position of the substituent on the aryl group may be any position, and there is no particular limit to the number or type of the substituent.
• a hydroxyl group, an amino group, or the like is included as a substituent on the aryl group, the hydroxyl group, the amino group, or the like may be further substituted with an acyl group, or the like.
• alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentyloxy, allyloxy, cyclohexyloxy, phenoxy, benzyloxy, and 1-naphthyloxy groups.
• the alkoxy group may be substituted, and the position of the substituent on the alkoxy group may be any position, with no particular restriction on the number or type of the substituent.
• the alkoxy group contains a hydroxyl group, an amino group, or the like as a substituent, the hydroxyl group or the amino group may be further substituted with an acyl group, or the like.
• the temperature-responsive ionic liquid of the present invention may contain at least one type of anion represented by the above general formula (I), and may contain two or more types. It may also contain an anion having a structure different from that of the anion represented by the above general formula (I).
• temperature-responsive ionic liquid of the present invention examples include temperature-responsive ionic liquids that contain an anion represented by the above general formula (I) and an ammonium ion (e.g., tetrabutylammonium ion) or a phosphonium ion (e.g., tetraalkylphosphonium ion).
• an anion represented by the above general formula (I) and an ammonium ion e.g., tetrabutylammonium ion
• phosphonium ion e.g., tetraalkylphosphonium ion
• temperature-responsive ionic liquids examples include tetrabutylammonium 4-methoxysalicylate, tetrabutylammonium 4-fluorosalicylate, tetrabutylammonium 6-fluorosalicylate, tetrabutylphosphonium 4-methoxysalicylate, tetrabutylphosphonium 4-fluorosalicylate, tetrabutylphosphonium 6-fluorosalicylate, and tetrabutylphosphonium 3-phenylsalicylate.
• the anion contained in the temperature responsive ionic liquid of the present invention is preferably an anion represented by the following general formula (II), and more preferably an anion represented by the following general formula (III) or (IV).
• R 1 represents a hydrogen atom or an acyl group
• R 2 represents an alkoxy group or a fluorine atom.
• R 1 represents a hydrogen atom or an acyl group
• R 2 represents an alkoxy group or a fluorine atom.
• Cations constituting the temperature-responsive ionic liquid of the present invention include, for example, those having a nitrogen atom as the ion center, those having a phosphorus atom as the ion center, those having a sulfur atom as the ion center, and those having a nitrogen atom and a sulfur atom as the ion center.
• Cations with a nitrogen atom as the ion center include, for example, imidazolium ion, ammonium ion, pyridinium ion, quinolinium ion, pyrrolidinium ion, piperidinium ion, piperazinium ion, morpholinium ion, pyridazinium ion, pyrimidinium ion, pyrazinium ion, pyrazolium ion, thiazolium ion, oxazolium ion, triazolium ion, guanidium ion, and 4-aza-1-azonia-bicyclo-[2,2,2]octanium ion.
• these cations may have a substituent such as an alkyl group at any position, and the number of substituents may be multiple.
• imidazolium ions, ammonium ions, pyridinium ions, pyrrolidinium ions, and piperidinium ions are preferred as cations with a nitrogen atom as the ion center, due to their ease of availability and structural transformation.
• imidazolium ions include 1-methylimidazolium ion, 1-ethylimidazolium ion, 1-propylimidazolium ion, 1-butylimidazolium 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, and 1-cyanopropyl-3-methylimidazolium.
• ammonium ions include tetraalkylammonium ions such as tetramethylammonium ion, tetraethylammonium ion, tetrapropylammonium ion, tetrabutylammonium ion, tetrahexylammonium ion, and trihexyltetradecylammonium ion, (2-hydroxyethyl)trimethylammonium ion, N,N-diethyl-N-(2-methoxyethyl)-N-methylammonium ion, tris(2-hydroxyethyl)methylammonium ion, trimethyl(1H,1H,2H,2H-heptadecafluorodecyl)ammonium ion, trimethyl-(4-vinylbenzyl)ammonium ion, tributyl-(4-vinylbenzyl)ammonium ion,
• pyridinium ions examples 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, and 1-(3-cyanopropyl)pyridinium ion.
• pyrrolidinium ions examples include 1-methyl-1-propylpyrrolidinium ion, 1-butyl-1-methylpyrrolidinium ion, 1-(2-hydroxyethyl)-1-methylpyrrolidinium ion, and 1-ethyl-1-methylpyrrolidinium ion.
• piperidinium ions examples include 1-methyl-1-propylpiperidinium ion, 1-butyl-1-methylpiperidinium ion, 1-(2-hydroxyethyl)-1-methylpiperidinium ion, and 1-ethyl-1-methylpiperidinium ion.
• Cations with a phosphorus atom as the ionic center are generally called phosphonium ions, and examples include tetraalkylphosphonium ions such as tetrapropylphosphonium ion, tetrabutylphosphonium ion, tetrahexylphosphonium ion, trihexyltetradecylphosphonium ion, triphenylmethylphosphonium ion, triisobutylmethylphosphonium ion, triethylmethylphosphonium ion, tributylmethylphosphonium ion, and tributylhexadecylphosphonium ion, (2-cyanoethyl)triethylphosphonium ion, (3-chloropropyl)trioctylphosphonium ion, tributyl(4-vinylbenzyl)phosphonium ion, and 3-(triphenylphosphonio)prop
• Cations with a sulfur atom as the ionic center are generally called sulfonium ions, and examples include triethylsulfonium ion, tributylsulfonium ion, 1-ethyltetrahydrothiophenium ion, and 1-butyltetrahydrothiophenium ion.
• the cation constituting the temperature responsive ionic liquid of the present invention is preferably an ammonium ion or a phosphonium ion, and more preferably a tetraalkylammonium ion or a tetraalkylphosphonium ion.
• the total carbon number of the four alkyl groups in the cation that constitutes the temperature-responsive ionic liquid is 13 or more and 35 or less.
• tetraalkylammonium ions examples include tetrabutylammonium ion, tetrapentylammonium ion, tetrahexylammonium ion, tetraheptylammonium ion, tetraoctylammonium ion, and trioctylmethylammonium ion.
• tetraalkylphosphonium ions include tetrabutylphosphonium ion, tetrapentylphosphonium ion, tetraoctylphosphonium ion, tributylhexylphosphonium ion, tributylheptylphosphonium ion, tributyloctylphosphonium ion, tributyldodecylphosphonium ion, tributyltridecylphosphonium ion, tributylpentadecylphosphonium ion, tributylhexadecylphosphonium ion, and trihexyltetradecylphosphonium ion.
• the four alkyl groups in the tetraalkylammonium ion or tetraalkylphosphonium ion may be the same or different.
• the temperature-responsive ionic liquid of the present invention can be synthesized according to a general method for synthesizing ionic liquids.
• the temperature-responsive ionic liquid is an ammonium salt
• examples of the method include (1) a method in which an ammonium salt obtained by reacting an amine with an alkyl halide compound or the like is subjected to anion exchange using a metal salt, followed by purification to obtain the desired ammonium salt (anion exchange method), and (2) a method in which an amine or ammonium hydroxide is directly reacted with an acid and neutralized to obtain the desired ammonium salt (neutralization method).
• the temperature-responsive ionic liquid is a phosphonium salt
• it can be synthesized by either the anion exchange method or the neutralization method.
• the desired phosphonium salt can be obtained by directly reacting a phosphonium hydroxide with an acid and neutralizing it.
• one type of cation and two or more types of anions two or more types of cations and one type of anion, or two or more types of cations and two or more types of anions may be used.
• anions salicylic acid and 4-methoxysalicylic acid in any ratio so that the total amount of both is 1 mole per mole of tetrabutylphosphonium hydroxide, the cation, a temperature-responsive ionic liquid containing one type of cation and two types of anions can be obtained.
• the LCST can be controlled to any value.
• an ionic liquid that contains two types of anions one anion that gives a temperature-responsive ionic liquid with a low LCST and the other anion that gives a temperature-responsive ionic liquid with a high LCST, it is possible to obtain a temperature-responsive ionic liquid that has an LCST between the LCSTs of the temperature-responsive ionic liquids that only contain the respective anions.
• the temperature-responsive ionic liquid of the present invention can improve the permeability of drugs not only through the epidermis but also through mucous membranes.
• it can improve the solubility of drugs, it can be used as a solubilizer, dissolution aid, transdermal absorption enhancer, and transdermal absorption enhancer assistant.
• the temperature-responsive ionic liquid of the present invention can be used in pharmaceuticals, quasi-drugs, cosmetics, etc.
• the temperature-responsive ionic liquid of the present invention can be used as a pharmaceutical composition containing a drug.
• a drug that is the active ingredient used in the pharmaceutical composition, and any known drug can be appropriately selected for use.
• Drugs include, for example, steroidal anti-inflammatory agents such as prednisolone, dexamethasone, hydrocortisone, fluocinolone acetonide, betamethasone valerate, betamethasone dipropionate, clobetasone butyrate, and prednisolone succinate; non-steroidal anti-inflammatory agents or ester derivatives thereof such as indomethacin, diclofenac, ibuprofen, ketoprofen, flufenamic acid, ketorolac, flurbiprofen, felbinac, suprofen, pranoprofen, tiaprofen, and loxoprofen; anti-allergic agents such as tranilast, azelastine, ketotifen, ibudilast, oxatomide, and emedastine; diphenhydramine, chlorpheniramine, promethazine, and tocopherol; antihistamines such as lipelen
• basic drugs are preferred because they can be suitably used in topical preparations, and more preferably, basic drugs selected from the group consisting of skeletal muscle relaxants, antiepileptic drugs, Parkinson's disease treatment drugs, antipsychotic drugs, dementia treatment drugs, attention deficit hyperactivity treatment drugs, Janus kinase inhibitors, and migraine treatment drugs.
• the above drugs may be in the form of pharmacologically acceptable salts or solvates thereof.
• pharmacologically acceptable salts include salts with inorganic acids or salts with organic acids.
• salts with inorganic acids include hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides, and phosphates.
• salts with organic acids include oxalates, malonates, citrates, fumarates, lactates, malates, succinates, tartrates, acetates, trifluoroacetates, maleates, gluconates, benzoates, ascorbates, glutarates, mandelates, phthalates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, camphorsulfonates, aspartates, glutamates, and cinnamates.
• solvates include hydrates.
• the pharmaceutical composition containing the temperature-responsive ionic liquid of the present invention can improve the solubility of drugs by including the temperature-responsive ionic liquid.
• administration routes such as oral administration or parenteral administration such as nasal administration, intravenous administration, pulmonary administration, or transdermal administration can be used.
• the dosage form may be, for example, a tablet (including sugar-coated tablets and film-coated tablets), a pill, a granule, a powder, a capsule (including soft capsules and microcapsules), a syrup, an emulsion, or a suspension.
• the preparation of oral administration formulations can be carried out according to known manufacturing methods commonly used in the pharmaceutical field, and can be produced by appropriately incorporating pharmacologically acceptable additives commonly used in the pharmaceutical field, such as excipients, binders, lubricants, disintegrants, sweeteners, surfactants, suspending agents, or emulsifiers.
• pharmacologically acceptable additives such as excipients, binders, lubricants, disintegrants, sweeteners, surfactants, suspending agents, or emulsifiers.
• examples of the dosage form include nasal preparations, eye drops, injections, infusions, drops, topical preparations, and suppositories. Because the pharmaceutical composition containing the temperature-responsive ionic liquid of the present invention has a permeation-promoting effect on the stratum corneum, topical preparations, which are a non-invasive administration method, are preferred.
• the topical agent may be in any conventionally used dosage form, such as an ointment, cream, gel, gel-like cream, lotion, spray, cataplasm, tape, or reservoir-type patch.
• topical preparations can be prepared according to known manufacturing methods commonly used in the pharmaceutical field, and can be manufactured by appropriately incorporating pharmacologically acceptable additives commonly used in the pharmaceutical field.
• Representative dosage forms, such as poultices and tapes, are described below, but are not limited to these.
• pharmacologically acceptable additives such as water-soluble polymers or polyhydric alcohols can be used.
• water-soluble polymers examples include gelatin, casein, pullulan, dextran, sodium alginate, soluble starch, carboxystarch, dextrin, carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyethylene oxide, polyacrylic acid, polyacrylamide, sodium polyacrylate, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl ether, methoxyethylene-maleic anhydride copolymer, isobutylene-maleic anhydride copolymer, N-vinylacetamide, N-vinylacetamide, acrylic acid or acrylate copolymer, etc.
• polyhydric alcohols examples include polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, isobutylene glycol, glycerin, diglycerin, and sorbitol.
• pharmacologically acceptable additives such as adhesive bases and tackifiers can be used.
• the adhesive base can be appropriately selected from known adhesives taking into consideration skin safety, medicinal ingredient release, adhesion to the skin, etc., and examples include acrylic adhesives, rubber adhesives, and silicone adhesives.
• Acrylic adhesives include, for example, homopolymers or copolymers of (meth)acrylic acid alkyl esters, or copolymers of the above (meth)acrylic acid alkyl esters with other functional monomers.
• rubber-based adhesives examples include natural rubber, synthetic isoprene rubber, polyisobutylene, polyvinyl ether, polyurethane, polyisoprene, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer, and styrene-isoprene-styrene block copolymer.
• silicone-based adhesives examples include polyorganosiloxane and polydimethylsiloxane.
• Tackifiers include rosin-based ones such as rosin or hydrogenated, disproportionated, polymerized or esterified rosin derivatives, and other ones such as terpene resins such as ⁇ -pinene or ⁇ -pinene, terpene-phenol resins, aliphatic, aromatic, alicyclic or copolymer petroleum resins, alkyl-phenyl resins or xylene resins.
• the content of the temperature-responsive ionic liquid in the pharmaceutical composition of the present invention containing the temperature-responsive ionic liquid is preferably an amount capable of improving the solubility and permeability of the drug, and is preferably, for example, 1% by mass or more and 1,000,000% by mass or less relative to the mass of the drug.
• ⁇ LCST measurement of ionic liquid> A mixture of ionic liquid and water was prepared, mixed thoroughly, and then the solution was injected into the measurement cell. At this time, for ionic liquids that are compatible with water at room temperature (samples 1, 5, and 7 described later), the ionic liquid was injected as an aqueous solution, and for ionic liquids that are separated from water at room temperature (samples 2 to 4, 6, and 8 described later), the suspension solution after mixing the sample thoroughly was injected into the measurement cell. Next, the solution was left at 4°C until it became transparent, and then the absorbance was measured under the conditions shown below. The obtained data on the absorbance change was analyzed by the differential method of the Tm (nucleic acid melting temperature) analysis program to calculate the LCST. The value rounded off to one decimal place was taken as the LCST.
• Tm nucleic acid melting temperature
• Chemical shifts are expressed as ⁇ (unit: ppm) relative to tetramethylsilane, and signals are indicated as s (singlet), d (doublet), t (triplet), q (quartet), sext (sexlet), m (multiplet), br (broad), or combinations thereof. If protons of hydroxyl groups, amino groups, etc., had very gentle peaks, they were not analyzed.
• FT-IR Measurement> The FT-IR of the obtained compound was measured under the conditions shown below.
• MS Measurement of Cations and Anions The MS of the cations and anions of the obtained compound was measured using the following device. Mass spectrometer (MS/MS): QTRAP-5500 (manufactured by Sciex Corporation)
• ⁇ Baricitinib permeability test using a human cultured epidermis model A human cultured epidermis model (LabCyte EPI-MODEL12, Japan Tissue Engineering Co., Ltd.) was used, with the stratum corneum side as the donor phase and the basal layer side as the receptor phase, and a permeability test of baricitinib from the donor phase to the receptor phase was performed. The test was performed in an incubator at 37°C.
• a solution of baricitinib dissolved in dimethylsulfoxide to a concentration of 25 mg/mL was prepared by diluting with water or a 5% aqueous solution or aqueous dispersion of a temperature-responsive ionic liquid to a concentration of baricitinib of 0.25 mg/mL.
• 300 ⁇ l of the prepared baricitinib-containing solution was added as the donor phase, and the receptor liquid was sampled after 24 hours.
• the permeation amount of baricitinib was determined by measuring LC-MS/MS under the conditions shown below. Hanks' balanced salt solution was used as the receptor liquid.
• LC Liquid chromatograph
• MS/MS Mass spectrometer
• MS/MS QTRAP-5500 (manufactured by Sciex Corporation)
• Gradient conditions: A:B 100:0 ⁇ 0:100
• Column temperature: 40°C Flow rate: 0.5 mL/min Measurement time: 5 min
• Sample injection volume 10 ⁇ L
• Memantine hydrochloride A solution was prepared using water or a 5% aqueous solution of the temperature-responsive ionic liquid so that the concentration of memantine hydrochloride was 1 mg/mL.
• Atomoxetine hydrochloride A solution was prepared using water or a 5% aqueous solution of the temperature-responsive ionic liquid so that the concentration of atomoxetine hydrochloride was 1 mg/mL.
• Sumatriptan succinate A solution was prepared using water or a 5% aqueous solution of the temperature-responsive ionic liquid so that the concentration of atomoxetine hydrochloride was 1 mg/mL.
• Venlafaxine hydrochloride A solution was prepared using water or a 5% aqueous solution of temperature-responsive ionic liquid to give a venlafaxine hydrochloride concentration of 1 mg/mL.
• Guanfacine hydrochloride A 20 mg/mL ethanol solution was prepared, then diluted with water or a 5% aqueous solution of the temperature-responsive ionic liquid to prepare a solution with a guanfacine hydrochloride concentration of 0.2 mg/mL.
• Leuprorelin acetate A solution was prepared using water or a 5% aqueous solution of temperature-responsive ionic liquid so that the concentration of leuprorelin acetate was 5 mg/mL.
• Octreotide acetate A solution was prepared using water or a 5% aqueous solution of temperature-responsive ionic liquid to give an octreotide acetate concentration of 5 mg/mL.
• Oxytocin acetate A solution was prepared using water or a 5% aqueous solution of temperature-responsive ionic liquid to give an oxytocin acetate concentration of 5 mg/mL.
• Example 1 As the cationic component, 3.46 g (5 mmol) of a 40% by mass aqueous solution of tetrabutylphosphonium hydroxide and 0.84 g (5 mmol) of 4-methoxysalicylic acid were weighed as the anionic component and charged into a glass vial. The mixture was stirred at room temperature for 2 hours, and the reaction was terminated after confirming that the 4-methoxysalicylic acid had completely dissolved, thereby quantitatively obtaining a mixed solution of tetrabutylphosphonium 4-methoxysalicylate and water (hereinafter referred to as "Sample 1").
• a portion of the obtained sample 1 was transferred to a screw bottle and placed in a desiccator under vacuum for several days to evaporate the water, thereby obtaining a viscous liquid, tetrabutylphosphonium 4-methoxysalicylate (hereinafter referred to as "compound 1").
• the measurement results of 1H -NMR, FT-IR and MS of the obtained compound 1 are as follows, and it was confirmed that the desired ionic liquid was obtained.
• Example 2 The same procedure as in Example 1 was repeated except that 0.78 g (5 mmol) of 4-fluorosalicylic acid was used as the anion component, to quantitatively obtain a mixed solution of tetrabutylphosphonium 4-fluorosalicylate and water (hereinafter referred to as "Sample 2").
• a portion of the obtained sample 2 was transferred to a screw bottle and placed in a desiccator under vacuum for several days to evaporate the water, thereby obtaining a viscous liquid, tetrabutylphosphonium 4-fluorosalicylate (hereinafter referred to as "compound 2").
• the measurement results of 1H -NMR, FT-IR and MS of the obtained compound 2 are as follows, and it was confirmed that the target ionic liquid was obtained.
• Example 3 The same procedure as in Example 1 was carried out except that 0.78 g (10 mmol) of 6-fluorosalicylic acid was used as the anion component, to quantitatively obtain a mixed solution of tetrabutylphosphonium 6-fluorosalicylate and water (hereinafter referred to as "Sample 3").
• a portion of the obtained sample 3 was transferred to a screw bottle and placed in a desiccator under vacuum for several days to evaporate the water, thereby obtaining a viscous liquid, tetrabutylphosphonium 6-fluorosalicylate (hereinafter referred to as "compound 3").
• the measurement results of 1H -NMR, FT-IR and MS of the obtained compound 3 are as follows, and it was confirmed that the desired ionic liquid was obtained.
• Example 4 The same operation as in Example 2 was carried out except that 3.24 g (5 mmol) of a 40% by mass aqueous solution of tetrabutylammonium hydroxide was used as the cationic component, and a mixed solution of tetrabutylammonium 4-fluorosalicylate and water (hereinafter referred to as "Sample 4") was quantitatively obtained.
• a portion of the obtained sample 4 was transferred to a screw bottle and placed in a desiccator under vacuum for several days to evaporate the water, thereby obtaining a viscous liquid, tetrabutylphosphonium 4-fluorosalicylate (hereinafter referred to as "compound 4").
• the measurement results of 1H -NMR, FT-IR and MS of the obtained compound 4 are as follows, and it was confirmed that the desired ionic liquid was obtained.
• Example 5 The same operation as in Example 3 was carried out except that 3.24 g (5 mmol) of a 40% by mass aqueous solution of tetrabutylammonium hydroxide was used as the cationic component, and a mixed solution of tetrabutylammonium 6-fluorosalicylate and water (hereinafter referred to as "Sample 5") was quantitatively obtained.
• Example 6 As the cationic component, 3.46 g (5 mmol) of a 40% by mass aqueous solution of tetrabutylphosphonium hydroxide and 1.07 g (5 mmol) of 3-phenylsalicylic acid were weighed as the anionic component and charged into a glass vial. The solids were pulverized with a vortex mixer while stirring at room temperature for 1 hour. Thereafter, the solution was cooled to 4°C and left to stand, and when the solution became clear, the solution was stirred at 4°C.
• Example 6 a mixed solution of tetrabutylphosphonium 3-phenylsalicylate and water
• a portion of the obtained sample 6 was transferred to a screw bottle and placed in a desiccator under vacuum for several days to evaporate the water, thereby obtaining a viscous liquid, tetrabutylphosphonium 3-phenylsalicylate (hereinafter referred to as "compound 6").
• the measurement results of 1H -NMR and MS of the obtained compound 6 are as follows, and it was confirmed that the desired ionic liquid was obtained.
• Example 7 A mixed solution of tetrabutylammonium 4-methoxysalicylate and water (hereinafter referred to as "Sample 7") was quantitatively obtained by the same operation as in Example 1, except that 3.24 g (5 mmol) of a 40 mass % aqueous solution of tetrabutylammonium hydroxide was used as the cationic component.
• a portion of the obtained sample 7 was transferred to a screw bottle and placed in a desiccator under vacuum for several days to evaporate the water, thereby obtaining a viscous liquid, tetrabutylammonium 4-methoxysalicylate (hereinafter referred to as "compound 7").
• the measurement results of 1H -NMR, FT-IR and MS of the obtained compound 7 are as follows, and it was confirmed that the desired ionic liquid was obtained.
• Samples 1 to 8 described in Examples 1 to 7 and Comparative Example 1 are temperature-responsive ionic liquids having an LCST.
• the temperature-responsive ionic liquids of Examples 1 to 5 significantly increased the amount of baricitinib permeated compared to the temperature-responsive ionic liquid of Comparative Example 1 and water of Comparative Example 2, demonstrating enhanced skin permeability of baricitinib.
• Example 3 As shown in Table 3, the temperature-responsive ionic liquid of Example 1 significantly increased the permeability of all drugs compared to water of Comparative Example 2, and enhanced skin permeability to various drugs was observed.
• Example 2 As shown in Table 4, the temperature-responsive ionic liquid of Example 2 was found to enhance the skin permeability of all three types of peptide compounds compared to the temperature-responsive ionic liquid of Comparative Example 1.
• the temperature responsive ionic liquid and the pharmaceutical composition containing the same of the present invention can improve the permeability of drugs through the skin, mucous membranes, etc., and can therefore be used as pharmaceuticals such as external preparations.

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