Flurbiprofen-containing transdermal formulation

Abstract

The present invention provides a transdermal formulation comprising flurbiprofen and an adhesive, wherein the solubility of the drug in the composition is increased, thereby improving the transdermal absorption of flurbiprofen, resulting in a smaller formulation that also offers excellent long-term storage capabilities. [Solution] A transdermal formulation comprising a support layer and an adhesive layer laminated on the support layer, wherein the adhesive layer contains flurbiprofen, at least one additive selected from a solubilizer and a transdermal absorption enhancer, a tackifier, and a plasticizer, and does not contain peppermint oil, wherein the flurbiprofen content is 3 to 20% by mass, the solubilizer content excluding cyclodextrin is 4 to 14% by mass, the transdermal absorption enhancer content is 3 to 40% by mass, the tackifier content is 5 to 60% by mass, and the plasticizer content is 5 to 50% by mass. Preferably, cyclodextrin is included separately as a solubilizer.

Description

Technical Field

[0001] The present invention relates to a transdermal absorption type preparation containing flurbiprofen as a main component.

Background Art

[0002] Flurbiprofen is a propanoic acid-based non-steroidal anti-inflammatory drug and is mainly used for relieving pain and reducing inflammation caused by arthritis as a topical preparation such as a tape agent or a patch agent. Oral preparations are also commercially available. As an injection, there is flurbiprofen axetil which is a prodrug and is widely used for postoperative pain relief and analgesia for various cancers. However, patients who cannot take medicine orally or patients who receive injections for the purpose of relieving cancer pain have to go to the hospital, so there is a demand from patients for a tape agent that is easy to administer and has a systemic effect (systemic action). However, a systemic action type tape agent containing flurbiprofen for relieving cancer pain has not yet been marketed.

[0003] Flurbiprofen is a racemic form of S- and R-2-(2-fluoro-4-biphenylyl)propionic acid. S-flurbiprofen is the active entity and has an inhibitory effect on COX2 involved in inflammation 1,000 times higher than that of R-flurbiprofen. "Roca (registered trademark) tape" is commercially available as a topical external preparation containing S-flurbiprofen and peppermint oil, and its indication is only anti-inflammatory and analgesic for osteoarthritis. The dosage and usage of a systemic transdermal absorption type preparation that is expected to have the efficacy and effect of relieving cancer pain and postoperative pain like tablets and injections as a tape agent have not been disclosed. As a flurbiprofen preparation that exhibits systemic effects, there is "Ropion® Injection 50mg" as an injectable formulation. This product uses flurbiprofen axetil, a flurbiprofen precursor, as its active ingredient. The precursor is administered intravenously and is rapidly converted to flurbiprofen, exerting its efficacy. As an oral formulation, there is "Froben® Tablets 40". Since both use racemic flurbiprofen, the activity expressed in the body is half that of when S-flurbiprofen is administered alone, even at the same concentration of flurbiprofen. Furthermore, Locoa® Tape has a restriction on the use of up to two large 10x14cm patches, as per the precautions related to usage and dosage. Since 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 10x14cm patches is burdensome for patients, and the large contact area with the skin increases the risk of skin irritation and other problems.

[0004] Various developments are underway regarding transdermal patches containing flurbiprofen as the active ingredient. It is known that adding light anhydrous silicic acid to a water-containing 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 a patch to stably maintain the high drug release and transdermal absorption of flurbiprofen (Patent Document 2); a 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, with the amount of rosin resin being 10 times or more by weight relative to flurbiprofen (Patent Document 3); a transdermal patch is known in which SIS, an tackifier, a terpene, a sebacate ester, an alkylglycerol ether, and a nonsteroidal anti-inflammatory drug (such as flurbiprofen) are present, with the sebacate ester content being 0.1 to 10% by mass of the patch and the nonsteroidal anti-inflammatory drug content being 0.1 to 10% by mass (Patent Document 4). Sebacate esters, like terpenes, are added as solubilizers and permeation enhancers; a patch comprising an ointment layer and support containing SIS, tackifiers, plasticizers, anti-inflammatory agents (such as flurbiprofen), and 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 drug solubilizers and transdermal absorption enhancers. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Japanese Patent Publication No. 2018-172340 (Patent No. 6877737) [Patent Document 2] Japanese Patent Publication No. 2011-20946 (Japanese Patent No. 5493163) [Patent Document 3] International Publication No. 2006 / 092829 (Patent No. 5280678) [Patent Document 4] Japanese Patent Publication No. 2008-13494 (Japanese Patent No. 5085062) [Patent Document 5] Japanese Patent Publication No. 2007-8927 (Patent No. 4939113) [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] This invention relates to a flurbiprofen-containing transdermal formulation, which is small and used for pain relief after surgery or cancer, applied once a day. Therefore, it is essential that 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 contain a higher concentration of the drug in the base than in the Locoa® tape, and to significantly increase the content per sheet and skin permeability. In the Locoa® tape, the effect of using peppermint oil to improve the solubility and transdermal absorption of S-flurbiprofen has already been disclosed, but as long as peppermint oil is used, it is difficult to further increase the drug concentration. When flurbiprofen is incorporated in a high content in the adhesive layer, crystals tend to precipitate and skin permeability decreases, which is a problem. Separately, there are individual differences in the smell of peppermint oil, and it can be unpleasant for some. In other words, the object of the present invention is to provide a transdermal formulation that is smaller in size and has excellent long-term storage properties, in which the solubility of the drug in the composition is increased, thereby improving the transdermal absorption of flurbiprofen, in a topical composition comprising flurbiprofen and an adhesive. [Means for solving the problem]

[0007] To solve the above problems, the inventors conducted diligent research and found that by dissolving 0.5 to 1.5 mg / cm2 of flurbiprofen per sheet in the adhesive layer, the transdermal drug permeability absorption is equivalent to that of tablets or injections, and furthermore, it has more than twice the transdermal drug permeability of commercially available Locoa® tape, thus completing the present invention. In this 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 permeation (or permeability)-time curve in in vitro skin permeation studies on various skin samples. AUC equivalence means that the AUC of this 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 this 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 in in vivo animal studies, preferably in animal studies in which the drug was administered to rats. Details of the animal studies 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 at least one additive selected from flurbiprofen, a solubilizer and a transdermal absorption enhancer, a tackifier and a plasticizer, and does not contain peppermint oil, wherein the flurbiprofen content is 3 to 20% by mass, the solubilizer content is 0% by mass or 4 to 14% by mass, the transdermal absorption enhancer content is 0% by mass or 3 to 40% by mass, the tackifier content is 5 to 60% by mass and the plasticizer content is 5 to 50% by mass. [2] The transdermal formulation according to [1], wherein the adhesive constituting the adhesive layer consists of at least one selected from the group consisting of styrene-isoprene-styrene block copolymer and polyisobutylene. [3] The transdermal formulation according to [1], wherein the flurbiprofen is S-flurbiprofen. [4] The transdermal formulation according to [1], wherein the solubilizer is 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], 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 [1], wherein the solubilizer is cyclodextrin. [8] The transdermal formulation according to [7], wherein the cyclodextrin content is 3 to 40% by mass. [9] The transdermal formulation according to [7], wherein the cyclodextrin is β-cyclodextrin.

[10] The transdermal formulation according to [7], wherein the cyclodextrin and flurbiprofen constitute an inclusion complex.

[11] The transdermal formulation according to [7], wherein an inclusion complex of cyclodextrin and flurbiprofen and a non-inclusion complex of flurbiprofen coexist in an adhesive layer.

[12] The transdermal formulation according to [1], wherein the transdermal absorption enhancer is at least one selected from the group consisting of lauric acid diethanolamide and isopropyl myristate.

[13] The transdermal formulation according to [1], wherein the tackifier is at least one selected from the group consisting of rosin glycerol ester and hydrogenated rosin glycerol ester.

[14] The transdermal formulation according to [1], wherein the plasticizer is liquid paraffin.

[15] The transdermal formulation according to [1], wherein the application area of ​​the transdermal formulation is 50 to 140 cm2 and each patch contains 20 mg to 200 mg of flurbiprofen.

[16] The transdermal formulation according to any one of [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 Froben® Tablet 40 or Ropion® Injection 50 mg administered in the same amount over 24 hours.

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

[15] , wherein the AUC when the transdermal formulation is applied to the skin for 24 hours is twice or more the AUC when the Locoa® Tape is applied for the same amount of time.

Advantages of the Invention

[0009] The transdermal preparation of the present invention contains flurbiprofen at 0.5 mg to 1.5 mg / cm2 in a dissolved state in an adhesive, and has an AUC equivalent to that of a tablet or an injection. It has an AUC more than twice that of the commercially available Locoid (registered trademark) tape.

Brief Description of the Drawings

[0010] [Figure 1] It is a graph showing the change over time in the blood concentration of a drug when the transdermal preparation of Example 7 and the commercially available products of Reference Examples 1-3 are administered to rats.

Modes for Carrying Out the Invention

[0011] The transdermal preparation of the present invention is a tape preparation, and includes a support layer and an adhesive layer laminated on the support layer. The adhesive layer is usually laminated on one surface of the support layer, and if necessary, a peelable film (release film) is laminated on the other surface of the adhesive layer. The adhesive layer is the part that adheres to the skin when the tape preparation is applied, and contains an adhesive and flurbiprofen. Each tape preparation contains 20 mg to 200 mg of flurbiprofen. It is further desirable to contain 30 mg to 170 mg of flurbiprofen per sheet, and 40 mg to 160 mg per sheet is even better. The size (adhesive area) of the tape preparation is suitably 50 to 140 cm2 per sheet, and 50 to 100 cm2 is more convenient for use.

[0012] In the present invention, flurbiprofen is a concept including the R form, S form, racemic form, and prodrug. Among flurbiprofen, especially S-flurbiprofen is the active entity of flurbiprofen and has higher activity than racemic flurbiprofen, so it is preferably contained as the main drug in the adhesive layer. Preferred examples of the "pharmaceutically acceptable salts" used in the present invention include sodium salt and potassium salt.

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

[0014] The adhesive may contain at least one adhesive selected from rubber-based adhesives, acrylic adhesives and silicone-based adhesives. Rubber-based adhesives are, for example, polyisoprene, polyisobutylene (PIB), polybutadiene, styrene-butadiene-styrene block copolymer, styrene-isoprene-styrene (SIS) block copolymer, styrene-butadiene rubber, styrene-isoprene rubber, or combinations thereof. Among these, SIS block copolymer and polyisobutylene are preferred from the viewpoint of enhancing the skin permeability of flurbiprofen. The SIS block copolymer is more preferred from the viewpoint of the solubility of flurbiprofen. The content in the adhesive layer of the adhesive is preferably 1 to 40% by mass, more preferably 5 to 30% by mass.

[0015] Acrylic adhesives are, for example, adhesives obtained by polymerizing or copolymerizing at least one of (meth)acrylic monomers such as (meth)acrylic acid, 2-ethylhexyl (meth)acrylate, methyl (meth)acrylate, butyl (meth)acrylate, hydroxyethyl (meth)acrylate, etc. Silicone-based adhesives are mainly composed of silicone rubbers such as polydimethylsiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane.

[0016] The adhesive layer may contain a solubilizer to dissolve flurbiprofen and improve its skin permeability. Suitable solubilizers include polyhydric alcohols and fatty acid esters. Examples of polyhydric alcohols include diethylene glycol, propylene glycol, triethylene glycol, polyethylene glycol, and dipropylene glycol. Examples of fatty acid esters include isopropyl myristate, isopropyl palmitate, hexyl laurate, diethyl sebacate, diisopropyl sebacate, triethyl citrate, and crotamiton. Medium-chain fatty acid esters are particularly preferred to prevent crystal precipitation of flurbiprofen in the adhesive layer. Dibasic fatty acids such as adipic acid and sebacic acid are preferred as medium-chain fatty acids. Ethanol and propanol are preferred alcohols for esterification. The solubilizer intended to stably dissolve the drug in the adhesive layer preferably has appropriate polarity. For example, an octanol-water partition ratio (XlogP) of 2.0 to 6.0 is desirable. If the XlogP value is less than 2.0 or greater than 6.0, the drug has poor affinity and is unlikely to function as a solubilizer.

[0017] To increase the solubility of flurbiprofen in the adhesive layer and prevent crystal precipitation, the addition of cyclodextrin (α-, β-, γ-cyclodextrin) in addition to the aforementioned solubilizer is effective. The cyclodextrin encapsulates flurbiprofen, suppressing its crystallization in the adhesive layer. As a result, the solubility of flurbiprofen in the adhesive layer is increased, improving the transdermal absorption of the drug. β-cyclodextrin is preferred as the 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. 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.

[0018] The amount of cyclodextrin in the adhesive layer is preferably 3 to 40% by mass, and more preferably 10 to 30% by mass. If the concentration in the adhesive layer is less than 3% by mass, it will not function as a solubilizing agent, and if it exceeds 40% by mass, it will be difficult to maintain the properties of the adhesive, such as degrading the physical properties of the adhesive.

[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 produced using ethanol, is also an example.

[0020] In this invention, the amount of solubilizers other than cyclodextrin incorporated into the adhesive layer is preferably 3 to 20% by mass, and more preferably 4 to 14% by mass. If the concentration in the adhesive layer is less than 3% by mass, it is insufficient to function as a solubilizer, and if it exceeds 20% by mass, it is difficult to maintain the properties of the adhesive, such as reducing the adhesiveness of the adhesive.

[0021] The ratio of flurbiprofen to solubilizer is preferably 1:0.2 to 1:3 by mass, from the standpoint of improving the skin permeability of flurbiprofen and preventing the precipitation of flurbiprofen crystals. A ratio of 1:0.4 to 1:2 is more preferable.

[0022] In the present invention, the adhesive layer may contain a transdermal absorption enhancer instead of, or together with, a solubilizer. The transdermal absorption enhancer is used to improve the skin permeability of the transdermal formulation of the present invention. Any conventionally known chemical transdermal absorption enhancer can be used. Examples of conventionally known chemical transdermal absorption enhancers include alcohols such as menthol, camphor, and cetyl alcohol; fatty acid esters such as isopropyl palmitate and isopropyl myristate; glycerin esters such as glycerin monolaurate and glycerin monooleate; acid amides such as diethanolamide laurate; and neutral surfactants such as polyethylene glycol dilauryl ether. Among these, isopropyl myristate and diethanolamide laurate are preferred because they also function as solubilizers and are excellent additives.

[0023] The amount of chemical transdermal absorption enhancer added should be 3 to 40% by mass, preferably 5 to 20% by mass, in the adhesive layer. Too little will not improve the transdermal absorption effect, and too much will reduce the adhesiveness. To further enhance transdermal absorption, two or more types may be mixed and used.

[0024] The adhesive layer may further contain other additives such as tackifiers, plasticizers, stabilizers, and fillers. Examples of tackifiers include rosin, rosin glycerin esters, hydrogenated rosin, hydrogenated rosin glycerin esters and rosin derivatives such as rosin pentaerythritol esters, 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. Among these, rosin ester resins, hydrogenated rosin glycerin esters, alicyclic saturated hydrocarbon resins, aliphatic hydrocarbon resins, or terpene resins are preferred, and hydrogenated rosin glycerin esters (e.g., trade name KE-311, manufactured by Arakawa Chemical Industries, Ltd.) are more preferred. Two or more of these tackifiers may be combined. By including a tackifier, the adhesion of the adhesive layer can be improved while maintaining other physical properties stably.

[0025] The tackifier content is preferably 5 to 60% by mass, particularly 10 to 50% by mass, based on the total mass of the adhesive layer, and is preferably 3 to 9 times the mass of the drug.

[0026] 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; liquid fatty acid esters such as isopropyl myristate, hexyl laurate, diethyl sebacate, and diisopropyl sebacate; diethylene glycol; polyethylene glycol; glycol salicylate; propylene glycol; dipropylene glycol; triacetin; triethyl citrate; and crotamiton. Among these, liquid paraffin, liquid polybutene, isopropyl myristate, diethyl sebacate, and hexyl laurate are preferred, isopropyl myristate and liquid paraffin are more preferred, and liquid paraffin is particularly preferred. Two or more of these plasticizers may be combined. The plasticizer content is preferably 5 to 50% by mass, and particularly preferably 10 to 45% by mass, relative to the total mass of the adhesive layer.

[0027] Examples of stabilizers 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, and camphor derivatives). Two or more of these stabilizers may be combined. The content of the stabilizer is preferably 0.05 to 10% by mass based on the total mass of the adhesive layer. The stability of flurbiprofen can be further improved by including a stabilizer in the adhesive layer.

[0028] 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.). Two or more of these fillers may be combined. The filler content is preferably 0.05 to 10% by mass, and more preferably 0.05 to 5% by mass, based on the total mass of the adhesive layer.

[0029] From the viewpoint of skin adhesion, the mass of the adhesive layer is preferably 10 g / m² to 1000 g / m², more preferably 30 g / m² to 300 g / m², and even more preferably 50 g / m² to 250 g / m². In this invention, "ointment" refers to 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 total mass of the adhesive layer.

[0030] The support layer is preferably a single layer or laminate of fibers in the form of a fabric (woven, nonwoven, or knitted fabric) or a non-porous or porous film (sheet). The material of the support layer is preferably one or more materials selected from polyester (polyethylene terephthalate (PET), polyethylene isophthalate, polypropylene terephthalate, polypropylene isophthalate, polybutylene terephthalate, or polyethylene naphthalate, etc.), polyolefin (polymer or copolymer of vinyl monomers such as ethylene, propylene, vinyl acetate, or acrylonitrile), polyamide (nylon or silk, etc.), polyurethane (PU), or cellulose (cotton or linen, etc.). The fabric (woven, nonwoven, or knitted fabric) may be coated with a rubber composition. From the viewpoint of flexibility and ease of fitting to the skin, a fabric (woven, nonwoven, or knitted fabric) of fibers is preferred, and from the viewpoint of small size and ease of use, a laminated film of PET and nonwoven fabric is also preferred. The basis weight of the support layer is 30 g / m² to 200 g / m².

[0031] The transdermal formulation of the present invention is a tape. To ensure sufficient adhesive strength and sufficient skin penetration of flurbiprofen, the application area per tape is preferably 50 to 140 cm², with 50 to 100 cm² being more convenient for use.

[0032] The adhesive tape can be manufactured by the following method, but is not limited thereto, and known methods can be used. The components constituting the adhesive layer are mixed in predetermined proportions to form a uniform solution, which is dissolved at 150-190°C, and the solution is spread on a release film or support layer to a predetermined thickness at a temperature of 80-120°C to form the adhesive layer. Then, the support layer is pressed onto the adhesive layer or 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 the hot melt method by cutting to an appropriate size at room temperature. Similarly, the adhesive layer may be formed by spreading the solution on a support layer to a predetermined thickness, and then the support layer may be pressed onto the release film. The above describes a hot-melt manufacturing method, but a solution coating method may also be used, in which each component constituting the adhesive layer is dissolved or partially dispersed in cyclohexane, toluene, or other suitable solvent, the solution is applied onto a release film or support layer, and an adhesive layer of a predetermined thickness is formed by heating and drying. [Examples]

[0033] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to these examples, and various modifications are possible without departing from the technical spirit of the invention.

[0034] (Preparation of flurbiprofen-containing tapes (solution coating method)) (Examples 1-20 and Comparative Examples 1-13) A tape containing flurbiprofen was prepared by the following method. The adhesive layer components were mixed with cyclohexane, ethanol, etc., to prepare an adhesive solution. This solution was spread onto a release film (release-treated PET film) so that the dried adhesive mass was approximately 120 g / m2, and dried at 80°C for 10 minutes. A support layer (PET nonwoven fabric, thickness: 40 μm) was laminated on the adhesive layer formed on the release film to obtain the tape. The size of the tape was 6 cm x 6 cm. This tape was cut to an appropriate size as needed for the purpose and used in the following experiments.

[0035] (Preparation of β-cyclodextrin inclusion complexes) An aqueous solution of β-cyclodextrin and an ethanol solution of S-flurbiprofen were mixed at 80°C, cooled to room temperature to form a precipitate of inclusion complexes, and purified by washing. The S-flurbiprofen content in the product inclusion complex was confirmed to be 20% by mass by extracting and quantifying S-flurbiprofen from the product 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 prepared separately as described above and mixed into the ointment. In Examples 18 and 19, an amount equivalent to the inclusion complex of S-flurbiprofen and β-cyclodextrin was mixed separately into the ointment. It is thought that the inclusion complex was formed during the heating and mixing process.

[0036] (Observation of the presence or absence of crystals in the obtained adhesive tape) The obtained adhesive tapes were sealed in aluminum laminate packaging bags and stored at room temperature (25°C) for one week. Microscopic observation was then performed to check for crystallization of the drug within the adhesive layer. Formulations in which no crystals were observed are shown as A, and formulations in which crystal precipitation was observed are shown as B.

[0037] (Evaluation of the cohesiveness (shape retention) of the obtained tape) The tape was placed on a horizontal surface, and a rubber roller was rolled over the ointment to observe the cohesiveness of the ointment. Formulations with good shape retention are indicated as A, and those with poor shape retention are indicated as B.

[0038] (Measurement of skin permeability) The tape formulation was applied to the stratum corneum side of a human excised skin sample (700 μm thick) and then mounted in a Franz-type diffusion cell for transdermal permeability experiments (5.7 mL of receptor solution, opening area 2.27 cm²). 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, and 4 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. Since the absolute value of permeability differs depending on the human excised skin even with the same tape, the permeability of Locoa Tape was measured simultaneously for reference in each test. Permeability relative to Locoa Tape is shown as "percentage of Locoa Tape permeability". 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: 250nm UV (Retention time 4 min) The S- and R-forms of flurbiprofen provide the same retention time.

[0039] (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 achieve a dose of 6mg / kg relative to the rat's body weight and administered via skin application. The Locoa® tape was administered in a preparation of 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's tail at 1, 2, 4, 6, 8, and 24 hours after administration (additional collections were made at 10 and 30 minutes after administration for the injectable drug). 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 various dosage forms was calculated from Table 2 and its graph, Figure 1, and is shown in the bottom column of Table 2.

[0040] [Table 1]

[0041] Example 6, in which a solubilizer and an absorption enhancer were present, exhibited the best physical properties and the highest transdermal absorption.

[0042] [Table 2]

[0043] Example 7 is a transdermal patch with the same formulation as Example 6. When the same amount of flurbiprofen per unit 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 than that of the example products, less than one-third.

[0044] [Table 3]

[0045] The comparative examples and examples demonstrate the effect of adding hydrogenated rosin esters and their effectiveness in improving drug solubility (crystallinity) based on the amount added. Examples 9-12 show that, in addition to the combination of "diisopropyl adipate + diethanolamide laurate," diisopropyl sebacate and isopropyl myristate are also effective. Based on the results in Table 3 and other considerations, the amount of hydrogenated rosin ester to add appears to be 16-44% by mass, more preferably 20-40% by mass.

[0046] [Table 4]

[0047] Examples 13 and 14 involved applying the tape formulation 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 observation 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.

[0048] [Table 5]

[0049] 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 (Comparative Example 13) worsened the cohesiveness of the adhesive layer and reduced its tackiness.

[0050] Example 20 A formulation (4cm x 4cm) 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 (13.7mg), confirming the stability of the drug.

[0051] (Preparation of flurbiprofen-containing tapes (hot melt method)) (Examples 21-22) In Table 6, component A was mixed at 160°C, the temperature was lowered to 130°C, component B was added and mixed, and component C was added and mixed at 120°C to form an ointment. This ointment was spread on a release film to a density of 120 g / m2 at 125°C, and a support film was laminated at room temperature to form a tape. The tape manufactured using 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.

[0052] [Table 6]

Claims

1. A transdermal formulation comprising a support layer and an adhesive layer laminated on the support layer, wherein the adhesive layer contains flurbiprofen, at least one additive selected from a solubilizer and a transdermal absorption enhancer, a tackifier, and a plasticizer, and does not contain peppermint oil, wherein the flurbiprofen content is 3 to 20% by mass, the solubilizer content excluding cyclodextrin is 0% by mass or 4 to 14% by mass, the transdermal absorption enhancer content is 0% by mass or 3 to 40% by mass, the tackifier content is 5 to 60% by mass, and the plasticizer content is 5 to 50% by mass.

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

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

4. The transdermal formulation according to claim 1, wherein the solubilizer is 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, 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 claim 1, wherein the solubilizer is cyclodextrin.

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

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

10. The transdermal formulation according to claim 7, wherein the cyclodextrin and flurbiprofen constitute an inclusion complex.

11. The transdermal formulation according to claim 7, wherein the inclusion complex of cyclodextrin and flurbiprofen and the non-inclusion complex flurbiprofen coexist in the adhesive layer.

12. The transdermal formulation according to claim 1, wherein the transdermal absorption enhancer is at least one selected from the group consisting of lauric acid diethanolamide and isopropyl myristate.

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

14. The transdermal formulation according to claim 1, wherein the plasticizer is liquid paraffin.

15. The transdermal formulation according to claim 1, wherein the application area of ​​the transdermal formulation is 50 to 140 cm² and each patch contains 20 mg to 200 mg of flurbiprofen.

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 after administering the same amount of Froben® tablets 40 or Ropion® intravenous injection 50 mg for 24 hours.

17. The transdermal formulation according to any one of claims 1 to 15, wherein the AUC when the transdermal formulation is applied to the skin for 24 hours is twice or more than the AUC when Locoa® Tape is applied for the same period of time.

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