CN110386869A - Brufen ionic liquid and preparation method thereof - Google Patents

Brufen ionic liquid and preparation method thereof Download PDF

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Publication number
CN110386869A
CN110386869A CN201810360232.6A CN201810360232A CN110386869A CN 110386869 A CN110386869 A CN 110386869A CN 201810360232 A CN201810360232 A CN 201810360232A CN 110386869 A CN110386869 A CN 110386869A
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ionic liquid
brufen
liquid
phosphonium
pharmaceutical composition
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洪鸣凰
任国宾
齐明辉
刘岩
吴浩
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East China University of Science and Technology
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East China University of Science and Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • 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
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • 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
    • C07F9/5407—Acyclic saturated phosphonium compounds

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Abstract

The present invention provides a kind of brufen ionic liquid and its preparations and application, and specifically, the present invention provides a kind of ionic liquid, the ionic liquid is by brufen and cation composition；Wherein, the cation is selected from the group: procaine, three hexyl Shi tetra- Wan Ji Phosphonium, four own ammoniums, or combinations thereof.The ionic liquid can be improved that ibuprofen pharmaceutical is water-soluble or fat-soluble, permeability, so that bioavilability is improved, further increase the therapeutic effect of ibuprofen pharmaceutical, reduce side effect, expand application range etc..

Description

Brufen ionic liquid and preparation method thereof
Technical field
The present invention relates to field of pharmaceutical preparations, and specifically, the present invention provides a kind of brufen ionic liquid and its preparations Method.
Background technique
What ionic liquid (ionic liquid) typically referred to be made of anions and canons, fusing point is lower than 100 DEG C of salt object Matter, wherein the ionic liquid of liquid, referred to as ionic liquid at room temperature are presented at room temperature.Ionic liquid is divided into three by Rogers etc. Generation, first generation ionic liquid mainly apply its " adjustable " physical property, specific by selecting suitable zwitterion preparation to have The ionic liquid of physical property, this ionic liquid can be used as functionality solvents；Second generation ionic liquid mainly applies its change Property is learned, by selecting suitable counter ion to obtain " adjustable " physical property, prepares the ion with specific physicochemical properties Liquid, this ionic liquid can be used as with special chemical property and the good functional material of physical property；The third generation from Sub- liquid mainly applies its bioactivity, by selection there is zwitterion of different nature to obtain " adjustable " physical chemistry Matter, preparation have special bioactivity and the good target product of physicochemical property.
Brufen, chemical name: 2- (4- isobutyl phenenyl) propionic acid, non-steroidal antipyretic-antalgic anti-inflammatory drug is world health group It knits, children's antipyretic that U.S. FDA is uniquely recommended jointly, suitable for migraine phase mild to moderate, rheumatoid joint The treatment in the joints such as inflammation, ankylosing arthritis, osteoarthritis and muscle changes.According to state food pharmaceuticals administration general bureau public affairs The data of cloth show that the commercially available preparation of brufen is mainly solid pharmaceutical preparation (tablets and capsules), at the same also have part it is transdermal to Medicine preparation (cream and gelling agent).
The main administration mode of solid pharmaceutical preparation be it is oral, drug dissolves in the gastrointestinal tract, by gastrointestinal tract epithelial cell film It is absorbed into blood circulation and plays its therapeutic effect.So the dissolubility and permeability of drug directly influence drug It absorbs.And brufen is poorly water soluble drugs, almost insoluble in water, the molten of drug can be improved in the solubility for improving brufen Out-degree and Dissolution behaviours, to improve the bioavilability of ibuprofen oral dosage.
Percutaneous drug administration preparation is expected to efficiently against side reaction caused by oral administration, such as GI irritation, while can To improve the local concentration of drug on the basis of reducing brufen toxicity, be conducive to the treatment of local disease.Currently, market is sold The brufen sold also has the preparation capable of permeating skin of external application, such as Sino-America Tianjin Shike Pharmaceutical Co., Ltd. and Kazakhstan other than oral dosage form The cream form of bioengineering Co., Ltd, medicine group exploitation.But commercially available Ibuprofen cream agent and gelling agent transdermal penetration Low efficiency causes its drug effect limited.
In conclusion this field be it is still necessary to develop further types of Motrin, to improve dissolution rate, the life of brufen Object availability, permeability and drug effect.
Summary of the invention
The object of the present invention is to provide the novel brufen objects of a kind of high-dissolution, bioavilability, permeability and drug effect Manage form and its pharmaceutical composition.
The first aspect of the present invention provides a kind of ionic liquid, and the ionic liquid is by brufen and cationic group At；Wherein, the cation is selected from the group: procaine, four own ammoniums, three hexyl Shi tetra- Wan Ji Phosphonium, or combinations thereof.
In another preferred example, the cation is selected from the group:
Or combinations thereof.
In another preferred example, the ionic liquid be procaine-brufen ionic liquid, four own ammonium-brufens from Sub- liquid, three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid, or combinations thereof.
In another preferred example, the molar ratio of brufen and cation is 1:0.8-1.2, preferably 1:1.
In another preferred example, the ionic liquid is the structure as shown in following formula 1, formula 2 or formula 3:
In another preferred example, the ionic liquid is the structure as shown in the following table 1, table 2 or table 3:
Table 1
Procaine-brufen ionic liquid
Table 2
Four own ammoniums-brufen ionic liquid
Table 3
Three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid.
In another preferred example, the procaine-brufen ionic liquid has selected from the group below one or more special Sign:
(1) glass transition temperature Tg is -30~-2 DEG C, preferably -20~-10 DEG C；
(2) solubility in pure water is 3000-5000 μ g/mL, preferably 3500-4500 μ g/mL；And/or
(3) at 100 DEG C the following are liquid, preferable 40 DEG C hereinafter, more preferably the following are liquid for 25 DEG C of room temperature.
In another preferred example, described four own ammoniums-brufen ionic liquid has one or more features selected from the group below:
(1) glass transition temperature Tg is -70~-40 DEG C, preferably -60~-50 DEG C；
(2) it is >=2, preferably 2.05≤logP≤4, more preferably 2.2≤logP≤3 that Determination of oil-water partition coefficient, which is logP,； And/or
(3) at 100 DEG C the following are liquid, preferable 40 DEG C hereinafter, more preferably the following are liquid for 25 DEG C of room temperature.
In another preferred example, the three hexyls Shi tetra- Wan Ji Phosphonium-brufen ionic liquid has one selected from the group below Or multiple features:
(1) it is >=2.4 that Determination of oil-water partition coefficient, which is logP, preferably 2.5≤logP≤4, more preferably 2.5≤logP≤ 3.5；And/or
(2) at 100 DEG C the following are liquid, preferable 40 DEG C hereinafter, more preferably the following are liquid for 25 DEG C of room temperature.
The second aspect of the present invention provides a kind of method for preparing ionic liquid as described in the first aspect of the invention, Comprising steps of
(a) solution is provided, the solution include the first solvent and the brufen that is dissolved in first solvent and Cationic donor；
(b) the first solvent in the solution is removed, the ion formed by brufen and the cationic donor is obtained Liquid.
In another preferred example, the step (a) is mixing brufen and cationic donor in the first solvent.
In another preferred example, the step (a) is by the brufen being dissolved in the first solvent and to be dissolved in first molten Cationic donor mixing in agent.
In another preferred example, the molar ratio of brufen and cation is 1:0.8-1.2 in the step (a), more preferably Ground 1:1.
In another preferred example, the first solvent is selected from the group in the step (a): water, alcohols, or combinations thereof.
In another preferred example, the alcohol that alcohols is C1-C10 in the step (a), the preferably alcohol of C1-C4, more preferably Ground is ethyl alcohol.
In another preferred example, in the step (b), solvent selection rotary evaporation is removed.
In another preferred example, stirring and/or filtering are further comprised the steps of: before step (b).
It in another preferred example, further include following steps before step (b): the ionic liquid that (b1) prepares step (a) Body is mixed with the second solvent.
In another preferred example, the second solvent is selected from the group in the step (b1): ketone (preferably acetone) or Methylene chloride.
In another preferred example, in step (b) further include: the salt in removal mixed solution.
The third aspect of the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes: (a) treatment is effective The ionic liquid as described in the first aspect of the invention of amount；(b) pharmaceutically acceptable carrier.
In another preferred example, it is 1-99%, preferably 10- that the ionic liquid, which accounts for the total weight of described pharmaceutical composition, 80%, more preferably 20-70%.
In another preferred example, the pharmaceutically acceptable carrier is selected from the group: solvent, preservative, dyestuff, coloring Agent, thickener, surfactant, stabilizer, antioxidant, viscosity improver, or combinations thereof.
In another preferred example, described pharmaceutical composition is preparation.
In another preferred example, the pharmaceutical composition is dosage form selected from the group below: oral preparation, ejection preparation, outer Use preparation.
In another preferred example, described pharmaceutical composition includes procaine-brufen ionic liquid, the pharmaceutical composition The dosage form of object is selected from the group: oral preparation, ejection preparation, Percutaneously administrable preparation, or combinations thereof.
In another preferred example, described pharmaceutical composition include three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid and/or Four own ammoniums-brufen ionic liquid, the dosage form of described pharmaceutical composition are Percutaneously administrable preparation.
In another preferred example, the external preparation is tape preparation.
The fourth aspect of the present invention provides a kind of ionic liquid as described in the first aspect of the invention or such as the present invention the The purposes of pharmaceutical composition described in three aspects is used to prepare prevention or treats the drug of migraine, joint or muscle changes, protects Strong product and food.
In another preferred example, the joint or muscle changes include rheumatoid arthritis, ankylosing arthritis, bone pass Section inflammation, or combinations thereof.
In another preferred example, the ionic liquid or composition are used to prepare analgesia anti-inflammation medicine.
The present invention also provides a kind of methods for treating disease, including use suitable present invention to object in need for the treatment of The ionic liquid or pharmaceutical composition.
In another preferred example, the disease includes migraine, rheumatoid arthritis, ankylosing arthritis, Bones and joints The joints such as inflammation and muscle changes.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, In This no longer tires out one by one states.
Detailed description of the invention
Fig. 1 is procaine in the embodiment of the present invention 1-brufen ionic liquid FT-IR map.
Fig. 2 is procaine in the embodiment of the present invention 1-brufen ionic liquid M-DSC map.
Fig. 3 is procaine in the embodiment of the present invention 1-brufen ionic liquid TGA map.
Fig. 4 is four own ammoniums in the embodiment of the present invention 3-brufen ionic liquid FT-IR map.
Fig. 5 is four own ammoniums in the embodiment of the present invention 3-brufen ionic liquid M-DSC map.
Fig. 6 is four own ammoniums in the embodiment of the present invention 3-brufen ionic liquid TGA map.
Fig. 7 is three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid FT-IR map in the embodiment of the present invention 5.
Fig. 8 is three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid TGA map in the embodiment of the present invention 5.
Specific embodiment
The present invention develops can be improved ibuprofen pharmaceutical water solubility or liposoluble for the first time by extensive and in-depth study Property, infiltrative ionic liquid.Ionic liquid of the invention is by brufen and cation composition, wherein the cation is general Shandong Cacaine (cation), three hexyl Shi tetra- Wan Ji Phosphonium, four own ammoniums, or combinations thereof.The ionic liquid can be improved ibuprofen pharmaceutical Water-soluble or fat-soluble, permeability further increases the therapeutic effect of ibuprofen pharmaceutical, reduces to improve bioavilability Side effect, expansion application range etc..Based on above-mentioned discovery, inventor completes the present invention.
Term
Unless otherwise defined, whole technology used in the present invention and scientific term all have the neck as belonging to the present invention The normally understood identical meanings of the those of ordinary skill in domain.
As described herein, term "comprising", " containing " are used interchangeably, and include not only closed definition, further include half envelope It closes and open definition.In other words, the term include " by ... form " and " substantially by ... form ".
As described herein, terms " formulation " and " dosage form " are used interchangeably, and are referred to adapt to the needs treated or prevented, Made according to certain dosage form requirement, the drug that medication object uses can be can finally be provided to.
The example of " alcohol " in the application includes C1-C10 lower alcohol such as ethyl alcohol, propyl alcohol, isopropanol, n-butanol, amylalcohol, pungent Alcohol, lauryl alcohol etc. or polyalcohol such as ethylene glycol, propylene glycol, 1,3-BDO, polyethylene glycol etc..The preferably alcohol of C1-C4, more It goodly is ethyl alcohol.
As described herein, term " composition " and " pharmaceutical composition " are used interchangeably, and include (a) cloth of therapeutically effective amount Ibuprofen ionic liquid, and (b) pharmaceutically acceptable carrier.
Brufen
Brufen, chemical name: 2- (4- isobutyl phenenyl) propionic acid, structure is as shown in formula A, non-steroidal antipyretic-antalgic anti-inflammatory Medicine is children's antipyretic that the World Health Organization, U.S. FDA are uniquely recommended jointly, suitable for migraine mild to moderate Phase, the treatment in the joints such as rheumatoid arthritis, ankylosing arthritis, osteoarthritis and muscle changes.According to state food medicine The data that product supervision and management general bureau announces show that the commercially available preparation of brufen is mainly solid pharmaceutical preparation (tablets and capsules), together When also have part Percutaneously administrable preparation (cream and gelling agent).
Brufen is poorly water soluble drugs, almost insoluble in water, and drug can be improved in the solubility for improving brufen Dissolution rate and Dissolution behaviours, to improve the bioavilability of ibuprofen oral dosage.Meanwhile commercially available Ibuprofen cream agent and Gelling agent transdermal penetration low efficiency causes its drug effect limited.Cuticula is the most important permeability barrier of drugs through skin, one As think, fat-soluble stronger drug is easy to through cuticula.Determination of oil-water partition coefficient is that one kind simply shows compound oleophylic parent Aqueous model, Log P value more fat-solubility are stronger.The Determination of oil-water partition coefficient of drug has certain correlation with infiltration rate, With the increase of Determination of oil-water partition coefficient value, the infiltration rate of drug can also be improved.Brufen is improved using Ionic liquids technologies Drug transdermal infiltration rate can be improved in lipophilicity.
For its disadvantage mentioned above, the present invention provides the brufen ionic liquids that modified form preparation can be further made in one kind Body can effectively improve the water solubility or lipophilicity of brufen, improve permeability, bioavilability and drug effect.
Ionic liquid
As used herein, term " ionic liquid ", " ionic liquid of the present invention " and " brufen ionic liquid " is interchangeable makes With referring both to ionic liquid described in first aspect present invention.
Ionic liquid of the present invention is by brufen and cation composition；Wherein, the cation is selected from the group: procaine Cation, four own ammoniums, three hexyl Shi tetra- Wan Ji Phosphonium, or combinations thereof.
Brufen provides anion, in conjunction with cationic components, forms the ionic liquid that liquid is presented at room temperature.
Representative, the ionic liquid is procaine-brufen ionic liquid, four own ammoniums-brufen ionic liquid Body, three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid.Ionic liquid structure as shown in formula 1, formula 2 or formula 3.
Present solution provides three kinds of new brufen ionic liquids, procaines-brufen [Pro] [Ibu], four own ammoniums- Brufen [N6,6,6,6] [Ibu] and three hexyl Shi tetra- Wan Ji Phosphonium-brufen [P6,6,6,14] [Ibu], belong to third generation ionic liquid. Procaine-brufen [Pro] [Ibu] ionic liquid water solubility in the present invention is better than brufen, four own ammonium-brufens [N6,6,6,6] [Ibu] and three hexyl Shi tetra- Wan Ji Phosphonium-brufen [P6,6,6,14] [Ibu] Determination of oil-water partition coefficient be higher than brufen.
The first brufen ionic liquid provided by the present invention: procaine-brufen ionic liquid [Pro] [Ibu], It is the equimolar salt that procaine and brufen are formed, glass transition temperature is -12.69 DEG C, solubility in 25 DEG C of pure water For 3941.63 μ g/mL.Brufen is insoluble in water, and equilbrium solubility is 67.22 μ g/mL in 25 DEG C of pure water.Brufen and general Shandong Cacaine can significantly improve the equilbrium solubility of brufen in water after forming ionic liquid.
Procaine-brufen ionic liquid
Second of brufen ionic liquid provided by the present invention: four own ammoniums-brufen ionic liquid [N6,6,6,6] [Ibu] is four own ammoniums and brufen forms equimolar salt, and glass transition temperature is -56.05 DEG C, and 25 DEG C of grease distributes system Number Log P value is 2.47.Four own ammoniums-brufen ionic liquid Determination of oil-water partition coefficient value is higher than brufen Determination of oil-water partition coefficient Log P value 1.89.
Four own ammoniums-brufen ionic liquid
The third brufen ionic liquid provided by the present invention: three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid [P6,6,6,14] [Ibu], it is that three hexyl Shi tetra- Wan Ji Phosphonium and brufen form equimolar salt, 25 DEG C of Determination of oil-water partition coefficient Log P Value is 3.04.Three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid Determination of oil-water partition coefficient value is higher than brufen grease distribution system Number Log P value 1.89.
Three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid
Pharmaceutical composition, method of administration and application
The present invention provides a kind of pharmaceutical composition, the ions as described in the first aspect of the invention of (a) therapeutically effective amount Liquid；(b) pharmaceutically acceptable carrier.
In another preferred example, with the total weight of described pharmaceutical composition, the weight percent of the ionic liquid contains Amount is 1-99%, preferably 10-80%, more preferably 20-70%.
" effective quantity " or " effective dose " refers to as described herein can generate function or active and can to people and/or animal The amount received by people and/or animal.It should be appreciated by those skilled in the art that " effective quantity " or " effective dose " It can combine with the form of pharmaceutical composition, administration route, excipient substance used, the severity of disease and with other drugs Situations such as medication it is different and different.
" pharmaceutically acceptable carrier " refers to as described herein: one or more biocompatible solids, semisolid, liquid Or gel filler, they are suitble to human or animal to use and it is necessary to have enough purity and enough toxicity." compatibility " refers to The active constituent of each component and drug in pharmaceutical composition and they between mutually admix, and significantly reduce drug effect.
It should be understood that in the present invention, the carrier is not particularly limited, material commonly used in the art can be selected, or use Conventional method is made, or is commercially available from market.
Pharmaceutically acceptable carrier partial example has cellulose and its derivates (such as methylcellulose, ethyl cellulose, hydroxyl Third methylcellulose, sodium carboxymethylcellulose etc.), gelatin, talcum powder, solid lubricant (such as stearic acid, magnesium stearate), sulfuric acid Calcium, vegetable oil (such as soya-bean oil, sesame oil, peanut oil, olive oil), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite Deng), emulsifier (such as), wetting agent (such as lauryl sodium sulfate), transdermal enhancer, colorant, flavoring agent, stabilizer, Antioxidant, preservative, apirogen water, etc..
Other than active pharmaceutical ingredient, liquid dosage form may include the inert diluent routinely used in this field, such as water or Other solvents, solubilizer and emulsifier, for example, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, Dimethylformamide and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these objects The mixture etc. of matter.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste Agent and fragrance.
In the present invention, the dosage form of pharmaceutical composition includes but is not limited to oral preparation, injection, external preparation.
In the present invention, a kind of dosage form of preferred pharmaceutical composition is oral preparation or Percutaneously administrable preparation.It is transdermal to give The type of medicine preparation can be divided into: film controlling type transdermal administration, framework controlled release type transdermal administration, pair micro-reservoirs control release type are transdermal Form of administration, adhesive control release type transdermal administration.In addition, Percutaneously administrable preparation also contains ointment, emplastrum, paint Deng.
In another preference of the invention, the dosage form of pharmaceutical composition includes tape preparation.
Generally, tape preparation is made of ionic liquid of the present invention and thickener, softening agent, filler, antioxidant etc., And any commonly employed and widely applied ingredient can be used in the present invention, it especially can optionally add or cancel filling Agent and antioxidant.
The example of above-mentioned filler includes zinc oxide, titanium oxide, calcium carbonate, silicic acid etc..
Above-mentioned " softening agent " means that height sticks the additive of object (adhesion layer) characteristic, such as gelled hydrocarbon.In addition, for any mesh , oil-extender such as atoleine, vaseline, operation oil or low molecular weight polycaprolactone butylene can be used；Fat oil softening agent such as castor Sesame oil or palm oil；Or the lanolin of purifying.In the present invention, individual gelled hydrocarbon or one kind or multiclass softening agent can be used Combination as softening agent.Preferably, the example for the softening agent being added in gelled hydrocarbon include oil-extender such as atoleine, Vaseline, operation oil or low molecular weight polycaprolactone butylene.
Plaster of the present invention comprising brufen ionic liquid of the present invention can be prepared according to known any method, for example, It can by by brufen ionic liquid of the present invention and excipient such as alcoholic solvent, ester solvent, softening agent or tackifier etc. together Dissolution is in a solvent, rear on being spread over release liner or backing to remove the solvent by dry, and finally with another Release liner or backing are covered.
Preparation of the invention includes (a) ionic liquid, and (b) pharmaceutically acceptable carrier.
Due to the barrier action of skin and the reasons such as physicochemical property of drug itself, many drugs pass through the logical of skin Saturating rate is very low, transdermal to reach intracorporal drug and be hard to reach effective treatment concentration.Therefore, skin penetration enhancer is transdermal gives A kind of critically important pharmaceutically acceptable carrier in medicine preparation.
Skin penetration enhancer is to refer to penetrate into skin reduction material of the drug by skin resistance, can be assisted Drug passes through cuticula, diffuses through skin, enters body circulation by capillary, is mainly used in Transdermal absorption drug-delivery preparation, Have the function that part works or whole body works.Typically, skin penetration enhancer includes organic alcohols, esters, laurel nitrogen Zhuo Ketone, surfactant, terpenes, wherein the organic alcohols be preferably ethyl alcohol, propylene glycol, ethyl acetate, dimethyl sulfoxide, N,N-Dimethylformamide etc., or combinations thereof；The wherein surfactant and biological membrane interaction, promote drug to inhale It receives.
The method of administration of pharmaceutical composition of the invention is not particularly limited, and representative method of administration includes (but not It is limited to): percutaneous dosing, oral, sucking, injection, subcutaneous etc..
Pharmaceutical preparation should match with administration mode.Representative, in the present invention, pharmaceutical composition is prepared to paste Agent passes through local percutaneous dosing；Or pharmaceutical composition is made into the form of injection, by vein, subcutaneous, intradermal, muscle Equal positions drug administration by injection.The dosage of active pharmaceutical ingredient is therapeutically effective amount, such as about 1 microgram/kg body weight-about 5 daily Mg/kg weight.In addition, drug of the present invention can also be with other therapeutic agents (such as other hypoglycemic drugs or other hypoglycemic associations Same drug) be used together (including before, among or use later).
It is that the ionic liquid of safe and effective amount and pharmaceutical composition are applied to mammal, certainly, specifically using drug Dosage is also contemplated that the factors such as administration route, patient health situation, within the scope of these are all skilled practitioners technical ability.
In the present invention, the ionic liquid and pharmaceutical composition are suitable for preparation prevention or treatment migraine, class wind The drug of the joints such as wet arthritis, ankylosing arthritis, osteoarthritis and muscle changes, health care product and food.
Differential scanning calorimetry
Also known as " differential scanning calorimetric analysis " (DSC) is during heating, to measure between measured matter and reference substance A kind of technology of relationship between energy difference and temperature.The property of peak position, shape and peak number mesh and substance on DSC map has It closes, therefore can qualitatively be used to identify substance.This method commonly used in the art detects phase transition temperature, the glass transition temperature of substance The many kinds of parameters such as degree, reaction heat.
Main advantages of the present invention include:
1, three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid and four own ammoniums-brufen ionic liquid oil of the invention Water partition coefficient is significantly higher than brufen, improves the fat-soluble and permeability of brufen, to improve the biological utilisation of brufen Degree.
2, procaine of the invention-brufen ionic liquid water solubility is better than brufen, is approximately 58.6 times of brufen, The dissolution rate and Dissolution behaviours of brufen are significantly improved, and then improves the bioavilability of ibuprofen oral dosage.
3, ionic liquid of the invention can improve the solubility and permeability of drug, to improve the biological utilisation of drug Degree, its pharmaceutical activity of energy fast onset.Therefore, ionic liquid of the present invention or pharmaceutical composition are effective for preventing and/or treating The joints such as migraine, rheumatoid arthritis, ankylosing arthritis, osteoarthritis and muscle changes.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Unless otherwise defined, it anticipates known to all professional and scientific terms as used herein and one skilled in the art Justice is identical.In addition, any method similar to or equal to what is recorded and material can be applied to the method for the present invention.Wen Zhong The preferred implement methods and materials are for illustrative purposes only.
1. procaines of example-brufen ionic liquid preparation
550mg (2.0mmol) procaine hydrochloride is dissolved in 4mL ultrapure water, and it is super that the Sodium ibuprofen of equimolar amounts is dissolved in 4mL It is slowly dropped to after pure water in the aqueous solution of procaine hydrochloride, 2h is stirred at room temperature.The stirring of 20mL methylene chloride, extraction is added, Removal sodium chloride is washed with water in dichloromethane layer, and silver nitrate detection ensures without remaining chloride ion.After Rotary Evaporators remove solvent, Steam empty drying for 24 hours.
(1) to the procaine prepared in embodiment 1-brufen ionic liquid do nuclear magnetic resonance spectroscopy (1H NMR) point Analysis, operates and be analyzed as follows: using Bruker solution NMR (400MHz), deuterated dimethyl sulfoxide is solvent, tetramethyl Silane is as internal standard.
Procaine-brufen ionic liquid nuclear magnetic resonance spectroscopy:1H NMR(400MHz,DMSO-d6)δ7.63(d,J =8.5Hz, 2H), 7.18 (d, J=7.9Hz, 2H), 7.09 (d, J=7.9Hz, 2H), 6.56 (d, J=8.5Hz, 2H), 5.98 (s, 2H), 4.19 (t, J=6.1Hz, 2H), 3.61 (q, J=7.1Hz, 1H), 2.71 (t, J=6.1Hz, 2H), 2.55 (q, J= 7.1Hz, 4H), 2.41 (d, J=7.1Hz, 2H), 1.80 (dp, J=13.5,6.8Hz, 1H), 1.33 (d, J=7.1Hz, 3H), 6.02-5.92 (m, 2H), 0.96 (t, J=7.1Hz, 6H), 0.85 (d, J=6.6Hz, 6H)
A: procaine hydrochloride；B: procaine-brufen
A: brufen；B: procaine-brufen
(2) fourier-transform infrared line (FT-IR) analysis, operation are done to the procaine-brufen prepared in embodiment 1 Be analyzed as follows: attenuated total reflection (ATR) is used to obtain IR spectrum, and instrument is Agilent infrared spectrometer (Cary 630), At room temperature, parameter setting: 400-4000cm-1,32scans,resolution of 8cm-1。
Procaine-brufen ionic liquid FT-IR map is as shown in Figure 1,1697cm-1Place's discovery is based on free carboxy acid The broad absorption band of the C=O stretching vibration of group, compared to brufen 1706cm-1The stretching vibration at place shifts.As the result is shown Procaine and brufen are not the mixtures of two kinds of compounds, there is bonding active force between the two.
(3) modulation system differential scanning calorimetry (M- is done to the procaine prepared in embodiment 1-brufen ionic liquid DSC it) analyzes, operation and analytical procedure are as follows: TA Q2000 differential scanning calorimeter is used, using N2Atmosphere, heating rate 1 DEG C/min, modulation period 60s.
Procaine-brufen ionic liquid M-DSC figure is as shown in Fig. 2, wherein glass transition temperature is -12.69 ℃。
(4) thermogravimetric (TGA) analysis, operation and analysis are done to the procaine prepared in embodiment 1-brufen ionic liquid Steps are as follows: TA Q500 thermogravimetric analyzer is used, using N2Atmosphere, heating rate are 10 DEG C/min.
Procaine-brufen ionic liquid TGA schemes as shown in figure 3, in 100 DEG C as a result TGA weightlessness is shown less than 5% Show that solvent does not influence the physical aspect of its final ionic liquid substantially.
2. procaines of example-brufen ionic liquid and brufen solubility compare
It weighs excessive procaine-brufen ionic liquid and brufen is suspended in pure water, after concussion for 24 hours, using height Effect liquid phase chromatogram instrument tests solubility, and test result is as follows:
Compound Solubility (μ g/mL)
Procaine-brufen 3941.63
Brufen 67.22
It can be seen that procaine-solubility of the brufen ionic liquid in pure water is apparently higher than brufen, it is approximately cloth 58.6 times of ibuprofen.Procaine-brufen ionic liquid water solubility is fabulous, significantly improves dissolution rate and the dissolution of brufen Property, and then improve the bioavilability of ibuprofen oral dosage.
The own ammonium of example 3. 4-brufen ionic liquid preparation
Four hexyl ammonium bromide of 434mg (1.0mmol) is dissolved in 4mL ultrapure water, and it is super that the Sodium ibuprofen of equimolar amounts is dissolved in 4mL It is slowly dropped to after pure water in the aqueous solution of four hexyl ammonium bromides, 2h is stirred at room temperature.The stirring of 20mL methylene chloride, extraction is added, Washing removal sodium chloride, silver nitrate detection ensure without remaining chloride ion.After Rotary Evaporators remove solvent, empty drying is steamed for 24 hours.
(1) to prepared in embodiment 3 four own ammonium-brufens do nuclear magnetic resonance spectroscopy (1H NMR) analysis, it operates and divides It analyses as follows: using Bruker solution NMR (400MHz), deuterated dimethyl sulfoxide is solvent, in tetramethylsilane conduct Mark.
Four own ammoniums-brufen ionic liquid nuclear magnetic resonance spectroscopy:1H NMR (400MHz, DMSO-d6) δ 7.13 (d, J= 7.7Hz, 2H), 6.94 (d, J=7.7Hz, 2H), 3.21-3.11 (m, 9H), 2.36 (d, J=7.1Hz, 2H), 1.78 (dt, J= 13.5,6.7Hz, 1H), 1.57 (m, J=10.6,5.8Hz, 8H), 1.35-1.22 (m, 24H), 1.17 (d, J=7.1Hz, 3H), 0.87 (q, J=6.6Hz, 18H)
A: four hexyl ammonium bromides；B: four own ammonium-brufens
A: brufen；B: four own ammonium-brufens
(2) to prepared in embodiment 3 four own ammonium-brufens do fourier-transform infrared line (FT-IR) analysis, operation and Be analyzed as follows: attenuated total reflection (ATR) is used to obtain IR spectrum, and instrument is Agilent infrared spectrometer (Cary 630), room Under temperature, parameter setting: 400-4000cm-1,32scans,resolution of 8cm-1。
Four own ammoniums-brufen ionic liquid FT-IR map is as shown in figure 4,1577cm-1Place's discovery is based on carboxylate anion (COO-) new absorption band, compared to brufen 1706cm-1The stretching vibration at place shifts.Four own ammoniums and cloth Lip river as the result is shown Sweet smell is not the mixture of two kinds of compounds, there is bonding active force between the two.
(3) modulation system differential scanning calorimetry (M-DSC) is done to prepare in embodiment 3 four own ammoniums-brufen ionic liquid Analysis, operation and analytical procedure are as follows: TA Q2000 differential scanning calorimeter are used, using N2Atmosphere, heating rate be 1 DEG C/ Min, modulation period 60s.
Four own ammoniums-brufen ionic liquid M-DSC figure is as shown in figure 5, wherein glass transition temperature is -56.05 DEG C.
(4) thermogravimetric (TGA) analysis, operation and analysis step are done to prepare in embodiment 3 four own ammoniums-brufen ionic liquid It is rapid as follows: TA Q500 thermogravimetric analyzer to be used, using N2Atmosphere, heating rate are 10 DEG C/min.
Four own ammoniums-brufen ionic liquid TGA schemes as shown in fig. 6, TGA weightlessness is less than 5% in 100 DEG C, as the result is shown Solvent does not influence the physical aspect of its final ionic liquid substantially.
The own ammonium of example 4. 4-brufen ionic liquid and brufen Determination of oil-water partition coefficient compare
Directive/guide No.107 (1995 editions) " n-octyl alcohol-moisture is tested according to the Organization of Economy and Cooperation Development's (OECD) chemicals Distribution coefficient: fask oscillating method " survey Determination of oil-water partition coefficient.Before test, n-octyl alcohol need to be handled with water through presaturation, i.e., under test temperature, Using two big liquid storage bottles, it is respectively charged into n-octyl alcohol and enough water, water and enough n-octyl alcohols, is placed in constant temperature oscillator and shakes After shaking for 24 hours, standing the sufficiently long time is kept completely separate two-phase, to respectively obtain water saturated n-octyl alcohol, n-octyl alcohol saturated water. The drug of 0.01mmol is added in the ampoule bottle of 10mL, adds the water saturated n-octyl alcohol of 4mL and the n-octyl alcohol saturation of 4mL Water, shaking table (200rpm) concussion reaches balance for 24 hours at a temperature of 25 DEG C, stands the sufficiently long time and is kept completely separate two-phase, HPLC detects the concentration of brufen in two-phase.Test result is as follows:
Compound Determination of oil-water partition coefficient Log P
Four own ammonium-brufens 2.47
Brufen 1.89
It can be seen that four own ammoniums-brufen ionic liquid Determination of oil-water partition coefficient value is apparently higher than brufen, it is approximately Bu Luo Fragrant 1.3 times.Four own ammoniums-brufen ionic liquid improves the fat-soluble and transdermal penetration rate of brufen, further increases The drug effect of ibuprofen transdermal preparation.
5. 3 hexyl Shi tetra- Wan Ji Phosphonium of example-brufen ionic liquid preparation
Three hexyl tetradecane Ji phosphonium chloride of 529mg (1.0mmol) is dissolved in 5mL ethyl alcohol, and the Sodium ibuprofen of equimolar amounts adds Enter into solution, 4h is stirred at room temperature, filter, 20mL acetone is added, stirs 2h, filtering.After Rotary Evaporators remove solvent, vacuum Drying is for 24 hours.
To the three hexyl Shi tetra- Wan Ji Phosphonium-brufen prepared in embodiment 5 do nuclear magnetic resonance spectroscopy (1H NMR) analysis, behaviour Make and be analyzed as follows: using Bruker solution NMR (400MHz), deuterated dimethyl sulfoxide is solvent, tetramethylsilane As internal standard.
The nuclear magnetic resonance spectroscopy of three hexyl Shi tetra- Wan Ji phosphonium ion liquid of brufen:1H NMR(400MHz,DMSO-d6)δ 7.14 (d, J=7.8Hz, 2H), 6.97 (d, J=7.8Hz, 2H), 2.37 (d, J=7.1Hz, 2H), 2.19 (td, J=13.0, 6.8Hz, 8H), 3.39-3.30 (m, 1H), 1.48-1.23 (m, 48H), 1.21 (d, J=7.0Hz, 3H), 0.94-0.81 (m, 18H),1.84–1.73(m,1H).
A: three hexyl tetradecane Ji phosphonium chlorides；B: three hexyl Shi tetra- Wan Ji Phosphonium-brufen
A: brufen；B: three hexyl Shi tetra- Wan Ji Phosphonium-brufen
(2) fourier-transform infrared line (FT-IR) is done to the three hexyl Shi tetra- Wan Ji Phosphonium-brufen prepared in embodiment 5 Analysis, operates and be analyzed as follows: attenuated total reflection (ATR) is used to obtain IR spectrum, and instrument is Agilent infrared spectrometer (Cary 630), at room temperature, parameter setting: 400-4000cm-1,32scans,resolution of 8cm-1。
Three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid FT-IR map is as shown in fig. 7,1580cm-1Place's discovery is based on Carboxylate anion (COO-) new absorption band, compared to brufen 1706cm-1The stretching vibration at place shifts.As the result is shown three Hexyl Shi tetra- Wan Ji Phosphonium and brufen are not the mixtures of two kinds of compounds, and three hexyl Shi tetra- Wan Ji Phosphonium have bonding between the two Active force.
(3) modulation system differential scanning amount is done to the three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid prepared in embodiment 5 Hot (M-DSC) analysis, operation and analytical procedure are as follows: TA Q2000 differential scanning calorimeter are used, using N2Atmosphere, heating speed Degree be 1 DEG C/min, modulation period 60s.
Three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid glass transition temperature is not found, is schemed unlisted.
(4) thermogravimetric (TGA) analysis, behaviour are done to the three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid prepared in embodiment 5 Make and analytical procedure is as follows: TA Q500 thermogravimetric analyzer is used, using N2Atmosphere, heating rate are 10 DEG C/min.
Three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid TGA schemes as shown in figure 8, TGA weightlessness is less than in 100 DEG C 5%, solvent does not influence the physical aspect of its final ionic liquid substantially as the result is shown.
6. 3 hexyl Shi tetra- Wan Ji Phosphonium of embodiment-brufen ionic liquid and brufen Determination of oil-water partition coefficient compare
Directive/guide No.107 (1995 editions) " n-octyl alcohol-moisture is tested according to the Organization of Economy and Cooperation Development's (OECD) chemicals Distribution coefficient: fask oscillating method " survey Determination of oil-water partition coefficient.Before test, n-octyl alcohol need to be handled with water through presaturation, i.e., under test temperature, Using two big liquid storage bottles, people's n-octyl alcohol and enough water, water and enough n-octyl alcohols are filled respectively, is placed in constant temperature oscillator and shakes After shaking for 24 hours, standing the sufficiently long time is kept completely separate two-phase, to respectively obtain water saturated n-octyl alcohol, n-octyl alcohol saturated water. The drug of 0.01mmol is added in the ampoule bottle of 10mL, adds the water saturated n-octyl alcohol of 4mL and the n-octyl alcohol saturation of 4mL Water, shaking table (200rpm) concussion reaches balance for 24 hours at a temperature of 25 DEG C, stands the sufficiently long time and is kept completely separate two-phase, HPLC detects the concentration of brufen in two-phase.Test result is as follows:
Compound Determination of oil-water partition coefficient Log P
Three hexyl Shi tetra- Wan Ji Phosphonium-brufen 3.04
Brufen 1.89
It can be seen that three hexyls, 14 alkane base Phosphonium-brufen ionic liquid Determination of oil-water partition coefficient value is apparently higher than Bu Luo Sweet smell is approximately 1.6 times of brufen.Three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid improves the fat-soluble and saturating of brufen Skin infiltration rate further improves the drug effect of ibuprofen transdermal preparation.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (10)

1. a kind of ionic liquid, which is characterized in that the ionic liquid is by brufen and cation composition；Wherein, described Cation is selected from the group: procaine, four own ammoniums, three hexyl Shi tetra- Wan Ji Phosphonium, or combinations thereof.
2. ionic liquid as described in claim 1, which is characterized in that the ionic liquid is procaine-brufen ion Liquid, four own ammoniums-brufen ionic liquid, three hexyl Shi tetra- Wan Ji Phosphonium-brufen ionic liquid, or combinations thereof.
3. ionic liquid as described in claim 1, which is characterized in that the ionic liquid is such as following formula 1, formula 2 or 3 institute of formula The structure shown:
4. ionic liquid as claimed in claim 2, which is characterized in that the procaine-brufen ionic liquid has choosing From the one or more features of the following group:
(1) glass transition temperature Tg is -30~-2 DEG C, preferably -20~-10 DEG C；
(2) solubility in pure water is 3000-5000 μ g/mL, preferably 3500-4500 μ g/mL；And/or
(3) at 100 DEG C the following are liquid, preferable 40 DEG C hereinafter, more preferably the following are liquid for 25 DEG C of room temperature.
5. ionic liquid as claimed in claim 2, which is characterized in that the four own ammoniums-brufen ionic liquid, which has, to be selected from The one or more features of the following group:
(1) glass transition temperature Tg is -70~-40 DEG C, preferably -60~-50 DEG C；
(2) it is >=2, preferably 2.05≤logP≤4, more preferably 2.2≤logP≤3 that Determination of oil-water partition coefficient, which is logP,；And/or
(3) at 100 DEG C the following are liquid, preferable 40 DEG C hereinafter, more preferably the following are liquid for 25 DEG C of room temperature.
6. ionic liquid as claimed in claim 2, which is characterized in that the three hexyls Shi tetra- Wan Ji Phosphonium-brufen ionic liquid Body has one or more features selected from the group below:
(1) it is >=2.4, preferably 2.5≤logP≤4, more preferably 2.5≤logP≤3.5 that Determination of oil-water partition coefficient, which is logP,； And/or
(2) at 100 DEG C the following are liquid, preferable 40 DEG C hereinafter, more preferably the following are liquid for 25 DEG C of room temperature.
7. a kind of prepare the method such as ionic liquid of any of claims 1-6, which is characterized in that comprising steps of
(a) solution is provided, the solution include the first solvent and the brufen that is dissolved in first solvent and sun from Sub- donor；
(b) the first solvent in the solution is removed, the ionic liquid formed by brufen and the cationic donor is obtained.
8. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes: (a) therapeutically effective amount such as claim Ionic liquid described in any one of 1-6；(b) pharmaceutically acceptable carrier.
9. pharmaceutical composition as claimed in claim 8, which is characterized in that the pharmaceutical composition is selected from the group below dose Type: oral preparation, ejection preparation, external preparation.
10. the purposes of a kind of ionic liquid as described in claim 1 or pharmaceutical composition as claimed in claim 8, special Sign is, is used to prepare prevention or treats drug, health care product and the food of migraine, joint or muscle changes.
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CN112755196A (en) * 2019-11-01 2021-05-07 华东理工大学 Donepezil ionic liquid
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