Composition for transdermal absorption preparation and transdermal absorption preparation

Abstract

One embodiment of the present invention relates to a composition for a transdermal absorption preparation or a transdermal absorption preparation that does not impair adhesive properties and exhibits excellent transdermal absorbability of a drug even when a component (such as a lipophilic component) that enhances transdermal absorbability of a drug is blended in a relatively large amount, wherein the composition for a transdermal absorption preparation comprises 50 to 300 parts by mass of a fatty acid ester (B) and 0.001 to 100 parts by mass of a drug (C) per 100 parts by mass of a polymer (A) that is a graft copolymer, the polymer (A) comprises a soft segment having a glass transition temperature (Tg) of -100°C or higher and lower than 0°C and a hard segment having a glass transition temperature (Tg) of 0°C or higher, and the content ratio of the hard segment in the polymer (A) is 1 to 30% by mass.

Description

Composition for Transdermal Absorption Preparation and Transdermal Absorption Preparation 【0001】 One embodiment of the present invention relates to a composition for a transdermal absorption preparation or a transdermal absorption preparation. 【0002】 When a drug is administered transdermally, it is often used as a tape-shaped transdermal absorption preparation. The tape-shaped transdermal absorption preparation is formed from a composition containing an adhesive component, a drug, a lipophilic component, etc., and the lipophilic component is blended to enhance the transdermal absorption of the drug. However, when a large amount of a lipophilic component is blended to further improve the transdermal absorption of the drug or to improve the transdermal absorption of a drug with low transdermal absorption, the adhesive layer in the tape preparation may be plasticized, and the adhesive physical properties such as adhesive force and cohesive force may be impaired. For this reason, there has been a demand for a composition for a transdermal absorption preparation that can achieve both the transdermal absorption of a drug and adhesive physical properties. 【0003】 Patent Document 1 discloses a transdermal absorption preparation in which an adhesive layer is formed on one side of a support, and the adhesive layer contains a specific copolymer (A), a specific copolymer (B), and an organic liquid component (C) that is compatible with the components (A) and (B), and the content of the component (C) is 0.5 to 1.5 in weight ratio with respect to the total amount 1 of the components (A) and (B). 【0004】 Japanese Patent Application Laid-Open No. 2000-44904 【0005】 However, when a larger amount of a lipophilic component or the like is blended to promote drug transferability, there is a problem that the adhesive physical properties cannot be maintained. 【0006】 One embodiment of the present invention provides a composition for a transdermal absorption preparation and a transdermal absorption preparation that do not impair the adhesive physical properties and are excellent in the transdermal absorption of a drug even when a relatively large amount of a component (such as a lipophilic component) that enhances the transdermal absorption of the drug is blended. 【0007】 As a result of intensive studies to solve the above problems, the present inventors have found that the above problems can be solved according to the following exemplary embodiments, and have completed the present invention. Exemplary embodiments of the present invention are shown below. 【0008】[1] A composition for transdermal absorption formulations comprising 100 parts by mass of a polymer (A) which is a graft copolymer, 50 to 300 parts by mass of a fatty acid ester (B), and 0.001 to 100 parts by mass of a drug (C), wherein the polymer (A) comprises a soft segment having a glass transition temperature (Tg) of -100°C or higher and less than 0°C, and a hard segment having a glass transition temperature (Tg) of 0°C or higher, and the content ratio of the hard segment in the polymer (A) is 1 to 30% by mass. [2] The composition for transdermal absorption formulations according to item [1], wherein the weight-average molecular weight (Mw) of the polymer (A) is 100,000 to 1,500,000. [3] The composition for transdermal absorption formulations according to item [1] or [2], comprising a drug (C) complexed with a surfactant. [4] A transdermal absorption formulation formed from the composition for transdermal absorption formulations according to any one of items [1] to [3]. 【0009】 According to one embodiment of the present invention, even when a relatively large amount of a component that enhances the transdermal absorption of a drug (such as a lipophilic component) is incorporated, it is possible to provide a composition for transdermal absorption formulations or a transdermal formulation that does not impair tackiness and exhibits excellent transdermal absorption of the drug. 【0010】 The present invention will now be described in detail. In this specification, "(meth)acrylic" is used as a general term for acrylic and methacrylic. For example, "(meth)acrylic acid" means acrylic acid or methacrylic acid. In this specification, A to B, which represent a numerical range, means A or greater and B or less, unless otherwise specified. 【0011】<Composition for Transdermal Absorption Formulation> A composition for transdermal absorption formulation according to one embodiment of the present invention comprises a polymer (A), a fatty acid ester (B), and a drug (C). Polymer (A) is a graft copolymer having a soft segment and a hard segment, wherein the soft segment has a lower glass transition temperature (Tg) than the hard segment. When forming a tape, i.e., an adhesive layer, from the transdermal absorption formulation composition containing polymer (A), it is believed that a microphase separation structure is formed in which the soft segment of polymer (A) is a dispersed phase and the hard segment is a domain, thereby exhibiting the cohesive force required for the tape. Furthermore, when the tape is formed, it is preferable that the fatty acid ester (B) is compatible with the soft segment of polymer (A) and incompatible with the hard segment. In this embodiment, even when a relatively large amount of fatty acid ester (B) is incorporated into the transdermal absorption formulation composition, a tape with excellent cohesive force and unimpaired adhesive properties can be obtained. 【0012】 <<Polymer (A)>> Polymer (A) is a graft copolymer having a soft segment with a glass transition temperature (Tg) of -100°C or higher and less than 0°C, and a hard segment with a Tg of 0°C or higher, wherein the hard segment content in polymer (A) is 1 to 30% by mass. When polymer (A) is in this form, a microphase separation structure is formed in which the soft segment is a dispersed phase and the hard segment is a domain, resulting in excellent cohesive force of the tape. 【0013】 [Hard Segment] The Tg of the hard segment is 0°C or higher, preferably 0 to 150°C, and more preferably 10 to 100°C. A Tg of the hard segment within the above range is preferable because it results in excellent cohesive force of the resulting tape. 【0014】The hard segment content in polymer (A) is 1 to 30% by mass, preferably 2 to 28% by mass, and more preferably 4 to 25% by mass. A hard segment content within this range is preferable because it results in excellent cohesive strength in the resulting tape. The hard segment content in polymer (A) can be calculated from the amount of monomer components constituting the hard segments added during the polymerization of polymer (A). 【0015】 [[Monomer Components Constituting the Hard Segment]] The monomer components constituting the hard segment are not particularly limited as long as the Tg of the hard segment is 0°C or higher, but it is preferable that it has at least one constituent unit derived from a monomer component (hereinafter referred to as monomer (a)) whose Tg when it is a homopolymer is 0°C or higher. 【0016】 [[Monomer (a)]] In the monomer components constituting the hard segment, the content of constituent units derived from monomer (a) is preferably 50% by mass or more, more preferably 50 to 100% by mass, and even more preferably 80 to 100% by mass. When the content of constituent units derived from monomer (a) is within the above range, it is considered that the adhesive layer is more likely to form a microphase separation structure when the tape is formed. 【0017】 Examples of monomer (a) include alkyl (meth)acrylates such as methyl (meth)acrylate, ethyl methacrylate, n-butyl methacrylate, iso-butyl methacrylate, tert-butyl (meth)acrylate, iso-octyl methacrylate, and stearyl (meth)acrylate; alicyclic alkyl (meth)acrylates such as cyclohexyl (meth)acrylate, isobornyl (meth)acrylate, and 3,3,5-trimethylcyclohexyl acrylate; and styrene monomers such as styrene, α-methylstyrene, methylstyrene, dimethylstyrene, ethylstyrene, diethylstyrene, propylstyrene, butylstyrene, methoxystyrene, fluorostyrene, chlorostyrene, and bromostyrene. Monomer (a) may be used alone or in combination of two or more types. 【0018】From the viewpoint of polymerizability, monomer (a) preferably contains 50% by mass or more of alkyl (meth)acrylate, and from the viewpoint of being immiscible with fatty acid ester (B) described later when used as a tape agent, it is particularly preferable that monomer (a) contains 50% by mass or more of methyl methacrylate and / or iso-butyl methacrylate. 【0019】[Other Monomers] The monomer components constituting the hard segment may include other monomer components other than monomer (a), as long as the Tg of the hard segment is in the range of 0°C or higher. Examples of other monomer components include ethyl acrylate, n-butyl acrylate, iso-butyl acrylate, pentyl (meth)acrylate, hexyl (meth)acrylate, heptyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, n-octyl (meth)acrylate, iso-octyl acrylate, nonyl (meth)acrylate, decyl (meth)acrylate, iso-decyl (meth)acrylate, and undecyl (meth)acrylate. (a)alkyl ester monomers other than monomers such as (a) lauryl (meth)acrylate and oleyl (meth)acrylate; alkyl (meth)acrylate monomers such as methoxymethyl (meth)acrylate, 2-methoxyethyl (meth)acrylate, 2-ethoxyethyl (meth)acrylate, 3-methoxypropyl (meth)acrylate, 3-ethoxypropyl (meth)acrylate, 4-methoxybutyl (meth)acrylate, and 4-ethoxybutyl (meth)acrylate. Coxyalkyl (meth)acrylates; aromatic ring-containing monomers such as phenyl (meth)acrylate, benzyl (meth)acrylate, and phenoxyethyl (meth)acrylate; acidic group-containing monomers such as (meth)acrylic acid, 5-carboxypentyl (meth)acrylate, mono(meth)acryloyloxyethyl succinate, ω-carboxypolycaprolactone mono(meth)acrylate, itaconic acid, crotonic acid, fumaric acid, and maleic acid; hydroxyl group-containing monomers such as 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 4-hydroxybutyl (meth)acrylate, 6-hydroxyhexyl (meth)acrylate, and 8-hydroxyoctyl (meth)acrylate; N-alkyl (meth)acrylamides such as (meth)acrylamide, N-methyl (meth)acrylamide, N-ethyl (meth)acrylamide, N-propyl (meth)acrylamide, and N-hexyl (meth)acrylamide;Examples include nitrogen atom-containing monomers such as N,N-dimethyl(meth)acrylamide, N,N-diethyl(meth)acrylamide, N-vinylpyrrolidone, N-vinylcaprolactam, (meth)acryloylmorpholine, N,N-dimethylaminoethyl(meth)acrylate, and N,N-diethylaminoethyl(meth)acrylate; and vinyl carboxylate esters such as vinyl acetate, vinyl propionate, vinyl butyrate, vinyl pivalate, vinyl caproate, vinyl octoate, vinyl caprate, vinyl laurate, vinyl mythystate, vinyl palmitate, vinyl stearate, vinyl benzoate, and vinyl cinnamate. Other monomers may be used individually or in combination of two or more. 【0020】 The content of the other monomer components in the monomer components constituting the hard segment is preferably 50% by mass or less, more preferably 0 to 50% by mass, and even more preferably 0 to 20% by mass. 【0021】 [Soft Segment] The Tg of the soft segment is -100°C or higher and less than 0°C, preferably -90 to -10°C, more preferably -80 to -15°C. When the Tg of the soft segment is within the above range, the resulting tape is preferable in that it has excellent tack. 【0022】 The soft segment content in polymer (A) is 70 to 99% by mass, preferably 72 to 98% by mass, and more preferably 75 to 96% by mass. A soft segment content within this range is preferable because the resulting tape has excellent tack. The soft segment content in polymer (A) can be calculated from the amount of monomer components constituting the soft segment. 【0023】The monomer components constituting the soft segment are not particularly limited as long as the Tg of the soft segment is between -100°C and 0°C, and the monomer components listed for the hard segment can be used as appropriate. However, from the viewpoint of exhibiting adhesive properties when used as a tape, methyl (meth)acrylate, ethyl (meth)acrylate, n-propyl (meth)acrylate, iso-propyl (meth)acrylate, n-butyl (meth)acrylate, iso-butyl (meth)acrylate, tert-butyl (meth)acrylate, pentyl (meth)acrylate, hexyl (meth)acrylate, heptyl (meth)acrylate, and 2-ethylhexyl are used. It is preferable to use alkyl ester monomers of (meth)acrylate such as (meth)acrylate, n-octyl(meth)acrylate, iso-octyl(meth)acrylate, nonyl(meth)acrylate, decyl(meth)acrylate, iso-decyl(meth)acrylate, undeca(meth)acrylate, lauryl(meth)acrylate, oleyl(meth)acrylate, n-stearyl(meth)acrylate, and iso-stearyl(meth)acrylate. In particular, it is preferable to include n-butyl acrylate and 2-ethylhexyl acrylate in order to improve compatibility with the fatty acid ester (B) described later when used as a tape agent. 【0024】 Polymer (A) can be made into a tape agent with excellent dispersibility of drug (C) described later, by having at least one constituent unit derived from the acidic group-containing monomer, hydroxyl group-containing monomer, or nitrogen atom-containing monomer in its hard segment and / or soft segment. In particular, having a constituent unit derived from a hydroxyl group-containing monomer suppresses excessive bleed-out of the drug component to the surface of the tape agent, resulting in a tape agent with excellent long-term stability. In particular, from the viewpoint of the cohesive force of the tape agent, it is preferable that polymer (A) has a soft segment that contains a constituent unit derived from an acidic group-containing monomer, a hydroxyl group-containing monomer, or a nitrogen atom-containing monomer. 【0025】If the hard segment and / or soft segment have constituent units derived from acidic group-containing monomers, hydroxyl group-containing monomers, or nitrogen atom-containing monomers, their content is 0.5 to 15% by mass of 100% by mass of the monomer components constituting polymer (A). 【0026】 If polymer (A) contains groups that can easily generate radicals through thermal decomposition, such as peroxide groups or mercapto groups, it can cause instability of the adhesive properties due to side reactions after tape formation. Therefore, it is preferable that polymer (A) does not contain peroxide groups or mercapto groups, and it is also preferable not to use monomer components that provide peroxide groups, mercapto groups, or similar groups to polymer (A). 【0027】 [Physical Properties of Polymer (A)] The Tg of the hard segment and soft segment of polymer (A) can be measured by differential scanning calorimeter using the method described in the examples. For example, the characteristic inflection point temperature observed by differential scanning calorimetry can be taken as Tg, but among the multiple inflection point temperatures observed by differential scanning calorimetry of polymer (A), the higher value can be taken as the Tg of the hard segment and the lower value as the Tg of the soft segment. If polymer (A) is manufactured after polymers corresponding to the hard segment or soft segment of polymer (A) have been manufactured in advance, Tg may be calculated using the polymers manufactured in advance. 【0028】 Furthermore, when using commercially available monomers or other components, the values ​​listed in the catalog may be used. 【0029】 The weight-average molecular weight (Mw) of polymer (A), measured by gel permeation chromatography (GPC), is typically between 100,000 and 1,500,000, preferably between 150,000 and 1,300,000, and more preferably between 200,000 and 1,000,000. When the Mw of polymer (A) is within this range, a tape material is obtained that has an excellent balance of cohesive force and tack, as well as excellent processability. Specifically, the Mw measured by GPC is determined by the method described in the examples. 【0030】[Method for producing polymer (A)] Polymer (A) according to one embodiment of the present invention can be produced by conventionally known methods. For example, polymer (A) can be produced by preparing macromonomers in advance as the hard segment portion of polymer (A), and copolymerizing the macromonomers with the monomer components constituting the soft segment. Alternatively, polymer (A) can also be produced by copolymerizing commercially available macromonomers with the monomer components constituting the soft segment. When polymer (A) is produced by copolymerizing macromonomers with the monomer components constituting the soft segment, the monomer components constituting polymer (A) are considered to be 100% by mass, with the total amount of macromonomers used and the monomer components constituting the soft segment being 100% by mass. 【0031】 Examples of known polymerization methods for producing polymer (A) include solution polymerization, bulk polymerization, suspension polymerization, and emulsion polymerization, but among these, solution polymerization is preferred. Specifically, monomer components and polymerization solvent, and a chain transfer agent if necessary, are placed in a reaction vessel, a polymerization initiator is added under an inert gas atmosphere such as nitrogen gas, the reaction start temperature is set to 40 to 100°C, preferably 50 to 90°C, and the reaction temperature is set to 50 to 90°C, preferably 60 to 90°C, and the reaction is carried out for 3 to 20 hours to obtain polymer (A). In addition, polymerization initiators, chain transfer agents, monomer components, and polymerization solvents may be added as appropriate during the polymerization reaction. 【0032】Examples of polymerization initiators include azo polymerization initiators and peroxide polymerization initiators. Examples of azo polymerization initiators include 2,2'-azobisisobutyronitrile, 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), 2,2'-azobis(2-cyclopropylpropionitrile), 2,2'-azobis(2,4-dimethylvaleronitrile), 2,2'-azobis(2-methylbutyronitrile), 1,1'-azobis(cyclohexane-1-carbonitride), 2-(carbamoylazo)isobutyronitrile, 2-phenylazo-4-methoxy-2,4-dimethylvaleronitrile, and 2,2'-azobis(2 Examples of azo compounds include amidinopropane dihydrochloride, 2,2'-azobis(N,N'-dimethylene isobutylamidine), 2,2'-azobis[2-methyl-N-(2-hydroxyethyl)-propionamide], 2,2'-azobis(isobutylamide) dihydrate, 4,4'-azobis(4-cyanopentanoic acid), 2,2'-azobis(2-cyanopropanol), dimethyl-2,2'-azobis(2-methylpropionate), and 2,2'-azobis[2-methyl-N-(2-hydroxyethyl)propionamide]. 【0033】 Examples of peroxide-based polymerization initiators include t-butyl hydroperoxide, cumene hydroperoxide, dicumyl peroxide, benzoyl peroxide, lauroyl peroxide, caproyl peroxide, di-i-propyl peroxydicarbonate, di-2-ethylhexyl peroxydicarbonate, t-butyl peroxypivalate, 2,2-bis(4,4-di-t-butyl peroxycyclohexyl)propane, 2,2-bis(4,4-di-t-amyl peroxycyclohexyl)propane, 2,2-bis(4,4-di-t-octyl peroxycyclohexyl)propane, 2,2-bis(4,4-di-α-cumyl peroxycyclohexyl)propane, and 2,2-bis(4,4-di-t-octyl peroxycyclohexyl)butane. 【0034】Polymerization initiators may be used alone or in combination of two or more. Furthermore, polymerization initiators may be added multiple times during polymerization. The polymerization initiator is typically used in an amount of 0.001 to 5 parts by mass, preferably 0.005 to 3 parts by mass, per 100 parts by mass of the monomer component forming the polymer (A). 【0035】 Examples of polymerization solvents used in the production of polymer (A) include aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as n-pentane, n-heptane, and n-octane; alicyclic hydrocarbons such as cyclopentane, cyclohexane, cycloheptane, and cyclooctane; ethers such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dibutyl ether, tetrahydrofuran, dioxane, anisole, phenylethyl ether, and diphenyl ether; halogenated hydrocarbons such as chloroform, carbon tetrachloride, 1,2-dichloroethane, and chlorobenzene; esters such as ethyl acetate, propyl acetate, butyl acetate, and methyl propionate; ketones such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone, and cyclohexanone; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; nitriles such as acetonitrile and benzonitrile; and sulfoxides such as dimethyl sulfoxide and sulfolane. The polymerization solvent may be used alone or in combination of two or more types. 【0036】 [Method for producing hard segments] Hard segments in polymer (A), i.e., macromonomers, can be produced according to known methods, for example, by the method described in paragraph

[0039] of Japanese Patent Application Publication No. 2013-018227. Commercially available macromonomers may also be used. 【0037】<<Fatty Acid Ester (B)>> When a composition for transdermal absorption formulations contains a fatty acid ester (B), the drug (C) described below can be delivered transdermally when it is made into a tape. From the viewpoint that the tape is applied to the human body (skin) and that the tape does not solidify even when stored in a cool, dark place, it is preferable that the fatty acid ester (B) is liquid at a temperature range of at least 10°C to 50°C. 【0038】 Examples of fatty acid esters (B) include lipophilic components commonly used as base oils, such as dibutyl adipate, diisopropyl adipate, dioctyl succinate, diethyl sebacate, diisopropyl sebacate, ethyl myristate, isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, isopropyl linoleate, ethyl oleate, decyl oleate, propylene glycol oleate, butyl stearate, and glycerin trioleate. Among these, isopropyl myristate is preferred from the viewpoint of achieving a configuration in which the tape is compatible with the soft segment of polymer (A) but incompatible with the hard segment. Fatty acid ester (B) may be used alone or in combination of two or more types. 【0039】 The content of fatty acid ester (B) is 50 to 300 parts by mass, preferably 60 to 280 parts by mass, and more preferably 80 to 250 parts by mass, per 100 parts by mass of polymer (A). When the content of fatty acid ester (B) is within the above range, a good balance is achieved between drug skin permeability and adhesive properties. 【0040】In the transdermal formulation composition according to one embodiment of the present invention, even when a relatively large amount of fatty acid ester (B) is blended, such as 100 parts by mass or more per 100 parts by mass of polymer (A), since polymer (A) is a graft copolymer having soft segments and hard segments, a microphase separation structure is formed in which the soft segments of polymer (A) are a dispersed phase and the hard segments are domains, thereby enabling the cohesive force required for a tape formulation to be exhibited. Furthermore, since the fatty acid ester (B) is miscible with the soft segments of polymer (A) and miscible with the hard segments, a tape formulation with excellent cohesive force without impairing adhesive properties is provided. 【0041】 <<Drug (C)>> Drug (C) is not particularly limited as long as it is used in known transdermal formulations. Furthermore, drug (C) is not limited to those absorbed through the skin, but may also act directly on skin wounds, etc. Examples of drug (C) include moisturizers, whitening / beauty ingredients, vitamins and other cosmetic ingredients; antipyretic, anti-inflammatory, and analgesic agents, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, narcotic analgesics, antiepileptic agents, antipsychotics, antidepressants / anxiolytics, anti-Parkinsonian agents, anti-dementia agents, hypnotics, sedatives, antispasmodics, muscle relaxants, autonomic nervous system agents, cerebral circulation / metabolism improvers, cardiac stimulants, anti-anginal agents, antihypertensive / arrhythmic agents, vasodilators, antihypertensive agents, vasopressors, diuretics, respiratory stimulants, antitussives and expectorants, bronchodilators, asthma / nasal allergy treatments, respiratory agents, cold remedies, antiemetics, antacids Examples of drugs used in the medical field include suppositories, anti-ulcer agents, laxatives, antidiarrheal intestinal agents, liver agents, pancreatic disease treatments, choleretic agents, female hormones, male hormones, hypothalamic and pituitary hormones, ovulation inducers, diabetes insipidus treatments, thyroid hormones, anabolic hormones, antithyroid agents, calcium metabolizers, anti-inflammatory enzymes, antihistamines, anti-rheumatic agents, gout treatments, hypoglycemic agents, vitamins, hematopoietic agents, hemostatic agents, hyperlipidemia treatments, antibiotics, antitumor agents, immunosuppressants, antidotes, emetics, anthelmintics, antiparasitic agents, hemorrhoid treatments, genitourinary agents, and anticoagulants. 【0042】As drugs specifically used in the field of cosmetics, there are, for example, humectants such as hyaluronic acid, ceramide, collagen, chitosan, elastin, albumin, sodium pyrrolidone carboxylate, casein, and heparinic acid; whitening and beauty components such as tranexamic acid, astaxanthin, albumin, placenta extract, kojic acid, rosmarinic acid, epidermal growth factor, FGF (fibroblast growth factor), and EGF (epidermal growth factor); vitamins such as vitamin A, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin K, vitamin E, biotin, niacin, retinol, and carnitine; amino acids such as arginine, glycine, serine, lysine, proline, glutamic acid, hydroxyproline, sarcosine, and functional peptides; coenzymes such as orotic acid, linoleic acid, quercetin, and ubiquinone; plant extracts such as licorice, coix seed, rice bran, and aloe; anti-inflammatory components such as glycyrrhizic acid; hair growth components such as minoxidil; phytochemicals such as ergothioneine; or salts and derivatives of the above components, vitamin derivatives such as ascorbyl glucoside, and niacin derivatives such as nicotinamide mononucleotide. The drug (C) may be used alone or in combination of two or more in the transdermal absorption preparation. 【0043】 When the drug (C) has poor compatibility with the fatty acid ester (B) due to reasons such as the hydrophilic nature of the drug (C), that is, when the drug (C) has no transdermal absorption ability or has poor transdermal absorption ability, the drug (C) may be complexed with a component such as a surfactant to be in a state compatible with the fatty acid ester (B). Also, when the efficacy of the drug (C) is impaired or the physical properties of the tape preparation obtained are impaired by the drug (C) coming into contact with the polymer (A) and / or the fatty acid ester (B), the drug (C) may be complexed with a component such as a surfactant. 【0044】The surfactant is not particularly limited as long as it is used in known transdermal formulations. Examples of surfactants include anionic surfactants, cationic surfactants, amphoteric surfactants, and nonionic surfactants, with nonionic surfactants being preferred. A single surfactant may be used, or two or more may be used. Specific examples of anionic surfactants include fatty acid soaps, naphthenic acid soaps, long-chain alcohol sulfates, polyoxyethylene alkylphenyl ether sulfates, fatty acid monoglyceride sulfates, fatty acid monoalkanolamide sulfates, alkali sulfonates, α-sulfo fatty acid salts, dialkyl sulfosuccinates, polyoxyethylene octylphenyl ether sulfonates, alkylbenzene sulfonates, polyoxyethylene alkylphenol ether phosphates, polyoxyethylene alkyl ether phosphates, and sodium lauryl sulfate. Specific examples of cationic surfactants include long-chain primary amine salts, alkyltrimethylammonium salts, dialkyldimethylammonium salts, alkylpyridinium salts, polyoxyethylene alkylamines, and alkylimidazolines. Specifically, amphoteric surfactants such as N-alkyl-β-aminopropionate and N-alkyl-β-iminodipropionate are used.Specific examples of nonionic surfactants include polyglyceryl decaoleate, polyglyceryl polyricinoleate, polyglyceryl diisostearate, polyglyceryl tetraisostearate, polyglyceryl pentaoleate, polyglyceryl decaisostearate, glyceryl monooleate, glyceryl monocaprate, and other (poly)glycerin fatty acid esters composed of hydrophilic (poly)glycerin and lipophilic fatty acids; sucrose stearate, sucrose palmitate, sucrose myristicate, sucrose oleate, sucrose laurate, sucrose erucate, and sucrose mixed fatty acid esters composed of hydrophilic sucrose and lipophilic fatty acids; polyoxyethylene glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, propylene glycol fatty acid esters, and polyoxyethylene castor oil / hydrogenated castor oil. 【0045】 When a hydrophilic drug (C) is incorporated into a transdermal formulation composition, the drug (C) may not be uniformly dispersed in the transdermal formulation, i.e., in the tape formulation, but rather localized, resulting in a decrease in the amount of drug delivered. However, this problem can be resolved by coating the hydrophilic drug (C) with a lipophilic surfactant and compounding them. An example of the form of the drug compounded with the surfactant is solid-in-oil. A drug in solid-in-oil form can be manufactured according to conventionally known methods, for example, by the method described in paragraphs

[0043] to

[0052] of Japanese Patent Application Publication No. 2008-179561. 【0046】 The content of drug (C) is 0.001 to 100 parts by mass, preferably 0.5 to 60 parts by mass, per 100 parts by mass of polymer (A). When the content of drug (C) is within the above range, the loss of the adhesive properties of the tape is minimal. If multiple types of drug (C) are contained, the above content refers to the total amount of drug (C) used. Furthermore, if drug (C) is compounded with components such as surfactants, the above content refers to the weight of the drug (C) after compounding. 【0047】 <<Other Components>> The composition for a transdermal absorption preparation according to an embodiment of the present invention may contain other components other than the polymer (A), fatty acid ester (B), and drug (C) as long as the object is not impaired. Examples of the other components include polymers other than the polymer (A), crosslinking agents, ultraviolet absorbers, antioxidants, tackifying resins, defoaming agents, fillers, stabilizers, wettability modifiers, coloring agents, fragrances, and the like. When the composition for a transdermal absorption preparation contains other components, the content thereof is 0 parts by mass or more and 30 parts by mass or less, preferably 0 parts by mass or more and 20 parts by mass or less, based on 100 parts by mass of the polymer (A). 【0048】 When the composition for a transdermal absorption preparation contains the polymer (A) having a crosslinkable functional group and a crosslinking agent, the crosslinkable functional group and the crosslinking agent can undergo a crosslinking reaction to form a crosslinked structure between the polymers (A), and the cohesive force of the tape preparation can be further improved. When the crosslinking agent causes a side reaction with the drug (C) or the percutaneous absorption ability of the drug (C) decreases due to the formation of a crosslinked structure by the polymer (A), it is preferable that the composition for a transdermal absorption preparation does not contain a crosslinking agent. 【0049】The crosslinking agent is not particularly limited as long as it is a crosslinking agent that can react with a crosslinkable functional group at room temperature or under heating to form a crosslinked structure. Examples include isocyanate-based crosslinking agents, epoxy-based crosslinking agents, metal chelate-based crosslinking agents, and aziridine-based crosslinking agents, with isocyanate-based crosslinking agents and epoxy-based crosslinking agents being particularly preferred. The crosslinking agent may be used alone or in combination of two or more. Examples of isocyanate-based crosslinking agents include isocyanate monomers such as xylylene diisocyanate, tolylene diisocyanate, chlorphenyl diisocyanate, hexamethylene diisocyanate, tetramethylene diisocyanate, isophorone diisocyanate, diphenylmethane diisocyanate, and hydrogenated diphenylmethane diisocyanate, as well as polyfunctional isocyanate compounds and isocyanurates containing two or more isocyanate groups in the molecule, obtained by adding these monomers to divalent or higher alcohols such as trimethylolpropane, and derivatives thereof. Examples of epoxy crosslinking agents include epoxy compounds having two or more epoxy groups per molecule. Specifically, these include ethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, glycerin diglycidyl ether, glycerin triglycidyl ether, 1,3-bis(N,N-diglycidylaminomethyl)cyclohexane, N,N,N',N'-tetraglycidyl-m-xylylenediamine, N,N,N',N'-tetraglycidylaminophenylmethane, triglycidyl isocyanurate, m-N,N-diglycidylaminophenylglycidyl ether, N,N-diglycidyltoluidine, and N,N-diglycidylaniline. The number of epoxy groups per molecule in these epoxy compounds is, for example, 2 to 10. 【0050】 In one embodiment of the present invention, the transdermal composition is a graft copolymer in which polymer (A) has soft segments and hard segments. Since a microphase separation structure is formed in which the soft segments of polymer (A) are a dispersed phase and the hard segments are domains, a tape formulation with excellent cohesive strength can be produced even if no crosslinking structure is formed between polymers (A). 【0051】<Preparation of the composition for transdermal absorption formulation> The composition for transdermal absorption formulation according to one embodiment of the present invention can be prepared, for example, by mixing a polymer (A), a fatty acid ester (B), a drug (C), and other components as needed, by conventionally known methods. In addition to the above components, the composition for transdermal absorption formulation according to one embodiment of the present invention may also contain an organic solvent, to the extent that it does not impair the effects of the present invention. Examples of organic solvents include those similar to the polymerization solvent used in the production of polymer (A). 【0052】 <Transdermal Absorption Formulation> One embodiment of the transdermal absorption formulation can take the form of a tape having an adhesive layer made from the above-mentioned transdermal absorption composition on one side of a base material. The base material is not particularly limited, and known base materials used in the art can be used. Examples of base materials include woven fabrics made of polyethylene, polypropylene, etc.; nonwoven fabrics; plastic films made of polycarbonate, polymethyl methacrylate, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polyethylene, polypropylene, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer, acrylonitrile-butadiene-styrene copolymer, polyamide, polyimide, polyvinyl chloride, polyurethane, etc.; paper; metal foil, etc. Among these, it is preferable to use woven fabrics or nonwoven fabrics from the viewpoint of how easily they conform to the unevenness of the skin and their breathability. 【0053】 The film thickness of the substrate is not particularly limited, but is usually 5 to 2000 μm, preferably 10 to 1500 μm. The substrate may also be subjected to treatments such as corona treatment or plasma discharge treatment, and may be coated with an anchor coating material. 【0054】 A transdermal absorbent (tape) according to one embodiment of the present invention may have a release liner on the side of the adhesive layer that does not have a substrate. The release liner protects the surface of the adhesive layer until the transdermal absorbent preparation is used and is removed when the transdermal absorbent preparation is used. The release liner is not particularly limited as long as it can be easily peeled off from the adhesive layer, and materials similar to those mentioned above for the substrate can be used. 【0055】 The film thickness of the release liner is not particularly limited, but is usually 10 to 500 μm, preferably 20 to 200 μm. Furthermore, it is preferable that at least one side of the release liner is treated with an easy-release agent such as a silicone-based, fluorine-based, long-chain alkyl-based, or aliphatic amide-based release agent, or embossed. 【0056】 <Method for Manufacturing Transdermal Absorption Preparations> A transdermal absorption preparation (tape) according to one embodiment of the present invention is manufactured using a known method. For example, the components contained in the transdermal absorption preparation composition according to one embodiment of the present invention are uniformly mixed and stirred, the composition is applied to the release surface of a substrate or release liner, and depending on the type of solvent contained in the composition, the solvent is removed by drying at a temperature of usually 50 to 150°C, preferably 60 to 100°C, for usually 1 to 10 minutes, preferably 2 to 7 minutes to form an adhesive layer. The thickness of the adhesive layer is usually 5 to 500 μm, preferably 10 to 300 μm. 【0057】 When a composition for transdermal absorption is applied to a release liner, a tape can be manufactured by bonding a substrate to the side of the adhesive layer that is not in contact with the release liner after the adhesive layer has formed. 【0058】 As a method for applying the composition for transdermal absorption formulations, for example, a method of applying and drying to a predetermined thickness can be used, such as the spin coating method, knife coating method, roll coating method, bar coating method, blade coating method, die coating method, or gravure coating method. After the application of the composition for transdermal absorption formulations and the subsequent drying process, a maturation period may be provided. If a maturation period is provided, the conditions are 1 to 10 days at 5 to 80°C and in an environment of 5 to 70% RH. 【0059】 <Use of transdermal formulations> The transdermal formulation (tape) according to one embodiment of the present invention is not limited to any particular site of application and can be applied to any part of the body such as the arm, shoulder, chest, abdomen, waist, buttocks, thigh, or leg. 【0060】The present invention will be described more specifically below based on examples, but the present invention is not limited in any way to these examples. In the following description, unless otherwise specified, "parts" refers to "parts by mass". 【0061】 [Measurement of Glass Transition Temperature (Tg)] The Tg of the hard and soft segments of polymer (A), or the macromonomers constituting the hard segment of polymer (A), was measured using a differential scanning calorimeter (DSC). Specifically, polymer (A) or macromonomers were sealed in a simple sealed pan, and the thermal change was measured using a differential scanning calorimeter under a nitrogen atmosphere, increasing the temperature from -100°C to 200°C at a rate of 10°C / min. A graph of "heat absorption" and "temperature" was drawn, and the characteristic inflection point observed at this time was defined as Tg. The Tg value used was obtained from the DSC curve using the midpoint method. 【0062】 [Measurement of Weight-Average Molecular Weight (Mw)] The Mw of polymer (A) or macromonomers constituting the hard segment of polymer (A) was determined by gel permeation chromatography (GPC) under the following conditions, on a standard polystyrene basis. • Measurement device: HLC-8220GPC (Tosoh Corporation) • GPC column configuration: The following five-column system (all Tosoh Corporation): (1) TSK-GEL HXL-H (guard column) (2) TSK-GEL G7000HXL (3) TSK-GEL GMHXL (4) TSK-GEL GMHXL (5) TSK-GEL G2500HXL • Sample concentration: 1.0 mg / cm³ ３ To achieve this, dilute with tetrahydrofuran; mobile phase solvent: tetrahydrofuran; flow rate: 1.0 cm ３ / min Column temperature: 40°C 【0063】(Manufacturing Example 1) In a glass flask equipped with a stirrer, dropping funnel, gas inlet tube, thermometer, and reflux condenser, 30 parts methyl methacrylate (MMA) and 50 parts toluene were charged. Separately, in a dropping funnel, 70 parts MMA, 50 parts toluene, 1.5 parts thioglycolic acid, and 2 parts 2,2'-azobisisobutyronitrile (AIBN) were charged. The contents of the flask were heated to 90°C while introducing nitrogen gas into the flask. While maintaining the temperature inside the flask at 90°C, the liquid in the dropping funnel was added dropwise over 4 hours. After the addition was complete, heating and cooling were performed for 2 hours to maintain the temperature of the contents inside the flask at 90°C to obtain a methyl methacrylate polymer solution. Next, 2.5 parts of glycidyl methacrylate, 1 part of N,N-dimethyllaurylamine as a catalyst, and 0.05 parts of hydroquinone monomethyl ether were added to the methyl methacrylate polymer solution, and the mixture was reacted at 90°C for 5 hours to obtain a solution containing macromonomer (MM-1). The obtained macromonomer (MM-1) had a Mw of 13,000 and a Tg of 52°C. 【0064】 (Production Example 2) A solution containing macromonomer (MM-2) was obtained in the same manner as in Production Example 1, except that MMA was replaced with iso-butyl methacrylate (i-BMA). The obtained macromonomer (MM-2) had a Mw of 13,000 and a Tg of 10°C. 【0065】 (Manufacturing Example 3) 90 parts of MMA, 30 parts of ethyl acetate, and 2.5 parts of RAFT agent 1 shown in the following formula were charged into a glass flask equipped with a stirrer, dropping funnel, gas inlet tube, thermometer, and reflux condenser. The contents of the flask were heated to 80°C while introducing nitrogen gas into the flask. Next, 0.02 parts of AIBN were added to the flask with stirring, and heating and cooling were carried out for 1 hour to maintain the temperature of the contents of the flask at 80°C. Next, heating and cooling were carried out for 10 hours to maintain the temperature of the contents of the flask at 80°C, and finally 20 parts of ethyl acetate were added to obtain a solution containing acrylic polymer (AP-1). The obtained acrylic polymer (AP-1) had a Mw of 7,000 and a Tg of 48°C. 【0066】 【0067】(Production Example 4) In a glass flask equipped with a stirrer, gas inlet tube, thermometer, and reflux condenser, 95 parts of 2-ethylhexyl acrylate (2EHA), 5 parts of the macromonomer (MM-1) obtained in Production Example 1, and 120 parts of ethyl acetate were charged, and the contents of the flask were heated to 80°C while introducing nitrogen gas into the flask. Next, 0.03 parts of AIBN were added to the flask, and the reaction was carried out for 11 hours while maintaining the temperature of the contents of the flask at 80°C. After the reaction was completed, 30 parts of ethyl acetate were added to obtain a polymer solution containing polymer (A-1), which is a graft copolymer. The Mw of polymer (A-1) was 400,000. Note that 2EHA corresponds to the constituent units of the soft segment in polymer (A-1), and macromonomer (MM-1) corresponds to the constituent units of the hard segment. That is, the Tg of the soft segment of polymer (A-1) is -70°C, and the Tg of the hard segment is 52°C. 【0068】 (Production Examples 5-9) Polymers (A-2) to (A-6) were obtained in the same manner as in Production Example 3, except that the monomer components and their amounts were changed as shown in Table 1. The Mw of polymers (A-2) to (A-6) are shown in Table 1. 【0069】 (Comparative Manufacturing Example 1) 90 parts of 2EHA, 10 parts of MMA, and 70 parts of ethyl acetate were charged into a glass T-flask equipped with a stirrer, gas inlet tube, thermometer, and reflux condenser. The contents of the flask were heated to 80°C while introducing nitrogen gas into the flask. Next, 0.03 parts of AIBN were added to the flask, and the reaction was carried out for 11 hours while maintaining the temperature of the contents of the flask at 80°C. After the reaction was complete, 80 parts of ethyl acetate were added to obtain a polymer solution containing polymer (cA-1). The Mw of polymer (cA-1) was 350,000. 【0070】(Comparative Manufacturing Example 2) An acrylic polymer (AP-1) solution was charged into a glass flask equipped with a stirrer, gas inlet tube, thermometer, and reflux condenser so that the solid content was 5 parts. Then, 95 parts of 2EHA and 50 parts of ethyl acetate were added, and the contents of the flask were heated to 80°C while introducing nitrogen gas into the flask. Next, 0.02 parts of AIBN were added to the flask, and the reaction was carried out for 10 hours while maintaining the temperature of the contents of the flask at 80°C. After the reaction was completed, 20 parts of ethyl acetate were added to obtain a polymer solution containing a triblock polymer (cA-2) of block A-block B-block A. Block B corresponds to the constituent unit of the acrylic polymer (AP-1). The Mw of polymer (cA-2) was 300,000. 【0071】 • 2EHA: 2-ethylhexyl acrylate • t-BA: tert-butyl acrylate • ISA: iso-stearyl acrylate • 4HBA: 4-hydroxybutyl acrylate • MMA: methyl methacrylate 【0072】 In Table 1, the values ​​next to 2EHA, t-BA, ISA, 4HBA, and MMA represent the Tg values ​​when the monomer is homopolymerized. The values ​​next to MM-1, MM-2, and AP-1 represent the Tg values ​​of MM-1, MM-2, and AP-1 themselves. 【0073】(Example 1) A solution was prepared by dissolving 10 mg (2.5 parts by mass) of hyaluronic acid as the aqueous phase in 2 mL of Milli-Q water (ultrapure water obtained from a Milli-Q® water production system manufactured by Merck KGaA) and a solution was prepared by dissolving 200 mg (50 parts by mass) of a surfactant (sucrose dielcate) in 4 mL of cyclohexane as the organic phase. These solutions were added to a glass vial and stirred at 26,000 rpm for 2 minutes using a Polytron homogenizer. The resulting emulsion was flash-frozen in liquid nitrogen and freeze-dried for 24 hours. The entire amount of the drug (C-1), which is a complex of hyaluronic acid and surfactant, was redispersed in 400 mg (100 parts by mass) of isopropyl myristate (IPM). The polymer (A-1) obtained in Production Example 4 was then mixed in an amount equivalent to 400 mg (100 parts by mass) of solids to obtain a composition for transdermal absorption. After degassing the composition, a coating film with a dry thickness of 30 μm was formed on a peeled polyethylene terephthalate (PET) film using a doctor blade. The nonwoven side of a nonwoven laminate film (30 μm polyethylene terephthalate nonwoven fabric / 20 μm PE film) was laminated to the surface of the coating film opposite to the surface in contact with the PET film to prepare a transdermal patch. The evaluation results are shown in Table 2. 【0074】 (Examples 2-9, Comparative Examples 1-4) Tape preparations for Examples 2-9 and Comparative Examples 1-4 were prepared in the same manner as in Example 1, except that the components and quantities used were changed as shown in Table 2. The evaluation results are shown in Table 2. 【0075】 (Example 10) The tape preparation according to Example 10 was prepared in the same manner as in Example 1, except that the surfactant (sucrose dielcate) of Example 1 (200 mg, 50 parts by mass) was replaced with 100 mg (25 parts by mass) of sucrose dielcate and 100 mg (25 parts by mass) of polyglyceryl-6 polyricinoleate to obtain a drug (C-2) which is a complex of hyaluronic acid and surfactant. 【0076】<Evaluation of the Tape> [Drug Skin Penetration] Subcutaneous tissue of Yucatan micropig skin (4 months old) was removed using a medical scalpel to obtain test skin. The skin was then cut into 2 cm x 2 cm sections and placed between the donor and acceptor phases of a longitudinal Franz cell with the stratum corneum facing upwards. 5 mL of phosphate-buffered saline (PBS) (pH 7.4) at 32°C was filled into the receptor phase. A tape, cut to the same area as the effective area of ​​the longitudinal Franz cell (a circle with a diameter of 10 mm), was applied to the top of the stratum corneum and incubated at 32°C for 24 hours. The tape was then removed, and the two outermost layers of the stratum corneum were removed by tape stripping. The remaining stratum corneum was stripped by tape stripping and immersed in an extract (PBS / methanol / acetonitrile = 2 / 1 / 1, v / v) and extracted by shaking at room temperature for 16 hours. The skin, excluding the stratum corneum, was divided into 16 sections using a scalpel, immersed in 1 mL of PBS, and extracted by shaking at room temperature for 16 hours. The amount of physiologically active drugs contained in the extract was quantified by LC-MS. The LC-MS measurement conditions are as follows: <Measurement Conditions> Apparatus: Waters (e2695 (LC section), 3100 (MS detector)) Column: InertSustainSwift C18 (2.1 mm I.D. x 100 mm) Column temperature: 40°C Detection mass (m / z): 510.4 Eluent: A: 0.1% formic acid aqueous solution, B: acetonitrile gradient Conditions: 0-10 min: B 20-35%, 10-11 min: B 35-100%, 11-16 min: B 100% Flow rate: 0.2 mL / min 【0077】 [Adhesion Strength and Failure Mode] Test pieces (25 mm wide) of the tape obtained in the examples and comparative examples were peeled off the polyethylene terephthalate (PET) film under 23°C / 50% RH conditions. The exposed adhesive layer was attached to a stainless steel (SUS) plate and pressed down with a 2 kg roller in three back-and-forth motions. Twenty minutes after attachment, the tape was peeled off at a peeling angle of 180° and a tensile speed of 300 mm / min, and the adhesive strength of the tape was measured. Furthermore, it was evaluated whether interfacial failure or cohesive failure occurred at the peeled joint surface during the adhesion strength test. 【0078】[Holding Force] The tape materials obtained in the examples and comparative examples were cut to a size of 20 mm x 100 mm to prepare test specimens. The release liner was peeled off the obtained test specimens, and the exposed adhesive layer was applied to a stainless steel plate (SUS) so that the application area was 20 mm x 20 mm, and pressed down with a 2 kg roller in three back-and-forth motions. After that, it was left to stand for 20 minutes in a 40°C / dry environment, and a 100 g load was applied to the test object in the shear direction under the same environment, and the time required from the start of loading until it fell was measured. The longer the time required until it fell, the higher the cohesive force of the tape material. 【0079】

Claims

1. A composition for transdermal formulations comprising 100 parts by mass of a polymer (A) which is a graft copolymer, 50 to 300 parts by mass of a fatty acid ester (B), and 0.001 to 100 parts by mass of a drug (C), wherein the polymer (A) comprises a soft segment having a glass transition temperature (Tg) of -100°C or higher and less than 0°C, and a hard segment having a glass transition temperature (Tg) of 0°C or higher, and the content ratio of the hard segment in the polymer (A) is 1 to 30% by mass.

2. The transdermal composition according to claim 1, wherein the weight-average molecular weight (Mw) of the polymer (A) is 100,000 to 1,500,000.

3. The transdermal formulation composition according to claim 1, comprising a drug (C) complexed with a surfactant.

4. A transdermal formulation formed from the transdermal composition described in any one of claims 1 to 3.

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