Non-aqueous transdermal absorption preparation

Abstract

Provided is a non-aqueous transdermally absorbable preparation which exhibits sufficient efficacy even if a small amount (2-4 mass%) of a drug is contained in an adhesive layer constituting the non-aqueous transdermally absorbable preparation, and which has sufficient adhesiveness and manufacturing suitability. A non-aqueous transdermal absorption preparation which is provided with a support body and an adhesive layer that is laminated on the support body, the adhesive layer contains 2-4 mass% of a non-steroidal anti-inflammatory and analgesic agent having a salt form of an alkali metal based on the total mass of the adhesive layer, 10-30 mass% of a rosin ester derivative based on the total mass of the adhesive layer, and an inorganic acid.

Description

Technical Field

[0001] The present invention relates to a non-aqueous percutaneous absorption preparation. Specifically, the present invention relates to a non-aqueous percutaneous absorption preparation containing a non-steroidal anti-inflammatory analgesic. Background Art

[0002] Non-steroidal anti-inflammatory analgesics do not show serious side effects such as those seen in steroidal anti-inflammatory analgesics, and are therefore widely used in clinical practice. However, it is also found that non-steroidal anti-inflammatory analgesics also show a side effect of damaging the gastric mucosa when administered orally because they also show inhibitory activity on cyclooxygenase, a prostaglandin-generating enzyme present in the body. In order to mitigate such side effects, preparations that absorb drugs from the skin, so-called percutaneous absorption preparations, have been developed.

[0003] Percutaneous absorption preparations are roughly divided into matrix type and reservoir type. Matrix type percutaneous absorption preparations are composed of an adhesive layer containing a drug and a support body that holds the adhesive layer. However, except for a very small number of drugs, most of them cannot obtain their efficacy even if they are applied alone on the skin, so means of improving the skin permeability of the drug are adopted. For example, a non-aqueous percutaneous absorption preparation is proposed, which improves the release and skin permeability of the non-steroidal anti-inflammatory analgesic by simultaneously using a non-steroidal anti-inflammatory analgesic in the form of an alkali metal salt and an inorganic acid in a free state that is more acidic than the non-steroidal anti-inflammatory analgesic (Patent Document 1).

[0004] Prior art literature

[0005] Patent Literature

[0006] Patent Document 1: Japanese Patent No. 4678532 Summary of the invention

[0007] 1. Technical issues to be resolved

[0008] It is generally believed that the higher the content of the drug in the adhesive layer constituting the transdermal absorption preparation, the higher the skin permeability of the drug. The non-aqueous transdermal absorption preparation with improved skin permeability of the drug proposed in Patent Document 1 contains 5% by mass of loxoprofen sodium, 0.5% by mass of phosphoric acid and 10% by mass of rosin glycerol ester (Example 2 of Patent Document 1).

[0009] In addition, it is also believed that the less the content of the component other than the medicine in the adhesive layer constituting the percutaneous absorption preparation, for example, tackifier (rosin ester derivatives etc.), the easier the medicine is to penetrate the skin, and the higher the skin permeability of the medicine. However, if the content of tackifier is few, for example, because the percutaneous absorption preparation does not have sufficient tackiness, it is difficult to meet the demand performance. In addition, because the adhesive layer forms the composition and does not have the viscosity suitable for industrial manufacture, the percutaneous absorption preparation is difficult to meet the manufacturing adaptability (hereinafter also referred to as "manufacturing adaptability") that can be manufactured by industrial method.

[0010] An object of the present invention is to provide a non-aqueous percutaneous absorption preparation which can fully exhibit its drug efficacy even if the drug in the adhesive layer constituting the non-aqueous percutaneous absorption preparation is a small amount (2% to 4% by mass) and has sufficient adhesiveness and manufacturing adaptability.

[0011] (II) Technical solution

[0012] In order to solve the above-mentioned technical problems, the inventors of the present application have conducted intensive studies and found that by using 2% to 4% by mass of a non-steroidal anti-inflammatory analgesic in the form of an alkali metal salt and 10% to 30% by mass of a rosin ester derivative simultaneously in an adhesive layer constituting a non-aqueous transdermal absorption preparation, the efficacy of the non-steroidal anti-inflammatory analgesic can be fully exhibited even if the amount of the non-steroidal anti-inflammatory analgesic is small (2% to 4% by mass), that is, excellent skin permeability of the non-steroidal anti-inflammatory analgesic can be exhibited, and a non-aqueous transdermal absorption preparation having such an adhesive layer has sufficient adhesiveness and manufacturing adaptability, thereby completing the present invention.

[0013] That is, the present invention relates to a non-aqueous percutaneous absorption preparation comprising a support and an adhesive layer laminated on the support, wherein:

[0014] The adhesive layer contains:

[0015] 2% to 4% by mass of a nonsteroidal anti-inflammatory analgesic in the form of an alkali metal salt based on the total mass of the adhesive layer,

[0016] 10% to 30% by mass of a rosin ester derivative based on the total mass of the adhesive layer, and

[0017] Inorganic acid.

[0018] As a preferred embodiment of the present invention, the following non-aqueous percutaneous absorption preparations can be listed:

[0019] The non-aqueous percutaneous absorption preparation, wherein the non-steroidal anti-inflammatory analgesic is loxoprofen sodium hydrate, and the rosin ester derivative is hydrogenated rosin glycerol ester;

[0020] The non-aqueous percutaneous absorption preparation, wherein the inorganic acid is phosphoric acid;

[0021] The non-aqueous percutaneous absorption preparation, wherein the adhesive layer comprises a rubber adhesive, and the rubber adhesive is a styrene-isoprene-styrene block copolymer;

[0022] The non-aqueous transdermal absorption preparation, wherein the adhesive layer further contains at least one selected from the group consisting of a plasticizer, a thickener, a transdermal absorption accelerator and a stabilizer; and

[0023] The non-aqueous percutaneous absorption preparation further comprises a liner layer laminated on the adhesive layer.

[0024] (III) Beneficial effects

[0025] According to the present invention, a non-aqueous percutaneous absorption preparation can be provided, which has excellent skin permeability of non-steroidal anti-inflammatory analgesics even if the drug in the adhesive layer constituting the non-aqueous percutaneous absorption preparation is a small amount (2% by mass to 4% by mass), and has sufficient adhesiveness and manufacturing adaptability. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Graph showing the relationship between the content of loxoprofen sodium and the content of hydrogenated rosin glycerol ester (10.0% by mass) in the results of the silicone membrane permeation test of Test Example 1.

[0027] Figure 2 Graph showing the relationship between the content of loxoprofen sodium and the content of hydrogenated rosin glycerol ester (20.0% by mass) in the results of the silicone membrane permeation test of Test Example 1.

[0028] Figure 3 Graph showing the relationship between the content of loxoprofen sodium (2.0% by mass) and the content of hydrogenated rosin glycerol ester in the results of the silicone membrane permeation test of Test Example 1.

[0029] Figure 4 Graph showing the relationship between the content of loxoprofen sodium (3.0% by mass) and the content of hydrogenated rosin glycerol ester in the results of the silicone membrane permeation test of Test Example 1.

[0030] Figure 5 Graph showing the relationship between the content of loxoprofen sodium (4.0% by mass) and the content of hydrogenated rosin glycerol ester in the results of the silicone membrane permeation test of Test Example 1. DETAILED DESCRIPTION

[0031] The present invention relates to a non-aqueous percutaneous absorption preparation comprising a support and an adhesive layer laminated on the support, wherein the adhesive layer contains:

[0032] 2% to 4% by mass of a nonsteroidal anti-inflammatory analgesic in the form of an alkali metal salt based on the total mass of the adhesive layer,

[0033] 10% to 30% by mass of a rosin ester derivative based on the total mass of the adhesive layer, and

[0034] Inorganic acid.

[0035] [Adhesive layer]

[0036] The adhesive layer contains a specific amount of a nonsteroidal anti-inflammatory analgesic in the form of an alkali metal salt, and specific amounts of a rosin ester derivative and an inorganic acid.

[0037] The thickness of the adhesive layer is not particularly limited, and is, for example, 35 μm to 400 μm, preferably 75 μm to 250 μm, and more preferably 100 μm to 200 μm.

[0038] In order to maintain the adhesive force and the ability to follow the skin, the weight of the adhesive layer of the non-aqueous transdermal absorption preparation is, for example, 0.3 g / 70 cm 2 Above, preferably 0.5g / 70cm 2 More preferably 0.7 g / 70 cm 2 above.

[0039] <Adhesive>

[0040] The adhesive is a component that imparts adhesiveness to the adhesive layer.

[0041] The adhesive is not particularly limited, and examples thereof include rubber-based adhesives, acrylic-based adhesives, and silicone-based adhesives.

[0042] The rubber adhesive is not particularly limited, and examples thereof include synthetic rubbers such as polyisoprene, polyisobutylene, styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), and styrene-butadiene rubber (SBR), and natural rubber.

[0043] The acrylic adhesive is not particularly limited, and examples thereof include polymers obtained by polymerizing or copolymerizing at least one of (meth)acrylic acid alkyl ester monomers such as ethyl (meth)acrylate, butyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, and isononyl (meth)acrylate. In addition, in this specification, (meth)acrylic acid refers to acrylic acid and / or methacrylic acid.

[0044] The silicone-based adhesive is not particularly limited, and examples thereof include silicone-based adhesives containing silicone rubbers such as polydimethylsiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane as a main component.

[0045] In the present invention, the adhesive may be used alone or in combination of two or more.

[0046] In the present invention, the adhesive is preferably a rubber adhesive, more preferably at least one selected from the group consisting of styrene-isoprene-styrene block copolymer (SIS) and polyisobutylene, and further preferably a combination of styrene-isoprene-styrene block copolymer (SIS) and polyisobutylene.

[0047] In the present invention, the content of the adhesive is usually 10 to 50% by mass, preferably 15 to 40% by mass, and more preferably 20 to 35% by mass, based on the total mass of the adhesive layer in the nonaqueous transdermal absorption preparation.

[0048] <Non-steroidal anti-inflammatory analgesic drugs in the form of alkali metal salts>

[0049] In the present invention, the nonsteroidal anti-inflammatory analgesic drug in the form of an alkali metal salt is a component that exerts anti-inflammatory and analgesic effects.

[0050] The nonsteroidal anti-inflammatory analgesics are not particularly limited, and examples thereof include propionic acid-based nonsteroidal anti-inflammatory analgesics, phenylacetic acid-based nonsteroidal anti-inflammatory analgesics, fenamic acid-based nonsteroidal anti-inflammatory analgesics, and acetic acid-based nonsteroidal anti-inflammatory analgesics.

[0051] Examples of the alkali metal include sodium and calcium.

[0052] Examples of the nonsteroidal anti-inflammatory analgesic in the form of an alkali metal salt include loxoprofen sodium hydrate, diclofenac sodium, tolmetin sodium, meclofenamic acid sodium, meclofenamic acid sodium hydrate, amfenac sodium hydrate, and zomepirate sodium hydrate.

[0053] In the present invention, the nonsteroidal anti-inflammatory analgesic in the form of an alkali metal salt may be used alone or in combination of two or more.

[0054] In the present invention, the nonsteroidal anti-inflammatory analgesic in the form of an alkali metal salt is preferably a propionic acid-based nonsteroidal anti-inflammatory analgesic and a phenylacetic acid-based nonsteroidal anti-inflammatory analgesic, more preferably loxoprofen sodium hydrate and diclofenac sodium, and particularly preferably loxoprofen sodium hydrate.

[0055] In the present invention, the content of the non-steroidal anti-inflammatory analgesic in the form of an alkali metal salt is 2% to 4% by mass based on the total mass of the adhesive layer in the non-aqueous percutaneous absorption preparation. In addition, when the non-steroidal anti-inflammatory analgesic is a hydrate, the content of the non-steroidal anti-inflammatory analgesic is the content converted to anhydrous. If the content of the non-steroidal anti-inflammatory analgesic in the form of an alkali metal salt is less than 2% by mass or greater than 4% by mass, the 24-hour cumulative permeation amount of the non-steroidal anti-inflammatory analgesic drops sharply.

[0056] <Rosin ester derivatives>

[0057] In the present invention, the rosin ester derivative is a component that exhibits sufficient adhesiveness and production suitability.

[0058] The rosin ester derivative is not particularly limited, and examples thereof include rosin glycerol ester, hydrogenated rosin glycerol ester, rosin pentaerythritol ester, and hydrogenated rosin pentaerythritol ester.

[0059] The rosin ester derivatives may be used alone or in combination of two or more.

[0060] In the present invention, the rosin ester derivative is preferably hydrogenated rosin glycerol ester.

[0061] In the present invention, the content of the rosin ester derivative is 10% to 30% by mass based on the total mass of the adhesive layer in the non-aqueous percutaneous absorption preparation. If the content of the rosin ester derivative is less than 10% by mass, sufficient adhesion and manufacturing adaptability will not be exhibited. In addition, if it is greater than 30% by mass, the 24-hour cumulative permeation amount of the non-steroidal anti-inflammatory analgesic drug in the form of an alkali metal salt will drop sharply.

[0062] <Inorganic acid>

[0063] In the present invention, the inorganic acid is a component that plays a role in improving the solubility of the nonsteroidal anti-inflammatory analgesic drug in the form of an alkali metal salt in the adhesive.

[0064] The inorganic acid is preferably an acid having a stronger acidity than the nonsteroidal anti-inflammatory analgesic in a free state, and pharmaceutically acceptable inorganic acids such as phosphoric acid, hydrochloric acid, nitric acid and sulfuric acid may be mentioned.

[0065] The inorganic acid may be used alone or in combination of two or more.

[0066] In the present invention, the inorganic acid is preferably phosphoric acid.

[0067] In the present invention, the content of the inorganic acid is, for example, 0.01 to 20% by mass, preferably 0.05 to 10% by mass, and more preferably 0.1 to 5% by mass, based on the total mass of the adhesive layer in the nonaqueous transdermal absorption preparation.

[0068] <Other additives>

[0069] In the range that does not impair the effects of the present invention, the adhesive layer in the non-aqueous percutaneous absorption preparation of the present invention may contain a plasticizer, a thickener, a percutaneous absorption accelerator, a stabilizer such as an antioxidant and a UV absorber, a filler, a crosslinking agent, and a preservative, etc. These additives may be used alone or in combination of two or more.

[0070] The plasticizer is not particularly limited, and petroleum oils (e.g., paraffin processing oils such as liquid paraffin, cycloparaffin processing oils, aromatic processing oils), squalane, squalene, vegetable oils (e.g., olive oil, camellia oil, castor oil, tall oil, peanut oil), silicone oil, dibasic acid esters (e.g., dibutyl phthalate, dioctyl phthalate), liquid rubber (e.g., liquid polybutene, liquid isoprene rubber), fatty acid esters (e.g., isopropyl myristate, hexyl laurate, diethyl sebacate, diisopropyl sebacate), diethylene glycol, polyethylene glycol, ethylene glycol salicylate, propylene glycol, dipropylene glycol, triacetin, triethyl citrate, crotamiton, etc. can be listed. One type of plasticizer can be used alone, or two or more types can be used simultaneously.

[0071] In the present invention, the plasticizer is preferably at least one selected from the group consisting of liquid paraffin, isopropyl myristate and crotamiton, and more preferably liquid paraffin.

[0072] Based on the total mass of the adhesive layer, the content of the plasticizer is, for example, 5% to 70% by mass, preferably 10% to 65% by mass, and more preferably 10% to 60% by mass. If the content of the plasticizer is less than 5% by mass, there is a possibility that the effect of the plasticizer on improving the cohesive force of the adhesive layer is not fully manifested, and on the other hand, if it is greater than 70% by mass, there is a possibility that the skin permeability of the non-steroidal anti-inflammatory analgesic in the form of an alkali metal salt is hindered.

[0073] The tackifier is not particularly limited, and examples thereof include alicyclic saturated hydrocarbon resins, aliphatic hydrocarbon resins, terpene resins, etc. The tackifier may be used alone or in combination of two or more.

[0074] In the present invention, the tackifier is preferably at least one selected from the group consisting of aliphatic hydrocarbon resins and terpene resins, and more preferably an aliphatic hydrocarbon resin.

[0075] Based on the total mass of the adhesive layer, the content of the thickener is, for example, 3% to 60% by mass, preferably 5% to 50% by mass, and more preferably 7% to 40% by mass. If the content of the thickener is less than 3% by mass, there is a possibility that the effect of the thickener on improving the adhesive force of the adhesive layer is not fully manifested. On the other hand, if it is greater than 60% by mass, there is a tendency for skin irritation to increase when peeling the non-aqueous percutaneous absorption preparation.

[0076] In the present invention, the percutaneous absorption enhancer is not particularly limited, and examples thereof include organic acids (e.g., cinnamic acid, salicylic acid), organic acid esters (e.g., methyl cinnamate, methyl salicylate, ethylene glycol salicylate, cetyl lactate, lauryl lactate, ethyl acetate, propyl acetate), fatty acids having 8 to 20 carbon atoms (e.g., caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid), fatty acid esters having 8 to 20 carbon atoms (e.g., methyl laurate, hexyl laurate, isopropyl myristate, myristyl myristate, octyldecyl myristate, cetyl palmitate), aliphatic alcohols (e.g., lauryl alcohol, myristyl alcohol, agaryl alcohol, isostearyl alcohol, oleyl alcohol), monoterpene compounds (e.g., l-menthol, geraniol, thymol, eugenol, pinoresinol, ice flakes, d-limonene, isoeugenol, isoborneol, nerol, dl-camphor), monoglyceryl fatty acid esters (e.g., glyceryl monocaprylate, glyceryl monocaprate, glyceryl monolaurate, glyceryl monooleate), sorbitan fatty acid esters (e.g., sorbitan monolaurate), sucrose fatty acid esters (e.g., sucrose monolaurate), polysorbates (e.g., polysorbate 20), polyols (e.g., propylene glycol), Alcohol), propylene glycol fatty acid esters (e.g., propylene glycol monolaurate), polyethylene glycol fatty acid esters (e.g., polyethylene glycol monolaurate, polyethylene glycol monostearate), polyoxyethylene alkyl ethers (e.g., polyoxyethylene lauryl ether), polyoxyethylene hydrogenated castor oils (e.g., polyoxyethylene hydrogenated castor oil), and pyrrolidones (e.g., pyrothiodecane), etc. The percutaneous absorption enhancer may be used alone or in combination of two or more.

[0077] In the present invention, the percutaneous absorption enhancer is preferably at least one selected from the group consisting of aliphatic alcohols, monoterpene compounds, monoglyceryl fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, polyoxyethylene alkyl ethers and pyrrolidones, and more preferably at least one selected from the group consisting of lauryl alcohol, myristyl alcohol, isostearyl alcohol, l-menthol, monocaprylic glyceryl, monocapric glyceryl, monooleic glyceryl, sorbitan monolaurate, propylene glycol monolaurate, polyoxyethylene lauryl ether and pyrothiodecane.

[0078] Based on the total mass of the adhesive layer, the content of the percutaneous absorption enhancer is, for example, 0.01% to 20% by mass, preferably 0.05% to 10% by mass, and more preferably 0.1% to 5% by mass. If the content of the percutaneous absorption enhancer is less than 0.01% by mass, there is a possibility that the effect of the percutaneous absorption enhancer on improving the skin permeability of the non-steroidal anti-inflammatory analgesic drug in the form of an alkali metal salt is not fully reflected. On the other hand, if it is greater than 20% by mass, there is a tendency for edema and other irritations to the skin to increase, and there is a tendency for the adhesion to the skin to decrease.

[0079] The antioxidant is not particularly limited, and examples thereof include tocopherol and its ester derivatives, ascorbic acid, ascorbyl stearate, nordihydroguaiaretic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), etc. The antioxidant may be used alone or in combination of two or more.

[0080] The content of the antioxidant is, for example, 0.01% by mass to 10% by mass, preferably 0.05% by mass to 5% by mass, and more preferably 0.1% by mass to 2% by mass based on the total mass of the adhesive layer.

[0081] The ultraviolet absorber is not particularly limited, and examples thereof include p-aminobenzoic acid derivatives, o-aminobenzoic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid compounds, imidazoline derivatives, benzophenone derivatives, cinnamic acid derivatives, pyrimidine derivatives, and tetrahydropyran derivatives. The ultraviolet absorber may be used alone or in combination of two or more.

[0082] The content of the ultraviolet absorber is, for example, 0.01% by mass to 10% by mass, preferably 0.05% by mass to 5% by mass, and more preferably 0.1% by mass to 2% by mass based on the total mass of the adhesive layer.

[0083] The filler is not particularly limited, and examples thereof include calcium carbonate, magnesium carbonate, light anhydrous silicic acid, hydrous silicon dioxide or silicates (e.g., aluminum silicate, magnesium silicate), barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide, bentonite, kaolin, and talc, etc. The filler may be used alone or in combination of two or more.

[0084] The content of the filler is, for example, 0.01% by mass to 10% by mass, preferably 0.05% by mass to 5% by mass, and more preferably 0.1% by mass to 2% by mass based on the total mass of the adhesive layer.

[0085] The crosslinking agent is not particularly limited, and examples thereof include thermosetting resins (e.g., amino resins, phenolic resins, epoxy resins, alkyd resins, unsaturated polyesters), isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents (e.g., organic peroxides), and inorganic crosslinking agents (e.g., metals, metal compounds), etc. The crosslinking agent may be used alone or in combination of two or more.

[0086] The content of the crosslinking agent is, for example, 0.01% by mass to 10% by mass, preferably 0.05% by mass to 5% by mass, and more preferably 0.1% by mass to 2% by mass based on the total mass of the adhesive layer.

[0087] The preservative is not particularly limited, and examples thereof include thymol, isopropylmethylphenol, benzoic acid and its salts, sorbic acid and its salts, methylparaben, ethylparaben, propylparaben, butylparaben, benzyl alcohol, benzalkonium chloride, benzethonium chloride, etc. The preservative may be used alone or in combination of two or more.

[0088] The content of the preservative is, for example, 0.01% by mass to 10% by mass, preferably 0.05% by mass to 5% by mass, and more preferably 0.1% by mass to 2% by mass based on the total mass of the adhesive layer.

[0089] [Support]

[0090] The support is not particularly limited, and woven fabric, nonwoven fabric, knitted fabric, resin film, paper, and laminates thereof can be used.

[0091] The material of the support is not particularly limited, and examples thereof include polyesters such as polyethylene terephthalate and polybutylene terephthalate, polyolefins such as polyethylene and polypropylene, and synthetic resins such as polyvinyl chloride, polycarbonate, polyurethane, and celluloid. Among them, the support is preferably a polyethylene terephthalate woven fabric or a polyethylene terephthalate nonwoven fabric.

[0092] The thickness of the support is not particularly limited, and is, for example, 5 μm to 1000 μm, preferably 50 μm to 800 μm, and more preferably 400 μm to 600 μm. If the thickness of the support is less than 5 μm, there is a tendency that the ease of handling when attaching the non-aqueous transdermal absorption preparation is reduced, while on the other hand, if the thickness of the support is greater than 1000 μm, there is a tendency that the ease of manufacturing is reduced, such as difficulty in cutting the support or the adhesive layer in the manufacturing process of the non-aqueous transdermal absorption preparation.

[0093] [lining]

[0094] The non-aqueous percutaneous absorption preparation of the present invention may have a backing layer laminated on the adhesive layer. By laminating the backing layer, the adhesive layer can be protected until the non-aqueous percutaneous absorption preparation is used.

[0095] The lining layer is not particularly limited, and examples thereof include films made of materials such as polyesters such as polyethylene terephthalate or polybutylene terephthalate, polyolefins such as polyethylene or polypropylene, polyvinyl chloride, polyamides such as nylon, and polyurethanes, aluminum foil, and paper, or laminates of these films. Among them, the lining layer is preferably a polyethylene terephthalate film.

[0096] Furthermore, the surface of the backing layer in contact with the adhesive layer may be subjected to silicone treatment or fluorine treatment, thereby facilitating the peeling of the backing layer from the adhesive layer when the non-aqueous transdermal absorption preparation is used.

[0097] The thickness of the lining layer is not particularly limited, and may be, for example, 35 μm to 200 μm, and preferably 50 μm to 100 μm.

[0098] The method for producing the non-aqueous percutaneous absorption preparation of the present invention is not particularly limited, and for example, the following methods can be cited: dissolving a non-steroidal anti-inflammatory analgesic in the form of an alkali metal salt, a rosin ester derivative, an inorganic acid, and any components added as needed in a solvent (e.g., toluene, xylene, ethyl acetate, butyl acetate, hexane, heptane, cyclohexane, ethanol, methanol, isopropanol) to prepare a coating solution, applying the coating solution on a support, evaporating the solvent in the coating solution to form an adhesive layer; or, heating and melting a non-steroidal anti-inflammatory analgesic in the form of an alkali metal salt, a rosin ester derivative, an inorganic acid, and any components added as needed, and extending the melt on a support to form an adhesive layer. Furthermore, by bonding the adhesive layer to the backing layer, etc., a backing layer is formed on the adhesive layer, thereby producing a non-aqueous percutaneous absorption preparation having a backing layer.

[0099] Example

[0100] Hereinafter, the present invention will be specifically described based on examples, but the present invention is not limited to these examples.

[0101] [Example]

[0102] A non-aqueous percutaneous absorption preparation having the composition shown in Table 1-1 and Table 1-2 was prepared. Specifically, hydrogenated rosin glycerol ester, styrene-isoprene-styrene block copolymer, polyisobutylene, liquid paraffin and butylated hydroxytoluene were melt-kneaded at about 150°C, and then loxoprofen sodium hydrate, phosphoric acid and l-menthol were added and mixed to obtain an adhesive layer forming composition. The adhesive layer was 1.0 g / 70 cm 2The obtained adhesive layer forming composition was stretched on the demoulding surface of a polyethylene terephthalate film having a thickness of 75 μm to form an adhesive layer having a thickness of about 150 μm. Then, a polyethylene terephthalate woven fabric having a thickness of 500 μm was bonded to the adhesive layer and cut into a desired size to obtain a non-aqueous percutaneous absorption preparation.

[0103] In addition, the amounts shown in Table 1-1 and Table 1-2 are mass %.

[0104] [Table 1-1]

[0105]

[0106] [Table 1-2]

[0107]

[0108] [Comparative Example]

[0109] The same operation procedure as in Example was used to prepare a non-aqueous percutaneous absorption preparation having the composition shown in Table 2. The amounts shown in Table 2 are in mass %.

[0110] [Table 2]

[0111]

[0112] [Test Example 1: Silicone membrane permeation test]

[0113] In a Franz-type diffusion cell for permeation testing in which warm water at 32°C was circulated, a silicone membrane (thickness: 0.2 mm) cut into 2.5 cm in both horizontal and vertical dimensions was set. The non-aqueous percutaneous absorption preparations prepared in the Examples or Comparative Examples were cut into 1 cm in diameter (effective area: 0.785 cm 2 ) to obtain a test piece. Peel off the polyethylene terephthalate film (peel-off liner) from the test piece to expose the adhesive layer, and stick the adhesive layer on the upper part of the silicone film to start the test. The lower part of the silicone film is filled with Tyrode's solution (4 mL) as a receiving liquid, and stirred with a magnetic stirrer until the end of the test. Collect 0.5 mL of the receiving liquid 24 hours after the start of the test, and determine the amount of drug contained by high performance liquid chromatography (HPLC). Calculate the 24-hour cumulative permeation amount (nmol / cm 2 ).

[0114] [Test Example 2: Adhesion Test]

[0115] The non-aqueous percutaneous absorption preparations obtained in Examples and Comparative Examples were evaluated by a finger touch tack test (after peeling off the release liner, pressing a finger on the surface of the adhesive layer for 1 to 2 seconds, and then evaluating the tackiness when the finger was released from the surface) according to the following criteria.

[0116] Evaluation Criteria

[0117] A: Very good adhesion.

[0118] B: Adhesiveness that does not cause any problem in the use of the non-aqueous percutaneous absorption preparation.

[0119] C: Unacceptable adhesion.

[0120] [Test Example 3: Manufacturing Adaptability Test]

[0121] When each of the examples and comparative examples was produced, the production suitability was evaluated according to the following criteria.

[0122] Evaluation Criteria

[0123] A: The adhesive layer-forming composition can be easily and uniformly stirred and spread.

[0124] B: Although there is a slight stress, the adhesive layer-forming composition can be uniformly stirred and spread.

[0125] C: It is difficult to uniformly stir and spread the adhesive layer-forming composition.

[0126] The results of Test Examples 1 to 3 are shown in Table 3.

[0127] [Table 3]

[0128]

[0129] ※1: The content of loxoprofen sodium is the value converted to anhydrous form.

[0130] ※2: Evaluation criteria for adhesiveness

[0131] A: Very good adhesion.

[0132] B: Adhesiveness that does not cause any problem in the use of the non-aqueous percutaneous absorption preparation.

[0133] C: Unacceptable adhesion.

[0134] ※3: Evaluation criteria for manufacturing adaptability

[0135] A: The adhesive layer-forming composition can be easily and uniformly stirred and spread.

[0136] B: Although there is a slight stress, the adhesive layer-forming composition can be uniformly stirred and spread.

[0137] C: It is difficult to uniformly stir and spread the adhesive layer-forming composition.

[0138] For the organic silicon membrane permeation test, the results of Example 1, Example 4 and Example 9 in Table 3 and the result of Comparative Example 8 are plotted and the resulting curve is shown in FIG. Figure 1 In addition, Comparative Example 8 corresponds to Example 2 described in Patent Document 1.

[0139] according to Figure 1 The results shown show that when the content of hydrogenated rosin glycerol ester (hereinafter also referred to as "HRGE") is 10.0 mass %, there is a significant difference between the 24-hour cumulative permeation amount of Examples 1, 4 and 9 and the 24-hour cumulative permeation amount of Comparative Example 8. Although the content of loxoprofen sodium (hereinafter also referred to as "LOX Na") in Examples 1, 4 and 9 is less than that in Comparative Example 8 (the contents of Examples 1, 4 and 9 are 2.0 mass %, 3.0 mass % and 4.0 mass %, respectively, while the content of Comparative Example 8 is 5.0 mass %), the non-aqueous percutaneous absorption preparations of Examples 1, 4 and 9 are superior to the non-aqueous percutaneous absorption preparation of Comparative Example 8 in terms of skin permeability.

[0140] For the organic silicon membrane permeation test, the results of Example 2, Example 6 and Example 10 in Table 3 and the results of Comparative Example 1 and Comparative Example 9 are plotted and the resulting curve is shown in FIG. Figure 2 In addition, Figure 2 In the figure, the long dashed line (-·-) is a line indicating the 24-hour cumulative permeation amount in Comparative Example 8.

[0141] according to Figure 2 The results shown show that even when the HRGE content is 20.0 mass %, there is a significant difference between the 24-hour cumulative permeation amount of Examples 2, 6, and 10 and the 24-hour cumulative permeation amount of Comparative Example 9. Figure 1 The results shown are the same. Although the content of LOX Na in Examples 2, 6 and 10 is less than that in Comparative Example 9 (the contents of LOX Na in Examples 2, 6 and 10 are 2.0 mass %, 3.0 mass % and 4.0 mass %, respectively, while the content in Comparative Example 9 is 5.0 mass %), the non-aqueous percutaneous absorption preparations of Examples 2, 6 and 10 are superior in skin permeability to the non-aqueous percutaneous absorption preparation of Comparative Example 9.

[0142] As described above, when the content of LOX Na is 2.0 mass % to 4.0 mass %, there is significant skin permeability, so the relationship between the content of LOX Na (2.0 mass % to 4.0 mass %) and the content of HRGE was studied.

[0143] For the organic silicon membrane permeation test, the results of Example 1 to Example 3 and the results of Comparative Examples 2 to Comparative Examples 4 in Table 3 are plotted and the resulting curve is shown in FIG. Figure 3 In addition, Figure 3 In the figure, the long dashed line (-·-) is a line indicating the 24-hour cumulative permeation amount in Comparative Example 8.

[0144] according to Figure 3 The results shown in Table 3 show that when the content of LOX Na is 2.0 mass %, if the content of HRGE is greater than 30.0 mass %, the 24-hour cumulative permeation amount decreases sharply. In addition, according to the results shown in Table 3, the adhesiveness and manufacturing suitability of Comparative Examples 2 and 3, in which the content of HRGE is 5.0 mass % or less, are unqualified, and the non-aqueous percutaneous absorption preparations of Comparative Examples 2 and 3 do not have sufficient adhesiveness and manufacturing suitability.

[0145] Therefore, according to Figure 3 As shown in the results in Table 3, when the content of LOX Na was 2.0 mass % and the content of HRGE was 10.0 mass % to 30.0 mass %, excellent skin permeability and sufficient adhesiveness and manufacturing adaptability were exhibited.

[0146] For the organic silicon membrane permeation test, the results of Examples 4 to 8 in Table 3 were plotted and the resulting curves were plotted as follows: Figure 4 In addition, Figure 4 In the figure, the long dashed line (-·-) is a line indicating the 24-hour cumulative permeation amount in Comparative Example 8.

[0147] according to Figure 4 The results shown show that when the content of LOX Na is 3.0 mass % and the content of HRGE is 10.0 mass % to 30.0 mass %, there is a significant difference between the 24-hour cumulative permeation amount of Examples 4 to 8 and the 24-hour cumulative permeation amount of Comparative Example 8, and the non-aqueous percutaneous absorption preparations of Examples 4 to 8 have excellent skin permeability compared to the non-aqueous percutaneous absorption preparation of Comparative Example 8.

[0148] Therefore, according to Figure 4 As shown in the results in Table 3, when the content of LOX Na was 3.0 mass % and the content of HRGE was 10.0 mass % to 30.0 mass %, excellent skin permeability and sufficient adhesiveness and manufacturing adaptability were exhibited.

[0149] For the organic silicon membrane permeation test, the results of Examples 9 to 12 in Table 3 and the results of Comparative Examples 5 to 7 are plotted and the resulting curve is shown in FIG. Figure 5 In addition, Figure 5 In the figure, the long dashed line (-·-) is a line indicating the 24-hour cumulative permeation amount in Comparative Example 8.

[0150] according to Figure 5 The results shown in Table 3 show that when the content of LOX Na is 4.0 mass %, if the content of HRGE is greater than 30.0 mass %, the 24-hour cumulative permeation amount decreases sharply. In addition, according to the results shown in Table 3, the adhesiveness and manufacturing suitability of Comparative Examples 5 and 6, in which the content of HRGE is 5.0 mass % or less, are unqualified, and the non-aqueous percutaneous absorption preparations of Comparative Examples 5 and 6 do not have sufficient adhesiveness and manufacturing suitability.

[0151] Therefore, according to Figure 5 As shown in the results in Table 3, when the content of LOX Na was 4.0 mass % and the content of HRGE was 10.0 mass % to 30.0 mass %, excellent skin permeability and sufficient adhesiveness and manufacturing adaptability were exhibited.

[0152] These results show that when the content of LOX Na is 2.0 mass % to 4.0 mass % and the content of HRGE is 10.0 mass % to 30.0 mass %, excellent skin permeability and sufficient adhesiveness and production suitability are exhibited.

Claims

1. A non-aqueous percutaneous absorption preparation comprising a support and an adhesive layer laminated on the support, in, The adhesive layer contains: 2% to 4% by mass of a nonsteroidal anti-inflammatory analgesic in the form of an alkali metal salt based on the total mass of the adhesive layer, 10% to 30% by mass of a rosin ester derivative based on the total mass of the adhesive layer, and Inorganic acid.

2. The non-aqueous percutaneous absorption preparation according to claim 1, in, The non-steroidal anti-inflammatory analgesic is loxoprofen sodium hydrate, The rosin ester derivative is hydrogenated rosin glycerol ester.

3. The non-aqueous percutaneous absorption preparation according to claim 1 or 2, in, The inorganic acid is phosphoric acid.

4. The non-aqueous percutaneous absorption preparation according to claim 3, in, The adhesive layer includes a rubber adhesive, The rubber adhesive is a styrene-isoprene-styrene block copolymer.

5. The non-aqueous percutaneous absorption preparation according to claim 4, in, The adhesive layer further contains at least one selected from the group consisting of a plasticizer, a thickener, a percutaneous absorption accelerator, and a stabilizer.

6. The non-aqueous percutaneous absorption preparation according to claim 5, in, The non-aqueous percutaneous absorption preparation is a non-aqueous percutaneous absorption preparation further comprising a backing layer laminated on the adhesive layer.

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