JP2018150281A - Patches - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide patches which is excellent in the percutaneous absorption properties of an active ingredient and can also suppress bleed out and paste residue.SOLUTION: The present invention provides a patch comprising a core-shell structure having a core part containing an active ingredient and a shell part containing a surfactant; and a styrene elastomer, a tackifier resin, a plasticizer, and a gelling agent, the HLB value of a the surfactant being 3.0 or more, the sum of the content of the styrene elastomer and tackifier resin being 0.5 part by weight or more to 5.0 parts by weight or less with respect to 1 part by weight of the core-shell structure, the sum of the content of the plasticizer and gelling agent being 0.25 part by weight or more to 3.25 parts by weight or less with respect to 1 part by weight of the core-shell structure, and the weight ratio of the styrene elastomer to the tackifier resin being 0.5 or more.SELECTED DRAWING: None

Description

  The present invention relates to a patch comprising a core-shell structure containing an active ingredient.

  In recent years, development of a patch capable of transdermally absorbing an active ingredient such as a drug has been actively performed.

  For example, Patent Document 1 below discloses a patch containing an S / O (Solid-in-Oil) suspension, a styrene elastomer, and liquid paraffin. The S / O type suspension includes a drug-containing complex in which a hydrophilic drug is coated with a surfactant.

  Patent Document 2 below discloses a patch having an adhesive layer containing S / O type particles and an acrylic polymer. Also in the S / O type particles, a hydrophilic drug is coated with a surfactant.

International Publication No. 2006/025583 JP 2014-172840 A

  However, when the patches of Patent Documents 1 and 2 were used, the transdermal absorbability of the active ingredient was still insufficient. Moreover, when the adhesive component containing a styrene elastomer and a plasticizer such as liquid paraffin is used for the adhesive base phase as in the patch of Patent Document 1, particles or plasticizers containing an active ingredient such as a drug are used. In some cases, bleeding out or adhesive residue on the release sheet side occurred.

  An object of the present invention is to provide a patch which is excellent in transdermal absorbability of an active ingredient and which can suppress bleed out and adhesive residue.

  A patch according to the present invention comprises a core-shell structure comprising a core part containing an active ingredient, and a shell part covering at least a part of the surface of the core part and containing a surfactant, and styrene An elastomer, a tackifier resin, a plasticizer, and a gelling agent, wherein the surfactant has an HLB value of 3.0 or more, and the content of the styrene elastomer and the tackifier resin The sum is 0.5 parts by weight or more and 5.0 parts by weight or less with respect to 1 part by weight of the core-shell structure, and the sum of the contents of the plasticizer and the gelling agent is the core-shell structure 1 It is 0.25 weight part or more and 3.25 weight part or less with respect to a weight part, and the weight ratio with respect to the said tackifying resin of the said styrene-type elastomer is 0.5 or more.

  On the specific situation with the patch which concerns on this invention, the HLB value of the said surfactant is 5.0 or more.

  In another specific aspect of the patch according to the present invention, a weight ratio of the gelling agent to a sum of weights of the plasticizer and the gelling agent is 7/100 or more and 13/100 or less.

  In another specific aspect of the patch according to the present invention, the sum of the contents of the plasticizer and the gelling agent is 2.5 parts by weight or more and 3.0 parts by weight with respect to 1 part by weight of the core-shell structure. Less than parts by weight.

  In still another specific aspect of the patch according to the present invention, the plasticizer is at least one oil selected from the group consisting of hydrocarbons, alcohol carboxylic acid esters, polyhydric alcohol fatty acid esters, and oxy acid esters. It is a liquid preparation.

  In still another specific aspect of the patch of the present invention, the gelling agent is selected from the group consisting of polyethylene, dextrin palmitate, dextrin palmitate / ethylhexanoate, dextrin myristate, and inulin stearate. At least one.

  In still another specific aspect of the patch according to the present invention, the patch is a tape.

  ADVANTAGE OF THE INVENTION According to this invention, the patch which is excellent in the percutaneous absorbability of an active ingredient, and can suppress bleed-out and adhesive residue can be provided.

6 is a simplified diagram of a drug skin permeation test cell used in Test Example 2. FIG.

  Details of the present invention will be described below.

[Patch]
The patch of the present invention includes a core-shell structure, a styrene-based elastomer, a tackifier resin, a plasticizer, and a gelling agent. The core shell structure includes a core part containing an active ingredient and a shell part covering at least a part of the surface of the core part and containing a surfactant. The surfactant has an HLB value of 3.0 or more. The sum of the contents of the styrenic elastomer and the tackifier resin is in the range of 0.5 parts by weight or more and 5.0 parts by weight or less with respect to 1 part by weight of the core-shell structure. The sum of the contents of the plasticizer and the gelling agent is in the range of 0.25 parts by weight or more and 3.25 parts by weight or less with respect to 1 part by weight of the core-shell structure. The weight ratio of the styrene elastomer to the tackifying resin is 0.5 or more.

  The patch of the present invention has the characteristics that since the content of the constituent components is in the specific range, the active ingredient has excellent transdermal absorbability and can suppress bleed-out and adhesive residue. . This point can be explained as follows.

  Conventionally, when a patch is prepared by mixing an adhesive component such as a styrene elastomer or a plasticizer with a core-shell structure containing an active ingredient and a surfactant, the core-shell structure or the plasticizer bleeds out, In some cases, adhesive residue remains on the release sheet side.

  With regard to this point, the inventors of the present application have developed a bleed-out effect by using a plasticizer contained in a large amount in a difference in polarity between a surfactant and an adhesive component, or a rubber adhesive (an adhesive using an elastomer such as a styrene elastomer). It has been found that adhesive residue tends to occur. In particular, it has been found that a hydrophilic surfactant having a high HLB value has a prominent tendency because of a larger polarity difference from an adhesive component containing a styrene elastomer.

  On the other hand, as a result of intensive studies, the inventors of the present application have found that the above-mentioned problems can be solved by setting the content of the constituent components of the patch within the above specific range, and the present invention has been achieved. It was.

  In particular, in the present invention, bleed-out and adhesive residue can be suppressed even when a surfactant having a high HLB value is used by setting the content of the constituent components of the patch to the specific range. Therefore, the active ingredient can be more securely transdermally absorbed, and the transdermal absorbability of the active ingredient can be enhanced. In the present invention, the percutaneous absorbability of the active ingredient can also be enhanced because a surfactant having an HLB value of 3.0 or higher and a high HLB value is used.

  The patch of the present invention is not particularly limited, and examples thereof include tapes (reservoir type, matrix type, etc.) such as plasters and plasters, cataplasms, patches, and microneedles. Especially, it is desirable that it is a tape agent.

  In the patch of the present invention, the content of the core-shell structure is not particularly limited, but is preferably 15 parts by weight or more, more preferably 20 parts by weight or more, preferably 40 parts when the entire patch is 100 parts by weight. It is 30 parts by weight or less, more preferably 30 parts by weight or less. When content of a core-shell structure is more than the said minimum, transdermal absorbability can be improved further. When the content of the core-shell structure is not more than the above upper limit, bleed out can be further suppressed.

  Hereafter, each component which comprises the patch of this invention is demonstrated in detail.

(Core shell structure)
In the present invention, the core-shell structure is a particle containing an active ingredient and a surfactant. More specifically, the core-shell structure includes a core part containing an active ingredient and a shell part containing a surfactant. The shell part covers at least a part of the surface of the core part. The shell part may cover a part of the surface of the core part, or may cover the whole.

  For example, 30% or more of the surface of the core part, preferably 50% or more, more preferably 70% or more, further preferably 85% or more, particularly preferably 95% or more, most preferably 99% or more directly or by the shell part. Indirect coating is preferred. More preferably, the surface of the core part is directly covered by the shell part.

  When the core-shell structure having such a configuration is applied to the skin, the active ingredient can be absorbed through the skin.

  In the present invention, the core part is preferably solid. When the core part is solid, the stability in the adhesive base phase described later is further improved. Therefore, in this case, a patch having an S / O (Solid in Oil) type structure can be formed by dispersing the core-shell structure in an adhesive base phase that is an oil phase.

  The shape and size of the core-shell structure are not particularly limited, but the number average particle diameter is preferably 1 to 500 nm, more preferably 1 to 100 nm, and still more preferably 1 to 20 nm.

  In the present invention, the number average particle size of the core-shell structure is calculated by, for example, a dynamic light scattering method during dispersion of a solvent such as squalane.

Active ingredients;
The active ingredient is not particularly limited, and is appropriately selected according to the purpose of use of the patch of the present invention.

  Specific examples of the active ingredient are not particularly limited, for example, dementia treatment drugs, antiepileptic drugs, antidepressants, antiparkinsonian drugs, antiallergic drugs, anticancer drugs, antidiabetic drugs, antihypertensive drugs, respiratory disease drugs, An ED therapeutic agent, a skin disease agent, a local anesthetic, an ADHD agent, an anti-rheumatic agent, a renal disease agent, a schizophrenia drug, an bulimia disorder drug, etc.

  The active ingredient is preferably a hydrophilic drug having a molecular weight of 300 or more, more preferably a molecular weight of 400 or more, and even more preferably a molecular weight of 500 or more. The hydrophilic drug is not particularly limited, and those that require a systemic action or a local action are usually used.

  From the viewpoint of further improving the transdermal absorbability, the molecular weight of the hydrophilic drug is preferably 6000 or less, more preferably 3000 or less, and even more preferably 1500 or less.

  The active ingredient is preferably a drug that is easily absorbed through the skin. The drug is not particularly limited, but is preferably a compound having an octanol water partition coefficient of −6 to 6. In that case, the transdermal absorbability can be further enhanced. From the viewpoint of further enhancing the transdermal absorbability, the octanol water partition coefficient is preferably −1 or more, more preferably 0 or more. The drug octanol water partition coefficient is preferably 4 or less, more preferably 1 or less. When the octanol water partition coefficient of the drug is not more than the above upper limit, the transdermal absorbability is further improved.

In the present invention, the octanol water partition coefficient is expressed by the formula: octanol water partition coefficient = Log ₁₀ from the drug concentration of each phase after adding the drug to a flask containing octanol and pH 7 aqueous buffer solution. It can be calculated and obtained by (concentration in octanol phase / concentration in aqueous phase).

  Examples where the active ingredient is a hydrophilic drug include basic drugs and acidic drugs.

  Specific examples of basic drugs are not particularly limited as long as they are pharmacologically acceptable salts of drugs. Donepezil hydrochloride (molecular weight 416), vardenafil hydrochloride hydrate (molecular weight 579) or memantine hydrochloride (molecular weight 216) ), Tartrate salts such as rivastigmine tartrate (molecular weight 400), and acetate salts such as octreotide acetate (molecular weight 1139) or teriparatide acetate (molecular weight 4418). As the basic drug, hydrochloride or acetate is particularly preferable.

  Specific examples of the acidic drug are not particularly limited as long as they are pharmacologically acceptable salts, and sodium salts such as sodium bucladecin (molecular weight 491) or sodium cromoglycate (molecular weight 512) can be mentioned.

  The amount of the active ingredient contained in the core-shell structure depends on the type of the active ingredient. For example, the raw material charge weight is 0.1 to 45% by weight (based on the total weight of all the raw materials contained in the core-shell structure) Preferably 20 to 40% by weight.

  The core-shell structure may contain two or more active ingredients as necessary.

Surfactants;
In the present invention, the surfactant has an HLB (Hydrophyl Lyophile Balance) value of 3.0 or more. The HLB value is an index for knowing whether the emulsifier is hydrophilic or lipophilic, and the larger the HLB value, the higher the hydrophilicity. In the present invention, since the HLB value of the surfactant is 3.0 or more, the transdermal absorbability of the active ingredient is enhanced.

  In the present invention, the HLB value is calculated from the following Griffin equation.

  HLB value = 20 × {(molecular weight of hydrophilic portion) / (total molecular weight)}

  Note that the HLB value in the present invention is a weighted average value of the HLB values.

  The weighted average value of the HLB value can be calculated using, for example, the following calculation formula.

  When there are surfactant raw materials with HLB values A, B, and C, and the weight of each core-shell structure is x, y, and z, the formula for calculating the weighted average value is (xA + yB + zC) / (x + y + z). .

  From the viewpoint of further enhancing the transdermal absorbability of the active ingredient, the HLB value of the surfactant is preferably 4.0 or more, more preferably 5.0 or more. The upper limit of the HLB value of the surfactant can be set to 12.0, for example.

  The surfactant is not particularly limited and can be appropriately selected depending on the application. For example, it can be widely selected from those that can be used as pharmaceuticals and cosmetics. A plurality of types of surfactants may be used in combination.

  The surfactant may be any of a nonionic surfactant, an anionic surfactant, a cationic surfactant, or an amphoteric surfactant.

  The nonionic surfactant is not particularly limited, and examples thereof include fatty acid esters, fatty alcohol ethoxylates, polyoxyethylene alkyl phenyl ethers, alkyl glycosides or fatty acid alkanolamides, or polyoxyethylene castor oil or hydrogenated castor oil. Can be mentioned.

  The fatty acid ester is not particularly limited, but a sugar fatty acid ester is preferable. Specific examples include esters of fatty acids such as erucic acid, oleic acid, lauric acid, stearic acid, and behenic acid and sucrose.

  The other fatty acid ester is not particularly limited, and examples thereof include esters of at least one of glycerin, polyglycerin, polyoxyethylene glycerin, sorbitan, and polyoxyethylene sorbit with a fatty acid.

  Examples of the anionic surfactant include alkyl sulfate ester salts, polyoxyethylene alkyl ether sulfate ester salts, alkylbenzene sulfonate salts, fatty acid salts, and phosphate ester salts.

  Examples of the cationic surfactant include alkyl trimethyl ammonium salts, dialkyl dimethyl ammonium salts, alkyl dimethyl benzyl ammonium salts, and amine salts.

  Examples of amphoteric surfactants include alkylamino fatty acid salts, alkylbetaines, and alkylamine oxides.

  The surfactant is not particularly limited, but may have a hydrocarbon chain (an alkyl chain, an alkenyl chain, an alkynyl chain, etc.). The hydrocarbon chain length is not particularly limited, but the number of carbon atoms on the main chain can be broadly selected from 8 to 30, and is particularly preferably 10 to 24.

  As the surfactant, in particular, sucrose fatty acid ester, glycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene sorbite fatty acid ester, polyoxyethylene castor oil, hydrogenated castor oil or Fatty acid alkanolamides are preferably used.

  Although it does not specifically limit as glycerol fatty acid ester in this invention, The ester of glycerol and a fatty acid, etc. are mentioned.

  As fatty acids, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid, ricinoleic acid, oleic acid, linoleic acid, linolenic acid, erucic acid, beef tallow, lard Coconut oil, palm oil, palm kernel oil, olive oil, rapeseed oil, rice bran oil, soybean oil, or castor oil.

  Specifically, the glycerin fatty acid ester is preferably decaglyceryl pentastearate, diglyceryl monostearate, glyceryl monostearate, glyceryl monostearate, mono from the viewpoint of further enhancing the immediate effect and absorbability of the active ingredient. Glyceryl stearate, glyceryl monostearate, glyceryl monostearate, glyceryl myristate, glyceryl tri (caprylate / caprate), glyceryl monooleate, fatty acid glyceryl monoolate, diglyceryl monooleate, diglyceryl monooleate, capryl Acid monoglyceride, capric acid monoglyceride, capric acid mono-diglyceride, capric acid diglyceride, lauric acid monoglyceride, glyceryl monoundecylenate, etc.

  As the glycerin fatty acid ester, more preferably, glyceryl monooleate, glyceryl monoolate fatty acid glyceryl monooleate, diglyceryl monooleate, diglyceryl monooleate, caprylic acid monoglyceride, capric acid monoglyceride, capric acid monoglyceride, capric acid diglyceride, Lauric acid monoglyceride or glyceryl monoundecylenate.

  Although it does not specifically limit as sorbitan fatty acid ester in this invention, The ester etc. of sorbitan and a fatty acid are mentioned.

  As fatty acids, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid, ricinoleic acid, oleic acid, linoleic acid, linolenic acid, erucic acid, beef tallow, lard Coconut oil, palm oil, palm kernel oil, olive oil, rapeseed oil, rice bran oil, soybean oil, or castor oil.

  Specifically, the sorbitan fatty acid ester is preferably sorbitan monostearate, sorbitan trioleate, sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate from the viewpoint of further improving the immediate effect and absorbability of the active ingredient. , Coconut oil fatty acid sorbitan, or sorbitan laurate.

  The propylene glycol fatty acid ester in the present invention is not particularly limited, and examples thereof include an ester of propylene glycol and a fatty acid.

  As fatty acids, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid, ricinoleic acid, oleic acid, linoleic acid, linolenic acid, erucic acid, beef tallow, lard Coconut oil, palm oil, palm kernel oil, olive oil, rapeseed oil, rice bran oil, soybean oil, or castor oil.

  Specifically, the propylene glycol fatty acid ester is preferably propylene glycol monostearate, propylene glycol monostearate, propylene glycol diisostearate, propylene glycol distearate, from the viewpoint of further enhancing the immediate effect and absorbability of the active ingredient. Preferred examples include propylene glycol monolaurate, propylene glycol monooleate, propylene glycol dioleate, propylene glycol dicaprylate, and propylene glycol dilaurate.

The fatty acid alkanolamide in the present invention has a structure in which R—CO and two —CH ₂ CH ₂ OH are substituted with hydrogen, centering on N, and has a chemical formula of R—CON (CH ₂ CH ₂ OH) ₂ . The one represented by

  Specific examples of fatty acid alkanolamides include oleic acid diethanolamide, lauric acid diethanolamide, lauric acid monoisopropanolamide, stearic acid diethanolamide, stearic acid monoethanolamide, stearic acid monoisopropanolamide, lauric acid myristic acid diethanolamide, palmitic acid. Examples include acid monoethanolamide, coconut oil fatty acid diethanolamide, coconut oil fatty acid monoisopropanolamide, coconut oil fatty acid N-methylethanolamide, coconut oil fatty acid monoethanolamide, and palm kernel oil fatty acid diethanolamide. From the viewpoint of further enhancing the transdermal absorbability, the fatty acid alkanolamide is preferably a diethanolamide such as oleic acid diethanolamide, lauric acid diethanolamide, or coconut oil fatty acid diethanolamide.

  In addition, said surfactant may be used independently and may use multiple types of surfactant together.

  Moreover, the compounding quantity of surfactant can be suitably set within the range with which the effect of this invention is show | played. The weight ratio of the active ingredient to the surfactant (active ingredient: surfactant) is preferably 1: 1 to 1: 100. In this case, the transdermal absorbability of the active ingredient can be further enhanced. From the viewpoint of further enhancing the transdermal absorbability of the active ingredient, the weight ratio of the active ingredient to the surfactant (active ingredient: surfactant) is more preferably 1: 1 to 1:50. : 1 to 1:30 is more preferable.

Other ingredients;
The core-shell structure may further contain other components in addition to the active ingredient and the surfactant. Although it does not specifically limit as another component, For example, a stabilizer, a transdermal absorption promoter, a skin irritation reducing agent, antiseptic | preservative, or an analgesic etc. are mentioned. These may be used alone or in combination.

  The stabilizer has a function of stabilizing the particle structure, prevents unintended collapse of the particle structure, and ensures a sustained release effect of the active ingredient.

  Although it does not specifically limit as a stabilizer, Specifically, a polysaccharide, protein, or a hydrophilic polymer material etc. are mentioned. A stabilizer may contain 1 type, or 2 or more types. The content of the stabilizer can be appropriately set depending on the type of the stabilizer. For example, the weight ratio of the active ingredient to the stabilizer (active ingredient: stabilizer) is 1: 0.1 to 1:10. It can mix | blend so that it may become.

  Although it does not specifically limit as a percutaneous absorption enhancer, Specifically, higher alcohol, N-acyl sarcosine or its salt, higher monocarboxylic acid, higher monocarboxylic acid ester, aromatic monoterpene fatty acid ester, carbon number 2 10 divalent carboxylic acids or salts thereof, polyoxyethylene alkyl ether phosphates or salts thereof, lactic acid, lactic acid esters, or citric acid. The percutaneous absorption enhancer may contain one kind or two or more kinds. The content of the percutaneous absorption enhancer can be appropriately set depending on the type of the percutaneous absorption enhancer. .01 to 1:50.

  The skin irritation reducing agent is not particularly limited. Specifically, hydroquinone glycoside, pantethine, tranexamic acid, lecithin, titanium oxide, aluminum hydroxide, sodium nitrite, sodium hydrogen nitrite, soybean lecithin, methionine, Examples include glycyrrhetinic acid, BHT, BHA, vitamin E or a derivative thereof, vitamin C or a derivative thereof, benzotriazole, propyl gallate, or mercaptobenzimidazole. The skin irritation reducing agent may contain one kind or two or more kinds. Although the content rate of a skin irritation reducing agent can be set as appropriate depending on the type, for example, it can be blended so as to be 0.1 wt% to 50 wt% with respect to the entire core-shell structure.

  The preservative is not particularly limited, and specific examples include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol, and thymol. Although the content rate of a preservative can be suitably set according to the kind, for example, it can mix | blend so that it may become 0.01 to 10 weight% with respect to the whole core-shell structure. An antiseptic | preservative may contain 1 type (s) or 2 or more types.

  Although it does not specifically limit as an analgesic, Specifically, local anesthetics, such as procaine, tetracaine, lidocaine, dibucaine, or prilocaine, its salt, etc. are mentioned. An analgesic may contain 1 type (s) or 2 or more types. Although the content rate in the core-shell structure of an analgesic can be suitably set according to the kind, for example, it can mix | blend so that it may become 0.1 to 30 weight% with respect to the whole core-shell structure.

Production method;
The core-shell structure can be produced, for example, by a method including a step of drying a W / O emulsion containing an active ingredient in an aqueous phase.

  The W / O emulsion is not particularly limited as long as it is a so-called water-in-oil emulsion, specifically, an emulsion in which droplets of an aqueous solvent are dispersed in an oily solvent.

  The W / O emulsion containing the active ingredient in the aqueous phase is a mixture of an aqueous solvent containing the active ingredient such as water or a buffered aqueous solution and an oily solvent such as cyclohexane, hexane or toluene containing the surfactant. Can be obtained. The aqueous solvent containing the active ingredient may contain an additive ingredient such as a stabilizer, an absorption promoter or an irritation reducing agent, if necessary, in addition to the active ingredient. Moreover, the oil-based solvent containing surfactant may also contain additional components, such as an irritation reducing agent, an analgesic agent, an absorption promoter, or a stabilizer, as needed, in addition to the surfactant. The mixing method is not particularly limited as long as it is a method capable of forming a W / O emulsion, and examples thereof include stirring with a homogenizer or the like.

  The conditions at the time of a homogenizer stirring are about 5000-50000 rpm, for example, More preferably, it is about 10000-30000 rpm.

  The weight ratio of the surfactant to the active ingredient in the W / O emulsion (surfactant / active ingredient) is not particularly limited, but is, for example, 2 to 100, preferably 3 to 50, more preferably 5 to 30.

  The method for drying the W / O emulsion containing the active ingredient in the aqueous phase is not particularly limited as long as it is a method capable of removing the solvent (aqueous solvent and oily solvent) in the emulsion. For example, freeze drying or drying under reduced pressure, etc. Preferably, freeze-drying is mentioned.

  Further, from the viewpoint of further reducing the number average particle size of the obtained core-shell structure, the method further comprises a step of heat-treating the W / O emulsion containing the active ingredient in the aqueous phase or the dried product of the W / O emulsion. Is preferred. Heat processing temperature is 30-60 degreeC, for example, Preferably it is 35-50 degreeC, More preferably, it is 35-45 degreeC.

  Although heat processing time is suitably adjusted according to heat processing temperature, it is 1 to 30 days, for example, Preferably it is 2 to 15 days, More preferably, it is 3 to 7 days. In addition, when this W / O emulsion is heat-processed, the core-shell structure of this invention can be obtained by performing the said drying after a process.

  Further, as another method for further reducing the number average particle size of the obtained core-shell structure, a W / O emulsion containing an active ingredient in an aqueous phase or a dried product of the W / O emulsion may be used as a solvent. The method of filtering with a filter etc. after carrying out dispersion | distribution etc., and the method of performing a centrifugal separation are mentioned. The filter pore diameter in the case of filter filtration is, for example, 1 μm or less, preferably 0.2 μm or less, more preferably 0.1 μm or less.

(Adhesive base phase)
The patch of the present invention contains a styrenic elastomer, a tackifier resin, a plasticizer, and a gelling agent in addition to the above core-shell structure. The styrenic elastomer, tackifying resin, plasticizer, and gelling agent may constitute an adhesive base phase. In this case, the core-shell structure is dispersed or dissolved in the adhesive base phase.

  As described above, the core-shell structure used in the present invention preferably has a solid core portion. When the adhesive base phase is an oil phase, an S / O (Solid in Oil) type patch can be formed by dispersing such a core-shell structure in the adhesive base phase that is an oil phase. it can. The S / O type patch can be obtained, for example, by dispersing the core-shell structure obtained by the production method including the step of drying the W / O emulsion described above in the oil phase.

Styrenic elastomers;
The patch of the present invention contains a styrene elastomer.

  The styrene elastomer is not particularly limited, and styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), styrene-ethylene-butylene-styrene block copolymer. Examples include coalescence (SEBS), polyisobutylene (PIB), isoprene rubber (IR), and the like. These styrenic elastomers may be used alone or in combination.

Tackifying resin;
The patch of the present invention contains a tackifier resin.

  The tackifying resin is not particularly limited, and examples thereof include alicyclic saturated hydrocarbon resins, terpene resins, terpene phenol resins, hydrogenated terpene resins, hydrogenated terpene phenol resins, and rosin derivatives. Preferred are alicyclic saturated hydrocarbon resins or rosin derivatives. These tackifier resins may be used alone or in combination.

  In this invention, the sum total of content of a styrene-type elastomer and tackifying resin is 0.5 weight part or more and 5.0 weight part or less with respect to 1 weight part of core-shell structures. The sum of the contents of the styrene-based elastomer and the tackifier resin is preferably 0.6 parts by weight or more, more preferably 1.0 parts by weight or more, preferably 3.0 parts by weight with respect to 1 part by weight of the core-shell structure. Below, more preferably 1.5 parts by weight or less.

  When the sum of the contents of the styrene-based elastomer and the tackifier resin is not less than the above lower limit, the adhesiveness of the patch can be further enhanced. Moreover, when the sum of content of a styrene-type elastomer and tackifying resin is below the said upper limit, the transdermal absorbability of an active ingredient can be improved further.

  In the present invention, the weight of the core-shell structure is determined by the sum of the weight of the core portion and the weight of the shell portion.

  In the present invention, the weight ratio of styrene elastomer to tackifier resin (styrene elastomer / tackifier resin) is 0.5 or more. The weight ratio (styrene-based elastomer / tackifier resin) is preferably 0.6 or more, more preferably 1.0 or more, preferably 9.0 or less, more preferably 3.0 or less. When the weight ratio (styrene elastomer / tackifier resin) is not less than the above lower limit, bleeding out and adhesive residue can be further suppressed. When the weight ratio (styrene-based elastomer / tackifier resin) is not more than the above upper limit, the adhesiveness of the patch can be further enhanced.

Plasticizers;
The patch of the present invention contains a plasticizer.

  As the plasticizer, an oily liquid agent is preferably used. However, the plasticizer may be an aqueous liquid agent.

  Examples of oily liquids as plasticizers include vegetable oils, animal oils, neutral lipids, synthetic fats and oils, sterol derivatives, waxes, hydrocarbons, alcohol carboxylic acid esters, oxyacid esters, polyhydric alcohol fatty acid esters, silicones, and higher alcohols. Higher fatty acids or fluorinated oils. Examples of the aqueous liquid agent include water and (polyhydric) alcohol. Preferably, it is an oily liquid agent such as hydrocarbon, alcohol carboxylic acid ester, polyhydric alcohol fatty acid ester, or oxy acid ester. These plasticizers may be used alone or in combination.

  Examples of the hydrocarbon include liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, α-olefin oligomer, polyisobutene, hydrogenated polyisobutene, polybutene, squalane, olive-derived squalane, squalene, petrolatum or solid paraffin. Can be mentioned.

  Examples of the alcohol carboxylate ester include octyl dodecyl myristate, hexyl decyl myristate, octyl dodecyl isostearate, cetyl parimate, octyl dodecyl palmitate, cetyl octoate, hexyl decyl octoate, isotridecyl isononanoate, isononanoyl isononanoate, Octonyl isononanoate, isotridecyl isononanoate, isodecyl neopentanoate, isotridecyl neopentanoate, isostearyl neopentanoate, octyldodecyl neodecanoate, oleyl oleate, octyldodecyl oleate, octyldodecyl, lanolin fatty acid octyldodecyl, hexyldecyl dimethyloctanoate, elca Octyldodecyl acid, isostearic acid hydrogenated castor oil, ethyl oleate, avocado oil Ethyl fatty acid, isopropyl myristate, isopropyl palmitate, octyl palmitate, isopropyl isostearate, isopropyl lanolin fatty acid, diethyl sebacate, diisopropyl sebacate, dioctyl sebacate, diisopropyl adipate, dibutyloctyl sebacate, diisobutyl adipate, succinate Examples include dioctyl acid or triethyl citrate.

  Examples of the polyhydric alcohol fatty acid ester include glyceryl trioctanoate, glyceryl trioleate, glyceryl triisostearate, glyceryl diisostearate, glyceryl tri (caprylic acid / capric acid), and tri (caprylic acid / capric acid / myristic acid / stearin). Acid) glyceryl, hydrogenated rosin triglyceride (hydrogenated ester gum), rosin triglyceride (ester gum), glyceryl behenate, trimethylolpropane trioctanoate, trimethylolpropane triisostearate, neopentylglycol dioctanoate, dicapric acid Neopentyl glycol, 2-butyl-2-ethyl-1,3-propanediol dioctanoate, propylene glycol dioleate, pentaoctanoate tetraoctanoate Lithricyl, hydrogenated rosin pentaerythrityl, triethylhexanoic acid ditrimethylolpropane, (isostearic acid / sebacic acid) ditrimethylolpropane, triethylhexanoic acid pentaerythrityl, (hydroxystearic acid / stearic acid / rosinic acid) dipentaerythrityl, diisostearic acid di Glyceryl, polyglyceryl tetraisostearate, polyglyceryl-10 nonaisostearate, deca (erucic acid / isostearic acid / ricinoleic acid) polyglyceryl-8, (hexyldecanoic acid / sebacic acid) diglyceryl oligoester, glycol distearate (ethylene glycol distearate) , Dineopentanoic acid 3-methyl-1,5-pentanediol, or dineopentanoic acid 2,4-diethyl-1,5 Pentane diol, and the like.

  Examples of the oxyester include cetyl lactate, diisostearyl malate, or monoisostearic acid hydrogenated castor oil.

  In the present invention, the plasticizer is preferably gelled by a gelling agent described in detail below.

  Here, the gelation means that molecules in a liquid containing a low molecule or a polymer or consisting of a low molecule or a polymer are partially crosslinked to form a three-dimensional network structure. Gelation may be performed by physical crosslinking or chemical crosslinking. However, in the present invention, gelation is performed by using a gelling agent, and thus gelation is performed by physical crosslinking.

Gelling agent;
The patch of the present invention contains a gelling agent.

  Although it does not specifically limit as a gelatinizer as long as a plasticizer can be gelatinized, For example, ester of 1 or more types of fatty acid and 1 type of polysaccharide is mentioned. The fatty acid is preferably a fatty acid having 5 to 26 carbon atoms, more preferably a fatty acid having 6 to 18 carbon atoms. Preferred examples of the polysaccharide include dextrin, inulin, sucrose, and the like.

  Specific examples of esters include dextrin palmitate, dextrin palmitate / ethylhexanoate, dextrin myristate, or inulin stearate.

  In addition, when gelling hydrocarbons such as liquid paraffin, polyethylene may be used. The polyethylene is preferably a low molecular weight polyethylene having a molecular weight of 50,000 or less, more preferably a molecular weight of 25,000 or less.

  The above gelling agents may be used alone or in combination.

  In the present invention, the sum of the contents of the plasticizer and the gelling agent is 0.25 parts by weight or more and 3.25 parts by weight or less with respect to 1 part by weight of the core-shell structure. The sum of the contents of the plasticizer and the gelling agent is preferably 0.8 parts by weight or more and 3.0 parts by weight or less with respect to 1 part by weight of the core-shell structure.

  When the sum of the content of the plasticizer and the gelling agent is not less than the above lower limit, the adhesiveness of the patch can be further increased, and the transdermal absorbability of the active ingredient can be further increased. Further, when the sum of the contents of the plasticizer and the gelling agent is not more than the above upper limit, bleeding out and adhesive residue can be further suppressed.

  In the present invention, the weight ratio of the gelling agent to the sum of the weight of the plasticizer and the gelling agent (gelling agent / plasticizer + gelling agent) is 7/100 or more and 13/100 or less. The weight ratio (gelator / plasticizer + gelator) is preferably 9/100 or more and 11/100 or less. When the weight ratio (gelator / plasticizer + gelator) is not less than the above lower limit, bleeding out and adhesive residue can be further suppressed. When the weight ratio (gelator / plasticizer + gelator) is less than or equal to the above upper limit, the adhesiveness of the patch can be further increased and the transdermal absorbability of the active ingredient can be further increased.

Other additive ingredients;
The patch of the present invention may contain other additive components depending on the purpose of use. Other additive components include, for example, excipients, colorants, lubricants, binders, emulsifiers, thickeners, wetting agents, stabilizers, preservatives, solvents, solubilizers, suspending agents, buffers. Agents, pH adjusters, antioxidants, transdermal absorption accelerators, irritation relaxation agents, preservatives, chelating agents or dispersants.

  Hereinafter, specific examples of the method for producing the patch of the present invention will be described.

(Manufacturing method of patch)
The patch of the present invention can be produced, for example, by a solution coating method. In the solution coating method, first, an adhesive base phase solution (adhesive layer solution) is prepared.

  As a method for preparing the adhesive base phase solution, for example, first, the above-described core-shell structure, styrene elastomer, tackifying resin, pregelatinized plasticizer, and the like are mixed in a solvent. Thereby, an adhesive base phase solution can be prepared.

  As a method for gelling the plasticizer, for example, a plasticizer and a gelling agent are mixed and heated at about 50 to 130 ° C. for about 0.5 to 5 hours to dissolve both components, and then 20 to 40 The method of curing at 1 degreeC for about 1 to 24 hours is mentioned.

  The adhesive base phase solution may be prepared by mixing the above-described core-shell structure, styrene elastomer, tackifying resin, plasticizer, gelling agent, and the like in a solvent. In this case, the plasticizer can be gelled when it is applied to a release sheet, which will be described later, and dried to remove the solvent.

  The mixing method of each component is not specifically limited, A well-known method can be used. For example, mixing can be performed by stirring with a vacuum mixer under conditions of 2000 rpm, 2 minutes, and 1 Pa.

  Examples of the solvent include cyclohexane, hexane, toluene, ethyl acetate, and the like.

  The solid content concentration in the adhesive base phase solution is preferably 10 to 80% by weight, more preferably 20 to 60% by weight.

  Next, the adhesive base phase solution is uniformly applied onto the release sheet using a coating machine such as a knife coater, comma coater, or reverse coater, and dried. Thus, the adhesive can be obtained by removing the solvent to complete the adhesive base phase layer (adhesive layer) and laminating the support on the adhesive base phase layer.

  As the release sheet, for example, a silicone-treated polyester film having resistance to organic solvents can be used.

  Examples of the support include polyester films and nonwoven fabrics having resistance to organic solvents. Depending on the type of the support, a release sheet may be laminated on the surface of the adhesive base phase after forming a layer of the adhesive base phase on the support.

  The patch thus obtained can be appropriately cut into a shape such as an ellipse, a circle, a square, or a rectangle according to the intended use.

  Next, the present invention will be clarified by giving specific examples and comparative examples of the present invention. In addition, this invention is not limited to a following example.

Preparation Example 1: Preparation of gelled liquid paraffin Gelled liquid paraffin was prepared by the following method.

  93.0 parts by weight of liquid paraffin (made by Wako Pure Chemical Industries, density 0.800 to 0.835 g / mL) as a plasticizer, and dextrin palmitate (manufactured by Chiba Flour Mills, trade name “Leopard KL2” as a gelling agent) ") 7.0 parts by weight were mixed. During mixing, a predetermined amount of dextrin palmitate was gradually added to liquid paraffin while stirring with a stirrer. Thereafter, the mixture was stirred at 90 ° C. for 2 hours to dissolve dextrin palmitate and then allowed to stand at 40 ° C. for 16 hours to prepare gelled liquid paraffin (gelled liquid paraffin).

Example 1
0.2 g of vardenafil hydrochloride trihydrate (manufactured by Atomax Chemicals, molecular weight 579) was dissolved in 40 g of pure water, and coconut oil fatty acid diethanolamide (manufactured by NOF Corporation, trade name “STAHOME DFC”), A solution obtained by dissolving 2.0 g of HLB value: 8.8) in 80 g of cyclohexane was added, followed by homogenizer stirring (25,000 rpm). Thereafter, freeze-drying was performed for 2 days to obtain particles containing an active ingredient and a surfactant (a core-shell structure having a core-shell structure containing an active ingredient in the core part and a surfactant in the shell part). To 20.0 parts by weight of the obtained particles, a styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, diblock amount: 78%) 33 8 parts by weight, 11.3 parts by weight of an alicyclic saturated hydrocarbon resin (tackifier resin, manufactured by Arakawa Chemical Co., Ltd., trade name “Arcon P100”), and a gel as a gelling plasticizer prepared in Preparation Example 1 Liquid phase paraffin 35.0 parts by weight was added, cyclohexane was added so that the solid content would be 30% by weight, and then mixed until uniform to prepare an adhesive layer solution.

  Next, a release sheet was prepared in which a release treatment was performed by applying silicone to one surface of a release base made of a polyethylene terephthalate film having a thickness of 38 μm. The prepared pressure-sensitive adhesive layer solution was applied to the release sheet surface of the release sheet and dried at 60 ° C. for 30 minutes to produce a laminate in which the pressure-sensitive adhesive layer was formed on the release sheet surface of the release sheet. And the support body which consists of a 38-micrometer-thick polyethylene terephthalate film was prepared. A patch was produced by superimposing one side of the support so that the adhesive layer of the laminate was opposed, transferring the adhesive layer of the laminate to the support, and integrating the laminate. The composition in the adhesive layer is shown in Table 1 below.

Preparation Example 2: Preparation of gelled liquid paraffin Gelled liquid paraffin was prepared by the following method.

  Liquid paraffin as a plasticizer (Wako Pure Chemical Industries, density 0.800 to 0.835 g / mL) 87.0 parts by weight and dextrin palmitate as a gelling agent (trade name “Leopard KL2” ] 13.0 parts by weight were mixed. During mixing, a predetermined amount of dextrin palmitate was gradually added to liquid paraffin while stirring with a stirrer. Thereafter, the mixture was stirred at 90 ° C. for 2 hours to dissolve dextrin palmitate and then allowed to stand at 40 ° C. for 16 hours to prepare gelled liquid paraffin (gelled liquid paraffin).

(Example 2)
A patch was produced in the same manner as in Example 1 except that the gelled liquid paraffin prepared in Preparation Example 2 was blended instead of the gelled liquid paraffin prepared in Preparation Example 1. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

Preparation Example 3: Preparation of gelled liquid paraffin Gelled liquid paraffin was prepared by the following method.

  90.0 parts by weight of liquid paraffin (made by Wako Pure Chemical Industries, density 0.800 to 0.835 g / mL) as a plasticizer, and dextrin palmitate (manufactured by Chiba Flour Mills, trade name “Leopard KL2” as a gelling agent) ]) 10.0 parts by weight were mixed. During mixing, a predetermined amount of dextrin palmitate was gradually added to liquid paraffin while stirring with a stirrer. Thereafter, the mixture was stirred at 90 ° C. for 2 hours to dissolve dextrin palmitate and then allowed to stand at 40 ° C. for 16 hours to prepare gelled liquid paraffin (gelled liquid paraffin).

(Example 3)
The blending amount of styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, diblock amount: 78%) is 22.5 parts by weight, and fat The blending amount of the cyclic saturated hydrocarbon resin (tackifier resin, manufactured by Arakawa Chemical Co., Ltd., trade name “Arcon P100”) is 7.5 parts by weight, and instead of the gelled liquid paraffin prepared in Preparation Example 1, Preparation Example 3 A patch was produced in the same manner as in Example 1 except that 50.0 parts by weight of the gelled liquid paraffin prepared in 1 was added. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Example 4)
The amount of styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, diblock amount: 78%) is 18.8 parts by weight, and fat The blending amount of the cyclic saturated hydrocarbon resin (tackifying resin, manufactured by Arakawa Chemical Co., Ltd., trade name “Arcon P100”) was 6.3 parts by weight, and instead of the gelled liquid paraffin prepared in Preparation Example 1, Preparation Example 3 A patch was produced in the same manner as in Example 1 except that 55.0 parts by weight of the gelled liquid paraffin prepared in 1 was added. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Example 5)
The blending amount of styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, diblock amount: 78%) is 15.0 parts by weight, and fat The gel prepared in Preparation Example 3 instead of the gelled liquid paraffin prepared in Preparation Example 1 with a blending amount of the cyclic saturated hydrocarbon resin (trade name “Arcon P100” manufactured by Arakawa Chemical Co., Ltd.) of 5.0 parts by weight. A patch was produced in the same manner as in Example 1 except that 60.0 parts by weight of liquid paraffin was added. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Example 6)
The amount of the particles containing the active ingredient and the surfactant is 30.0 parts by weight, and a styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15 %, Diblock amount: 78%) is 26.3 parts by weight, and the amount of alicyclic saturated hydrocarbon resin (tackifier resin, manufactured by Arakawa Chemical Co., Ltd., trade name “Arcon P100”) is 8. The patch was prepared in the same manner as in Example 1 except that 8 parts by weight and 35.0 parts by weight of the gelled liquid paraffin prepared in Preparation Example 3 were blended in place of the gelled liquid paraffin prepared in Preparation Example 1. Manufactured. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Example 7)
The amount of the particles containing the active ingredient and the surfactant is 40.0 parts by weight, and a styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15 %, Diblock amount: 78%) is 18.8 parts by weight, and the amount of alicyclic saturated hydrocarbon resin (tackifier resin, manufactured by Arakawa Chemical Co., Ltd., trade name “Arcon P100”) is 6. The patch was prepared in the same manner as in Example 1 except that 3 parts by weight and 35.0 parts by weight of the gelled liquid paraffin prepared in Preparation Example 3 were blended instead of the gelled liquid paraffin prepared in Preparation Example 1. Manufactured. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Example 8)
The amount of styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, diblock amount: 78%) is 40.5 parts by weight, and fat The blending amount of the cyclic saturated hydrocarbon resin (tackifier resin, manufactured by Arakawa Chemical Co., Ltd., trade name “Arcon P100”) is 4.5 parts by weight, and instead of the gelled liquid paraffin prepared in Preparation Example 1, Preparation Example 3 A patch was produced in the same manner as in Example 1 except that 35.0 parts by weight of the gelled liquid paraffin prepared in 1 was added. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

Example 9
The blending amount of styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, diblock amount: 78%) is 27.0 parts by weight, and fat A patch was produced in the same manner as in Example 8, except that the amount of the cyclic saturated hydrocarbon resin (tackifying resin, manufactured by Arakawa Chemical Co., Ltd., trade name “Arcon P100”) was 18.0 parts by weight. . The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Example 10)
The blending amount of styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, diblock amount: 78%) is 22.5 parts by weight, and fat A patch was produced in the same manner as in Example 8, except that the amount of the cyclic saturated hydrocarbon resin (trade name “Arcon P100” manufactured by Arakawa Chemical Co., Ltd.) was 22.5 parts by weight. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Example 11)
The amount of styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, diblock amount: 78%) is 18.0 parts by weight, and fat A patch was produced in the same manner as in Example 8, except that the amount of the cyclic saturated hydrocarbon resin (trade name “Arcon P100” manufactured by Arakawa Chemical Co., Ltd.) was 27.0 parts by weight. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Example 12)
A patch was prepared in the same manner as in Example 6 except that oleic acid diethanolamide (manufactured by NOF Corporation, trade name “STAHOME DOS”, HLB value: 7.2) was used instead of coconut oil fatty acid diethanolamide. Manufactured. The adhesive layer composition in the adhesive layer is shown in Table 1.

(Example 13)
A patch was prepared in the same manner as in Example 12 except that glyceryl monooleate (manufactured by Riken Vitamin Co., Ltd., trade name “Riquemar XO-100”, HLB value: 6.7) was used instead of oleic acid diethanolamide. Manufactured. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Example 14)
A patch was prepared in the same manner as in Example 12 except that sorbitan trioleate (manufactured by Nikko Chemicals, trade name “NIKKOL SO-30V”, HLB value: 5.8) was used instead of oleic acid diethanolamide. Manufactured. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Example 15)
The amount of particles containing the active ingredient and the surfactant is 15.0 parts by weight, and a styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15 %, Diblock amount: 78%) is 37.5 parts by weight, and the amount of alicyclic saturated hydrocarbon resin (tackifier resin, manufactured by Arakawa Chemical Co., Ltd., trade name “Arcon P100”) is 12. The patch was prepared in the same manner as in Example 1 except that 5 parts by weight and 35.0 parts by weight of the gelled liquid paraffin prepared in Preparation Example 3 were blended in place of the gelled liquid paraffin prepared in Preparation Example 1. Manufactured. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Comparative Example 1)
The amount of the particles containing the active ingredient and the surfactant is 10.0 parts by weight, and a styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15 %, Diblock amount: 78%) is 41.3 parts by weight, and the amount of alicyclic saturated hydrocarbon resin (tackifier resin, manufactured by Arakawa Chemical Co., Ltd., trade name “Arcon P100”) is 13. 8 parts by weight, except that 35.0 parts by weight of liquid paraffin (manufactured by Wako Pure Chemical Industries, Ltd., density 0.800 to 0.835 g / mL) was blended instead of the gelled liquid paraffin prepared in Preparation Example 1. A patch was produced in the same manner as in Example 1. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Comparative Example 2)
The amount of particles containing the active ingredient and the surfactant is 15.0 parts by weight, and a styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15 %, Diblock amount: 78%) is 37.5 parts by weight, and the amount of alicyclic saturated hydrocarbon resin (tackifier resin, manufactured by Arakawa Chemical Co., Ltd., trade name “Arcon P100”) is 12. A patch was produced in the same manner as in Comparative Example 1 except that the amount was 5 parts by weight. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Comparative Example 3)
Instead of coconut oil fatty acid diethanolamide, sucrose laurate (trade name “L-195”, HLB value: 1.0, manufactured by Mitsubishi Chemical Foods Co., Ltd.) is used instead of the gelled liquid paraffin prepared in Preparation Example 1. A patch was produced in the same manner as in Example 1 except that 35.0 parts by weight of liquid paraffin (manufactured by Wako Pure Chemical Industries, Ltd., density 0.800 to 0.835 g / mL) was blended. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Comparative Example 4)
Similar to Example 1 except that 35.0 parts by weight of liquid paraffin (manufactured by Wako Pure Chemical Industries, Ltd., density 0.800 to 0.835 g / mL) was blended in place of the gelled liquid paraffin prepared in Preparation Example 1. Thus, a patch was produced. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Comparative Example 5)
The amount of styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, diblock amount: 78%) is 7.5 parts by weight, and fat The blending amount of the cyclic saturated hydrocarbon resin (tackifying resin, manufactured by Arakawa Chemical Co., Ltd., trade name “Arcon P100”) is 2.5 parts by weight, and instead of the gelled liquid paraffin prepared in Preparation Example 1, Preparation Example 3 A patch was produced in the same manner as in Example 1 except that 70.0 parts by weight of the gelled liquid paraffin prepared in 1 was added. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Comparative Example 6)
The amount of the particles containing the active ingredient and the surfactant is 45.0 parts by weight, and a styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15 %, Diblock amount: 78%) is 15.0 parts by weight, and the amount of alicyclic saturated hydrocarbon resin (tackifying resin, manufactured by Arakawa Chemical Co., Ltd., trade name “Arcon P100”) is 5. A patch was produced in the same manner as in Example 6 except that the amount was 0 parts by weight. The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Comparative Example 7)
The blending amount of styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, diblock amount: 78%) is 11.3 parts by weight, and fat A patch was produced in the same manner as in Example 8, except that the amount of the cyclic saturated hydrocarbon resin (tackifier resin, manufactured by Arakawa Chemical Co., Ltd., trade name “Arcon P100”) was 33.8 parts by weight. . The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Comparative Example 8)
The blending amount of styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, diblock amount: 78%) is 4.5 parts by weight, and fat. A patch was produced in the same manner as in Example 8, except that the amount of the cyclic saturated hydrocarbon resin (tackifying resin, manufactured by Arakawa Chemical Co., Ltd., trade name “Arcon P100”) was 40.5 parts by weight. . The adhesive layer composition in the adhesive layer is shown in Table 1 below.

(Evaluation)
Test Example 1: Evaluation of Bleed Out and Adhesive Residue The adhesive paste obtained in Examples 1 to 15 and Comparative Examples 1 to 8 was visually observed to exude from the adhesive layer (bleed out), and adhesive. The state of the remaining agent (adhesive residue) was evaluated according to the following criteria. The results are shown in Table 1 below.

1: No bleed-out or adhesive residue 2: Bleed-out or adhesive residue is observed on only a part of the release sheet 3: Bleed-out or adhesive residue is observed on the outer edge of the release sheet 4: Bleed-out or adhesive residue appears on the entire surface of the release sheet

  Bleed-out is a state where particles are lifted as droplets on the release sheet, and adhesive residue is a state where the adhesive is separated at the time of peeling and the adhesive is attached to the release sheet. Immediately after the production, the patch was peeled off at room temperature, and the release sheet was visually checked for evaluation.

Test Example 2: Hairless rat skin permeability test Hairless rat skin (extracted from Japan SLC, HWY / Slc, 8 weeks old) was set in a drug skin permeation test cell (Fig. 1). 3.14 cm ^{2 of} the patches obtained in Examples 1 to 15 and Comparative Examples 1 to 8 were applied to the upper part of the device. In the lower receptor layer, NaH ₂ PO ₄ in distilled water is 5 × 10 ⁻⁴ M, Na ₂ HPO ₄ is 2 × 10 ⁻⁴ M, NaCl is 1.5 × 10 ⁻⁴ M, gentamicin sulfate (Wako Pure Chemical Industries, Ltd.). A buffer containing 10 ppm of G1658 (manufactured by Yakuhin Co., Ltd.) and adjusted to pH 7.2 with NaOH was added. The apparatus was installed in the thermostat kept at 32 degreeC after the test start. Twenty-four hours after the start of the test, 1 ml of the solution in the tank was collected from the lower receptor layer, and immediately after that, 1 ml of the same composition was replenished. Methanol was added to each collected receptor fluid sample to extract the eluted lipids and centrifuged, and then the concentration of vardenafil hydrochloride trihydrate in the supernatant was quantified by high performance liquid chromatography (HPLC) (apparatus) : System controller; manufactured by Shimadzu Corporation, product number “CBM-20A”, liquid feeding unit; manufactured by Shimadzu Corporation, product number “LC-20AD”, column oven; manufactured by Shimadzu Corporation, product number “CTO-” 20A ", detector: manufactured by Shimadzu Corporation, product number" SPD-20A ", detection wavelength: 271 nm, column used: Thermoscience, Inc., product number" Hypersi GOLD ", 150 × 4.6 mm, 3 μm). Based on the determined amount of active ingredient, the cumulative permeation amount after 24 hours was calculated. The calculated cumulative permeation amount after 24 hours (mg / cm ² ) is shown in Table 1 below.

  In Table 1 below, the sum of the contents of SIS (styrene elastomer, B) and tackifying resin (C) with respect to 1 part by weight of the particles (core-shell structure, A) is expressed as (B + C) / A. Yes. The sum of the contents of the plasticizer (D) and the gelling agent (E) with respect to 1 part by weight of the particles (core-shell structure, A) is expressed as (D + E) / A. The weight ratio of SIS (styrene elastomer, B) to the tackifier resin (C) is expressed as B / C. The weight ratio of the gelling agent (E) to the sum of the weights of the plasticizer (D) and the gelling agent (E) is expressed as E / (D + E).

DESCRIPTION OF SYMBOLS 1 ... Parafilm 2 ... Skin 3 ... Patch 4 ... Receptor solution (pH = 7.2 phosphate buffer solution)
5 ... Stir bar

Claims (7)

A core-shell structure comprising: a core part containing an active ingredient; and a shell part covering at least a part of the surface of the core part and containing a surfactant;
A styrenic elastomer,
A tackifying resin;
A plasticizer,
A gelling agent;
Including
The surfactant has an HLB value of 3.0 or more,
The sum of the contents of the styrenic elastomer and the tackifying resin is 0.5 parts by weight or more and 5.0 parts by weight or less with respect to 1 part by weight of the core-shell structure,
The sum of the contents of the plasticizer and the gelling agent is 0.25 parts by weight or more and 3.25 parts by weight or less with respect to 1 part by weight of the core-shell structure,
The patch, wherein a weight ratio of the styrene-based elastomer to the tackifying resin is 0.5 or more.   The patch according to claim 1, wherein the surfactant has an HLB value of 5.0 or more.   The patch according to claim 1 or 2, wherein a weight ratio of the gelling agent to a sum of weights of the plasticizer and the gelling agent is 7/100 or more and 13/100 or less.   The sum of the contents of the plasticizer and the gelling agent is 2.5 parts by weight or more and 3.0 parts by weight or less with respect to 1 part by weight of the core-shell structure. The patch according to Item 1.   5. The plasticizer according to claim 1, wherein the plasticizer is at least one oily liquid selected from the group consisting of hydrocarbons, alcohol carboxylic acid esters, polyhydric alcohol fatty acid esters, and oxyacid esters. The patch described in 1.   The gelling agent is at least one selected from the group consisting of polyethylene, dextrin palmitate, dextrin palmitate / ethylhexanoate, dextrin myristate, and inulin stearate. The patch according to Item.   The patch according to any one of claims 1 to 6, which is a tape.

Images