JP6488021B2 - Acrylic adhesive fluidization suppression method - Google Patents

Description

  The present invention relates to a patch, and particularly relates to a patch containing emedastin.

Emedastine is 1- (2-ethoxyethyl) -2- (4-methyl-1,4-diazepan-1-yl) -1H-benzimidazole (1- (2-Ethoxyethyl) -2- (4-methyl-1 , 4-diazepan-1-yl) -1H-benzoimidazole). Emedastine is known as a drug having an antiallergic action and an antihistamine action (Japanese Patent Laid-Open No. 58-79983 (Patent Document 1)). For example, emedastine difumarate (Emedastine Difumarate, molecular formula: C ₁₇ H ₂₆ Oral preparations such as capsules containing N ₄ O.2C ₄ H ₄ O ₄ , molecular weight: 534.56) are on the market.

  However, when administered orally, there is a problem that side effects such as sleepiness tend to occur because the fluctuation range of the blood concentration of emedastin increases. Further, for example, JP-A-3-83924 (Patent Document 2) discloses parenteral administration agents such as oily ointments, gelling agents, creams, lotions, and sprays using a liquid composition containing emedastin. Although described, from the viewpoint of reducing the above-mentioned side effects and improving the stability of medicinal effects, development of a patch capable of continuous administration of emedastine more stably is desired.

  As a patch containing emedastine, for example, in International Publication No. 2012/144405 (Patent Document 3), an alkali metal diacetate, emedastine fumarate, and a non-aqueous adhesive base are mixed. A patch comprising a pressure-sensitive adhesive layer formed using the obtained pressure-sensitive adhesive layer composition is disclosed in International Publication No. 2014/057928 (Patent Document 4) with emedastine and / or a pharmaceutically acceptable salt thereof. A patch comprising an adhesive layer containing a rubber-based adhesive and / or a silicone-based adhesive and fumaric acid as a cohesive strength improver for the adhesive layer is described.

  Furthermore, for example, JP-A-7-33665 (Patent Document 5) discloses an adhesive layer (adhesive layer) comprising an acrylic adhesive base, a silicone adhesive base, or a rubber adhesive base and emedastin. In JP-A-8-193030 (Patent Document 6), a patch having a pressure-sensitive adhesive layer containing an acrylic polymer substantially free of acid residues and emedastin. Are described respectively.

  International Publication No. 2005/115355 (Patent Document 7) describes a patch comprising a pressure-sensitive adhesive layer containing a basic drug such as fentanyl, oxybutynin and a volatile organic acid. Numerous organic acids or organic acid salts containing sodium fumarate are described as compounds that can be added as needed for the purpose of promoting percutaneous absorption of drugs. However, in Patent Document 7, there is no description regarding emedastine.

Japanese Patent Laid-Open No. 58-79983 JP-A-3-83924 International Publication No. 2012/144405 International Publication No. 2014/057928 JP-A-7-33665 JP-A-8-193030 International Publication No. 2005/115355

  When the acrylic adhesive is mainly used as the adhesive in the patch containing emedastin, the present inventors have higher transdermal permeability to emedastin than when the rubber adhesive is simply used. Although there is a tendency, in a patch containing emedastine and acrylic adhesive in the adhesive layer, the adhesive layer protrudes from the side surface (that is, end face or cross section) of the patch due to temperature and pressure during storage I found out that the problem occurs. The phenomenon that the pressure-sensitive adhesive layer protrudes is also referred to as “glue protrusion” or “tongue protrusion”, and is covered with the support layer from the side surface of the patch on which the support layer and the pressure-sensitive adhesive layer are laminated. If the pressure-sensitive adhesive layer protrudes outside the range, the protruding pressure-sensitive adhesive layer adheres to the inner surface of the packaging material of the patch, making it difficult to take out the patch, or the protruding adhesive layer causes the support of the patch. This causes problems such as contamination of the layers and fingers and difficulty in applying the patch to the target site.

  The present invention has been made in view of the above-described problems of the prior art, and provides a patch in which adhesive sticking out of the pressure-sensitive adhesive layer is sufficiently suppressed and the skin permeability and stability of emedastin are excellent. With the goal.

  As a result of intensive studies to achieve the above object, the present inventors have found that in an adhesive patch comprising a support layer and an adhesive layer, emedastine and / or a pharmaceutically acceptable salt thereof, an acrylic adhesive, In addition, the present inventors have found that by incorporating fumarate in the pressure-sensitive adhesive layer, even if the content of the acrylic pressure-sensitive adhesive is large, the sticking out of the pressure-sensitive adhesive layer is sufficiently suppressed. In addition, the present inventors have found that such a patch is also excellent in skin permeability and stability of emedastin, and have completed the present invention.

That is, the method for suppressing fluidization of the acrylic pressure-sensitive adhesive of the present invention is as follows.
A patch comprising a support layer and an adhesive layer, wherein the adhesive layer contains at least one drug selected from the group consisting of emedastine and a pharmaceutically acceptable salt thereof, and an acrylic adhesive In the fluidization suppression method of the acrylic pressure-sensitive adhesive that suppresses fluidization of the acrylic pressure-sensitive adhesive,
Including the fumarate in the adhesive layer, the patch,
A support layer and an adhesive layer;
The pressure-sensitive adhesive layer contains at least one drug selected from the group consisting of emedastine and a pharmaceutically acceptable salt thereof, an acrylic pressure-sensitive adhesive, and a fumarate; and
Content of the said acrylic adhesive is 30-98 mass% in the said adhesive layer,
It is a method to make a patch ,
The fumarate is disodium fumarate .

In the fluidization suppression method of the acrylic pressure-sensitive adhesive of the present invention, the number of moles converted to fumaric acid of the fumarate to 1 mole converted to emedastine free form of the emedastine and pharmaceutically acceptable salt thereof. but preferably Rukoto to contain the fumarate salt such that 0.1 to 4.3 mol. Furthermore, in the fluidization suppressing method of the acrylic pressure-sensitive adhesive of the present invention, the fumarate is contained so that the content of the fumarate is 0.5 to 35% by mass in the pressure-sensitive adhesive layer. It is preferable.

Furthermore, in the method for suppressing fluidization of an acrylic pressure-sensitive adhesive of the present invention, it is preferable that the drug is an emedastine free form. The acrylic pressure-sensitive adhesive fluidization inhibitor of the present invention is an acrylic pressure-sensitive adhesive fluidization inhibitor for use in the fluidization suppression method of the acrylic pressure-sensitive adhesive of the present invention, and disodium fumarate is an active ingredient. It is a thing.

  ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to provide the patch which the adhesive paste protrusion of the adhesive layer was fully suppressed and was excellent in the skin permeability and stability of emedastine.

  Hereinafter, the present invention will be described in detail with reference to preferred embodiments thereof.

  The patch of the present invention is a patch comprising a support layer and an adhesive layer, wherein the adhesive layer is at least one drug selected from the group consisting of emedastine and a pharmaceutically acceptable salt thereof. , An acrylic adhesive, and a fumarate.

(Support layer)
The support layer according to the present invention is a layer that physically supports the pressure-sensitive adhesive layer and protects the pressure-sensitive adhesive layer from an external environment. Such a support layer is not particularly limited, and any known support layer for a patch can be appropriately employed. Examples of the material of the support layer include polyesters such as polyethylene terephthalate (PET), polybutylene terephthalate, and polyethylene naphthalate; polyolefins such as polyethylene and polypropylene; synthetic resins such as nylon and polycarbonate; and metals such as aluminum. Examples of the form of the support layer include films; sheets such as foam sheets and porous sheets; fabrics such as woven fabrics, knitted fabrics and nonwoven fabrics; foils; and laminates thereof. Among these, a polyester film is preferable from the viewpoint of excellent flexibility and drug impermeability. The thickness of the support layer is not particularly limited, but is usually preferably about 2 to 300 μm.

  The patch of the present invention preferably has a structure in which the pressure-sensitive adhesive layer is laminated on one surface of the support layer. Moreover, it is more preferable that a release liner layer for protecting the pressure-sensitive adhesive layer is further laminated on the surface of the pressure-sensitive adhesive layer opposite to the support layer until the adhesive is used.

  The release liner layer is not particularly limited, and any known release liner layer for patches can be appropriately employed. Polyesters such as polyethylene terephthalate (PET), polybutylene terephthalate, polyethylene naphthalate; polyethylene, polypropylene Polyolefins such as: films made of paper and the like, and laminates thereof. As such a release liner layer, a surface in contact with the pressure-sensitive adhesive layer is preferably coated with a silicone compound or a fluorine compound so that it can be easily peeled off from the pressure-sensitive adhesive layer. A polyethylene terephthalate film coated with a compound is preferred. Further, the thickness of the release liner layer is not particularly limited, but is usually preferably about 2 to 300 μm.

(Adhesive layer)
The pressure-sensitive adhesive layer according to the present invention contains at least one drug selected from the group consisting of emedastine and a pharmaceutically acceptable salt thereof, an acrylic pressure-sensitive adhesive, and a fumarate. Although it does not restrict | limit especially as thickness of such an adhesive layer, Usually, it is preferable that it is about 20-300 micrometers.

[Drug]
The pressure-sensitive adhesive layer according to the present invention contains at least one drug selected from the group consisting of emedastine and pharmaceutically acceptable salts thereof as a drug. Emedastine has the following formula:

(1- (2-Ethoxyethyl) -2- (4-methyl-1,4-diazepan-1-yl) -1H-benzimidazole (1- (2-Ethoxyethyl) -2- (4- methyl-1,4-diazepan-1-yl) -1H-benzoimidazole)), which has antiallergic and antihistaminic effects, suppresses histamine release by substance P, and migration and infiltration of eosinophils. Allergic rhinitis sneezing, nasal discharge, nasal congestion, funeral measles, eczema / dermatitis, skin carcinosis, pruritus itching, rash, etc. have been found to have an improving effect.

  Such emedastin may be an emedastin free form (free base), a pharmaceutically acceptable salt of emedastin, or a mixture thereof, but it has a higher release property from the adhesive layer. From the viewpoint of improving, it is preferable that at least a part of the pressure-sensitive adhesive layer is contained in the form of an emedastin free body.

  In addition, the above-mentioned emedastine free form is produced from a pharmaceutically acceptable salt of emedastin during and / or after production even if it is added as the free form during the manufacture of the patch. It may be contained in the agent. Examples of a method for producing emedastin free form from a pharmaceutically acceptable salt of emedastin (hereinafter sometimes referred to as “emedastin salt”) include, for example, the pressure-sensitive adhesive layer or the pressure-sensitive adhesive layer composition forming the pressure-sensitive adhesive layer. Examples thereof include a method in which the emedastine salt and a desalting agent are blended and the emedastine salt is desalted to obtain a free form thereof.

  Examples of the pharmaceutically acceptable salt of emedastine include an acid addition salt of emedastin, and the acid includes monobasic acids such as hydrochloric acid, hydrobromic acid, methanesulfonic acid, and phosphoric acid; fumaric acid, Examples thereof include polybasic acids such as maleic acid, citric acid, and tartaric acid. Among these, fumaric acid is preferable from the viewpoint that the following fumarate can be produced in the pressure-sensitive adhesive layer when the pressure-sensitive adhesive layer contains the desalting agent in combination.

  The content of emedastine and the pharmaceutically acceptable salt thereof according to the present invention varies depending on the purpose of treatment, and thus cannot be generally specified. However, normally, in the pressure-sensitive adhesive layer, release of emedastin The content in terms of body is preferably 1 to 20% by mass. In addition, from the viewpoint of the balance between the adhesive protrusion of the pressure-sensitive adhesive layer and the skin permeability of emedastine, the content of emedastine and its pharmaceutically acceptable salt is more preferably in the pressure-sensitive adhesive layer, It is 2 to 20% by mass and 2.5 to 17% by mass in terms of emedastine free form.

  The pressure-sensitive adhesive layer according to the present invention may further contain a drug other than emedastine within a range not inhibiting the effects of the present invention. Examples of such drugs include, but are not limited to, antiemetics (eg, granisetron, azasetron, ondansetron, ramosetron, etc.), therapeutic drugs for frequent urination in overactive bladder (eg, oxybutynin, tolterodine, etc.), Angiotensin converting enzyme inhibitors (eg, captopril, delapril, etc.), Ca antagonists (eg, nifedipine, etc.), coronary vasodilators (eg, diltiazem, nicorandil, etc.), local anesthetics (eg, lidocaine, procaine, etc.), Thymus hormones (eg, serum thymic factor), muscle relaxants (eg, tizanidine, eperisone, dantrolene, etc.), stimulant stimulants, antihypertensives (eg, alprenolol, nifedipine, etc.), antitumor drugs, psychotropic drugs ( Examples: imipramine, fentanyl, morphine, etc.), antibiotics, antiparkinson drugs (eg, rotigotine, amantaji) , Levodopa, cocaine, etc.), Alzheimer's treatment (eg, donepezil, rivastigmine, galantamine, tacrine, memantine, etc.), antihistamine, anti-vertigo (eg, diphenidol, betahistine, etc.), hypnotic sedative, anti-inflammatory analgesic (eg, : Indomethacin, ketoprofen, diclofenac, etc.), drugs for autonomic nerves, cardiac / vascular drugs (eg, benzodiazepine, etc.), drugs for improving cerebral circulation metabolism (eg, vinpocetine, etc.), vitamins, polypeptide hormones (eg: Routinizing hormone-releasing hormone, thyrotropin releasing hormone, etc., peripheral vasodilators, immunomodulators (eg, polysaccharides, auranofin, lobenzarit, etc.), and antibacterial drugs (eg, ursodesoxychol) Acid), diuretics (eg hydroflumethiazide, etc.), Examples include urinary drugs (eg, tolbutamide), gout drugs (eg, colchicine), antiallergic drugs (eg, tacrolimus, cyclosporine, etc.) and pharmaceutically acceptable salts thereof. One of these may be used alone, or two or more may be used in combination. When such a drug other than emedastine is further contained in the pressure-sensitive adhesive layer, its content varies depending on the purpose of treatment, and thus cannot be generally specified, but usually in the pressure-sensitive adhesive layer. The content is preferably 0.1 to 20% by mass, and more preferably 10% by mass or less in the pressure-sensitive adhesive layer from the viewpoint that the adhesive sticking out effect of the pressure-sensitive adhesive layer is excellent and the skin permeability of emedastine is excellent. .

[Adhesive]
The pressure-sensitive adhesive layer according to the present invention contains an acrylic pressure-sensitive adhesive as a pressure-sensitive adhesive. In the present invention, the pressure-sensitive adhesive expresses pressure-sensitive adhesiveness at the temperature at which the patch is applied (preferably 0 ° C. to 50 ° C., more preferably 10 ° C. to 40 ° C., more preferably 15 ° C. to 40 ° C.). A compound that can be used.

  Examples of the acrylic pressure-sensitive adhesive according to the present invention include a homopolymer having a (meth) acrylic acid alkyl ester as a monomer, and a copolymer of (meth) acrylic acid alkyl ester as a main monomer and other comonomers. Can be mentioned. In the present invention, “(meth) acrylic acid” refers to acrylic acid and methacrylic acid.

  Examples of the main monomer ((meth) acrylic acid alkyl ester) include butyl (meth) acrylate, isobutyl (meth) acrylate, hexyl (meth) acrylate, octyl (meth) acrylate, and (meth) acrylic acid 2- Examples thereof include ethylhexyl and decyl (meth) acrylate, and one of these may be used alone or two or more thereof may be combined. Examples of the comonomer include hydroxyalkyl (meth) acrylate, ethylene, propylene, styrene, vinyl acetate, N-vinyl-pyrrolidone, acrylic amide, and the like. It may be a combination of the above.

  Examples of such acrylic pressure-sensitive adhesives include acrylic acid / octyl acrylate ester copolymers, 2-ethylhexyl acrylate, and the like that are listed in the “Pharmaceutical Additives Dictionary 2007 (edited by Japan Pharmaceutical Additives Association)”. Vinylpyrrolidone copolymer solution, acrylic acid ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate copolymer, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, acrylic resin Examples include acrylic polymers contained in the alkanolamine liquid, and one of these may be used alone or two or more of them may be combined. Moreover, as said acrylic adhesive, you may use commercial items, such as DURO-TAK acrylic adhesive series (made by Henkel), Eudragit series (made by Higuchi trading company).

  The acrylic pressure-sensitive adhesive includes a crosslinked type having a crosslinked structure in which polymers are crosslinked and a non-crosslinked type having no crosslinked structure. In the pressure-sensitive adhesive layer containing a non-crosslinked acrylic pressure-sensitive adhesive, the present inventors have a tendency that adhesive protrusion is more noticeable, but a fumarate is combined and contained in the pressure-sensitive adhesive layer. Thus, even when the pressure-sensitive adhesive layer contains a non-crosslinked acrylic pressure-sensitive adhesive, the fumarate functions as a fluidization inhibitor of the acrylic pressure-sensitive adhesive, and paste sticking is sufficiently suppressed. I found out. As described above, the acrylic pressure-sensitive adhesive according to the present invention is not particularly limited. However, from the viewpoint of particularly suppressing the sticking out of the pressure-sensitive adhesive layer, it may be a non-functional group or an OH group. It is particularly preferable that it has an OH group.

  Content of the acrylic adhesive which concerns on this invention is 30 mass% or more in the said adhesive layer. As content of the said acrylic adhesive, in the said adhesive layer, it is preferable that it is 30-98 mass% and 30-97 mass% especially, 35-98 mass%, 35-97 mass%, More preferably, they are 50-98 mass%, 50-97 mass%, 60-98 mass%, 60-97 mass%, and 75-95 mass%. When the content of the acrylic pressure-sensitive adhesive is less than the lower limit, the skin permeability of emedastine tends to decrease, or the adhesive force and cohesive force of the pressure-sensitive adhesive layer tend to decrease. In addition, in the patch in which emedastine and acrylic adhesive are contained in the adhesive layer, the amount of the acrylic adhesive tends to be more prominent when the content of the acrylic adhesive is increased. Even when the content of the acrylic pressure-sensitive adhesive is not less than the above lower limit, the paste is sufficiently suppressed.

  The pressure-sensitive adhesive layer according to the present invention includes, as necessary, a styrene-based block copolymer; a natural rubber; a polyisobutylene; a rubber-based pressure-sensitive adhesive such as polyisoprene; and a silicone-based pressure-sensitive adhesive such as organopolysiloxane (silicone). Other pressure-sensitive adhesives may further be contained, but when these other pressure-sensitive adhesives are contained in the pressure-sensitive adhesive layer according to the present invention, they become difficult to be compatible with the acrylic pressure-sensitive adhesive. From the viewpoint of preventing the layer from becoming nonuniform, the content thereof is preferably 60% by mass or less, and preferably 10% by mass or less in the pressure-sensitive adhesive layer. More preferably not.

[Fumarate]
The pressure-sensitive adhesive layer according to the present invention further contains a fumarate. In the pressure-sensitive adhesive layer, the present inventors combine the emedastine and / or a pharmaceutically acceptable salt thereof, the acrylic pressure-sensitive adhesive, and the fumarate to form the pressure-sensitive adhesive layer. It was found that the sticking out of the paste was sufficiently suppressed. On the other hand, in order to suppress paste sticking out of the pressure-sensitive adhesive layer, when a filler or tackifier such as silica or talc is added as a fluidization inhibitor of an acrylic pressure-sensitive adhesive instead of fumarate, emedastin Skin permeability tends to decrease.

  The fumarate salt has the following formula:

Or a salt in which at least one of the hydrogen atoms of the carboxy group of the compound is substituted with a metal or ammonium.

  Examples of the metal include lithium (Li), sodium (Na), potassium (K), calcium (Ca), magnesium (Mg), and the like. It may be a combination. The fumarate according to the present invention includes at least one fumarate selected from the group consisting of monosodium fumarate, disodium fumarate, monopotassium fumarate, dipotassium fumarate, magnesium fumarate, and calcium fumarate. An acid alkali metal salt is preferred.

Such a fumarate may be added as the compound at the time of manufacture of the patch, or may be generated during and / or after manufacture and contained in the pressure-sensitive adhesive layer. Good. Examples of the method for containing such a fumarate in the pressure-sensitive adhesive layer include, for example, using an emedastine acid addition salt as the emedastine salt, and 0.5 to 4 equivalents relative to the acid-base equivalent of the emedastine acid addition salt. Examples thereof include a method in which a desalting agent (more preferably 1 to 2 equivalents) is added to desalinate the emedastine acid addition salt to produce an emedastin free form in the pressure-sensitive adhesive layer and a fumarate salt. More specifically, for example, a desalting agent (for example, 4 mol in the case of sodium hydroxide) is added to 1 mol of emedastine difumarate and mixed, and the following formula:
Emedastine difumarate + sodium tetrahydroxide →
Emedastine free form + disodium 2 fumarate + 4H ₂ O
The method of desalting emedastine fumarate as described above to form emedastine free form and disodium fumarate in the pressure-sensitive adhesive layer can be mentioned.

  The content of the fumarate according to the present invention is preferably 0.5 to 35% by mass, more preferably 1 to 35% by mass, and 1 to 20% by mass in the pressure-sensitive adhesive layer. 1 to 18% by mass, 1 to 15% by mass, and 1 to 13% by mass are more preferable. When the content (concentration) of the fumarate is less than the lower limit, the effect of suppressing the adhesive paste from the pressure-sensitive adhesive layer tends to decrease.

  Moreover, as content of the said fumarate, the number of moles converted to fumaric acid of the fumarate (hereinafter referred to as “fumedic acid”) relative to the number of moles of 1 converted to the emedastine free form of the emedastine and its pharmaceutically acceptable salt. In some cases, the number of moles of “fumaric acid” is preferably 0.1 to 4.3 moles, 0.3 to 4.3 moles, 0.5 to 4.3 moles, 0.5 to 3 moles. 0.7 to 3 mol, 0.7 to 2.7 mol, 1 to 2.7 mol, and 1 to 2.4 mol are more preferable. When the content of the fumarate is less than the lower limit, the sticking out of the pressure-sensitive adhesive layer is not sufficiently suppressed, and the skin permeability and utilization rate of emedastine tend to decrease. On the other hand, when it exceeds the upper limit, the stability, skin permeability, and utilization rate of emedastine tend to be reduced. In the present invention, the concentration and the number of moles of fumarate in the pressure-sensitive adhesive layer are not particularly limited from the viewpoint that the adhesive layer is particularly prevented from sticking and the skin permeability and stability of emedastin are sufficient. It is particularly preferable that the above condition is satisfied. In particular, in the pressure-sensitive adhesive layer, the content of the fumarate is preferably 0.5 to 35% by mass, and the number of moles of fumaric acid is preferably 0.1 to 4.3 mol. The content of the fumarate is 1 to 35% by mass (more preferably 1 to 20% by mass, 1 to 18% by mass, and 1 to 15% by mass), and the number of moles of fumaric acid is 0.3. The content of the fumarate is 1 to 13% by mass, and the number of moles of fumaric acid is 0.5 to 4.3 mol (more preferably 0.3 mol). 5 to 3 mol, 0.7 to 3 mol, 0.7 to 2.7 mol, 1 to 2.7 mol, and 1 to 2.4 mol) are more preferable.

[Additives]
The pressure-sensitive adhesive layer according to the present invention may further contain a salt produced by the desalting agent and / or the desalting agent as long as the effects of the present invention are not impaired. Examples of the desalting agent include metal ion-containing desalting agents such as sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and alkali metal salts of organic acids; ammonia and the like. Examples of the acid include acetic acid, diacetic acid, propionic acid, butyric acid and the like. Among these, as said desalting agent, the said metal ion containing desalting agent is preferable. When the salt produced by the desalting agent and the desalting agent is contained in the pressure-sensitive adhesive layer, the content is preferably 40% by mass or less in the pressure-sensitive adhesive layer, It is more preferably 30% by mass, and the acid-base equivalent converted to a desalting agent is 0.5 to 4 with respect to the acid-base equivalent converted to the acid addition salt of emedastin and its pharmaceutically acceptable salt. The amount is preferably an equivalent amount, and more preferably 1 to 2 equivalents.

  The pressure-sensitive adhesive layer according to the present invention further includes additives such as a tackifier resin, a plasticizer, a transdermal absorption accelerator, a stabilizer, a filler, and a fragrance, as long as the effects of the present invention are not impaired. It may be contained. When such an additive is contained in the pressure-sensitive adhesive layer, the content thereof is preferably 20% by mass or less and more preferably 0.5 to 20% by mass in the pressure-sensitive adhesive layer. Preferably, it is 1-15 mass%.

<Method for producing patch>
The patch of the present invention is not particularly limited and can be produced by a conventionally known method. For example, in addition to the solvent method and the hot melt method, first, the emedastine and / or the above-mentioned by roll mixing, Banbury mixer mixing, etc. A pressure-sensitive adhesive layer composition containing the pharmaceutically acceptable salt, the acrylic pressure-sensitive adhesive, the fumarate, and, if necessary, the desalting agent and the additive is prepared. A method of laminating the support layer after forming a pressure-sensitive adhesive layer by coating on a release liner layer, or forming a pressure-sensitive adhesive layer by directly coating the pressure-sensitive adhesive layer composition on the support layer Is mentioned.

  For example, according to the solvent method, first, in the organic solvent, the emedastine and / or pharmaceutically acceptable salt thereof, the acrylic adhesive, the fumarate, and optionally the desalting agent or The pressure-sensitive adhesive layer composition is prepared by mixing the additive, applied to one surface of the release liner layer at a desired thickness, and then the solvent is removed by drying to laminate the support layer. Then, the patch of the present invention can be obtained by appropriately cutting this. Alternatively, after the adhesive layer composition is applied on one surface of the support layer to a desired thickness, the solvent is dried and removed, and the release liner layer is laminated as necessary, and this is appropriately cut. By doing so, the patch of the present invention can be obtained.

  The organic solvent is not particularly limited and can be appropriately selected depending on the type of drug, adhesive, fumarate, etc. used, for example, ethyl acetate, toluene, cyclohexane, hexane, ethanol, methanol, isopropanol, etc. Can be used.

  In addition, when the above-mentioned emedastin free substance and the fumarate salt are produced during production and / or after production and contained in the pressure-sensitive adhesive layer, for example, instead of the pressure-sensitive adhesive layer composition, emedas By using a composition containing chin fumarate, the acrylic pressure-sensitive adhesive, the desalting agent, the organic solvent, and, if necessary, the additive, emedastine free substance and the above-mentioned Fumarate can be included.

  Furthermore, the patch of the present invention is preferably sealed in a packaging bag. The packaging bag is not particularly limited, and those that can be used as a packaging bag for normal patches can be appropriately used.

  EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example and a comparative example, this invention is not limited to a following example. In addition, about each patch obtained by each Example and the comparative example, the paste protrusion evaluation test, the stability evaluation test, and the skin permeability test were each performed by the method shown below.

<Glue protrusion evaluation test>
For each of the three patches of a predetermined area immediately after production obtained in each Example and Comparative Example, first, the adhesive layer does not protrude from the side of the patch to the outside of the edge of the surface of the support layer. The mass was measured using an electronic balance with a sensitivity of 0.1 mg to obtain mass 1. Next, each patch is enclosed in an aluminum laminate bag, and the patch is kept horizontal (the surface of the support layer of the patch is perpendicular to the direction of gravity). Left at rest. After 1 day, 2 days, or 7 days from the start of standing, each aluminum laminate bag is taken out from the chamber and opened, and the adhesive layer protrudes beyond the area covered by the support layer from the side of the patch (The paste protruding part) was removed, and the mass of the patch after the paste protruding part was removed was measured using the electronic balance to obtain a mass of 2. Subsequently, all the remaining pressure-sensitive adhesive layers were also removed from the support layer using a solvent, and the masses of the support layer and the release liner layer were measured using the electronic balance to obtain a mass of 3. Using the obtained masses 1 to 3, the following formula:
Adhesive protrusion rate [%] = Adhesive protrusion mass / Adhesive layer total mass [%] = (mass 1-mass 2) / (mass 1-mass 3) x 100
Thus, in each patch, the mass ratio of the adhesive layer that protruded after standing for 1 day, 2 days, or 7 days and the total mass of the adhesive layer before standing (adhesive protrusion rate) respectively. The average of three images was calculated.

<Stability evaluation test>
First, after adding the following mobile phase solution to a solution obtained by dissolving a certain amount of the adhesive layer collected from the patches immediately after production obtained in each Example and Comparative Example in tetrahydrofuran so that the total amount becomes 50 ml. Then, filter filtration was performed to obtain a measurement sample. About the obtained measurement sample, a high performance liquid chromatography apparatus (manufactured by Shimadzu Corporation, column: ODS column, mobile phase liquid: 3 mM sodium 1-heptanesulfonate-0.1% glacial acetic acid / methanol (45/55 ( Using the volume ratio)) and the detection wavelength: 280 nm), the content (initial content) of emedastine was measured. Next, the patch was enclosed in an aluminum laminate bag and allowed to stand in a constant temperature chamber at 80 ° C. One week after the start of standing (after 7 days), each aluminum laminate bag is removed from the chamber and opened, and an adhesive layer of the same amount as that collected before standing is collected from the patch, and the same as above. The content of emedastine (content after storage) was measured. From the obtained content, the following formula:
Drug residual ratio [%] = content after storage / initial content × 100
From the above, the drug residual ratio in the patch after standing for 1 week was calculated. From the drug residual rate obtained, the following criteria:
A: Drug residual ratio is 90.0% or more B: Drug residual ratio is 85.0% or more and less than 90.0% C: Drug (emedastine) stability in each patch according to drug residual ratio is less than 85.0% Sex was evaluated.

<Skin permeability test>
First, the skin on the back of the hairless mouse is peeled off, the patches obtained in each Example and Comparative Example are applied to the epidermis side, and the flow-through type Franz type permeation test cell (the dermis side is the receptor tank side) 3 cm ² ). Next, the receptor bath was filled with a phosphate buffer solution as a receptor solution, and the receptor solution was sampled every 4 hours up to 24 hours while circulating hot water at 32 ° C. around the permeation test cell. The amount of emedastine in the sampled solution was measured using a high performance liquid chromatography apparatus (manufactured by Shimadzu Corporation, column: ODS column, mobile phase solution: 3 mM sodium 1-heptanesulfonate-0.1% glacial acetic acid / methanol (45 / 55 (volume ratio)), detection wavelength: 280 nm). The drug skin permeation rate (Jmax) per hour and the cumulative skin permeation amount up to 24 hours were calculated from the obtained measured values. Further, the emedastine content in the patch (3 cm ² ) was measured in the same manner as in the stability evaluation test, and the following formula:
Drug utilization [%] = cumulative skin permeation up to 24 hours / emedastin content × 100
From the above, the drug utilization rate at 24 hours was calculated.

Example 1
First, emedastine free body 2.83 parts by mass, disodium fumarate 2.99 parts by mass, acrylic adhesive 1 (non-crosslinked polyacrylic acid copolymer having an OH group, DURO-TAK87-2510 (Henkel Corporation) 94.18 parts by mass in ethyl acetate was stirred to obtain a pressure-sensitive adhesive layer composition. The obtained pressure-sensitive adhesive layer composition was applied onto the silicone compound-coated surface of the polyethylene terephthalate film (release liner layer) coated with the silicone compound, then dried to remove the solvent, and the pressure-sensitive adhesive having a thickness of 200 μm. An adhesive layer was formed, and a polyester film (support layer) was laminated and cut on the surface of the pressure-sensitive adhesive layer opposite to the release liner layer to obtain a patch. In Table 1, the molar ratio of emedastine to fumaric acid (emedastine: fumaric acid) is the fumaric acid of fumarate with respect to 1 mol of mol converted to emedastin free form and / or emedastine free form of emedastine salt. The number of moles converted to is shown below (the same applies in Tables 2 to 6 below).

(Examples 2-3, Comparative Examples 1-3)
The patches of Examples 2-3 and Comparative Examples 1-3 were obtained in the same manner as in Example 1 except that the composition of the pressure-sensitive adhesive layer was changed to the composition shown in Table 1. In Table 1, acrylic pressure-sensitive adhesive 2 represents a cross-linked polyacrylic acid copolymer having an OH group (solid content of DURO-TAK87-2516 (manufactured by Henkel)). Moreover, in Example 3, the mass converted into the emedastine free body of emedastine difumarate (10.00 mass parts) is 5.66 mass parts.

Table 1 shows the results of the paste protrusion evaluation tests for the patches obtained in Examples 1 to 3 and Comparative Examples 1 to 3, together with the composition of each patch. In addition, the result of the paste protrusion evaluation test in the patches obtained in Examples 1 and 3 and Comparative Examples 1 and 3 shows the result after standing for 1 day, and the patches obtained in Example 2 and Comparative Example 2 The result of the paste protrusion evaluation test in the preparation shows the result after standing for 7 days. Moreover, the paste protrusion improvement rate of Example 1 with respect to Comparative Example 1, the paste protrusion improvement rate of Example 2 with respect to Comparative Example 2, and the paste protrusion improvement rate of Example 3 with respect to Comparative Example 3 are respectively expressed by the following formulas:
Adhesive protrusion improvement rate [%] = {1- (Adhesive protrusion ratio in Examples / Adhesive protrusion ratio in Comparative Examples)} × 100
Calculated by Table 1 also shows the obtained paste protrusion improvement rate.

(Example 5, Reference Examples 1-2 , Comparative Examples 4-5)
The patches of Example 5, Reference Examples 1-2 , and Comparative Examples 4-5 were obtained in the same manner as in Example 1 except that the composition of the pressure-sensitive adhesive layer was changed to the composition shown in Table 2. In Table 2, the rubber adhesive is styrene-isoprene-styrene block copolymer (SIS), polyisobutylene (PIB), alicyclic saturated hydrocarbon resin (Alcon P-100, manufactured by Arakawa Chemical Industries). , Shows a mixture containing liquid paraffin in a mass ratio of 17.5: 7.5: 55: 20.

For the patches obtained in Example 5, Reference Examples 1 to 2 and Comparative Examples 4 to 5, a paste protrusion evaluation test (1 day standing (Comparative Examples 4 to 5 standing for 2 days)) was performed. . Example 5 with respect to Comparative Example 3 and the paste protrusion improvement rate of Reference Examples 1 and 2 and the paste protrusion improvement rate of Comparative Example 4 with respect to Comparative Example 5 are the paste protrusion improvement rate of Example 1 with respect to Comparative Example 1 and The same calculation was performed. Table 2 shows the obtained paste protrusion improvement rate together with the composition of each patch. The composition of the patch obtained in Comparative Example 3 is also shown in Table 2 for reference.

(Examples 7 to 10, Comparative Example 6)
The adhesive layers of Examples 7 to 10 were obtained in the same manner as in Example 1 except that the composition of the adhesive layer was as shown in Table 3 and the thickness of the adhesive layer was 50 μm. Moreover, the patch of the comparative example 6 was obtained like the comparative example 3 except having made the thickness of the adhesive layer into 50 micrometers.

  Table 3 shows the results of a stability evaluation test and a skin permeability test for the patches obtained in Examples 7 to 10 and Comparative Example 6, respectively, together with the composition of each patch. In addition, about the patch obtained in Examples 7-10, when the paste protrusion evaluation test was done, it became a result equivalent to the result in Examples 1-3, and 5 and the result in following Examples 13-15 Both results were equivalent.

(Examples 11 to 17)
The patches of Examples 11 to 17 were obtained in the same manner as Example 1 except that the composition of the adhesive layer was changed to the composition shown in Table 4, respectively. About the patch obtained in Examples 11-17, the paste protrusion evaluation test (1 day standing) was performed, respectively. The adhesive protrusion improvement rates of Examples 11 to 17 for Comparative Example 3 were calculated in the same manner as the adhesive protrusion improvement rate of Example 1 for Comparative Example 1 described above. Table 4 shows the improvement rate of the obtained paste protrusion together with the composition of each patch. Table 4 also shows the composition of the patches obtained in Example 5 and Comparative Example 3 and the rate of improvement in paste protrusion for reference.

(Examples 18 to 21)
The adhesive layers of Examples 18 to 21 were obtained in the same manner as in Example 1 except that the composition of the adhesive layer was as shown in Table 5 and the thickness of the adhesive layer was 50 μm. For the patches obtained in Examples 18 to 21, the results of the respective stability evaluation tests are shown in Table 5 together with the composition of each patch. Moreover, the composition and evaluation result of the patches obtained in Examples 7 to 10 and Comparative Example 6 are also shown in Table 5 for reference.

(Examples 22-24, Comparative Examples 7-11)
The patches of Examples 22 to 24 and Comparative Examples 7 to 11 were obtained in the same manner as in Example 1 except that the composition of the pressure-sensitive adhesive layer was changed to the composition shown in Table 6. In Table 6, the rubber-based adhesive is styrene-isoprene-styrene block copolymer (SIS), polyisobutylene (PIB), alicyclic saturated hydrocarbon resin (Alcon P-100, manufactured by Arakawa Chemical Industries). , Shows a mixture containing liquid paraffin in a mass ratio of 17.5: 7.5: 55: 20.

  About the patch obtained by each Example and the comparative example, the paste protrusion evaluation test (1 day stationary) was done, respectively. Example 22 for Comparative Example 7, Example 23 for Comparative Example 8, Example 24 for Comparative Example 9, and Comparative Example 10 for Comparative Example 10 show the paste protrusion improvement rates, respectively. Calculation was performed in the same manner as the protrusion improvement rate. Table 6 shows the obtained paste protrusion improvement rate together with the composition of each patch. In addition, the composition and evaluation results of the patches obtained in Example 5 and Comparative Example 3 are also shown in Table 6 for reference.

  As apparent from the results shown in Tables 1 to 6, in the patch of the present invention in which the fumarate salt is contained in the pressure-sensitive adhesive layer containing a large amount of the acrylic pressure-sensitive adhesive, the skin permeability and stability of emedastine are It was confirmed that the sticking out of the pressure-sensitive adhesive layer during storage was sufficiently suppressed while being sufficiently maintained.

  As described above, according to the present invention, it is possible to provide a patch in which adhesive sticking out of the pressure-sensitive adhesive layer is sufficiently suppressed and the skin permeability and stability of emedastine are excellent.

Claims (5)

A patch comprising a support layer and an adhesive layer, wherein the adhesive layer contains at least one drug selected from the group consisting of emedastine and a pharmaceutically acceptable salt thereof, and an acrylic adhesive In the fluidization suppression method of the acrylic pressure-sensitive adhesive that suppresses fluidization of the acrylic pressure-sensitive adhesive,
Including the fumarate in the adhesive layer, the patch,
A support layer and an adhesive layer;
The pressure-sensitive adhesive layer contains at least one drug selected from the group consisting of emedastine and a pharmaceutically acceptable salt thereof, an acrylic pressure-sensitive adhesive, and a fumarate; and
Content of the said acrylic adhesive is 30-98 mass% in the said adhesive layer,
It is a method to make a patch ,
The fumarate salt is disodium fumarate ;
A method for suppressing fluidization of an acrylic adhesive.   The mole number of fumaric acid converted to fumaric acid with respect to 1 mole of mole converted to emedastine free form of emedastine and pharmaceutically acceptable salt thereof is 0.1 to 4.3 mol. The method for suppressing fluidization of an acrylic pressure-sensitive adhesive according to claim 1, wherein a fumarate is contained.   Flow suppression of the acrylic adhesive of Claim 1 or 2 which makes the said fumarate contain so that content of the said fumarate may be 0.5-35 mass% in the said adhesive layer. Method. The method for suppressing fluidization of an acrylic pressure-sensitive adhesive according to any one of claims 1 to 3 , wherein the drug is emedastine free form. An acrylic pressure-sensitive adhesive fluidization inhibitor for use in the method for suppressing fluidization of an acrylic pressure-sensitive adhesive according to any one of claims 1 to 4 , comprising disodium fumarate as an active ingredient. -Based adhesive fluidization inhibitor.