Diclofenac-containing patch

Abstract

Disclosed is a diclofenac-containing patch which exhibits good physical properties, wearability, and attains good skin permeability. This patch comprises a plaster and a support, wherein the plaster comprises (A) diclofenac or a pharmaceutically acceptable salt thereof, (B) polyisoprene, and (C) N-methyl-2-pyrrolidone.

Description

Diclofenac-containing patches REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority to an earlier filed Japanese patent application, Patent Application No. 2023-204947 (filing date: December 4, 2023), the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to a diclofenac-containing patch.

[0003] Nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac or its salts have excellent anti-inflammatory and analgesic effects and are widely used in clinical settings as oral preparations or suppositories. They are also widely used in transdermal formulations as patches for the treatment or prevention of various inflammatory diseases such as chronic rheumatism, spondylosis deformans, and lower back pain.

[0004] There are various types of patches containing nonsteroidal anti-inflammatory drugs, and formulations using dimethyl sulfoxide (DMSO) as an additive for dissolving the drug have been frequently studied.

[0005] For example, Patent Document 1 discloses a patch comprising a support layer and an adhesive layer, which contains diclofenac sodium, dimethyl sulfoxide, and citric acid in a specific ratio.

[0006] Furthermore, Patent Document 2 discloses a patch comprising a support layer and an adhesive layer laminated on the support layer, which contains diclofenac sodium and a specific concentration of dimethyl sulfoxide.

[0007] However, it is difficult to say that such patches using dimethyl sulfoxide are sufficiently good in terms of storage stability, feel when used, etc. Therefore, there is still a demand for patches containing nonsteroidal anti-inflammatory drugs with excellent effects.

[0008] International Publication No. 2013 / 191128 Japanese Patent Application Laid-Open No. 2022-036194

[0009] The present invention provides a diclofenac-containing patch.

[0010] The present inventors have found that the addition of dimethyl sulfoxide can adversely affect the physical properties of diclofenac-containing patches, such as by causing a peculiar odor in the patches, and that its relatively high melting point of 19°C can adversely affect production efficiency depending on the working environment. However, diclofenac-containing patches containing specific components exhibit good physical properties, usability, and skin permeability. Furthermore, the present inventors have found that diclofenac-containing patches containing the above-mentioned specific components can be stably provided without using dimethyl sulfoxide as a raw material. The present invention is based on these findings.

[0011] The present invention provides the following: (1) A patch comprising a paste and a support, wherein the paste comprises (A) diclofenac or a pharmaceutically acceptable salt thereof, (B) polyisoprene, and (C) N-methyl-2-pyrrolidone. (2) The patch according to (1), which is for the treatment of pain. (3) The patch according to (2), wherein the treatment of pain is pain relief for various cancers, or pain relief or anti-inflammation for lower back pain, scapulohumeral periarthritis, cervico-omo-brachial syndrome, or tenosynovitis. (4) The patch according to (2) or (3), wherein the treatment of pain is pain relief for various cancers. (5) The patch according to any of (2) to (4), wherein the treatment of pain is pain relief or anti-inflammation for lower back pain, scapulohumeral periarthritis, cervico-omo-brachial syndrome, or tenosynovitis. (6) The patch according to any of (1) to (5), wherein the (A) component is diclofenac sodium. (7) The patch according to any one of (1) to (6), wherein the blending amount of the component (A) relative to the total amount of the paste is 1 to 20% by mass. (8) The patch according to any one of (1) to (7), wherein the blending amount of the component (B) relative to the total amount of the paste is 10 to 50% by mass. (9) The patch according to any one of (1) to (8), wherein the blending amount of the component (C) relative to the total amount of the paste is 1 to 15% by mass.

[0012] According to the present invention, a diclofenac-containing patch containing specific components is provided, which exhibits good physical properties, a feeling of use, and skin permeability. According to the present invention, a diclofenac-containing patch can be stably provided without using dimethyl sulfoxide as a material.

[0013] FIG. 1 is a graph showing the cumulative permeation amount of diclofenac sodium when a diclofenac-containing patch was applied to the skin of a mouse. Specific Description of the Invention

[0014] According to one aspect of the present invention, there is provided a patch comprising a paste and a support, the paste comprising (A) diclofenac or a pharmaceutically acceptable salt thereof, (B) polyisoprene, and (C) N-methyl-2-pyrrolidone.

[0015] The patch of the present invention may be either a non-aqueous patch (for example, a plaster, a plaster, a tape, etc.) or an aqueous patch (for example, a cataplasm, etc.), but is preferably a non-aqueous patch.

[0016] The shape of the patch of the present invention is not particularly limited, and may be various shapes according to the area to be applied, such as a quadrangle (square, rectangle, etc.), quadrilateral (trapezoid, rhombus, etc.), polygon, circle, ellipse, semicircle, triangle, crescent, or a combination thereof.

[0017] The adhesive base of the present invention contains (A) diclofenac or a pharmaceutically acceptable salt thereof, (B) polyisoprene, and (C) N-methyl-2-pyrrolidone, and may also contain other ingredients that can be used in adhesive bases for general patches.

[0018] Diclofenac in the present invention is also commonly known as 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid.

[0019] Examples of the pharmaceutically acceptable salt of diclofenac in the present invention include diclofenac sodium, diclofenac potassium, diclofenac diethylammonium, diclofenac hydroxyethylpyrrolidine, etc. Preferred as the pharmaceutically acceptable salt of diclofenac in the present invention is diclofenac sodium.

[0020] The amount of component (A) in the paste in the patch of the present invention is not particularly limited as long as it can be formulated, but is preferably 1% by mass to 20% by mass relative to the total amount of the paste, more preferably 1.5% by mass to 15% by mass relative to the total amount of the paste, more preferably 2% by mass to 12.5% ​​by mass relative to the total amount of the paste, and more preferably 5% by mass to 10% by mass relative to the total amount of the paste.

[0021] The paste component (B) in the adhesive patch of the present invention is polyisoprene, i.e., a polymer of an isoprene monomer. The polyisoprene used in the present invention is not particularly limited as long as it is used as a raw material for pharmaceuticals, etc., and commercially available products may be used. For example, Cariflex IR0307KU from Kraton Polymers may be used as the polyisoprene used in the present invention. The paste component (B) in the adhesive patch of the present invention has advantages such as more stable quality than natural products (e.g., natural rubber, raw rubber, etc.) and less allergy-inducing properties than natural products (e.g., natural rubber, raw rubber, etc.), and can contribute to the good physical properties and / or usability of the adhesive patch of the present invention.

[0022] The amount of component (B) in the paste in the patch of the present invention is not particularly limited as long as it allows formulation, but is preferably 10% by mass to 50% by mass, and more preferably 13.5% by mass to 40% by mass, based on the total amount of the paste.

[0023] The paste component (C) in the patch of the present invention is N-methyl-2-pyrrolidone, commonly known as NMP. The N-methyl-2-pyrrolidone used in the present invention is not particularly limited as long as it is used as a raw material for pharmaceuticals, etc., and commercially available products may be used. For example, Pharmasolve from Serendipit Pharmaceuticals may be used as the N-methyl-2-pyrrolidone used in the present invention. The paste component (C) in the patch of the present invention has advantages such as high solubility of diclofenac sodium, effective suppression of crystallization, and good compatibility with bases (i.e., good compatibility with bases), which may contribute to the good skin permeability of the patch of the present invention.

[0024] The amount of component (C) in the paste in the patch of the present invention is not particularly limited as long as it can be formulated, but is preferably 1% by mass to 15% by mass relative to the total amount of the paste, more preferably 2.5% by mass to 11.5% by mass relative to the total amount of the paste, and more preferably 4% by mass to 8% by mass relative to the total amount of the paste.

[0025] The adhesive base of the patch of the present invention may contain, as other optional ingredients, ingredients that are generally incorporated into the adhesive base of conventional non-aqueous patches or aqueous patches, such as bases such as elastomers, adsorbents, tackifiers, softeners, cooling agents, surfactants, humectants, stabilizers, antioxidants, inorganic powders, colorants, fragrances, preservatives, ultraviolet absorbers, sequestering agents, etc. These optional ingredients may be used either alone or in combination of two or more.

[0026] The backing for the patch of the present invention is not particularly limited as long as it is generally usable for patches, and for example, nonwoven fabric, woven fabric, knitted fabric, PET film, etc. can be used alone or in combination.

[0027] The patch of the present invention may be provided with a release film, also called a liner, that covers the surface of the adhesive layer, and in this case, a film that has been appropriately treated for release properties may be used. The film may be made of, for example, polyester.

[0028] The patch of the present invention can be produced using desired raw materials by a method generally used in the production of patches, such as the hot melt method or solvent method.

[0029] Diclofenac contained in the patch of the present invention is classified as a nonsteroidal anti-inflammatory analgesic drug, and since it selectively inhibits cyclooxygenase 2, it is highly effective in treating pain, and is used, for example, for pain relief in various cancers, and for pain relief or anti-inflammation in lower back pain, periarthritis of the shoulder, cervicobrachial syndrome, and tenosynovitis.

[0030] Therefore, according to a preferred embodiment of the present invention, the patch of the present invention is for the treatment of pain. Such pain treatment is preferably pain relief in various cancers, or pain relief or anti-inflammation in lower back pain, scapulohumeral periarthritis, cervicobrachial syndrome or tenosynovitis, and therefore, according to a more preferred embodiment of the present invention, the patch of the present invention is for pain relief in various cancers, or pain relief or anti-inflammation in lower back pain, scapulohumeral periarthritis, cervicobrachial syndrome or tenosynovitis.

[0031] According to another more preferred embodiment of the present invention, the patch of the present invention is for pain relief in various cancers.

[0032] According to another more preferred embodiment of the present invention, the patch of the present invention is for the purpose of relieving pain or anti-inflammation in lumbago, periarthritis shoulder, cervicobrachial syndrome or tenosynovitis.

[0033] The present invention will be specifically described based on the following examples, but the present invention is not limited to these examples. Contents are expressed in mass % unless otherwise specified.

[0034] Preparation of Plaster Fluid for Patch of Test Example 1 A plaster fluid for the patch of Test Example 1 was prepared. In the amounts shown in Table 1 below, polyisoprene (Cariflex IR0307KU, manufactured by Kraton Polymers), alicyclic saturated hydrocarbon resin (Arcon P-100, manufactured by Arakawa Chemical Industries, Ltd.), liquid paraffin (Hycol M352, manufactured by Kaneda Co., Ltd.), N-methyl-2-pyrrolidone (Pharmasolve, manufactured by Serendipit Co., Ltd.), DL-malic acid (Fuso Malate, manufactured by Fuso Chemical Co., Ltd.), and diclofenac sodium were sequentially added with stirring to a mixer (ZZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.) containing an appropriate amount of toluene. Stirring was continued thoroughly after each addition of each raw material until the mixture was homogenous. Next, toluene was further added with stirring until the amount of toluene reached approximately 240 g, yielding a mixed solution. The resulting mixture was placed in a desiccator and deaerated to obtain a plaster fluid for the patch of Test Example 1.

[0035] Preparation of Plaster Fluid for Patch of Test Example 2 A plaster fluid for the patch of Test Example 2 was prepared. In the amounts shown in Table 1 below, polyisoprene (Cariflex IR0307KU, manufactured by Kraton Polymers), alicyclic saturated hydrocarbon resin (Arcon P-100, manufactured by Arakawa Chemical Industries, Ltd.), liquid paraffin (Hicol M352, manufactured by Kaneda Co., Ltd.), dimethyl sulfoxide (Toray Fine Chemicals Co., Ltd.), DL-malic acid (Fuso Malate, manufactured by Fuso Chemical Co., Ltd.), and diclofenac sodium were sequentially added with stirring to a mixer (ZZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.) containing an appropriate amount of toluene. Stirring was continued thoroughly after each addition of each raw material until the mixture was homogenous. Next, additional toluene was added with stirring until the toluene amount reached approximately 240 g, yielding a mixed solution. The resulting mixed solution was placed in a desiccator and degassed, yielding a plaster fluid for the patch of Test Example 2.

[0036] Preparation of Plaster Fluid for Patch of Test Example 3 A plaster fluid for the patch of Test Example 3 was prepared. In the amounts shown in Table 1 below, styrene-isoprene-styrene block copolymer (ENEOS Kraton Elastomers, SIS5229), alicyclic saturated hydrocarbon resin (Arakawa Chemical Industries, Ltd., Alcon P-100), liquid paraffin (Kaneda Co., Ltd., Hicol M352), N-methyl-2-pyrrolidone (Serendipit, Pharmasolve), DL-malic acid (Fuso Malate, Fuso Chemical Co., Ltd.), and diclofenac sodium were sequentially added with stirring to a mixer (Tokyo Rikakikai, ZZ-1200) containing an appropriate amount of toluene. Stirring was continued thoroughly after each addition of each raw material until the mixture was uniform. Next, toluene was added with stirring until the amount of toluene reached approximately 60 g, yielding a mixed solution. The resulting mixture was placed in a desiccator and deaerated to obtain a plaster fluid for the patch of Test Example 3.

[0037] Preparation of Plaster Fluid for Patch of Test Example 4 A plaster fluid for the patch of Test Example 4 was prepared. In the amounts shown in Table 1 below, styrene-isoprene-styrene block copolymer (SIS5229, manufactured by ENEOS Kraton Elastomers), alicyclic saturated hydrocarbon resin (Arcon P-100, manufactured by Arakawa Chemical Industries, Ltd.), liquid paraffin (Hicol M352, manufactured by Kaneda Co., Ltd.), dimethyl sulfoxide (Toray Fine Chemicals Co., Ltd.), DL-malic acid (Fuso Malate, manufactured by Fuso Chemical Co., Ltd.), and diclofenac sodium were sequentially added with stirring to a mixer (ZZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.) containing an appropriate amount of toluene. Stirring was continued thoroughly after each addition of each raw material until the mixture was homogenous. Next, additional toluene was added with stirring until the toluene amount reached approximately 60 g, yielding a mixed solution. The resulting mixed solution was placed in a desiccator and degassed, yielding a plaster fluid for the patch of Test Example 4.

[0038] Preparation of patches of Test Examples 1 to 4 The prepared plaster solutions of Test Examples 1 to 4 were each applied to a silicone-treated PET film in an amount of 1.5 g / 70 cm ２ The PET film was then naturally dried to remove the toluene, and a PET film or woven fabric was attached to prepare the patches of Test Examples 1 to 4. The prepared patches were cut into rectangles measuring approximately 7 cm x 10 cm, packaged in aluminum packaging, and stored at room temperature.

[0039] Evaluation of Physical Properties of Patches For the patches of Test Examples 1 to 4, test pieces of approximately 2 cm x approximately 3 cm were prepared for each patch (patches using PET film as the backing were used as samples), and physical properties were evaluated in three categories: whether or not the plaster remains on the skin after the patch is removed, the adhesiveness between the plaster and the backing of the patch, and the adhesive strength of the patch to the skin. Physical property evaluations were performed by four panelists trained to the extent that they were able to assign the same score to the same sample, based on the following evaluation criteria. The results are shown in Table 1.

[0040] Presence or absence of plaster remaining on the skin after peeling off the patch A: No plaster remaining on the skin after peeling off the patch B: Some plaster remaining on the skin after peeling off the patch C: Some plaster remaining on the skin after peeling off the patch

[0041] Adhesion between the patch support and the plaster A: The plaster does not peel off from the support B: The plaster peels off easily from the support C: The plaster peels off easily from the support

[0042] Adhesion of the patch to the skin A: Strong adhesion B: Medium adhesion C: Weak adhesion

[0043]

[0044] Evaluation of adhesive strength of patches by probe tack method Measurements were performed using a small desktop tester EZ-LX (Shimadzu Corporation) in accordance with "3.4 Probe tack test method" in "6.12 Adhesion test method" of the general test method of the 18th edition of the Japanese Pharmacopoeia. Three test specimens (1.4 cm length x 1.4 cm width) were cut out from each of the patches of Test Examples 1 to 4 (patches using woven fabric as the support were used as samples). The liner was peeled off and removed from the test specimen to expose the adhesive surface, and the test specimen was attached to a weight ring without slack and placed on the test table. The probe was brought into contact with the exposed adhesive surface of the test specimen at a speed of 10 mm per second, and a force of 0.98 N / cm was applied. ２ The contact load was maintained at 1.0 sec. for 1.0 sec. Immediately thereafter, the probe was peeled off from the plaster surface in the vertical direction at a speed of 10 mm per second. The maximum load (N / cm) required for peeling was ２ ) was used as the value of the probe tack test. After the measurement for each test example was completed, the test piece was replaced with one that had not yet been subjected to the test, and the adhesive strength was measured again, and this was repeated to obtain three measured values. The average value and standard deviation were calculated from the obtained measured values. The results are shown in Table 2. In Table 2, the measured values ​​are shown as the average value ± standard deviation. The unit of the measured value is N / cm ２ It was decided.

[0045]

[0046] The results in Tables 1 and 2 reveal that the patch of Test Example 1 exhibits better physical properties than the patches of the other Test Examples.

[0047] Evaluation of the Feeling of Usability of Patches Next, for the patches of Test Examples 1 to 4, test pieces of approximately 2 cm x approximately 3 cm were prepared for each patch (patches using woven fabric as a support were used as samples), and evaluation of the feeling of use was performed. A trained panel peeled the liner from the test piece, pressed their thumb against the patch surface for several seconds, and evaluated the sensation upon peeling (evaluation by finger tack), and the feeling of use when applied to a joint. In addition, taking these evaluation results into consideration, the adhesiveness of each patch was also evaluated according to the following evaluation criteria. The results are shown in Table 3.

[0048] Adhesiveness A: Can be used as a patch product B: Can be used as a patch product C: Cannot be used as a patch product

[0049]

[0050] The results in Table 3 reveal that the patch of Test Example 1 exhibits a better feel when used than the patches of the other Test Examples.

[0051] Preparation of Plaster Fluid for Patch of Test Example 5 A plaster fluid for the patch of Test Example 5 was prepared. In the amounts shown in Table 4 below, polyisoprene (Cariflex IR0307KU, manufactured by Kraton Polymers), alicyclic saturated hydrocarbon resin (Arcon P-100, manufactured by Arakawa Chemical Industries, Ltd.), liquid paraffin (Hycol M352, manufactured by Kaneda Co., Ltd.), N-methyl-2-pyrrolidone (Pharmasolve, manufactured by Serendipit Co., Ltd.), isostearic acid (Isostearic Acid EX, manufactured by Kokyu Alcohol Kogyo Co., Ltd.), and diclofenac sodium were sequentially added with stirring to a mixer (ZZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.) containing an appropriate amount of hexane. Stirring was continued thoroughly after each addition of each raw material until the mixture was homogenous. Next, hexane was further added with stirring until the amount of hexane reached approximately 150 g, and the plaster fluid for the patch of Test Example 5 was obtained.

[0052] Preparation of Plaster Fluid for Patch of Test Example 6 The plaster fluid for the patch of Test Example 6 was prepared. In the amounts shown in Table 4 below, polyisoprene (Cariflex IR0307KU, manufactured by Kraton Polymers), alicyclic saturated hydrocarbon resin (Arcon P-100, manufactured by Arakawa Chemical Industries, Ltd.), liquid paraffin (Hycol M352, manufactured by Kaneda Co., Ltd.), N-methyl-2-pyrrolidone (Pharmasolve, manufactured by Serendipit Co., Ltd.), isostearic acid (Isostearic Acid EX, manufactured by Kokyu Alcohol Kogyo Co., Ltd.), lactic acid (Lactic Acid, manufactured by Showa Kako Co., Ltd.), and diclofenac sodium were sequentially added with stirring to a mixer (ZZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.) containing an appropriate amount of hexane. Stirring was continued thoroughly after each addition of each raw material until the mixture was homogenous. Next, hexane was further added with stirring until the amount of hexane reached approximately 150 g, and the plaster fluid for the patch of Test Example 6 was obtained.

[0053] Preparation of Plaster Fluid for Patch of Test Example 7 A plaster fluid for the patch of Test Example 7 was prepared. In the amounts shown in Table 4 below, polyisoprene (Cariflex IR0307KU, manufactured by Kraton Polymers), alicyclic saturated hydrocarbon resin (Arcon P-100, manufactured by Arakawa Chemical Industries, Ltd.), liquid paraffin (Hycol M352, manufactured by Kaneda Co., Ltd.), N-methyl-2-pyrrolidone (Pharmasolve, manufactured by Serendipit Co., Ltd.), isostearic acid (Isostearic Acid EX, manufactured by Kokyu Alcohol Kogyo Co., Ltd.), isopropyl myristate (IPM-R, manufactured by NOF Corporation), and diclofenac sodium were sequentially added with stirring to a mixer (ZZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.) containing an appropriate amount of hexane. Stirring was continued thoroughly after each addition of each raw material until the mixture was homogenous. Next, hexane was further added with stirring until the amount of hexane reached approximately 150 g, and the plaster fluid for the patch of Test Example 7 was obtained.

[0054] Preparation of Plaster Fluid for Patch of Test Example 8 A plaster fluid for the patch of Test Example 8 was prepared. In the amounts shown in Table 4 below, polyisoprene (Cariflex IR0307KU, manufactured by Kraton Polymers), alicyclic saturated hydrocarbon resin (Arcon P-100, manufactured by Arakawa Chemical Industries, Ltd.), liquid paraffin (Hycol M352, manufactured by Kaneda Co., Ltd.), N-methyl-2-pyrrolidone (Pharmasolve, manufactured by Serendipit Co., Ltd.), isostearic acid (EX Isostearic Acid, manufactured by Kokyu Alcohol Kogyo Co., Ltd.), propylene glycol caprylate (Sefsol-218, manufactured by Nippon Surfactant Kogyo Co., Ltd.), and diclofenac sodium were sequentially added with stirring to a mixer (ZZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.) containing an appropriate amount of hexane. Stirring was continued thoroughly after each addition of each raw material until the mixture was uniform. Next, hexane was further added with stirring so that the amount of hexane became about 150 g, and a plaster fluid for the patch of Test Example 8 was obtained.

[0055] Preparation of Plaster Fluid for Patch of Test Example 9 A plaster fluid for the patch of Test Example 9 was prepared. In the amounts shown in Table 4 below, polyisoprene (Cariflex IR0307KU, manufactured by Kraton Polymers), alicyclic saturated hydrocarbon resin (Arcon P-100, manufactured by Arakawa Chemical Industries, Ltd.), liquid paraffin (Hycol M352, manufactured by Kaneda Co., Ltd.), N-methyl-2-pyrrolidone (Pharmasolve, manufactured by Serendipit Co., Ltd.), isostearic acid (Isostearic Acid EX, manufactured by Kokyu Alcohol Kogyo Co., Ltd.), propylene glycol dicaprylate (Sefsol-228, manufactured by Nippon Surfactant Kogyo Co., Ltd.), and diclofenac sodium were sequentially added with stirring to a mixer (ZZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.) containing an appropriate amount of hexane. Stirring was continued thoroughly after each addition of each raw material until the mixture was uniform. Next, hexane was further added with stirring so that the amount of hexane became about 150 g, and a plaster fluid for the patch of Test Example 9 was obtained.

[0056] Preparation of Plaster Fluid for Patch of Test Example 10 A plaster fluid for the patch of Test Example 10 was prepared. In the amounts shown in Table 4 below, polyisoprene (Cariflex IR0307KU, manufactured by Kraton Polymers), alicyclic saturated hydrocarbon resin (Arcon P-100, manufactured by Arakawa Chemical Industries, Ltd.), hydrogenated rosin glycerin ester (PINECRYSTAL KE-311, manufactured by Arakawa Chemical Industries, Ltd.), liquid paraffin (Hicol M352, manufactured by Kaneda Co., Ltd.), N-methyl-2-pyrrolidone (Pharmasolve, manufactured by Serendipit Co., Ltd.), isostearic acid (Isostearic Acid EX, manufactured by Kokyu Alcohol Kogyo Co., Ltd.), and diclofenac sodium were sequentially added with stirring to a mixer (ZZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.) containing an appropriate amount of hexane. Stirring was continued thoroughly after each addition of each raw material until the mixture was uniform. Next, hexane was further added with stirring so that the amount of hexane became about 150 g, and a plaster fluid for the patch of Test Example 10 was obtained.

[0057] Preparation of Plaster Fluid for Patch of Test Example 11 A plaster fluid for the patch of Test Example 11 was prepared. In the amounts shown in Table 4 below, polyisoprene (Cariflex IR0307KU, manufactured by Kraton Polymers), hydrogenated rosin glycerin ester (PINECRYSTAL KE-311, manufactured by Arakawa Chemical Industries, Ltd.), liquid paraffin (Hicol M352, manufactured by Kaneda Co., Ltd.), N-methyl-2-pyrrolidone (Pharmasolve, manufactured by Serendipit Co., Ltd.), isostearic acid (Isostearic Acid EX, manufactured by Kokyu Alcohol Kogyo Co., Ltd.), and diclofenac sodium were sequentially added with stirring to a mixer (ZZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.) containing an appropriate amount of hexane. Stirring was continued thoroughly after each addition of each raw material until the mixture was homogenous. Next, hexane was further added with stirring until the amount of hexane reached approximately 150 g, and the plaster fluid for the patch of Test Example 11 was obtained.

[0058] Preparation of Plaster Fluids for Patches of Test Examples 12 and 13 Plaster fluids for the patches of Test Examples 12 and 13 were prepared. In the amounts shown in Table 4 below, polyisoprene (Cariflex IR0307KU, manufactured by Kraton Polymers), alicyclic saturated hydrocarbon resin (Arcon P-100, manufactured by Arakawa Chemical Industries, Ltd.), liquid paraffin (Hycol M352, manufactured by Kaneda Co., Ltd.), N-methyl-2-pyrrolidone (Pharmasolve, manufactured by Serendipit Co., Ltd.), isostearic acid (Isostearic Acid EX, manufactured by Kokyu Alcohol Kogyo Co., Ltd.), and diclofenac sodium were sequentially added with stirring to a mixer (ZZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.) containing an appropriate amount of hexane. Stirring was continued thoroughly after each addition of each raw material until the mixture was homogenous. Next, hexane was further added with stirring until the amount of hexane reached approximately 150 g, and the plaster fluids for the patches of Test Examples 12 and 13 were obtained.

[0059] Preparation of patches for Test Examples 5 to 13 The prepared plaster solution for Test Examples 5 to 13 was applied to a silicone-treated PET film in such a manner that the plaster weight was 1.0 g / 70 cm for Test Examples 5 to 11. ２ , Test Examples 12 to 13 are 0.75 g / 70 cm ２ The PET film was then dried to remove the hexane, and a PET film or woven fabric was attached to prepare the patches of Test Examples 5 to 13. The prepared patches were cut into rectangles measuring approximately 7 cm x 10 cm, packaged in aluminum packaging, and stored at room temperature.

[0060] The physical properties and usability of the patches of Test Examples 5, 6, and 10 to 13 were evaluated in the same manner as above. The results are shown in Table 5.

[0061]

[0062]

[0063] The patches of Test Examples 5, 6, and 10 to 13 all exhibited good physical properties and a feeling of use comparable to those of Test Example 1.

[0064] Evaluation of Mouse Skin Permeability of Patches If the stability of a patch is poor, storing the patch for a certain period of time can reduce the content of the active ingredient due to decomposition, crystallization, etc., resulting in a decrease in the amount of the active ingredient that permeates the skin. Therefore, a skin permeation test was performed on the patches of Test Examples 1 to 4 (samples were patches using PET film as a support) that had been stored for two weeks after preparation, and their transdermal absorbability was evaluated. The test was performed using a commonly used method using a side-by-side diffusion cell as the permeation test device. A 20 mm diameter circular patch was cut from the dorsal skin of a 7-week-old male hairless mouse (strain: Hos:HR-1, Hoshino Laboratory Animal Breeding Co., Ltd.) and attached to cover the opening of a horizontal diffusion cell so that the dermis side was in contact with receptor fluid (phosphate-buffered saline (PBS) at pH 7.4). A 14 mm diameter circular patch (a patch from Test Examples 1 to 4) with the liner removed was attached to the stratum corneum side of the skin, and 0.2 mL of receptor fluid was sampled over time (after sampling, an equal volume of drug-free PBS at pH 7.4 was added to the receptor fluid to maintain the total volume of receptor fluid). Warm water at 37°C was circulated through the water jacket of the cell. The diclofenac sodium concentration in the sampled solution was measured using liquid chromatography (HPLC). The cumulative permeation amount of diclofenac sodium [μg / cm ２ The change over time in the amount of HCl was measured. The measurement results are shown in Figure 1.

[0065] The results in FIG. 1 clearly show that the patch of Test Example 1 exhibits good permeability even two weeks after preparation, compared to the patches of the other Test Examples.

[0066] The cumulative permeation amounts after 4 hours for the patches of Test Examples 1 to 4 stored for 1 day and 2 weeks after preparation are shown in Table 6 below. All values ​​in the table are in μg / cm ２ 〕

[0067]

[0068] The results of Figure 1 and Table 6 show that the cumulative permeation amount of the patch of Test Example 1 did not change significantly even after two weeks had passed since preparation compared to one day after preparation, demonstrating stable permeability.

[0069] The cumulative permeation amounts after 4 hours for the patches of Test Example 5 and Test Example 12 stored for about 2 weeks and about 2 months after preparation are shown in Table 7 below. All values ​​in this table are in units of μg / cm ２ The storage periods for Test Example 5 were 10 days and 59 days after preparation, and the storage periods for Test Example 12 were 14 days and 63 days after preparation.

[0070]

[0071] The results in Table 7 show that the patches of Test Examples 5 and 12 have stable permeability, with the cumulative permeation amount remaining almost unchanged even after about two months from preparation compared to about two weeks from preparation.

Claims

1. A patch comprising a paste and a support, the paste comprising: (A) diclofenac or a pharma- ceutical acceptable salt thereof; (B) polyisoprene; and (C) N-methyl-2-pyrrolidone.

2. The patch according to claim 1 for treating pain.

3. The patch according to claim 2, wherein the treatment of pain is pain relief in various cancers, or pain relief or anti-inflammation in lower back pain, shoulder periarthritis, neck-shoulder-arm syndrome or tendonitis.

4. The patch according to claim 2, wherein the pain treatment is pain relief for various types of cancer.

5. The patch according to claim 2, wherein the treatment of pain is analgesia or anti-inflammation in lower back pain, shoulder periarthritis, neck-shoulder-arm syndrome or tendonitis.

6. The patch according to any one of claims 1 to 5, wherein the component (A) is diclofenac sodium.

7. A patch according to any one of claims 1 to 5, wherein the blending amount of said component (A) is 1 to 20 mass% based on the total amount of said base.

8. The patch according to any one of claims 1 to 5, wherein the blending amount of said component (B) is 10 to 50 mass% based on the total amount of said base.

9. The patch according to any one of claims 1 to 5, wherein the blending amount of said component (C) is 1 to 15 mass% based on the total amount of said base.

Images