JP7385614B2 - patch preparation - Google Patents

Description

The present invention relates to a patch preparation containing an active ingredient and comprising an adhesive layer.

BACKGROUND ART In recent years, development of patch preparations that allow active ingredients such as drugs to be absorbed transdermally has become more and more popular.

For example, Patent Document 1 listed below discloses an adhesive composition that includes a core-shell structure containing an active ingredient and a surfactant, and two types of elastomers. The core-shell structure includes a core portion containing an active ingredient and a shell portion covering at least a portion of the surface of the core portion and containing a surfactant. Patent Document 1 describes that a patch using such an adhesive composition can improve both transdermal absorption of the active ingredient and adhesive properties such as retention power. .

International Publication No. 2020/013241

However, even when using a patch as in Patent Document 1, when trying to improve transdermal absorption, the problem of peeling still occurs when it is applied to the skin.

An object of the present invention is to provide a patch preparation that can enhance transdermal absorption of active ingredients and is less likely to cause peeling problems when applied to the skin.

The adhesive preparation according to the present invention includes a base material, an adhesive layer provided on the main surface of the base material,
, the adhesive layer includes an active ingredient, a surfactant, an inorganic filler, and an adhesive, the surfactant has a hydrocarbon group having 7 or more and 15 or less carbon atoms, and the The surfactant contains at least one selected from the group consisting of sorbitan fatty acid ester, glycerin fatty acid ester, propylene glycol fatty acid ester, and fatty acid alkanolamide, and the content of the surfactant is such that the content of the surfactant is distributed throughout the adhesive layer. On the other hand, it is 35% by weight or less, and the ratio of the content of the inorganic filler to the content of the surfactant (content of inorganic filler/content of surfactant) is 0.15 or more.

In a particular aspect of the patch preparation according to the present invention, the adhesive layer includes a core portion containing the active ingredient and the surfactant, and covers at least a portion of the core portion. and a core-shell structure having a shell portion.

In another specific aspect of the adhesive preparation according to the present invention, the adhesive includes a first elastomer and a second elastomer different from the first elastomer.

In yet another specific aspect of the adhesive preparation according to the present invention, the inorganic filler is a hydrophobic filler.

In still another specific aspect of the adhesive preparation according to the present invention, the inorganic filler includes silica, titanium oxide, light anhydrous silicic acid, magnesium aluminate metasilicate, magnesium aluminum silicate, hydrated silicon dioxide, zinc oxide, and At least one member selected from the group consisting of silicon.

In yet another specific aspect of the adhesive preparation according to the present invention, the adhesive layer further contains a water-soluble polymer.

In yet another specific aspect of the adhesive preparation according to the present invention, the water-soluble polymer is at least one of polyvinylpyrrolidone and aminoalkyl methacrylate copolymer.

According to the present invention, it is possible to provide a patch preparation that can enhance transdermal absorption of an active ingredient and is less likely to cause peeling problems when applied to the skin.

FIG. 1 is a schematic cross-sectional view showing a patch preparation according to an embodiment of the present invention. FIG. 2 is a schematic cross-sectional view showing a modification of the patch preparation according to one embodiment of the present invention. FIG. 3 is a schematic cross-sectional view showing a core-shell structure according to an embodiment of the present invention.

The details of the present invention will be explained below.

FIG. 1 is a schematic cross-sectional view showing a patch preparation according to an embodiment of the present invention.

As shown in FIG. 1, the patch preparation 1 includes a base material 2 and an adhesive layer 3. The base material 2 has a first main surface 2a and a second main surface 2b facing each other. An adhesive layer 3 is laminated on the first main surface 2a of the base material 2. Further, a liner 4 is laminated on the main surface 3a of the adhesive layer 3 on the side opposite to the base material 2. Thus, in this embodiment, patch preparation 1 is a tape preparation.

In this embodiment, the adhesive layer 3 contains an active ingredient, a surfactant, an inorganic filler, and an adhesive. The surfactant has a hydrocarbon group having 7 or more and 15 or less carbon atoms. The surfactant contains at least one selected from the group consisting of sorbitan fatty acid ester, glycerin fatty acid ester, propylene glycol fatty acid ester, and fatty acid alkanolamide. The content of the surfactant is 35% by weight or less based on the entire pressure-sensitive adhesive layer 3. Further, the ratio of the inorganic filler content to the surfactant content (inorganic filler content/surfactant content) is 0.15 or more.

Since the adhesive preparation 1 of the present embodiment has the above-described configuration, it is possible to improve the percutaneous absorption of the active ingredient, and moreover, it is unlikely to cause peeling problems when applied to the skin.

Conventionally, even with patch preparations using adhesive layers containing active ingredients and surfactants, when trying to increase transdermal absorption, problems of peeling still occurred when applied to the skin. .

Regarding this point, as a result of intensive studies by the present inventors, we found that when the content of surfactant is increased in an attempt to increase transdermal absorption, adhesive properties such as retention strength tend to decrease, and as a result, the above-mentioned It has been found that such peeling problems are likely to occur.

The present inventors focused on the adhesive layer 3 constituting the patch preparation 1, made the adhesive layer 3 contain the above-mentioned specific surfactant in the above-mentioned specific content, and It has been found that by setting the ratio of the content of the inorganic filler to the above specific range, it is possible to increase the percutaneous absorption of the active ingredient, and also to prevent the problem of peeling off when applied to the skin. .

Note that, as in the above embodiment, the adhesive layer 3 may be laminated only on one main surface 2a of the base material 2, or may be laminated on both main surfaces 2a and 2b. good. Further, the liner 4 may not be provided as in the patch preparation 11 in the modified example shown in FIG. However, by providing the liner 4, the adhesive layer 3 can be more reliably protected until the patch preparation 11 is applied to the skin, so it is preferable to provide the liner 4. The liner 4 is preferably one that can be easily peeled off.

The patch preparation of the present invention is preferably a tape preparation (reservoir type, matrix type, etc.) such as a plaster or plaster as in the above embodiment. However, the adhesive preparation of the present invention may be, for example, a poultice, a patch, or a microneedle, and is not particularly limited.

The patch preparation of the present invention can be appropriately cut into, for example, an oval, circular, square, or rectangular shape depending on the intended use.

Hereinafter, each member constituting the patch preparation of the present invention will be explained in detail.

[Base material]
The base material is not particularly limited as long as it supports the adhesive layer, and examples thereof include resin films, fibers, nonwoven fabrics, and the like. Examples of the resin film include films of polyester, polyolefin, and the like. The resin film is preferably a polyester film. Examples of the polyester include polyethylene terephthalate and polybutylene phthalate, with polyethylene terephthalate being preferred.

The thickness of the base material is not particularly limited, and can be, for example, 20 μm or more and 100 μm or less.

[Adhesive layer]
The adhesive layer contains an active ingredient, a surfactant, an inorganic filler, and an adhesive. Further, the adhesive layer may contain the active ingredient and the surfactant in the form of a core-shell structure, which includes a core part containing the active ingredient and a shell part containing the surfactant. In this case, the percutaneous absorption of the active ingredient can be further enhanced. Moreover, the adhesive layer may further contain a water-soluble polymer. In this case, even when moisture such as sweat is attached, the retention force can be maintained at a high level, and peeling of the patch preparation due to moisture such as sweat can be further suppressed. This is considered to be because the pressure-sensitive adhesive layer further contains a water-soluble polymer, thereby making it possible to further increase the sweat resistance.

(active ingredient)
Specific examples of active ingredients include, but are not limited to, anti-dementia drugs, anti-epileptic drugs, anti-depressants, anti-Parkinson's drugs, anti-allergic drugs, anti-cancer drugs, anti-diabetic drugs, antihypertensive drugs, drugs for respiratory diseases, Examples include ED treatment drugs, skin disease drugs, and local anesthetics. Note that one type of active ingredient may be used alone, or a plurality of types may be used in combination.

More specifically, memantine, donepezil, diphenhydramine, vardenafil, octreotide, rivastigmine, galantamine, nitroglycerin, lidocaine, fentanyl, male hormones, female hormones, nicotine, clomipramine, nalfurafine, metoprolol, fesoterodine, tandospirone, beraprost sodium, Taltirelin, lurasidone, nefazodone, rifaximin, benidipine, doxazosin, nicardipine, formoterol, lomerizine, amlodipine, teriparatide, bucladesine, cromoglycic acid, lixenatide, exenatide, liraglutide, lanreotide, glucagon, oxytocin, calcitonin, elcatonin, glatiramer, risedronic acid, clofenac , ascorbic acid, and pharmaceutically acceptable salts thereof.

The pharmaceutically acceptable salt is not particularly limited, and both acidic salts and basic salts can be employed. Examples of acid salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, tartrate, fumarate, maleate, malate. Examples include organic acid salts such as salts, citrates, methanesulfonates, benzenesulfonates or paratoluenesulfonates. Examples of basic salts include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts. Specific salts of active ingredients include, for example, memantine hydrochloride, donepezil hydrochloride, rivastigmine tartrate, galantamine hydrobromide, clomipramine hydrochloride, diphenhydramine hydrochloride, nalfurafine hydrochloride, metoprolol tartrate, fesoterodine fumarate. , vardenafil hydrochloride hydrate, nalfurafine hydrochloride, tandospirone citrate, beraprost sodium, lurasidone hydrochloride, nefazodone hydrochloride, benidipine hydrochloride, doxazosin mesylate, nicardipine hydrochloride, formoterol fumarate, lomerizine hydrochloride, or amlodipine besylate.

Preferably, the active ingredient is hydrophilic. When the active ingredient is a hydrophilic drug, a drug that requires systemic or local action is usually used.

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 exhibiting an octanol-water partition coefficient of -2 to 6. In this case, the skin permeability of the active ingredient is further improved. From the viewpoint of further improving the skin permeability of the active ingredient, the octanol-water partition coefficient is preferably -1 or more, and more preferably 0 or more. Further, the octanol-water partition coefficient of the active ingredient is preferably 4 or less, more preferably 1 or less. When the octanol-water partition coefficient of the active ingredient is below the above upper limit, the skin permeability of the active ingredient is further improved.

In the present invention, the octanol-water partition coefficient is determined from the concentration of the active ingredient in each phase after adding the active ingredient to a flask containing octanol and an aqueous buffer solution of pH 7, followed by shaking. Specifically, it can be calculated using the formula: octanol-water partition coefficient=Log ₁₀ (concentration in octanol phase/concentration in aqueous phase).

The amount of active ingredient contained in the adhesive layer depends on the type of active ingredient, but is preferably 0.5% by weight or more, more preferably 2.5% by weight or more, and preferably 50% by weight or more, based on the entire adhesive layer. It is not more than 30% by weight, more preferably not more than 30% by weight.

(surfactant)
The HLB value of the surfactant is not particularly limited, but is preferably 4 or more and 14 or less, more preferably 5 or more and 12 or less. When a plurality of surfactants are included, the weighted average value of the HLB values is preferably within the above range.

The HLB (abbreviation for Hydrophile Lypophile Balance) value is an indicator of whether the emulsifier is hydrophilic or lipophilic, and takes a value of 0 to 20. The smaller the HLB value, the stronger the lipophilicity.

The HLB value is calculated using the following Griffin formula.

HLB value = 20 x {(molecular weight of hydrophilic part)/(total molecular weight)}

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

When there are surfactants with HLB values A, B, and C, and the weight of each surfactant is x, y, and z, the formula for calculating the weighted average value is (xA+yB+zC)÷(x+y+z).

The surfactant preferably has at least one of a saturated hydrocarbon group such as an alkyl group and an unsaturated hydrocarbon group such as an alkenyl group and an alkynyl group. Among these, it is preferable that the hydrocarbon group of the surfactant contains a saturated hydrocarbon having 7 or more and 11 or less carbon atoms, or an unsaturated hydrocarbon having 7 or more and 11 or less carbon atoms.

When the surfactant contains a plurality of hydrocarbon groups, the hydrocarbon group contained in the surfactant in the highest proportion is the hydrocarbon group of the surfactant in the present invention.

In particular, when a surfactant contains multiple hydrocarbon groups with different numbers of carbon atoms, the number of carbon atoms of the hydrocarbon group that the surfactant contains in the largest proportion is determined as the number of carbon atoms of the hydrocarbon group of the surfactant. do.

For example, specifically, when the surfactant is a coconut oil fatty acid ester, the hydrocarbon group of the coconut oil fatty acid ester contains the largest number of saturated hydrocarbon groups having 11 carbon atoms in the surfactant. It is a hydrogen group, and the number of carbon atoms in the hydrocarbon group is 11.

The number of carbon atoms in the hydrocarbon group is 7 or more and 15 or less, preferably 7 or more and 11 or less, more preferably 7 or 9. When the number of carbon atoms in the hydrocarbon group is within the above range or a preferable number, the percutaneous absorption of the active ingredient can be further improved.

The molecular weight of the hydrophilic part of the surfactant is preferably 100 g/mol or more and 350 g/mol or less, more preferably 100 g/mol or more and 300 g/mol or less, and still more preferably 100 g/mol or more and 200 g/mol or less. be. When the molecular weight of the hydrophilic portion of the surfactant is within the above range, the percutaneous absorption of the active ingredient can be further enhanced.

The surfactant contains at least one selected from the group consisting of sorbitan fatty acid ester, glycerin fatty acid ester, propylene glycol fatty acid ester, and fatty acid alkanolamide. Among these, the surfactant is selected from the group consisting of sorbitan fatty acid ester, glycerin fatty acid ester, and propylene glycol fatty acid ester, from the viewpoint of achieving both transdermal absorption and skin hypoallergenicity at an even higher level. It is preferable that at least one kind is included.

Sorbitan fatty acid esters include, but are not particularly limited to, esters of sorbitan and fatty acids.

Examples of fatty acids include caprylic acid, capric acid, lauric acid, undecylenic acid, myristic acid, palmitic acid, and the like. Such fatty acids may also be fatty acids obtained from natural fats and oils such as 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 monolaurate (NIKKOL SL-10, manufactured by Nippon Surfactant Industries, Ltd.) and coconut oil fatty acid sorbitan (EMALEX SPC) from the viewpoint of further increasing the transdermal absorption of the active ingredient. -10, manufactured by Nippon Emulsion Co., Ltd.), or sorbitan laurate (Rikemar L-250A, manufactured by Riken Vitamin Co., Ltd.).

Glycerin fatty acid esters in the present invention include, but are not particularly limited to, esters of glycerin and fatty acids.

Glycerin may be polyglycerin. The degree of polymerization n of polyglycerin is not particularly limited, but is preferably 5 or less, more preferably 4 or less, still more preferably 3 or less. Among these, monoglycerin, diglycerin, or triglycerin is preferable as glycerin. Specifically, the glycerin fatty acid ester is preferably monoglycerin fatty acid ester, diglycerin fatty acid ester, or triglycerin fatty acid ester. In this case, the percutaneous absorption of the active ingredient can be further enhanced.

Examples of fatty acids include caprylic acid, capric acid, lauric acid, undecylenic acid, myristic acid, palmitic acid, and the like. Such fatty acids may also be fatty acids obtained from natural fats and oils such as 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 tri(caprylic/capric) glyceryl (NIKKOL Triester F-810, manufactured by Nippon Surfactant Industries, Ltd.) and monocapryl from the viewpoint of further increasing the transdermal absorption of the active ingredient. Acid glyceryl (Sunsoft No. 700P-2-C, manufactured by Taiyo Kagaku Co., Ltd.), monoglyceryl caprylate (Capmul 808G, manufactured by ABITEC), glyceryl monocaprylate (Capmul MCM C8, manufactured by ABITEC), glyceryl monocaprylate (Sunsoft No. 760-C, manufactured by Taiyo Kagaku Co., Ltd.), glyceryl caprylate (Capmul MCM C10, manufactured by ABITEC), glyceryl caprylic acid/capric acid (Capmul MCM, manufactured by ABITEC), glyceryl caprylic acid/capric acid (Capmul MCM, manufactured by ABITEC) Capmul 471, made by ABITEC), capric acid mono-diglyceride (Sunsoft No. 707-C, made by Taiyo Kagaku Co., Ltd.), capric acid diglyceride (Sunfat GDC-S, made by Taiyo Kagaku Co., Ltd.), glyceryl monolaurate (Sunsoft No. 707-C, made by Taiyo Kagaku Co., Ltd.) No. 750-C, manufactured by Taiyo Kagaku Co., Ltd.), or glyceryl monoundecylenate (NIKKOL MGU, manufactured by Nippon Surfactant Kogyo Co., Ltd.).

Propylene glycol fatty acid esters are not particularly limited, but include esters of propylene glycol and fatty acids.

Examples of fatty acids include caprylic acid, capric acid, lauric acid, undecylenic acid, myristic acid, palmitic acid, and the like. Such fatty acids may also be fatty acids obtained from natural fats and oils such as 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 esters are preferably propylene glycol monolaurate (Rikemar PL-100, manufactured by Riken Vitamin Co., Ltd.) and propylene glycol dicaprylate (NIKKOL SEFSOL-) from the viewpoint of further increasing the transdermal absorption of the active ingredient. 228, manufactured by Nippon Surfactant Kogyo Co., Ltd.), or propylene glycol dilaurate (EMALEX PG-ML, manufactured by Nippon Emulsion Co., Ltd.).

Fatty acid alkanolamide has a structure in which R-CO and two -CH ₂ CH ₂ OH are bonded around N, and is represented by the chemical formula R-CON(CH ₂ CH ₂ OH) ₂ . means.

Specifically, fatty acid alkanolamides include lauric acid diethanolamide, lauric acid monoisopropanolamide, lauric acid myristic acid diethanolamide, palmitic acid monoethanolamide, coconut oil fatty acid diethanolamide, coconut oil fatty acid monoisopropanolamide, and coconut oil fatty acid N. - Methylethanolamide, coconut oil fatty acid monoethanolamide, palm kernel oil fatty acid diethanolamide, etc. From the viewpoint of further increasing skin permeability, the fatty acid alkanolamide is preferably a diethanolamide such as lauric acid diethanolamide.

In the present invention, the surfactant may further contain a surfactant other than sorbitan fatty acid ester, glycerin fatty acid ester, propylene glycol fatty acid ester, or fatty acid alkanolamide, and these can be appropriately selected depending on the purpose. For example, a wide range of drugs can be selected from among those that can be used as pharmaceuticals. Furthermore, multiple types of surfactants may be used in combination.

Surfactants other than sorbitan fatty acid ester, glycerin fatty acid ester, prolylene glycol fatty acid ester, or fatty acid alkanolamide are nonionic surfactants, anionic surfactants, cationic surfactants, or amphoteric surfactants. It may be either.

Examples of nonionic surfactants include, but are not limited to, fatty acid esters, fatty alcohol ethoxylates, polyoxyethylene alkylphenyl ethers, alkyl glycosides, polyoxyethylene castor oil, hydrogenated castor oil, and the like.

The fatty acid ester is not particularly limited, but includes at least one of glycerin, polyglycerin, polyoxyethylene glycerin, polyoxyethylene, sorbitan, propylene glycol, and polyoxyethylene sorbitol, and caproic acid, caprylic acid, capric acid, Examples include esters with lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid, ricinoleic acid, oleic acid, linoleic acid, linolenic acid, ricinolenic acid, erucic acid, and the like. Such fatty acid esters may be esters with fatty acids obtained from natural fats and oils such as beef tallow, lard, coconut oil, palm oil, palm kernel oil, olive oil, rapeseed oil, rice bran oil, soybean oil, and castor oil. .

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

Examples of the cationic surfactant include alkyltrimethylammonium salts, dialkyldimethylammonium salts, alkyldimethylbenzylammonium salts, and amine salts.

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

Surfactants other than sorbitan fatty acid ester, glycerin fatty acid ester, propylene glycol fatty acid ester, or fatty acid alkanolamide include, in particular, sucrose fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene castor Oil or hydrogenated castor oil is preferred.

Surfactants other than sorbitan fatty acid ester, glycerin fatty acid ester, propylene glycol fatty acid ester, or fatty acid alkanolamide may have a hydrocarbon chain such as an alkyl chain, an alkenyl chain, or an alkynyl chain.

The content of the surfactant can be appropriately set within the range in which the effects of the present invention can be achieved, but the weight ratio of the surfactant to the active ingredient (active ingredient: surfactant) is 1:0.5 to 1. :100 is preferable, and 1:5 to 1:100 is more preferable. In this case, the percutaneous absorption of the active ingredient can be further enhanced. From the viewpoint of further increasing the percutaneous absorption of the active ingredient, it is more preferable that the weight ratio of the active ingredient to the surfactant (active ingredient: surfactant) is 1:0.5 to 1:50. , 1:0.5 to 1:30 is particularly preferred. From the viewpoint of further increasing the absorption of the active ingredient, it is more preferable that the weight ratio between the active ingredient and the surfactant (active ingredient: surfactant) is 1:5 to 1:50, and 1:5. It is particularly preferable to set the ratio to 1:30.

Further, in the present invention, the weight ratio of the active ingredient to the surfactant (active ingredient: surfactant) may be 1:0.5 to 1:2. Generally, in patch preparations such as tape preparations, when the content of the active ingredient increases, the dispersibility of the active ingredient in the tape preparation tends to deteriorate. However, when a surfactant having the above HLB value and a saturated hydrocarbon group or an unsaturated hydrocarbon group is used, the dispersibility in the tape agent can be further improved even if the content of the active ingredient is large. .

The content of the surfactant contained in the adhesive layer is preferably 7% by weight or more, more preferably 10% by weight or more, and 35% by weight or less, preferably 30% by weight or less, based on the entire adhesive layer. More preferably, it is 25% by weight or less. When the content of the surfactant is at least the above lower limit, the percutaneous absorption of the active ingredient can be further improved. Moreover, when the content of the surfactant is below the above-mentioned upper limit, adhesive properties such as holding power can be further improved.

(core shell structure)
The core-shell structure includes a core portion containing the above-mentioned active ingredient and a shell portion containing the above-mentioned surfactant. As the active ingredient, two or more types of active ingredients may be contained as necessary. Furthermore, two or more types of surfactants may be contained as the surfactant, if necessary.

The core portion and the shell portion may be bound together by intermolecular force or the like to form an aggregate. However, from the viewpoint of further increasing the percutaneous absorption of the active ingredient, it is preferable that at least a portion of the surface of the core portion is covered with the shell portion.

Hereinafter, an example of the core-shell structure used in the present invention will be described with reference to the drawings.

FIG. 3 is a schematic cross-sectional view showing a core-shell structure according to an embodiment of the present invention.

As shown in FIG. 3, the core-shell structure 21 includes a core portion 22 and a shell portion 23. The surface of the core portion 22 is covered with a shell portion 23.

It is preferable that 30% or more of the surface of the core part 22 is covered by the shell part 23, more preferably 50% or more, still more preferably 70% or more, still more preferably 85% or more, particularly preferably 95% or more. , most preferably 99% or more. However, the surface of the core portion 22 may be completely covered with the shell portion 23. Since the core-shell structure 21 has the above-described configuration, for example, when applied to the skin, the active ingredient contained in the core portion 22 can be released into the body.

In the present invention, the core portion is preferably solid. When the core portion is solid, stability in the adhesive layer can be further improved. Further, in this case, by dispersing the core-shell structure in the adhesive layer, which is an oil phase, a patch preparation having an S/O (Solid-in-Oil) type structure can be formed.

As explained in the manufacturing method section below, a core-shell structure in which the core portion is solid (S/O (Solid-in-Oil) type S) can be obtained by, for example, drying a W/O emulsion. , obtained by removing the solvent (aqueous solvent and oily solvent). Note that it is preferable that water is substantially completely removed by the step of drying the W/O emulsion. Specifically, for example, the moisture content of the core-shell structure is preferably 5% by weight or less, more preferably 2% by weight or less, still more preferably 1% by weight or less, particularly preferably 0. It is 5% by weight or less. Therefore, the core-shell structure is preferably different from the W/O emulsion.

The shape of the core-shell structure is not particularly limited, and may be, for example, a spherical particle. However, the core-shell structure may be a particle having a rod shape, cubic shape, lens shape, micelle shape, lamella shape, hexagonal shape, bicell shape, sponge shape, or sea urchin shape, and may have an irregular shape. Good too.

Further, the size of the core-shell structure is not particularly limited. From the viewpoint of further increasing the percutaneous absorption of the active ingredient, the average size of the core-shell structure can preferably be 1 nm to 100 μm.

Note that the average size of the core-shell structure is the number average diameter calculated by a dynamic light scattering method during dispersion in a solvent (for example, squalane, etc.) using, for example, "Zetasizer Nano S" manufactured by Malvern Panalytical. shall be.

In the present invention, the content of the core-shell structure is not particularly limited, but is preferably 30% by weight or more, more preferably 35% by weight or more, preferably 55% by weight or less, more preferably 50% by weight or more, based on the entire adhesive layer. % by weight or less. When the content of the core-shell structure is at least the above lower limit, the percutaneous absorption of the active ingredient can be further improved. When the content of the core-shell structure is below the above upper limit, adhesive properties such as holding power can be further improved.

In addition to the active ingredient and the surfactant, the core-shell structure may further contain at least one other ingredient. Other components include, but are not particularly limited to, stabilizers, transdermal absorption enhancers, skin irritation reducers, preservatives, analgesics, and the like.

The stabilizer has the effect of stabilizing the particle structure. Further, the stabilizer has the role of preventing unintended early collapse of the particle structure and further enhancing the effect of sustained release of the active ingredient.

Stabilizers include, but are not particularly limited to, polysaccharides, proteins, hydrophilic polymer materials, and the like. The stabilizer may contain one type or two or more types. The content of the stabilizer can be appropriately set depending on the type thereof. For example, the weight ratio of the active ingredient to the stabilizer (active ingredient: stabilizer) may be 1:0.1 to 1:10.

Transdermal absorption enhancers include, but are not particularly limited to, higher alcohols, N-acylsarcosine or its salts, higher monocarboxylic acids, higher monocarboxylic acid esters, aromatic monoterpene fatty acid esters, and those having 2 to 10 carbon atoms. Examples include divalent carboxylic acids or salts thereof, polyoxyethylene alkyl ether phosphates or salts thereof, lactic acid, lactic acid esters, and citric acid. The transdermal absorption enhancer may contain one type or two or more types. The content of the transdermal absorption enhancer can be appropriately set depending on the type thereof. For example, the weight ratio of the active ingredient to the transdermal absorption enhancer (active ingredient: transdermal absorption enhancer) may be 1:0.01 to 1:50.

Examples of skin irritation reducing agents include, but are not limited to, hydroquinone glycosides, pantethine, tranexamic acid, lecithin, titanium oxide, aluminum hydroxide, sodium nitrite, sodium hydrogen nitrite, soybean lecithin, methionine, glycyrrhetinic acid, Examples include BHT, BHA, vitamin E or its derivatives, vitamin C or its derivatives, benzotriazole, propyl gallate, or mercaptobenzimidazole. The skin irritation reducing agent may contain one type or two or more types. The content ratio of the skin irritation reducing agent can be appropriately set depending on the type thereof. The skin irritation reducing agent can be blended, for example, in an amount of 0.1% to 50% by weight based on the entire core-shell structure.

Examples of the preservative include, but are not limited to, methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol, or thymol. The content ratio of the preservative in the core part can be set as appropriate depending on the type of preservative. The preservative can also be blended, for example, in an amount of 0.01% to 10% by weight based on the entire core-shell structure. The preservative may contain one type or two or more types.

Examples of analgesics include, but are not particularly limited to, local anesthetics such as procaine, tetracaine, lidocaine, dibucaine, or prilocaine, or salts thereof. The analgesic may contain one or more types. The content ratio of the analgesic in the core-shell structure can be set as appropriate depending on the type of the analgesic. The analgesic can be blended, for example, in an amount of 0.1% to 30% by weight based on the entire core-shell structure.

The method for producing the core-shell structure is not particularly limited, but it can be produced, for example, by a method that includes a step of drying a W/O emulsion containing an active ingredient in the 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.

A W/O emulsion containing an active ingredient in the aqueous phase is made by mixing an aqueous solvent such as water or a buffered aqueous solution containing the active ingredient with an oily solvent such as cyclohexane, hexane, or toluene containing a surfactant. You can get it by doing In addition to the active ingredient, the aqueous solvent containing the active ingredient may contain additional ingredients such as a stabilizer, an absorption enhancer, or an irritation reducing agent, as necessary. In addition to the surfactant, the oily solvent containing a surfactant may optionally contain additional components such as an irritation reducing agent, analgesic, an absorption enhancer, or a stabilizer. The mixing method is not particularly limited as long as it can form a W/O emulsion, and examples thereof include stirring using a homogenizer or the like.

The conditions for stirring with a homogenizer are, for example, about 5,000 rpm to 50,000 rpm, preferably about 10,000 rpm to 30,000 rpm.

The weight ratio of the active ingredient to the surfactant (active ingredient: surfactant) in the above W/O emulsion is preferably in the range of 1:0.5 to 1:100, and 1:5 to 1: More preferably, it is within the range of 100. The above weight ratio (active ingredient: surfactant) is more preferably in the range of 1:0.5 to 1:50, particularly preferably in the range of 1:5 to 1:50. Further, the above weight ratio (active ingredient: surfactant) is more preferably in the range of 1:0.5 to 1:30, particularly preferably in the range of 1:5 to 1:30. The weight ratio of the active ingredient to the surfactant (active ingredient:surfactant) may be 1:0.5 to 1:2.

The method for drying the W/O emulsion containing the active ingredient in the aqueous phase is not particularly limited as long as the method can remove the solvent (aqueous solvent and oily solvent) in the emulsion. Examples of methods for drying the W/O emulsion include freeze drying and reduced pressure drying, preferably freeze drying.

Moreover, from the viewpoint of further reducing the number average particle diameter of the obtained core-shell structure, it is preferable to further include a step of heat-treating the W/O emulsion or a dried product of the W/O emulsion. The heat treatment temperature is, for example, 30°C to 60°C, preferably 35°C to 50°C, more preferably 35°C to 45°C.

The heat treatment time is appropriately adjusted depending on the heat treatment temperature, and is, for example, 1 day to 30 days, preferably 2 days to 15 days, and more preferably 3 days to 7 days.

Another method for further reducing the number average particle diameter of the resulting core-shell structure is to disperse a W/O emulsion or a dried product of the W/O emulsion in a solvent, etc. as necessary, and then filter it. Examples include a method of filtration and a method of centrifugal separation. In the case of filter filtration, the filter pore diameter is, for example, 1 μm or less, preferably 0.2 μm or less, and more preferably 0.1 μm or less.

(Adhesive)
Preferably, the adhesive contains an elastomer. However, the adhesive may contain a tackifier resin and other additives, if necessary.

Elastomer;
Examples of the elastomer include, but are not limited to, acrylic elastomers, styrene elastomers, olefin elastomers, polyisoprene, polyisobutylene, urethane elastomers, and silicone elastomers. These may be used alone or in combination.

Examples of the acrylic elastomer include polymers of (meth)acrylic monomers. Note that meth (acrylic) refers to methacryl or acrylic.

Specific examples of (meth)acrylic monomers include acrylic acid, dodecyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, hydroxyethyl acrylate, acrylic ester, octyl acrylate, methyl acrylate, butyl acrylate, n-octadecyl acrylate, ethyl acrylate, alkyl acrylate, alkyl acrylate, octyl acrylate, 2-methoxyethyl acrylate, hydroxypropyl acrylate, methoxyethyl acrylate, methacrylic acid, ethyl methacrylate, methacrylic acid Glycidyl, octyl methacrylate, 2-ethylhexyl methacrylate, dodecyl methacrylate, acetoacetoxyethyl methacrylate, methyl methacrylate, 2-methoxyethyl methacrylate, alkyl methacrylate, alkyl methacrylate, or n-octadecyl methacrylate, etc. Can be mentioned. These may be homopolymers or copolymers of two or more of the above (meth)acrylic monomers.

The acrylic elastomer may be a copolymer of a (meth)acrylic monomer and another monomer. Examples of other monomers include vinyl acetate, vinylpyrrolidone, acrylamide monomer, styrene monomer, vinyl ether monomer, diacetone acrylamide monomer, or acrylamide monomer.

Further, as a method for polymerizing the (meth)acrylic monomer, conventionally known methods can be used, such as a method using a polymerization initiator. Examples of the polymerization initiator include 2,2'-azobisisobutyronitrile (AIBN), 1,1'-azobis(cyclohexane-1-carbonitrile), 2,2'-azobis-(2,4' -dimethylvaleronitrile), organic peroxides such as benzoyl peroxide (BPO), lauroyl peroxide (LPO), and ditertiary butyl peroxide. Preferred are lauroyl peroxide, benzoyl peroxide, and the like. These polymerization initiators may be used alone or in combination of two or more.

Examples of acrylic elastomers include acrylic acid/octyl acrylate copolymer, 2-ethylhexyl acrylate/vinyl acetate/hydroxyethyl acrylate/glycidyl methacrylate copolymer, acrylic ester/vinyl acetate copolymer, 2-ethylhexyl acrylate/methyl acrylate/acrylic acid/glycidyl methacrylate copolymer, 2-ethylhexyl acrylate/diacetone acrylamide/acetoacetoxyethyl methacrylate/methyl methacrylate copolymer, 2-ethylhexyl acrylate/vinyl acrylate Pyrrolidone copolymer, 2-ethylhexyl acrylate/2-ethylhexyl methacrylate/dodecyl methacrylate copolymer, methyl acrylate/2-ethylhexyl acrylate copolymer, acrylic acid/2-ethylhexyl acrylate copolymer, acrylic Acrylic acid/butyl acrylate copolymer, acrylic acid/2-ethylhexyl acrylate/vinyl acetate copolymer, acrylic acid/2-ethylhexyl acrylate/hydroxyethyl acrylate copolymer, acrylic acid/hydroxyethyl acrylate/vinyl acrylate Pyrrolidone copolymer, acrylic acid/2-ethylhexyl acrylate/hydroxyethyl acrylate/vinylpyrrolidone copolymer, acrylic acid/acrylic acid amide/ethyl acrylate copolymer, acrylic acid/2-ethylhexyl acrylate/styrene copolymer Polymer, acrylic acid amide/styrene copolymer, acrylic acid alkyl ester/methacrylic acid alkyl ester/diacetone acrylamide/methacrylic acid copolymer, alkyl acrylate/vinyl acetate copolymer, alkyl acrylate/styrene copolymer , octyl acrylate/acrylic ester copolymer, hydroxyethyl acrylate/butyl acrylate/methoxyethyl acrylate copolymer, hydroxyethyl acrylate/methoxyethyl acrylate copolymer, butyl acrylate/acrylonitrile/styrene Examples include copolymers, acrylic acid/alkyl methacrylate copolymers, and the like. Further, a crosslinking agent may be added as necessary. Examples of the crosslinking agent include amino compounds, phenol compounds, epoxy compounds, isocyanate compounds, organic peroxides, metal alcoholates, metal chelates, and the like.

Examples of styrenic elastomers include styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), and styrene-ethylene butylene-styrene block copolymer (SEBS). ), styrene-ethylene-propylene-styrene block copolymer (SEPS), styrene-isobutylene-styrene block copolymer (SIBS), and the like.

Examples of the olefin elastomer include crystalline olefin-ethylene butene-crystalline olefin (CEBC) copolymer, styrene-ethylene butene-crystalline olefin (SEBC) copolymer, and the like.

The adhesive may include a first elastomer and a second elastomer. The second elastomer is a different elastomer from the first elastomer.

The first elastomer can be appropriately selected from the above-mentioned elastomers, but is preferably an acrylic elastomer or a styrene elastomer, more preferably an acrylic elastomer.

The second elastomer can be appropriately selected from the above-mentioned elastomers, but is preferably an acrylic elastomer or a styrene elastomer, more preferably an acrylic elastomer.

Note that the second elastomer may be the same type of elastomer as the first elastomer. Specifically, when the first elastomer is an acrylic elastomer, the second elastomer may be another acrylic elastomer.

Further, in the present invention, the difference between the SP value of the first elastomer and the SP value of the second elastomer is preferably 0.1 or more, more preferably 0.5 or more, and still more preferably 1.0 or more. Yes, preferably 3.0 or less, more preferably 2.5 or less, even more preferably 2.0 or less. When the difference between the SP value of the first elastomer and the SP value of the second elastomer is within the above range, both the transdermal absorption of the active ingredient and the adhesive properties such as retention power can be further enhanced. can.

Note that in this specification, the SP value means a calculated value calculated by the Fedors formula δ ² =ΣE/ΣV (δ means the SP value, E means evaporation energy, and V means molar volume). Note that the unit of SP value is (cal/cm ³ ) ^0.5 . Fedors' method is described in the Journal of Japan Adhesive Association, 1986, Vol. 22, p. 566.

The SP value of the first elastomer is preferably 8.0 or more, more preferably 8.5 or more, even more preferably 9.0 or more, particularly preferably 9.5 or more, preferably 12.0 or less, and more preferably It is 11.5 or less, more preferably 11.0 or less, particularly preferably 10.5 or less. When the SP value of the first elastomer is within the above range, both the transdermal absorption of the active ingredient and the adhesive properties such as holding power can be further enhanced.

The SP value of the second elastomer is preferably 6.5 or more, more preferably 7.0 or more, even more preferably 7.5 or more, particularly preferably 8.0 or more, preferably 11.0 or less, and more preferably It is 10.5 or less, more preferably 10.0 or less, particularly preferably 9.5 or less. When the SP value of the second elastomer is within the above range, both the transdermal absorption of the active ingredient and the adhesive properties such as holding power can be further enhanced.

In the present invention, the sum of the contents of the first elastomer and the second elastomer is not particularly limited, but is preferably at least 20 parts by weight, more preferably at least 30 parts by weight, based on 100 parts by weight of the entire adhesive. is 80 parts by weight or less, more preferably 70 parts by weight or less, still more preferably 60 parts by weight or less. When the sum of the contents of the first elastomer and the second elastomer is within the above range, both the transdermal absorbability of the active ingredient and the adhesive properties such as holding power can be further enhanced.

The combination of the first elastomer and the second elastomer is preferably a combination in which one is an acrylic elastomer and the other is a styrene elastomer, or a combination in which both are acrylic elastomers, more preferably both. Both are a combination of acrylic elastomers. In this case, the dispersibility of the core-shell structure can be more effectively improved.

The weight ratio of the second elastomer to the first elastomer (second elastomer/first elastomer) is preferably 0.1 or more, more preferably 0.2 or more, preferably 10 or less, and more preferably 5 or less. It is. When the weight ratio (second elastomer/first elastomer) is within the above range, both the transdermal absorption of the active ingredient and the adhesive properties such as holding power can be further enhanced.

In addition, when the adhesive contains three or more types of elastomers, select two types of elastomers with a large weight ratio in the adhesive, and use the one with a large SP value as the first elastomer and the one with a small SP value as the second elastomer. 2 elastomer.

Tackifying resin;
The adhesive may further contain a tackifying resin. The tackifier 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. Note that these tackifying resins may be used alone or in combination.

The content of the tackifier resin is not particularly limited, and can be, for example, 1 part by weight or more and 40 parts by weight or less based on 100 parts by weight of the entire adhesive. When the content of the tackifying resin is within the above range, both the transdermal absorption of the active ingredient and the adhesive properties such as holding power can be further enhanced.

Other additives;
The adhesive may contain other additives depending on the purpose of use. Other additives include, for example, elastomers and resins different from the above-mentioned elastomers, plasticizers, gelling agents, excipients, colorants, lubricants, binders, emulsifiers, thickeners, wetting agents, and stabilizers. Agents, preservatives, solvents, solubilizing agents, suspending agents, buffers, pH adjusters, antioxidants, transdermal absorption enhancers, irritation relievers, preservatives, chelating agents, dispersing agents, and the like.

As the plasticizer, it is preferable to use an oil-based liquid agent. However, the plasticizer may be an aqueous solution.

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

The plasticizer may be gelled. Here, gelation means that molecules in a liquid containing or consisting of low molecules or polymers partially crosslink with each other to form a three-dimensional network structure. Gelation may be performed by physical or chemical crosslinking.

The gelling agent is not particularly limited as long as it can gel the plasticizer, but includes, for example, esters of one or more fatty acids and one polysaccharide. 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, and sucrose. These gelling agents may be used alone or in combination.

The content of other additives is not particularly limited, but may be, for example, 0.1 parts by weight or more and 20 parts by weight or less, based on 100 parts by weight of the entire adhesive.

(Inorganic filler)
The inorganic filler is not particularly limited, and for example, silica, titanium oxide, light anhydrous silicic acid, magnesium aluminate metasilicate, magnesium aluminum silicate, hydrous silicon dioxide, zinc oxide, silicon dioxide, and the like can be used. Among these, the inorganic filler is preferably a hydrophobic inorganic filler, and more preferably hydrophobic silica. By using a hydrophobic inorganic filler, both the retention force and the adhesive force (peel force) can be further increased.

Moreover, a hydrophilic filler may be sufficient as an inorganic filler. In this case, the holding power can be further increased, and in particular, the above-mentioned sweat-proof holding power can be further increased.

Moreover, one type of inorganic filler may be used alone, or a plurality of types may be used in combination. Further, a hydrophilic inorganic filler and a hydrophobic inorganic filler may be used in combination. For example, hydrophobic silica and magnesium aluminate metasilicate can be used in combination.

The content of the inorganic filler is not particularly limited, and is preferably 1% by weight or more, more preferably 3% by weight or more, and preferably 10% by weight or less, more preferably 8% by weight or less, based on the entire adhesive layer. It is. When the content of the inorganic filler is at least the above lower limit, adhesive properties such as holding power can be further improved. On the other hand, when the content of the inorganic filler is below the above upper limit, the percutaneous absorption of the active ingredient can be further improved.

Further, in the present invention, the ratio of the inorganic filler content to the surfactant content (inorganic filler content/surfactant content) is 0.15 or more, preferably 0.2 or more, and It is preferably 0.25 or more, preferably 0.6 or less, and more preferably 0.5 or less. When the ratio (inorganic filler content/surfactant content) is equal to or greater than the lower limit, adhesive properties such as holding power can be further improved. Moreover, when the said ratio (content of an inorganic filler/content of surfactant) is below the said upper limit, the percutaneous absorption of an active ingredient can be further improved.

(Water-soluble polymer)
Water-soluble polymers are not particularly limited, and include, for example, polyvinylpyrrolidone, vinyl acetate/vinylpyrrolidone copolymer, polyvinyl alcohol, polyvinylphenol, polyacrylamide, polyacrylic acid, polymethacrylic acid, polyethylene glycol, methylcellulose, and hydroxypropylcellulose. , hydroxypropyl methylcellulose, carboxymethylcellulose, cluster dextrin, cycloamylose, agar, gelatin, dimethylaminoethyl methacrylate/butyl methacrylate/methyl methacrylate copolymer, methacrylic acid/ethyl acrylate copolymer, methyl methacrylate/methacrylate Examples include acid copolymers, methyl acrylate/methyl methacrylate/methacrylic acid copolymers, acrylic acid/acrylamide copolymers, acrylic acid/methacrylic acid copolymers, methyl methacrylate/diethylaminoethyl methacrylate copolymers, etc. It will be done. These may be used alone or in combination of two or more. Among these, polyvinylpyrrolidone or aminoalkyl methacrylate copolymers such as dimethylaminoethyl methacrylate/butyl methacrylate/methyl methacrylate copolymer are preferably used from the viewpoint of further increasing sweat resistance. .

The content of the water-soluble polymer is not particularly limited, and is preferably 1% by weight or more, more preferably 2% by weight or more, and preferably 10% by weight or less, more preferably 5% by weight based on the entire adhesive layer. It is as follows. When the content of the water-soluble polymer is at least the above lower limit, the sweat resistance can be further improved. On the other hand, when the content of the water-soluble polymer is below the above upper limit, the percutaneous absorption of the active ingredient can be further improved.

(Adhesive layer)
The thickness of the adhesive layer is not particularly limited, and can be, for example, 10 μm or more and 150 μm or less.

[liner]
The liner is not particularly limited as long as it is coated with silicone or the like, from the viewpoint of protecting the adhesive layer until the patch preparation is applied to the skin and making it easy to peel off. Examples of the liner include polyethylene terephthalate and polypropylene coated with silicone. However, the liner may not be provided. Further, when forming the adhesive layer, the adhesive layer solution described below may be applied to the base material side or the liner side.

[Method for manufacturing patch preparation]
Hereinafter, a specific example of the method for manufacturing the patch preparation of the present invention will be described.

The method for producing the patch preparation of the present invention is not particularly limited, and can be produced by a solution coating method. In the solution coating method, first, an adhesive layer solution is prepared.

As a method for preparing the adhesive layer solution, for example, first, the above-mentioned adhesive, an active ingredient, a surfactant, an inorganic filler, and, if necessary, a water-soluble polymer are mixed in a solvent. Thereby, an adhesive layer solution can be prepared.

The method of mixing each component is not particularly limited, and any known method can be used. For example, the mixture can be mixed by stirring with a magnetic stirrer at 500 rpm for 1 hour.

Examples of the solvent include cyclohexane, hexane, methylcyclohexane, toluene, heptane, ethyl acetate, n-butyl acetate, isobutyl acetate, isopropyl acetate, methyl acetate, propyl acetate, tetrahydrofuran, acetone, pentane, methyl isobutyl ketone, or methyl ethyl ketone. can be mentioned.

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

Next, the adhesive layer solution is uniformly applied onto the liner using a coating machine such as a knife coater, comma coater, or reverse coater, and dried. Thereby, the adhesive layer is completed by removing the solvent, and a patch preparation can be obtained by laminating the base material on the adhesive layer. Note that a curing step may be further provided. Curing may be performed, for example, at 20° C. to 80° C. for 1 day to 7 days. Curing may be performed after applying and drying the adhesive layer solution, or may be performed after laminating the base material on the adhesive layer. Note that as the liner and base material, the above-mentioned liner and base material can be used, respectively.

Next, the present invention will be clarified by giving specific examples and comparative examples of the present invention. Note that the present invention is not limited to the following examples.

(Example 1)
1 g of vardenafil hydrochloride hydrate (manufactured by Atomax Chemicals, molecular weight: 579 g/mol) as an active ingredient was dissolved in 40 g of pure water, and glyceryl monocaprylate (manufactured by Taiyo Kagaku Co., Ltd., a commercial product) as a surfactant was dissolved in this. A solution of 0.5 g of ``Sunsoft No. 700P-2-C'', HLB value: 10.9, carbon number of saturated hydrocarbon group: 7) dissolved in 80 g of cyclohexane was added, and the mixture was stirred with a homogenizer (25,000 rpm). This was followed by freeze-drying for 2 days to obtain particles having a core-shell structure containing an active ingredient in the core and a surfactant in the shell.

Separately, an adhesive (1) containing 40 parts by weight of an acrylic elastomer as a first elastomer and 60 parts by weight of an acrylic elastomer as a second elastomer was prepared. The acrylic elastomer used as the first elastomer was manufactured by Cosmedi Pharmaceutical Co., Ltd. under the trade name "MAS-683" (2-ethylhexyl acrylate/vinylpyrrolidone copolymer, SP value of polymer: 10.4). there was. The acrylic elastomer as the second elastomer is manufactured by Cosmedi Pharmaceutical Co., Ltd. and has the trade name "MAS811B" (2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, dodecyl methacrylate copolymer, SP value of polymer: 9.1 ) was used.

45 parts by weight of the prepared particles and 2.5 parts by weight of hydrophobic silica (AERSIL R972) as an inorganic filler were blended into 52.5 parts by weight of the prepared adhesive (1), so that the solid content concentration was 35% by weight. Toluene was added so that Thereafter, the mixture was mixed until homogeneous to prepare an adhesive layer solution. Hydrophobic silica as an inorganic filler was manufactured by EVONIC and has a trade name of "AERSIL R972".

Next, a release sheet was prepared in which silicone was applied to one side of a release base made of a polyethylene terephthalate film having a thickness of 38 μm, and a release treatment was performed. By applying the prepared adhesive layer solution on the release-treated surface of this release sheet and drying it at 90°C for 20 minutes, a laminate with a 100 μm adhesive layer formed on the release-treated surface of the release sheet was prepared. did. Then, a base material made of a polyethylene terephthalate film having a thickness of 38 μm was prepared. One surface of this base material and the adhesive layer of the laminate were overlapped so as to face each other, and the adhesive layer of the laminate was transferred to the base material to be integrated, thereby producing a patch preparation.

(Example 2)
A patch preparation was produced in the same manner as in Example 1, except that 45 parts by weight of particles and 5 parts by weight of hydrophobic silica (AERSIL R972) as an inorganic filler were blended with 50 parts by weight of adhesive (1).

(Example 3)
A patch preparation was prepared in the same manner as in Example 1, except that 47.5 parts by weight of the adhesive (1), 45 parts by weight of particles, and 7.5 parts by weight of hydrophobic silica (AERSIL R972) as an inorganic filler were blended. was manufactured.

(Example 4)
A patch preparation was produced in the same manner as in Example 2, except that the amount of active ingredient added was 1 g, and the amount of surfactant added was 0.3 g.

(Example 5)
A patch preparation was produced in the same manner as in Example 2, except that the amount of active ingredient added was 1 g and the amount of surfactant added was 2 g.

(Example 6)
A patch preparation was prepared in the same manner as in Example 4, except that 30 parts by weight of particles and 2.5 parts by weight of hydrophobic silica (AERSIL R972) as an inorganic filler were added to 67.5 parts by weight of adhesive (1). was manufactured.

(Example 7)
A patch preparation was produced in the same manner as in Example 4, except that 60 parts by weight of particles and 5 parts by weight of hydrophobic silica (AERSIL R972) as an inorganic filler were blended with 35 parts by weight of adhesive (1).

(Example 8)
A patch preparation was prepared in the same manner as in Example 1, except that 60 parts by weight of particles and 7.5 parts by weight of hydrophobic silica (AERSIL R972) as an inorganic filler were added to 32.5 parts by weight of adhesive (1). was manufactured.

(Example 9)
A patch preparation was produced in the same manner as in Example 2, except that light anhydrous silicic acid (manufactured by Freund Sangyo Co., Ltd., product number "Ad Solider 101") was used as the inorganic filler instead of hydrophobic silica.

(Example 10)
A patch preparation was produced in the same manner as in Example 2, except that hydrated silicon dioxide (SiO ₂ , manufactured by Freund Sangyo Co., Ltd., product number "Ad Solider 102") was used as the inorganic filler instead of hydrophobic silica.

(Example 11)
A patch preparation was produced in the same manner as in Example 2, except that titanium oxide (TiO ₂ , manufactured by Freund Sangyo Co., Ltd., product number "Titanium Oxide FG") was used as the inorganic filler instead of hydrophobic silica.

(Example 12)
A patch preparation was produced in the same manner as in Example 2, except that hydrophilic silica (manufactured by EVONIC, product number "AERSIL200") was used as the inorganic filler instead of hydrophobic silica.

(Example 13)
A patch preparation was produced in the same manner as in Example 2, except that magnesium aluminate metasilicate (Mg) (manufactured by Fuji Chemical Industry Co., Ltd., product number "Neusilin UFL2") was used as the inorganic filler instead of hydrophobic silica. .

(Example 14)
As an inorganic filler, instead of 5 parts by weight of hydrophobic silica, 2.5 parts by weight of hydrophobic silica and 2.5 parts by weight of magnesium aluminate metasilicate (Mg) (manufactured by Fuji Chemical Industry Co., Ltd., product number "Neusilin UFL2") were used. A patch preparation was produced in the same manner as in Example 2, except that the following was used.

(Example 15)
Except that instead of the adhesive (1), an adhesive (2) containing 20 parts by weight of an acrylic elastomer as a first elastomer and 80 parts by weight of an acrylic elastomer as a second elastomer was prepared. A patch preparation was obtained in the same manner as in Example 2.

(Example 16)
Except that instead of the adhesive (1), an adhesive (3) containing 80 parts by weight of an acrylic elastomer as a first elastomer and 20 parts by weight of an acrylic elastomer as a second elastomer was prepared. A patch preparation was obtained in the same manner as in Example 2.

(Example 17)
When preparing the adhesive layer solution, 2.5 parts by weight of polyvinylpyrrolidone (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd., trade name "Polyvinylpyrrolidone K90") as a water-soluble polymer was substituted for 2.5 parts by weight of the hydrophobic silica. A patch preparation was obtained in the same manner as in Example 2, except that the following ingredients were added:

(Example 18)
When preparing the adhesive layer solution, dimethylaminoethyl methacrylate/butyl methacrylate/methyl methacrylate copolymer (manufactured by EVONIK, trade name) as a water-soluble polymer was used instead of 2.5 parts by weight of the hydrophobic silica. A patch preparation was obtained in the same manner as in Example 2, except that 2.5 parts by weight of "EUDRAGIT EPO" was added.

(Comparative example 1)
A patch preparation was produced in the same manner as in Example 1, except that 45 parts by weight of particles were blended with 55 parts by weight of adhesive (1) and no inorganic filler was used.

(Comparative example 2)
A patch preparation was produced in the same manner as in Example 2, except that the amount of active ingredient added was 1 g and the amount of surfactant added was 5 g.

(Comparative example 3)
A patch preparation was prepared in the same manner as in Example 5, except that 60 parts by weight of particles and 7.5 parts by weight of hydrophobic silica (AERSIL R972) as an inorganic filler were added to 32.5 parts by weight of adhesive (1). was manufactured.

(Comparative example 4)
A patch preparation was prepared in the same manner as in Example 5, except that 30 parts by weight of particles and 2.5 parts by weight of hydrophobic silica (AERSIL R972) as an inorganic filler were blended with 67.5 parts by weight of adhesive (1). was manufactured.

(Comparative example 5)
A patch preparation was prepared in the same manner as in Example 17, except that 50 parts by weight of the adhesive (1), 45 parts by weight of particles, and 5 parts by weight of polyvinylpyrrolidone as a water-soluble polymer were blended, and no inorganic filler was used. Manufactured.

(Comparative example 6)
50 parts by weight of adhesive (1), 45 parts by weight of particles, and a water-soluble polymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate copolymer (manufactured by EVONIK, trade name "EUDRAGIT EPO") 5 A patch preparation was produced in the same manner as in Example 18, except that parts by weight were blended and no inorganic filler was used.

(evaluation)
45℃ holding power (holding time);
According to JIS Z 0237:2009, the patch preparation was attached to a SUS board with a width of 12 mm and a length of 12 mm. In an environment of 45° C., the elapsed time (retention time) from when a 1.0 kg weight was attached to the end of the patch until the patch completely peeled off from the SUS plate was measured. As a holding force tester, a product manufactured by Tester Sangyo Co., Ltd., product number "BE-502" was used.

Peeling force;
For Examples 2, 9, 10 to 12, according to JIS Z 0237:2009, a test piece was prepared by pasting the patch on a SUS board with a width of 24 mm and a length of 100 mm, and when it was peeled off in a 90° direction. The strength at the time of peeling was defined as the peeling force. The peel force was determined by measuring with a tensile tester. As a tensile tester, a product manufactured by Imada Seisakusho Co., Ltd., product number "SVZ-50NB-1R1" was used. Note that the peeling speed was 300 mm/min.

Sweat resistance;
For Examples 2, 13, 14, 17, 18 and Comparative Examples 5 and 6, the conditions were the same as in the evaluation of the 45°C holding power above, except that the patch preparation was attached to a SUS board onto which 20 μL of artificial sweat fluid had been applied. The sweat resistance retention power (retention time) was measured.

Hairless rat skin permeability test;
Hairless rat skin (Japan SLC, HWY/Slc, removed from 8 weeks of age) was set in a drug skin permeation test cell. 1.33 cm ² of the patch preparations obtained in Examples 1 to 3, 9, 10, and 13 and Comparative Example 1 were applied to the upper part of this device. In addition, in distilled water, 5×10 ⁻⁴ M of NaH ₂ PO ₄ , 2×10 ⁻⁴ M of Na ₂ HPO ₄ , 1.5×10 ⁻⁴ M of NaCl, and gentamicin sulfate (manufactured by Wako Pure Chemical Industries, Ltd., G1658) were added. ) was adjusted to pH 7.2 with NaOH to prepare a buffer solution, which was then introduced into the lower receptor layer. Furthermore, the apparatus was placed in a constant temperature bath kept at 32°C from the start of the test. Immediately after 1 ml of the liquid in the tank was collected from the lower receptor layer after a predetermined time after the start of the test, 1 ml of a liquid of the same composition was replenished. Methanol was added to each collected receptor fluid sample to extract eluted lipids and the like, followed by centrifugation. After centrifugation, the concentration of active ingredient in the supernatant was determined by high performance liquid chromatography (HPLC). Based on the quantified amount of active ingredient, the 24-hour cumulative skin permeation amount was calculated.

Sensory test;
Five adults applied 1.33 cm ² of the patch preparations obtained in Examples 1 to 3, 9, 10, 13 and Comparative Example 1 to their upper arms, and checked for peeling after 12 hours. If none of the 5 people peeled off, it was rated ◎, 4 people rated it ○, and 2 or more people rated it x if there was peeling.

The results are shown in Tables 1 to 3 below.

1, 11... Patch preparation 2... Base materials 2a, 2b... First and second main surfaces 3... Adhesive layer 3a... Main surface 4... Liner 21... Core shell structure 22... Core part 23... Shell part

Claims (6)

base material and
an adhesive layer provided on the main surface of the base material;
Equipped with
The adhesive layer includes an active ingredient, a surfactant, an inorganic filler, and an adhesive,
The adhesive layer includes a core-shell structure having a core portion containing the active ingredient and a shell portion containing the surfactant and covering at least a portion of the core portion,
The surfactant has a hydrocarbon group having 7 or more and 15 or less carbon atoms,
The surfactant includes at least one selected from the group consisting of sorbitan fatty acid ester, glycerin fatty acid ester, propylene glycol fatty acid ester, and fatty acid alkanolamide,
The content of the surfactant is 35% by weight or less based on the entire adhesive layer,
A patch preparation, wherein the ratio of the inorganic filler content to the surfactant content (inorganic filler content/surfactant content) is 0.15 or more. The adhesive preparation according to claim 1, wherein the adhesive includes a first elastomer and a second elastomer different from the first elastomer. The adhesive preparation according to claim 1 or 2 , wherein the inorganic filler is a hydrophobic filler. The inorganic filler is at least one selected from the group consisting of silica, titanium oxide, light anhydrous silicic acid, magnesium aluminate metasilicate, magnesium aluminum silicate, hydrated silicon dioxide, zinc oxide, and silicon dioxide. The patch preparation according to any one of Items 1 to 3 . The adhesive preparation according to any one of claims 1 to 4 , wherein the adhesive layer further contains a water-soluble polymer. The adhesive preparation according to claim 5 , wherein the water-soluble polymer is at least one of polyvinylpyrrolidone and aminoalkyl methacrylate copolymer.

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