JP2014172840A - Patch - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a patch which can ensure percutaneous absorbability and its persistence in percutaneously administering hydrophilic drugs.SOLUTION: A patch has an adhesive layer containing an adhesive composition which includes solid-in-oil fine particles (A) including a hydrophilic drug coated with a surfactant and an acrylic polymer (B) having a constitutional unit represented by the specified general formula (1).

Description

  The present invention relates to a patch.

  Conventional preparations containing a hydrophilic drug as an active ingredient have been mainly oral preparations. However, in the case of oral administration, there are drawbacks such as the possibility of receiving the first-pass effect in the liver after the drug is absorbed, and the possibility that a blood concentration more than necessary may be temporarily observed after administration.

  In recent years, a transdermal therapeutic system (TTS) has been developed as a pharmaceutical administration method that allows a desired medicinal component to permeate through the skin systemically and develop a therapeutic effect over a long period of time. Nitroglycerin and nitric acid for treating angina Isosorbide, clonidine for the treatment of hypertension, estradiol for the treatment of menopause, etc. have already been put into practical use.

  However, the percutaneous administration method of the active ingredient has a defect that the absorption of the active ingredient is remarkably low as compared with the oral or injection administration method, and this is particularly remarkable when the active ingredient is hydrophilic.

  As a method of transdermally administering a hydrophilic drug, a method of physically perforating or rubbing the stratum corneum of skin with a microneedle is disclosed (Patent Documents 1 and 2). In addition, a Solid in Oil (hereinafter abbreviated as S / O) type external preparation in which a hydrophilic drug is solubilized and coated with a surfactant has been proposed (Patent Document 3).

JP 2012-025723 A JP 2001-157715 A Japanese Patent No. 4844494

  However, the methods described in Patent Documents 1 and 2 are highly invasive, and infection by viruses or the like from the invasive site of the skin becomes a problem. Although the external preparation described in Patent Document 3 is highly non-invasive, since the external preparation is in a liquid state, there is a possibility that percutaneous absorption and its sustainability cannot be ensured by evaporation or the like.

  An object of the present invention is to provide a patch capable of ensuring percutaneous absorbability and its sustainability when a hydrophilic drug is administered transdermally.

  The present invention uses an S / O type fine particle in which a hydrophilic agent is coated with a surfactant, and a sticking agent containing a pressure-sensitive adhesive composition combined with an acrylic polymer containing a predetermined structural unit as a pressure-sensitive adhesive layer. Another object of the present invention is to provide a patch excellent in transdermal absorbability and sustainability of a hydrophilic drug.

  The patch of the present invention comprises S / O type fine particles (A) in which a hydrophilic drug is coated with a surfactant, an acrylic polymer (B) containing a structural unit represented by the following general formula (1), It has the adhesive layer which consists of an adhesive composition containing this, It is characterized by the above-mentioned.

（一般式（１）において、Ｒ¹は水素原子又はメチル基を示し、Ｒ²は炭素数６〜１４のアルキル基を示す。）

(In General Formula (1), R ¹ represents a hydrogen atom or a methyl group, and R ² represents an alkyl group having 6 to 14 carbon atoms.)

  The acrylic polymer (B) preferably further contains a structural unit derived from a vinyl monomer having a reactive functional group selected from the group consisting of a hydroxyl group, an amino group, and a carboxyl group.

  Furthermore, it is preferable that the pressure-sensitive adhesive composition further contains a crosslinking agent (C).

  And a crosslinking agent (C) contains at least 1 type selected from the group which consists of a polyfunctional amino compound, a polyfunctional isocyanate compound, a polyfunctional epoxy compound, a polyfunctional aziridine compound, a polyfunctional oxazoline compound, and a polyfunctional metal compound. Is preferred.

  According to the present invention, it is possible to provide a patch excellent in transdermal absorbability and sustainability of a hydrophilic drug.

FIG. 1 is a cross-sectional view schematically showing the structure of an example of the patch of the present invention.

[S / O type fine particles (A)]
The S / O type fine particles (A) in the present invention have a structure in which a hydrophilic drug is coated with a surfactant, and usually the hydrophilic part of the surfactant is associated with the hydrophilic drug to cover the surroundings. ing.

  Hydrophilic drugs are not particularly limited, for example, loxoprofen sodium, diclofenac sodium, piroxicam, indomethacin, triamcinolone, acetaminophen, fenbufen, tolmetine sodium, haloperidol, propranolol hydrochloride, estradiol, clonidine hydrochloride, tetracycline, chloramphenicol, Examples include fradiomycin sulfate, nifedipine, clotrimazole, benzalkonium chloride, nystatin, nicorandil, nifedrine hydrochloride, hydrocortisone, diphenhydramine hydrochloride, fluocinolone acetonide, and the like.

  The molecular weight of the hydrophilic drug in the present invention is preferably 10,000 or less, more preferably 5000 or less, and still more preferably 1000 or less.

  The surfactant can be used without particular limitation as long as it is acceptable in pharmaceutical preparations. Examples thereof include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants. Among these, it is preferable to use a nonionic surfactant.

  Nonionic surfactants include, for example, polyglycerol condensed ricinoleic acid ester, decaglycerol ester, glycerol fatty acid ester, polyglycerol fatty acid ester, polyoxyethylene glycerol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbite fatty acid ester, polyoxy Ethylene castor oil, polyoxyethylene hydrogenated castor oil, sucrose fatty acid ester (sucrose stearate ester, sucrose palmitate ester, sucrose myristic acid ester, sucrose oleate ester, sucrose laurate ester, sucrose erucic acid Ester, sucrose mixed fatty acid ester) and the like. One of these may be selected and used, or a mixture of two or more may be used.

  As the nonionic surfactant, an ester compound using an unsaturated fatty acid such as erucic acid or oleic acid as a raw material is suitable, and more preferably, sucrose erucic acid ester, sucrose oleic acid ester, sucrose mixed fatty acid ester Is mentioned. Nonionic surfactants include sucrose fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene sorbit fatty acid ester, glycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene castor oil and polyoxyethylene hardened One or two or more selected from the group consisting of castor oil can also be used. Among these, one or more selected from the group consisting of sucrose fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene sorbite fatty acid ester, glycerin fatty acid ester, polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil It is preferable.

  The HLB value of the surfactant is preferably 10 or less, more preferably 9 or less, and even more preferably 6 or less. The structure of the surfactant molecule is generally a linear or branched, saturated or unsaturated aliphatic group which is a lipophilic group, and a hydrophilic group bonded thereto, and any of them can be used in the present invention. As the lipophilic group, a linear aliphatic group is preferable, and a linear unsaturated aliphatic group is more preferable. Moreover, it is preferable that carbon number of the aliphatic group which is a lipophilic group in surfactant is 14-22. By using such a surfactant, the compatibility of the S / O type fine particles (A) with the acrylic polymer (B) can be improved.

  The S / O type fine particles (A) in the present invention may contain a stabilizer.

  As the stabilizer, hydrophilic proteins and polysaccharides are preferably used. When the stabilizer is coated with a hydrophilic agent and a surfactant, the stability of the S / O type fine particles (A) is improved, and the hydrophilicity to the outside of the S / O type fine particles (A) in the patch. Leakage of sex medicine can be prevented.

  Examples of the protein that is a stabilizer include serum albumin (molecular weight: about 67,000), ovalbumin (molecular weight: about 45,000), casein (molecular weight: about 19,000 or more), lysozyme (molecular weight: about 14). , 5,000 or more), lipase (molecular weight: about 45,000), and the like. One of these can be selected, or two or more can be selected and mixed for use. Preferably, one or more selected from the group consisting of serum albumin, ovalbumin and casein can be used. The molecular weight of the protein as a stabilizer is preferably 10,000 to 150,000, and more preferably 20,000 to 100,000.

  Examples of polysaccharides that are stabilizers include LM (low methoxyl) pectin, HM (high methoxyl) pectin, hydroxypropylmethylcellulose phthalate, heparin, alginic acid, and carboxymethylcellulose. Or two or more can be selected and mixed for use. Preferably, one or more selected from the group consisting of LM pectin, HM pectin and hydroxypropyl methylcellulose phthalate can be used.

  The mass ratio of the stabilizer to the hydrophilic drug is preferably in the range of 0.01 to 100, more preferably in the range of 0.1 to 10, and particularly preferably in the range of 0.5 to 5.

  Moreover, when mix | blending a stabilizer, the mass ratio of surfactant with respect to the sum total of a hydrophilic chemical | medical agent and a stabilizer has the preferable range of 0.5-100, More preferably, it is the range of 1-50, More preferably, it exists in the range of 2-25.

  An example of a method for producing the S / O type fine particles (A) is as follows. An organic solvent solution containing a surfactant and, if necessary, a stabilizer is added to an aqueous solution containing a hydrophilic agent and, if necessary, a water-in oil (W / O). An O) type emulsion is prepared, and then this emulsion is dried by freeze drying or the like to produce S / O type fine particles. Examples of the organic solvent used in the organic solvent solution include hydrocarbon solvents such as hexane, cyclohexane, and toluene. The aggregate of S / O type fine particles may be liquid or solid at room temperature, but is preferably liquid. Since the S / O type fine particles (A) are obtained by lyophilization or the like as described above, they usually do not substantially contain a volatile organic solvent. “Substantially free” means that the content of the solvent as measured by headspace gas chromatography is below the detection limit, and is preferably 0.

  The S / O type fine particles are preferably dispersed in fats and oils before blending with other components of the pressure-sensitive adhesive composition.

  Examples of the fats and oils include soybean oil, cottonseed oil, rapeseed oil, sesame oil, corn oil, peanut oil, safflower oil, sunflower oil, olive oil, perilla oil, fennel oil, cacao oil, cinnamon oil, mint oil, bergamot oil, etc. Vegetable oils; animal oils such as beef tallow, pork oil, fish oil; neutral lipids such as medium chain fatty acid triglycerides, triolein, trilinolein, tripalmitin, tristearin, trimyristin, triarachidonin; synthetic lipids such as azone; cholesteryl ole Sterol derivatives such as ate, cholesteryl linoleate, cholesteryl myristate, cholesteryl palmidate, cholesrelyl arachidate; isopropyl myristate, octyldodecyl myristate, cetyl myristate, ethyl oleate, ethyl linoleate, isopropyl linoleate, palmitate Long-chain fatty acid esters such as isopropyl acetate and butyl stearate; lactic acid esters such as ethyl lactate and cetyl lactate; polyvalent carboxylic acid esters such as triethyl citrate, diisopropyl adipate, diethyl sebacate and diisopropyl sebacate; 2-ethyl Examples include esters of other carboxylic acids such as cetyl hexanoate; hydrocarbons such as petrolatum and paraffin squalane; silicones and the like. One of these may be selected and used, or two or more may be selected and mixed for use. As fats and oils, vegetable oils, neutral lipids, and long-chain fatty acid esters are preferable. The preferred vegetable oil is one or more selected from the group consisting of soybean oil, sesame oil, olive oil, safflower oil, sunflower oil, rapeseed oil and perilla oil, more preferably a vegetable oil based on triglyceride. is there. A practically preferred vegetable oil is soybean oil, and soybean oil refined to a high purity is more preferred. A preferred neutral lipid is triglyceride and a preferred long chain fatty acid ester is isopropyl myristate.

  When the S / O type fine particles are dispersed in fats and oils, the mass ratio of the fats and oils to the S / O type fine particles is preferably 0.1 to 5, and more preferably 0.15 to 1.

（一般式（１）において、Ｒ¹は水素原子又はメチル基を示し、Ｒ²は炭素数６〜１４のアルキル基を示す。） [Acrylic polymer (B)]
The acrylic polymer (B) in the present invention includes a structural unit represented by the following general formula (1). Since the acrylic polymer (B) is excellent in compatibility with the S / O type fine particles (A) and has excellent releasability of the S / O type fine particles (A), the patch of the present invention has a good It can exhibit skin absorbability and durability.

(In General Formula (1), R ¹ represents a hydrogen atom or a methyl group, and R ² represents an alkyl group having 6 to 14 carbon atoms.)

When the alkyl group R ² has 6 or more carbon atoms, the compatibility of the S / O type fine particles (A) with the acrylic polymer (B) can be maintained. Further, when it is 14 or less, it is possible to prevent a decrease in adhesive performance due to an increase in crystallinity or the like.

  Examples of the monomer for forming the structural unit represented by the general formula (1) include (meth) acrylic acid alkyl esters in which the alkyl group of the ester moiety has 6 to 14 carbon atoms. Specifically, Is hexyl (meth) acrylate, n-octyl (meth) acrylate, isooctyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, dodecyl (meth) acrylate, decyl (meth) acrylate, isodecyl (meth) acrylate, lauryl (meth) ) Acrylate, myristyl (meth) acrylate, and the like. These may be used individually by 1 type and may be used in combination of 2 or more type.

  The content of the structural unit represented by the general formula (1) in the acrylic polymer (B) is preferably 60 mol% or more, more preferably 70 mol% or more, and 80 mol% or more. More preferably.

  The acrylic polymer (B) may contain a structural unit other than the structural unit represented by the general formula (1). For example, the acrylic polymer (B) may contain a structural unit derived from a vinyl monomer containing a reactive functional group. Thereby, reaction with another structural unit can be made easy, and when a crosslinking agent (C) is contained especially, reaction with a crosslinking agent (C) can be made easy. In this case, the content of the structural unit derived from the vinyl monomer containing a reactive functional group in the acrylic polymer (B) is preferably 0.01 mol% to 20 mol%, preferably 0.1 mol% to It is more preferably 10 mol%, and further preferably 0.2 mol% to 5 mol%. Moreover, as a reactive functional group, a hydroxyl group, an amino group, a carboxyl group, a thiol group etc. are mentioned, for example. Such reactive functional groups may be contained singly or in combination of two or more. Among these reactive functional groups, a hydroxyl group, an amino group, and a carboxyl group are preferable.

  When the acrylic polymer (B) contains a structural unit derived from a vinyl monomer having a reactive functional group, the cohesive force of the pressure-sensitive adhesive composition can be controlled.

  Examples of the vinyl monomer containing a reactive functional group described above include hydroxyl group-containing (meth) acrylates such as hydroxyethyl (meth) acrylate, hydroxypropyl (meth) acrylate, and hydroxybutyl (meth) acrylate; 1,4-di (Meth) acryloxyethyl pyromellitic acid, 4- (meth) acryloxyethyl trimellitic acid, N- (meth) acryloyl-p-aminobenzoic acid, 2- (meth) acryloyloxybenzoic acid, N- (meth) Carboxyl group-containing (meth) acrylates such as acryloyl-5-aminosalicylic acid, acrylic acid, and methacrylic acid; aminoethyl (meth) acrylate, ethylaminoethyl (meth) acrylate, aminopropyl (meth) acrylate, ethylaminopropyl (meth) Such as acrylate Primary to secondary amino group-containing (meth) acrylate; and 2- (methylthio) containing a thiol group such as ethyl methacrylate (meth) acrylate. These may be used alone or in combination of two or more.

  Further, the acrylic polymer (B) may contain a structural unit derived from a monomer having a plurality of polymerizable unsaturated groups. That is, the acrylic polymer (B) is a co-polymer of a monomer composition containing (meth) acrylic acid alkyl ester having 6 to 14 carbon atoms in the ester moiety and a monomer having a plurality of polymerizable unsaturated groups. It may be a polymer.

  In addition, when the acrylic polymer (B) contains a structural unit derived from a monomer having a plurality of polymerizable unsaturated groups, the acrylic polymer (B) contains a structural unit derived from a vinyl monomer containing the reactive functional group described above. However, when a hydrophilic drug whose decomposition is accelerated by the reactive functional group is used, it is better not to contain the structural unit. Thereby, the acrylic polymer (B) used as the constituent material of the adhesive composition excellent in the temporal stability of the hydrophilic drug can be obtained.

  Examples of the monomer having a plurality of polymerizable unsaturated groups include (poly) ethylene glycol, (poly) propylene glycol, (poly) butylene glycol, (poly) pentamethylene glycol, alkylene glycol such as (poly) hexamethylene glycol, Examples include trimethylolpropane, glycerin polyoxyethylene glycol, polyoxypropylene glycol, di- or tri (meth) acrylates of polyols such as (poly) glycerin, diallyl phthalate, and divinylbenzene, and one of these. Alternatively, two or more kinds can be used in combination. Among the above-mentioned, since alkylene glycol diacrylate is excellent in the reactivity with another monomer, it can improve the cohesion force of an acrylic polymer (B) suitably.

  When the acrylic polymer (B) contains a structural unit derived from a monomer having a plurality of polymerizable unsaturated groups, the content of the structural unit is preferably 0.000005 mol% to 0.5 mol%. 0.00001 mol% to 0.1 mol% is more preferable. Thereby, the adhesive layer excellent in adhesive performance and cohesion force can be formed.

  The mass average molecular weight of the acrylic polymer (B) is preferably 70,000 to 2,000,000, and more preferably 90000 to 1500,000. By setting the mass average molecular weight in such a range, the adhesive performance can be improved.

  In the pressure-sensitive adhesive composition, when the blending amount of the S / O type fine particles (A) is A parts by mass and the blending amount of the acrylic polymer (B) is B parts by mass, the mass ratio A / B is 1/99. It is preferably ˜60 / 40, more preferably 3/97 to 50/50.

  The method for producing the acrylic polymer (B) is not particularly limited, and can be obtained by polymerizing raw material monomers corresponding to each structural unit by solution polymerization or the like.

[Crosslinking agent (C)]
The crosslinking agent (C) in the present invention is at least one selected from the group consisting of a polyfunctional amino compound, a polyfunctional isocyanate compound, a polyfunctional epoxy compound, a polyfunctional aziridine compound, a polyfunctional oxazoline compound, and a polyfunctional metal compound. It is preferable. As the cross-linking agent (C), for example, a component that cross-links the pressure-sensitive adhesive by reacting with the reactive functional group of the acrylic polymer (B) can be used.

  Examples of the polyfunctional amino compound include melamine resins such as methylated melamine resins and butylated melamine resins; urea resins such as methylated urea resins and butylated urea resins; benzoguanamines such as methylated benzoguanamine resins and butylated benzoguanamine resins. Resins; Examples include diamines such as ethylenediamine, tetramethylenediamine, hexamethylenediamine, N, N′-diphenylethylenediamine, and p-xylylenediamine.

  Examples of the polyfunctional isocyanate compound include diphenylmethane diisocyanate (MDI), tolylene diisocyanate (TDI), hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), trimethylhexamethylene diisocyanate (TMDI), xylene diisocyanate (XDI), Examples thereof include naphthalene diisocyanate (NDI), trimethylolpropane (TMP) adduct TDI, TMP adduct HDI, TMP adduct IPDI, and TMP adduct XDI.

  Examples of the polyfunctional epoxy compound include N, N, N ′, N′-tetraglycidylmetaxylenediamine, 1,3-bis (N, N-diglycidylaminomethyl) cyclohexane, and the like.

  Examples of the polyfunctional aziridine compound include diphenylmethane-4,4′-bis (1-aziridinecarboxamide), trimethylolpropane tri-β-aziridinyl propionate, and tetramethylolmethane tri-β-aziridini. Lupropionate, toluene-2,4-bis (1-aziridinecarboxamide), triethylenemelamine, bisisophthaloyl-1- (2-methylaziridine), tris-1- (2-methylaziridine) phosphine And trimethylolpropane tri-β- (2-methylaziridine) propionate.

  Examples of the polyfunctional oxazoline compound include addition polymerizable 2-oxazoline (for example, 2-isopropenyl-2-oxazoline) having a substituent having an unsaturated carbon-carbon bond at the 2-position carbon position and other unsaturated compounds. Examples include copolymers with monomers.

  Examples of the polyfunctional metal compound include aluminum chelate compounds such as aluminum trisacetylacetonate, aluminum ethylacetoacetate / diisopropylate; titanium tetraacetylacetonate, titanium acetylacetonate, titanium octylene glycolate, tetraisopropoxy Titanium chelate compounds such as titanium and tetramethoxytitanium; and trimethoxyaluminum.

  When the crosslinking agent (C) is included, the amount of the crosslinking agent (C) is preferably 0.1 to 30 parts by mass with respect to 100 parts by mass of the acrylic polymer (B). More preferably, it is -20 mass parts. Thereby, the adhesive layer excellent in adhesive performance and cohesion force can be formed.

[Transdermal absorption enhancer (D)]
The pressure-sensitive adhesive composition (D) in the present invention preferably contains a transdermal absorption enhancer.

  The percutaneous absorption enhancer (D) may be any compound that has been recognized to absorb absorption in the skin, for example, fatty acids having 6 to 20 carbon chains, aliphatic alcohols, fatty acid amides, fatty acid ethers. , Aromatic organic acids, aromatic alcohols, aromatic organic acid esters or ethers, lactic acid esters, acetic acid esters, monoterpene compounds, sesquiterpene compounds, glycerin fatty acid esters, propylene glycol fatty acid esters, Examples include sorbitan fatty acid esters, polysorbate series, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil series, polyoxyethylene alkyl ethers, sucrose fatty acid esters, and vegetable oils.

  The content of the transdermal absorption enhancer in the pressure-sensitive adhesive composition is preferably 0.1% by mass to 60% by mass, and more preferably 10% by mass to 55% by mass. Thereby, the rapid effect of the effect of a drug can be exhibited more effectively.

[Adhesive composition and adhesive layer]
In this invention, the manufacturing method of an adhesive composition is not specifically limited, Each component which comprises a composition can be mixed and manufactured. As described above, it is preferable that the S / O fine particles (A) are dispersed in oils and fats and then used for mixing.

  The pressure-sensitive adhesive layer only needs to contain the pressure-sensitive adhesive composition, and may be composed of only the pressure-sensitive adhesive composition, or may contain other components as necessary. The average thickness of the pressure-sensitive adhesive layer is usually 10 to 500 μm, preferably 30 to 150 μm.

[Supporting substrate]
The patch of the present invention preferably has a support substrate on one side of the pressure-sensitive adhesive layer and the pressure-sensitive adhesive layer. It is preferable that the support base material has flexibility (softness), has curved surface followability at the time of sticking, and is suitable for cutting or punching at the time of processing.

  Such a supporting substrate is not particularly limited, and examples thereof include polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyester such as polyethylene naphthalate (PEN), polyethylene (PE), polypropylene (PP), and the like. Polyolefin, polyarylate, polyurethane, polycarbonate, polyamide, polyimide, ethylene vinyl acetate copolymer, polyvinyl chloride, polytetrafluoroethylene, silicone, polysulfone, nylon, polylactic acid, rayon, acrylic, etc. It is possible to use knitted fabrics and nonwoven fabrics. Furthermore, it is possible to use a laminate sheet of two or more layers of a plastic film and a plastic film, a woven fabric, a knitted fabric, a nonwoven fabric or paper.

  The average thickness of the supporting substrate is preferably 2 μm to 4000 μm, and more preferably 10 μm to 300 μm.

[Peeling sheet]
The patch of the present invention preferably has a release sheet on at least one surface of the pressure-sensitive adhesive layer and the pressure-sensitive adhesive layer. The release sheet has a function of protecting the adhesive surface of the pressure-sensitive adhesive layer when the patch is stored (when not used).

  As such a release sheet, for example, laminated paper such as polyethylene laminated paper and polypropylene laminated paper; polyester film such as polyethylene terephthalate; synthetic resin film such as polyolefin film such as polyethylene and polypropylene can be used. Further, the release sheet may be subjected to a release treatment with a silicone resin or the like on one side or both sides of these materials as necessary.

  The average thickness of the release sheet is preferably 10 μm to 200 μm, and more preferably 15 μm to 100 μm.

[Patch]
The patch of the present invention may have an adhesive layer, but preferably further has a release sheet or a support substrate as described above, and has both a release sheet and a support substrate. Is more preferable. FIG. 1 is a cross-sectional view schematically showing the structure of an example of a patch. A patch 100 shown in FIG. 1 includes a pressure-sensitive adhesive layer 11, a release sheet 12 and a support base material 13 provided on both surfaces of the pressure-sensitive adhesive layer 11, respectively.

  Next, the present invention will be specifically described with reference to examples. However, the present invention is not limited by these examples.

<Example 1>
[Preparation of S / O type fine particles (A)]
In an aqueous solution in which 0.085 parts by mass of loxoprofen sodium dihydrate as a hydrophilic drug was dissolved in 40 parts by mass of ultrapure water, sucrose oleate as a surfactant (manufactured by Mitsubishi Chemical Foods, trade name “O- 170 ", oleic acid: 70% by mass, HLB: 1) Add a solution of 2.065 parts by mass in cyclohexane 80 parts by mass and stir at 24,000 rpm for 5 minutes with a homogenizer to prepare a W / O emulsion. did. This emulsion was freeze-dried for 2 days to obtain S / O type fine particles 1. The aggregate of the obtained S / O type fine particles 1 was a transparent liquid at room temperature.

  The content of sodium loxoprofen dihydrate in the S / O type fine particles 1 was 4.0% by mass.

[Preparation of acrylic polymer (B)]
Acrylic polymer 1 is obtained by subjecting a monomer composition containing 95 mol% of lauryl acrylate and 5 mol% of 2-hydroxyethyl acrylate to solution polymerization using a radical polymerization initiator (azobisisobutyronitrile). (Solid content 34% by mass, solvent: ethyl acetate) was obtained. The obtained acrylic polymer 1 had a mass average molecular weight of 1.14 million.

[Preparation of patch]
Dispersion 1 was prepared by adding 2.15 parts by mass of S / O type fine particles 1 to 0.43 parts by mass of isopropyl myristate, and preparing 6.3 parts by mass of acrylic polymer 1 solution. 2.58 parts by mass of 1 and 0.026 parts by mass of a polyfunctional isocyanate compound-containing solution (trade name “BHS8515”, manufactured by Toyo Ink Co., Ltd., solid content 37.5% by mass) as a crosslinking agent were added and stirred. Thus, an adhesive layer forming coating solution 1 was prepared.

  Next, a release liner made of polyethylene terephthalate (PET) as a release sheet (trade name “SP-PET381031C”, thickness: 38 μm, manufactured by Lintec Corporation) is prepared, and the pressure-sensitive adhesive layer-forming coating is formed on the release surface. The working liquid 1 was applied so that the average thickness after drying was about 100 μm. Thereafter, the formed coating film was dried by heating, and a pressure-sensitive adhesive layer (containing 45.2% by mass of S / O type fine particles 1, 1.8% by mass of loxoprofen sodium dihydrate, and 9% by mass of isopropyl myristate) Formed.

  Subsequently, a PET film (trade name “Lumirror”, manufactured by Toray Industries, Inc.) having an average thickness of 50 μm as a supporting substrate was laminated on the pressure-sensitive adhesive layer formed on the release sheet to prepare a patch.

<Example 2>
In Example 1, the production of the acrylic polymer (B) was carried out by the following method, except that the adhesive layer forming coating solution 2 prepared using the obtained acrylic polymer 2 solution was used. A patch was prepared in the same manner as in Example 1.

[Preparation of acrylic polymer (B)]
A monomer composition containing 95 mol% of 2-ethylhexyl acrylate and 5 mol% of 2-hydroxyethyl acrylate is subjected to solution polymerization using a radical polymerization initiator (azobisisobutyronitrile). A solution of polymer 2 (solid content: 34% by mass, solvent: ethyl acetate) was obtained. The obtained acrylic polymer 2 had a mass average molecular weight of 1.03 million.

<Comparative Example 1>
In Example 1, the patch was prepared in the following manner without using the S / O type fine particles (A).

[Preparation of patch]
A dispersion 2 was prepared by adding 2.065 parts by mass of sucrose oleate and 0.085 parts by mass of loxoprofen sodium dihydrate to 0.43 parts by mass of isopropyl myristate, and then preparing an acrylic polymer. 2.58 parts by mass of the dispersion 2 was added to 2.15 parts by mass of the solution 2 and stirred to prepare a coating solution 4 for forming an adhesive layer.

  Next, a release liner made of polyethylene terephthalate (PET) as a release sheet (trade name “SP-PET381031C” manufactured by Lintec Corporation) is prepared, and the pressure-sensitive adhesive layer forming coating solution 4 is dried on the release surface. It apply | coated so that later average thickness might be set to about 100 micrometers. Thereafter, the formed coating film was dried by heating to form an adhesive layer (containing 1.8% by mass of loxoprofen sodium dihydrate and 9.0% by mass of isopropyl myristate).

  Next, on the pressure-sensitive adhesive layer formed on the release sheet, a PET film (trade name “Lumirror”, manufactured by Toray Industries, Inc.) having an average thickness of 50 μm as a supporting substrate was laminated to prepare a patch.

<Comparative example 2>
A patch containing commercially available loxoprofen sodium dihydrate (trade name “Loxonin Tape 100 mg”, manufactured by Reed Chemical Co., Ltd., containing 5% by mass of loxoprofen sodium dihydrate in a rubber adhesive) Using.

<Comparative Example 3>
In Example 1, the production of the acrylic polymer (B) was carried out by the following method, except that the pressure-sensitive adhesive layer forming coating solution 3 prepared using the solution of the obtained acrylic polymer 3 was used. A patch was prepared in the same manner as in Example 1, but when the dispersion 1 was added to and mixed with the acrylic polymer 3 solution, the compatibility was poor and phase separation occurred, and a uniform adhesive layer could be formed. No patch was obtained. This cause is considered to be due to lack of compatibility between the structural unit derived from butyl acrylate in the acrylic polymer 3 and the surfactant (sucrose oleate) in the S / O type fine particles 1.

[Preparation of acrylic polymer (B)]
Acrylic polymer 3 is obtained by subjecting a monomer composition containing 95 mol% of butyl acrylate and 5 mol% of 2-hydroxyethyl acrylate to solution polymerization using a radical polymerization initiator (azobisisobutyronitrile). Solution (solid content 30% by mass, solvent: ethyl acetate). The resulting acrylic polymer 3 had a mass average molecular weight of 970,000.

[Transfer rate of hydrophilic drug to pig skin]
The patches of each Example and Comparative Example were cut into 4 cm ² and pasted on pig skin. The patch was peeled off 3 hours, 9 hours and 24 hours after the start of application, and the amount of the hydrophilic drug transferred to the pig skin was quantified by high performance liquid chromatography. Next, the hydrophilic drug migration rate calculated from the content of the hydrophilic drug in each patch was calculated.

DESCRIPTION OF SYMBOLS 100 Patch 11 Adhesive layer 12 Release sheet 13 Support base material

Claims (8)

A pressure-sensitive adhesive containing Solid-in-Oil type fine particles (A) in which a hydrophilic drug is coated with a surfactant and an acrylic polymer (B) containing a structural unit represented by the following general formula (1) A patch having a pressure-sensitive adhesive layer containing the composition.

(In General Formula (1), R ¹ represents a hydrogen atom or a methyl group, and R ² represents an alkyl group having 6 to 14 carbon atoms.)   The patch according to claim 1, wherein the acrylic polymer (B) further comprises a structural unit derived from a vinyl monomer having a reactive functional group selected from the group consisting of a hydroxyl group, an amino group, and a carboxyl group.   The patch according to claim 1 or 2, wherein the pressure-sensitive adhesive composition further contains a crosslinking agent (C).   The cross-linking agent (C) includes at least one selected from the group consisting of a polyfunctional amino compound, a polyfunctional isocyanate compound, a polyfunctional epoxy compound, a polyfunctional aziridine compound, a polyfunctional oxazoline compound, and a polyfunctional metal compound. Item 4. The patch according to Item 3.   The acrylic polymer (B) is a co-polymer of a monomer composition containing (meth) acrylic acid alkyl ester having 6 to 14 carbon atoms in the ester moiety alkyl group and a monomer having a plurality of polymerizable unsaturated groups. The patch according to any one of claims 1 to 4, comprising a coalescence.   The patch according to any one of claims 1 to 5, wherein the surfactant comprises a nonionic surfactant having an HLB value of 10 or less.   The surfactant includes at least one selected from the group consisting of sucrose fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene sorbite fatty acid ester, glycerin fatty acid ester, polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil. The patch according to any one of claims 1 to 6.   The patch according to any one of claims 1 to 7, wherein the aliphatic group which is a lipophilic group in the surfactant has 14 to 22 carbon atoms.

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