WO2017014306A1 - Formulation - Google Patents

Abstract

Provided is a formulation having excellent percutaneous absorptivity of an active ingredient. The formulation includes a core-shell structure, provided with a core portion containing an active ingredient and a shell portion covering at least part of the surface of the core portion and containing a surfactant, and at least one polymer selected from the group consisting of styrene elastomers having a styrene content of 10-50% by weight, polymers having aminoalkyl groups, and polymers having structural units based on a monomer with an SP value of 8.7-12.

Description

Formulation

The present invention relates to a preparation, and more particularly to a preparation used for external preparations and cosmetics.

In the field of external preparations and cosmetics, techniques for transdermal absorption of active ingredients such as drugs have been developed.

In the percutaneous absorption process of these drugs, etc., they are affected by skin barrier function and metabolism. These effects vary from drug to drug.

It has been reported that the amount of transdermal absorption was increased by a preparation using particles containing a drug or the like and a surfactant (Patent Document 1).

Patent Document 2 below describes an external preparation in which an S / O suspension, a styrene-isoprene-styrene block copolymer, and liquid paraffin are mixed. The S / O type suspension includes a drug-containing complex in which a hydrophilic drug is coated with a surfactant.

Patent Document 3 below discloses an external preparation comprising an adhesive base layer containing a drug. The adhesive base layer is composed of an aminoalkyl methacrylate copolymer, a styrene isoprene block copolymer, or the like.

Patent Document 4 below discloses a percutaneous absorption preparation containing an anti-dementia therapeutic drug, a polymer compound having an amino group, a fatty acid alkyl ester, and a styrene polymer compound.

Japanese Patent No. 4844494 International Publication No. 2006/025583 JP2015-145429A International Publication No. 2011/074635

However, when the preparations of Patent Documents 1 to 4 are used for external preparations such as plasters, the transdermal absorbability of active ingredients such as drugs is still insufficient.

An object of the present invention is to provide a preparation excellent in transdermal absorbability of an active ingredient.

The inventors of the present invention have made extensive studies to solve the above problems, and (A) a core-shell structure containing an active ingredient and a surfactant, and (B) a styrene content is 10 wt% to 50 wt%. By using at least one polymer selected from the group consisting of a styrene-based elastomer, a polymer having an aminoalkyl group, and a polymer having a structural unit based on a monomer having an SP value of 8.7 to 12, the above problem can be solved I found. The present invention has been completed through further trial and error based on this finding, and includes the following aspects.

Item 1. A core-shell structure comprising: an active ingredient-containing core part; and a shell part covering at least a part of the surface of the core part and containing a surfactant;
At least one selected from the group consisting of a styrene elastomer having a styrene content of 10 wt% to 50 wt%, a polymer having an aminoalkyl group, and a polymer having a structural unit based on a monomer having an SP value of 8.7 to 12 A kind of polymer,
A formulation comprising

Item 2. Item 2. The preparation according to Item 1, which has an S / O type structure in which the core-shell structure is dispersed in an adhesive containing the polymer.

Item 3. The styrene elastomer is selected from the group consisting of styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), and styrene-ethylene-butylene-styrene block copolymer (SEBS). Item 3. The preparation according to Item 1 or 2, which is at least one selected.

Item 4. The styrene elastomer is a styrene-isoprene-styrene block copolymer (SIS),
Item 4. The preparation according to Item 3, wherein the content of the styrene-isoprene-styrene block copolymer (SIS) is in the range of 0.1 to 4 parts by weight with respect to 1 part by weight of the core-shell structure. .

Item 5. Further comprising a tackifying resin,
Item 5. The preparation according to any one of Items 1 to 4, wherein the tackifying resin has a softening point of 60 ° C. or higher and 150 ° C. or lower.

Item 6. Item 6. The preparation according to any one of Items 1 to 5, wherein a content of the tackifying resin with respect to 100 parts by weight of the styrene-based elastomer is in a range of 160 parts by weight or less.

Item 7. Item 7. The preparation according to any one of Items 1 to 6, wherein the polymer having an aminoalkyl group is an aminoalkyl methacrylate copolymer.

Item 8. Items 1 to 6 wherein the monomer having an SP value of 8.7 to 12 is at least one monomer selected from the group consisting of compounds represented by the following general formulas (1) and (2) and vinylpyrrolidone compounds: The preparation according to any one of the above.

(In the formula, R1 represents a hydrogen atom or a methyl group, and R2 represents an alkyl group having 5 or less carbon atoms)

(In the formula, R3 represents a hydrogen atom or a methyl group, and R4 represents an alkyl group having 5 or less carbon atoms)

Item 9. Item 9. The preparation according to any one of Items 1 to 6 and 8, wherein the monomer has an SP value of 9 to 11.

Item 10. Item 10. The preparation according to any one of Items 1 to 6, 8, and 9, wherein the polymer having a structural unit based on a monomer having an SP value of 8.7 to 12 is an aminoalkyl methacrylate copolymer.

Item 11. A core shell structure comprising an active ingredient, a core portion, and a shell portion covering at least a part of the surface of the core portion and containing a surfactant, and a styrene content of 10% by weight And at least one polymer selected from the group consisting of a styrene-based elastomer that is ˜50 wt%, a polymer having an aminoalkyl group, and a polymer having a structural unit based on a monomer having an SP value of 8.7-12 Has a layer,
The layer has a structural unit based on 0.2 to 5 parts by weight of the styrenic elastomer, a polymer having an aminoalkyl group, and a monomer having an SP value of 8.7 to 12 with respect to 1 part by weight of the core-shell structure. Item 11. The preparation according to any one of Items 1 to 10, comprising at least one polymer selected from the group consisting of polymers having.

Item 12. Item 12. The preparation according to any one of Items 1 to 11, further comprising a liquid agent.

Item 13. Item 13. The preparation according to any one of Items 1 to 12, further comprising a gelling agent.

Item 14. The preparation according to claim 12 or 13, wherein the liquid is gelled.

According to the present invention, a preparation excellent in transdermal absorbability of an active ingredient can be provided.

1 is a simplified diagram of a drug skin permeation test cell used in Test Example 1. FIG. FIG. 2 is a graph showing the results of Examples 1 to 4 and Comparative Examples 1 and 2. FIG. 3 is a graph showing the results of Example 5 and Comparative Examples 3 and 4. FIG. 4 is a graph showing the results of Examples 14 to 16 and Comparative Examples 1 and 2. FIG. 5 is a graph showing the relationship between the SIS ratio (%) with respect to the total mass of SIS and Eudragit and the 48-hour cumulative skin permeation amount.

1. Formulation of the Present Invention The formulation of the present invention comprises at least (A) a core-shell structure containing an active ingredient and a surfactant,
(B) selected from the group consisting of a styrene elastomer having a styrene content of 10 wt% to 50 wt%, a polymer having an aminoalkyl group, and a polymer having a structural unit based on a monomer having an SP value of 8.7 to 12 At least one polymer,
including.

1.1. (A) Core-shell structure containing active ingredient and surfactant (A) A core-shell structure containing an active ingredient and a surfactant (hereinafter sometimes referred to as “core-shell structure (A)”) A core-shell structure comprising 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. The core part is preferably a solid. When the core part is a solid, the stability in the base described later is further improved. Therefore, in this case, a preparation having an S / O (Solid in Oil) type structure can be formed by dispersing the core-shell structure (A) in a base phase that is an oil phase.

In addition, it is preferable that the said base phase is an adhesive base phase containing the said polymer (B). In that case, an S / O (Solid in Oil) type patch can be formed by dispersing the core-shell structure (A) in the adhesive base phase.

When the core-shell structure (A) having such a configuration is applied to the skin, the active ingredient can be gradually released over a long period of time and percutaneously absorbed.

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

In the present invention, the number average particle size of the core-shell structure (A) is the number average particle size calculated by a dynamic light scattering method when a solvent (for example, squalane or the like) is dispersed.

1.1.1. Active ingredient An active ingredient is not specifically limited, According to the intended purpose of the formulation of this invention, it selects suitably.

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 drug, a renal disease agent, a schizophrenia drug, an bulimia disorder drug, and the like.

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 skin permeability, the hydrophilic drug preferably has a molecular weight of 6,000 or less, more preferably 3,000 or less, and even more preferably 1,500 or less.

The active ingredient is preferably a drug that is easily absorbed through the skin. The active ingredient is not particularly limited, but is preferably a compound having an octanol water partition coefficient of −6 to 6. Therefore, the skin permeability is improved. From the viewpoint of further improving skin permeability, the water octanol partition coefficient is preferably −1 or more, more preferably 0 or more. The water octanol partition coefficient of the hydrophilic drug is preferably 4 or less, and more preferably 1 or less. When the water octanol distribution coefficient of the hydrophilic drug is not more than the above upper limit, the skin permeability 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 of hydrophilic compounds 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 acidic acidic drugs are not particularly limited as long as they are pharmacologically acceptable salts, and include sodium salts such as sodium bucladecin (molecular weight 491) or sodium cromoglycate (molecular weight 512).

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

The core-shell structure (A) may contain two or more active ingredients as necessary. In this case, the highly permeable preparation in the present invention containing the core-shell structure (A) can be used as a compounding agent.

1.1.2. Surfactant The surfactant is not particularly limited as long as it is associated with the active ingredient and can form the core-shell structure (A).

Moreover, multiple types of surfactants may be used in combination.

As the surfactant, a weighted average value of HLB values is preferably 10 or less, more preferably 5 or less, and even more preferably 3 or less.

In the present invention, an HLB (abbreviation of Hydrophile Lipophile Balance) value is an index for knowing whether an emulsifier is hydrophilic or lipophilic, and takes a value of 0 to 20, for example. It shows that lipophilicity is so strong that an HLB value is small. 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)}

The surfactant is not particularly limited, and can be selected from a wide range of agents that can be used as preparations such as external preparations.

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 alkylphenyl ethers, alkyl glycosides, and fatty acid alkanolamides.

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.

Other fatty acid esters are not particularly limited, and examples include esters of fatty acids with at least one of glycerin, polyglycerin, polyoxyethylene glycerin, sorbitan, and polyoxyethylene sorbit.

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 preferably one containing at least one selected from the group consisting of an alkyl chain, an alkenyl group and an alkynyl group.

The surfactant is more preferably one containing at least one selected from the group consisting of an alkyl group, an alkenyl group, and an alkynyl group having 5 or more carbon atoms in the longest straight chain portion.

The surfactant has an alkyl group or an alkenyl group having a carbon number of the longest straight chain portion, more preferably 8 to 30, and still more preferably 10 to 24. Therefore, the skin permeability of the hydrophilic drug is enhanced. Further, the surfactant preferably has at least one of an alkyl group or alkenyl group having 10 to 15 carbon atoms and an alkenyl group having 16 to 20 carbon atoms. More preferably, the surfactant has an alkyl group or alkenyl group having 10 to 15 carbon atoms. In this case, the skin permeability of the hydrophilic drug can be further enhanced.

Examples of the surfactant having an alkyl group or alkenyl group having 10 to 20 carbon atoms include sucrose oleate, sucrose laurate, sucrose palmitate, sucrose stearate, glycerin Examples thereof include lauric acid ester, glycerin oleic acid ester, glycerin stearic acid ester, sorbitan laurate, sorbitan oleate, sorbitan palmitate, and sorbitan stearate. Among these, examples of the surfactant having an alkyl group or alkenyl group having 10 to 15 carbon atoms include sucrose laurate, glycerol laurate, and sorbitan laurate. Examples of the surfactant having an alkenyl group having 16 to 20 carbon atoms include sucrose oleate.

The surfactant is preferably a sucrose fatty acid ester. Of these, sucrose laurate and / or sucrose oleate are preferred, and sucrose laurate is more preferred from the viewpoint of further enhancing the skin permeability of the hydrophilic drug.

The blending amount of the surfactant can be appropriately set within the range in which the effect of the present invention is exerted. For example, the mass ratio with respect to the active ingredient (active ingredient: surfactant) is 1: 3 to 1: 100. At this time, the formulation of the present invention is even more excellent in percutaneous absorption. In this respect, the weight ratio with respect to the active ingredient (active ingredient: surfactant) is more preferably 1: 3 to 1:50, and further preferably 1: 5 to 1:30.

1.1.3. Other components The core-shell structure (A) may further contain at least one other component in addition to the active component. 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.

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

The stabilizer is not particularly limited, and specific examples include polysaccharides, proteins, and hydrophilic polymer materials. 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.

The percutaneous absorption enhancer is not particularly limited. Specifically, higher alcohol, N-acyl sarcosine or a salt thereof, 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. For example, the weight ratio of the active ingredient to the percutaneous absorption enhancer (active ingredient: percutaneous absorption enhancer) is 1: 0. It can also be blended so as to be 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. The content ratio of the skin irritation reducing agent can be set as appropriate depending on the type of the skin irritation reducing agent. .

The preservative is not particularly limited, and specific examples include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol, and thymol. The content of the preservative in the core portion can be appropriately set depending on the type of the preservative, but for example, it may be blended so as to be 0.01 wt% to 10 wt% with respect to the entire core shell structure (A). it can. An antiseptic | preservative may contain 1 type (s) or 2 or more types.

The analgesic is not particularly limited, and specific examples include local anesthetics such as procaine, tetracaine, lidocaine, dibucaine or prilocaine, or salts thereof. An analgesic may contain 1 type (s) or 2 or more types. The content ratio of the analgesic agent in the core-shell structure (A) can be set as appropriate depending on the type of the analgesic agent. For example, the content is 0.1 to 30% by weight with respect to the entire core-shell structure (A). It can also be blended.

As described above, when the core part is solid, the core-shell structure (A) is dispersed in the base phase that is the oil phase, whereby a preparation having an S / O (Solid in Oil) type structure is obtained. Can be formed.

In addition, it is preferable that the said base phase is an adhesive base phase containing the said polymer (B). In that case, an S / O (Solid in Oil) type patch can be formed by dispersing the core-shell structure (A) in the adhesive base phase.

The core-shell structure (A) having such a 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 stirring the homogenizer are, for example, about 5000 to 50000 rpm, more preferably about 10,000 to 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.

In addition, from the viewpoint of further reducing the number average particle size of the obtained core-shell structure (A), a step of heat-treating a W / O emulsion containing an active ingredient in the aqueous phase or a dried product of the W / O emulsion It is preferable to further provide. The heat treatment temperature is, for example, 30 to 60 ° C., preferably 35 to 50 ° C., more preferably 35 to 45 ° C.

The heat treatment time is appropriately adjusted according to the heat treatment temperature, and is, for example, 1 to 30 days, preferably 2 to 15 days, more preferably 3 to 7 days. In addition, when this W / O emulsion is heat-processed, the core-shell structure (A) 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), a W / O emulsion containing an active ingredient in the aqueous phase or a dried product of the W / O emulsion is required. Accordingly, after dispersion in a solvent or the like, a method of filtering with a filter or the like, or a method of performing centrifugal separation is exemplified. 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.

1.2. Base In the present invention, (B) a styrene elastomer having a styrene content of 10 to 50% by weight, a polymer having an aminoalkyl group, and a structural unit based on a monomer having an SP value of 8.7 to 12 The base can be constituted by at least one polymer selected from the group consisting of polymers. When the core-shell structure (A) is dispersed or dissolved (including partially dissolved) in this base, the transdermal absorption amount of the active ingredient can be further effectively improved.

Examples of the form of the base include a pressure-sensitive adhesive. The pressure-sensitive adhesive comprises (B) a styrene elastomer having a styrene content of 10% by weight to 50% by weight, a polymer having an aminoalkyl group, and a polymer having a structural unit based on a monomer having an SP value of 8.7-12. It can be composed of at least one polymer selected from the group consisting of: Further, the core-shell structure (A) can be dispersed or dissolved (including partially dissolved) in the pressure-sensitive adhesive.

As other forms of the base, at least one selected from the group consisting of an ointment, a lotion, a cream, an aerosol, a plaster, a tape, a patch, a poultice, a gel, a microneedle and the like. The base etc. which are normally used for a seed | species external preparation may be sufficient. Such a base has a structural unit based on (B) a styrene elastomer having a styrene content of 10% to 50% by weight, a polymer having an aminoalkyl group, and a monomer having an SP value of 8.7-12. It can be composed of at least one polymer selected from the group consisting of polymers. In the base, the core-shell structure (A) can be dispersed or dissolved (including partially dissolved) and used.

1.2.1. Styrenic elastomer The elastomer is not particularly limited. It can be appropriately selected from those usually used according to specific uses such as pharmaceuticals and cosmetics.

The above elastomers may be used alone or in combination of two or more.

The styrene elastomer is not particularly limited as long as the styrene content is in the range of 10 to 50% by weight, and is a styrene-isoprene-styrene block copolymer (SIS) or a styrene-butadiene-styrene block copolymer (SBS). Or hydrogenated products such as styrene-ethylene-butylene-styrene block copolymer (SEBS) and styrene-ethylene-propylene-styrene block copolymer (SEPS). However, from the viewpoint of enhancing transdermal absorbability, an unhydrogenated type is preferable, and a styrene-isoprene-styrene block copolymer (SIS) is more preferable.

As described above, the styrene content of the styrene elastomer is 10 to 50% by weight. Therefore, transdermal absorbability is improved.

From the viewpoint of further enhancing transdermal absorbability, the styrene content is preferably 15 to 35% by weight, more preferably 15 to 25% by weight, and even more preferably 10 to 20% by weight. In addition, styrene content can be measured by conventionally well-known measuring methods, such as NMR (nuclear magnetic resonance spectrum method), for example.

The styrenic elastomer preferably contains both a diblock copolymer and a triblock copolymer from the viewpoint of enhancing transdermal absorbability, and is based on the total mass of the diblock copolymer and the triblock copolymer. The mass (diblock amount) of the diblock copolymer is preferably 10 to 90%, more preferably 20 to 80%, and still more preferably 30 to 80%.

In addition, the quantitative analysis of the diblock copolymer and the triblock copolymer of the styrene elastomer can be performed by a known means such as GPC. As the GPC column, an organic solvent column having a logical number of 14,000 or more and a particle size of 5 to 7 μm is used. Under the condition that each retention time of the diblock copolymer and the triblock copolymer is well separated, the organic solvent column is used. It is preferable to select an eluent, a flow rate (0.5 to 3 mL / min), and a temperature (25 to 50 ° C.). RI can be used as a detection method, and polystyrene can be used in terms of molecular weight.

The content of the styrene-based elastomer is not particularly limited and can be set as appropriate. For example, the amount can be 0.1 to 4 parts by weight with respect to 1 part by weight of the core-shell structure (A). Preferably, the amount is 0.3 to 3 parts by weight with respect to 1 part by weight of the core-shell structure (A), and more preferably 0.5 to 1 part by weight with respect to 1 part by weight of the core-shell structure (A). .

The styrene-based elastomer is not particularly limited, and, for example, one having a solubility parameter (SP value) calculated by the Okitsu equation of 8.7 or less can be used. From the viewpoint of further enhancing the transdermal absorbability, it is preferable to use a styrene thermoplastic elastomer having an SP value of 7 to 8.7.

Note that the SP value calculated by the Okitsu equation is an index representing hydrophilicity, and the Okitsu equation is a technique for calculating ΔF in the solubility parameter represented by the following equation (3) (reference) : Toshinao Okitsu, Journal of the Adhesion Society of Japan, vol. 29, No. 5, 204-211 (1993)).

Δδ = ΔF / ΔV (3)
In formula (3), δ represents a solubility parameter, F represents a molar attractive constant, and V represents a molar volume.

The styrene-based elastomer can be used as an adhesive after being dispersed in a liquid such as liquid paraffin. You may add the liquid agent which has an absorption promotion effect to the said styrene-type elastomer. For example, cyclohexane or the like can be used as the solvent for the styrene elastomer. In addition, the adhesive strength can be finely adjusted by adding, for example, tackifier (tackifier resin) or a plasticizer to the styrene-based elastomer.

Examples of tackifying resins include alicyclic saturated hydrocarbon resins, rosin derivatives (rosin, glycerin ester of rosin, hydrogenated rosin, hydrogenated rosin glycerin ester, rosin pentaerythritol ester, hydrogenated rosin pentaerythritol ester, etc.), terpene resin Petroleum resin or maleic acid resin. Among these, alicyclic saturated hydrocarbon resins and hydrogenated rosin glycerin esters are particularly preferable. These tackifiers may be used alone or in combination of two or more.

The softening point of the tackifying resin is not particularly limited, but is preferably within a range of 60 ° C. to 150 ° C., and more preferably within a range of 70 ° C. to 120 ° C. When the softening point of the tackifying resin is within the above range, the adhesive force can be further increased.

The content of the tackifying resin is not particularly limited and can be set as appropriate. For example, the amount may be 0 to 160 parts by weight with respect to 100 parts by weight of the styrene elastomer. The amount is preferably 0 to 130 parts by weight based on 100 parts by weight of the styrene elastomer, and more preferably 0 to 100 parts by weight based on 100 parts by weight of the styrene elastomer. When content of tackifying resin exists in the said range, the transdermal absorbability of an active ingredient and the stability of a formulation can be improved further.

1.2.2. Polymer having aminoalkyl group The polymer having an aminoalkyl group is not particularly limited. It can be appropriately selected from those usually used according to specific uses such as pharmaceuticals and cosmetics.

The polymer having an aminoalkyl group may be used alone or in combination of two or more.

Specific examples of the polymer having an aminoalkyl group include an aminoalkyl methacrylate copolymer, an aminoalkyl acrylate copolymer, an aminoalkyl methacrylate polymer, an aminoacryl acrylate polymer, an aminoalkyl group-containing polysiloxane, an aminoalkyl group-containing polyurethane, or a derivative thereof. Etc.

The amount of the polymer having an aminoalkyl group used is not particularly limited and can be set as appropriate. For example, the amount can be 0.1 to 10 parts by weight with respect to 1 part by weight of the core-shell structure (A). Preferably, the amount can be 0.2 to 5 parts by weight with respect to 1 part by weight of the core-shell structure (A), and more preferably 0.3 to 3 parts by weight with respect to 1 part by weight of the core-shell structure (A). Part.

The polymer having an aminoalkyl group may be used in combination with the styrene-based elastomer (hereinafter sometimes referred to as an elastomer). In that case, although it depends on the type of the active ingredient, the mass ratio of the elastomer to the sum of the mass of the elastomer and the polymer having an aminoalkyl group (the mass of the elastomer / the sum of the mass of the polymer having the elastomer and the aminoalkyl group) is 0. It is preferably 2 or more and 0.9 or less. When the said mass ratio exists in the said range, transdermal absorbability can be improved much more effectively. From the viewpoint of further enhancing the transdermal absorbability, the mass ratio (sum of elastomer / sum of mass of elastomer and polymer having aminoalkyl group) is preferably 0.3 or more, more preferably 0.4. As mentioned above, Preferably it is 0.8 or less, More preferably, it is 0.7 or less.

1.2.3. Polymer having a structural unit based on a monomer having an SP value of 8.7 to 12 The polymer having a structural unit based on a monomer having an SP value of 8.7 to 12 is not particularly limited as long as the SP value is within the above range. It can be appropriately selected from those usually used according to specific uses such as pharmaceuticals and cosmetics. A polymer having a structural unit based on a monomer having an SP value of 8.7 to 12 may be contained in the adhesive, and the polymer itself having a structural unit based on a monomer having an SP value of 8.7 to 12 is an adhesive. There may be. By using the core-shell structure (A) dispersed in such a polymer, the transdermal absorbability of the active ingredient can be enhanced. The SP value refers to a solubility parameter calculated by the Okitsu equation.

In the present invention, the SP value is calculated by the Okitsu equation. The SP value is an index representing hydrophilicity, and the Okitsu equation is a method for calculating ΔF in the solubility parameter represented by the following equation (3) (reference: Toshinao Okitsu, Journal of the Adhesion Society of Japan, vol.29, No. 5, 204-211 (1993)).

Δδ = ΔF / ΔV (3)
(In formula (3), δ represents a solubility parameter, F represents a molar attractive constant, and V represents a molar volume.)

The polymer having a structural unit based on a monomer having an SP value of 8.7 to 12 is not particularly limited. It can be appropriately selected from those usually used according to specific uses such as pharmaceuticals and cosmetics.

A polymer having a structural unit based on a monomer having an SP value of 8.7 to 12 may be used alone or in combination of two or more.

Examples of the monomer having an SP value of 8.7 to 12 include compounds represented by the following general formulas (1) and (2), and at least one monomer selected from the group consisting of vinylpyrrolidone compounds.

(In the formula, R1 represents a hydrogen atom or a methyl group, and R2 represents an alkyl group having 5 or less carbon atoms.)

(In the formula, R3 represents a hydrogen atom or a methyl group, and R4 represents an alkyl group having 5 or less carbon atoms.)

Specific examples of the compound represented by the general formula (1) include methyl acrylate (<SP value> = 9.0), ethyl acrylate (<SP value> = 8.9), methyl methacrylate (<SP Value> = 9.3) or ethyl methacrylate (<SP value> = 8.7).

Specific examples of the compound represented by the general formula (2) include vinyl acetate (<SP value> = 9.0), vinyl propionate (<SP value> = 8.9), or vinyl butyrate (<SP value). > = 8.8).

Specific examples of vinyl pyrrolidone compounds include N-vinyl pyrrolidone (<SP value> = 11.1), N-vinyl piperidone (<SP value> = 10.6), and the like.

The SP value of monomers having an SP value of 8.7 to 12 is preferably 9 to 11. In this case, the transdermal absorbability of the active ingredient can be further enhanced. Examples of monomers having an SP value of 9 to 11 include methyl acrylate (<SP value> = 9.0), vinyl acetate (<SP value> = 9.0), and N-vinylpiperidone (<SP value> = 10). .6), methyl methacrylate (<SP value> = 9.3), dimethylaminoethyl methacrylate (<SP value> = 9.0), vinyl ethyl ketone (<SP value> = 9.4), vinylidene chloride (<SP value> = 9.9), allyl chloride (<SP value> = 10.4), allyl glycidyl ether (<SP value> = 10.0), vinyl propionate (<SP value> = 10.2) ), Vinyl butyrate (<SP value> = 10.0), N, N-dibutylacrylamide (<SP value> = 10.4), diethyl maleate (<SP value> = 10.6) or dioctyl maleate ( <SP value> = 9.4).

The monomer having an SP value of 8.7 to 12 may be a polymer having an aminoalkyl group. In addition, as a polymer which has an aminoalkyl group, the above-mentioned polymer can be used.

The amount of the polymer having a structural unit based on a monomer having an SP value of 8.7 to 12 is not particularly limited and can be set as appropriate. For example, the amount can be 0.1 to 10 parts by weight with respect to 1 part by weight of the core-shell structure (A). Preferably, the amount can be 0.2 to 5 parts by weight with respect to 1 part by weight of the core-shell structure (A), and more preferably 0.3 to 3 parts by weight with respect to 1 part by weight of the core-shell structure (A). Part.

As the pressure-sensitive adhesive composed of a polymer having a structural unit based on a monomer having an SP value of 8.7 to 12, for example, a commercially available product for use as a pharmaceutical additive can be suitably used. Examples of commercially available pharmaceutical additives include DURO-TAK 387-2287, DUROTAK 387-2510, or DURO-TAK 387-2516 (all manufactured by Henkel).

In addition, the preparation of the present invention may further contain a monomer other than the polymer having a structural unit based on a monomer having an SP value of 8.7 to 12. In that case, from the viewpoint of further increasing the percutaneous absorption amount of the active ingredient, the proportion of monomers having an SP value of 8.7 to 12 in the total monomers is preferably 5% by weight or more, more preferably 10% by weight or more, Preferably it is 20 weight% or more, Preferably it is 100 weight% or less, More preferably, it is 90% or less, More preferably, it is 75% or less.

1.2.4. Other Base Components The preparation of the present invention further contains other base components, and the base components are the core-shell structure (A) and (B) styrene elastomer, a polymer having an aminoalkyl group, and SP. It may contain a polymer having a constitutional unit based on a monomer having a value of 8.7 to 12.

Other base components are not particularly limited, and can be widely selected from those that can be used as external preparations, for example. Other base components include bases used for external preparations such as adhesives, ointments, lotions, creams, aerosols, plasters, tapes, patches, poultices, gels or microneedles. Components and the like.

Other base components can be appropriately selected from those suitable for dispersing the core-shell structure (A) according to the purpose of use, and are not particularly limited.

Also, multiple types of base components may be used in combination.

Other base components are not particularly limited, but include, for example, vegetable oils, animal oils, neutral lipids, synthetic fats and oils, sterol derivatives, waxes, hydrocarbons, monoalcohol carboxylic acid esters, oxyacid esters, polyvalent acids. Examples include alcohol fatty acid esters, silicones, alcohols such as higher alcohols and polyhydric alcohols, higher fatty acids, or fluorine-based oils.

Examples of vegetable oils include, but are not limited to, soybean oil, sesame oil, olive oil, palm oil, palm oil, rice bran oil, cottonseed oil, sunflower oil, rice bran oil, cacao butter, corn oil, bean flower oil or rapeseed oil. .

Animal oil is not particularly limited, and examples thereof include mink oil, turtle oil, fish oil, cow oil, horse oil, pork oil, and salmon squalane.

The neutral lipid is not particularly limited, and examples thereof include triolein, trilinolein, trimyristin, tristearin, and triarachidonin.

Synthetic fats and oils are not particularly limited, and examples thereof include phospholipids and azone.

The sterol derivative is not particularly limited, and examples thereof include dihydrocholesterol, lanosterol, dihydrolanosterol, phytosterol, cholic acid, and cholesteryl linoleate.

Examples of waxes include candelilla wax, carnauba wax, rice wax, wood wax, beeswax, montan wax, ozokerite, ceresin, paraffin wax, microcrystalline wax, petrolatum, Fischer-Tropsch wax, polyethylene wax or ethylene / propylene copolymer. Can be mentioned.

Examples of hydrocarbons 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. It is done.

Examples of monoalcohol carboxylates include octyldodecyl myristate, hexyldecyl myristate, octyldodecyl isostearate, cetyl palmitate, octyldodecyl palmitate, cetyl octoate, hexyldecyl octoate, isotridecyl isononanoate, isononanoyl isononanoate, Octonyl isononanoate, isodecyl isononanoate, isodecyl neopentanoate, isotridecyl neopentanoate, isostearyl neopentanoate, octyldodecyl neodecanoate, oleyl oleate, octyldodecyl oleate, octyldodecyl ricinoleate, octyldodecyl dimethyloctanoate, hexyldecyl dimethyloctanoate Octyldodecyl erucate, isostearic acid hydrogenated castor oil, ethyl oleate, Bocado oil fatty acid ethyl, isopropyl myristate, isopropyl palmitate, octyl palmitate, isopropyl isostearate, lanolin fatty acid isopropyl, diethyl sebacate, diisopropyl sebacate, dioctyl sebacate, diisopropyl adipate, dibutyloctyl sebacate, diisobutyl adipate, Examples include dioctyl succinate or triethyl citrate.

Examples of oxyacid esters include cetyl lactate, diisostearyl malate, or monoisostearic acid hydrogenated castor oil.

Polyhydric alcohol fatty acid esters include glyceryl trioctanoate, glyceryl trioleate, glyceryl triisostearate, glyceryl diisostearate, glyceryl tri (caprylic acid / capric acid), tri (caprylic acid / capric acid / myristic acid / stearic acid) ) Glyceryl, hydrogenated rosin triglyceride (hydrogenated ester gum), rosin triglyceride (ester gum), glyceryl behenate, trimethylolpropane trioctanoate, trimethylolpropane triisostearate, neopentylglycol dioctanoate, neopentyl glycol dicaprate Pentyl glycol, 2-butyl-2-ethyl-1,3-propanediol dioctanoate, propylene glycol dioleate, pentaerythrate tetraoctanoate Lithyl, hydrogenated rosin pentaerythrityl, triethylhexanoic acid ditrimethylolpropane, (isostearic acid / sebacic acid) ditrimethylolpropane, diethyl sebacate, triethylhexanoic acid pentaerythrityl, (hydroxystearic acid / stearic acid / rosin acid) dipentaerythrityl Diglyceryl diisostearate, polyglyceryl tetraisostearate, polyglyceryl-10 nonaisostearate, deca (erucic acid / isostearic acid / ricinoleic acid) polyglyceryl-8, (hexyldecanoic acid / sebacic acid) diglyceryl oligoester, glycol distearate (distearic acid) Acid ethylene glycol), dineopentanoic acid 3-methyl-1,5-pentanediol or dineopentanoic acid 2,4-di Chill-1,5-pentanediol.

Silicones include dimethicone (dimethylpolysiloxane), highly polymerized dimethicone (highly polymerized dimethylpolysiloxane), cyclomethicone (cyclic dimethylsiloxane, decamethylcyclopentasiloxane), phenyltrimethicone, diphenyldimethicone, phenyldimethicone, stearoxypropyl. Polyether modification such as dimethylamine, (aminoethylaminopropylmethicone / dimethicone) copolymer, dimethiconol, dimethiconol crosspolymer, silicone resin, silicone rubber, amino-modified silicone such as aminopropyldimethicone or amodimethicone, cation-modified silicone, dimethicone copolyol Silicone, polyglycerin modified silicone, sugar modified silicone, carboxylic acid modified silicone, phosphoric acid modified silicone , Sulfuric acid modified silicone, alkyl modified silicone, fatty acid modified silicone, alkyl ether modified silicone, amino acid modified silicone, peptide modified silicone, fluorine modified silicone, cationic modified or polyether modified silicone, amino modified or polyether modified silicone, alkyl modified or poly Examples thereof include ether-modified silicone or polysiloxane / oxyalkylene copolymer.

Examples of alcohols include glycerin, ethylene glycol, cetanol, myristyl alcohol, oleyl alcohol, lauryl alcohol, cetostearyl alcohol, stearyl alcohol, aralkyl alcohol, behenyl alcohol, jojoba alcohol, chimyl alcohol, seraalkyl alcohol, batyl alcohol, hexyl decanol, Examples include isostearyl alcohol, 2-octyldodecanol, and dimer diol.

Higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, undecylenic acid, 12-hydroxystearic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, erucic acid, docosahexaenoic acid Eicosapentaenoic acid, isohexadecanoic acid, anteisohenicosanoic acid, long-chain branched fatty acid, dimer acid or hydrogenated dimer acid.

Fluorine-based oils include perfluorodecane, perfluorooctane, perfluoropolyether, and the like.

1.3. Solution and Gelling Agent A solution may be added to the preparation of the present invention. The plasticity is further improved by adding the liquid agent. When added to the base, a component present in a liquid state at room temperature (for example, within a range of 15 ° C. to 35 ° C.) before being added to the base is referred to as a liquid.

The liquid agent is not particularly limited. For example, hydrocarbons (liquid paraffin, heavy liquid isoparaffin, light liquid isoparaffin, α-olefin oligomer, squalane, olive-derived squalane, squalene, etc.), alcohol carboxylates (myristin) Isopropyl acid, isopropyl palmitate, isopropyl isostearate, isononyl isononanoate, isotridecyl isononanoate, diethyl sebacate, etc.), polyhydric alcohol fatty acid esters (glyceryl tri (caprylate / caprate)), glyceryl trioctanoate, neopentyl dioctanoate Glycol), or oxyesters (monoisostearic acid hydrogenated castor oil, etc.). Preferred examples include liquid paraffin, isopropyl myristate, isononyl isononanoate, isotridecyl isononanoate, and diethyl sebacate. These liquid agents may be used alone or in combination.

The content of the above liquid agent can be appropriately set according to the type of preparation. Preferably, it is 50 to 80% by weight, more preferably 10 to 60% by weight.

The liquid agent is preferably gelled. In that case, the particle shape can be further stabilized, and the stability of the preparation can be further enhanced.

Gelation refers to the formation of a three-dimensional network structure by partially cross-linking molecules in a liquid containing or containing a low molecule or polymer. Gelation may be performed by physical crosslinking or chemical crosslinking, but in order to further enhance the transdermal absorbability of the active ingredient, the crosslinking is strong and semi-permanent chemical crosslinking. It is preferable to carry out by physical cross-linking, in which the cross-linking is reversible.

The method of physical cross-linking is not particularly limited, and a method of cross-linking by adding a gelling agent and causing hydrogen bonds to molecules in the liquid, heating the liquid containing the molecules, and hydrophobic interaction of the molecules Examples include a method of cross-linking by causing hydrophobic aggregation due to the above, or a microcrystalline cross-linking. Preferred is physical crosslinking with a gelling agent or physical crosslinking by heating or the like, and more preferred is physical crosslinking with a gelling agent. A plurality of physical crosslinking methods may be combined. On the other hand, examples of the chemical crosslinking method include a polycondensation method and a radical polymerization method.

The gelling agent is not particularly limited as long as the base or liquid can be gelled, and examples thereof include one or more fatty acids and one polysaccharide ester. As the fatty acid, a fatty acid having preferably 5 to 26 carbon atoms, more preferably a fatty acid having 6 to 18 carbon atoms can be used. Examples of the polysaccharide include dextrin, inulin, or sucrose. Examples of polysaccharide esters include dextrin palmitate, dextrin palmitate / hexanoate, dextrin myristate, or inulin stearate. These esters may be used alone or in combination.

The content of the gelling agent with respect to the base when the base is 100% by weight is preferably 0.1 to 10% by weight, more preferably 0.2 to 8% by weight. Further, the content of the gelling agent with respect to the liquid agent when the liquid agent is 100% by weight is preferably 1 to 30% by weight, more preferably 2 to 20% by weight, and further preferably 2.5 to 10% by weight. .

1.4. Other additive components The preparation of the present invention may contain other additive components depending on the dosage form, purpose of use, and the like.

Further, the preparation of the present invention further contains, as an adhesive, (B) a styrene-based elastomer, a polymer having an aminoalkyl group, and a polymer not having a constitutional unit based on a monomer having an SP value of 8.7 to 12 In that case, from the viewpoint of further increasing the percutaneous absorption amount of the active ingredient, (B) a styrene-based elastomer, a polymer having an aminoalkyl group, and an SP value of 8.7 to 12 in the entire pressure-sensitive adhesive The proportion of at least one selected from the group consisting of polymers having structural units based on the monomers is preferably 10% by weight or more, more preferably 20% by weight or more, and even more preferably 25% by weight or more. .

Additive components are not particularly limited, but include excipients, colorants, lubricants, binders, emulsifiers, thickeners, wetting agents, stabilizers, preservatives, solvents, solubilizers, suspending agents, Examples include a buffer, a pH adjuster, a tackifier, an antioxidant, a transdermal absorption enhancer, an irritation relaxation agent, a preservative, a chelating agent, or a dispersant.

2. Characteristics of the preparation of the present invention Although the preparation of the present invention is not particularly limited, the water content is preferably 20% by weight or less, more preferably 5% by weight or less from the viewpoint of further increasing the percutaneous absorption of the active ingredient. More preferably, it is 1% by weight or less.

3. Production method of the preparation of the present invention The external preparation of the present invention is not particularly limited, but can be produced, for example, as follows.

First, although not particularly limited, the core-shell structure (A) of the present invention can be produced, for example, as follows. The drug and, if desired, additive components such as a stabilizer, a transdermal absorption enhancer, or a skin irritation reducing agent are dissolved in a solvent such as pure water or phosphate buffer. To this, a solution in which an additional component such as a surfactant and, if desired, a skin irritation reducing agent, an analgesic agent, a percutaneous absorption enhancer or a stabilizer is dissolved in a solvent such as cyclohexane, hexane or toluene is added, and the mixture is agitated. . Thereafter, the core-shell structure (A) of the present invention can be prepared by lyophilization.

Using the core-shell structure (A), for example, an external preparation can be produced by a solution coating method. In the solution coating method, the core-shell structure (A) and (B) of the present invention is selected from the group consisting of a styrene-based elastomer, a polymer having an aminoalkyl group, and a polymer having a structural unit based on a monomer having an SP value of 8.7-12. In addition to at least one selected, hexane, toluene, and other base components, tackifiers, percutaneous absorption promoters, thickeners, gelling agents, and other additive components as required. Alternatively, it is added to a solvent such as ethyl acetate and stirred to prepare a uniform solution. The solid content concentration in the solution is preferably 10 to 80% by weight, more preferably 20 to 60% by weight.

Next, the above solution containing each component is uniformly applied on a release liner (silicone-treated polyester film, etc.) using a coating machine such as a knife coater, comma coater, or reverse coater, and dried. A drug-containing layer is completed, and a support is laminated on the drug-containing layer layer. Thereby, a transdermally absorbable preparation can be obtained. Depending on the type of the support, after the layer is formed on the support, a release liner may be laminated on the surface of the layer.

As another method, for example, the core-shell structure (A) and (B) a styrene elastomer, a polymer having an aminoalkyl group, and a polymer having a structural unit based on a monomer having an SP value of 8.7 to 12 are used. Add at least one selected from the group to other base components and additional components such as a percutaneous absorption enhancer, stabilizer, thickener or gelling agent, if necessary, and mix according to use. , Natural fabric members such as gauze or absorbent cotton, synthetic fiber fabric members such as polyester or polyethylene, or a combination of these appropriately processed into a woven fabric or nonwoven fabric, or laminated or impregnated on a permeable membrane, etc. It can also be used by covering it with an adhesive cover material or the like.

The percutaneous absorption-type preparation thus obtained is appropriately cut into a shape such as an ellipse, a circle, a square, or a rectangle according to the intended use. Moreover, you may provide an adhesive phase etc. in the periphery as needed.

4). Uses of the Formulation of the Present Invention The formulation of the present invention is not particularly limited, but is usually sustained for 1 day to 1 week, and in a preferred embodiment, it is used so as to be applied once a day to 1 week.

¡Uses vary depending on the type of active ingredient.

The preparation of the present invention is not particularly limited, and can be used as, for example, a patch having an adhesive layer containing the preparation of the present invention.

In this case, in addition to the preparation of the present invention, the adhesive layer further includes an excipient, a colorant, a lubricant, a binder, an emulsifier, a thickener, a wetting agent, a stabilizer, a preservative, a solvent, and a dissolution agent. Add adjuvants, suspending agents, buffering agents, pH adjusters, gelling agents, tackifiers, antioxidants, percutaneous absorption accelerators, stimulant relaxation agents, preservatives, chelating agents or dispersing agents. Can do.

Hereinafter, the present invention will be described in detail by way of examples and test examples, but the present invention is not limited to these examples.

Example 1
Donepezil hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd., molecular weight 416, water octanol partition coefficient 4.3) 0.2 g was dissolved in 40 g of pure water, and sucrose erucic acid ester (Mitsubishi Chemical Foods Co., Ltd., trade name) “ER-290”; HLB value 2) A solution of 3.0 g in 80 g of cyclohexane was added and stirred with a homogenizer (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). The number of particles obtained by dispersing the obtained particles in olive squalane (manufactured by Nikko Chemicals) and calculating by a dynamic light scattering method using a dynamic light scattering apparatus (product name “Zetasizer-Nano S” manufactured by Spectris Co., Ltd.) The average particle size was 4 nm. 20 parts by weight of styrene-isoprene-styrene block copolymer (SIS, trade name “Quintac 3520”, styrene content: 15%, diblock amount: 78%) manufactured by Nippon Zeon Co., Ltd. are added to 30 parts by weight of the obtained particles. , 10 parts by weight of an alicyclic saturated hydrocarbon resin (trade name “Arcon P100” manufactured by Arakawa Chemical Co., Ltd.) and 40 parts by weight of liquid paraffin (manufactured by Wako Pure Chemical Industries, Ltd., density 0.800 to 0.835 g / mL). After mixing, cyclohexane was added so that the solid content was 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 substrate made of a polyethylene terephthalate film having a thickness of 38 μm. The adhesive layer solution was applied to the release treatment surface of the release sheet, and dried at 60 ° C. for 30 minutes to produce a laminate in which the adhesive layer was formed on the release treatment 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 adhesive layer composition in the adhesive layer is shown in Table 1.

(Example 2)
Styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, to 30 parts by weight of particles (core-shell structure) containing an active ingredient and a surfactant (Diblock amount: 78%) A patch was produced in the same manner as in Example 1 except that 30 parts by weight, 10 parts by weight of an alicyclic saturated hydrocarbon resin, and 30 parts by weight of liquid paraffin were blended. The adhesive layer composition in the adhesive layer is shown in Table 1.

(Example 3)
Similar to Example 1 except that sucrose laurate (trade name “L-195”; HLB value 1 manufactured by Mitsubishi Chemical Foods Co., Ltd.) was used instead of sucrose erucate used in Example 1. Thus, a patch was prepared. In addition, after dispersing particles (core-shell structure) containing active ingredients and surfactants in olive squalane (manufactured by Nikko Chemicals), a dynamic light scattering device (Spectris Co., Ltd., product name “Zetasizer-Nano S”) is used. The number average particle diameter calculated by the dynamic light scattering method was 220 nm.

Example 4
A patch was prepared in the same manner as in Example 3 except that the amount of donepezil hydrochloride in Example 3 was 0.1 g. In addition, after dispersing particles (core-shell structure) containing active ingredients and surfactants in olive squalane (manufactured by Nikko Chemicals), a dynamic light scattering device (Spectris Co., Ltd., product name “Zetasizer-Nano S”) is used. The number average particle size calculated by the dynamic light scattering method was 3 nm.

(Example 5)
Instead of donepezil hydrochloride used in Example 1, vardenafil hydrochloride trihydrate (manufactured by Atomax Chemicals, molecular weight 579, water octanol partition coefficient 3.2) was used in the same manner as in Example 1. A patch was prepared. In addition, after dispersing particles (core-shell structure) containing active ingredients and surfactants in olive squalane (manufactured by Nikko Chemicals), a dynamic light scattering device (Spectris Co., Ltd., product name “Zetasizer-Nano S”) is used. The number average particle diameter calculated by the dynamic light scattering method was 9 nm.

(Example 6)
Styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, to 30 parts by weight of particles (core-shell structure) containing an active ingredient and a surfactant (Diblock amount: 78%) A patch was produced in the same manner as in Example 1 except that 28 parts by weight, 21 parts by weight of an alicyclic saturated hydrocarbon resin, and 21 parts by weight of liquid paraffin were blended. The adhesive layer composition in the adhesive layer is shown in Table 1.

(Example 7)
Styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3280”, styrene content: 25%, to 30 parts by weight of particles (core-shell structure) containing an active ingredient and a surfactant (Diblock amount: 17%) A patch was produced in the same manner as in Example 1 except that 28 parts by weight, 21 parts by weight of an alicyclic saturated hydrocarbon resin, and 21 parts by weight of liquid paraffin were blended. The adhesive layer composition in the adhesive layer is shown in Table 1.

(Example 8)
Styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, to 30 parts by weight of particles (core-shell structure) containing an active ingredient and a surfactant (Diblock amount: 78%) A patch was produced in the same manner as in Example 1 except that 24.5 parts by weight, 24.5 parts by weight of an alicyclic saturated hydrocarbon resin, and 21 parts by weight of liquid paraffin were blended. . The adhesive layer composition in the adhesive layer is shown in Table 1.

Example 9
Styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, amount of styrene: 15%, 30 parts by weight of particles containing an active ingredient and a surfactant (core-shell structure) A patch was produced in the same manner as in Example 1 except that 19.0 parts by weight, 30 parts by weight of an alicyclic saturated hydrocarbon resin, and 21 parts by weight of liquid paraffin were blended. The adhesive layer composition in the adhesive layer is shown in Table 1.

(Example 10)
Styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, to 30 parts by weight of particles (core-shell structure) containing an active ingredient and a surfactant (Diblock amount: 78%) A patch was produced in the same manner as in Example 1 except that 16.0 parts by weight and 54 parts by weight of liquid paraffin were blended. The adhesive layer composition in the adhesive layer is shown in Table 1.

(Example 11)
Styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, in 40 parts by weight of particles (core shell structure) containing an active ingredient and a surfactant (Diblock amount: 78%) A patch was produced in the same manner as in Example 1 except that 24.0 parts by weight, 18 parts by weight of an alicyclic saturated hydrocarbon resin, and 18 parts by weight of liquid paraffin were blended. The adhesive layer composition in the adhesive layer is shown in Table 1.

Example 12
Styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, in 45 parts by weight of particles (core-shell structure) containing an active ingredient and a surfactant (Diblock amount: 78%) A patch was produced in the same manner as in Example 1 except that 22 parts by weight, 16.5 parts by weight of an alicyclic saturated hydrocarbon resin, and 16.5 parts by weight of liquid paraffin were blended. . The adhesive layer composition in the adhesive layer is shown in Table 1.

(Example 13)
Styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, to 30 parts by weight of particles (core-shell structure) containing an active ingredient and a surfactant (Diblock amount: 78%) A patch was produced in the same manner as in Example 1 except that 18 parts by weight, 32 parts by weight of an alicyclic saturated hydrocarbon resin, and 20 parts by weight of liquid paraffin were blended. The adhesive layer composition in the adhesive layer is shown in Table 1.

(Example 14)
(Preparation of acrylic adhesive A)
Acrylic adhesive A was prepared as follows. A reaction comprising 150 parts by weight of ethyl acrylate (<SP value> = 8.9) and 50 parts by weight of N-vinylpyrrolidone (<SP value> = 11.1), and 200 parts by weight of ethyl acetate After supplying the liquid to the separable flask, the inside of the separable flask was set to a nitrogen atmosphere at 80 ° C. Then, the monomer is polymerized while adding a polymerization initiator solution in which 1 part by weight of benzoyl peroxide is dissolved in 100 parts by weight of ethyl acetate to this reaction liquid over 27 hours. Ethyl acetate was added to obtain an acrylic adhesive solution A having an acrylic adhesive A content of 25% by weight.

After mixing 70 parts by weight of acrylic pressure-sensitive adhesive A with 30 parts by weight of particles (core shell structure) containing an active ingredient and a surfactant, ethyl acetate is added so that the solid content is 30% by weight. A patch was produced in the same manner as in Example 1 except that the adhesive layer solution was adjusted by mixing until uniform. The adhesive layer composition in the adhesive layer is shown in Table 2.

(Example 15)
Preparation of acrylic adhesive B;
Acrylic adhesive B was prepared as follows. A monomer comprising 60 parts by weight of 2-ethylhexyl acrylate (<SP value> = 8.5) and 40 parts by weight of vinyl acetate (<SP value> = 9.0), and 50 parts by weight of ethyl acetate The reaction solution was supplied to a 40 liter polymerization machine. Thereafter, the inside of the polymerization machine was set to a nitrogen atmosphere at 80 ° C. Then, the monomer was copolymerized while adding a polymerization initiator solution prepared by dissolving 0.5 part by weight of benzoyl peroxide in 50 parts by weight of cyclohexane to the reaction liquid over 24 hours. After the completion of the polymerization, ethyl acetate was further added to the reaction solution to obtain an acrylic pressure-sensitive adhesive solution B having a content of 51% by weight of the acrylic pressure-sensitive adhesive B made of a copolymer.

After adding 70 parts by weight of acrylic adhesive B to 30 parts by weight of particles (core-shell structure) containing active ingredients and surfactants, and adding ethyl acetate so that the solid content is 30% by weight A patch was produced in the same manner as in Example 1 except that the adhesive layer solution was adjusted by mixing until uniform. The adhesive layer composition in the adhesive layer is shown in Table 2.

(Example 16)
Preparation of acrylic adhesive C;
Acrylic adhesive C was prepared in the following manner. A reaction liquid comprising 60 parts by weight of 2-ethylhexyl acrylate and 5 parts by weight of methyl acrylate (<SP value> = 9.0) and 50 parts by weight of ethyl acetate was put into a 40 liter polymerization machine. Supplied. Thereafter, the inside of the polymerization machine was set to a nitrogen atmosphere at 80 ° C. Then, the monomer was copolymerized while adding a polymerization initiator solution prepared by dissolving 0.5 part by weight of benzoyl peroxide in 50 parts by weight of cyclohexane to the reaction liquid over 24 hours. After completion of the polymerization, ethyl acetate was further added to the reaction solution to obtain an acrylic pressure-sensitive adhesive solution C in which the content of the acrylic pressure-sensitive adhesive C made of a copolymer was 40% by weight.

After adding 70 parts by weight of acrylic pressure-sensitive adhesive C to 30 parts by weight of particles (core shell structure) containing an active ingredient and a surfactant, ethyl acetate was added so that the solid content was 30% by weight. A patch was produced in the same manner as in Example 1 except that the adhesive layer solution was prepared by mixing until uniform. The adhesive layer composition in the adhesive layer is shown in Table 2.

(Example 17)
Styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, to 20 parts by weight of particles (core shell structure) containing an active ingredient and a surfactant (Diblock amount: 78%) A patch was produced in the same manner as in Example 1 except that 32.0 parts by weight, 24 parts by weight of an alicyclic saturated hydrocarbon resin, and 24 parts by weight of liquid paraffin were blended. The adhesive layer composition in the adhesive layer is shown in Table 3.

Production Example: Preparation of Gelled Liquid Paraffin A gelled liquid paraffin component was prepared by the following method.
92.5 parts by weight of liquid paraffin (manufactured by Wako Pure Chemical Industries, Ltd., density 0.800 to 0.835 g / mL) and 7.5 parts by weight of dextrin palmitate (manufactured by Chiba Flour Mills, trade name “Leopard KL2”) did. 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 18)
Except that the amount of donepezil hydrochloride was changed to 1.3 parts by weight, 20 parts by weight of particles (core-shell structure) obtained in the same manner as in Example 1, styrene-isoprene-styrene block copolymer (SIS, Japan) Zeon Corporation, trade name “Quintac 3520”, styrene content: 15%, diblock content: 78%) 32 parts by weight, alicyclic saturated hydrocarbon resin 24 parts by weight, and gelled liquid paraffin prepared in the above example 24 weights A patch was produced in the same manner as in Example 1 except that the parts were blended. The adhesive layer composition in the adhesive layer is shown in Table 3.

(Example 19)
Except that the amount of donepezil hydrochloride was changed to 1.3 parts by weight, 20 parts by weight of particles (core-shell structure) obtained in the same manner as in Example 1, styrene-isoprene-styrene block copolymer (SIS, Japan) Product name “Quintac 3520” manufactured by Zeon, 24 parts by weight of styrene content: 15%, diblock content: 78%, aminoalkyl methacrylate copolymer (Eudragid, manufactured by Evonik Japan Co., Ltd., product name “EUDRAGIT E100”) 8 weight Parts (a ratio of the mass of the elastomer to the sum of the masses of the elastomer and the polymer having an aminoalkyl group of 0.75), 18 parts by weight of the alicyclic saturated hydrocarbon resin, 18 parts by weight of the gelled liquid paraffin prepared in the above-mentioned examples, 6 parts by weight of diethyl sebacate (manufactured by Wako Pure Chemical Industries) and glycerin (Wako Pure Chemical Industries) A patch was produced in the same manner as in Example 1 except that 6 parts by weight of (trade company) was blended. The adhesive layer composition in the adhesive layer is shown in Table 3.

(Example 20)
Styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, diblock content: 78%) 21.4 parts by weight, aminoalkyl methacrylate copolymer (Eudragid, 10.6 parts by weight (trade name “EUDRAGIT E100” manufactured by Evonik Japan Co., Ltd.) (ratio of mass of elastomer to sum of mass of elastomer and polymer having aminoalkyl group: 0.67), alicyclic saturated hydrocarbon resin 16 Other than blending 16 parts by weight of gelled liquid paraffin prepared in the above examples, 8 parts by weight of diethyl sebacate (manufactured by Wako Pure Chemical Industries), and 8 parts by weight of glycerin (manufactured by Wako Pure Chemical Industries) Produced a patch in the same manner as in Example 19. The adhesive layer composition in the adhesive layer is shown in Table 3.

(Example 21)
Styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, diblock content: 78%) 16 parts by weight, aminoalkyl methacrylate copolymer (Eudragid, Evonik 16 parts by weight (trade name “EUDRAGIT E100” manufactured by Japan) (ratio of mass of elastomer to sum of mass of elastomer and polymer having aminoalkyl group: 0.50), 12 parts by weight of alicyclic saturated hydrocarbon resin, Except for blending 12 parts by weight of gelled liquid paraffin prepared in Examples, 12 parts by weight of diethyl sebacate (manufactured by Wako Pure Chemical Industries), and 12 parts by weight of glycerin (manufactured by Wako Pure Chemical Industries) A patch was produced in the same manner as in Example 19. The adhesive layer composition in the adhesive layer is shown in Table 3.

(Example 22)
Styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, diblock amount: 78%) 10.6 parts by weight, aminoalkyl methacrylate copolymer (eudragit) , Made by Evonik Japan Co., Ltd., trade name “EUDRAGIT E100”) 21.4 parts by weight (ratio of mass of elastomer to sum of mass of elastomer and polymer having aminoalkyl group: 0.33), alicyclic saturated hydrocarbon resin 8 parts by weight, 8 parts by weight of the gelled liquid paraffin prepared in the above example, 16 parts by weight of diethyl sebacate (manufactured by Wako Pure Chemical Industries), and 16 parts by weight of glycerin (manufactured by Wako Pure Chemical Industries) A patch was produced in the same manner as in Example 19 except for the above. The adhesive layer composition in the adhesive layer is shown in Table 3.

(Example 23)
Styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, diblock amount: 78%), 8 parts by weight, aminoalkyl methacrylate copolymer (Eudragid, Evonik) -Japan Co., Ltd., trade name "EUDRAGIT E100") 24 parts by weight (ratio of mass of elastomer to sum of mass of elastomer and polymer having aminoalkyl group: 0.25), 6 parts by weight of alicyclic saturated hydrocarbon resin, Except for blending 6 parts by weight of gelled liquid paraffin prepared in the above example, 18 parts by weight of diethyl sebacate (Wako Pure Chemical Industries), and 18 parts by weight of glycerin (Wako Pure Chemical Industries) A patch was produced in the same manner as in Example 19. The adhesive layer composition in the adhesive layer is shown in Table 3.

(Example 24)
20 parts by weight of particles (core shell structure) obtained in the same manner as in Example 1 except that the amount of donepezil hydrochloride was 1.3 parts by weight, aminoalkyl methacrylate copolymer (Eudragid, manufactured by Evonik Japan Co., Ltd., product) Name “EUDRAGIT E100”, monomer composition ratio; methyl methacrylate (<SP value> = 9.3): butyl methacrylate (<SP value> = 8.8): dimethylaminoethyl methacrylate (<SP value> = 9.0) = 1: 1: 2) Except for blending 32 parts by weight, diethyl sebacate (made by Wako Pure Chemical Industries) 24 parts by weight, and glycerin (made by Wako Pure Chemical Industries) 24 parts by weight, A patch was produced in the same manner as in Example 1. The pressure-sensitive adhesive layer composition and the pressure-sensitive adhesive layer thickness in the pressure-sensitive adhesive layer are shown in Table 3.

(Example 25)
A patch was produced in the same manner as in Example 21 except that isononyl isononanoate was used in place of the gelled liquid paraffin (the ratio of the mass of the elastomer to the sum of the mass of the elastomer and the polymer having an aminoalkyl group was 0). .50). The adhesive layer composition in the adhesive layer is shown in Table 3.

(Example 26)
A patch was produced in the same manner as in Example 21, except that isononyl isononanoate was gelled in the same manner as in the preparation of the gelled liquid paraffin except that isononyl isononanoate was used instead of liquid paraffin. (Ratio of the mass of the elastomer to the sum of the mass of the elastomer and the polymer having aminoalkyl groups is 0.50). The adhesive layer composition in the adhesive layer is shown in Table 3.

(Example 27)
A patch was produced in the same manner as in Example 21 except that isopropyl myristate was used in place of the gelled liquid paraffin (the ratio of the mass of the elastomer to the sum of the mass of the elastomer and the polymer having aminoalkyl groups was 0). .50). The adhesive layer composition in the adhesive layer is shown in Table 3.

(Example 28)
A patch was produced in the same manner as in Example 21, except that isopropyl myristate was gelled in the same manner as in the preparation of the gelled liquid paraffin except that isopropyl myristate was used instead of liquid paraffin. (Ratio of the mass of the elastomer to the sum of the mass of the elastomer and the polymer having aminoalkyl groups is 0.50). The adhesive layer composition in the adhesive layer is shown in Table 3.

(Comparative Example 1)
Donepezil hydrochloride 1.9 parts by weight, styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520” styrene content: 15%, diblock amount: 78%), 20 parts by weight, Adhesive layer solution by blending 10 parts by weight of alicyclic saturated hydrocarbon resin and 40 parts by weight of liquid paraffin, adding cyclohexane so that the solid content is 30% by weight, and mixing until uniform. Was prepared. Thereafter, a patch was produced in the same manner as in Example 1. The adhesive layer composition in the adhesive layer is shown in Table 4.

(Comparative Example 2)
Preparation of acrylic adhesive D;
The acrylic pressure-sensitive adhesive D was prepared as follows. 13 parts by weight of dodecyl methacrylate (<SP value> = 8.3), 78 parts by weight of 2-ethylhexyl methacrylate (<SP value> = 8.4) and 9 parts by weight of 2-ethylhexyl acrylate (<SP value> = 8.5) The monomer-containing monomer and 50 parts by weight of ethyl acetate were fed to a 40 liter polymerization machine. Thereafter, the inside of the polymerization machine was set to a nitrogen atmosphere at 80 ° C. Then, the monomer was copolymerized while adding a polymerization initiator solution prepared by dissolving 0.5 part by weight of benzoyl peroxide in 50 parts by weight of cyclohexane to the reaction liquid over 24 hours. After the completion of the polymerization, ethyl acetate was further added to the reaction solution, and an acrylic pressure-sensitive adhesive solution D containing 35% by weight of an acrylic pressure-sensitive adhesive D made of a dodecyl methacrylate-2-ethylhexyl methacrylate-2-ethylhexyl acrylate copolymer. Got.

70 parts by weight of acrylic pressure-sensitive adhesive D was mixed with 30 parts by weight of the particles containing the active ingredient and the surfactant obtained in the same manner as in Example 1, and acetic acid was added so that the solid content would be 30% by weight. A patch was produced in the same manner as in Example 14 except that ethyl was added and mixed until uniform to prepare an adhesive layer solution. The adhesive layer composition in the adhesive layer is shown in Table 2.

(Comparative Example 3)
A patch was prepared in the same manner as in Comparative Example 1 except that vardenafil hydrochloride trihydrate was used instead of donepezil hydrochloride used in Comparative Example 1. The adhesive layer composition in the adhesive layer is shown in Table 4.

(Comparative Example 4)
A patch was produced in the same manner as in Comparative Example 2 except that particles containing an active ingredient and a surfactant obtained in the same manner as in Example 5 were used. The adhesive layer composition in the adhesive layer is shown in Table 2.

(Comparative Example 5)
Instead of particles, 1.3 parts by weight of donepezil hydrochloride was used, and a styrene-isoprene-styrene block copolymer (SIS, manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”, styrene content: 15%, diblock amount: 78%) Same as Example 18 except that 39.5 parts by weight, 29.6 parts by weight of alicyclic saturated hydrocarbon resin, and 29.6 parts by weight of gelled liquid paraffin prepared in the above example were blended. Thus, a patch was produced. The adhesive layer composition in the adhesive layer is shown in Table 4.

Test Example 1 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). A test piece having a diameter of 2 cm was cut out from the various patches prepared in Examples 1 to 28 and Comparative Examples 1 to 5 at the upper part of this apparatus, and the release sheet was peeled off. Then, the test piece was attached to the upper end of the skin by the adhesive layer. Affixed. In the lower receptor layer, in distilled water, NaH ₂ PO ₄ is 5 × 10 ⁻⁴ M, Na ₂ HPO ₄ is 2 × 10 ⁻⁴ M, NaCl is 1.5 × 10 ⁻⁴ M, and gentamicin sulfate ( A solution containing 10 ppm of G1658) manufactured by Wako Pure Chemical Industries, Ltd. was added with a buffer solution adjusted to pH 7.2 with NaOH, and the apparatus was installed in a thermostatic bath maintained at 32 ° C. from the start of the test. After starting the test, 1 ml of the liquid in the tank was collected from the lower receptor layer after a predetermined time, and immediately after that, 1 ml of the liquid having 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 each drug in the supernatant was quantified by high performance liquid chromatography (HPLC) (device: system controller; Shimadzu) Manufactured by Seisakusho Co., Ltd., product number “CBM-20A”, liquid feeding unit: manufactured by Shimadzu Corp., product number “LC-20AD”, column oven: manufactured by Shimadzu Corp., product number “CTO-20A”, detector: manufactured by Shimadzu Corp. Product number “SPD-20A”, detection wavelength: 271 nm, column used: Thermoscience, product number “Hypersi GOLD” 150 × 4.6 mm, 3 μm).

FIG. 2 is a graph showing the results of Examples 1 to 4 and Comparative Examples 1 and 2. FIG. 3 is a graph showing the results of Example 5 and Comparative Examples 3 and 4. FIG. 4 is a graph showing the results of Examples 14 to 16 and Comparative Examples 1 and 2. Tables 1 to 4 show the cumulative skin permeation amount after 48 hours (48 hour cumulative skin permeation amount).

2, 3, and 4, it was found that the 48-hour cumulative skin permeation amount of the patch of the example was significantly improved compared to the patch of the comparative example.

FIG. 5 is a diagram showing the relationship between the SIS ratio (%) with respect to the total mass of SIS and Eudragit, and the accumulated permeation amount.

Further, from the results of FIG. 5, the patch of the example has a 48-hour cumulative skin permeation amount when the SIS ratio (the ratio of SIS to the total mass of SIS and Eudragit (%)) is 20% or more and 90% or less. It was found that it was further improved.

Test Example 2 Particle Shape Stability Test The patches of Examples 1 to 13 and 17 to 28 were stored at room temperature for 7 days and 14 days, and then observed with an optical microscope.

In Examples 13 and 27, crystal precipitation was observed after 7 days, and in Examples 1 to 12, 17, 25, and 28, crystal precipitation was observed after 14 days. This is presumably because the active ingredient leaked out and precipitated due to the shape change of the particles. On the other hand, in Examples 18 to 24 and 26, no change such as crystal precipitation was observed even after 14 days, so that it was confirmed that the particle shape was more stable.

Criteria ◎… No crystal deposition after 14 days ○… Crystal deposition after 14 days △… Crystal deposition after 7 days

The results are shown in Tables 1 and 3 below.

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

Claims (14)

A core-shell structure comprising: an active ingredient-containing core part; and a shell part covering at least a part of the surface of the core part and containing a surfactant;
At least one selected from the group consisting of a styrene elastomer having a styrene content of 10 wt% to 50 wt%, a polymer having an aminoalkyl group, and a polymer having a structural unit based on a monomer having an SP value of 8.7 to 12 A kind of polymer,
A formulation comprising The preparation according to claim 1, which has an S / O type structure in which the core-shell structure is dispersed in an adhesive containing the polymer. The styrene elastomer is selected from the group consisting of styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), and styrene-ethylene-butylene-styrene block copolymer (SEBS). The preparation according to claim 1 or 2, which is at least one selected. The styrene elastomer is a styrene-isoprene-styrene block copolymer (SIS),
The content of the styrene-isoprene-styrene block copolymer (SIS) is in the range of 0.1 to 4 parts by weight with respect to 1 part by weight of the core-shell structure. Formulation. Further comprising a tackifying resin,
The preparation according to any one of claims 1 to 4, wherein the softening point of the tackifying resin is 60 ° C or higher and 150 ° C or lower. The preparation according to any one of claims 1 to 5, wherein the content of the tackifying resin with respect to 100 parts by weight of the styrene elastomer is in the range of 160 parts by weight or less. The preparation according to any one of claims 1 to 6, wherein the polymer having an aminoalkyl group is an aminoalkyl methacrylate copolymer. The monomer having an SP value of 8.7 to 12 is at least one monomer selected from the group consisting of compounds represented by the following general formulas (1) and (2) and vinylpyrrolidone compounds: 6. The preparation according to any one of 6.

(In the formula, R1 represents a hydrogen atom or a methyl group, and R2 represents an alkyl group having 5 or less carbon atoms)

(In the formula, R3 represents a hydrogen atom or a methyl group, and R4 represents an alkyl group having 5 or less carbon atoms) The preparation according to any one of claims 1 to 6 and 8, wherein the SP value of the monomer is 9 to 11. The preparation according to any one of claims 1 to 6, 8, and 9, wherein the polymer having a structural unit based on a monomer having an SP value of 8.7 to 12 is an aminoalkyl methacrylate copolymer. A core shell structure comprising an active ingredient, a core portion, and a shell portion covering at least a part of the surface of the core portion and containing a surfactant, and a styrene content of 10% by weight And at least one polymer selected from the group consisting of a styrene-based elastomer that is ˜50 wt%, a polymer having an aminoalkyl group, and a polymer having a structural unit based on a monomer having an SP value of 8.7-12 Has a layer,
The layer has a structural unit based on 0.2 to 5 parts by weight of the styrenic elastomer, a polymer having an aminoalkyl group, and a monomer having an SP value of 8.7 to 12 with respect to 1 part by weight of the core-shell structure. The preparation according to any one of claims 1 to 10, comprising at least one polymer selected from the group consisting of polymers having. The preparation according to any one of claims 1 to 11, further comprising a liquid agent. The preparation according to any one of claims 1 to 12, further comprising a gelling agent. The preparation according to claim 12 or 13, wherein the liquid is gelled.

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