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(12) Patent Application Publication (10) Pub. No.: US 2012/0004305 A1 Miura Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2012/0004305 A1 Miura Et Al US 201200.04305A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0004305 A1 Miura et al. (43) Pub. Date: Jan. 5, 2012 (54) EXTERNAL PREPARATION CONTAINING Publication Classification ANALGESCAANTI-NFLAMMATORY AGENT (51) Int. Cl. A6II 3/196 (2006.01) (75) Inventors: Seiji Miura, Shizuoka (JP): A6IP 29/00 (2006.01) Makoto Kanebako, Shizuoka (JP) A6II 47/44 (2006.01) A6II 47/08 (2006.01) (73) Assignee: Kowa Co., Ltd., Nagoya-shi (JP) A6II 47/10 (2006.01) (52) U.S. Cl. ......................................... 514/567; 514/772 (21) Appl. No.: 13/256,024 (57) ABSTRACT (22) PCT Fled: Mar. 11, 2010 An external preparation containing the following compo nents (A), (B), (C), and (D): (86) PCT NO.: PCT/P10/01760 (A) a non-steroidal analgesic/anti-inflammatory agent, (B) a terpene and/or an essential oil containing a terpene, S371 (c)(1), (C) a higher alcohol, and (2), (4) Date: Sep. 12, 2011 (D) a polyoxyalkylene alkyl ether and/or a polyoxyalky lene alkenyl ether. The external preparation of the (30) Foreign Application Priority Data present invention has improved skin permeation, and can thus be effective at a low concentration, and also has Mar. 11, 2009 (JP) ................................. 2009-057972 excellent appearance. US 2012/0004305 A1 Jan. 5, 2012 EXTERNAL PREPARATION CONTAINING external application containing alkyl pyrrolidone, hydro ANALGESCAANTI-NFLAMMATORY AGENT philic polyether, hydrophilic nonionic Surfactants, water soluble polymer Substances having a carboxyl group, water TECHNICAL FIELD soluble vinyl polymers, water-insoluble multivalent metal salts, polyhydric alcohol, organic hydroxy acid, and water 0001. The present invention relates to an external prepa (see Patent Document 6), a piroXicam-containing transder ration containing a non-steroidal analgesic/anti-inflamma mal system containing, as an adhesive, a copolymer com tory agent. posed of N-vinyl-2-pyrrolidone and (meth)acrylic acid ester, as a drug solubilizing aid, polyvinyl pyrrolidone, and as a BACKGROUND ART penetration enhancer, polyoxyethylene alkyl ether and/or 0002 Amfenac or a salt thereof, a phenyl acetate type fatty acid alkylolamide (see Patent Document 7), a ketoprofen non-steroidal anti-inflammatory analgesic agent, is indicated liquid preparation for external application containing poly for relieving inflammation and pain associated with chronic oxyethylenepolyoxypropylene alkyl ether, hydroxyalkyl cel rheumatoid arthritis, osteoarthritis, low back pain, Scapulo lulose, isopropyl adipate, and/or isopropyl myristate, a mix humeral periarthritis, cervico-omo-brachial syndrome, and ture of water and ethanol, and the like (see Patent Document temporomandibular arthrosis as well as following Surgery, 8), and an external preparation containing oleic acid or oleyl injury, tooth extraction, and the like, and a capsule containing alcohol and a non-steroidal anti-inflammatory analgesic 50 mg of amfenac sodium per capsule is used. However, agent in an aqueous alcohol solvent (see Patent Document 9) because of the short blood half-life of amfenac or a salt are known. thereof, four times-daily administration has been necessary 0006. However, none of these documents specifically for oral administration. Also, because amfenac or a salt describes or suggests improvement of the percutaneous thereof inhibits biosynthesis of prostaglandin, there is a pos absorbability of amfenac or a salt thereof by use of a terpene sibility of digestive tract mucosal injury being caused as a and/or an essential oil containing a terpene, a higher alcohol, side effect (Non Patent Document 1). and a polyoxyalkylene alkyl ether and/or a polyoxyalkylene 0003. In order to solve such a problem, it has been alkenyl ether in combination. Further, none of these docu demanded that amfenac or a salt thereof be provided as an ments also specifically describes or suggests a pharmaceuti external preparation. As an external preparation containing cal preparation in which amfenac or a salt thereof is effective amfenac sodium, for example, a patch for external application at a low concentration, which has excellent appearance. in which an acrylic adhesive layer is provided on a support (refer to Patent Document 1) and an anti-inflammatory anal PRIOR ART DOCUMENT gesic patch in which a pressure sensitive adhesive material layer containing an organic acid more strongly acidic than Patent Document amfenac in the free state is laminated onto a flexible support 0007 Patent Document 1 JP-A-61-126020 (refer to Patent Document 2) are known. However, amfenac 0008 Patent Document 2.JP-A-62-126119 Sodium is a compound exhibiting a deep yellow color and 0009 Patent Document 3 JP-A-58-39616 there is a tendency that the color tone becomes stronger in a 0010 Patent Document 4.JP-A-58-103311 manner dependent on the concentration. There is concern that 0011 Patent Document 5 JP-A-6-9394 an external preparation with strong color tone may cause 0012 Patent Document 6.JP-A-2002-20274 staining, etc., if it adheres to clothes upon application. Thus, 0013 Patent Document 7 JP-A-3-251534 it is required that amfenac sodium be prepared into a well 0014 Patent Document 8 JP-A-1-143831 absorbable pharmaceutical preparation in a range of low con 00.15 Patent Document 9.JP-A-2000-143540 centration, within which it appears light yellow in color. However, either of the external preparations described in Non Patent Document Patent Documents 1 and 2 contains such a high concentration of amfenac sodium as 5% by weight or more, leaving the 0016 Non Patent Document 1 “Drugs in Japan, Ethical aforementioned problem unsolved. drugs, 2006, Jiho, Inc., page 221 0004 Further, amfenac or a salt thereof is extremely SUMMARY OF INVENTION unstable to an acidic Substance, and there is concern that the stability of the external preparation described in Patent Docu 0017. An object of the present invention is to provide an ment 2 may be decreased by mixing a strongly acidic organic external preparation containing a non-steroidal analgesic/ acid. anti-inflammatory agent (particularly, amfenac or a salt 0005 Meanwhile, various technologies for improving the thereof), which has improved skin permeation and is effective percutaneous absorbability of a non-steroidal analgesic/anti at a low concentration, and also has excellent appearance. inflammatory agent have also been proposed. For example, a 0018. The present inventors conducted a study on an exter ketoprofen ointment prepared with an oily base composed of nal preparation containing a non-steroidal analgesic/anti-in fatty acid ester, waxes, Surfactants, and hydrocarbons (refer to flammatory agent. As a result, they have found that a phar Patent Document 3), a ketoprofen ointment prepared with an maceutical preparation with high percutaneous absorbability emulsion base composed of higher alcohol, hydrocarbons, and excellent appearance can be obtained by mixing a terpene water, and emulsifiers (see Patent Document 4), an indometa and/or an essential oil containing a terpene, a higher alcohol, cin-containing liquid preparation prepared by blending a spe and a polyoxyalkylene alkyl ether and/or a polyoxyalkylene cific polyoxyethylene-based nonionic Surfactant in a lower alkenyl ether. alcohol-water-based base containing vitamin Es and medium 0019. The present invention provides an external prepara chain fatty acid ester (see Patent Document 5), a non-steroidal tion containing the following components (A), (B), (C), and anti-inflammatory analgesic agent-containing patch for (D): US 2012/0004305 A1 Jan. 5, 2012 0020 (A) a non-steroidal analgesic/anti-inflammatory thone, ionol, ionone, linalool, and limonene. These terpenes agent, include a single stereoisomer and a mixture thereof. Also, 0021 (B) a terpene and/or an essential oil containing a examples of the essential oil containing a terpene include terpene, anise oil, ylang-ylang oil, orris oil, fennel oil, orange oil, 0022 (C) a higher alcohol, and cananga oil, chamomile oil, cajuput oil, caraway oil, cubeb 0023 (D) a polyoxyalkylene alkyl ether and/or a polyoxy oil, grapefruit oil, cinnamon oil, coriander oil, saffron oil, alkylene alkenyl ether. Zanthoxylum fruit oil, perilla oil, citriodora oil, citronella oil, 0024. The external preparation of the present invention ginger oil, cardamom oil, camphor oil, ginger glass oil, spear has improved skin permeation, and can thus be effective at a mint oil, peppermint oil, geranium oil, star aniseed oil, clove low concentration, and also has excellent appearance. oil, turpentine oil, bitter orange peel oil, neroli oil, basil oil, mentha oil, palmarosa oil, pimento oil, petitgrain oil, bay oil, MODES FOR CARRYING OUT THE INVENTION pennyroyal oil, chenopodium oil, bergamot oil, bois de rose 0025 Component (A): Non-Steroidal Analgesic/Anti-In oil, hosho oil, majoran oil, mandarin oil, melissa oil, euca flammatory Agent lyptus oil, lime oil, lavender oil, linaloe oil, lemon oil, lem 0026. Although no particular limitation is imposed on the onglass oil, rose oil, rosemary oil, and Roman chamomile oil. non-steroidal analgesic/anti-inflammatory agent of Compo nent (A) used in the present invention, examples thereof 0029. In the present invention, preferable examples of the include actarit, acemetacin, ampiroXicam, amfenac, ibupro terpene include camphor, d-camphor, d1-camphor, geraniol, fen, indometacin, etodolac, ketoprofen, Zaltoprofen, citronellal, terpineol, borneol, d-borneol, menthol, d1-men diclofenac, Sulindac, celecoxib, tiaprofenic acid, tenoxicam, thol, 1-menthol,
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