Flurbiprofen-including transdermal absorption type preparation

Abstract

By increasing the dissolved concentration of a drug in a composition for external use, said composition including flurbiprofen and an adhesive agent, the present invention provides a transdermal absorption type preparation that demonstrates increased transdermal absorption of flurbiprofen, is smaller, and also has a superior long-term drug preservation property.　This transdermal absorption type preparation comprises a support body layer and an adhesive agent layer that is layered on the support body layer. The adhesive agent layer includes an adhesive agent, flurbiprofen, at least one component selected from a solubilizer and a transdermal absorption promoter, a tackifier, and a plasticizer. The solubilizer includes or does not include cyclodextrin. The adhesive agent layer does not include peppermint oil. Per 100 mass% of the adhesive agent layer, the flurbiprofen content is 3 mass% to 20 mass%, the solubilizer content excluding cyclodextrin is 0 mass% to 20 mass%, the transdermal absorption promoter content is 0 mass% to 40 mass%, the tackifier content is 5 mass% to 60 mass%, and the plasticizer content is 5 mass% to 50 mass%.

Description

Flurbiprofen-containing transdermal formulation

[0001] This invention relates to a transdermal formulation containing flurbiprofen as its main component.

[0002] Flurbiprofen is a propanoate-based nonsteroidal anti-inflammatory drug (NSAID) primarily used to relieve pain and reduce inflammation associated with arthritis. Oral medications containing flurbiprofen are also commercially available. Flurbiprofen axetil, a prodrug containing flurbiprofen, is widely used for postoperative pain relief and pain management in various cancers. However, patients who cannot take oral medication or who require injections for cancer pain relief must go to the hospital, so there is a demand from patients for a transdermal patch that is easy to administer and has systemic effects. However, a transdermal patch containing systemic flurbiprofen for cancer pain relief has not yet been launched.

[0003] Flurbiprofen is a racemic mixture of S- and R- of 2-(2-fluoro-4-biphenylyl)propionic acid. S-flurbiprofen is the active ingredient, and it has 1,000 times higher inhibitory activity against COX-2, which is involved in inflammation, compared to R-flurbiprofen. A topical preparation containing S-flurbiprofen and peppermint oil as active ingredients, "Locoa® Tape," is commercially available, and its indication is limited to anti-inflammatory and analgesic effects for osteoarthritis. The dosage and administration of a systemic transdermal formulation, such as a tablet or injection, that is expected to have efficacy in relieving cancer pain or postoperative pain, has not been disclosed. As a flurbiprofen preparation (injectable) that exhibits systemic effects, there is "Ropion® Injection 50 mg." This injection uses flurbiprofen axetil, a flurbiprofen precursor, as its active ingredient. The precursor is administered intravenously and rapidly converted to flurbiprofen, exerting its effects. An oral formulation is available, "Floben® Tablets 40." This oral formulation uses racemic flurbiprofen, so while the concentration of flurbiprofen is the same as when only S-flurbiprofen is administered, the activity is half. Furthermore, regarding the dosage and administration of Locoa® Tape, there is a restriction on the use of more than two large 10cm x 14cm patches. Because the systemic exposure when two patches are applied reaches a level similar to that of the usual dose of oral flurbiprofen, the number of patches applied per day should not exceed two. Although it is a transdermal formulation intended for systemic effects, applying two large 10cm x 14cm patches is burdensome for the patient, and the large contact area with the skin poses a significant risk of skin irritation.

[0004] Various developments have been made regarding transdermal patches containing flurbiprofen as the active ingredient. It is known that adding light anhydrous silicic acid to a water-based adhesive containing flurbiprofen suppresses the decrease in content over time and enhances long-term stability (Patent Document 1). It is known that calcium hydroxide is added to transdermal patches to stably maintain the high drug release and transdermal absorption of flurbiprofen (Patent Document 2). A transdermal patch is known in which flurbiprofen is incorporated into an adhesive consisting only of styrene-isoprene-styrene block copolymer (SIS), rosin resin, and liquid paraffin, and the amount of rosin resin to flurbiprofen is 10 times or more by weight ratio (Patent Document 3). A transdermal patch containing SIS, an tackifier, a terpene, a sebacate ester, an alkylglycerol ether, and a nonsteroidal anti-inflammatory drug (such as flurbiprofen) is known (Patent Document 4). In Patent Document 4, the sebacate ester is added as a solubilizer and permeation enhancer, similar to the terpene. A patch comprising an ointment layer and a support containing SIS, an tackifier, a plasticizer, an anti-inflammatory agent (such as flurbiprofen), and a hydrogenated oil is known (Patent Document 5). Patent Document 5 describes that fatty acid esters such as isopropyl myristate and diisopropyl adipate can be added as a drug solubilizer and transdermal absorption enhancer.

[0005] Japanese Patent Publication No. 2018-172340 (Patent No. 6877737), Japanese Patent Publication No. 2011-20946 (Patent No. 5493163), International Publication No. 2006 / 092829 (Patent No. 5280678), Japanese Patent Publication No. 2008-13494 (Patent No. 5085062), Japanese Patent Publication No. 2007-8927 (Patent No. 4939113)

[0006] This invention relates to a transdermal formulation containing flurbiprofen, which is small and can be applied once a day for pain relief after surgery or cancer. Preferably, the tape of this invention exhibits an AUC (area under the blood drug concentration-time curve) equivalent to that of tablets or injections. To achieve this, it is necessary to include a higher concentration of the drug in the base than in the Locoa® tape, significantly increasing the drug content per sheet and skin permeability. While the Locoa® tape has already demonstrated improved solubility and transdermal absorption of S-flurbiprofen using peppermint oil, further increasing the drug concentration is difficult as long as peppermint oil is used. A challenge is that incorporating flurbiprofen in high concentrations into the adhesive layer tends to cause crystal precipitation and reduced skin permeability. Additionally, while there are individual differences in the scent of peppermint oil, it can sometimes be unpleasant. In other words, the object of the present invention is to provide a smaller transdermal formulation that is also excellent in terms of long-term drug storage, in which a topical composition containing flurbiprofen and an adhesive increases the solubility of the drug in the composition, thereby improving the transdermal absorption of flurbiprofen.

[0007] To solve the above problems, the inventors conducted diligent research and found that by dissolving flurbiprofen in a specific amount in the adhesive layer, it is possible to provide drug transdermal permeability equivalent to the AUC of tablets or injections, and furthermore, it is possible to achieve drug transdermal permeability more than twice that of commercially available Locoa® tape, thus completing the present invention. In the present invention, AUC (Area under the blood drug concentration-time curve) refers to the area under the blood drug concentration-time curve in in vivo animal studies or human drug administration studies, or the area under the permeability (or permeability rate)-time curve in in vitro skin permeability studies on various skin samples. AUC equivalent means that the AUC of the present invention is the same as or within ±45% of the AUC of a comparative example or reference example. Specifically, it is preferable that the AUC when the transdermal formulation of the present invention is applied to the skin for 24 hours is 0.5 to 1.5 times the AUC of 24 hours after administration of the same amount of Froben® Tablet 40 or Ropion® Injection 50 mg. When evaluating AUC equivalence, the AUC used is the value (mean) obtained from an in vivo animal study, preferably an animal study in which the drug was administered to rats. Details of the animal study are described in the Examples.

[0008] The present invention is as follows: [1] A transdermal formulation comprising a support layer and an adhesive layer laminated on the support layer, wherein the adhesive layer contains an adhesive, flurbiprofen, at least one component selected from a solubilizer and a transdermal absorption enhancer, a tackifier, and a plasticizer, wherein the solubilizer does not contain or contains cyclodextrin, the adhesive layer does not contain peppermint oil, the content of flurbiprofen in 100% by mass of the adhesive layer is 3% to 20% by mass, the content of the solubilizer excluding cyclodextrin is 0% to 20% by mass, the content of the transdermal absorption enhancer is 0% to 40% by mass, the content of the tackifier is 5% to 60% by mass, and the content of the plasticizer is 5% to 50% by mass. [2] The transdermal formulation according to [1], wherein the adhesive is at least one selected from the group consisting of styrene-isoprene-styrene block copolymer and polyisobutylene. [3] The transdermal formulation according to [1] or [2], wherein the flurbiprofen is S-flurbiprofen. [4] The transdermal formulation according to any one of [1] to [3], wherein the adhesive layer contains the solubilizer, and the solubilizer contains a dibasic fatty acid ester. [5] The transdermal formulation according to [4], wherein the octanol / water partition coefficient (XlogP) of the dibasic fatty acid ester is 2.0 to 6.0. [6] The transdermal formulation according to [4] or [5], wherein the dibasic fatty acid ester is at least one selected from the group consisting of diisopropyl adipate, di-n-propyl adipate, diisopropyl sebacate, and diethyl sebacate. [7] The transdermal formulation according to any one of [1] to [6], wherein the adhesive layer contains the solubilizer, and the solubilizer contains cyclodextrin. [8] The transdermal formulation according to [7], wherein the cyclodextrin content in 100% by mass of the adhesive layer is 3% to 40% by mass. [9] The transdermal formulation according to [7] or [8], wherein the cyclodextrin is β-cyclodextrin.

[10] The transdermal formulation according to any one of [7] to [9], wherein the adhesive layer contains an inclusion complex of the cyclodextrin and flurbiprofen.

[11] The transdermal formulation according to any one of [7] to

[10] , wherein the adhesive layer comprises an inclusion complex of the cyclodextrin and the flurbiprofen and the flurbiprofen as an uninclusion complex.

[12] The transdermal formulation according to any one of [1] to

[11] , wherein the adhesive layer comprises the transdermal absorption enhancer, and the transdermal absorption enhancer is lauric acid diethanolamide.

[13] The transdermal formulation according to any one of [1] to

[12] , wherein the tackifier is at least one selected from the group consisting of rosin glycerin ester and hydrogenated rosin glycerin ester.

[14] The transdermal formulation according to any one of [1] to

[13] , wherein the plasticizer is liquid paraffin.

[15] The transdermal formulation is a tape, and the application area per sheet of the transdermal formulation is 50 cm². ２ ~140cm ２ A transdermal preparation according to any one of [1] to

[14] , wherein the amount of flurbiprofen per transdermal preparation is 20 mg to 200 mg.

[16] A transdermal preparation according to any one of [1] to

[15] , wherein the area under the blood drug concentration-time curve (AUC) when the transdermal preparation is applied to the skin for 24 hours is 0.5 to 1.5 times the AUC after administering the same amount of Froben® Tablet 40 or Ropion® Injection 50 mg for 24 hours.

[17] A transdermal preparation according to any one of [1] to

[16] , wherein the AUC when the transdermal preparation is applied to the skin for 24 hours is 2 times or more the AUC when Rocoa® Tape is applied to the skin for 24 hours.

[0009] The transdermal formulation of the present invention can contain a specific amount of flurbiprofen dissolved in an adhesive, thereby improving the transdermal absorption of flurbiprofen. The transdermal formulation of the present invention can have an AUC equivalent to that of a tablet or an injectable formulation. Furthermore, it can have an AUC more than twice that of commercially available Locoa® tape.

[0010] Figure 1 is a graph showing the time course of plasma drug concentrations when the transdermal formulation of Example 7 and the commercially available products of Reference Examples 1-3 were administered to rats.

[0011] The transdermal formulation of the present invention comprises a support layer and an adhesive layer laminated on the support layer. The adhesive layer is laminated on a first surface of the support layer. A peelable film (release film, release film) may be laminated on a second surface of the adhesive layer (on the surface opposite to the first surface). The adhesive layer is the portion that is pressed against the skin when the transdermal formulation is applied.

[0012] The adhesive layer described above contains flurbiprofen. In the present invention, flurbiprofen is a concept that includes the R-isomer, S-isomer, racemic mixture, and prodrug. Among flurbiprofen, S-flurbiprofen in particular is the active component of flurbiprofen and has higher activity than racemic flurbiprofen, so it is preferable to include it as the main ingredient in the adhesive layer. That is, it is preferable that the flurbiprofen is S-flurbiprofen. Examples of "pharmaceutically acceptable salts" used in the present invention include sodium salts and potassium salts.

[0013] In the above adhesive layer, the flurbiprofen content is 3% to 20% by mass, preferably 4% to 14% by mass. If the flurbiprofen content is less than 3% by mass, the transdermal absorption flux is small, requiring the formulation to be made over a large area. If the flurbiprofen content exceeds 20% by mass, the drug concentration is high, making it difficult to maintain a stable dissolved state in the adhesive layer.

[0014] The adhesive layer described above contains an adhesive. The adhesive may be of one type only, or two or more types may be used in combination. Preferably, the adhesive is at least one adhesive selected from rubber-based adhesives, acrylic-based adhesives, and silicone-based adhesives. Examples of rubber-based adhesives include polyisoprene, polyisobutylene (PIB), polybutadiene, styrene-butadiene-styrene block copolymer, styrene-isoprene-styrene (SIS) block copolymer, styrene-butadiene rubber, styrene-isoprene rubber, and combinations thereof. From the viewpoint of increasing the skin permeability of flurbiprofen, it is preferable that the adhesive is at least one selected from the group consisting of SIS block copolymer and polyisobutylene. From the viewpoint of flurbiprofen solubility, it is more preferable that the adhesive contains a SIS block copolymer.

[0015] Examples of the acrylic adhesives mentioned above include adhesives obtained by polymerizing or copolymerizing at least one of the (meth)acrylic monomers such as (meth)acrylic acid, (meth)acrylic acid-2-ethylhexyl, (meth)acrylate, (meth)acrylate, and (meth)acrylate, and hydroxyethyl (meth)acrylate. Examples of the silicone adhesives mentioned above include adhesives mainly composed of silicone rubber such as polydimethylsiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane.

[0016] In 100% by mass of the above adhesive layer, the content of the above adhesive is preferably 1% to 40% by mass, more preferably 5% to 40% by mass, even more preferably 10% to 40% by mass, and particularly preferably 20% to 40% by mass.

[0017] The adhesive layer contains at least one component selected from a solubilizer and a transdermal absorption enhancer. The component may contain a solubilizer, a transdermal absorption enhancer, or both a solubilizer and a transdermal absorption enhancer. The adhesive layer may contain a solubilizer, a transdermal absorption enhancer, or both a solubilizer and a transdermal absorption enhancer.

[0018] To dissolve flurbiprofen and improve its skin permeability, the adhesive layer preferably contains a solubilizer. The solubilizer may be used alone or in combination of two or more. Examples of the solubilizer include cyclodextrin, polyhydric alcohol, and fatty acid ester. In this specification, solubilizers other than cyclodextrin may be referred to as the "first solubilizer," and cyclodextrin may be referred to as the "second solubilizer." The solubilizer may or may not contain the first solubilizer. The solubilizer may or may not contain the second solubilizer (cyclodextrin). The solubilizer may contain the first solubilizer, may contain the second solubilizer, or may contain both the first and second solubilizers. The first solubilizer is preferably at least one selected from the group consisting of polyhydric alcohol and fatty acid ester. The above-mentioned solubilizer preferably contains at least one selected from the group consisting of polyhydric alcohols and fatty acid esters. Examples of the above-mentioned polyhydric alcohols include diethylene glycol, propylene glycol, triethylene glycol, polyethylene glycol, and dipropylene glycol. Examples of the above-mentioned fatty acid esters include isopropyl myristate, isopropyl palmitate, hexyl laurate, diethyl sebacate, diisopropyl sebacate, triethyl citrate, and crotamiton. From the viewpoint of preventing crystal precipitation in the adhesive layer of flurbiprofen, the above-mentioned first solubilizer is preferably a medium-chain fatty acid ester. The medium-chain fatty acid in the medium-chain fatty acid ester is preferably a dibasic fatty acid such as adipic acid and sebacic acid. That is, the above-mentioned first solubilizer is preferably a dibasic fatty acid ester. The above-mentioned solubilizer preferably contains a dibasic fatty acid ester. The alcohol for esterification is preferably ethanol or propanol. The solubilizer for the purpose of stably dissolving the drug in the adhesive layer preferably has appropriate polarity. For example, the octanol-water partition ratio (XlogP) of the above-mentioned dibasic fatty acid ester is preferably 2.0 to 6.0.If the XlogP level is below 2.0 or above 6.0, the drug has poor affinity and is unable to function as a solubilizer.

[0019] Among the dibasic fatty acid esters, diisopropyl adipate (XlogP: 2.2), di-n-propyl adipate, and diisopropyl sebacate (XlogP: 4.4) are particularly preferred as propyl alcohol esters of dibasic fatty acids, and diethyl sebacate (XlogP: 3.5), which is an ester made using ethanol, is also an example. From the viewpoint of preventing crystal precipitation in the adhesive layer of flurbiprofen, it is more preferable that the above-mentioned dibasic fatty acid ester is at least one selected from the group consisting of diisopropyl adipate, di-n-propyl adipate, diisopropyl sebacate, and diethyl sebacate.

[0020] In 100% by mass of the above adhesive layer, the content of the above solubilizer excluding cyclodextrin (i.e., the content of the first solubilizer) is 0% by mass to 20% by mass, preferably 0% by mass to 14% by mass, more preferably 3% by mass to 14% by mass, and even more preferably 4% by mass to 14% by mass. If the content of the first solubilizer is less than 3% by mass, it tends to be less effective as a solubilizer compared to when it is 3% by mass or more. If the content of the first solubilizer exceeds 14% by mass, it becomes difficult to maintain the properties of the adhesive layer, such as reducing its tackiness.

[0021] To increase the solubility of flurbiprofen in the adhesive layer and prevent crystal precipitation, the solubilizer preferably contains the second solubilizer (cyclodextrin), and more preferably contains both the first and second solubilizers. Examples of cyclodextrins include α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. The cyclodextrin encapsulates flurbiprofen, suppressing crystallization of flurbiprofen in the adhesive layer. As a result, the solubility of flurbiprofen in the adhesive layer is increased, and the transdermal absorption of the drug is increased. Therefore, the adhesive layer preferably contains an inclusion complex of the cyclodextrin and flurbiprofen. The cyclodextrin is preferably β-cyclodextrin. In the present invention, all of the flurbiprofen in the adhesive layer may be added as a cyclodextrin inclusion complex, or some may be added as an inclusion complex and the remainder as an uninclusion complex. The coexistence of the uninclusion-dissolved form of flurbiprofen and the cyclodextrin-inclusion-enclosed form of flurbiprofen in the adhesive layer is particularly effective for transdermal drug delivery. That is, it is preferable that the adhesive layer contains an inclusion complex of the cyclodextrin and the flurbiprofen, and flurbiprofen as an uninclusion complex. Even if flurbiprofen and cyclodextrin are mixed together with other additives to form the adhesive layer, the same effect as when an inclusion complex is formed during the mixing process and mixed as an inclusion complex is achieved.

[0022] In 100% by mass of the above adhesive layer, the content of the second solubilizer (cyclodextrin) is preferably 3% to 40% by mass, and more preferably 10% to 30% by mass. If the content of the second solubilizer is less than 3% by mass, it will not function as a solubilizer, and if it exceeds 40% by mass, it will degrade the physical properties of the adhesive layer and make it difficult to maintain the properties of the adhesive layer.

[0023] The mass ratio of flurbiprofen to the solubilizer in the adhesive layer (flurbiprofen:solubilizer) is preferably 1:0.2 to 1:3, and more preferably 1:0.4 to 1:2, from the viewpoint of improving the skin permeability of flurbiprofen and preventing the precipitation of flurbiprofen crystals.

[0024] From the standpoint of increasing the concentration of flurbiprofen and reducing unpleasant odors, the adhesive layer does not contain peppermint oil.

[0025] The above transdermal absorption enhancer is suitably used to improve the skin permeability of the transdermal formulation of the present invention. The above transdermal absorption enhancer may be used alone or in combination of two or more. Any conventionally known transdermal absorption enhancer can be used as the above transdermal absorption enhancer. Examples of the above transdermal absorption enhancer include alcohols such as menthol, camphor, and cetyl alcohol; glycerin esters such as glyceryl monolaurate and glyceryl monooleate; acid amides such as lauric acid diethanolamide; and neutral surfactants such as polyethylene glycol dilauryl ether. From the viewpoint of further improving skin permeability, the above transdermal absorption enhancer is preferably lauric acid diethanolamide.

[0026] If the amount of the above-mentioned transdermal absorption enhancer is too low, the transdermal absorption effect will not improve, and if it is too high, the tackiness of the adhesive layer will decrease. The amount of the above-mentioned transdermal absorption enhancer in 100% by mass of the adhesive layer is 0% to 40% by mass, preferably 1% to 40% by mass, more preferably 3% to 40% by mass, and even more preferably 5% to 20% by mass.

[0027] The above adhesive layer contains a tackifier. The use of the above tackifier can improve the adhesion and physical stability of the above adhesive layer. Only one type of tackifier may be used, or two or more types may be used in combination. Examples of the above tackifier include rosin, rosin glycerol ester, hydrogenated rosin (also called hydrogenated rosin), hydrogenated rosin glycerol ester and rosin pentaerythritol ester, and other rosin derivatives; alicyclic saturated hydrocarbon resins such as Alcon P100 (trade name, manufactured by Arakawa Chemical Industries, Ltd.); aliphatic hydrocarbon resins such as Quinton B170 (trade name, manufactured by Nippon Zeon Co., Ltd.); terpene resins such as Clearon P-125 (trade name, manufactured by Yasuhara Chemical Co., Ltd.); and maleic acid resins. From the viewpoint of further improving the adhesion and physical stability of the adhesive layer, the tackifier is preferably at least one selected from the group consisting of rosin ester resin, hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, and terpene resin, more preferably at least one selected from the group consisting of rosin glycerin ester and hydrogenated rosin glycerin ester, and more preferably hydrogenated rosin glycerin ester (for example, trade name KE-311, manufactured by Arakawa Chemical Industries, Ltd.).

[0028] In 100% by mass of the above adhesive layer, the content of the tackifier is 5% to 60% by mass, preferably 10% to 50% by mass, more preferably 16% to 44% by mass, and even more preferably 20% to 40% by mass. Furthermore, in the above adhesive layer, the mass ratio of the content of the tackifier to the content of flurbiprofen (content of tackifier / content of flurbiprofen) is preferably 3 to 9.

[0029] The adhesive layer contains a plasticizer. The plasticizer may be used alone or in combination of two or more types. Examples of plasticizers include petroleum oils such as paraffinic process oils, naphthenic process oils and aromatic process oils; squalane; squalene; vegetable oils such as olive oil, camellia oil, castor oil, tall oil and peanut oil; silicone oil; dibasic acid esters such as dibutyl phthalate and dioctyl phthalate; liquid rubbers such as polybutene and liquid isoprene rubber; glycol salicylate; triacetin, etc. The plasticizer is preferably at least one selected from the group consisting of liquid paraffin and liquid polybutene, and more preferably liquid paraffin. The content of the plasticizer in 100% by mass of the adhesive layer is 5% to 50% by mass, and preferably 10% to 45% by mass.

[0030] The adhesive layer described above preferably contains a stabilizer. The use of the stabilizer can further improve the stability of flurbiprofen. The stabilizer may be used alone or in combination of two or more types. Examples of the stabilizer include fatty acid metal salts (such as magnesium stearate), antioxidants (such as tocopherol derivatives, ascorbic acid derivatives, erythorbic acid derivatives, nordihydroguaiaretinic acid, gallic acid derivatives, dibutylhydroxytoluene (BHT), butylhydroxyanisole, 2-mercaptobenzimidazole, sulfites, etc.), and ultraviolet absorbers (such as imidazole derivatives, benzotriazole derivatives, p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, cinnamic acid derivatives, benzophenone derivatives, coumaric acid derivatives, camphor derivatives, etc.). From the viewpoint of further improving the stability of flurbiprofen, the stabilizer is preferably dibutylhydroxytoluene (BHT). In 100% by mass of the adhesive layer, the content of the stabilizer is preferably 0.05% to 10% by mass, and more preferably 0.1% to 5% by mass.

[0031] The adhesive layer may contain a filler. Only one type of filler may be used, or two or more types may be used in combination. Examples of fillers include metal oxides (zinc oxide, titanium oxide, etc.), metal salts (calcium carbonate, magnesium carbonate, anhydrous silicic acid, zinc stearate, etc.), silicic acid compounds (kaolin, talc, bentonite, aerosil, hydrated silica, aluminum silicate, magnesium silicate, magnesium aluminometasilicate, etc.), and metal hydroxides (aluminum hydroxide, etc.). The content of the filler in 100% by mass of the adhesive layer is preferably 0.05% to 10% by mass, and more preferably 0.05% to 5% by mass.

[0032] The mass of the adhesive layer (mass of the ointment) is 10 g / m², from the viewpoint of skin adhesion. ２ ~1000g / m ２ Preferably, 30 g / m ２ ~300g / m ２ More preferably, 50 g / m ２ ~250g / m ２ This is even more preferable. In the present invention, "ointment" is a concept that includes both the adhesive and the drugs and other components contained in the adhesive. The mass of the ointment refers to the mass of the entire adhesive layer.

[0033] The support layer may have a single-layer structure or a structure of two or more layers. The support layer may be a single layer or a laminate. The support layer preferably includes a support layer in which fibers are in a cloth form (woven fabric, non-woven fabric, or knitted fabric), a non-porous film (non-porous sheet), or a porous film (porous sheet). The material of the support layer is preferably at least one selected from the group consisting of polyester (such as polyethylene terephthalate (PET), polyethylene isophthalate, polypropylene terephthalate, polypropylene isophthalate, polybutylene terephthalate, or polyethylene naphthalate), polyolefin (a polymer or copolymer of vinyl-based monomers such as ethylene, propylene, vinyl acetate, or acrylonitrile), polyamide (such as nylon or silk), polyurethane (PU), and cellulose (such as cotton or hemp). The cloth (woven fabric, non-woven fabric, or knitted fabric) may be coated with a rubber composition. From the viewpoint of flexibility and ease of fitting to the skin, the support layer preferably includes a woven fabric, non-woven fabric, or knitted fabric. From the viewpoint of being small-sized and easy to use, the support layer is also preferably a laminate film of PET and non-woven fabric. The basis weight of the support layer is preferably 30 g / m ２ to 200 g / m ２ .

[0034] The transdermal absorption type preparation of the present invention is preferably a tape preparation. In order to ensure sufficient adhesiveness and a sufficient amount of flurbiprofen permeating through the skin, the sticking area per sheet of the transdermal absorption type preparation is preferably 50 cm ２ to 140 cm ２ , and more preferably 50 cm ２ to 100 cm ２ . Also, the content of flurbiprofen per sheet of the transdermal absorption type preparation is preferably 20 mg to 200 mg, more preferably 30 mg to 170 mg, and even more preferably 40 mg to 160 mg.

[0035] The transdermal preparation in the form of a tape can be produced by the following method, but is not limited thereto, and known methods can be used. Each component constituting the adhesive layer is mixed at a predetermined ratio and melted at 150 to 190 °C. This melt is spread on a release film or a support layer at a temperature of 80 to 120 °C to a predetermined thickness to form an adhesive layer. Then, the support layer is pressure-bonded to the adhesive layer or the release film so that the adhesive layer is sandwiched between the release film and the support layer. The tape of the present invention can be obtained by cutting it to an appropriate size at room temperature and using the hot melt manufacturing method. Similarly, after spreading the melt on the support layer to a predetermined thickness to form an adhesive layer, the support layer may be pressure-bonded to the release film. The above is the hot melt manufacturing method, but each component constituting the adhesive layer may be dissolved or partially dispersed in cyclohexane, toluene, or other appropriate solvents, and a solution coating manufacturing method may be used in which a solution is applied on a release film or a support layer and dried by heating to form an adhesive layer having a predetermined thickness.

[0036] Hereinafter, examples will be shown to more specifically explain the present invention. The present invention is not limited to these examples, and various modifications can be made without departing from the technical idea of the present invention.

[0037] (Preparation of tape containing flurbiprofen (solution coating method)) (Examples 1-20 and Comparative Examples 1-13) A tape agent containing flurbiprofen was prepared by the following method. A paste solution prepared by mixing each component of the adhesive layer using cyclohexane, ethanol, etc. was spread on a release film (a PET film subjected to a release treatment) so that the mass of the paste after drying was about 120 g / m ２ and dried at 80 °C for 10 minutes. A support layer (PET non-woven fabric, thickness: 40 μm) was laminated on the adhesive layer formed on the release film to obtain a tape agent. The size of the tape was 6 cm × 6 cm. This tape was cut into an appropriate size according to the purpose and used in the following experiments.

[0038] (Preparation of β-cyclodextrin inclusion complex) An aqueous solution of β-cyclodextrin and an ethanol solution containing S-flurbiprofen were mixed at 80°C, cooled to room temperature to form a precipitate of the inclusion complex, and purified by washing. The S-flurbiprofen content in the resulting inclusion complex was confirmed to be 20% by mass by extracting and quantifying S-flurbiprofen from the resulting inclusion complex. Considering the molecular weights of S-flurbiprofen and β-cyclodextrin, the inclusion complex is assumed to be a 1:1 inclusion complex of β-cyclodextrin and S-flurbiprofen. In Examples 15 - 17, the inclusion complex was separately prepared and mixed into the paste as described above. In Examples 18 and 19, an amount of S-flurbiprofen equivalent to the inclusion complex and β-cyclodextrin were separately mixed into the paste. It is considered that the inclusion complex was formed during the heat mixing process.

[0039] (Observation of the presence or absence of crystals in the obtained tape preparation) The obtained tape preparation was sealed in an aluminum laminate packaging bag and stored at room temperature (25°C) for 1 week, and then observed by microscopy to see if crystallization of the drug occurred in the adhesive layer. Preparations in which no crystals were observed were designated as A, and preparations in which crystal precipitation was observed were designated as B.

[0040] (Evaluation of the paste cohesiveness (shape retention) of the obtained tape preparation) The tape preparation was placed on a horizontal plane. A rubber roll was rolled over the surface of the adhesive layer to observe the cohesiveness of the paste. Preparations with good shape retention were designated as A, and preparations with poor shape retention were designated as B.

[0041] (Measurement of skin permeation amount) After the tape preparation was attached to the stratum corneum side of human excised skin (thickness 700 μm), a Franz-type diffusion cell for percutaneous permeation experiment (receptor solution 5.7 mL, opening area 2.27 cm ２The tape was attached to the receptor. The receptor side was filled with phosphate buffer (pH 7.4) as the receptor solution, and a skin permeability test was performed at 32°C for 24 hours. After 24 hours, 500 μL of the receptor solution was sampled, and the same amount of receptor solution was added. The amount of drug that permeated into the receptor solution was measured by HPLC (high-performance liquid chromatography), and the cumulative amount of drug that permeated the skin was determined. The results are shown in Tables 1, 3-5 as "permeability" as the amount of drug per unit area. In the tables, "permeability" refers to the amount of drug permeated the skin after 24 hours. The absolute value of permeability differs depending on the human excised skin even with the same tape, so the permeability of the Locoa tape was measured simultaneously for reference in each test. Permeability relative to Locoa tape is shown as "percentage of Locoa tape permeability".

[0042] HPLC conditions Mobile phase: Acetonitrile:Water:Phosphoric acid (600:400:0.5, v / v / v), Flow rate: 1.0 mL / min Column temperature: 40°C, Injection volume: 20 μL Column: COSMOSIL 5C18-AR-II Elution conditions: Acetonitrile:Water:Phosphoric acid (600:400:0.5, v / v / v) Detection: 250 nm UV (Retention time 4 min) S- and R-isomers of flurbiprofen give the same retention time.

[0043] (Measurement of rat pharmacokinetic study (AUC)) Male rats (body weight 200g-250g) were administered a transdermal patch (Example 7), an injectable drug (Ropion® 50mg intravenous injection), and an oral drug (Floben® 40mg tablets) at a dose of 6mg / kg. The transdermal patch was cut into 1.3cm x 1.3cm pieces to a dose of 6mg / kg relative to the rat's body weight and administered via skin. The Locoa® tape was administered in a preparation cut to the same size as the transdermal patch (Example 7) (1.3cm x 1.3cm), resulting in a dose of 2mg / kg. Blood was collected from the rat tails 1, 2, 4, 6, 8, and 24 hours after administration (additional collections for the injectable drug were made at 10 and 30 minutes after administration). The blood samples were transferred to microtubes containing heparin sodium solution, centrifuged, and separated to obtain plasma samples. Deproteinization was performed with acetonitrile, and the drug amount was measured by HPLC. The HPLC conditions were the same as described above. The results are shown in Table 2. The AUC for each dosage form was calculated from Table 2 and its graph, Figure 1, and is shown in the bottom column of Table 2.

[0044] In the table below, the symbols listed alongside the compound names have the following meanings: (a): Tackifier (b): Tackifier (c): Plasticizer (d): Solubilizer (e): Transdermal absorption enhancer (f): Filler (g): Stabilizer

[0045]

[0046] Example 6, which contained both a solubilizer (a solubilizer other than peppermint oil) and a transdermal absorption enhancer, exhibited the best physical properties and the highest transdermal absorption.

[0047]

[0048] Example 7 is a transdermal patch with the same formulation as Example 6. When the same amount of flurbiprofen per unit of body weight was administered to rats, the administration of the injectable and oral formulations showed an AUC equivalent to that of the transdermal patch in Example 7. The Locoa® Tape had the same application area as Example 7, but its AUC was much smaller, less than one-third of that of Example 7.

[0049]

[0050] The comparative examples and examples demonstrate the effect of adding hydrogenated rosin esters and their effectiveness in improving drug solubility (crystallinity) depending on the amount. Examples 9-12 show that, in addition to the combination of "diisopropyl adipate + diethanolamide laurate," diisopropyl sebacate and isopropyl myristate are also effective. Regarding the amount of hydrogenated rosin ester to add, considering the results in Table 3 and other factors, it appears to be 16-44% by mass, more preferably 20-40% by mass.

[0051]

[0052] Examples 13 and 14 involved applying the tape to the stratum corneum side of excised human skin (700 μm thick) and then conducting transdermal penetration experiments using a Franz-type diffusion cell. Post-test skin observations showed that the adhesion of the test tape to the skin was stronger in Example 14 compared to Example 13. This is thought to be due to the better absorption of moisture seeping to the skin surface by anhydrous silicic acid, thus maintaining good adhesion between the skin and the tape.

[0053]

[0054] Examples 15, 16, 17, 18, and 19 demonstrate the effect of β-cyclodextrin. An increase in drug permeability was observed. It was also found that increasing the amount of β-cyclodextrin added worsened the cohesiveness of the adhesive layer and reduced its tackiness.

[0055] (Example 20) A formulation (4 cm x 4 cm) with the same composition as in Example 7 was sealed in an aluminum laminate packaging bag and stored at 60°C for 4 weeks. The S-flurbiprofen content in the adhesive layer was measured by high-performance liquid chromatography (HPLC). The measurement conditions were the same as described above. The content after 4 weeks at 60°C was 99.7% of the initial content (13.7 mg), confirming the stability of the drug.

[0056] (Preparation of flurbiprofen-containing tape (hot melt method)) (Examples 21-22) In Table 6, component A was mixed at 160°C, the temperature was lowered to 130°C and component B was added and mixed, and component C was added and mixed at 120°C to form an ointment. 120 g / m² of this ointment was applied to the release film. ２The material was spread at 125°C to achieve the desired consistency, and a support film was laminated at room temperature to form a tape. The tape produced by the hot-melt method also showed good properties. The lower permeability value in this test compared to previous examples is due to the properties of the human skin used, and the value is extremely high compared to the permeability of Locoa Tape measured simultaneously using the same skin.

[0057]

Claims

1. A transdermal formulation comprising a support layer and an adhesive layer laminated on the support layer, wherein the adhesive layer contains an adhesive, flurbiprofen, at least one component selected from a solubilizer and a transdermal absorption enhancer, a tackifier, and a plasticizer, wherein the solubilizer may or may not contain cyclodextrin, the adhesive layer may not contain peppermint oil, and in 100% by mass of the adhesive layer, the content of flurbiprofen is 3% to 20% by mass, the content of the solubilizer excluding cyclodextrin is 0% to 20% by mass, the content of the transdermal absorption enhancer is 0% to 40% by mass, the content of the tackifier is 5% to 60% by mass, and the content of the plasticizer is 5% to 50% by mass.

2. The transdermal formulation according to claim 1, wherein the adhesive is at least one selected from the group consisting of styrene-isoprene-styrene block copolymer and polyisobutylene.

3. The transdermal formulation according to claim 1 or 2, wherein the flurbiprofen is S-flurbiprofen.

4. The transdermal formulation according to any one of claims 1 to 3, wherein the adhesive layer comprises the solubilizer, and the solubilizer comprises a dibasic fatty acid ester.

5. The transdermal formulation according to claim 4, wherein the octanol / water partition coefficient (XlogP) of the dibasic fatty acid ester is 2.0 to 6.

0.

6. The transdermal formulation according to claim 4 or 5, wherein the dibasic fatty acid ester is at least one selected from the group consisting of diisopropyl adipate, di-n-propyl adipate, diisopropyl sebacate, and diethyl sebacate.

7. The transdermal formulation according to any one of claims 1 to 6, wherein the adhesive layer comprises the solubilizer, and the solubilizer comprises cyclodextrin.

8. The transdermal formulation according to claim 7, wherein the content of the cyclodextrin in 100% by mass of the adhesive layer is 3% to 40% by mass.

9. The transdermal formulation according to claim 7 or 8, wherein the cyclodextrin is β-cyclodextrin.

10. The transdermal formulation according to any one of claims 7 to 9, wherein the adhesive layer comprises an inclusion complex of the cyclodextrin and the flurbiprofen.

11. The transdermal formulation according to any one of claims 7 to 10, wherein the adhesive layer comprises an inclusion complex of the cyclodextrin and the flurbiprofen and the flurbiprofen as an uninclusion complex.

12. The transdermal formulation according to any one of claims 1 to 11, wherein the adhesive layer contains the transdermal absorption enhancer, and the transdermal absorption enhancer is lauric acid diethanolamide.

13. The transdermal formulation according to any one of claims 1 to 12, wherein the tackifier is at least one selected from the group consisting of rosin glycerin ester and hydrogenated rosin glycerin ester.

14. The transdermal formulation according to any one of claims 1 to 13, wherein the plasticizer is liquid paraffin.

15. The transdermal formulation is a tape, and the application area per sheet of the transdermal formulation is 50 cm². ２ ~140cm ２ The transdermal formulation according to any one of claims 1 to 14, wherein the amount of flurbiprofen per transdermal formulation is 20 mg to 200 mg.

16. The transdermal formulation according to any one of claims 1 to 15, wherein the area under the blood drug concentration-time curve (AUC) when the transdermal formulation is applied to the skin for 24 hours is 0.5 to 1.5 times the AUC of 40 mg of Froben® tablets or 50 mg of Ropion® intravenous injection administered in the same amount over 24 hours.

17. The transdermal formulation according to any one of claims 1 to 16, wherein the AUC when the transdermal formulation is applied to the skin for 24 hours is at least twice the AUC when the Locoa® Tape is applied to the skin for 24 hours.

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