WO1996004902A1 - Composition pour preparation a usage externe - Google Patents
Composition pour preparation a usage externe Download PDFInfo
- Publication number
- WO1996004902A1 WO1996004902A1 PCT/JP1995/001576 JP9501576W WO9604902A1 WO 1996004902 A1 WO1996004902 A1 WO 1996004902A1 JP 9501576 W JP9501576 W JP 9501576W WO 9604902 A1 WO9604902 A1 WO 9604902A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- fatty acid
- composition
- external preparation
- diclofenac
- Prior art date
Links
- 239000000203 mixture Substances 0.000 description 51
- 238000002360 preparation method Methods 0.000 description 40
- 235000014113 dietary fatty acids Nutrition 0.000 description 35
- 239000000194 fatty acid Substances 0.000 description 35
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- 150000003839 salts Chemical class 0.000 description 25
- -1 polyoxyethylene Polymers 0.000 description 24
- 229960001259 diclofenac Drugs 0.000 description 21
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 21
- 150000001408 amides Chemical class 0.000 description 15
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- 229960001193 diclofenac sodium Drugs 0.000 description 12
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 12
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
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- 239000007864 aqueous solution Substances 0.000 description 3
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- YSXKPIUOCJLQIE-UHFFFAOYSA-N biperiden Chemical class C1C(C=C2)CC2C1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 YSXKPIUOCJLQIE-UHFFFAOYSA-N 0.000 description 1
- MGDNLGRMXPBCOR-UHFFFAOYSA-N bis(2-hydroxyethyl)azanium;dodecanoate Chemical compound OCCNCCO.CCCCCCCCCCCC(O)=O MGDNLGRMXPBCOR-UHFFFAOYSA-N 0.000 description 1
- FQORDWZQSLBUAD-UHFFFAOYSA-N bromo 4-hydroxybenzoate Chemical compound BrOC(C1=CC=C(C=C1)O)=O FQORDWZQSLBUAD-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N butyl alcohol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- QZXCCPZJCKEPSA-UHFFFAOYSA-N chlorfenac Chemical compound OC(=O)CC1=C(Cl)C=CC(Cl)=C1Cl QZXCCPZJCKEPSA-UHFFFAOYSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 208000021930 chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids Diseases 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- 229940031569 diisopropyl sebacate Drugs 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- XFKBBSZEQRFVSL-UHFFFAOYSA-N dipropan-2-yl decanedioate Chemical compound CC(C)OC(=O)CCCCCCCCC(=O)OC(C)C XFKBBSZEQRFVSL-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- XDCZBGLKMJMACF-UHFFFAOYSA-N ethanol Chemical compound CCO.CCO.CCO XDCZBGLKMJMACF-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 239000008311 hydrophilic ointment Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WPFVBOQKRVRMJB-UHFFFAOYSA-N hydroxycitronellal Chemical compound O=CCC(C)CCCC(C)(C)O WPFVBOQKRVRMJB-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940031957 lauric acid diethanolamide Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229940049918 linoleate Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 229940105132 myristate Drugs 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- ZGYVHQOLUBDUMV-UHFFFAOYSA-N phosphoric acid hydrochloride Chemical compound P(=O)(O)(O)O.Cl.P(O)(O)(O)=O ZGYVHQOLUBDUMV-UHFFFAOYSA-N 0.000 description 1
- 238000000554 physical therapy Methods 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000000475 sunscreen effect Effects 0.000 description 1
- 239000000516 sunscreening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
Definitions
- the present invention relates to an external preparation composition containing a water-soluble salt of diclofenac, and more particularly, to a composition of a pharmaceutical preparation in which a water-soluble salt of diclofenac is dissolved in a base.
- a composition of a pharmaceutical preparation in which a water-soluble salt of diclofenac is dissolved in a base is used as an external preparation that is used as a stable and highly absorbable pharmaceutical preparation.
- Diclofenac sodium also referred to as diclofenac sodium
- diclofenac sodium a water-soluble salt of diclofenac
- diclofenac sodium is currently the most popular non-steroidal anti-inflammatory antipyretic and pain-relieving drug. It is one of the medicines used and is used in oral and suppositories in clinical practice. However, because of its potent efficacy, its use may be limited, for example, as a side effect due to a sudden rise in blood concentration, or when there is a concern about gastrointestinal pain.
- Japanese Patent Application Laid-Open No. Sho 62-110315 discloses that if a fatty acid monoalkylolamide is mixed with a composition containing a drug as an absorption enhancer, the drug is effective from the skin swelling. It states that it is absorbed at a high rate.
- diclofenac sodium is also disclosed as an example of the drug.However, the only practical example of the diclofenac sodium composition is an oily suppository. In suppository compositions, Nakunadium is uniformly dispersed, but not completely dissolved in the formulation.
- Japanese Patent Publication No. 63-9-11318 discloses that dichlorophenacnatrium and a crosslinked hydrogel in which 1,3-butyrene glycol is dispersed are placed on a support. A patch containing diclofenacna film which is spread out is described. Further, Japanese Patent Application Laid-Open No. 3-229122 discloses a transparent gel-like tablet containing no emulsified fat. A topical pharmaceutical composition containing Lofenakunatrium is described.
- the present inventors have made intensive studies to ensure the solubility of a water-soluble salt of diclofenac in a drug product and to develop an external preparation composition having excellent stability and transdermal absorption. As a result, they have found that a stable preparation can be obtained by dissolving a water-soluble salt of dicyclofenac in an aqueous solution of a fatty acid dialkylol amide or a polyoxyethylene adduct thereof, thereby achieving the above object.
- the present invention is an external preparation composition characterized by containing a water-soluble salt of dicyclofenac, water, and a dialkylol amide and / or a polyoxyethylene adduct thereof.
- Examples of the water-soluble salt of diclofenac which is an active ingredient of the external preparation composition of the present invention, include sodium salt, potassium salt, pyrrolidine salt, and bipyridine salt of diclofenac.
- the fatty acid dialkyl amide which is an essential component of the external preparation composition of the present invention, is a compound obtained by condensing a fatty acid and a dialkylamine, and the fatty acid portion is coconut oil.
- Fatty acids, palm kernel oil fatty acids, palmitic acid, myristic acid, stearic acid, lauric acid, oleic acid, linoleic acid, isostearic acid, cabric acid and Cabyl acids and the like, and the dialkylolamine to be condensed include di-lower alkanolamines such as diethanolamine and diisobrono-S-noramine.
- These fatty acid dialkyl amides can be used alone or in combination.
- the fatty acid dialkylolamide polyoxyethylene adduct is obtained by adding ethylenoxide to the hydroxyl group of the above-mentioned fatty acid dialkyl amide, and the number of moles of the addition is 1 to 10.
- Preferred fatty acid dialkyl amides include pear oil fatty acid diethanol amide, palm kernel oil fatty acid diethanol amide, stearate diethanol amide, and lauric acid diethanol amide. Mid, Ore Examples include diethanolamide diphosphate, diethanolamide linoleate, and diethanolamide diisostearate.Ethylene oxide adducts of dialkylamide fatty acids include: Ethylenoxide adducts of these compounds are preferred. Of these, particularly preferred are coconut oil fatty acid diethanolamide, lauric acid genoleamide, and diethanolamine stearate.
- the external preparation composition of the present invention can be prepared by mixing and formulating a water-soluble salt of diclofenac, water and the above-mentioned components according to a conventional method.
- a water-soluble salt of fatty acid dialkyrolamide and diclofenac is added to purified water and dissolved, and an aqueous solution of a water-soluble salt of diclofenac is formed into a cocoon. If necessary, other additives may be added to obtain a desired formulation.
- the BE compounding amount of the water-soluble salt of diclofenac to be incorporated in the external preparation composition of the present invention may be an amount which achieves the desired effect depending on the purpose, but is usually 0.05 to 5% by weight. The degree is compounded. If the amount of diclofenac water-soluble salt is less than 0.05% by weight, sufficient pharmacological effects cannot be expected, and if it exceeds 5% by weight, the absorption exceeding the absorption range is not possible. The absorption rate will decrease.
- the amount of the fatty acid dialkylol amide or its ethylenoxide adduct is adjusted so that the total amount is about 0.01 to 10% by weight based on the weight of the external preparation composition of the present invention. It is preferable to mix them, and it is particularly preferable to mix them in the range of 0.1 to 5% by weight.
- the amount of the fatty acid dialkyl amide is less than 0.01% by weight, the solubility of diclofenac or a salt thereof is reduced, and when the amount is more than 10% by weight, irritation is caused. Sex question a occurs.
- the pH of the external preparation composition of the present invention is preferably pH 7 to 9, and particularly preferably pH 7.5 to 8.5.
- the pH of the composition can be adjusted by increasing or decreasing the amount of fatty acid dialkylolamide added, but can also be adjusted by adding a pH adjuster described below.
- the external preparation composition of the present invention can be in a form usually used as a dosage form of the external preparation, and is not particularly limited, and various liquids, ointments, creams, and pubs can be used. It is advantageously used as a physiotherapy body.
- additives in the external preparation composition of the present invention, various conventionally used additives can be used depending on the dosage form. The following are mentioned as these additives.
- the hydrophilic polymer include carboxymethylcellulose or its satisfactorily, polyacrylic acid or a salt thereof, lipoxyvinyl polymer or a salt thereof, alginic acid or a salt thereof, and alginic acid.
- this polyvalent alcohol include propylene glycol, 1,3-butylene glycol, glycerin, sorbitol, mannitol and the like.
- hydrophilic polymer it is a substance added to the base of the external preparation.
- Ointments include cetanol, stearyl alcohol, cetostearyl alcohol, stearic acid, white petrolatum, hydrophilic ointment, water-absorbing ointment, light caustic anhydride, hydrous silicon dioxide, and anhydrous caustic Acids, titanium oxide, zinc oxide, etc .; and, in the case of liquid preparations, setanol, stearyl alcohol, setostearyl alcohol, stearic acid, Examples thereof include light silicic anhydride, hydrous silicon dioxide, silicic anhydride,
- Stabilizers include sodium edetate, cunic acid, sodium citrate, oxybenzone, ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, Examples include gallic acid pro- yl acid and sodium bisulfite.
- PH regulator sodium edetate, cunic acid, sodium citrate, oxybenzone, ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, Examples include gallic acid pro- yl acid and sodium bisulfite.
- PH nodal agents examples include tartaric acid, citric acid, lingic acid, lactic acid, phosphoric acid hydrochloride, sulfuric acid, fumaric acid, maleic acid, sodium hydroxide, ammonia, urea, and ethylenediamine. And triisobutyl noramine, triethanolamine, triisorubanol, triethanolamine and the like.
- absorption enhancer examples include ethanol, isosorbyl alcohol, benzyl alcohol, oleyl alcohol, octyl dodecanol, isosorbyl myristate, diisobrovir adipate, Emulsifying agents including getyl sebacate, diisopropyl sebacate, propylene glycol carboxylate, medium chain fatty acid triglycerides, squalane, etc .:
- Emulsifiers include lecithin, lecithin derivatives, propylene glycol fatty acid esters, glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acids
- Examples include esters, polyoxyethylene hardened castor oil, polyoxyalkylene alkyl ether, and bull nicks.
- preservatives include balavens such as methylparaben, ethylparapen, and propylparaben, benzyl alcohol, benzylconium chloride, benzenetonium chloride, chlorobutanol, and the like.
- a particularly preferable use form is to spread the composition as a poultice plaster on a supporting substrate such as cloth or nonwoven fabric. It is a cataplasm to be obtained.
- the polyhydric alcohol When used as a bub plaster, the polyhydric alcohol is blended so as to be about 0.01 to 80% by weight based on the amount of the external preparation composition of the present invention. However, it is particularly preferable to combine them in the range of 0.1 to 50% by weight. When the blending amount of the polyhydric alcohol is lower than 0.01% by weight, the moisturizing effect is reduced, and when the blending amount is higher than 80% by weight, the stimulation becomes stronger. Even when the dosage form is a liquid, it is preferable to add the same polyvalent alcohol.
- the hydrophilic polymer is used in an amount of about 0.01 to 50% by weight based on the weight of the external preparation composition of the present invention. It is preferable to mix them in such a manner as to be more preferable, and it is particularly preferable to mix them in the range of 0.1 to 30% by weight. If the content of the hydrophilic polymer is less than 0.01% by weight, it becomes very difficult to make a semi-solid preparation, and it becomes higher than 50% by weight. In this case, the viscosity increases and the absorbability decreases.
- the external preparation composition of the present invention thus obtained can stably dissolve the water-soluble salt of Jiku-guchi fenac in the preparation and has excellent skin absorption as described later, so that the anti-inflammatory agent for external use can be obtained.
- It can be used advantageously as an analgesic or sunscreen cosmetics.
- Example 1 Example 1
- composition (% by weight)
- Diclofenac sodium and lauric acid phenol amide are added to the sugar-making water to prepare a uniform solution.
- Other additives are added to this and emulsified with a homomixer to obtain a primary emulsion.
- the primary emulsion was further treated with a mantongoline homogenizer at 300 kg / cm 2 five times to obtain a milky lotion.
- Example 2
- composition (% by weight)
- Dichlorophenacnatrium, diethanol laurate, and coconut oil fatty acid phenol amide are added to purified water and dissolved.
- the oil phase is setanol, stearyl alcohol, octyl dodecanol, triglycerides of medium-chain fatty acids, butylhydroxyanisole, and propylparaben. Heat sensitize with C.
- Example 3 The above aqueous phase and oil phase were vulcanized using a vacuum emulsifier, and then cooled to obtain a uniform milky softener.
- Example 3 The above aqueous phase and oil phase were vulcanized using a vacuum emulsifier, and then cooled to obtain a uniform milky softener.
- composition (% by weight)
- Diclofenac sodium 2.0 Polysodium acrylate 4.0 Carmellose sodium 2.0 Hydroxybyl bilumetyl cell 2.0 Coconut oil fatty acid diethanola 2.0
- Dichlorophenacnatrium, coconut oil fatty acid diethanol amide and hydroxymethyl bilmethyl cellulose are added to purified water to make a uniform solution. Add the remaining additives to this and stir to obtain a uniform gel. This was spread on a non-woven fabric so as to have a uniform thickness, and a cataplasm was obtained.
- Example 5 To the purified water is added diclofenacnatrium and lauric acid genoleamide to make a homogeneous solution. Other additives are added to this and emulsified with a homomixer to obtain a primary emulsion. Further, this primary emulsion was treated with a mantongoline homogenizer five times at 300 kg / cm 2 to obtain a milky lotion.
- Example 5 To the purified water is added diclofenacnatrium and lauric acid genoleamide to make a homogeneous solution. Other additives are added to this and emulsified with a homomixer to obtain a primary emulsion. Further, this primary emulsion was treated with a mantongoline homogenizer five times at 300 kg / cm 2 to obtain a milky lotion.
- Example 5 To the purified water is added diclofenacnatrium and lauric acid genoleamide to make a homogeneous solution. Other additives are added
- composition (% by weight)
- Dichlorofenac sodium, diethanol laurate, and coconut fatty acid diethanol amide are added to the purified water and dissolved, and polysorbate 60, sorbitol, and methyl paraben are further dissolved. Add about 75. Heat and dissolve in C to form an aqueous phase.
- oils such as cenorol, stearyl alcohol, octyl dodecanol, triglycerides of medium-chain fatty acids, butylhydroxyanisole, and brovirparaben are approximately 75. Heat and dissolve with C.
- composition (% by weight)
- Diclofenac ureum and diethanolamine laurate are added to purified water to make a uniform solution. To this, add 70% sorbitol solution and lauryl alcohol, and stir to obtain a uniform solution. Further, the remaining additives are dispersed in brobilene glycol, added to the previously prepared solution, and the mixture is stirred to obtain a uniform gel. This was spread on a nonwoven fabric so as to have a uniform thickness, and a poultice was obtained.
- composition (% by weight)
- Dichlorophenacnatrium and coconut oil fatty acid ethanol in purified water Add amide and hydroxybile pillmethyl cellulose to make a uniform solution. Add the remaining additives to the mixture and stir to obtain a uniform gel. This was spread on a non-woven fabric so as to have a uniform thickness, and a bubble agent was obtained.
- Example 1 except that no diethanolamine amide was added.
- a lotion preparation was prepared in the same manner as in 1. Comparative Example 2
- a cataplasm was prepared in the same manner as in Example 3 except that coconut oil fatty acid amide was not added.
- Percutaneous permeability was tested using a Franz-type expansion cell (diameter of the transmissive surface: 15 mm), using the back skin of the rat as a permeable membrane.
- the permeability is the same as that of Giculo Fenacnatrium on the sunset side of Receive. Judgment was made based on excess amount.
- As a sample about 2 g of the gel prepared in Example 3 and Comparative Example 3 was used without being spread on a nonwoven fabric.
- Table 2 shows the time-dependent cumulative permeability (gZ cm 2 ) of diclofenac sodium.
- Table 3 shows changes in the blood concentration (ZigZinl) of diclofenac sodium over time.
- composition 902 Composition 902
- the external preparation composition of the present invention was a composition having high transdermal permeability and transdermal absorbability.
- the external preparation composition of the present invention it is possible to obtain a stable external preparation of diclofenac which is excellent in the absorption of the water-soluble salt of diclofenac, has high solubility in the preparation, and is stable. it can.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95944455A EP0788794A4 (en) | 1994-08-09 | 1995-08-08 | MEANS FOR EXTERNAL USE |
US08/776,700 US5795916A (en) | 1994-08-09 | 1995-08-08 | Composition of external preparation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP20613994 | 1994-08-09 | ||
JP6/206139 | 1994-08-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996004902A1 true WO1996004902A1 (fr) | 1996-02-22 |
Family
ID=16518439
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1995/001576 WO1996004902A1 (fr) | 1994-08-09 | 1995-08-08 | Composition pour preparation a usage externe |
Country Status (3)
Country | Link |
---|---|
US (1) | US5795916A (ja) |
EP (1) | EP0788794A4 (ja) |
WO (1) | WO1996004902A1 (ja) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH09169635A (ja) * | 1995-12-20 | 1997-06-30 | Sekisui Chem Co Ltd | 経皮吸収製剤 |
WO1997028794A1 (fr) * | 1996-02-07 | 1997-08-14 | Tsumura & Co. | Solution aqueuse transparente de diclofenac sodique, compositions medicinales, et utilisations |
WO2009066457A1 (ja) * | 2007-11-22 | 2009-05-28 | Medrx Co., Ltd. | 脂肪酸系イオン液体を有効成分とする外用剤組成物 |
WO2009119836A1 (ja) * | 2008-03-28 | 2009-10-01 | アンジェスMg株式会社 | 転写因子デコイを有効成分とする外用剤組成物 |
US7615237B1 (en) | 1999-07-15 | 2009-11-10 | Hisamitsu Pharmaceutical Co., Inc. | Percutaneously absorbable preparations |
JP2011500863A (ja) * | 2007-10-30 | 2011-01-06 | ノバルティス アーゲー | 局所用組成物 |
JP2016193862A (ja) * | 2015-03-31 | 2016-11-17 | 小林製薬株式会社 | 外用医薬組成物 |
JP2018070644A (ja) * | 2014-05-20 | 2018-05-10 | 海南美合泰バイオテクノロジー カンパニー リミテッド | 天然ビタミンcとコラーゲンペプチドの組成物及びその製造方法 |
JP2020109111A (ja) * | 2015-01-30 | 2020-07-16 | 株式会社 メドレックス | 水性外用剤 |
Families Citing this family (12)
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US5932495A (en) * | 1996-09-04 | 1999-08-03 | Kimberly-Clark Worldwide, Inc. | Enhanced odor absorption by natural and synthetic polymers |
BR0001144B1 (pt) * | 2000-02-21 | 2013-10-22 | Composicão farmacêutica de diclofenaco à base de vitamina-e, papaína e hialuronidase | |
US20040146548A1 (en) * | 2001-05-31 | 2004-07-29 | Yasunori Takada | Percutaneously absorbable patches |
AR036755A1 (es) * | 2002-10-07 | 2004-09-29 | Thalas Group Inc | Una composicion en forma de gel transparente para la administracion de diclofenac sodico a traves de la piel |
US20060079640A1 (en) * | 2002-10-30 | 2006-04-13 | Tetsuya Ishii | Adhesive composition for dermal patch and production process thereof |
JP4876500B2 (ja) * | 2005-09-22 | 2012-02-15 | 日油株式会社 | ゲル状手指消毒剤 |
JP4526598B2 (ja) * | 2007-08-29 | 2010-08-18 | 祐徳薬品工業株式会社 | 乳化型外用剤およびその製造方法 |
US7943668B2 (en) * | 2008-03-03 | 2011-05-17 | Altergon S.A. | Process for preparing a pharmaceutical composition with anti-inflammatory and analgesic activity for administration via a patch for external use, and composition thus obtained |
CN104173321B (zh) * | 2008-03-03 | 2017-10-31 | 阿尔特根有限公司 | 制备通过外用贴剂给药的、具有消炎镇痛活性的药物组合物的方法,及以此获得的组合物 |
US9555025B2 (en) * | 2011-03-31 | 2017-01-31 | Maruho Co., Ltd. | Ointment with excellent formulation stability |
WO2014068600A1 (en) | 2012-11-02 | 2014-05-08 | Zydus Technologies Limited | Stable transdermal pharmaceutical drug delivery system comprising diclofenac |
JP6449554B2 (ja) * | 2014-03-30 | 2019-01-09 | 小林製薬株式会社 | 外用医薬組成物 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS62153227A (ja) * | 1985-12-26 | 1987-07-08 | Sekisui Chem Co Ltd | 経皮・経粘膜製剤 |
JPS62228027A (ja) * | 1985-08-26 | 1987-10-06 | Sekisui Chem Co Ltd | 経皮・経粘膜製剤 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH666621A5 (de) * | 1986-06-27 | 1988-08-15 | Ciba Geigy Ag | Topisch applizierbare pharmazeutische zusammensetzungen mit systemischer wirkung. |
JPS6391318A (ja) * | 1986-10-03 | 1988-04-22 | Teikoku Seiyaku Kk | ジクロフエナクナトリウム含有貼付剤 |
JP2849937B2 (ja) * | 1990-04-18 | 1999-01-27 | 日東電工株式会社 | 医療用貼付剤 |
JPH0425929A (ja) * | 1990-05-22 | 1992-01-29 | Casio Comput Co Ltd | 入力位置指定装置 |
-
1995
- 1995-08-08 EP EP95944455A patent/EP0788794A4/en not_active Withdrawn
- 1995-08-08 WO PCT/JP1995/001576 patent/WO1996004902A1/ja not_active Application Discontinuation
- 1995-08-08 US US08/776,700 patent/US5795916A/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS62228027A (ja) * | 1985-08-26 | 1987-10-06 | Sekisui Chem Co Ltd | 経皮・経粘膜製剤 |
JPS62153227A (ja) * | 1985-12-26 | 1987-07-08 | Sekisui Chem Co Ltd | 経皮・経粘膜製剤 |
Non-Patent Citations (1)
Title |
---|
See also references of EP0788794A4 * |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH09169635A (ja) * | 1995-12-20 | 1997-06-30 | Sekisui Chem Co Ltd | 経皮吸収製剤 |
WO1997028794A1 (fr) * | 1996-02-07 | 1997-08-14 | Tsumura & Co. | Solution aqueuse transparente de diclofenac sodique, compositions medicinales, et utilisations |
US6054484A (en) * | 1996-02-07 | 2000-04-25 | Tsumura & Co. | Transparent aqueous solution of diclofenac sodium and medicinal compositions with the use of the same |
US7615237B1 (en) | 1999-07-15 | 2009-11-10 | Hisamitsu Pharmaceutical Co., Inc. | Percutaneously absorbable preparations |
JP2011500863A (ja) * | 2007-10-30 | 2011-01-06 | ノバルティス アーゲー | 局所用組成物 |
WO2009066457A1 (ja) * | 2007-11-22 | 2009-05-28 | Medrx Co., Ltd. | 脂肪酸系イオン液体を有効成分とする外用剤組成物 |
JP5333972B2 (ja) * | 2007-11-22 | 2013-11-06 | 株式会社 メドレックス | 脂肪酸系イオン液体を有効成分とする外用剤組成物 |
US8623387B2 (en) | 2007-11-22 | 2014-01-07 | Medrx Co., Ltd. | External preparation composition comprising fatty acid-based ionic liquid as active ingredient |
WO2009119836A1 (ja) * | 2008-03-28 | 2009-10-01 | アンジェスMg株式会社 | 転写因子デコイを有効成分とする外用剤組成物 |
JP5674020B2 (ja) * | 2008-03-28 | 2015-02-18 | アンジェスMg株式会社 | 転写因子デコイを有効成分とする外用剤組成物 |
JP2018070644A (ja) * | 2014-05-20 | 2018-05-10 | 海南美合泰バイオテクノロジー カンパニー リミテッド | 天然ビタミンcとコラーゲンペプチドの組成物及びその製造方法 |
JP2020109111A (ja) * | 2015-01-30 | 2020-07-16 | 株式会社 メドレックス | 水性外用剤 |
JP2016193862A (ja) * | 2015-03-31 | 2016-11-17 | 小林製薬株式会社 | 外用医薬組成物 |
Also Published As
Publication number | Publication date |
---|---|
EP0788794A4 (en) | 2000-06-28 |
US5795916A (en) | 1998-08-18 |
EP0788794A1 (en) | 1997-08-13 |
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