JPWO2009031318A1 - Topical analgesic / anti-inflammatory agent - Google Patents

Abstract

An external preparation containing the following components (A) and (B). (A) non-steroidal analgesic / anti-inflammatory agent (B) polyoxyalkylene alkyl ether and / or polyoxyalkylene alkenyl ether As a result, the effect can be exhibited at a low concentration, and the aesthetic appearance is also excellent.

Description

  The present invention relates to an external preparation containing a non-steroidal analgesic / anti-inflammatory agent.

  Phenylacetic acid-based non-steroidal anti-inflammatory analgesics, ampenac or its salts, are rheumatoid arthritis, osteoarthritis, low back pain, shoulder periarthritis, cervical arm and arm syndrome, temporomandibular disorders, and after surgery, after trauma, Capsules containing 50 mg of ampenac sodium in one capsule are used for anti-inflammatory and analgesic effects after tooth extraction. However, since ampenac or its salt has a short blood half-life, oral administration required administration four times a day. Moreover, since amfenac or its salt suppresses biosynthesis of prostaglandins, gastrointestinal mucosal damage may occur as a side effect (Non-patent Document 1).

  In order to solve such problems, it has been demanded to use ampenac or a salt thereof as an external preparation. As an external preparation containing amphenac sodium, for example, an external adhesive patch in which an acrylic adhesive layer is provided on a support (see Patent Document 1), a pressure-sensitive property containing an organic acid that is more strongly acidic than free ampenac. An anti-inflammatory analgesic patch (see Patent Document 2) obtained by laminating an adhesive material layer on a flexible support is known. However, ampenac sodium is a compound that exhibits a deep yellow color and tends to have a strong color tone depending on the concentration. Since external preparations having a strong color tone are likely to be colored when used on clothes during use, it is required to form a preparation with good absorbability in a low concentration range with a light yellow appearance. However, the external preparations described in Patent Documents 1 and 2 both contain ampenac sodium at a high concentration of 5% by weight or more, and have not yet solved the above problem.

  Furthermore, ampenac or a salt thereof is very unstable with respect to an acidic substance, and in the external preparation described in Patent Document 2, there is a concern that stability may be lowered due to the addition of a strongly acidic organic acid.

  By the way, various techniques for improving transdermal absorbability of non-steroidal analgesic / anti-inflammatory agents have been proposed. For example, ketoprofen ointment (see Patent Document 3) using an oleaginous base composed of fatty acid esters, waxes, surfactants, and hydrocarbons (see Patent Document 3), an emulsion base composed of higher alcohols, hydrocarbons, water and emulsifiers An indomethacin-containing liquid formulation (see Patent Document 4) containing a specific polyoxyethylene nonionic surfactant in a lower alcohol-water base containing vitamin E and medium chain fatty acid ester (see Patent Document 4) Patent Document 5), alkylpyrrolidone, hydrophilic polyether, hydrophilic nonionic surfactant, water-soluble polymer substance having a carboxyl group, water-soluble vinyl polymer, water-insoluble polyvalent metal salt, polyhydric alcohol, organic Non-steroidal anti-inflammatory analgesic external patch containing hydroxy acid and water (see Patent Document 6), N-Bi as adhesive Copolymer of ru-2-pyrrolidone and (meth) acrylic acid ester, polyvinyl pyrrolidone as drug solubilizer, piroxicam containing polyoxyethylene alkyl ethers and / or fatty acid alkylolamides as absorption promoter Transdermal absorption preparation (see Patent Document 7), polyoxyethylene polyoxypropylene alkyl ether, hydroxyalkyl cellulose, isopropyl adipate and / or isopropyl myristate, ketoprofen topical solution containing water and ethanol, etc. (Patent Document 8) For example, an external preparation (see Patent Document 9) containing oleic acid or oleyl alcohol and a nonsteroidal anti-inflammatory analgesic in an aqueous alcoholic solvent is known.

  However, in any document, polyoxyalkylene alkyl ether and / or polyoxyalkylene alkenyl ether improves transdermal absorbability of ampenac or a salt thereof, and further uses terpene or higher alcohol in combination. Thus, there is no specific description or suggestion regarding the further improvement of the transdermal absorbability. In addition, there is no specific description or suggestion regarding a preparation in which ampenac or a salt thereof exhibits an effect at a low concentration and is excellent in aesthetics.

“Nippon Pharmaceuticals Medicinal Medicine 2006 Edition”, Jiho Co., Ltd., page 221 JP-A-61-126020 JP-A-62-126119 JP 58-39616 A JP 58-103311 A JP-A-6-9394 Japanese Patent Laid-Open No. 2002-20274 JP-A-3-251534 Japanese Unexamined Patent Publication No. 1-143831 JP 2000-143540 A

  The present invention relates to an external preparation containing a non-steroidal analgesic / anti-inflammatory agent (especially ampenac or a salt thereof), the permeability of the analgesic / anti-inflammatory agent to the skin is improved, and an effect is expressed at a low concentration, And it aims at providing the external preparation excellent in aesthetics.

  The present inventors examined a topical preparation containing a non-steroidal analgesic / anti-inflammatory agent. By blending polyoxyethylene alkyl ether and / or polyoxyethylene alkyl phenyl ether, high transdermal absorbability was obtained. It has been found that a preparation having excellent aesthetics can be obtained.

The present invention provides an external preparation containing the following components (A) and (B).
(A) Non-steroidal analgesic / anti-inflammatory agent
(B) Polyoxyalkylene alkyl ether and / or polyoxyalkylene alkenyl ether

  The external preparation of the present invention has improved skin permeability, and can thereby exert an effect at a low concentration, and is excellent in aesthetic appearance.

[Component (A): Non-steroidal analgesic / anti-inflammatory agent]
The non-steroidal analgesic / anti-inflammatory agent of component (A) used in the present invention is not particularly limited, and examples thereof include actarit, acemetacin, ampiroxicam, ampenac, ibuprofen, indomethacin, etodolac, ketoprofen, and zaltoprofen. , Diclofenac, sulindac, celecoxib, thiaprofenic acid, tenoxicam, naproxen, piroxicam, felbinac, pranoprofen, flurbiprofen, mefenamic acid, medicoxib, meloxicam, mofezolac, lefecoxib, loxoprofen, robenzalit, rololoxicam, Among them, ampenac or a salt thereof is preferable. More specifically, actarit, acemetacin, ampiroxicam, ampenac sodium, ibuprofen, indomethacin, indomethacin farnesyl, etodolac, ketoprofen, zaltoprofen, diclofenac sodium, sulindac, celecoxib, thiaprofenic acid, tenoxicam, naproxen, piroxicam, proloxicam Examples include phen, flurbiprofen, flurbiprofen axetil, mefenamic acid, medoxixib, meloxicam, mofezolac, lefecoxib, loxoprofen sodium, lobenzalit disodium, lornoxicam, and particularly preferred is ampenac sodium.

  In the external preparation of the present invention, the non-steroidal analgesic / anti-inflammatory agent of component (A) can be used alone or in combination of two or more, and the content thereof is not particularly limited. 0.001 to 20 mass% is preferable, 0.01 to 10 mass% is more preferable, and 0.05 to 5 mass% is particularly preferable. In addition, the content of each component in the external preparation of the present invention, unless otherwise specified, excluding members for preparation such as a support, a release liner, and a container, “parts containing components (A) and (B)” The ratio of the mass of each component to the total mass of For example, in a poultice, the content in a poultice base layer, and in a patch, the content in a pressure-sensitive adhesive layer.

[(B): polyoxyalkylene alkyl ether and / or polyoxyalkylene alkenyl ether]
The polyoxyalkylene alkyl ether and polyoxyalkylene alkenyl ether of the component (B) used in the present invention are those obtained by addition polymerization of alkylene oxide to an alcohol having an alkyl group or an alkenyl group or a phenol having an alkyl group or an alkenyl group. It means what is obtained. Here, as an alcohol having an alkyl group or an alkenyl group, an alkyl group having 1 to 22 carbon atoms (straight chain having 1 to 22 carbon atoms, or branched or cyclic having 3 to 22 carbon atoms), or 2 carbon atoms. Means an alcohol having an alkenyl group of -22 (linear with 2 to 22 carbon atoms, branched or cyclic with 3 to 22 carbon atoms), and examples of the alkyl group and alkenyl group include a methyl group and an ethyl group Propyl group, isopropyl group, cyclopropyl group, allyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, isodecyl group, undecyl group, dodecyl group (lauryl group), tridecyl group , Tetradecyl group (myristyl group), pentadecyl group, hexadecyl group (cetyl group, palmityl group), heptadecyl group, octadecyl group (stearyl group) , Isostearyl group, oleyl group, a nonadecyl group, eicosyl group, behenyl group and the like. The phenol having an alkyl group or alkenyl group means the above-mentioned phenol having a linear, branched or cyclic alkyl group or alkenyl group. Examples of the alkylene oxide include ethylene oxide and propylene oxide.

  When an alkylene oxide is addition-polymerized to an alcohol having an alkyl group or an alkenyl group, or to a phenol having an alkyl group or an alkenyl group, the alkylene oxide may be either ethylene oxide alone, propylene oxide alone, ethylene oxide or propylene oxide. May be subjected to addition polymerization. Addition polymerization may be based on a known method, and when both are addition-polymerized, block polymerization or random polymerization may be used. The average added mole number of alkylene oxide is preferably 2 to 50, more preferably 2 to 5, and particularly preferably 2 to 4.

The component (B) polyoxyalkylene alkyl ether and polyoxyalkylene alkenyl ether used in the present invention can be represented by the following general formula (1).
R—X—O— (AO) _n —H (1)
[In the formula, R represents an alkyl group having 1 to 22 carbon atoms or an alkenyl group having 2 to 22 carbon atoms, X represents a single bond or a phenylene group, A represents an ethylene group or a propylene group, and n represents 2 to 2. An average added mole number of 50 is shown. n A may be any one of ethylene group and propylene group, or a combination thereof. ]

In the present invention, in the above formula (1),
(I) R is an alkyl group or alkenyl group having 8 to 22 carbon atoms, X is a single bond, 2 ≦ n ≦ 5, and (ii) R is an alkyl group having 1 to 9 carbon atoms. And X is a phenylene group, preferably 2 ≦ n ≦ 5. Among them, in (i) and (ii), those meaning 2 ≦ n ≦ 4 are particularly preferable.

  The component (B) polyoxyalkylene alkyl ether and polyoxyalkylene alkenyl ether used in the present invention can be produced based on known methods as described above, but commercially available products can also be used. Examples of polyoxyalkylene alkyl ethers and polyoxyalkylene alkenyl ethers include, for example, polyoxyethylene (2) 2-ethylhexyl ether, polyoxyethylene (4) 2-ethylhexyl ether, polyoxyethylene (6) 2-ethylhexyl ether , Polyoxyethylene (11) 2-ethylhexyl ether, polyoxyethylene (30) 2-ethylhexyl ether, polyoxyethylene (3) decyl ether, polyoxyethylene (5) decyl ether, polyoxyethylene (6) decyl ether, Polyoxyethylene (7) decyl ether, polyoxyethylene (10) decyl ether, polyoxyethylene (3.5) isodecyl ether, polyoxyethylene (5) isodecyl ether, polyoxyethylene (5.5) isodecyl ether, polyoxy Ethylene (6) Isodecyl A Polyoxyethylene (6.5) isodecyl ether, polyoxyethylene (7) isodecyl ether, polyoxyethylene (8.5) isodecyl ether, polyoxyethylene (2) lauryl ether, polyoxyethylene (2.2) lauryl ether, Polyoxyethylene (3) lauryl ether, polyoxyethylene (4.2) lauryl ether, polyoxyethylene (5) lauryl ether, polyoxyethylene (6) lauryl ether, polyoxyethylene (7) lauryl ether, polyoxyethylene (7.5 ) Lauryl ether, polyoxyethylene (8) lauryl ether, polyoxyethylene (9) lauryl ether, polyoxyethylene (10) lauryl ether, polyoxyethylene (12) lauryl ether, polyoxyethylene (13) lauryl ether, poly Oxyethylene (15) lauryl ether, Lioxyethylene (19) lauryl ether, polyoxyethylene (21) lauryl ether, polyoxyethylene (25) lauryl ether, polyoxyethylene (30) lauryl ether, polyoxyethylene (40) lauryl ether, polyoxyethylene (3 ) Tridecyl ether, polyoxyethylene (5) tridecyl ether, polyoxyethylene (6.5) tridecyl ether, polyoxyethylene (7) tridecyl ether, polyoxyethylene (7.5) tridecyl ether, polyoxyethylene (8 ) Tridecyl ether, polyoxyethylene (8.5) tridecyl ether, polyoxyethylene (9) tridecyl ether, polyoxyethylene (10) tridecyl ether, polyoxyethylene (12) tridecyl ether, polyoxyethylene (15 ) Tridecyl ether, polyoxyethylene (20) tride Ether, polyoxyethylene (3) myristyl ether, polyoxyethylene (7) myristyl ether, polyoxyethylene (12) myristyl ether, polyoxyethylene (2) cetyl ether, polyoxyethylene (5) cetyl ether, polyoxyethylene (5.5) Cetyl ether, polyoxyethylene (7) cetyl ether, polyoxyethylene (8) cetyl ether, polyoxyethylene (10) cetyl ether, polyoxyethylene (13) cetyl ether, polyoxyethylene (15) cetyl ether , Polyoxyethylene (20) cetyl ether, polyoxyethylene (23) cetyl ether, polyoxyethylene (25) cetyl ether, polyoxyethylene (30) cetyl ether, polyoxyethylene (40) cetyl ether, polyoxyethylene ( 2) Stearyl ether, polyoxyethylene ( 3.3) Stearyl ether, polyoxyethylene (4) stearyl ether, polyoxyethylene (5) stearyl ether, polyoxyethylene (7) stearyl ether, polyoxyethylene (10) stearyl ether, polyoxyethylene (11) stearyl ether, Polyoxyethylene (15) stearyl ether, polyoxyethylene (20) stearyl ether, polyoxyethylene (30) stearyl ether, polyoxyethylene (50) stearyl ether, polyoxyethylene (4) isostearyl ether, polyoxyethylene ( 8) Isostearyl ether, polyoxyethylene (12) isostearyl ether, polyoxyethylene (16) isostearyl ether, polyoxyethylene (2) oleyl ether, polyoxyethylene (4) oleyl ether, polyoxyethylene (5) Olei Ether, polyoxyethylene (6) oleyl ether, polyoxyethylene (7) oleyl ether, polyoxyethylene (8.5) oleyl ether, polyoxyethylene (9) oleyl ether, polyoxyethylene (10) oleyl ether, polyoxyethylene (11) oleyl ether, polyoxyethylene (13) oleyl ether, polyoxyethylene (13.5) oleyl ether, polyoxyethylene (14) oleyl ether, polyoxyethylene (15) oleyl ether, polyoxyethylene (20) oleyl ether , Polyoxyethylene (30) oleyl ether, polyoxyethylene (40) oleyl ether, polyoxyethylene (50) oleyl ether, polyoxyethylene (5) behenyl ether, polyoxyethylene (10) behenyl ether, polyoxyethylene ( 20) Behenyl ether Polyoxyethylene (30) behenyl ether, polyoxyethylene (3) octyl phenyl ether, polyoxyethylene (6) octyl phenyl ether, polyoxyethylene (8) octyl phenyl ether, polyoxyethylene (10) octyl phenyl ether, poly Oxyethylene (15) octyl phenyl ether, polyoxyethylene (20) octyl phenyl ether, polyoxyethylene (40) octyl phenyl ether, polyoxyethylene (5) nonyl phenyl ether, polyoxyethylene (9) nonyl phenyl ether, poly Oxyethylene (9.5) nonylphenyl ether, polyoxyethylene (10) nonylphenyl ether, polyoxyethylene (11) nonylphenyl ether, polyoxyethylene (15) nonylphenyl ether, polyoxyethylene (18) nonylphenyl Ether, polyoxyethylene (20) nonylphenyl ether, polyoxyethylene (5) polyoxypropylene (2) decyl ether, polyoxyethylene (7) polyoxypropylene (2) decyl ether, polyoxyethylene (10) polyoxy Propylene (2) decyl ether, polyoxyethylene (8) polyoxypropylene (2) lauryl ether, polyoxyethylene (10) polyoxypropylene (2) lauryl ether, polyoxyethylene (13) polyoxypropylene (2) lauryl Ether, polyoxyethylene (9) polyoxypropylene (2) tridecyl ether, polyoxyethylene (12) polyoxypropylene (2) tridecyl ether, polyoxyethylene (16) polyoxypropylene (2) tridecyl ether, Polyoxyethylene (1) Polyoxypropylene (1) Cetyl ether, Polyoxy Tylene (1) polyoxypropylene (4) cetyl ether, polyoxyethylene (1) polyoxypropylene (8) cetyl ether, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polyoxyethylene (17) poly Oxypropylene (23) cetyl ether, polyoxyethylene (20) polyoxypropylene (4) cetyl ether, polyoxyethylene (20) polyoxypropylene (8) cetyl ether, polyoxyethylene (4) polyoxypropylene (30) Examples include stearyl ether.

  In the present invention, among the above, those having an average addition mole number of alkylene oxide of 2 to 5, particularly 2 to 4 are preferable. In the above examples, polyoxyethylene (2) 2-ethylhexyl ether, polyoxyethylene (4) 2-ethylhexyl ether, polyoxyethylene (3) decyl ether, polyoxyethylene (5) decyl ether, polyoxyethylene ( 3.5) Isodecyl ether, polyoxyethylene (5) isodecyl ether, polyoxyethylene (2) lauryl ether, polyoxyethylene (2.2) lauryl ether, polyoxyethylene (3) lauryl ether, polyoxyethylene (4.2) lauryl Ether, polyoxyethylene (5) lauryl ether, polyoxyethylene (3) tridecyl ether, polyoxyethylene (5) tridecyl ether, polyoxyethylene (3) myristyl ether, polyoxyethylene (2) cetyl ether, poly Oxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether, polyoxyethylene (3.3) stearyl ether, polyoxyethylene (4) stearyl ether, polyoxyethylene (5) stearyl ether, polyoxyethylene (4) isostearyl ether, polyoxyethylene (2) Oleyl ether, polyoxyethylene (4) oleyl ether, polyoxyethylene (5) oleyl ether, polyoxyethylene (5) behenyl ether, polyoxyethylene (3) octylphenyl ether, polyoxyethylene (5) nonylphenyl ether, Polyoxyethylene (1) polyoxypropylene (1) cetyl ether, polyoxyethylene (1) polyoxypropylene (4) cetyl ether, etc. are preferred, polyoxyethylene (2) 2-ethylhexyl ether, polyoxyethylene (4) 2-ethylhexyl ether, polyoxyethylene (3) Decyl ether, polyoxyethylene (3.5) isodecyl ether, polyoxyethylene (2) lauryl ether, polyoxyethylene (2.2) lauryl ether, polyoxyethylene (3) lauryl ether, polyoxyethylene (3) trioxyethylene Decyl ether, polyoxyethylene (3) myristyl ether, polyoxyethylene (2) cetyl ether, polyoxyethylene (2) stearyl ether, polyoxyethylene (3.3) stearyl ether, polyoxyethylene (4) stearyl ether, polyoxy Ethylene (4) isostearyl ether, polyoxyethylene (2) oleyl ether, polyoxyethylene (4) oleyl ether, polyoxyethylene (3) octylphenyl ether, polyoxyethylene (1) polyoxypropylene (1) cetyl ether Listed as particularly preferred It is.

  In the external preparation of the present invention, the polyoxyalkylene alkyl ether and / or polyoxyalkylene alkenyl ether of component (B) can be used alone or in combination of two or more, and the content thereof is particularly limited. However, it is preferably 0.01 to 50% by mass, more preferably 0.1 to 30% by mass, still more preferably 0.2 to 28% by mass, and particularly preferably 1 to 25% by mass.

[(C): terpene and / or essential oil containing terpene]
In order to further improve the transdermal absorbability of component (A), the external preparation of the present invention may further contain a terpene of component (C) and / or an essential oil containing a terpene. The essential oil containing terpene and / or terpene is not particularly limited, and examples thereof include monoterpene, sesquiterpene and / or essential oil containing these. Terpenes include, for example, isoborneol, iron, osimene, carveol, carbotanaceton, carbomenton, carvone, caren, caron, camphene, camphor, geraniol, cymen, sabinene, safranal, cyclocitral, citral, citronellal, citronellol, citronellol, Cineole, sylvestrene, twill alcohol, thuyon, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinoccampheol, pinol, piperithenone, ferrandral, ferrandrane, fenchen, fentil alcohol, perillyl alcohol, perillyl Examples include aldehyde, borneol, myrcene, menthol, menthone, yonor, yonon, linalool, limonene and the like. Examples of essential oils containing terpenes include anise oil, ylang ylang oil, iris oil, fennel oil, orange oil, cananga oil, chamomile oil, kayap oil, caraway oil, kubeb oil, grapefruit oil, cinnamon oil and coriander oil. , Saffron oil, salamander oil, perilla oil, citriodora oil, citronella oil, ginger oil, gizzard oil, camphor oil, gingergrass oil, spearmint oil, mint oil, geranium oil, daikyo ginger oil, clove oil, turpentine oil, Spruce oil, neroli oil, basil oil, peppermint oil, palmarosa oil, pimento oil, petitgren oil, bay oil, peniroyal oil, henoposi oil, bergamot oil, bored rose oil, pepper oil, marjolan oil, mandarin oil, melissa oil, eucalyptus oil , Lime oil, lavender oil, Lina E oil, lemon oil, lemon grass oil, rose oil, rosemary oil, and Roman chamomile oil, and the like.

  In the present invention, as the terpene, camphor, geraniol, citronellal, terpineol, borneol, menthol, limonene and the like are preferable, and menthol is particularly preferable. The essential oils containing terpenes include ylang ylang oil, fennel oil, orange oil, chamomile oil, cinnamon oil, perilla oil, citronella oil, ginger oil, camphor oil, mint oil, geranium oil, clove oil, turpentine oil, Spruce oil, neroli oil, mint oil, palmarosa oil, bergamot oil, eucalyptus oil, lavender oil, linaloe oil, lemon oil, rose oil, rosemary oil, roman chamomile oil, etc. are preferred, and mint oil is particularly preferred.

  In the external preparation of the present invention, the terpene of component (C) and / or the essential oil containing terpene can be used alone or in combination of two or more, and the content thereof is not particularly limited. 0.0001 to 20 mass% is preferable, 0.001 to 15 mass% is more preferable, and 0.005 to 10 mass% is particularly preferable.

[(D): Higher alcohol]
In order to further improve the transdermal absorbability of the component (A), the external preparation of the present invention can further contain a higher alcohol of the component (D). Although it does not specifically limit as a higher alcohol, C8-C22 saturated or unsaturated aliphatic alcohol can be mentioned. Specifically, for example, octyl alcohol, nonyl alcohol, decyl alcohol, isodecyl alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, isostearyl Examples include linear or branched saturated or unsaturated compounds such as alcohol, oleyl alcohol, linoleyl alcohol, nonadecyl alcohol, eicosyl alcohol, and behenyl alcohol.

  In the present invention, a saturated or unsaturated aliphatic alcohol having 8 to 20 carbon atoms, particularly 8 to 18 carbon atoms, is more preferable. Of these, octyl alcohol, nonyl alcohol, decyl alcohol, isodecyl alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, isostearyl alcohol, oleyl alcohol, linoleyl alcohol and the like are particularly preferable.

  In the external preparation of the present invention, the higher alcohol of component (D) can be used alone or in combination of two or more, and the content thereof is not particularly limited, but is 0.0001 to 30% by mass. Is preferable, 0.001 to 20 mass% is more preferable, and 0.005 to 15 mass% is particularly preferable.

[Dosage form, additive]
Although the dosage form of the external preparation of the present invention is not particularly limited, for example, liquid, gel, ointment, cream, gel cream, poultice, patch, liniment, lotion, transdermal Examples thereof include those described in the General Formulation of the 15th revision Japanese Pharmacopoeia, such as absorption preparations and aerosols, and these can be produced by known methods. In production, in addition to the essential components of the present invention, additives such as a pH adjuster, an antioxidant, a surfactant, an ultraviolet absorber, and a transdermal absorption accelerator may be added.

  Examples of transdermal absorption enhancers include caprylic acid, capric acid, caproic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid and the like; and hexyl laurate; , Isopropyl myristate, cetyl myristate, isocetyl myristate, myristyl myristate, octyldodecyl myristate, isopropyl palmitate, ethyl hexyl palmitate, cetyl palmitate, ethyl stearate, isocetyl stearate, stearyl stearate, ethyl isostearate, Isopropyl isostearate, hexyldecyl isostearate, isostearyl isostearate, ethyl oleate, decyl oleate, oleyl oleate, ethyl linoleate, Fatty acid esters of isopropyl Nord acid and the like.

  In the external preparation of the present invention, as the component (A), a non-steroidal analgesic / anti-inflammatory agent having a carboxy group in the chemical structure (for example, acemetacin, ampenac sodium, ibuprofen, indomethacin, indomethacin farnesyl, etodolac, ketoprofen, zaltoprofen Menthol and / or essential oil containing diclofenac sodium, sulindac, thiaprofenic acid, piroxicam, felbinac, pranoprofen, flurbiprofen, flurbiprofen axetil, mefenamic acid, loxoprofen sodium, etc.) When contained, menthol ester is generated by the reaction of the carboxy group in the non-steroidal analgesic / anti-inflammatory agent with menthol, and the content of non-steroidal analgesic / anti-inflammatory agent in the external preparation decreases. It is known problem that. Therefore, fatty acid metal salts such as zinc undecylate, zinc stearate, aluminum stearate, calcium stearate, magnesium stearate, sodium stearate, zinc palmitate, zinc myristate, magnesium myristate, zinc laurate, sodium laurate Add metal oxides such as zinc oxide, calcium oxide, titanium oxide and magnesium oxide, or add metal hydroxides such as aluminum hydroxide, potassium hydroxide, calcium hydroxide and sodium hydroxide. May be.

  In addition, when the external preparation of the present invention contains a terpene such as menthol or an essential oil containing the same, triethylene glycol may be further blended from the viewpoint of skin permeability of the component (A).

  In addition, when the non-steroidal analgesic / anti-inflammatory agent of component (A) is ampenac sodium, one or two selected from magnesium oxide, magnesium carbonate and calcium carbonate from the viewpoint of improving the temporal stability of ampenac sodium It is preferable to blend more than one species.

[Eating agent]
The case where the dosage form is a cataplasm will be described. The poultice has a structure in which a support, a poultice base, and a release liner are laminated in this order, and the essential component of the present invention is contained in the poultice base layer. As the support, known materials may be used, and are not particularly limited. Examples thereof include nonwoven fabrics such as polyethylene, polypropylene, polyester, nylon, and rayon, and knitted fabrics.

  The poultice base may be a known base and is not particularly limited. For example, polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, N-vinylacetamide / sodium acrylate Polymer, polyvinyl alcohol, polyvinylpyrrolidone, hydroxymethylcellulose, sodium carboxymethylcellulose, alginic acid, sodium alginate, gelatin, gum arabic and the like, and these metal salts such as aluminum, zinc, magnesium and calcium Cross-linked with In addition to the essential components of the present invention, additives such as fillers such as kaolin, talc and titanium oxide, and percutaneous absorption accelerators may be added to the poultice base layer. When the non-steroidal analgesic / anti-inflammatory agent of component (A) is amphenac sodium, it is unstable under acidic conditions, so it is preferable to adjust the pH of the poultice base layer to 6.5-8.

  The release liner may be a known one, and is not particularly limited, and examples thereof include films of polyester, polyethylene, polypropylene, ethylene / vinyl acetate copolymer, cellophane, and the like.

  The poultice agent is based on a known method, and the palp base layer produced by adding the essential components of the present invention and, if desired, additives is spread on a support or release liner, and the release liner or support is bonded together. Can be manufactured.

  The ratio of the poultice base layer in the cataplasm of the present invention is preferably 50 to 99% by mass, more preferably 60 to 99% by mass, and particularly preferably 70 to 95% by mass with respect to the total amount of the cataplasm.

  The preferred contents of component (A), component (B), desired component (C) and desired component (D) in the poultice base layer are as described above, and the poultice base in the poultice base layer 1-60 mass% is preferable, as for content of an agent, 10-50 mass% is more preferable, and 20-40 mass% is especially preferable.

[Patch]
Next, the case where the dosage form is a patch will be described. The patch has a structure in which a support, a pressure-sensitive adhesive layer, and a release liner are laminated in this order, and the essential component of the present invention is contained in the pressure-sensitive adhesive layer. The support may be a known one, and is not particularly limited, but is not limited to paper, cloth, nonwoven fabric, polyester, polyethylene, polypropylene, polybutadiene, polyurethane, polyvinyl acetate, nylon, polyvinylidene chloride, etc. A single layer film or a laminate of these materials can be used.

  The pressure-sensitive adhesive may be a known one, and is not particularly limited. Examples thereof include acrylic pressure-sensitive adhesives, synthetic rubber-based pressure-sensitive adhesives, and natural rubber-based pressure-sensitive adhesives. Two or more kinds can be used in combination. These may be emulsified.

  Acrylic adhesives include acrylic acid, sodium acrylate, methacrylic acid, acrylic acid methyl ester, acrylic acid ethyl ester, acrylic acid butyl ester, acrylic acid octyl ester, acrylic acid isononyl ester, acrylic acid 2-ethylhexyl ester , Methacrylic acid methyl ester, methacrylic acid butyl ester, methacrylic acid 2-ethylhexyl ester, methacrylic acid hydroxyethyl ester, methacrylic acid dodecyl ester and the like, and polymers containing two or more of these as a monomer Copolymer of (meth) acrylic acid alkyl ester and vinyl compound such as vinyl acetate, vinyl propionate, styrene, N-vinyl-2-pyrrolidone ((meth) acrylic acid alkyl ester-vinyl Compound copolymer) and the like. These can be used alone or in combination of two or more. Specifically, acrylic acid / octyl acrylate ester copolymer, acrylic ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / vinyl pyrrolidone copolymer solution, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate・ Dodecyl methacrylate copolymer solution, ethyl acrylate / methyl methacrylate copolymer dispersion, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, acrylic resin alkanolamine solution, methacrylic acid / n-butyl acrylate copolymer , Silk fibroin acrylate copolymer resin, Starch acrylate 300, Starch acrylate 1000, Butyl acrylate / 2-ethylhexyl methacrylate / diacetone acrylamide copolymer, Butyl acrylate / 2-hydroxyethyl methacrylate / Acetone acrylamide copolymer, butyl acrylate, ethyl acrylate, 2-hydroxyethyl methacrylate, diacetone acrylamide copolymer, butyl acrylate, 2-ethylhexyl acrylate, 2-hydroxyethyl methacrylate, diacetone acrylamide copolymer Polymer, isononyl acrylate, 2-hydroxyethyl methacrylate, diacetone acrylamide copolymer, 2-ethylhexyl acrylate, 2-hydroxyethyl methacrylate, diacetone acrylamide copolymer, butyl acrylate, ethyl acrylate, methacrylic acid 3-hydroxypropyl / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, butyl acrylate / ethyl acrylate / 3-hydroxypropyl methacrylate / diacetone acrylamide copolymer, etc. It is below. In addition, when the non-steroidal analgesic / anti-inflammatory agent is ampenac sodium, the acrylic adhesive is a copolymer containing diacetone acrylamide as a monomer in terms of the stability and drug release of ampenac sodium. Is preferably used.

  Synthetic rubber adhesives include cis-isoprene rubber, styrene-isoprene rubber, cis-polyisoprene rubber, high-cis-polyisoprene rubber, styrene-butadiene rubber, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer. , Polyisoprene, polyisobutylene, chloroprene rubber, polybutene, natural rubber latex, SBR synthetic latex and the like. These can be used alone or in combination of two or more.

  In the pressure-sensitive adhesive layer, in addition to the essential components of the present invention, a plasticizer, a tackifier resin, a filler, an ultraviolet absorber, a transdermal absorption accelerator, a water-soluble / water-swellable polymer, etc. Additives may be added.

  Plasticizers include liquid paraffin, light liquid paraffin, cetyl octanoate, hexyl laurate, isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, butyl stearate, myristyl lactate, dioctyl adipate, diethyl sebacate, sebacate Diisopropyl, dioctyl sebacate, diisopropyl adipate, dioctyl succinate, octyldodecanol, hexyl decanol, almond oil, olive oil, camellia oil, castor oil, peanut oil, mint oil, l-menthol, diethylene glycol, propylene glycol, dipropylene glycol, Examples include polyethylene glycol, polypropylene glycol, triacetin, triethyl citrate, and the like. These may be used alone or in combination of two or more. It is possible to use Te Align.

  Examples of tackifying resins include rosin, hydrogenated rosin glycerin ester, ester gum, maleated rosin glycerin ester, terpene resin, petroleum resin, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, and the like. Or two or more types can be used in combination.

  Examples of the filler include zinc oxide, aluminum oxide, titanium dioxide, magnesium oxide, iron oxide, zinc stearate, calcium carbonate, silica and the like, and these can be used alone or in combination of two or more.

  Water-soluble and water-swellable polymers include carboxyvinyl polymer, polyvinyl alcohol (completely saponified product), polyvinyl alcohol (partially saponified product), povidone, methylcellulose, hydroxyethylcellulose, carboxymethylethylcellulose, carmellose, carmellose potassium, carme Examples include roast calcium, carmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium alginate, propylene glycol alginate, sodium carboxymethyl starch, xanthan gum, dextran, dextrin, and these are used alone or in combination of two or more. can do.

  The release liner may be a known one and is not particularly limited, and examples thereof include films of polyester, polyethylene, polypropylene, ethylene / vinyl acetate copolymer, cellophane, and the like.

  The patch can be produced based on a known method (solvent method, hot melt method, emulsion method, etc.). For example, the essential components of the present invention, pressure-sensitive adhesive layer components and, if necessary, additives are immersed in a suitable organic solvent, stirred and dispersed evenly to produce a paste liquid, and this is used as a support or a release liner. It can be produced by spreading, volatilizing and drying the solvent, and bonding the release liner or the support. Moreover, after a pressure-sensitive adhesive layer component is spread and applied to a support or a release liner by a spreader, it can be produced by bonding the release liner or the support.

  When the non-steroidal analgesic / anti-inflammatory agent of component (A) is in a salt form such as ampenac sodium, citric acid, succinic acid, tartaric acid, maleic acid, Carboxylic acids such as fumaric acid, salicylic acid and acetic acid may be further blended.

  When the non-steroidal analgesic / anti-inflammatory agent of component (A) is amphenac sodium, this is unstable under acidic conditions, so when making a patch using the emulsion method, a pressure-sensitive adhesive layer When producing the product, it is preferable to adjust the pH to 6.5 to 8 in the production process.

  Moreover, when using an acrylic adhesive as a pressure-sensitive adhesive, it is preferable to add magnesium oxide in an adhesive layer from the point of the time-dependent stability improvement of anfenac sodium. In this case, the amount of magnesium oxide may be equal to or less than the equivalent of ampenac sodium.

  The ratio of the pressure-sensitive adhesive layer in the patch of the present invention is not particularly limited, but is preferably 1 to 70% by mass, more preferably 10 to 60% by mass, and more preferably 25 to 25% with respect to the total amount of the patch. 50% by weight is particularly preferred.

  The preferred contents of component (A), component (B), desired component (C) and desired component (D) in the pressure-sensitive adhesive layer are as described above, and the pressure-sensitive adhesive in the pressure-sensitive adhesive layer The content of the agent is preferably 50 to 99% by mass, more preferably 60 to 95% by mass, and particularly preferably 70 to 90% by mass.

[Liquid]
When the dosage form of the external preparation of the present invention is, for example, a liquid, it may be prepared using a solvent that can be used as an external liquid based on a known method. Examples of the solvent include, but are not limited to, lower alcohols such as methanol, ethanol, propanol, and isopropanol, polyhydric alcohols such as ethylene glycol, propylene glycol, isopropylene glycol, and 1,3-butylene glycol, and water. To one or more selected from the above, the essential components of the present invention are added as appropriate with additives such as pH adjusters, antioxidants, surfactants, ultraviolet absorbers and percutaneous absorption accelerators as desired. It can be manufactured by dissolving. When the non-steroidal analgesic / anti-inflammatory agent is amphenac sodium, it is unstable under acidic conditions, so the pH of the solution is preferably adjusted to 6.5-8.

[Ratio of each component]
In the external preparation of the present invention, the content of each of the components (A) to (D) is as described above, but as the relationship between the contents of each component, within the above-described content range, the following ratios: It is preferable that

That is, the ratio of the content of component (B) to 1 part by mass of component (A) is preferably 0.01 to 20 parts by mass, more preferably 0.1 to 15 parts by mass, and particularly preferably 1 to 11 parts by mass.
The ratio of the content of the desired component (C) to the content of 1 part by mass of the component (A) is preferably 0.01 to 10 parts by mass, more preferably 0.1 to 8 parts by mass, and particularly preferably 0.25 to 5 parts by mass. .
Moreover, the ratio of the content of the desired component (D) to 1 part by mass of the component (A) is preferably 0.01 to 20 parts by mass, more preferably 0.1 to 15 parts by mass, and particularly preferably 0.25 to 10 parts by mass. .

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention should not be limited by these examples.

Example 1 Patch Styrene / isoprene / styrene block copolymer (Clayton D-1161JP: Kraton Polymer Japan Co., Ltd.) 30.0 g, Terpene resin (YS resin PX1150N: Yasuhara Chemicals Co., Ltd.) 24.0 g, Polybutene (Nisseki) After mixing 20.0 g of polybutene HV-300F: Shin Nippon Oil Co., Ltd. and 15.0 g of light liquid paraffin (CARNATION, J72: ExxonMobil), it was dissolved at 150 ° C. to obtain an adhesive phase.
Add 1.0 g of amphenac sodium to 10 g of polyoxyethylene (2) lauryl ether (NIKKOL BL-2: Nippon Surfactant Kogyo Co., Ltd.), and after confirming dissolution, add the adhesive phase prepared earlier and mix well. Got.
This drug solution is spread on a PET film that has been treated with silicone using a plaster manufacturing device, and laminated with a support (knitted fabric: TV-105: Nihon Vileen Co., Ltd.) before the plaster is cooled, and 1% by mass of ampenac sodium A combined patch was obtained.

Example 2 Patch The same procedure as in Example 1 was repeated except that polyoxyethylene (2) lauryl ether was changed to polyoxyethylene (4.2) lauryl ether (NIKKOL BL-4.2: Nippon Surfactant Co., Ltd.). A patch containing 1% by mass of Enac sodium was obtained.

Example 3 Patch In the same manner as in Example 1 except that polyoxyethylene (2) lauryl ether was changed to polyoxyethylene (3) decyl ether (Finesurf EL-1303: Aoki Yushi Kogyo Co., Ltd.) A patch containing 1% by mass of amfenac sodium was obtained.

Example 4 Patch The same procedure as in Example 1 was repeated except that polyoxyethylene (2) lauryl ether was changed to polyoxyethylene (2) oleyl ether (NIKKOL BO-2V: Nippon Surfactant Kogyo Co., Ltd.). A patch containing 1% by mass of Enac sodium was obtained.

Comparative Example 1 Patch A patch containing 1% by mass of amfenac sodium was used in the same manner as in Example 1 except that polyoxyethylene (2) lauryl ether was changed to propylene glycol (propylene glycol: Showa Denko KK). Obtained.

Comparative Example 2 Patch In the same manner as in Example 1 except that polyoxyethylene (2) lauryl ether was changed to triethylene glycol (triethylene glycol: Maruzen Petrochemical Co., Ltd.), 1% by mass of amphenac sodium was added. A patch was obtained.

Comparative Example 3 Patch Anfenac sodium 1 in the same manner as in Example 1 except that the polyoxyethylene (2) lauryl ether was changed to N-methyl-2-pyrrolidone (Pharmasolve: IS Japan Co., Ltd.). A patch containing a mass percent was obtained.

Comparative Example 4 Patch Amphenac sodium as in Example 1 except that polyoxyethylene (2) lauryl ether was changed to polyethylene glycol monolaurate (EO10) (MYL-10: Nippon Surfactant Kogyo Co., Ltd.) A patch of 1% by mass was obtained.

Comparative Example 5 Patch Styrene / isoprene / styrene block copolymer (Clayton D-1161JP: Kraton Polymer Japan Co., Ltd.) 30.0 g, Terpene resin (YS Resin PX1150N: Yasuhara Chemicals Co., Ltd.) 24.0 g, Polybutene (Nisseki) After mixing 20.0 g of polybutene HV-300F: Shin Nippon Oil Co., Ltd. and 23.75 g of light liquid paraffin (CARNATION, J72: Exxon Mobil), the mixture was dissolved at 150 ° C. to obtain an adhesive phase.
1.0 g of amphenac sodium was added to 1.25 g of propylene glycol (propylene glycol: Showa Denko KK), and after confirming dissolution, the previously prepared adhesive phase was added and mixed well to obtain a chemical solution.
This drug solution is spread on a PET film that has been treated with silicone using a plaster manufacturing device, and laminated with a support (knitted fabric: TV-105: Nihon Vileen Co., Ltd.) before the plaster is cooled, and 1% by mass of ampenac sodium A combined patch was obtained.

Comparative Example 6 Patch Styrene / isoprene / styrene block copolymer (Clayton D-1161JP: Clayton Polymer Japan Co., Ltd.) 30.0 g, Terpene resin (YS Resin PX1150N: Yasuhara Chemicals Co., Ltd.) 24.0 g, Polybutene (Nisseki) After mixing 20.0 g of polybutene HV-300F: Shin Nippon Oil Co., Ltd. and 23.4 g of light liquid paraffin (CARNATION, J72: ExxonMobil), it was dissolved at 150 ° C. to obtain an adhesive phase.
1.0 g of amphenac sodium was added to 1.6 g of triethylene glycol (triethylene glycol: Maruzen Petrochemical Co., Ltd.), and after confirming dissolution, the previously prepared adhesive phase was added and mixed well to obtain a chemical solution.
This drug solution is spread on a PET film that has been treated with silicone using a plaster production device. Before the plaster is cooled, it is laminated with a support (knitted fabric: TV-105: Nippon Vilene Co., Ltd.) and 1% by weight of ampenac sodium is added. A patch was obtained.

Example 5 Patch Styrene / isoprene / styrene block copolymer (Clayton D-1161JP: Clayton Polymer Japan Co., Ltd.) 30.0 g, Terpene resin (YS resin PX1150N: Yasuhara Chemicals Co., Ltd.) 24.0 g, Polybutene (Nisseki) After mixing 20.0 g of polybutene HV-300F: Shin Nippon Oil Co., Ltd. and 15.0 g of light liquid paraffin (CARNATION, J72: ExxonMobil), it was dissolved at 150 ° C. to obtain an adhesive phase.
After adding 1.0 g of amphenac sodium and 1.0 g of mint oil (PEPPERMINT OIL: Toyoda Flavor Co., Ltd.) to 10 g of polyoxyethylene (2) lauryl ether (NIKKOL BL-2: Nippon Surfactant Co., Ltd.) The previously prepared adhesive phase was added and mixed well to obtain a chemical solution.
This drug solution is spread on a PET film that has been treated with silicone using a plaster production device. Before the plaster is cooled, it is laminated with a support (knitted fabric: TV-105: Nippon Vilene Co., Ltd.) and 1% by weight of ampenac sodium is added. A patch was obtained.

Example 6 Patch Styrene / isoprene / styrene block copolymer (Clayton D-1161JP: Kraton Polymer Japan Co., Ltd.) 30.0 g, Terpene resin (YS resin PX1150N: Yasuhara Chemicals Co., Ltd.) 24.0 g, Polybutene (Nisseki) After mixing 20.0 g of polybutene HV-300F: Shin Nippon Oil Co., Ltd. and 6.0 g of light liquid paraffin (CARNATION, J72: ExxonMobil), it was dissolved at 150 ° C. to obtain an adhesive phase.
Add 1.0 g of amphenac sodium to 10 g of polyoxyethylene (2) lauryl ether (NIKKOL BL-2: Nippon Surfactant Kogyo Co., Ltd.), and after confirming dissolution, oleyl alcohol (NOVOL J: Croda Japan Co., Ltd.) 5.0 g and l-menthol (L-menthol: Takasago International Corporation) were added and dissolved. This solution was mixed with the previously prepared pressure-sensitive adhesive phase to obtain a chemical solution.
This drug solution is spread on a PET film that has been treated with silicone using a plaster production device. Before the plaster is cooled, it is laminated with a support (knitted fabric: TV-105: Nippon Vilene Co., Ltd.) and 1% by weight of ampenac sodium is added. A patch was obtained.

Example 7 Patch A patch containing 1% by mass of amfenac sodium was obtained in the same manner as in Example 5 except that mint oil was changed to isopropyl myristate (NIKKOL IPM-EX: Nikko Chemicals Co., Ltd.).

Example 8 Patch A patch containing 1% by mass of amfenac sodium was obtained in the same manner as in Example 5 except that mint oil was changed to oleyl oleate (CRODAMOL OO-V: Croda Japan Co., Ltd.).

Example 9 Patch Styrene / isoprene / styrene block copolymer (Clayton D-1161JP: Kraton Polymer Japan Co., Ltd.) 30.0 g, Terpene resin (YS resin PX1150N: Yasuhara Chemicals Co., Ltd.) 24.0 g, Polybutene (Nisseki) After mixing 20.0 g of polybutene HV-300F: Shin Nippon Oil Co., Ltd. and 11.0 g of light liquid paraffin (CARNATION, J72: Exxon Mobil), the mixture was dissolved at 150 ° C. to obtain an adhesive phase.
Add 1.0 g of amphenac sodium and 4.0 g of l-menthol (L-menthol: Takasago International Corporation) to 10 g of polyoxyethylene (2) lauryl ether (NIKKOL BL-2: Nippon Surfactant Industries) and dissolve. After confirming, the previously prepared pressure-sensitive adhesive phase was added and mixed well to obtain a chemical solution.
This drug solution is spread on a PET film that has been treated with silicone using a plaster production device. Before the plaster is cooled, it is laminated with a support (knitted fabric: TV-105: Nippon Vilene Co., Ltd.) and 1% by weight of ampenac sodium is added. A patch was obtained.

Example 10 Patch A patch containing 1% by mass of ampenac was obtained in the same manner as in Example 6 except that oleyl alcohol was changed to decyl oleate (Cetiol V: Cognis Japan Co., Ltd.).

Example 11 Patch A patch containing 1% by mass of ampenac was obtained in the same manner as in Example 6 except that oleyl alcohol was changed to oleyl oleate (CRODAMOL OO-V: Croda Japan Co., Ltd.).

Example 12 Patch Styrene / isoprene / styrene block copolymer (Clayton D-1161JP: Kraton Polymer Japan Co., Ltd.) 30.0 g, terpene resin (YS resin PX1150N: Yasuhara Chemicals Co., Ltd.) 24.0 g, polybutene (Nisseki) After mixing 20.0 g of polybutene HV-300F: Shin Nippon Oil Co., Ltd. and 10.0 g of light liquid paraffin (CARNATION, J72: Exxon Mobil), the mixture was dissolved at 150 ° C. to obtain an adhesive phase.
Add 1.0 g of amphenac sodium to 10 g of polyoxyethylene (2) lauryl ether (NIKKOL BL-2: Nippon Surfactant Kogyo Co., Ltd.), and after confirming dissolution, oleyl alcohol (NOVOL J: Croda Japan Co., Ltd.) 5.0 g was added and dissolved. This solution was mixed with the previously prepared pressure-sensitive adhesive phase to obtain a chemical solution.
This drug solution is spread on a PET film that has been treated with silicone using a plaster production device. Before the plaster is cooled, it is laminated with a support (knitted fabric: TV-105: Nippon Vilene Co., Ltd.) and 1% by weight of ampenac sodium is added. A patch was obtained.

Test example 1
The transdermal absorbability of the patches prepared in Comparative Examples 1 to 6 and Examples 1 to 12 was measured by the following method.
The patch was used as a donor, and Macrogol 400 / physiological saline (5/5) + sodium dodecyl sulfate 0.01% solution was used as a receptor solution. As the permeable membrane, the abdominal excised skin of a Wistar rat (male, 8 weeks old) was used. In the permeation part of the vertical diffusion cell (Frantz cell), the keratinous surface of the skin was fixed with the donor side, one patch (2 cmΦ) was filled on the donor side, and 31 mL of the receptor solution was filled on the receptor side. A permeation experiment was conducted while maintaining the vertical diffusion cell at 32 ° C. Steel ball No. 3 (7 pieces: 7.3 g) was placed as a weight to prevent the exfoliation of the preparation during the experiment. Further, the sampling port was covered with a film (PARAFILM; manufactured by American National Can) for the purpose of preventing evaporation of moisture and the like during the experiment.
2, 4, 6, and 8 hours after the start, 1 mL of the receptor solution was sampled from the sampling port, and the drug concentration in the receptor solution was quantified by HPLC using an ODS column. From the measured value, the amount of drug permeation (μg / cm ² ) per unit area was calculated. Further, the transmission coefficient (cm / h) was calculated from the following formula from the measured values after 4 to 8 hours. The results are shown in Table 1.

(Permeability coefficient) = slope (measured value after 4 to 8 hours) / (ampenac sodium concentration in the preparation)

Test example 2
The appearance of the patches obtained in Comparative Examples 1 to 6 and Examples 1 to 12 was evaluated. The appearance was evaluated visually for the color tone of the plaster immediately after production. The results are shown in Table 1.

  As is apparent from Table 1, it was found that the external preparation of the present invention greatly improved the skin permeability of the non-steroidal analgesic / anti-inflammatory agent and has an excellent aesthetic appearance.

Production Example 1 Patch Styrene / isoprene / styrene block copolymer (Clayton D-1161JP: Clayton Polymer Japan Co., Ltd.) 30.0 g, Terpene resin (YS resin PX1150N: Yasuhara Chemicals Co., Ltd.) 24.0 g, Polybutene (Nisseki) After mixing 3.0 g of polybutene HV-300F: Shin Nippon Oil Co., Ltd. and 15.0 g of light liquid paraffin (CARNATION, J72: ExxonMobil), the mixture was dissolved at 150 ° C. to obtain an adhesive phase.
Add 1.0 g of amphenac sodium to 10 g of polyoxyethylene (2) lauryl ether (NIKKOL BL-2: Nippon Surfactant Kogyo Co., Ltd.), and after confirming dissolution, oleyl alcohol (NOVOL J: Croda Japan Co., Ltd.) 5.0 g And 4.0 g of l-menthol (L-menthol: Takasago International Corporation) was added and dissolved. Thereafter, 3.0 g of polyvinyl alcohol (partially saponified product) (Kuraray Poval 217S: Kuraray Co., Ltd.) was further added and dispersed, and then the previously prepared adhesive phase was added and mixed well to obtain a chemical solution.
This drug solution is spread on a PET film that has been treated with silicone using a plaster manufacturing device, and laminated with a support (knitted fabric: TV-105: Nihon Vileen Co., Ltd.) before the plaster is cooled, and 1% by mass of ampenac sodium A combined patch was obtained.

Production Example 2 Patch A patch containing 1% by mass of amphenac sodium in the same manner as in Production Example 1 except that polyvinyl alcohol (partially saponified product) was changed to hydroxypropylcellulose (HPC-SSL: Nippon Soda Co., Ltd.). Got.

Production Example 3 Patch Styrene / isoprene / styrene block copolymer (Clayton D-1161JP: Clayton Polymer Japan Co., Ltd.) 30.0 g, Terpene resin (YS resin PX1150N: Yasuhara Chemicals Co., Ltd.) 24.0 g, Polybutene (Nisseki) After mixing 20.0 g of polybutene HV-300F: Shin Nippon Oil Co., Ltd. and 3.0 g of light liquid paraffin (CARNATION, J72: Exxon Mobil), it was dissolved at 150 ° C. to obtain an adhesive phase.
Add 4.0 g of amphenac sodium to 10.0 g of polyoxyethylene (2) lauryl ether (NIKKOL BL-2: Nippon Surfactant Kogyo Co., Ltd.). After confirming dissolution, oleyl alcohol (NOVOL J: Croda Japan Co., Ltd.) 5.0 g and l-menthol (L-menthol: Takasago International Corporation) were added and dissolved. The previously prepared adhesive phase was added to this solution and mixed well to obtain a chemical solution.
This drug solution is spread on a PET film that has been treated with silicone using a plaster production device, and laminated with a support (knitted fabric: TV-105: Nihon Vileen Co., Ltd.) before the plaster cools down. A patch was obtained.

Production Example 4 Patch Methyl acrylate / -2-ethylhexyl acrylate copolymer resin emulsion (Nicazole TS-620: Nippon Carbide Industries Co., Ltd.) Adjusted to pH 8.0 by adding a trace amount of sodium hydroxide to 89.0 g equivalent of solid content Thus, an adhesive phase was obtained.
Add 4.0 g of amphenac sodium to 10.0 g of polyoxyethylene (2) lauryl ether (NIKKOL BL-2: Nihon Surfactant Kogyo Co., Ltd.). After confirming dissolution, add the adhesive phase prepared earlier and mix well. A chemical was obtained.
This drug solution is spread and dried on a silicone-treated PET film using a plaster production device, and then laminated with a support (knitted fabric: TV-105: Nippon Vilene Co., Ltd.) to obtain a patch containing 1% by mass of ampenac sodium. It was.

Production Example 5 Patch Methyl acrylate / -2-ethylhexyl acrylate copolymer resin emulsion (Nicazole TS-620: Nippon Carbide Industry Co., Ltd.) Adjust the pH to 8.0 by adding a small amount of sodium hydroxide to 80.0 g equivalent of solid content. Thus, an adhesive phase was obtained.
Add 4.0 g of amphenac sodium to 10.0 g of polyoxyethylene (2) lauryl ether (NIKKOL BL-2: Nippon Surfactant Kogyo Co., Ltd.). After confirming dissolution, oleyl alcohol (NOVOL J: Croda Japan Co., Ltd.) 5.0 g and l-menthol (L-menthol: Takasago International Corporation) were added and dissolved. The previously prepared adhesive phase was added to this solution and mixed well to obtain a chemical solution.
This drug solution is spread and dried on a silicone-treated PET film using a plaster production device, and then laminated with a support (knitted fabric: TV-105: Nippon Vilene Co., Ltd.) to obtain a patch containing 1% by mass of ampenac sodium. It was.

Production Example 6 Patch Methyl acrylate / -2-ethylhexyl acrylate copolymer resin emulsion (Nicazole TS-620: Nippon Carbide Industries Co., Ltd.) Adjusted to pH 8.0 by adding a small amount of sodium hydroxide to 77.0 g solids did. To this solution, 3.0 g of polyvinyl alcohol (partially saponified product) (Kuraray Poval 217S: Kuraray Co., Ltd.) was added and dissolved to obtain an adhesive phase.
Add 4.0 g of amphenac sodium to 10.0 g of polyoxyethylene (2) lauryl ether (NIKKOL BL-2: Nippon Surfactant Kogyo Co., Ltd.). After confirming dissolution, oleyl alcohol (NOVOL J: Croda Japan Co., Ltd.) 5.0 g and l-menthol (L-menthol: Takasago International Corporation) were added and dissolved. The previously prepared adhesive phase was added to this solution and mixed well to obtain a chemical solution.
This drug solution is spread and dried on a silicone-treated PET film using a plaster production device, and then laminated with a support (knitted fabric: TV-105: Nippon Vilene Co., Ltd.) to obtain a patch containing 1% by mass of ampenac sodium. It was.

Production Example 7 Patch A patch containing 1% by mass of amfenac sodium was prepared in the same manner as in Production Example 6 except that polyvinyl alcohol (partially saponified product) was changed to hydroxypropylcellulose (HPC-SSL: Nippon Soda Co., Ltd.). Got.

Claims (12)

An external preparation containing the following components (A) and (B).
(A) Non-steroidal analgesic / anti-inflammatory agent
(B) Polyoxyalkylene alkyl ether and / or polyoxyalkylene alkenyl ether (B) Polyoxyalkylene alkyl ether and polyoxyalkylene alkenyl ether are represented by the formula (1)
R—X—O— (AO) _n —H (1)
[In the formula, R represents an alkyl group having 1 to 22 carbon atoms or an alkenyl group having 2 to 22 carbon atoms, X represents a single bond or a phenylene group, A represents an ethylene group or a propylene group, and n represents 2 to 2. An average added mole number of 50 is shown. n A may be any one of ethylene group and propylene group, or a combination thereof. ]
The external preparation according to claim 1, which is represented by:   The external preparation according to claim 2, wherein n in the formula (1) is 2 to 5. Furthermore, the external preparation in any one of Claims 1-3 containing the following component (C).
(C) Terpenes and / or essential oils containing terpenes   (C) terpene is isoborneol, iron, osimene, carveol, carbotanaceton, carbomenton, carvone, caren, caron, camphene, camphor, geraniol, cymen, sabinene, safranal, cyclocitral, citral, citronellal, citronellal, citronellol Cineole, sylvestrene, twill alcohol, thuyon, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinoccampheol, pinol, piperithenone, ferrandral, ferrandrane, fenchen, fentil alcohol, perillyl alcohol, perillyl Selected from the group consisting of aldehyde, borneol, myrcene, menthol, menthone, yonor, yonon, linalool and limonene The external preparation according to claim 4, wherein that.   (C) An essential oil containing terpene is anise oil, ylang ylang oil, iris oil, fennel oil, orange oil, cananga oil, chamomile oil, kayap oil, caraway oil, kubeb oil, grapefruit oil, cinnamon oil, coriander oil, saffron Oil, salamander, perilla oil, citriodora oil, citronella oil, ginger oil, gingergrass oil, gingergrass oil, spearmint oil, mint oil, geranium oil, geranium oil, clove oil, turpentine oil, spruce oil , Neroli oil, basil oil, peppermint oil, palmarosa oil, pimento oil, petitgren oil, bay oil, peniroyal oil, henoposi oil, bergamot oil, bored rose oil, pepper oil, marjolan oil, mandarin oil, melissa oil, eucalyptus oil, lime Oil, lavender oil, linaloe oil, lemon oil, Mongurasu oil, rose oil, external preparation according to claim 4, wherein those selected from the group consisting of rosemary oil and chamomile oil. Furthermore, the external preparation in any one of Claims 1-3 containing the following component (D).
(D) Higher alcohol   The external preparation according to claim 7, wherein (D) the higher alcohol is a saturated or unsaturated aliphatic alcohol having 8 to 22 carbon atoms.   (D) Higher alcohol is octyl alcohol, nonyl alcohol, decyl alcohol, isodecyl alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, isostearyl The external preparation according to claim 7, which is selected from the group consisting of alcohol, oleyl alcohol, linoleyl alcohol, nonadecyl alcohol, eicosyl alcohol, and behenyl alcohol.   (A) Non-steroidal analgesic / anti-inflammatory drugs are actarit, acemetacin, ampiroxicam, ampenac, ibuprofen, indomethacin, etodolac, ketoprofen, zaltoprofen, diclofenac, sulindac, celecoxib, thiaprofenic acid, tenoxicam, naproxen, piroxicam The profen, flurbiprofen, mefenamic acid, medoxixib, meloxicam, mofezolac, lefecoxib, loxoprofen, robenzalit, lornoxicam, and salts thereof are selected from any one of claims 1 to 9. Topical agent.   The external preparation according to any one of claims 1 to 10, wherein (A) the nonsteroidal analgesic / anti-inflammatory agent is ampenac or a salt thereof.   The dosage form is a liquid preparation for external use, a gel, an ointment, a cream, a gel cream, a patch, a patch, a liniment, a lotion, a transdermal preparation, or an aerosol. Item 1. An external preparation according to item 1.