Water-based adhiesive patch

Abstract

Provided is an aqueous patch which is capable of stably blending only one of S-type and R-type drugs, which are optical isomers, at a relatively high concentration for a long period of time, and which has excellent adhesiveness and shape retention while exhibiting high drug transdermal properties. Specifically, the present invention provides an aqueous patch containing, as an active ingredient, only one of optical isomers of a drug in a paste.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202511362222.2 (22) Application Date 2017.10.11 (30) Priority Data 2016-201134 2016.10.12 JP (62) Divisional Application Data 201780063071.8 2017.10.11 (71) Applicant Teikoku Pharmaceutical Co., Ltd. Address Kagawa Prefecture, Japan (72) Inventors Satoshi Shirai Inatsumi Masahiro (74) Patent Agency China Patent Agency (Hong Kong) Limited 72001 Patent Attorney Mei Li Huang Nian (51) Int.Cl. A61K 9 / 70 (2006.01) A61K 31 / 192 (2006.01) A61K 47 / 18 (2017.01) A61P 29 / 00 (2006.01) (54) Invention Title: Aqueous Patch (57) Abstract: This invention provides an aqueous patch that can stably and continuously contain only one of the optical isomers of a drug, either S-type or R-type, as optical isomers at a high concentration over a long period, exhibiting excellent adhesion and shape retention, while also showing high drug transdermal permeability. Specifically, this invention provides an aqueous patch containing only one of the optical isomers of a drug as an active ingredient in an ointment. Claims: 1 page Description: 17 pages Drawings: 1 page CN 121243121 A 2026.01.02 CN 1 21 24 31 21 A 1. An aqueous patch containing only one of the optical isomers of a drug as an active ingredient in an ointment. 2. The aqueous patch of claim 1, wherein the drug is an anti-inflammatory agent or an analgesic, or an adjuvant thereof. 3. The aqueous patch according to claim 1 or 2, wherein the drug is selected from one or more of flurbiprofen, ketoprofen, and ibuprofen. 4. The aqueous patch according to any one of claims 1 to 3, wherein the drug is flurbiprofen. 5. The aqueous patch according to any one of claims 1 to 4, wherein the amount of drug incorporated is 0.5 to 6 w / w% relative to the mass of the patch. 6. The aqueous patch according to any one of claims 1 to 5, wherein the patch further contains a water-soluble organic amine. 7. The aqueous patch according to claim 6, wherein the water-soluble organic amine is selected from one or more of the following: monoethanolamine, monoethanolamine, monopropanolamine, monoisopropanolamine, diethanolamine, diethanolamine, dipropanolamine, diisopropanolamine, dibutanolamine, diisobutanolamine, triethanolamine, triethanolamine, tripropanolamine, triisopropanolamine, tributanolamine, triisobutanolamine, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, triethylamine, tripropylamine, and triisopropylamine.8. The aqueous patch according to claim 6 or 7, wherein the amount of water-soluble organic amine blended is 0.2 to 5 w / w% relative to the mass of the patch. 9. The aqueous patch according to any one of claims 6 to 8, wherein the blending ratio of water-soluble organic amine relative to the optical isomer of the drug is 0.25 to 5 by mass. 10. The aqueous patch according to any one of claims 1 to 9, wherein the optical isomer of the drug is S-type. 11. The aqueous patch according to any one of claims 1 to 10, wherein the patch further contains one or more components selected from water, polyacrylic acid or its salts, cellulose derivatives, crosslinking agents, humectants, and pH adjusters. 12. The aqueous patch of claim 11, wherein the polyacrylic acid or its salts are selected from one or more of polyacrylic acid, sodium polyacrylate, and partially neutralized polyacrylic acid; the cellulose derivative is selected from one or more of sodium carboxymethyl cellulose, hydroxypropyl cellulose, and hydroxymethyl cellulose; the crosslinking agent is selected from one or more of aluminum dihydroxyacetate, magnesium aluminosilicate, aluminum hydroxide, and synthetic hydrotalcite; the moisturizer is selected from one or more of glycerin, 1,3-butanediol, propylene glycol, polypropylene glycol, D-sorbitol, and polyethylene glycol 400; and the pH adjuster is selected from one or more of tartaric acid, lactic acid, and malic acid. 13. The aqueous patch according to claim 11 or 12, wherein, relative to the mass of the paste, the amount of water is 20-70 w / w, the amount of polyacrylic acid or its salts is 2-20 w / w, the amount of cellulose derivative is 2-20 w / w, the amount of crosslinking agent is 0.02-3.5 w / w, the amount of moisturizer is 5-60 w / w, and the amount of pH adjuster is 0.2-10 w / w. Claims 1 / 1 page 2 CN 121243121 A Aqueous Patch

[0001] This application is a divisional application of the invention patent application filed on October 11, 2017, entitled "Aqueous Patch", with national application number 201780063071.8. Technical Field

[0002] This invention relates to aqueous patches. In order to improve the therapeutic effect of aqueous patches containing optically active drugs, the aqueous patches contain optically active drugs at a high concentration for a long period of time with stable properties and also have excellent drug transdermal properties. Background Art

[0003] Drugs contain S-type and R-type as optical isomers. For example, flurbiprofen, an anti-inflammatory analgesic, contains optical isomers (+)-2-(2-fluoro-4-biphenyl)propionic acid (hereinafter referred to as S-flurbiprofen) and (-)-2-(2-fluoro-4-biphenyl)propionic acid (hereinafter referred to as R-flurbiprofen).

[0004] In the pharmaceutical field, in the case of flurbiprofen, S-flurbiprofen and R-flurbiprofen, which are inexpensive racemic mixtures (hereinafter referred to as racemic flurbiprofen), are commonly used in equal amounts.

[0005] In recent years, patent documents 1 and 2 have been disclosed as technologies related to aqueous patches (or poultices) containing S-type anti-inflammatory and analgesic agents. Patent document 1 describes a topical preparation containing S-flurbiprofen and a polyol, and an aqueous patch is also exemplified therein. In addition, patent document 2 describes an aqueous patch containing S-flurbiprofen with sodium carboxymethyl cellulose and sodium polyacrylate as the constituent matrix.

[0006] The aqueous patches described in each patent document show the potential to improve therapeutic effects by using the pharmacologically potent S-type, but there is almost no research on the stability of the preparation. In particular, there are many areas that need improvement, such as drug solubility when mixed with drugs at higher concentrations, drug solubility of preparations that have been stored for a long time, and maintenance of the physical properties of the preparation. There is a desire for an aqueous patch that can improve both therapeutic effects and preparation stability.

[0007] Prior Art Documents Patent Document 1: Japanese Patent Application Publication No. 06-199701; Patent Document 2: Japanese Patent Application Publication No. 08-119859. Summary of the Invention

[0008] Problem to be Solved by the Invention Generally, the higher the drug concentration, the better the transdermal absorption, and the better the therapeutic effect can be expected. Therefore, in order to improve the therapeutic effect, it is only necessary to increase the amount of drug mixed in. However, the drugs mixed in transdermal absorption preparations are mostly highly lipid-soluble substances, which are very difficult to stably mix in a high concentration and in a dissolved state in aqueous patches with water as the main component.

[0009] For example, in existing aqueous patches, it is difficult to mix flurbiprofen in the ointment at a high concentration. Its concentration relative to the mass of the ointment is about 0.3 w / w%, which is extremely low.

[0010] Regarding flurbiprofen, as an S-type drug, S-flurbiprofen itself has a very strong anti-inflammatory and analgesic effect. However, without being mixed into an aqueous patch at a certain high concentration, a better therapeutic effect cannot be expected. Therefore, maintaining a high concentration of the drug stably in the formulation for a long period is a significant problem for practical application.

[0011] Means for Solving the Problem In view of the above problems, the inventors have repeatedly conducted in-depth research and discovered that by mixing only one of the optical isomers of the S-type and R-type drugs (which are optical isomers), preferably with a water-soluble organic amine, and even more preferably with a paste matrix appropriately combined with water, a moisturizer, a water-soluble polymer, a crosslinking agent, and a pH (pH value) adjuster, an aqueous patch with excellent adhesion and shape retention, capable of being stably mixed at a high concentration for a long period, and exhibiting higher drug transdermal activity, the present invention was thus completed.

[0012] That is, the present invention relates to the following.

[0013] [1] Aqueous patch, which contains only one of the optical isomers of a drug as an active ingredient in the ointment.

[0014] [2] [1] The aqueous patch, wherein the drug is an anti-inflammatory agent or an analgesic, or an adjuvant thereof.

[0015] [3] [1] or [2] The aqueous patch, wherein the drug is one or more selected from flurbiprofen, ketoprofen and ibuprofen.

[0016] [4] [1] to [3] The aqueous patch, wherein the drug is flurbiprofen.

[0017] [5] [1] to [4] The aqueous patch, wherein the amount of drug mixed is 0.5 to 6 w / w% relative to the mass of the paste.

[0018] [6] [1] to [5] The aqueous patch, wherein the paste further contains a water-soluble organic amine.

[0019] [7] [6] The aqueous patch, wherein the water-soluble organic amine is selected from one or more of the following: monoethanolamine, monoethanolamine, monopropanolamine, monoisopropanolamine, diethanolamine, diethanolamine, dipropanolamine, diisopropanolamine, dibutanolamine, diisobutanolamine, triethanolamine, triethanolamine, tripropanolamine, triisopropanolamine, tributanolamine, triisobutanolamine, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, triethylamine, tripropylamine, and triisopropylamine.

[0020] [8] [6] or [7] The aqueous patch, wherein the amount of water-soluble organic amine mixed is 0.2 to 5 w / w relative to the mass of the paste.

[0021] The aqueous patch according to any one of [9] [6] to [8], wherein the proportion of water-soluble organic amine in the mixture is 0.25 to 5 by mass relative to the optical isomer of the drug.

[0022] The aqueous patch according to any one of [1] to [9], wherein the optical isomer of the drug is S-type.

[0023] The aqueous patch according to any one of [1] to

[10] , wherein the patch further contains one or more components selected from water, polyacrylic acid or its salts, cellulose derivatives, crosslinking agents, humectants and pH adjusters.

[0024]

[12]

[11] The aqueous patch, wherein the polyacrylic acid or its salts are selected from one or more of polyacrylic acid, sodium polyacrylate and partially neutralized polyacrylic acid; the cellulose derivative is selected from one or more of sodium carboxymethyl cellulose, hydroxypropyl cellulose and hydroxymethyl cellulose; the crosslinking agent is selected from one or more of aluminum aminoacetate, magnesium aluminosilicate, aluminum hydroxide and synthetic hydrotalcite; the moisturizer is selected from one or more of glycerin, 1,3-butanediol, propylene glycol, polypropylene glycol, D-sorbitol and polyethylene glycol 400; and the pH adjuster is selected from one or more of tartaric acid, lactic acid and malic acid.

[0025]

[13]

[11] or

[12] of the aqueous patch, wherein, relative to the mass of the paste, the amount of water is 20-70 w / w, the amount of polyacrylic acid or its salts is 2-20 w / w, the amount of cellulose derivative is 2-20 w / w, the amount of binder is 0.02-3.5 w / w, the amount of moisturizer is 5-60 w / w, and the amount of pH adjuster is 0.2-10 w / w.

[0026] In addition, the present invention also relates to the following.

[0027]

[14] [1] to

[13] of the aqueous patch, wherein the drug is one or more selected from S flurbiprofen, S ketoprofen and S ibuprofen.

[0028]

[15] The aqueous patch according to any one of [1] to

[14] , wherein the drug is flurbiprofen.

[0029]

[16] The aqueous patch according to any one of [6] to

[15] , wherein the water-soluble organic amine is one or more selected from diisopropanolamine, monoethanolamine, diethanolamine, triethanolamine and triethylamine.

[0030]

[17] The aqueous patch according to any one of [1] to

[16] , wherein the ointment further contains crotamiton.

[0031]

[18] The aqueous patch according to any one of [1] to

[17] , wherein the ointment further contains one or more components selected from water-soluble polymers other than polyacrylic acid or its salts and cellulose derivatives, excipients, stabilizers and preservatives.

[0032]

[19] [1] to

[18] of any one of the aqueous patches, wherein the ointment comprises one of the optical isomers of the drug, and one or more components selected from water-soluble organic amines, water, polyacrylic acid or its salts, cellulose derivatives, crosslinking agents, humectants and pH adjusters, and water-soluble polymers other than clomiphene, polyacrylic acid or its salts and cellulose derivatives, excipients, stabilizers and preservatives as optional components.

[0033] Effects of the Invention According to the present invention, in an aqueous patch containing only one of the optical isomers of the drug, by preferably combining the optical isomer and the water-soluble organic amine, an aqueous patch can be provided that allows the drug to be stably mixed and maintained in the formulation at a high concentration, and exhibits high drug permeability, while also having excellent adhesion and shape retention. Brief Description of the Drawings FIG1 is a graph showing the cumulative skin permeation of flurbiprofen using the aqueous patch of the present invention and the aqueous patch of a comparative example. Detailed Description of Embodiments

[0035] Hereinafter, the aqueous patch of the present invention will be further described in detail.

[0036] The aqueous patch of the present invention refers to an aqueous patch in which, in order to obtain a high therapeutic effect, a drug is typically and stably mixed in at a high concentration in an ointment, the drug has good skin permeability, and the drug has excellent preservation stability. The ointment is an adhesive ointment composition containing a drug. In addition, the ointment matrix refers to the ointment obtained by removing the drug from the ointment.

[0037] As for the drug that can be mixed in the aqueous patch of the present invention, it is not limited as long as it contains S-type and R-type drugs as optical isomers. Examples include: anti-inflammatory agents or analgesics, or adjuvants thereof; antihypertensive drugs; antiemetics; drugs that improve cerebral circulation; antidepressants; sex hormones; antitussives; antitumor drugs; antihistamines; coronary vasodilators; antifungal agents; antibacterial agents; general anesthetics; hypnotics and sedatives; antidementia drugs; anti-Parkinson's drugs; mental stabilizers; and bactericides and disinfectants, etc. However, anti-inflammatory agents or analgesics, or adjuvants thereof, which can be expected to have a combined effect with the cooling sensation shown by the aqueous patch are preferred. Examples of anti-inflammatory agents or analgesics, or their adjuvants, that can be used in the aqueous patches of this invention include: anti-inflammatory analgesics, local anesthetics, opioids and opioid antagonists, specifically, examples include flurbiprofen, ketoprofen, ibuprofen, naproxen, loxoprofen, zaltoprofen, ketorolac (see page 3 / 17 of the specification, CN 121243121 A), cortisol, prednisolone, methylprednisolone, and triamcinolone. Dexamethasone, betamethasone, morphine, oxycodone, methadone, codeine, buprenorphine, tramadol, tapentadol, pentazocine, nalprofen, butorphanol, levallorphan, eptazocine, nalbuphine, nalfurafine, naloxone, prilocaine, mepivacaine, bupivacaine, ropivacaine, and their pharmaceutically acceptable salts or esters may be used alone or in combination of two or more. The preferred anti-inflammatory agent or analgesic, or its adjuvant, is an anti-inflammatory analgesic, more preferably one or more of flurbiprofen, ketoprofen and ibuprofen, and particularly preferably flurbiprofen.Although S-type and R-type optical isomers exist, only one type of optical isomer must be mixed into these drugs. It can be only S-type or only R-type, with S-type, which has significant pharmacological effects, being preferred. However, the amount of the other optical isomer that inevitably mixes in during the manufacturing of the original drug, or the amount of the other optical isomer generated by decomposition reaction during the storage of the original drug, is trace and will not be a problem in substance.

[0038] The amount of drug mixed in relative to the mass of the ointment is preferably 0.5 to 6 w / w%, more preferably 1 to 3 w / w%, and even more preferably 1 to 2 w / w%. If the amount of drug mixed in is less than 0.5 w / w%, there is a lack of therapeutic effect, and if it exceeds 6 w / w%, the drug will precipitate in the ointment, and the transdermal absorption of the aqueous patch may be deteriorated. It should be noted that, in this specification, the term "higher concentration" when referring to the amount of drug mixed in means the range described above.

[0039] In one embodiment, the aqueous patch of the present invention contains a water-soluble organic amine in the ointment. The water-soluble organic amine has the function of stably dissolving one of the optical isomers of the drug in the ointment.

[0040] Here, water-soluble organic amine refers to amines substituted with 1 to 3 unsubstituted alkyl groups (e.g., C1-C4 alkyl groups), or amines having substituents, preferably 1 to 3 alkyl groups (e.g., C1-C4 alkyl groups) with 1 to 3 hydroxyl groups, further selected from those stably soluble in water, preferably monoethanolamine, monoethanolamine, monopropanolamine, monoisopropanolamine, diethanolamine, diethanolamine, dipropanolamine, diisopropanolamine, dibutanolamine, diisobutanolamine, triethanolamine, triethanolamine, tripropanolamine, triisopropanolamine, tributanolamine, triethanolamine, triisopropanolamine, tributanolamine, triethanolamine, triethanolamine, tripropanolamine, triisopropanolamine, tributanolamine, triethanolamine, triethanolamine, tripropanolamine, triisopropanolamine, tributanolamine, Triisobutanolamine, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, triethylamine, tripropylamine, and triisopropylamine, etc., may be used, either one or a combination of two or more thereof. More preferably, it is a combination of one or more of diisopropanolamine, monoethanolamine, diethanolamine, triethanolamine, and triethylamine.

[0041] The amount of water-soluble organic amine blended can be adjusted according to the amount of one of the optical isomers of the drug, preferably 0.2 to 5 w / w% relative to the mass of the paste, more preferably 0.5 to 3 w / w%, and even more preferably 0.8 to 2 w / w%. If the blending amount is less than 0.2 w / w%, the drug cannot dissolve in the paste, and if the blending amount exceeds 5 w / w%, the adhesiveness of the paste deteriorates, which is not preferred.

[0042] The mixing ratio (mass ratio) of the water-soluble organic amine relative to the optical isomer of the drug is preferably 0.25 to 5, more preferably 0.25 to 3, and even more preferably 0.3 to 1. When it is less than 0.25, drug precipitates will be generated in the ointment; if it exceeds 5, the adhesiveness and shape retention of the ointment will deteriorate, which is not preferred.

[0043] In one embodiment, the aqueous patch of the present invention may contain one or more components selected from water, water-soluble polymers, crosslinking agents, humectants, and pH adjusters in the paste.

[0044] Water is the medium used to dissolve the water-soluble polymers. The amount of water mixed relative to the mass of the paste is preferably 20-70 w / w%, more preferably 30-60 w / w%, and even more preferably 30-50 w / w%. If the amount of water mixed is less than 20 w / w%, the water-soluble polymers cannot be fully dissolved and become uneven, resulting in insufficient adhesion and shape retention of the paste. If the amount of water mixed exceeds 70 w / w%, the shape retention of the paste becomes weak, which is not preferred. It should be noted that this amount of water mixed refers to the total amount of all water, including the purified water added during the preparation of the patch and the water contained in other components (such as sorbitol solution).

[0045] Water-soluble polymers, through their thickening function when dissolved in water and the formation of cross-links, have the function of improving the adhesive strength of the paste and maintaining its shape retention. They are typically used in combination with materials selected from polyacrylic acid or its salts and cellulose derivatives.

[0046] Polyacrylic acid or its salts improve the adhesive strength of the paste through their thickening function when dissolved in water and the formation of cross-links by a cross-linking agent. Examples of polyacrylic acid or its salts include polyacrylic acid, sodium polyacrylate, and partially neutralized polyacrylic acid. One or more of these can be used, preferably a combination of polyacrylic acid and sodium polyacrylate.

[0047] The amount of polyacrylic acid or its salts mixed with the paste is preferably 2 to 20 w / w%, more preferably 3 to 15 w / w%, and even more preferably 5 to 10 w / w%. If it is less than 2 w / w%, the adhesive strength of the paste decreases; if it exceeds 20 w / w%, water-insoluble portions are produced, the paste becomes uneven, and the adhesive strength becomes insufficient.

[0048] Cellulose derivatives utilize their thickening properties when dissolved in water to adjust the shape retention of the paste. Examples of cellulose derivatives include sodium carboxymethyl cellulose, hydroxypropyl cellulose, and hydroxymethyl cellulose. One or more of these derivatives can be used, and combinations of one or more containing sodium carboxymethyl cellulose are particularly preferred.

[0049] The amount of cellulose derivative blended relative to the mass of the paste is preferably 2 to 20 w / w%, more preferably 3 to 15 w / w%, and even more preferably 3 to 10 w / w%. If it is less than 2 w / w%, the viscosity is low and the shape retention of the paste cannot be maintained. In addition, if it exceeds 20 w / w%, water-insoluble portions are generated, the paste becomes uneven, and the shape retention cannot be kept constant.

[0050] A crosslinking agent forms a crosslinked body with polyacrylic acid or its salts, which has the function of maintaining the shape retention of the paste. It is selected from sparingly soluble polyvalent metal salts.Examples include: aluminum glycine, magnesium aluminosilicate, aluminum hydroxide, and synthetic hydrotalcite. One or more of these can be used, preferably one or more of aluminum glycine, magnesium aluminosilicate, and synthetic hydrotalcite.

[0051] The amount of crosslinking agent mixed with the paste is preferably 0.02 to 3.5 w / w%, more preferably 0.03 to 2 w / w%, and even more preferably 0.04 to 0.5 w / w%. If it is less than 0.02 w / w%, the crosslinking is not formed sufficiently, and the shape retention of the paste deteriorates. If it exceeds 3.5 w / w%, more crosslinks are formed, and the adhesiveness of the formulation deteriorates.

[0052] The moisturizer has the function of improving the moisturizing effect on the skin and adjusting the shape retention of the paste.

[0053] These humectants are selected from water-soluble polyols, preferably glycerin, 1,3-butanediol, propylene glycol, polypropylene glycol, D-sorbitol, and polyethylene glycol 400, and one or more of them may be used. A combination of one or more of glycerin, propylene glycol, and D-sorbitol is particularly preferred.

[0054] The amount of humectant blended relative to the mass of the paste is preferably 5-60 w / w%, more preferably 10-50 w / w%, and even more preferably 20-40 w / w%. If it is less than 5 w / w%, the shape retention of the paste becomes insufficient; if it exceeds 60 w / w%, other blending materials, especially water, are insufficient, and the adhesion and shape retention of the paste become insufficient, which is not preferred.

[0055] The pH adjuster has the function of adjusting the pH of the paste and is selected from organic acids, such as tartaric acid, lactic acid, and malic acid, etc. One or more of them may be used, with tartaric acid being preferred.

[0056] The amount of pH adjuster mixed in relative to the mass of the ointment is preferably 0.2 to 10 w / w%, more preferably 0.3 to 7 w / w%, and even more preferably 0.5 to 5 w / w%. In order to maintain the drug in a dissolved state in the ointment and to maintain adhesion and shape retention, the pH of the ointment is preferably adjusted to the range of 4 to 7.

[0057] In addition, when studying raw materials that stabilize the dissolved state of the drug under environmental conditions such as long-term cold storage, crotamiton was found as a material that can be mixed into an aqueous matrix. The amount of crotamiton mixed in relative to the mass of the ointment is preferably 0.1 to 3 w / w%, more preferably 0.1 to 2 w / w%, and even more preferably 0.1 to 1 w / w%.

[0058] Furthermore, other therapeutic agents may also be mixed into the aqueous patch of the present invention.In addition, the materials typically used in water-based patches, such as water-soluble polymers other than polyacrylic acid or its salts and cellulose derivatives (e.g., polyvinyl alcohol, etc., in an amount of 0.1-3 w / w%, more preferably 0.1-2 w / w%, and even more preferably 0.1-1 w / w%), excipients (e.g., kaolin, etc., in an amount of 0.1-10 w / w%, more preferably 0.3-5 w / w%, and even more preferably 0.5-3 w / w%), stabilizers (e.g., sodium edetate, etc., in an amount of 0.01-1 w / w%, more preferably 0.03-0.5 w / w%, and even more preferably 0.05-0.1 w / w%), and preservatives (e.g., parabens, etc., in an amount of 0.1-3 w / w%, and even more preferably 0.1-2 w / w%), are also included. The concentrations are w%, more preferably 0.1 to 1 w / w%), etc. During long-term storage or use, the material itself may volatilize, or the drug may precipitate in the ointment, etc., as long as the transdermal absorption is not worsened and the therapeutic effect is not impaired. Any one of these can be mixed.

[0059] In the aqueous patch of the present invention, the ointment is spread or applied between the support and the release liner. The support is only required to hold the applied ointment and is not particularly limited.

[0060] Examples of supports include: non-woven fabrics, woven fabrics, etc.; fabrics with a thin plastic film laminated on them; laminated materials with a film sandwiched between fabrics, etc. Examples of materials used for these supports include: polyethylene, polypropylene, polyvinyl chloride, polyester, polyethylene terephthalate, nylon, polyurethane, rayon, polyacrylonitrile, polystyrene, and polyethylene naphthalate, etc. The support can be either breathable or not. As for the laminating material, a material with moisture permeability can be selected, or the membrane can be treated with through holes, etc.

[0061] There is no particular limitation on the method of applying the ointment to the support, and the ordinary manufacturing method of water-based patches can be used. It should be noted that the mass of the applied ointment is preferably 200 to 1500 g / m2, more preferably 300 to 1200 g / m2, and the water-based patch can be cut into an appropriate shape and size according to the affected area for use.

[0062] The release liner can be, for example, polyester, polyethylene terephthalate, polypropylene or paper, etc., and polyester is particularly preferred. In order to achieve the best release force, the release liner can be treated with silicone as needed.

[0063] Hereinafter, the present invention will be specifically described by way of examples, comparative examples and test examples. It should be noted that the present invention is not limited to these examples. Examples

[0064] Example 1 A water-based patch was prepared according to the formulation composition in Table 1 in the following order.

[0065] Add S flurbiprofen and diisopropanolamine to pure water to dissolve (solution).

[0066] Sodium polyacrylate, partially neutralized polyacrylic acid, sodium carboxymethyl cellulose, carboxypropyl cellulose, and synthetic hydrotalcite were added to concentrated glycerin and dispersed (dispersion).

[0067] A solution of purified water, a solution of polyvinyl alcohol dissolved in purified water, a solution of polyacrylic acid dissolved in purified water, a sorbitol solution (70% D-sorbitol), kaolin, and tartaric acid were mixed, and the dispersion was slowly added while stirring the solution. Then the dissolving solution was added and stirred to prepare a paste.

[0068] The paste was spread between a nonwoven fabric and a polyester film and cut to an appropriate size to prepare an aqueous patch.

[0069] Example 2 The desired aqueous patch was prepared according to the formulation composition shown in Table 1, following the order of Example 1.

[0070] Comparative Examples 1, 2, and 3 The desired aqueous patches were prepared according to the formulation composition shown in Table 1, following the order of Example 1.

[0071] [Table 1] Instruction manual 6 / 17 pages 8 CN 121243121 A Test Example 1 Observation using a polarizing microscope to observe whether drug crystals precipitate in the ointments of each prepared formulation.

[0072] The results are shown in Table 2.

[0073] As shown in Table 2, no drug precipitation was observed in the ointments of Examples 1 and 2, but drug crystal precipitation was observed in all comparative examples. In particular, a large amount of drug crystals precipitated in Comparative Example 1, where the optical isomer ratio was 1:1 (racemate). In formulations where only one optical isomer is used as the drug to be mixed, the drug dissolves well, but if optical isomers are mixed in, the solubility deteriorates significantly.

[0074] [Table 2] Ointment Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Drug crystal precipitation No precipitation No precipitation Large amount of precipitation Precipitation Precipitation Precipitation Precipitation Examples 3, 4, 5 and 6 According to the formulation composition shown in Table 3, the desired aqueous patch was prepared in the order of Example 1.

[0075] Comparative Examples 4 and 5 According to the formulation composition shown in Table 3, the desired aqueous patch was prepared in the order of Example 1.

[0076] [Table 3] Instruction manual 7 / 17 pages 9 CN 121243121 A Test Example 2 The presence of drug crystal precipitation in the ointments of each formulation was observed using a polarizing microscope. In addition, the adhesion and shape retention of the ointment were observed by rolling a rubber roller on the ointment of each formulation.

[0077] The results are shown in Table 4.

[0078] As shown in Table 4, no drug precipitation was found in the ointments of Examples 3 to 6. In Comparative Example 4, drug precipitation was observed, and the adhesiveness of the ointment also deteriorated. In Comparative Example 5, drug crystal precipitation was observed, and the adhesiveness and shape retention of the ointment were poor, making it unsuitable for use as an aqueous patch.

[0079] It is believed that in Comparative Example 4, since no water-soluble organic amine was added, S-flurbiprofen did not dissolve in the ointment; in Comparative Example 5, since sodium hydroxide, as an inorganic water-soluble alkali metal salt, was used instead of water-soluble organic amine, S-flurbiprofen did not dissolve stably in the ointment.

[0080] [Table 4] Ointment Example 3 Example 4 Example 5 Example 6 Comparative Example 4 Comparative Example 5 Drug crystal precipitation No precipitation No precipitation No precipitation No precipitation Large amount of precipitation Large amount of precipitation Adhesion, shape retention Good Good Good Good Adhesion deteriorates Adhesion and shape retention Poor Examples 7 and 8 According to the formulation composition shown in Table 5, the desired aqueous patch was prepared in the order following Example 1.

[0081] Comparative Examples 6 and 7 According to the formulation composition shown in Table 5, the desired aqueous patch was prepared in the order following Example 1.

[0082] [Table 5] Instruction Manual 8 / 17 pages 10 CN 121243121 A Test Example 3 A polarizing microscope was used to observe whether drug crystals precipitated in the ointments of each preparation. Additionally, a rubber roller was rolled on the ointment of each preparation to observe the adhesiveness and shape retention of the ointment.

[0083] The results are shown in Table 6.

[0084] As shown in Table 6, in Examples 7 and 8, no drug crystals precipitated in the ointment, and the adhesiveness and shape retention of the ointment were good. In Comparative Example 6, a large amount of drug precipitated in the ointment. In Comparative Example 7, no drug precipitate was found in the ointment, but the ointment did not solidify, and its adhesiveness and shape retention were poor, making it unsuitable for use as a water-based patch.

[0085] [Table 6] Ointment Example 7 Example 8 Comparative Example 6 Comparative Example 7 Drug crystal precipitation No precipitation No precipitation A large amount of precipitation No precipitation Good adhesion and shape retention Good Good Ointment not cured, adhesion and shape retention significantly worse Examples 9, 10, 11, 12 and 13 According to the formulation composition shown in Table 7, the desired aqueous patch was prepared in the order of Example 1.

[0086] Comparative Examples 8 and 9 According to the formulation composition shown in Table 7, the desired aqueous patch was prepared in the order of Example 1.

[0087] [Table 7] Specification 9 / 17 pages 11 CN 121243121 A Test Example 4 The presence of drug crystal precipitation in the ointment of each formulation was observed using a polarizing microscope. In addition, the adhesion and shape retention of the ointment were observed by rolling a rubber roller on the ointment of each formulation.

[0088] The results are shown in Table 8.

[0089] As shown in Table 8, in Examples 9-13, no drug was precipitated in the ointment, and the adhesiveness and shape retention of the ointment were also good. In Comparative Example 8, drug crystals were precipitated in the ointment.In Comparative Example 9, no drug crystals precipitated in the ointment, but the ointment had weak curing, poor adhesion and shape retention, and could not be used as an aqueous patch.

[0090] The mass ratio of diisopropanolamine / S-flurbiprofen in Examples 9 to 13 was in the range of 0.25 to 5. In Comparative Example 8, the mass ratio was 0.20, which is less than 0.25. It was considered that the amount of diisopropanolamine was low relative to the amount of drug, and as a result, drug precipitation occurred in the ointment. In Comparative Example 9, the amount of diisopropanolamine was 6 w / w%, and the mass ratio of diisopropanolamine / S-flurbiprofen reached 6. According to this ratio, the amount of diisopropanolamine was too high, and therefore it was considered that the adhesion and shape retention of the ointment could not be maintained.

[0091] [Table 8] Ointment Example 9 Example 10 Example 11 Example 12 Example 13 Comparative Example 8 Comparative Example 9 Drug crystal precipitation No precipitation No precipitation No precipitation No precipitation No precipitation Precipitation No precipitation Adhesion and shape retention Good Good Good Good Good Good Ointment curing weak, significantly worse Examples 14, 15, 16 and 17 According to the formulation composition shown in Table 9, the desired aqueous patch was prepared in the order of Example 1.

[0092] Comparative Examples 10 and 11 According to the formulation composition shown in Table 9, the desired aqueous patch was prepared in the order of Example 1.

[0093] [Table 9] Instruction manual 10 / 17 pages 12 CN 121243121 A Test Example 5 The presence of drug crystal precipitation in the ointment of each formulation was observed using a polarizing microscope. In addition, the adhesion and shape retention of the ointment were observed by rolling a rubber roller on the ointment of each formulation. The pH of each formulation was then measured.

[0094] The results are shown in Table 10.

[0095] As shown in Table 10, in Examples 14-17, no drug crystals precipitated in the ointment, and the adhesiveness and shape retention of the ointment were also good. In Comparative Example 10, drug crystals precipitated in the ointment. In Comparative Example 11, no drug crystals precipitated in the ointment, but the ointment had weak curing, poor adhesiveness and shape retention, and could not be used as an aqueous patch.

[0096] The pH of the ointment was as follows: the pH range of each example was 4-7, Comparative Example 10 was pH 3.6, and Comparative Example 11 was pH 7.8. The formulations of the examples with pH in the range of 4-7 showed good drug solubility and excellent adhesiveness and shape retention, but the formulation of Comparative Example 10 had low drug solubility, and the formulation of Comparative Example 11 had poor adhesiveness and shape retention. Although the diisopropanolamine / s-flurbiprofen mass ratio of the formulation in Comparative Example 10 was 0.67, the low pH of the paste resulted in the precipitation of drug crystals. Comparative Example 11 was deemed to have an excessively high pH, ​​which prevented it from maintaining its adhesiveness and shape retention.

[0097] [Table 10] Ointment Example 14 Example 15 Example 16 Example 17 Comparative Example 10 Comparative Example 11 Drug crystal precipitation No precipitation No precipitation No precipitation No precipitation Precipitation No precipitation Adhesion, shape retention Good Good Good Good Good Curing of ointment weak, significantly worse pH 4.2 4.8 5.8 6.7 3.6 7.8 Example 18 According to the formulation composition in Table 11, an aqueous patch was prepared in the following order.

[0098] Flurbiprofen and diisopropanolamine were added to purified water for dissolution (solution).

[0099] Sodium polyacrylate, sodium carboxymethyl cellulose, carboxypropyl cellulose and aluminum glycine were added to concentrated glycerin and dispersed (dispersion).

[0100] Add purified water, a solution of polyvinyl alcohol dissolved in purified water, a solution of polyacrylic acid dissolved in purified water, sorbitol solution (70% D-sorbitol), kaolin, tartaric acid, sodium edetate, and clomiphene. While stirring the solution, slowly add the dispersion. Next, add the dissolving solution and stir to prepare a paste. Instruction manual 11 / 17 pages 13 CN 121243121 A

[0101] Spread the paste between polyester nonwoven fabric and polyester film, cut to an appropriate size, and prepare an aqueous patch.

[0102] Examples 19, 20, 21, 22 and 23 According to the formulation composition shown in Table 11, the desired aqueous patches were prepared in the order following Example 18.

[0103] [Table 11] Test Example 6 Each test formulation was wrapped with an aluminum laminate film and heat-sealed to make it sealed. The sealed products were stored in constant temperature baths at 4°C, 25°C, or 40°C. They were removed over time, and a polarizing microscope was used to observe whether drug crystals precipitated in the ointment.

[0104] The observation results are shown in Table 12.

[0105] As shown in Table 12, at 25°C or 40°C, no drug crystals precipitated in Examples 18-23 after 6 months of storage, maintaining a dissolved state. Furthermore, the formulations of Examples 18 and 20-23, which contained cromata, also showed no drug crystal precipitation under storage conditions at 4°C. Based on the above, it is determined that the aqueous patch of the present invention exhibits high drug stability. It is further determined that the aqueous patch of the present invention, containing cromata, can maintain a drug dissolved state for a long time even under harsh low-temperature storage conditions, and is a very stable formulation.

[0106] [Table 12] Specification 12 / 17 pages 14 CN 121243121 A Example 24 An aqueous patch was prepared according to the formulation composition in Table 13 in the following order.

[0107] Add S flurbiprofen and diisopropanolamine to pure water to dissolve (solution).

[0108] Polyacrylic acid, sodium polyacrylate, sodium carboxymethyl cellulose, and synthetic hydrotalcite were added to concentrated glycerin and dispersed (dispersion).

[0109] Purified water, sorbitol solution (70% D-sorbitol), kaolin, tartaric acid, and clomiphene were added, and the dispersion was slowly added while stirring the solution. Then, the dissolving liquid was added and stirred to prepare a paste.

[0110] The paste was spread between a polyester nonwoven fabric and a polyester film and cut to an appropriate size to prepare an aqueous patch.

[0111] Comparative Examples 12 and 13 Comparative Example 12 was a reproduction of "Example 12 of the Invention" of Example 6 described in Patent Document 1. In addition, Comparative Example 13 was prepared by increasing the concentration of flurbiprofen in Comparative Example 12 from 0.3% to 1.5%, and instead decreasing the concentration of purified water from 49.05% to 47.85%.

[0112] Comparative Examples 14 and 15 Comparative Example 14 reproduced the preparation of the poultice A described in Patent Document 2. In addition, Comparative Example 15 was prepared by increasing the concentration of flurbiprofen in Comparative Example 14 from 0.2% to 1.5%, and instead decreasing the concentration of purified water from 49.2% to 47.9%.

[0113] [Table 13] Specification 13 / 17 pages 15 CN 121243121 A Test Example 7 The presence of drug crystals in the ointments of each preparation was observed using a polarizing microscope. In addition, the adhesion and shape retention of the ointment were observed by rolling a rubber roller on the ointment of each preparation. The adhesion force of the ointment of each preparation was then measured according to the JIS Z0237 adhesion test method (hereinafter referred to as the ball adhesion test). The results are shown in Table 14.

[0114] As shown in Table 14, in Example 24, no drug crystals were precipitated in the ointment, and the adhesion and shape retention were also good. In addition, when the adhesive strength of the paste was measured, a steel ball with a diameter of 23.8 mm could be held, indicating that it has adhesive strength suitable for use as a water-based patch.

[0115] On the other hand, in Comparative Example 12, no drug crystals were precipitated in the paste, and the adhesiveness and shape retention of the paste were good. However, in the rolling ball adhesion test, only a slightly smaller steel ball with a diameter of 14.3 mm could be held, indicating that it was a formulation with weak adhesive strength. In addition, in Comparative Example 13, which had the same matrix composition as Comparative Example 12 but increased the drug concentration to 1.5%, a large number of drug crystals were generated, and the adhesiveness and shape retention were also poor. In addition, in the rolling ball adhesion test, only a steel ball with a diameter of 9.5 mm could be held, indicating that it was a formulation with very weak adhesive strength.

[0116] Moreover, in Comparative Example 14, although no drug crystals were precipitated in the paste, the paste did not solidify, and the adhesiveness and shape retention were significantly poor. Similarly, in Comparative Example 15, which had the same matrix composition as Comparative Example 14 and only increased the drug concentration to 1.5%, the paste did not solidify, producing a large number of drug crystals, resulting in a formulation with significantly poor adhesion and shape retention.Comparative Examples 14 and 15 had no retainable steel balls and were formulations with very poor adhesion.

[0117] [Table 14] Ointment Example 24 Comparative Example 12 Comparative Example 13 Comparative Example 14 Comparative Example 15 Drug crystal precipitation No precipitation No precipitation Produces a large amount of drug precipitation No precipitation Produces a large amount of drug precipitation Adhesion, shape retention Good Good Shape retention Good adhesion Poor Ointment not cured, significantly worse Ointment not cured, significantly worse Rolling ball adhesion test Diameter 23.8 mm Diameter 14.3 mm Diameter 9.5 mm Cannot be determined Cannot be determined Instructions for use 14 / 17 pages 16 CN 121243121 A Test Example 8 Regarding Example 24 and Comparative Examples 12, 13, 14 and 15, in vitro transdermal tests of the drug were performed using skin removed from the abdomen of hairless rats. The test method is as follows, and the test results are shown in Figure 1.

[0118] (Test Method) Abdominal skin of hairless rats was removed and placed in a Franz diffusion tank. The dermal side was used as the receiving side, and phosphate buffer was injected into its inner side. The temperature was maintained at 37°C, and the mixture was stirred. Each test preparation was cut into a circle with a diameter of 14 mm, applied to the skin, and the receiving fluid was collected as a sample. The amount of drug that migrated from the test preparation through the skin to the buffer solution (permeability) was determined using a liquid chromatography apparatus.

[0119] The test results were evaluated based on the cumulative drug permeability (μg / cm2·24h) at 24 hours after the start of the test.

[0120] As shown in Figure 1, Example 24 showed the highest permeability and was considered to be a preparation that could exert excellent therapeutic effects.

[0121] On the other hand, the permeability of Comparative Examples 12 and 14 was quite low. Comparative Examples 13 and 15, which had the same matrix composition as Comparative Examples 12 and 14, but with an increased drug content, showed a slight increase in permeability, but their permeability was lower than that of Example 24 with the same drug content. This is believed to be the effect caused by the crystal precipitation of the drug in the ointment of Comparative Example 13 or Comparative Example 15.

[0122] Test Example 9 Example 24 and Example 25, which had the same matrix composition as Example 24 but was mixed with R flurbiprofen instead of S flurbiprofen, and a commercially available tape preparation (mixed with 2.38% racemic flurbiprofen) were used as test preparations. Anti-inflammatory tests were conducted on rats to compare their effects. The test methods are described below, and the test results are shown in Table 15.

[0123] (Test Method) After measuring the paw volume (initial volume) of the rats, each test preparation (3×4cm) was fixed to the paw. After 4 hours of attachment, the test preparations were removed, and 0.1mL of 1% carrageenan suspension was injected to induce paw edema. The paw volume was measured 2, 3 and 4 hours after induction, and the edema rate of each animal was calculated as ((paw volume after carrageenan injection - initial volume) / initial volume × 100).

[0124] It is known that Examples 24 and 25 both have anti-inflammatory effects that inhibit edema. In particular, Example 24, which is mixed with S-flurbiprofen, has a significant effect, which is superior to commercially available adhesive tape formulations.

[0125] [Table 15] Example 26 According to the formulation composition in Table 16, an aqueous patch was prepared in the following order.

[0126] The active ingredient and diisopropanolamine were added to purified water for dissolution (solution solution). Instructions 15 / 17 pages 17 CN 121243121 A

[0127] Concentrated glycerol, propylene glycol, sodium polyacrylate, sodium carboxymethyl cellulose and magnesium aluminosilicate were added for dispersion (dispersion solution).

[0128] Purified water, a solution of polyacrylic acid dissolved in purified water, a sorbitol solution (70% D-sorbitol), kaolin and tartaric acid were added, and the dispersion solution was slowly added while stirring the solution. Then the solution solution was added and stirred to prepare an ointment.

[0129] The paste was spread between nonwoven fabric and polyester film, cut to an appropriate size, and an aqueous patch was prepared.

[0130] Example 27 The desired aqueous patch was prepared according to the formulation composition shown in Table 16, following the order of Example 26.

[0131] Comparative Examples 16 and 17 The desired aqueous patches were prepared according to the formulation composition shown in Table 16, following the order of Example 26.

[0132] [Table 16] Test Example 10 The drug state in the pastes of each prepared formulation was observed using a polarizing microscope.

[0133] The results are shown in Table 17.

[0134] As shown in Table 17, no drug was precipitated in the pastes of Examples 26 and 27, but a large amount of drug was precipitated in Comparative Examples 16 and 17, which had an optical isomer ratio of 1:1 (racemate).

[0135] Formulations using only one of the optical isomers as the drug to be blended, like flurbiprofen, show good drug solubility, but if optical isomers are mixed in, the solubility is significantly worsened.

[0136] [Table 17] Ointment Example 26 Example 27 Comparative Example 16 Comparative Example 17 Drug State No Precipitation No Precipitation Large Amount of Precipitation Large Amount of Precipitation Industrial Applicability According to the present invention, an aqueous patch can be provided that can stably blend only one of the optical isomers of the drug, the S-type and the R-type, at a high concentration over a long period of time, exhibiting excellent adhesion and shape retention, while also showing high drug transdermal permeability. The aqueous patch of the present invention is effective, for example, as an aqueous patch with anti-inflammatory and analgesic effects.Page 17 / 17 of the specification, 19 CN 121243121 A, Figure 1, Page 1 / 1 of the attached drawings of the specification, 20 CN 121243121 A, HKP2520397, Title: WATER-BASED ADHIESIVE PATCH, Abstract: The present invention provides a water-based adhesive patch which can stably contain only one of the optical isomers, S- and R-isomers, of a drug in a relatively high concentration over a long period and which has excellent tackiness and shape retentivity while enables the drug to highly permeate the skin. Specifically, the present invention provides a water-based adhesive patch which contains only one of the optical isomers of a drug as an active ingredient in a plaster. Abstract.

Claims

1. An aqueous patch containing only one of optical isomers of a drug as an effective ingredient in a paste.

2. The aqueous patch of claim 1, wherein, The drug is an anti-inflammatory agent or analgesic agent, or an adjuvant thereof.

3. The aqueous patch of claim 1 or 2, wherein, The drug is one or two or more selected from the group consisting of flurbiprofen, ketoprofen and ibuprofen.

4. The aqueous patch of any one of claims 1 to 3, wherein, The drug is flurbiprofen.

5. The aqueous patch of any one of claims 1-4, wherein, The drug is incorporated in an amount of 0.5 to 6 w / w% relative to the mass of the paste.

6. The aqueous patch of any one of claims 1-5, wherein, The paste further contains a water-soluble organic amine.

7. The aqueous patch of claim 6, wherein, The water-soluble organic amine is one or two or more selected from the group consisting of monomethanolamine, monoethanolamine, monopropanolamine, monoisopropanolamine, dimethanolamine, diethanolamine, dipropanolamine, diisopropanolamine, dibutanolamine, diisobutanolamine, trimethanolamine, triethanolamine, tripropanolamine, triisopropanolamine, tributanolamine, triisobutanolamine, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, triethylamine, tripropylamine and triisopropylamine.

8. The aqueous patch of claim 6 or 7, wherein, The water-soluble organic amine is incorporated in an amount of 0.2 to 5 w / w% relative to the mass of the paste.

9. The aqueous patch of any one of claims 6-8, wherein, The water-soluble organic amine is incorporated in a ratio of 0.25 to 5 by mass relative to the optical isomer of the drug.

10. The aqueous patch of any one of claims 1-9, wherein, The optical isomer of the drug is S-form.

11. The aqueous patch of any one of claims 1-10, wherein, The paste further contains one or two or more selected from the group consisting of water, polyacrylic acid or a salt thereof, a cellulose derivative, a crosslinking agent, a humectant and a pH adjustor.

12. The aqueous patch according to claim 11, wherein The polyacrylic acid or a salt thereof is one or two or more selected from the group consisting of polyacrylic acid, sodium polyacrylate and a partially neutralized polyacrylic acid; The cellulose derivative is one or two or more selected from the group consisting of sodium carboxymethylcellulose, hydroxypropylcellulose and hydroxymethylcellulose; The crosslinking agent is one or two or more selected from the group consisting of dihydroxyaluminum aminoacetate, magnesium metasilicate aluminate, aluminum hydroxide and synthetic hydrotalcite; The humectant is one or two or more selected from the group consisting of glycerin, 1,3-butanediol, propylene glycol, polypropylene glycol, D-sorbitol and polyethylene glycol 400; and The pH adjustor is one or two or more selected from the group consisting of tartaric acid, lactic acid and malic acid.

13. The aqueous patch of claim 11 or 12, wherein, The water is incorporated in an amount of 20 to 70 w / w%, the polyacrylic acid or a salt thereof is incorporated in an amount of 2 to 20 w / w%, the cellulose derivative is incorporated in an amount of 2 to 20 w / w%, the crosslinking agent is incorporated in an amount of 0.02 to 3.5 w / w%, the humectant is incorporated in an amount of 5 to 60 w / w%, and the pH adjustor is incorporated in an amount of 0.2 to 10 w / w% relative to the mass of the paste.

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