TWI498131B - 含有凱妥普洛芬之水性貼附劑及其製造方法 - Google Patents
含有凱妥普洛芬之水性貼附劑及其製造方法 Download PDFInfo
- Publication number
- TWI498131B TWI498131B TW100108261A TW100108261A TWI498131B TW I498131 B TWI498131 B TW I498131B TW 100108261 A TW100108261 A TW 100108261A TW 100108261 A TW100108261 A TW 100108261A TW I498131 B TWI498131 B TW I498131B
- Authority
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- Taiwan
- Prior art keywords
- ketoprofen
- patch
- aqueous
- weight
- polyethylene glycol
- Prior art date
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- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 title claims description 44
- 229960000991 ketoprofen Drugs 0.000 title claims description 44
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 20
- 239000002202 Polyethylene glycol Substances 0.000 claims description 19
- 150000001412 amines Chemical class 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical group CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 claims description 6
- 229940043276 diisopropanolamine Drugs 0.000 claims description 6
- 230000000052 comparative effect Effects 0.000 description 22
- -1 fatty acid esters Chemical class 0.000 description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 14
- 238000012360 testing method Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 210000003491 skin Anatomy 0.000 description 11
- 235000014113 dietary fatty acids Nutrition 0.000 description 9
- 239000000194 fatty acid Substances 0.000 description 9
- 229930195729 fatty acid Natural products 0.000 description 9
- 235000011187 glycerol Nutrition 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 230000035515 penetration Effects 0.000 description 8
- 238000003860 storage Methods 0.000 description 8
- 229920002125 Sokalan® Polymers 0.000 description 7
- 238000004321 preservation Methods 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000004584 polyacrylic acid Substances 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 5
- 206010040880 Skin irritation Diseases 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000004745 nonwoven fabric Substances 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 230000036556 skin irritation Effects 0.000 description 4
- 231100000475 skin irritation Toxicity 0.000 description 4
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 102000015933 Rim-like Human genes 0.000 description 3
- 108050004199 Rim-like Proteins 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000007864 aqueous solution Substances 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
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 3
- 229920000573 polyethylene Polymers 0.000 description 3
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 3
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229940037001 sodium edetate Drugs 0.000 description 3
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- RODZIAKMFCIGPL-UHFFFAOYSA-N P.I.I Chemical compound P.I.I RODZIAKMFCIGPL-UHFFFAOYSA-N 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 125000002843 carboxylic acid group Chemical group 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 239000011505 plaster Substances 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 229920006267 polyester film Polymers 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229920000915 polyvinyl chloride Polymers 0.000 description 2
- 239000004800 polyvinyl chloride Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229960003415 propylparaben Drugs 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000341 volatile oil Substances 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- 239000002759 woven fabric Substances 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- SLINHMUFWFWBMU-UHFFFAOYSA-N Triisopropanolamine Chemical compound CC(O)CN(CC(C)O)CC(C)O SLINHMUFWFWBMU-UHFFFAOYSA-N 0.000 description 1
- HDYRYUINDGQKMC-UHFFFAOYSA-M acetyloxyaluminum;dihydrate Chemical compound O.O.CC(=O)O[Al] HDYRYUINDGQKMC-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- BWZOPYPOZJBVLQ-UHFFFAOYSA-K aluminium glycinate Chemical compound O[Al+]O.NCC([O-])=O BWZOPYPOZJBVLQ-UHFFFAOYSA-K 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229940009827 aluminum acetate Drugs 0.000 description 1
- KLMDYFUUSKOJAX-UHFFFAOYSA-K aluminum;acetate;dihydroxide Chemical compound CC(=O)O[Al](O)O KLMDYFUUSKOJAX-UHFFFAOYSA-K 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- AMEDKBHURXXSQO-UHFFFAOYSA-N azonous acid Chemical compound ONO AMEDKBHURXXSQO-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- 229960003608 clomifene Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000003851 corona treatment Methods 0.000 description 1
- DNTGGZPQPQTDQF-XBXARRHUSA-N crotamiton Chemical compound C/C=C/C(=O)N(CC)C1=CC=CC=C1C DNTGGZPQPQTDQF-XBXARRHUSA-N 0.000 description 1
- 229960003338 crotamiton Drugs 0.000 description 1
- 210000003298 dental enamel Anatomy 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- YLQWCDOCJODRMT-UHFFFAOYSA-N fluoren-9-one Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3C2=C1 YLQWCDOCJODRMT-UHFFFAOYSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent 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
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003993 interaction Effects 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
- 230000007774 longterm Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-N methyl hydrogen carbonate Chemical compound COC(O)=O CXHHBNMLPJOKQD-UHFFFAOYSA-N 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000002985 plastic film Substances 0.000 description 1
- 229920006255 plastic film Polymers 0.000 description 1
- 229940113115 polyethylene glycol 200 Drugs 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229940057847 polyethylene glycol 600 Drugs 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- GRLPQNLYRHEGIJ-UHFFFAOYSA-J potassium aluminium sulfate Chemical compound [Al+3].[K+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O GRLPQNLYRHEGIJ-UHFFFAOYSA-J 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
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- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F13/00—Bandages or dressings; Absorbent pads
- A61F2013/00361—Plasters
- A61F2013/00544—Plasters form or structure
- A61F2013/00646—Medication patches, e.g. transcutaneous
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本發明係關於含有凱妥普洛芬(Ketoprofen)當做活性成分的水性貼附劑,詳言之,係關於凱妥普洛芬的主要藥物成分安定性及經皮吸收性優異的水性貼附劑。
含有具抗發炎活性的凱妥普洛芬當做活性成分的水性貼附劑係為人所熟知。凱妥普洛芬由於對水溶解度低,因此當摻合於水性貼附劑時,常需要使用克羅米通(crotamiton)、脂肪酸、脂肪酸酯、精油類、多元醇、界面活性劑等特定溶解劑當做難溶解性藥物的溶解劑(專利文獻1及2)。但是,當製造該等貼附劑時,於其製造方法需要有某些操作,有製造上的作業效率差的基本缺點。
亦即,為了溶解凱妥普洛芬而使用的特定溶解劑,一般而言多為親油性溶劑,當製造水性貼附劑時添加此等溶劑時,若不小心進行,可能會發生水溶性高分子化合物不溶、或者親油性溶劑分離等對於貼附劑物性有不好的影響。
而且,在通常的水性貼附劑中常會以高濃度摻合甘油等多元醇,但是若摻合的藥物為凱妥普洛芬時,在具有羧酸基的凱妥普洛芬與具有羥基的多元醇(例如甘油)、低級醇、或薄荷醇等溶解劑之間,為水性貼附劑的基劑成分的有機酸、聚丙烯酸等弱酸成為觸媒,造成即使在較低溫度仍會進行酯化反應,有保存安定性低的問題。
為了解決此問題,有人提議藉由使含有分子中具有羧酸基的凱妥普洛芬的非類固醇消炎鎮痛劑分散於甘油及碳數3至30的乙二醇類以使安定化(專利文獻3)。
但是,即使是該專利文獻記載的貼附劑,由於甘油係當做水性貼附劑的基劑的必要成分,因此考量長期安定性時,會有由於酯化反應造成保存安定性降低的顧慮。又,一般而言,若藥物於貼附劑中以分散狀態存在,雖保存安定性會增高,但另一方面,會成為經皮吸收性降低的原因,故希望能有保存安定性與經皮吸收性同時為良好的水性貼附劑。
另一方面,摻合於一般的油性貼附劑的貼附劑基劑當中,有許多是凱妥普洛芬的溶解性優異者,而且,通常使用為當做對凱妥普洛芬的溶解劑的脂肪酸酯、精油類或克羅米通等,有許多與凱妥普洛芬的互溶性亦為良好。
所以,摻合有凱妥普洛芬的油性貼附劑的經皮吸收性高而且即使此等油性貼附劑未摻合多元醇類也能維持其物性,因此可得到凱妥普洛芬的高度安定性。
由上述理由,自以往已有許多關於摻合凱妥普洛芬的油性貼附劑的發明提出(專利文獻4及5),實際上的醫藥品市場中,也有多數與此等油性貼附劑相關的產品流通。但是,油性貼附劑對皮膚有刺激性的問題,提供安全性更高的產品成為課題。
[專利文獻]
[專利文獻1]日本特開昭58-083623號公報
[專利文獻2]日本特開昭61-275212號公報
[專利文獻3]日本特開2002-193793號公報
[專利文獻4]國際公開WO93/04677號
[專利文獻5]日本特開2004-43512號公報
本發明有鑑於上述現狀,課題在於提供一種貼附劑,係含有凱妥普洛芬當做活性成分,具有凱妥普洛芬的優異經皮吸收性與安全性,而且有高度保存安定性。
本案發明人為了解決該課題努力研究,結果發現:藉由選擇對於凱妥普洛芬顯示優異溶解性的溶劑即胺類當做主要藥物成分溶解劑,並且使凱妥普洛芬溶解於摻合有與凱妥普洛芬的交互作用小的聚乙二醇的水性基劑中,可獲得呈現凱妥普洛芬的優異經皮吸收性、安全性、及高度保存安定性的水性貼附劑,乃完成本發明。
因此,本發明的基本態樣為一種水性貼附劑,其特徵為含有凱妥普洛芬、胺類、及聚乙二醇而成。
更具體而言,為一種水性貼附劑,其中在膏體中,凱妥普洛芬之摻合量為0.1至5重量%,胺類之摻合量為0.5至10重量%,且聚乙二醇之摻合量為5至30重量%。
最具體的本發明為一種水性貼附劑,其係使用二異丙醇胺當做胺類。
依照本發明可提供一種水性貼附劑,就凱妥普洛芬的溶解劑而言選擇胺類,並且使凱妥普洛芬溶解於摻合有聚乙二醇的水性基劑中,藉此能使凱妥普洛芬安定地溶解於水性基劑中。
尤其本發明提供一種含有凱妥普洛芬之水性貼附劑,其含有對水溶解性低的凱妥普洛芬當做活性成分,且對於凱妥普洛芬的溶解劑使用胺類,尤其是二異丙醇胺,而且,使凱妥普洛芬溶解於摻合有與凱妥普洛芬的交互作用小的聚乙二醇的水性貼附劑基劑中,藉此使皮膚穿透性高且皮膚刺激性低,並且主要藥物成分安定性高。
含有凱妥普洛芬之水性貼附劑中,胺類與聚乙二醇的組合係極特別的,因此,本發明提供的水性貼附劑,兼具習知的水性貼附劑所無法具備的凱妥普洛芬的優異經皮吸收性、安全性及高保存安定性,其效果巨大。
如上所述,本發明之基本的態樣,係特徵為含有凱妥普洛芬、胺類、及聚乙二醇而成的水性貼附劑。
以下就本發明更詳細說明。
本發明提供的水性貼附劑中,製劑中的凱妥普洛芬的摻合量,只要能夠製劑化即可,無特殊限制,較佳為相對於膏體總重量摻合0.1至5重量%。更佳為,0.5至2重量%。
膏體中的凱妥普洛芬的含量若低於0.1重量%,則凱妥普洛芬的經皮吸收性變得不足夠,而且,即使摻合超過5重量%,使用後也不能經皮吸收,在製劑中殘存的主要藥物成分會變多而不佳。
本發明使用的胺類,一般而言在水性貼附劑中多使用於當做對於基劑成分的pH調整劑,在本發明則是摻合以當做對於難溶性的凱妥普洛芬的溶解劑。
使用的胺類,例如單乙醇胺、二乙醇胺、三乙醇胺、二異丙醇胺、三異丙醇胺等,尤其二異丙醇胺較佳。
本發明提供的水性貼附劑中,胺類的摻合量只要能製劑化即可,無特殊限定,但較佳為相對於膏體總重量為0.5至10重量%,更佳為1至5重量%的範圍摻合。
膏體中的胺含量若低於0.5重量%,則製劑中的凱妥普洛芬的溶解變得不充分,結果可能會造成結晶析出或經皮吸收性降低等不好的影響。
另一方面,若摻合超過10重量%,則製劑的pH升高過度,且會造成黏著力降低等對於製劑的物性有不好的影響。
本發明中,在水性貼附劑的基劑中摻合的聚乙二醇,具有當做凱妥普洛芬的酯化抑制劑的功能。該聚乙二醇宜為平均分子量600以下者,具體而言,為由聚乙二醇200、聚乙二醇300、聚乙二醇400、聚乙二醇600構成的群組中選擇1種或2種以上所構成的聚乙二醇。
關於平均分子量大於600的聚乙二醇,由於其熔點超過40℃,因此當摻合於本發明之水性貼附劑時,無法將水溶性高分子等基劑成分充分分散,可能顯現出未溶解的基劑成分故為不佳。
使用的聚乙二醇的摻合量,只要能製劑化即可,無特殊限定,但較佳為相對於膏體總重量為5至30重量%,更佳為10至20重量%的範圍摻合。
膏體中的聚乙二醇的含量若低於5重量%,則製劑中的凱妥普洛芬的安定性下降,而且超過30重量%時,當貼附時會產生滴液,對於製劑物性會影響為不佳。
本發明提供的水性貼附劑中,只要不造成其他影響,可使用通常的外用製劑使用的各種基劑成分。
如此的基劑成分無特別限定,例如:通常使用的聚丙烯酸鈉、聚丙烯酸、羧基乙烯基聚合物、羧甲醚纖維素鈉、羥基丙基纖維素、聚乙烯醇、明膠等水溶性高分子化合物;甘油、丙二醇、1,3-丁二醇等多元醇類;氫氧化鋁、硫酸鋁鉀、甘胺酸鋁等交聯劑;高嶺土、氧化鈦等無機粉末;檸檬酸、依地酸鈉、酒石酸等pH調整劑;聚氧乙烯山梨糖醇酐單油酸酯、山梨糖醇酐單油酸酯、聚氧乙烯單油酸酯、甘油脂肪酸酯、聚甘油脂肪酸酯、聚氧乙烯脂肪酸酯、山梨糖醇酐脂肪酸酯、聚氧乙烯山梨糖醇酐脂肪酸酯、聚氧乙烯山梨醇脂肪酸酯、聚氧乙烯硬化篦麻子油、聚氧乙烯烷醚等界面活性劑;對羥基苯甲酸甲酯、對羥基苯甲酸丙酯等防腐劑;及精製水等。
再者,視需要可適當適量添加吸收促進劑、抗氧化劑、香味劑、著色劑等。
在該等之中,於貼附劑膏體成分中,水溶性高分子化合物於1至30重量%、交聯劑於0.01至5重量%、精製水於10至90重量%、無機粉末於0至20重量%的範圍內摻合較佳。而多元醇類,必需視前述聚乙二醇摻合量增減,但是宜與聚乙二醇一倂以10至50重量%摻合。
使用上述各成分製備的本發明之水性貼附劑(膏體層)的厚度(不含後述支持體及被覆表面的膜厚度),無法一概而限定,但是就塗布量而言為150至1000g/m2
即為足夠,更佳為300至700g/m2
。
本發明之水性貼附劑的膏體,可藉由將前述成分依常法混合、攪拌、熟成等而製造,本發明之水性貼附劑可將獲得的膏體在不織布或織布、片材、膜等支持體上展延、擔持後,以保護膜被覆而藉此製備。
使用的支持體的材料,例如聚乙烯、聚丙烯、聚氯乙烯、聚酯、耐綸、聚胺酯、嫘縈等,尤其膏體層薄時,宜使用以此等當做材料的多孔體或發泡體與織布或不織布的層合品等。
就被覆膏體表面的塑膠膜而言,可將聚乙烯、聚丙烯、聚酯、聚氯乙烯、剝離紙單獨或貼合使用,也可使用對於此等施以矽酮處理、電暈放電處理、凹凸處理、電漿處理等者。
以下,利用具體的實施例、及比較例,及進一步的各種試驗例更詳細說明本發明,但本發明不限於此等實施例。
均勻混合甘油142.5g、聚乙二醇(400)150g、聚丙烯酸7.5g、聚丙烯酸鈉40g、羧甲醚纖維素鈉40g、羥基丙基纖維素5g、依地酸鈉0.6g、二羥基胺基乙酸鋁0.9g、對羥基苯甲酸甲酯1g、對羥基苯甲酸丙酯0.5g、酒石酸15g、20%聚丙烯酸水溶液200g、精製水適量,製備成含水凝膠。
其次,將二異丙醇胺10g與溶於適量水的凱妥普洛芬20g在先前製備的凝膠中混合使均勻,獲得貼附劑用膏體。
將獲得的膏體塗布在層合不織布使膏體重量為500g/m2
,並以聚酯膜被覆黏著面,得到所望的水性貼附劑。
與上述實施例1同樣進行,依據下表1所示處方,獲得實施例2至4的水性貼附劑。
又,表中也顯示實施例1的處方,其摻合量以重量%表示,但是於各實施例製造時,係以其10倍量的單位(g換算)製備。
比較例1使用市售的含有凱妥普洛芬2重量%的硬膏劑(膏體厚:143g/m2
)。
均勻混合甘油350g、聚丙烯酸50g、聚丙烯酸鈉40g、羧甲醚纖維素鈉40g、羥基丙基纖維素5g、依地酸鈉0.6g、二羥基胺基乙酸鋁0.9g、丙二醇30g、對羥基苯甲酸甲酯1g、對羥基苯甲酸丙酯0.5g、酒石酸15g、20%聚丙烯酸水溶液200g、33%聚乙烯醇水溶液20g、精製水適量,製備成含水凝膠。
接著,將克羅米通20g與溶解於聚乙二醇(400) 40g的凱妥普洛芬20g,在先前製備的凝膠中混合使均勻,獲得貼附劑用膏體。
將獲得的膏體塗布在層合不織布,使膏體重量為500g/m2
,並以聚酯膜被覆黏著面,獲得比較例2的水性貼附劑。
與上述比較例2同樣進行,依據下表2所示處方,獲得比較例3至4的水性貼附劑。
又,表中亦顯示比較例2的處方,且其摻合量係以重量%表示,但是於各比較例製造時,係以其10倍量的單位(g換算)製備。
將上述獲得的實施例1、及比較例2至4的各貼附劑密封包裝於鋁袋後,於4℃的保存條件下保存1個月的期間後,以目視觀察各製劑中是否有凱妥普洛芬的結晶析出。結果如下表3所示。
表中的○代表無結晶析出的試樣,×代表有結晶析出的試樣。
將上述獲得的實施例1、及比較例2至4的各貼附劑密封包裝於鋁袋後,於40℃/75%RH的保存條件下保存3個月期間,之後以高速液體層析法測定此等各製劑中的凱妥普洛芬含量。
其結果如下表4所示。
結果係以起始摻合量定為100%,而且保存後的凱妥普洛芬的含量以%表示。
又,關於實施例1及比較例3的貼附劑,以高速液體層析法測定於同樣的保存條件下,在製劑中的類緣物質(凱妥普洛芬的甘油酯)生成量。
結果如下表5所示。類緣物質的生成量,係以類緣物質相對於摻合的凱妥普洛芬重量的生成重量比率(%)表示。
由上述各安定性試驗的結果可知:本發明之貼附劑與比較例的各製劑比較時,凱妥普洛芬的安定性特別優異。尤其未摻合聚乙二醇的比較例3,凱妥普洛芬的安定性低而且凱妥普洛芬的類緣物質生成量亦多。
又,關於未摻合胺類的比較例2及比較例4的水性貼附劑,亦為凱妥普洛芬的安定性低,其中又以比較例4在4℃的保存條件有結晶析出等,各比較例的製劑中,凱妥普洛芬在製劑中係以非常不安定的狀態存在。
針對實施例1獲得的水性貼附劑、及為市售品的比較例1的含有凱妥普洛芬2重量%的硬膏劑,使用大鼠皮膚進行活體外皮膚穿透試驗。
將經除毛的雄性大鼠(Wistar系,7週大)的背部摘出皮膚,固定於保溫在37℃的縱型穿透試驗用擴散小室,並將試驗對象製劑貼附於摘出皮膚的角質層側,於內側(真皮層側)加入磷酸緩衝生理食鹽水(PBS)10ml當做接受液。之後,經時採取接受液0.2ml,以液體層析測定凱妥普洛芬穿透量,從其值計算皮膚穿透速度(flux)。
其結果如第1圖所示。
針對實施例1獲得的水性貼附劑、及為市售品的比較例1的含有凱妥普洛芬2重量%的硬膏劑,進行兔皮膚一次刺激性試驗。
將各製劑貼附於經除毛的兔背部24小時,從剝離後第1小時、第24小時及第48小時的皮膚症狀求刺激指數(P.I.I.)。
刺激指數(P.I.I.)的評價基準如下表6所示。
其結果如下表7所示。
從第1圖及表7所示結果可知,本發明之水性貼附劑與比較例1的硬膏劑比較時,經皮吸收性、皮膚刺激性均為本發明之水性貼附劑較優異。
由以上的結果可得出以下結論:本發明提供的水性貼附劑係兼具優異的凱妥普洛芬的經皮吸收性、安全性、及高度保存安定性的製劑。
由以上所述,依照本發明可提供一種含有凱妥普洛芬之水性貼附劑,其係以對水溶解性低的凱妥普洛芬當做活性成分,使用胺類當做溶解劑,而且藉由溶解於摻合有聚乙二醇的貼附劑基劑中,而得到皮膚穿透性高、皮膚刺激性低、且主要藥物成分安定性高的含有凱妥普洛芬之水性貼附劑。
本發明提供的水性貼附劑,比起習知的含有凱妥普洛芬的貼附劑,為兼具高凱妥普洛芬的優異經皮吸收性、安全性、及高度保存安定性者,其在醫療上的有用性巨大。
第1圖顯示試驗例3中的活體外大鼠皮膚穿透性試驗之結果的圖表。
Claims (3)
- 一種水性貼附劑,其特徵為該水性貼付劑中的凱妥普洛芬之摻合量為0.1至5重量%,胺類之摻合量為0.5至10重量%,且聚乙二醇之摻合量為5至30重量%。
- 如申請專利範圍第1項之水性貼附劑,其中胺類為二異丙醇胺。
- 一種如申請專利範圍第1項之水性貼附劑之製造方法,其特徵為在含有聚乙二醇之膏體中,摻合溶解於胺類的凱妥普洛芬。
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JP2010056098A JP5622410B2 (ja) | 2010-03-12 | 2010-03-12 | ケトプロフェン含有水性貼付剤 |
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JP (1) | JP5622410B2 (zh) |
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CN (2) | CN106913560A (zh) |
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TWI803469B (zh) * | 2016-10-12 | 2023-06-01 | 日商帝國製藥股份有限公司 | 水性貼附劑 |
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JP6444305B2 (ja) * | 2013-08-09 | 2018-12-26 | 帝國製薬株式会社 | ベラプロスト含有貼付剤 |
ES2753584T3 (es) * | 2014-12-22 | 2020-04-13 | Hisamitsu Pharmaceutical Co | Cataplasma |
JP2020066592A (ja) * | 2018-10-24 | 2020-04-30 | 帝國製薬株式会社 | 水性貼付剤 |
CN112206222A (zh) * | 2018-11-09 | 2021-01-12 | 北京德默高科医药技术有限公司 | 含有布洛芬结构类似物的多层经皮给药系统 |
WO2020166665A1 (ja) | 2019-02-14 | 2020-08-20 | 久光製薬株式会社 | パップ剤 |
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TWI803469B (zh) * | 2016-10-12 | 2023-06-01 | 日商帝國製藥股份有限公司 | 水性貼附劑 |
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EP2545912B1 (en) | 2014-09-03 |
CN106913560A (zh) | 2017-07-04 |
KR101819249B1 (ko) | 2018-01-16 |
ES2523126T3 (es) | 2014-11-21 |
KR20130059322A (ko) | 2013-06-05 |
CA2791498A1 (en) | 2011-09-15 |
WO2011111809A1 (ja) | 2011-09-15 |
US20160136277A1 (en) | 2016-05-19 |
JP2011190194A (ja) | 2011-09-29 |
CA2791498C (en) | 2017-04-18 |
US20130005817A1 (en) | 2013-01-03 |
JP5622410B2 (ja) | 2014-11-12 |
AU2011225100B2 (en) | 2013-08-15 |
AU2011225100A1 (en) | 2012-10-04 |
EP2545912A1 (en) | 2013-01-16 |
HK1177690A1 (zh) | 2013-08-30 |
EP2545912A4 (en) | 2013-10-16 |
US9271944B2 (en) | 2016-03-01 |
CN102858332A (zh) | 2013-01-02 |
TW201138864A (en) | 2011-11-16 |
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