WO1998031369A1 - External preparations for percutaneous absorption - Google Patents

Abstract

External preparations of methotrexate for percutaneous absorption, having systemic therapeutic effects on, for example, chronic inflammatory diseases such as autoimmune diseases (rheumatoid arthritis, etc.) and cancerous diseases such as leukemia and aiming at relieving the side effects of methotrexate and improving the compliance and quality of life of patients. These preparations contain a chemical (i.e., methotrexate) in the bases and exert systemic therapeutic effects on the patients.

Description

 Description Transdermal external preparation Technical field

 The present invention relates to an external preparation for percutaneous absorption, and more particularly to a topical external preparation having a systemic therapeutic effect for the treatment of chronic inflammatory diseases such as autoimmune diseases (eg, rheumatoid arthritis) or cancer diseases such as leukemia. Agent. Background art

 Methotrexate has been used as an antineoplastic drug in the form of tablets and injections for diseases such as acute leukemia, chronic myeloid leukemia, and villous disease. In recent years, administration as an immunosuppressant for chronic articular rheumatism has also been attempted (Pharmaceutical Journal, Vol. 27, No. 3, p544-25447, 1999). 1 year). Also, JP-A-63-27432 discloses a preparation comprising methotrexate or an analog thereof, a skin-penetrating reagent and a carrier, for example, a hyperproliferative epithelial disease such as psoriasis. It is disclosed that a therapeutic effect is produced by local administration to the skin. It has also recently been shown to be highly effective against breast cancer (Cancer and Chemotherapy, Vol. 21, No. 12, pl 949, 1994).

 However, when used in the form of methotrexatoca tablets or injections, hepatic dysfunction, gastrointestinal dysfunction, renal dysfunction, blood disorders due to bone marrow suppression (leukopenia, thrombocytopenia, anemia), etc. Serious side effects are a problem (rheumatism; 3 1

(5), p 5 4 4—5 53, 1991).

 Also, the method described in Japanese Patent Application Laid-Open No. 63-27432 discloses that permeation of methotrexate into basal epidermal cells of a mammal to locally inhibit DNA synthesis in epidermal cells. It acts locally and exerts its efficacy, and it absorbs methotrexate percutaneously, for example, chronic inflammatory diseases such as autoimmune diseases.

It does not relate to an external preparation for percutaneous absorption having a systemic therapeutic effect in the treatment of cancer diseases such as rheumatoid arthritis and leukemia. An object of the present invention is to reduce the above-mentioned side effects of methotrexate and to improve the patient's compliance and quality of life. For example, chronic inflammatory diseases such as autoimmune diseases (for example, chronic It is an object of the present invention to provide an external preparation for transdermal absorption of methotrexate having a systemic therapeutic effect in treating cancer diseases such as rheumatoid arthritis) and leukemia. Summary of the Invention

 The present invention relates to an external preparation for percutaneous absorption comprising a drug in a base and having a systemic therapeutic effect on a disease to be treated, wherein the drug is methotrexate. Agent. BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 is a schematic diagram for explaining a rat skin permeability test using a diffusion cell in Test Example 6. 1 represents a diffusion cell. 2 represents one receptor tank. 3 represents a donor tank. 4 represents an opening. 5 represents a flange. 6 represents a flange. 7 indicates the sampling port. 8 represents a piece of skin. 9 represents a magnetic stirrer.

 10 represents the center of the skin piece. Detailed Disclosure of the Invention

 Hereinafter, the present invention will be described in detail.

 The external preparation for transdermal absorption of the present invention contains a drug in a base. In the transdermal preparation for transdermal absorption of the present invention, the drug is methotrexate.

The external preparation for transdermal absorption of the present invention uses methotrexate as a form of the external preparation for transdermal absorption, not the conventional form of tablets or injections. As a result, the effect of maintaining the blood concentration can be maintained, which not only reduces the number of administrations of the drug but also simplifies the administration and allows patients to withstand long-term administration. As a result, improvements in patient compliance and quality of life are achieved. Furthermore, since the blood concentration of methotrexate can be controlled without temporarily increasing the blood concentration, hepatic metabolism can be particularly avoided. You. In addition, since it is administered parenterally, its effects on the digestive tract are reduced, especially when compared to tablets.

 The content of the above-mentioned methotrexate in the base is preferably 0.001 to 30% by weight. If the amount is too small, the transdermal absorption of mettrexate will be insufficient, so that effective drug efficacy may not be exhibited.If the amount is too large, the amount of transdermal absorption will be too large, which may cause side effects. is there. More preferably, it is from 0.001 to 20% by weight, and even more preferably from 0.005 to 15% by weight.

 The base is not particularly limited as long as it is pharmaceutically acceptable. In the present invention, polymers, inorganic fillers, oils and fats, hydrocarbons, polyhydric alcohols, higher fatty acids, higher alcohols, lower alcohols Alcohol and water are preferably used. These may be used alone or in combination of two or more. Further, a composition containing these may be used.

 The polymer is not particularly limited, and examples thereof include sodium alginate, gelatin, corn starch, tragacanth, methylcellulose, hydroxyshethyl cellulose, hydroquinine propylcellulose, carboquin methylcellulose, sodium propyloxymethylcellulose, and dextrin. , Carboxymethyl starch, polyvinyl alcohol, polyacrylic acid, polyacrylate (eg, sodium salt), meth- oxyethylene-maleic anhydride copolymer, polyvinyl ether, polyvinylpyrrolidone, polyacrylamide and the like.

 The inorganic filler is not particularly restricted but includes, for example, colloidal hydrous aluminum silicates such as kaolin and bentonite; colloidal hydrous magnesium silicates such as veegum; aluminum-based minerals; titanium oxide; Zinc, gay acid and the like.

 The fats and oils are not particularly limited, and include, for example, beeswax, olive oil, cocoa oil, sesame oil, soybean oil, camellia oil, laccase oil, beef oil, pork oil, lanolin and the like.

The hydrocarbon is not particularly limited, and includes, for example, white petrolatum, paraffin, liquid paraffin, hide mouth carbon gel ointment (for example, “Plastibase” (manufactured by Bristol-Myers Squibb)) and the like. The polyhydric alcohol is not particularly limited, and includes, for example, ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, sorbitol and the like.

 The higher fatty acid is not particularly limited, and includes, for example, pupuric acid, nonanoic acid, puprilic acid, pendecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, lumitic acid, heptadecylic acid, stearic acid, Saturated or unsaturated fatty acids such as oleic acid, nonadenic acid, arachidonic acid, linoleic acid, behenic acid, lignoceric acid, cerotic acid, hebutacosanoic acid, palmitoleic acid, vaccenic acid, and linolenic acid.

 The higher alcohol is not particularly limited. Examples thereof include lauryl alcohol, dodecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, hexadecyl alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, and nona. Decyl alcohol, eicosyl alcohol, ceryl alcohol, mesyl alcohol, cetyl alcohol and the like. The lower alcohol is not particularly limited, and includes, for example, isopropyl alcohol, ethanol and the like.

 The base preferably contains a transdermal absorption enhancer. The above-mentioned percutaneous absorption enhancer is not particularly limited as long as it is usually used in a percutaneous absorption preparation. In the present invention, alcohols, organic acids, higher fatty acid esters, and hydroxycarboxylic acid esters are used. , N-acyl sarcosine and a surfactant are preferably used. These may be used alone or in combination of two or more.

As the alcohol, a monohydric alcohol or a polyhydric alcohol is preferable. The above monohydric alcohol is preferably one having 8 to 14 carbon atoms. If the number of carbon atoms is less than 8, volatility may increase, and if the number of carbon atoms exceeds 14, the effect of promoting absorption may decrease. Such a monohydric alcohol is not particularly limited, and examples thereof include lauryl alcohol, oleyl alcohol, and cetyl alcohol. The polyhydric alcohol is not particularly limited, and examples thereof include propylene glycol, 1,3-butanediol, glycerin, and polyethylene glycol. As the organic acid, a monovalent organic acid or a polyvalent organic acid is preferable. Such organic acids are not particularly limited, and include, for example, monocarboxylic acids, dicarboxylic acids or salts thereof, and hydroxydicarboxylic acids or salts thereof.

 The monocarboxylic acid as the organic acid is preferably one having 8 to 20 carbon atoms. If the number of carbon atoms is less than 8, the acidity is so strong that it may be difficult to apply to the human body. If the number of carbon atoms exceeds 20, the absorption promoting effect may be reduced. Such a monocarboxylic acid is not particularly limited, and examples thereof include aliphatic monocarboxylic acids, nonanoic acid, caprylic acid, lauric acid, myristic acid, panolemitic acid, stearinic acid, and oleic acid. Carboxylic acids and the like can be mentioned.

 The dicarboxylic acid or a salt thereof, which is the organic acid, preferably has 2 to 8 carbon atoms.崁 If the prime number exceeds 8, the absorption promotion effect may be reduced. Such dicarboxylic acids or salts thereof are not particularly limited, and include, for example, saturated aliphatic linear dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, pimelic acid, suberic acid, and adibic acid; Unsaturated aliphatic dicarboxylic acids such as fumaric acid and maleic acid Aromatic dicarboxylic acids such as phthalic acid, isophthalic acid and terephthalic acid; sodium salts, potassium salts, magnesium salts, calcium salts and aluminum salts thereof; No.

 The above-mentioned hydroxydicarboxylic acid or a salt thereof as the above-mentioned organic acid preferably has 3 to 8 carbon atoms. When the number of carbon atoms exceeds 8, the absorption promoting effect may be reduced. Such a hydroxydicarboxylic acid or a salt thereof is not particularly limited, and examples thereof include malic acid and tartaric acid; and salts thereof such as sodium salt, potassium salt, magnesium salt, calcium salt, and aluminum salt.

 The higher fatty acid ester preferably has 11 to 36 carbon atoms. If the number of carbon atoms is less than 11, volatilization may easily occur, and if the number of carbon atoms exceeds 36, the absorption promotion effect may decrease. Such higher fatty acid esters are not particularly limited, and include, for example, isopropyl myristate, isopropyl palmitate, isopropyl laurate, isopropyl stearate and the like.

The higher fatty acid ester can be obtained, for example, by reacting a higher fatty acid with an alcohol. The higher fatty acid constituting the higher fatty acid ester is preferably one having 10 to 18 carbon atoms. When the number of carbon atoms is less than 10, the above-mentioned higher fatty acid ester as a product may be easily volatilized. When the number of carbon atoms exceeds 18, the transdermal absorption effect may be reduced. Such higher fatty acids are not particularly limited, and include, for example, saturated aliphatic monocarboxylic acids such as capric acid, lauric acid, myristic acid, palmitic acid, and stearic acid; palmitoleic acid, oleic acid, Unsaturated aliphatic monocarboxylic acids such as vaccenic acid, linoleic acid, and linolenic acid; and saturated aliphatic dicarboxylic acids such as sebacic acid.

The alcohol constituting the higher fatty acid ester preferably has 1 to 18 carbon atoms. If the carbon number exceeds 18, the transdermal absorption effect may be reduced. Such alcohols are not particularly restricted but include, for example, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, pentino oleanol, hexino oleanol, heptyl alcohol, octyl alcohol, force prills alcohol, nonyl alcohol, particularly limited as decyl alcohol, lauryl alcohol, millimeter myristyl alcohol, Parumichi alcohol, _c the hydroxycarboxylic acid ester aliphatic saturated alcohols and the like, such as stearyl alcohol Examples include myristyl lactate and cetyl lactate.

 The above hydroxycarboxylic acid ester can be obtained, for example, by reacting hydroxycarboxylic acid with alcohol.

 The hydroxycarboxylic acid constituting the hydroxycarboxylic acid ester preferably has 3 to 6 carbon atoms. If the number of carbon atoms is less than 3, the product hydroquinone carboxylate may be easily volatilized. If the number of carbon atoms exceeds 6, the transdermal absorption effect may be reduced. Such hydroxycarboxylic acids are not particularly limited, and include, for example, monocarboxylic acids such as lactic acid and glyceric acid, malic acid, and dicarboxylic acids such as tartaric acid.

The alcohol constituting the above hydroquinone carboxylate is preferably an alcohol having 1 to 20 carbon atoms. If the carbon number exceeds 20, the transdermal absorption effect may decrease. Such alcohol is not particularly limited. The above-mentioned alcohols and the like exemplified as those used in producing the higher fatty acid ester are exemplified.

 The N-acyl sarcosine is not particularly limited, and includes, for example, N-lauroyl sarcosine, N-ylrail sarcosine, N-palmitoyl sarcosine, coconut oil fatty acid sarcosine and the like. Further, the sodium salt, potassium salt, magnesium salt, calcium salt, aluminum salt and the like of N-acylsarcosine can also be used.

 As the surfactant, any of a nonionic surfactant, an anionic surfactant, a surfactant, and an amphoteric surfactant can be used.

 The nonionic surfactant is not particularly limited and includes, for example, sorbitan alkyl ethers such as sorbitan monolaurate and sorbitan mononoremitrate; polyoxyethylene (9) lauryl ether, polyoxyethylene (2) lauryl ether and the like. Polyoxyethylene alkyl ethers; fatty acid amides such as ethanoyl laurate; and polyoxoxylene fatty acid amides, alkyl amides, and the like.

 The anionic surfactant is not particularly limited, and examples thereof include a surfactant having at least one selected from the group consisting of a carboxyl group, a sulfo group, a sulfate group, and a phosphate group. Can be Examples of the surfactant having a carboxyl group include fatty acid stones, ether carboxylic acids and salts thereof, and carboxylate salts such as condensates of amino acids and fatty acids. Examples of the surfactant include an alkyl sulfonate, a sulfosuccinic acid, an ester sulfonate, an alkylaryl or an alkylnaphthalene sulfonate, and an N-acyl sulfonate. Oiled oils, ester sulfates, ether sulfates, alkylaryl ether sulfates, amide sulfates, and the like are examples of surfactants having the above phosphate group. , Ether phosphates, alkylaryl phosphates and the like.

The cationic surfactant is not particularly limited, and examples thereof include fatty acid amines, alkyl quaternary ammonium salts, aromatic quaternary ammonium salts, pyridium salts, and imidium salts. Dazolym salts and the like.

 The amphoteric surfactant is not particularly limited, and examples thereof include carboquinbetaine such as betaine lauryldimethylaminoacetate, sulfobetaine, aminocarboxylate, and imidazoline derivative.

 In the present invention, N-lauroylsarcosine, isopropyl myristate, and NO are particularly preferred as the transdermal absorption enhancer. Isopropyl noremitate, fumaric acid, maleic acid, myristyl lactate, cetyl lactate, polyoxetylene (2) lauryl ether, polyquinethylene (9) lauryl ether, lauryl diethanolamide, polyhydric alcohol , Glycerin and propylene glycol are preferably used.

 As the percutaneous absorption enhancer, not only those exemplified above but also conventionally known ones can be used.

 In the external preparation for percutaneous absorption of the present invention, the content of the percutaneous absorption enhancer in the base is preferably 0.1 to 80 parts by weight, when the total amount of the base is 100 parts by weight. More preferably, it is 0.1 to 50 parts by weight. In addition, depending on the dosage form, the above-mentioned transdermal absorption enhancer itself can be used as a base.

 In the percutaneous absorption external preparation of the present invention, a humectant, a viscosity modifier, an antioxidant, a pH adjuster, a preservative, a flavoring agent, a stabilizer, and the like may be further added to the base as necessary. It can also be added.

 The external preparation for percutaneous absorption of the present invention can be composed of at least one base selected from the group consisting of ointments, creams, jelly, pastes, liniments, and lotions. That is, the external preparation for transdermal absorption of the present invention can be used as an ointment, cream, jelly, paste, liniment or lotion, or a combination of these forms.

 Further, the external preparation for transdermal absorption of the present invention is a transdermal absorption patch in which a pressure-sensitive adhesive layer is provided on one surface of a support, and the pressure-sensitive adhesive layer is composed of a base containing a drug. It can also be used as an external preparation for skin absorption.

That is, the external preparation for transdermal absorption of the present invention can be prepared, for example, by providing a pressure-sensitive adhesive layer comprising the above-mentioned base containing methotrexate on one surface of a support, for example, It can be in the form of a star, tape, etc.

 The support is appropriately selected according to the dosage form of the external preparation for transdermal absorption of the present invention (eg, cataplasm, blaster, tape, etc.). Are preferred. Such a support is not particularly restricted but includes, for example, polyethylene, polypropylene, polyvinyl chloride, vinyl acetate-vinyl chloride copolymer, ethylene monovinyl acetate copolymer, ethylene monovinyl acetate carbon monoxide copolymer Resin films such as ethylene-butylacrylate carbon monoxide copolymer, polyvinylidene chloride, polyurethane, nylon, polyethylene terephthalate, polybutylene terephthalate; aluminum sheets, woven fabrics, non-woven fabrics, and laminated sheets of these And the like.

 The pressure-sensitive adhesive constituting the pressure-sensitive adhesive layer is not particularly limited as long as it is pharmaceutically acceptable, and any conventionally known suitable pressure-sensitive adhesive can be used. Adhesives, rubber-based adhesives, silicone-based adhesives, and urethane-based adhesives are preferably used. These may be used alone or in combination of two or more.

 As the properties of the pressure-sensitive adhesive when the pressure-sensitive adhesive is spread on the support, it is possible to use appropriate properties such as a dissolution type, an emulsion type and a hot melt type.

 The acryl-based pressure-sensitive adhesive includes a functional monomer and / or a polyfunctional monomer (b-2) copolymerizable with an alkyl (meth) acrylate (b-1) and an alkyl (meth) acrylate. It is preferably composed of a copolymer as a component.

 The alkyl (meth) acrylate (b-1) is not particularly restricted but includes, for example, methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, n-octyl (meth) acrylate, dodecyl (meth) acrylate, and the like. These may be used alone or in combination of two or more.

The alkyl (meth) acrylate (b-1) preferably has 4 to 12 carbon atoms in the alkyl group. When the number of carbon atoms is less than 4, the cohesive strength is improved, but the adhesive strength is reduced. When the number of carbon atoms exceeds 12, the adhesive strength may be improved, but the cohesive strength may be reduced.

 The functional monomer is not particularly limited. For example, (meth) acrylic acid,

2-Hydroxyquinethyl (meta) acrylate, 2-hydroxypropyl (meth) acrylate, glycidyl methacrylate, N-methylol (meth) acrylamide, N-butyne methyl Acrylamide and the like can be mentioned. In the acrylic pressure-sensitive adhesive, these functional monomers are copolymerized to form, for example, metal salts such as sodium hydroxide, calcium hydroxide, and aluminum hydroxide; isocyanate, epoxy resin, melamine resin, Crosslinking with a urea resin, ammonia, or the like can improve the cohesive strength of the pressure-sensitive adhesive.

 The polyfunctional monomer is copolymerized to improve the cohesive strength of the pressure-sensitive adhesive. The above-mentioned polyfunctional monomer is not particularly limited, and examples thereof include 1,6-hexane glycol dimethacrylate, tetraethylene glycol diacrylate, trimethylolpropane triacrylate, divinylbenzene, divinyltoluene, and diacyl. Ril phthalate, diaryl maleate, diaryl diadipate, diaryl glycolate, triaryl isocyanurate, diethylene glycol bisaryl carbonate and the like can be mentioned.

 As the above-mentioned acrylic pressure-sensitive adhesive, those comprising the above-mentioned alkyl (meth) acrylate (b-1) and a copolymer containing a vinyl compound as a functional monomer as a monomer component are also preferable. . Such vinyl compounds are not particularly limited, and include, for example, butyl acetate, acrylonitrile, styrene, N-vinyl-1-pyrrolidone, and the like. Of these, N-vinyl-2-pyrrolidone is more preferred. Such acrylic pressure-sensitive adhesives include, in particular, 55-95% by weight of 2-ethylhexyl acrylate, 5-45% by weight of N-vinyl-2-pyrrolidone, and the above-mentioned polyfunctional adhesives. It is preferable to use a copolymer comprising 0 to 0.5% by weight of a monomer having a monomer component.

As the acrylic pressure-sensitive adhesive, one composed of a copolymer containing two or more kinds of the alkyl (meth) acrylates (b-1) as a monomer component is also preferable. Such acryl-based adhesives include, in particular, 2-ethylhexyl acrylate. It is preferable to use a copolymer containing 5 to 30% by weight, dodecyl methacrylate 5 to 30% by weight, and a monomer component containing the above-mentioned polyfunctional monomer 0 to 0.5% by weight.

 As described above, the acrylic pressure-sensitive adhesive has an alkyl (meth) acrylate as a main component, and the amounts of other components may be appropriately determined according to required performance. The functional monomer is preferably copolymerized in an amount of 1 to 10% by weight in the acrylic pressure-sensitive adhesive, and the polyfunctional monomer is preferably copolymerized in an amount of 0 to 0.5% by weight. When the above-mentioned vinyl compound is used, it is preferable that 50% by weight or less is copolymerized in the above-mentioned acrylic pressure-sensitive adhesive. More preferably, it is 1 to 40% by weight.

 The acrylic pressure-sensitive adhesive may include, if necessary, inorganic fillers such as caic acid, zinc oxide and titanium oxide; plasticizers such as higher fatty acid esters; tackifiers such as ester gum; It may be added within.

 The rubber-based pressure-sensitive adhesive is obtained by adding a tackifier to rubber.

 The rubber is not particularly limited, and examples thereof include natural rubber, styrene-butadiene rubber, polyisobutylene, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, and styrene-one-year-old styrene-styrene. And block copolymers.

 The tackifier is not particularly limited, and includes, for example, rosin, hydrogenated rosin, rosin ester, terpene resin, terpene fuynol resin, petroleum resin, cumarone resin, cumarone-indene resin and the like.

 If necessary, a softening agent may be added to the rubber-based pressure-sensitive adhesive. The above-mentioned denaturing agents are not particularly limited, and include, for example, armor oil, olive oil, camellia oil, Pacific oil, peanut oil, sesame oil, soybean oil, mink oil, cottonseed oil, corn oil, and safari oil. Oils such as mono-oil, coconut oil and castor oil; higher fatty acids such as oleic acid and lauric acid; liquid paraffin and polybutene.

 As the silicone-based pressure-sensitive adhesive, any of the silicone-based pressure-sensitive adhesives conventionally used for pressure-sensitive adhesives for transdermal patches can be used, and is not particularly limited.

As the urethane-based adhesive, it has been used in adhesives for transdermal patches Any of the urethane-based pressure-sensitive adhesives used can be used, and is not particularly limited.

 The pressure-sensitive adhesive layer is preferably made of a pressure-sensitive adhesive containing at least one water-soluble polymer.

 The water-soluble polymer is not particularly limited, and examples thereof include those containing a vinyl group, polysaccharides, and other water-soluble polymers.

 The thing containing the vinyl group is not particularly limited, and examples thereof include polyacrylic acid, polyacrylate, and others. Examples of the above polyacrylate include monovalent metal salts of polyacrylic acid such as sodium polyacrylate and potassium polyacrylate; monoethanolamine polyacrylate, jetanolamine polyacrylate, triacrylate polyacrylate. Amino salts of polyacrylic acid such as ethanolamine; and ammonium salts of polyacrylic acid. Other examples of the above include, for example, polyvinyl alcohol, polyvinyl virolidone, polyvinyl ether, meth- oxyethylene-maleic anhydride copolymer, methacrylic acid polymer and the like.

 The polysaccharides are not particularly limited, and include, for example, sodium alginate, ammonium alginate, carboxymethylcellulose, sodium carboquine methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, and hydroxyquinepropylethylcellulose. , Methylcellulose, soluble starch, carboxymethylamylose, dextrin and the like.

 The other water-soluble polymers are not particularly limited, and include, for example, hemicelluloses such as pectin and agar powder; and plant gums such as gum arabic, tragacanth, and xanthan gum.

As the water-soluble polymer, those having at least one selected from the group consisting of a carboxyl group, a hydroxyl group, and a salt thereof in the molecule are preferably used. For example, an acrylic acid polymer, Examples include acrylate polymer, maleic anhydride polymer, methacrylic acid polymer, carboxycellulose, polyvinyl alcohol, and hydroxycellulose. Specifically, among those exemplified above, for example, those having a carboxyl group include polyacrylic acid, sodium polyacrylate, meth- oxyethylene-maleic anhydride copolymer, and styrene acrylate. Copolymer, acrylic acid-methacrylic acid amide copolymer, butyl acrylate-methacrylic acid copolymer, styrene-methacrylic acid copolymer, carboxyvinyl polymer, carboxymethylcellulose, sodium alginate and the like. Examples of those having a hydroxyl group include polyvinyl alcohol, hydroxymethyl cellulose, hydroxyquin propyl cellulose, and hydroxyquin propylethyl cellulose.

 The water-soluble polymer can be used not only as a base of the pressure-sensitive adhesive layer but also as an additive of the acrylic pressure-sensitive adhesive, the rubber-based pressure-sensitive adhesive, the silicone-based pressure-sensitive adhesive, and the urethane-based pressure-sensitive adhesive. .

 The external preparation for transdermal absorption of the present invention can be produced by a conventional method. For example, in the case of ointments, creams, lotions, pastes, liniments, and jelly bases, the base materials were manufactured by kneading, emulsifying, suspending, or dissolving the necessary base materials according to each dosage form. Thereafter, it can be produced by adding a drug, and if necessary, a transdermal absorption enhancer, other additives, and the like, and mixing with a commonly used kneader.

 Further, when the external preparation for transdermal absorption of the present invention is a patch, the production method varies depending on the type of the adhesive, but it is appropriately determined according to the dosage form (for example, plaster, tape, cataplasm, etc.). It can be manufactured by a conventional method such as hot melt type, solvent type and emulsion type.

 Examples of the disease to be treated by the topical preparation for percutaneous absorption of the present invention include chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, polymyositis and the like; leukemia, etc. Cancer diseases and the like. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to only these Examples. Example 1

0.05 g of methotrexate (manufactured by Wako Pure Chemical Industries, Ltd.), 3 g of diethanolamide laurate (manufactured by NOF Corporation) and gelled hydrocarbons (Bristol-Myers Squid) 96.5 g was weighed in a mortar and mixed well to prepare a uniform external preparation. C Comparative Example 1

 3 g of lauric acid diethanolamide (manufactured by NOF CORPORATION) and 97 g of gelled hydrocarbon (manufactured by Bristol-Myers Squibb) were weighed in a mortar and mixed well to prepare a uniform external preparation. Comparative Example 2

 Metre Trexate (Wako Pure Chemical Industries, Ltd.) 5 mg, Carboquin methylcellulose sodium (Wako Pure Chemical Industries, Ltd.) 50 Omg and 100 ml of purified water are weighed out, stirred thoroughly, and uniformly orally. A solution was prepared. Comparative Example 3

 50 mg of sodium carboxymethylcellulose (manufactured by Wako Pure Chemical Industries, Ltd.) and 100 ml of purified water were weighed out and thoroughly stirred to prepare a uniform oral liquid preparation. Test example 1 (Effect on rat adjuvant arthritis)

 The effects on adjuvant arthritis of the external preparations and oral liquid preparations of Example 1 and Comparative Examples 1 to 3 were examined as follows. A 6-week-old male Lewis rat weighing 120 to 200 g was used as a test animal.

 First, arthritis was induced by subcutaneously injecting 1 ml of MycobaccteriumumtubercculosiSHSTRACmgZmUO.1 suspended in flowing paraffin subcutaneously into the right hind leg of the rat. After the induction, an external preparation and an oral solution were administered as described below. After induction, to examine the degree of swelling of the right and left hind legs of the rat, the volume of the hind legs was measured before and after the induction of arthritis using Plethy smometer Cugo Bai 1e). The difference between the pre-challenge volume and the post-challenge volume was determined (this difference is shown in Table 1 as paw edema volume (m)).

In the rat of the external preparation administration group of Example 1, the external preparation of Example 1 was applied to the shaved back skin for 2 days from the first day of each week at a rate of 0.1 g rat from the day of arthritis induction. Apply, cover with gauze (Kitakawa Sanitary Materials Co., Ltd.) from above, fix with elastic adhesive band (Silky Tex, product name of Alcare Co., Ltd.), peel off and remove on the third day After wiping off the adhering drug with gauze, the drug was closed on days 3-7. As a control for this test, the external preparation of Comparative Example 1 was administered in the same manner. In the rats of the group receiving the oral liquid preparation of Comparative Example 2, the oral liquid preparation of Comparative Example 2 was divided into three parts per week at a rate of 10 m1 Z kg Z1 from the induction of arthritis (that is, the first liquid of each week). , Twice daily (9: 00 and 17: 00), once on the second day (9: 00), and on days 3-7, the drug was discontinued. As a control for this test, the oral liquid preparation of Comparative Example 3 was administered in the same manner.

 Table 1 shows the paw edema volumes (ml) as defined above, 14 days and 21 days after the day of arthritis induction.

 In addition, the above-mentioned test was performed using a rat of 6 animals per group, and Table 1 shows an average value of paw edema volume. table 1

As can be seen from Table 1, the degree of swelling of the left and right hind limbs was significantly suppressed in the topical drug administration group of Example 1 compared to the topical drug administration group of Comparative Example 1, and the degree of the suppression was compared with Comparative Example 2. The degree of suppression was equal to or greater than that of the oral solution administration group of Comparative Example 3 and the oral solution administration group of Comparative Example 3. Met. That is, the external preparation for transdermal absorption of the present invention had remarkable inhibitory activity against chronic inflammatory diseases. Next, the external preparations and oral liquid preparations of Example 2 and Comparative Examples 1, 3 and 4 below were prepared, and the obtained external preparations and oral liquid preparations suppressed the immune inflammatory reaction (the effect on the rat tuberculin reaction). Was tested. Example 2

 0.5 g of methotrexate (manufactured by Wako Pure Chemical Industries), 3 g of lauric acid diethanolamide (manufactured by NOF Corporation) and 96.5 g of gelled hydrocarbons (manufactured by Bristol Myers Squibb) were mortared. The mixture was thoroughly weighed and mixed well to prepare a uniform external preparation. Comparative Example 4

 Metriclexate (manufactured by Wako Pure Chemical Industries, Ltd.) 100 mg, sodium carboxymethylcellulose sodium (manufactured by Wako Pure Chemical Industries, Ltd.) 500 mg and purified water 100 ml are weighed and thoroughly stirred. A homogeneous oral solution was prepared. Test Example 2 (Effect on la sototuberculin reaction)

 In order to examine the effects on the tuberculin reaction, which is an immune inflammatory reaction that causes chronic inflammatory diseases, the external preparations and oral liquids of Example 2 and Comparative Examples 1, 3, and 4 were used as test substances. The effect on tuberculin response was tested.

 Wistar male rats weighing 170-250 g were used as test animals. The specific test procedure was as follows.

According to the method of Kuriyama et al. (Journal of the Pharmacological Society of Japan, Vol. 94, pp. 113-118, 1989), Bacillus Calmette suspended in saline in the above-mentioned rat was used. Guerin (BCG, manufactured by Nippon BSI Inc.) Purified tubercu〗 i π (PPD, Mitsui 1 ml of the solution was injected intradermally on the back of the shaved rat to induce a tuberculin reaction. In the rat of the external preparation administration group of Example 2, the external preparation of Example 2 was applied to the shaved back skin at a rate of 0.1 g Z rat two days before induction, and gauze (Kitakawa Sanitary) was applied from above. (Made by Material Co., Ltd.), and then fixed with a non-sticky adhesive pad (manufactured by Alcare Inc., trade name: Silky Tex). Before induction 1, the gauze, elastic adhesive band and external preparation were separated, and the external preparation remaining on the skin was removed with absorbent cotton. The external preparation of Comparative Example 1 was administered in the same manner as a control for this test.

 In the rat of the group to which the oral solution was administered in Comparative Example 4, the oral solution in Comparative Example 4 was orally administered at a ratio of 10 m1Zkg two days before the induction. As a control for this test, the oral liquid preparation of Comparative Example 3 was orally administered in the same manner.

 Twenty-four hours after the induction, the erythema intensity at the reaction induction site was measured according to the criteria of Draise, and then the skin of the reaction part was punched out with a punch having a diameter of 8 cm, and the skin weight was measured.

 This test was performed using 5 rats each, and the erythema intensity and skin weight were determined by averaging 皡 obtained for these rats.

 Table 2 shows the test results. Table 2

As is evident from Table 2, the erythema intensity and skin weight were significantly reduced in the group administered with the external preparation of Example 2 as compared with the group administered with the external preparation of Comparative Example 1. It was equivalent. That is, the topical preparation for percutaneous absorption of the present invention is a replacement sheet (Rule 26) due to chronic inflammatory diseases. It had significant inhibitory activity against certain immune inflammatory responses. Test Example 3 (Evaluation of the sustainability of the effect on Rattrabellulin reaction)

 In order to examine the persistence of the action on the rat tuberculin reaction, the effect on the rat tuberculin reaction was tested using the external preparations and oral liquid preparations of Example 2 and Comparative Examples 1, 3, and 4 as test substances.

 As a test animal, a male male rat weighing 180 to 230 g was used. The specific test procedure was as follows.

 According to the method of Kuriyama et al. (Journal of the Pharmacological Society of Japan, Vol. 94, pp. 113-118, 1989), Bacillus Calmette suspended in saline on the above-mentioned rat was used. Gueri ri (BCG, manufactured by Nippon Business Inc.) 0.2 ml of the bacterial solution was injected intraperitoneally into the rat, and after 7 days, purified tubercu] in saline was dissolved. (PPD, manufactured by Mitsui Pharmaceutical Co., Ltd.) 0.1 ml of the solution was injected into the back of the shaved skin to induce a tuberculin reaction.

 In the rat of the external preparation administration group of Example 2, the external preparation of Example 2 was applied to the shaved back skin at a rate of 0.1 g / rat 4, 4, 2, 1 day before or at the time of induction. After covering with gauze (made by Kitagawa Sanitary Materials Co., Ltd.) from above, it was fixed with an elastic adhesive band (manufactured by Alcare, trade name Silky Tex). On the next day, the gauze, the elastic adhesive band and the external preparation were separated, and the external preparation remaining on the skin was removed with absorbent cotton. The external preparation of Comparative Example 1 was administered in the same manner as a control in this test.

 In the rat of the group to which the oral solution was administered in Comparative Example 4, the oral solution of Comparative Example 4 was orally administered at a rate of 10 m 1 g before or at the time of induction 4, 3, 2, or 1. As a control for this test, the oral liquid preparation of Comparative Example 3 was orally administered in the same manner. Twenty-four hours after the induction, the skin of the reaction site was punched out with a punch having a diameter of 8 cm, and the skin weight was measured.

 This test was performed using 5 rats each, and the skin weight was the average of the values obtained for these rats.

Table 3 shows the test results. Table 3

As is evident from Table 3, it was found that the effect of the topical preparation of Example 2 lasted longer than that of the group of oral liquid preparation of Comparative Example 4. That is, the external preparation for percutaneous absorption of the present invention had an excellent persistence in the effect on the immune inflammatory reaction that causes chronic inflammatory diseases. Next, the external preparations and oral liquid preparations of Example 2 and Comparative Example 4 were prepared, and a rat blood concentration measurement test of the obtained external preparations and oral liquid preparations was performed. Test example 4 (rat blood kinetic measurement test)

 As a test animal, a Wistar male rat weighing 170.250 g was used. In the rat of the external preparation administration group of Example 2, the external preparation of Example 2 was applied to the shaved back skin at a rate of 0.1 lat and covered with gauze (made by Kitagawa Sanitary Materials Co., Ltd.) from above. After that, fix it with an elastic adhesive band (manufactured by Alcare, Silky Tex) o

 In the rat of the group to which the oral solution was administered in Comparative Example 4, the oral solution of Comparative Example 4 was orally administered at a rate of 10 ml / kg.

One, two, three, four, eight and four hours after administration, blood was collected from the jugular vein, and the amount of methotrexate in the blood was measured by high performance liquid chromatography. Replacement form (Rule 26) Table 4 shows the results. Note that this test was performed with the number of repetitions of 3, and the average value was shown. Table 4

As can be seen from Table 4, in the group to which the external preparation of Example 2 was administered, the continuation of the blood concentration was observed as compared with the group to which the oral liquid preparation of Comparative Example 4 was administered. This result supports the persistence of the rat-tuberculin reaction. Example 3

 1 g of methotrexate (manufactured by Wako Pure Chemical Industries, Ltd.), 3 g of diethanolamide laurate (manufactured by NOF Corporation) and 96 g of gelled hydrocarbons (manufactured by Bristol Tomisayas Squibb) are weighed in a mortar. A well-mixed, uniform external preparation was prepared. Example 4

 10 g of methotrexate (manufactured by Wako Pure Chemical Industries), 3 g of diethanolamide laurate (manufactured by NOF Corporation) and 87 g of gelled hydrocarbon (manufactured by Bristol-Myers Squibb) are weighed in a mortar and weighed sufficiently. And a uniform external preparation was prepared. Comparative Example 5

Methotrexate (manufactured by Wako Pure Chemical Industries, Ltd.) 500 mg, carboxymethyl cell mouth —Sodium (Wako Pure Chemical Industries, Ltd.) 500 mg and purified water 100 ml are weighed and replaced. 26) And mixed well to prepare a uniform oral solution. Test Example 5 (Effect on rat leukocytes)

 In order to examine the effects on leukemia, the effects on rat leukocytes were tested using the external preparations and oral solutions of Examples 3 and 4 and Comparative Examples 1, 3, and 5 as test substances.

Wistar male rats weighing 170-250 g were used as test animals. In order to examine the changes in the white blood cell count of the rat, a 3Q0 L, heparin jugular vein was collected before and after the administration of the test substance, and the white blood cell count in the blood was measured using an automatic hemocytometer (manufactured by Sysmex Corporation, trade name: K-1 1 0 0 0) was measured using a speed change amount leukocytes (X 1 0 ² Roh / 1) = after administration the number of white blood cells - was determined white blood cell count before administration (the white blood cell count variation is shown in Table 5) .

 In the rats of the external preparation administration groups of Examples 3 and 4, the external preparations of Examples 3 and 4 were applied to the shaved back skin at a rate of 0.1 g Z rat, and gauze (Kitakawa Sanitary) was applied from above. After that, it was fixed with an elastic adhesive band (manufactured by Alcare, trade name: Silky Tex). On the next day, the gauze, the elastic adhesive band and the external preparation were separated, and the external preparation remaining on the skin was removed with absorbent cotton. As a control for this test, the external preparation of Comparative Example 1 was administered in the same manner.

 In the rat of the group to which the oral solution was administered in Comparative Example 5, the oral solution of Comparative Example 5 was orally administered at a rate of 10 ml / kg. As a control for this test, the oral liquid preparation of Comparative Example 3 was administered in the same manner.

After 3 days from the administration day, the white blood cell count variation as defined above for (X 1 0 ² 1) are shown in Table 5.

The above test was performed using a group of 5 rats each, and Table 5 shows the average value of leukocyte change. Table 5

As can be seen from Table 5, leukocytes were significantly reduced in the groups administered with the external preparations of Examples 3 and 4 compared to the group administered with the external preparations of Comparative Example 1, and the effect was equivalent to that of Comparative Example 5. Was. That is, the external preparation for percutaneous absorption of the present invention had a remarkable leukocyte count-inhibiting effect, which is responsible for leukemia treatment effect. Next, a rat skin permeability test was performed on the external preparations of Example 1 and Examples 5 to 9 described below. Example 5

65 mol% (302.0 g) of 2-ethylhexyl acrylate (hereinafter referred to as “EHA”), 35 mol% (98.80%) of N-vinyl-1-pyrrolidone (hereinafter referred to as “VP”) 0 g), and hexamethylene glycol dimethacrylate were charged into a separable flask with 0.02 parts by weight (80 mg) per 100 parts by weight of EHA and VP. 70.6 g of ethyl acetate was added to give 85% by weight. The solution was heated to 65 ° C. under a nitrogen atmosphere, and lauroyl peroxide and ethyl acetate as polymerization initiators were added sequentially and little by little, and polymerization was performed for 32 hours. After removing the polymer, the methotrexate was suspended in ethyl acetate, and the solid content (the sum of the polymer after drying the ethyl acetate and the methotrexate) was 30% by weight. Replacement paper (Rule 26) In addition, the mixture was added so that the methotrexate concentration in the solid content was 0.5% by weight, and the mixture was stirred and mixed. This solution was applied to a silicon-treated polyethylene terephthalate (PET) film having a thickness of 35〃ηι to a thickness of about 100 after drying, and then dried. After bonding a PET film having a thickness of 35, it was cut into a circle having an area of 3.14 cm ² to prepare a transdermal absorption external preparation. Example 6

 An external preparation for transdermal absorption was prepared in the same manner as in Example 5, except that the content of methotrexate in the solid content was changed to 5% by weight. Example 7

A percutaneous absorption external preparation was prepared in the same manner as in Example 5 except that the content of methotrexate in the solid content was changed to 10% by weight, and the adhesive surface was treated with an acrylic gel (Sekisui Resin). The product was bonded to a trade name, Technogel CR), and cut into a circle having an area of 3.14 cm ² to prepare a transdermal absorption external preparation. Example 8

3 g of sodium polyacrylate (manufactured by Nippon Junyaku Co., Ltd., trade name: Aronbis AH) is added to 0.3 g of dried aluminum hydroxide gel (manufactured by Maruishi Pharmaceutical Co., Ltd.), 7.5 g of glycerin, 0.3 g of tartaric acid, After adding 15 g of distilled water and mixing with stirring, 0.12 g of methotrexant was added and mixed with stirring. This was coated on a silicon-treated 35-m-thick PET film so that the thickness after drying was about 200 m, and then a 35-m-thick PET film was laminated. Thereafter, the preparation was cut into a circle having an area of 3.14 cm ² to prepare an external preparation for transdermal absorption. Example 9

Emulsion of polymer (acrylic acid-n-butyl acrylate, manufactured by ROHM 'And'Haas' Japan, trade name N-580) 8 g of methotrexate 0.02 g, After adding 4 g of distilled water and mixing with stirring, the solution was siliconized. On a 35 m-thick PET film so that the thickness after drying is about 100 μm, and then, after adhering a 35 / zm-thick PET film, 3. Cut into a circular shape of 14 cm ² to prepare a transdermal absorption external preparation. Test Example 6 (Lat skin captive permeability test)

 The diffusion cell shown in FIG. 1 was prepared. The diffusion cell 1 is formed by a bottomed cylindrical receptor tank 2 and a bottomed cylindrical donor vessel 3 arranged on the receptor tank 2. An opening 4 is provided in the center of the bottom wall of the donner tank 3, the bottom wall extends in the peripheral direction, and a flange 5 is provided. A flange 6 is provided at the upper part of the receptor tank 2, and a laterally protruding sample ring 7 is attached to the side wall.c The flange 5 and the flange 6 are overlapped so as to face each other. Are airtightly and concentrically stacked. Further, a magnet stirrer 9 is placed inside the receptor tank 2.

Wistar male rats weighing 170-250 g were used as test animals. The tissue and muscle layer were removed to obtain a captive piece 8 of approximately 5 cm x 5 cm. The obtained skin piece 8 was attached between the flange 5 and the flange 6 of the diffusion cell 1, and the opening 4 of the donor vessel 3 was completely closed with the skin piece 8. The external preparations of Examples 1 and 5 to 7 shown above were applied to the central portion 10 of the skin piece 8 so as to be in contact with the skin piece 8. The external preparation of Example 1 was prepared by uniformly applying 0.1 g to one surface of a circular (area of 3.14 cm ² ) polyethylene terephthalate and contacting the skin piece 8 with the skin piece 8. It was affixed to the center 10 of 8. Receptor tank 2 was filled with the receptor liquid, placed in a thermostat maintained at 37 ° C., and stirred by rotating magnet stirrer 9 with a magnet stirring device. 18 and 24 hours after the start of the test, 1 ml of the receptor solution was sampled from the sampling port 7, and 1 ml of the fresh receptor solution was replenished instead. Drugs that have permeated the skin are dissolved in the collected receptor solution. The drug concentration in the collected receptor solution was measured by high performance liquid chromatography, and the drug permeation amount (unit: Ug / cm ² ) was calculated.

 This test was performed with 2 repetitions, and the average value was shown.

Receptor fluid adjustment method: in distilled _{water, N a H 2 P 0 4} 5 x 1 0- 4 M, _{N a 2 HP 0 4 2 X} 1 0- 4 M, NaC l l. 5 X 1 0 and, in a buffer containing sulfuric acid Gentama leucine 1 0 〃 g / m 1, by adding 1 N-N a OH solution PH was adjusted to 7.2.

¾6

As can be seen from Table 6, the external preparations of Examples 5 to 9 showed excellent skin permeability of methotrexate to the skin which was equal to or higher than that of the external preparation of Example 1. Availability

 The external preparation for percutaneous absorption of the present invention has the above-mentioned constitution, and is effective for chronic inflammatory diseases such as autoimmune diseases (for example, rheumatoid arthritis) and cancer diseases such as leukemia. is there. In other words, it has a systemic therapeutic effect on these diseases, continuously exerts effective drug effects, can reduce the side effects seen in oral drugs, etc. And improvement of quality, quality, life, etc. can be achieved.

Replacement paper (Kaikai IJ26)

Claims

The scope of the claims

1. An external preparation for percutaneous absorption, which contains a drug in the base and has a systemic therapeutic effect on the disease to be treated,

The drug is methotrexate

An external preparation for percutaneous absorption characterized in that:

2. The external preparation for transdermal absorption according to claim 1, wherein the content of the drug in the base is 0.001 to 30% by weight.

3. The external preparation for percutaneous absorption according to claim 1 or 2, wherein the disease to be treated is a chronic inflammatory disease.

4. The external preparation for percutaneous absorption according to claim 3, wherein the chronic inflammatory disease is rheumatoid arthritis.

5. The external preparation for transdermal absorption according to claim 1 or 2, wherein the disease to be treated is a cancer disease.

6. The external preparation for percutaneous absorption according to claim 5, wherein the cancer disease is leukemia.

7. The base is at least one (a) selected from the group consisting of polymers, inorganic fillers, fats and oils, hydrocarbons, polyhydric alcohols, higher fatty acids, higher alcohols, lower alcohols and water; 7. The external preparation for transdermal absorption according to claim 1, which is a composition containing (a).

8. The base comprises at least one transdermal absorption enhancer selected from the group consisting of alcohols, organic acids, higher fatty acid esters, hydroquinone carboxylate esters, N-acyl sarcosine and surfactants. 8. The external preparation for percutaneous absorption according to claim 1, 2, 3, 3, 4, 5.6 or 7, which contains the composition.

9. The external preparation for percutaneous absorption comprises at least one base selected from the group consisting of ointments, creams, gels, pastes, liniments and lotions. The external preparation for percutaneous absorption according to 4, 5, 6, 7, or 8.

10. The transdermal absorption external preparation is a transdermal absorption patch in which a pressure-sensitive adhesive layer is provided on one surface of a support, and the pressure-sensitive adhesive layer is composed of a drug-containing base. 2. The external preparation for percutaneous absorption according to 2, 3, 4, 5, 6, 7, or 8.

11. The pressure-sensitive adhesive layer according to claim 10, wherein the pressure-sensitive adhesive layer comprises at least one selected from the group consisting of an acrylic pressure-sensitive adhesive, a rubber-based pressure-sensitive adhesive, a silicone-based pressure-sensitive adhesive, and a urethane-based pressure-sensitive adhesive. External preparation for transdermal absorption.

12. The pressure-sensitive adhesive layer is composed of an acrylic pressure-sensitive adhesive, and the acrylic pressure-sensitive adhesive is copolymerized with an alkyl (meth) acrylate (b-1) and an alkyl (meth) acrylate. Possible functional monomers and Z or polyfunctional monomers

21. The external preparation for transdermal absorption according to claim 11, wherein the external preparation comprises a copolymer containing (b-2) as a monomer component.

13. The external preparation for transdermal absorption according to claim 12, wherein the acrylic pressure-sensitive adhesive comprises a copolymer containing two or more alkyl (meth) acrylates (b-1) as monomer components.

14. The transdermal agent for transdermal absorption according to claim 10, 11, 12, 13 or 13, wherein the pressure-sensitive adhesive layer comprises a pressure-sensitive adhesive containing at least one kind of water-soluble polymer.

15. The external preparation for transdermal absorption according to claim 14, wherein the water-soluble polymer has at least one selected from the group consisting of a carboxyl group, a hydroxyl group and a salt thereof.