JPH11199521A - Preparation for external use for skin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a preparation for external use for skin which gives reduced irritation to the skin, gives an enhanced warm sense, and has an excellent sustainability of the warm sense, improved percutaneous absorption of a non- steroidal antiinflammatory agent as an active ingredient, and excellent sustainability, by including both a warm sense-giving substance and at least too percutaneous absorption-enhancing agents. SOLUTION: This preparation is obtained by including (A) a non-steroidal antiinflammatory agent (preferably, felbinac or the like), (B) a warm sense-giving substance (preferably. combination of capsicoside and other substance(s) from red pepper at 0.0001-5 wt.%, and (C) at least two percutaneous absorption- enhancing agents, as a sum, at 0.1-10 wt.% per the final preparation for external use. Component C includes pyrrolidone, higher alcohol, and non-ionic surfactant. It is preferable to use, as component C, a non-ionic surfactant having a HLB of 10-20 when a non-ionic surfactant is used together with other percutaneous absorption-enhancing agents because irritation to the skin is more reduced.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention not only improves the skin irritation at the time of application, but also enhances the applied warm feeling, further enhances the persistence of the warm feeling, and also improves the non-steroidal anti-inflammatory properties. The present invention relates to an external preparation for skin which has improved percutaneous absorbability of an inflammatory agent and is also excellent in sustainability.

[0002]

2. Description of the Related Art Conventionally, a skin external preparation containing a nonsteroidal anti-inflammatory agent, which has been used as an anti-inflammatory and analgesic agent, has a cold feeling at the site of inflammation. It has been proposed to add a substance that gives a sense of warmth in order to eliminate the problem.

However, in order to maintain the warm sensation, it is necessary to incorporate a large amount of a warming substance. There was a possibility that a composition problem might occur. On the other hand, for skin external preparations containing non-steroidal anti-inflammatory agents, various technologies for improving the transdermal absorbability have been proposed, but at present, sufficient transdermal absorbability has not yet been obtained. It is.

[0004] The present invention has been made in view of the above circumstances,
The skin irritancy at the time of application is improved, the warm feeling by the warming substance is enhanced, and not only the persistence of the warm feeling is excellent, but also the percutaneous absorption of the nonsteroidal anti-inflammatory agent is improved,
It is still another object of the present invention to provide an external preparation for skin having excellent long-lasting properties.

[0005]

Means for Solving the Problems and Embodiments of the Invention As a result of intensive studies to achieve the above object, the present inventor has found that
The combined use of a warming substance and two or more transdermal absorption enhancers not only alleviates the skin irritation caused by the warming substance, but also enhances the warmth imparted and increases its durability. After finding that it could be improved,
By adding these in predetermined amounts to an external preparation for skin containing a non-steroidal anti-inflammatory drug, the percutaneous absorbability of the non-steroidal anti-inflammatory drug is significantly improved and a long-lasting effect is obtained. Having found this, the present invention has been accomplished.

Accordingly, the present invention comprises a non-steroidal anti-inflammatory agent, a warming agent and two or more transdermal absorption enhancers, and the compounding amount of the warming agent is And a total amount of the transdermal absorption enhancer is 0.1 to 10% by weight of the skin external preparation. here,
It is more preferable to combine two or more nonionic surfactants as the above-mentioned transdermal absorption enhancer and combine them so that the HLB value when they are mixed is 8 or more.

Hereinafter, the present invention will be described in more detail. The external preparation for skin of the present invention comprises a nonsteroidal anti-inflammatory agent, a warming agent and two or more transdermal absorption enhancers, It is prepared as a cream, a gel, a lotion, an ointment, and the like. By adding the above-mentioned warming-imparting substance, the sustainability of the warmth of the external preparation for skin is improved. Here, as the non-steroidal anti-inflammatory agent, the type thereof is not particularly limited as long as it can be added to a skin external preparation. For example, aspirin, azulene, acetaminophen, acemethacin, alclofenac, aluminoprofen , Ampiroxicam, ampfenac, isoxicam, isoxevac, ibfenac,
Ibuprofen, indosine, indoprofen, indomethacin, etodolac, emorphazone, oxaprozin, oxabrofen, oxicam, oxebinac,
Orsenone, orthophenamic acid, carprofen, clidanac, cliprofen, ketotifen, ketoprofen, ketorolac, zaltoprofen, diclofenac, cycloprofen, zidomethacin, diflunisal,
Isosorbide dinitrate, sudoxicam, suprofen, sulindac, zomevirac, thiaprofen, thioxaprofen, thiobinac, tenilac, tenoxicam, tramadol, tolmetin, tolfenamic acid, naproxen,
Niflumic acid, viruprofen, piroxicam, phenidone, fenoprofen, felbinac, fenclofenac, fentiazac, fenbufen, bucloxic acid, bufexamac, planoprofen, fluprofen, flufenamic acid, flufenisal, flurbiprofen, flurbi Profen axetil, flotafenin, protidic acid, flofenac, benoxaprofen, benolylate, bendazac, miloprofen, meclofenamic acid, mepyrizole, mefenamic acid, lisiffen, loxoprofen and salts thereof, and one of these alone. Alternatively, two or more kinds can be used in combination. In the case of the present invention, considering anti-inflammatory action, safety and the like, among these, flurbiprofen,
Felbinac, bufexamac, suprofen, ibuprofen, diclofenac sodium, piroxicam,
Indomethacin, zaltoprofen, mefenamic acid and the like are preferred, especially flurbiprofen, felbinac,
It is effective when it contains bufexamac, suprofen and the like.

The amount of the non-steroidal anti-inflammatory agent to be added to the whole skin external preparation of the present invention is not particularly limited, and can be appropriately selected depending on the dosage form of the skin external preparation, the purpose of use, and the like. 0.1 to 10% of total external preparation
(% By weight, hereinafter the same), more preferably 0.2 to 5%,
More preferably, it is 0.3 to 3%. If the amount of the non-steroidal anti-inflammatory agent is too small, sufficient drug efficacy may not be obtained, and if it is too large, side effects of skin irritation may occur.

The warming substance to be incorporated in the external preparation for skin of the present invention may be any substance that gives a warm feeling when applied to the skin. Examples of such warming substances include capsaicinoid, capsaicin, and capsaicin. Capsicin analogs such as dihydroxycapsaicin and capsanthin, capsicumside, capsicum extract, capsicum tincture, capsicum-derived substances such as capsicum powder, benzyl nicotinate,
Examples thereof include β-butoxyethyl nicotinate, N-acylvanylamide, and nonylate vanilamide, and these can be used alone or in combination of two or more.
In the case of the present invention, in view of further improving the percutaneous absorbability and the long-lasting effect of the non-steroidal anti-inflammatory agent, it is more preferable to use two or more kinds of the above-mentioned warming-imparting substances. The derived warming substance is more useful in that it alleviates skin irritation, and is particularly effective when combined with capsicoside and other capsicum-derived substances. Specific examples of capsaicin include 8-methyl-N-vanillyl-6E-nonenamide and N-vanillylnonanamide, and specific examples of capsaicinoid include N-vanillyl-9-octadeceneamide and dihydroxy. Specific components of capsaicin analogs such as capsaicin and capsanthin include N-
Examples include vanillyl-alkadienamide, N-vanillyl-alkanedienyl, N-vanillyl-cis-monounsaturated alkenamide.

[0010] The blending amount of the above warming-imparting substance to the whole skin external preparation of the present invention (total blending amount when two or more kinds are used in combination)
Is 0.0001 to 5% of the total skin external preparation, preferably 0.001 to 3%, more preferably 0.01 to 1%.
%. If the amount of the warming substance is too small, a sufficient warm feeling is not provided, and if it is too large, skin irritation may occur. The mixing ratio of the warming-imparting substance to the non-steroidal anti-inflammatory agent is preferably such that the non-steroidal anti-inflammatory agent: the warming-imparting substance (weight ratio) = 1: 1.
0.0001 to 1: 1, more preferably 1: 0.001
１ ： 1: 0.7, more preferably 1: 0.002 to 1:
0.5. If the proportion of the non-steroidal anti-inflammatory agent is too small, the efficacy may be insufficient. If the proportion is too large, no difference is obtained in the effect of improving the transdermal absorbability even if the proportion is more than that. When two or more kinds of the above-mentioned warming sensation imparting substances are used in combination, it is more preferable that the compounding ratio (weight) is such that one compounding amount is 1 to 5000 times, especially 1 to 2000 times the other. When capsicoside is used in combination with other capsicum-derived substances, it is more effective to mix the capsicoside with other capsicum-derived substances in an amount of 1 to 5000 times, especially 1 to 2000 times.

The percutaneous absorption enhancer to be incorporated into the external preparation for skin of the present invention may be any as long as it enhances the percutaneous absorption of the active ingredient in the external preparation for skin. (1-dodecylazacycloheptane-
2-one), pyrrolidones, calcium thioglycolate, higher alcohols, enamines and derivatives thereof, fatty acids, salicylic acids, polybasic acids, crotamiton, terpenes, benzyl alcohol, squalane, nonionic surfactants, etc. In the case of the present invention, these are used in combination of two or more. Particularly, when one kind of nonionic surfactant is used alone and combined with another transdermal absorption enhancer, the HLB value is 8%. Above, preferably 8 to
The use of a nonionic surfactant of 25, more preferably 10 to 20 can further alleviate skin irritation, and when two or more nonionic surfactants are combined, mixed nonionic surfactants can be used. HL of whole ionic surfactant
B value is 8 or more, preferably 8 to 25, more preferably 1
When combined in such a manner as to be 0 to 20, skin irritation can be further effectively alleviated. HL
If the B value is too low, stickiness may occur when the preparation is used, and the usability may be poor.

Here, as the pyrrolidones, specifically, for example, 2-pyrrolidone, 1-methyl-2-pyrrolidone,
5-methyl-2-pyrrolidone, 1,5-dimethyl-2-
Pyrrolidone, derivatives and salts thereof, such as pyrrolidone, 1-ethyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid and salts thereof, may be mentioned. Specific examples of higher alcohols include oleyl alcohol and lauryl. Alcohol, myristyl alcohol, 2-octyldodecanol, 2-hexyldodecanol, etc., having 8 carbon atoms
To 22 saturated or unsaturated higher alcohols and derivatives thereof having a transdermal absorption promoting action, specifically as polybasic acids, for example, those having 2 carbon atoms such as diethyl adipate, isopropyl adipate, diisopropyl adipate and the like. The above-mentioned polybasic acids and derivatives thereof, which have a transdermal absorption promoting action, specifically, as fatty acids, include, for example, sodium caprate, linoleic acid, oleic acid, sodium lauryl sulfate, sodium cetyl sulfate, etc. 8-22 fatty acids and salts thereof, ethyl myristate,
Octyldodecyl myristate, isopropyl myristate, diisopropyl sebacate, diethyl sebacate, isopropyl palmitate, decyl oleate, ethyl laurate, ethyl butyrate, ethyl caprate,
Fatty acid derivatives which are esters of a fatty acid having 8 or more carbon atoms such as capric acid monoglyceride and a linear or branched alkyl group having 8 to 22 carbon atoms and have a transdermal absorption promoting action, and specific examples of salicylic acids Specifically, for example, salicylic acid such as salicylic acid, sodium salicylate, methyl salicylate, ethyl salicylate, 5-methoxysalicylate, glycol salicylate, etc., salts thereof and derivatives thereof,
Specific examples of terpenes include peppermint oil and eucalyptus, and examples of other specific compounds include diethyl succinate, triacetin, and tributyrin.

Examples of the nonionic surfactant include ester types such as propylene glycol fatty acid ester, sorbitan fatty acid ester, and polyethylene glycol fatty acid ester, polyoxyethylene (hereinafter referred to as POE) sorbitan fatty acid ester, POE sorbitol fatty acid ester, and POE. Castor oil, POE hardened castor oil, ether ester type such as POE glycerin fatty acid ester, PO
E alkyl ether and its phosphate, POE polyoxypropylene (hereinafter referred to as POP) alkyl ether, PO
E-alkyl phenyl ether, ether type such as POE lanolin alcohol and the like can be used. More specifically, as propylene glycol fatty acid ester,
Examples of glycerin fatty acid esters such as propylene glycol monostearate (self-emulsifying type) (HLB 4.0) and propylene glycol monostearate (3.5) include glyceryl monostearate (1.5 to 1.5).
4.0), glyceryl monostearate (self-emulsifying type)
(3.0-10.0) and the like as sorbitan fatty acid esters, for example, sorbitan monooleate (4.3,5.
0), sorbitan sesquioleate (3.7, 4.
5), sorbitan trioleate (1.7, 4.0),
Sorbitan monolaurate (8.6), sorbitan monopalmitate (6.7), sorbitan monostearate (4.7), sorbitan tristearate (2.1)
As polyethylene glycol fatty acid esters, for example, polyethylene glycol monolaurate (10E
O) (12.5), polyethylene glycol monostearate (2EO) (4.0), polyethylene glycol monostearate (4EO) (6.5), polyethylene glycol monostearate (10EO) (11.
0), polyethylene glycol monostearate (25
EO) (15.0), polyethylene glycol monostearate (40EO) (17.5) [POE fatty acid esters such as POE (40) monostearate (17.0)], polyethylene glycol monostearate (45)
EO) (18.0), polyethylene glycol monostearate (55EO) (18.0), polyethylene glycol monooleate (2EO) (4.5), polyethylene glycol monooleate (6EO) (8.5),
Ethylene glycol monostearate (3.5), polyethylene glycol distearate (8.5,16.
5) and the like. Further, as POE sorbitan fatty acid esters, for example, monooleic acid POE
(6) Sorbitan (10.0), POE monooleate
(20) Sorbitan (15.0), monopalmitic acid P
OE (20) sorbitan (15.6), POE monostearate (6) sorbitan (9.6), POE (20) sorbitan monostearate (14.9), POE
(4) sorbitan tristearate (1.0), POE tristearate (20) sorbitan (10.5), POE trioleate (20) sorbitan (11.0),
POE (20) sorbitan monolaurate (16.0)
As POE sorbitol fatty acid esters, for example, POE (6) sorbitol tetraoleate (8.
5), POE tetraoleate (30) sorbitol (11.5), POE tetraoleate (40) sorbitol (12.5), POE tetraoleate (60)
Sorbitol (14.0), POE monolaurate
(6) As POE castor oil such as sorbitol (15.5), for example, POE (3) castor oil (3.0), POE
(10) Castor oil (6.5), POE (20) Castor oil (10.5), POE (30) Castor oil (11.0),
As a POE-hardened castor oil such as POE (40) castor oil (12.5), for example, POE (5) -hardened castor oil (6.
0), POE (10) hydrogenated castor oil (6.5), POE
(20) Hardened castor oil (10.5), POE (30) Hardened castor oil (11.0), POE (40) Hardened castor oil (12.5), POE (50) Hardened castor oil (13.
5), POE (60) hydrogenated castor oil (14.0), PO
E (100) hydrogenated castor oil (16.5) and the like and POE glycerin fatty acid esters such as POE (5) glyceryl monostearate (9.5), POE (15) glyceryl monostearate (13.5) and the like. Can be mentioned.

Further, as POE alkyl ethers, for example, POE (2) lauryl ether (9.5),
POE (3) lauryl ether (6.0), POE
(4.2) Lauryl ether (11.5), POE
(5) Lauryl ether (9.0), POE (7) lauryl ether (10.0), POE (9) lauryl ether (14.5), POE (10) lauryl ether (12.0), POE (12) ) Lauryl ether (1
3.0), POE (15) lauryl ether (14.
0), POE (20) lauryl ether (16.0),
POE (25) lauryl ether (19.5), POE
(30) Lauryl ether (18.0), POE (5
0) lauryl ether (21.0), POE (2) cetyl ether (8.0), POE (5.5) cetyl ether (10.5), POE (7) cetyl ether (11.
5), POE (10) cetyl ether (13.5), P
OE (15) cetyl ether (15.5), POE (2
0) cetyl ether (17.0), POE (23) cetyl ether (18.0), POE (25) cetyl ether (18.5), POE (30) cetyl ether (1)
9.5), POE (40) cetyl ether (20.
0), POE (2) stearyl ether (8.0), P
OE (4) stearyl ether (9.0), POE
(6) Stearyl ether (7.0), POE (20)
Stearyl ether (18.0), POE (2) oleyl ether (7.5), POE (7) oleyl ether (10.5), POE (10) oleyl ether (1
4.0), POE (15) oleyl ether (16.
0), POE (20) oleyl ether (17.0),
POE (50) oleyl ether (HLB 18.0),
POE (5) behenyl ether (HLB 7.0), PO
E (10) Behenyl ether (HLB 10.0), PO
E (20) Behenyl ether (HLB 16.5), PO
E (30) behenyl ether (HLB18.0), P
As OE alkyl ether phosphate, for example, POE
(10) Sodium lauryl ether phosphate (HLB1
7.0), POE (4) sodium lauryl ether phosphate (HLB 13.0), POE (5) sodium cetyl ether phosphate (HLB 10.0), POE (8) sodium oleyl ether phosphate (HLB 12.5)
Etc., as POEPOP alkyl ethers, for example, PO
E (10) POP (4) cetyl ether (HLB10.
5), POE (20) POP (4) cetyl ether (H
LB16.5), POE (20) POP (8) cetyl ether (HLB12.5), etc., as POE alkylphenyl ethers, for example, POE (2) nonylphenyl ether (HLB4.5), POE (5) nonylphenyl ether ( HLB 8.0), POE (7.5) nonyl phenyl ether (HLB 14.0), POE (10) nonyl phenyl ether (HLB 16.5), POE (1
5) Nonylphenyl ether (HLB 18.0), PO
E (18) nonylphenyl ether (HLB19.
0), POE (20) nonylphenyl ether (HLB
20.0), POE (10) octyl phenyl ether (HLB 13.5), POE (30) octyl phenyl ether (HLB 20.0), etc., as POE lanolin alcohols, for example, POE (5) lanolin alcohol (HLB 12.5), POE (10) lanolin alcohol (HLB 15.5), POE (20) lanolin alcohol (HLB 16.0), POE (40) lanolin alcohol (HLB 17.0), and the like. In addition, POE lanolin (HLB 15. 0) and the like, POE (6) sorbit beeswax (HLB7.
5), POE (20) Sorbit beeswax (HLB9.
POE beeswax derivatives such as 5), POE (15) POE alkylamines such as oleylamine (HLB15.5), fatty acid esters such as cetyl octanoate (HLB0.0), and trifatty acid glycerins such as glyceryl trioctanoate (HLB1.0). Coconut oil fatty acid diethanolamide (HLB11.0), methylphenyl polysiloxane (HLB0.0), lauric acid diethanolamide (HLB)
LB11.0) and the like.

In the case of the present invention, two or more of the above-mentioned percutaneous absorption enhancers are used in an appropriate combination, and as described above, two or more of the above-mentioned percutaneous absorption enhancers except for the above-mentioned nonionic surfactant are appropriately used. When used in combination, when one of the nonionic surfactants is combined with a transdermal absorption enhancer other than the nonionic surfactant, two or more nonionic surfactants may be combined, When one of the nonionic surfactants is combined with a transdermal absorption enhancer other than the nonionic surfactant, as described above, among the nonionic surfactants, those having an HLB value of 8 or more are used. Is more preferable, and when combining two or more nonionic surfactants, the above nonionic surfactants are combined so that the overall HLB value is 8 or more. Ri is preferred. The mixing ratio (weight ratio) when two or more transdermal absorption enhancers are used in an appropriate combination is not particularly limited, and depends on the dosage form of the target preparation, the combination of the transdermal absorption enhancer, and the like. Selected as appropriate.

The total amount of the above-mentioned percutaneous absorption enhancer in the whole skin external preparation of the present invention is 0.1 to 0.1% of the whole skin external preparation.
10%, preferably 0.3 to 8%, more preferably 0.5 to 5%. If the total amount of the percutaneous absorption enhancer is too small, the effect of the combination cannot be sufficiently obtained, and if the total amount is too large, there is no difference in the effect even if it is added more. Further, the mixing ratio (weight ratio) to the warming substance is preferably the warming substance: transdermal absorption enhancer (total amount) = 0.0
001: 1 to 1: 1, more preferably 0.001: 1 to
0.7: 1, more preferably 0.002: 1 to 0.5:
It is one. If the compounding ratio of the transdermal absorption enhancer is too small, skin irritation may not be sufficiently mitigated,
If it is too large, it may be difficult to mix a sufficient amount of a warming-imparting substance from the viewpoint of formulation design, and it may not be possible to obtain a sufficient warming feeling.
The blending ratio of the above-mentioned percutaneous absorption enhancer (total) to the above-mentioned non-steroidal anti-inflammatory agent is preferably such that the above-mentioned non-steroidal anti-inflammatory agent: percutaneous absorption enhancer (weight ratio) = 1:
0.1 to 1:50, more preferably 1: 0.5 to 1: 3
0, more preferably 1: 1 to 1:10. If the compounding ratio of the nonsteroidal anti-inflammatory agent is too small, the drug effect may be insufficient, and if it is too large, a sufficient effect of improving the transdermal absorbability may not be obtained.

The external preparation for skin of the present invention may optionally contain, in addition to the above essential components, active ingredients other than the non-steroidal anti-inflammatory agent, pigments, fragrances, and the like, if necessary. In addition,
The amounts of the above-mentioned active ingredients and the like can be set to ordinary amounts within a range not to impair the effects of the present invention.

Further, the external preparation for skin of the present invention can be prepared by a usual method of each preparation by adding an appropriate component corresponding to the dosage form as other optional components. For example, when a patch is prepared, water-based adhesives include polyacrylic acid, polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, polyvinylpyrrolidone / vinyl acetate copolymer, carboxyvinyl copolymer, methylcellulose, carboxymethylcellulose, and the like. One or two of carboxymethyl cellulose salt, carboxyethyl cellulose, carboxyethyl cellulose salt, hydroxypropyl cellulose, sodium alginate, gelatin, pectin, polyethylene oxide, methyl vinyl ether / maleic anhydride copolymer, carboxymethyl starch, etc.
More than one kind of water-soluble polymer substance (1 to 1
15%), one or more inorganic powders such as kaolin, bentonite, montmorillonite, titanium oxide, zinc oxide, aluminum hydroxide, silicic anhydride, etc. (0 to 10% of the total amount of the base), propylene It is possible to use one or more humectants such as glycol, glycerin, sorbitol, sodium lactate and the like (mixing amount: usually 0 to 20% of the total amount of the base) and water mixed at an appropriate ratio.

In this case, such an aqueous pressure-sensitive adhesive contains a metal ion-crosslinkable hydrogel base, particularly polyacrylic acid and polyacrylate, and further contains sodium carboxymethylcellulose and / or an alkali metal alginate. Non-gelatin bases can be preferably used.
That is, the water-containing gel base having the above composition has a high adhesive strength, a high water content, and excellent shape retention.By using this water-containing gel base, the non-steroidal anti-inflammatory agent is added thereto. When incorporated, the active ingredient is efficiently absorbed by the skin and a good warm feeling is felt.
The hydrogel base having the above composition can obtain a base having an arbitrary pH by changing the mixing ratio of polyacrylic acid and polyacrylate.
In this case, the blending ratio (weight) of polyacrylic acid and polyacrylate is preferably 1: 9 to 8: 2. When the amount of polyacrylic acid is too small, sufficient adhesion to the skin cannot be obtained. If the amount of polyacrylic acid is too large, sufficient thickening is not performed, and the paste (base) may be sagged. Further, when the hydrogel base composed of the above components is metal-crosslinked with a polyvalent metal salt, examples of the polyvalent metal salt include calcium chloride, magnesium chloride, aluminum chloride, potassium alum, ammonium alum, iron alum,
Soluble salts such as aluminum sulfate, ferric sulfate, magnesium sulfate, ethylenediaminetetraacetic acid (EDTA, the same applies hereinafter) -calcium, EDTA-aluminum, EDTA-magnesium, stannous chloride, calcium hydroxide, ferric hydroxide, Aluminum hydroxide, calcium carbonate, magnesium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, magnesium stearate, aluminum stearate, calcium citrate,
Barium sulfate, barium hydroxide, aluminum allantoinate, aluminum acetate, aluminum glycinate, stannous hydroxide, one or more selected from sparingly soluble salts such as α-stannic acid, etc., and further crosslinking An organic acid, organic acid salt, organic base or the like having a chelate or coordinating ability with respect to metal ions such as sodium EDTA-2, citric acid, tartaric acid, urea, and ammonia can be blended as a reaction rate regulator.

In the case of acrylic pressure-sensitive adhesives, (co) polymers of (meth) alkyl acid alkyl esters obtained from aliphatic alcohols having 4 to 18 carbon atoms and (meth) acrylic acid, A copolymer of the above-mentioned alkyl (meth) acrylate and other functional monomers is preferably used.

The above (meth) acrylates include butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, and acrylic acid-2-
Ethylhexyl, isooctyl acrylate, decyl acrylate, isodecyl acrylate, lauryl acrylate,
Stearyl acrylate, methyl methacrylate, butyl methacrylate, isobutyl methacrylate, methacrylic acid
Examples include 2-ethylhexyl, isooctyl methacrylate, isodecyl methacrylate, lauryl methacrylate, and stearyl methacrylate. The functional monomers include:
Examples include a monomer having a hydroxyl group, a monomer having a carboxyl group, a monomer having an amide group, and a monomer having an amino group. Examples of the monomer having a hydroxyl group include hydroxyalkyl (meth) acrylates such as 2-hydroxyethyl (meth) acrylate and hydroxypropyl (meth) acrylate. Examples of the monomer having a carboxyl group include α, β unsaturated carboxylic acids such as acrylic acid and methacrylic acid, monoalkyl maleates such as butyl maleate, maleic acid, coumaric acid, crotonic acid and the like. Maleic anhydride also provides the same (co) polymerization component as maleic acid. Examples of the monomer having an amide group include alkyl (meth) acrylamide such as acrylamide, dimethylacrylamide, and diethylacrylamide, alkyl ether methylol (meth) acrylamide such as butoxymethylacrylamide, and ethoxymethylacrylamide, diacetone acrylamide, and vinylpyrrolidone. Examples of the monomer having an amino group include dimethylaminoacrylate. Other copolymerizable monomers other than the above,
Examples thereof include vinyl acetate, styrene, α-methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene, and butadiene, which may be copolymerized.

As the rubber-based pressure-sensitive adhesive, natural rubber, synthetic isoprene rubber, polyisobutylene, polyvinyl ether, polyurethane, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer and the like are used. As the silicone resin-based pressure-sensitive adhesive, silicone rubber such as polyorganosiloxane is used.

In the present invention, polybutene, latex, vinyl acetate emulsion, acrylic resin, etc. may be added to the base, if necessary, as an agent for controlling the physical properties of the paste (softness, tackiness, shape retention, etc.). High molecular substances such as emulsions, various polyvalent metal salts as cross-linking gelling agents, organic cross-linking agents such as dialdehyde starch, and lanolin, liquid paraffin, vegetable oil, lard, tallow, higher alcohol as stable compounding agents for active ingredients , A higher fatty acid, an activator and the like. Further, if necessary, various compounding agents, for example, tackifiers such as rosin-based resins, polyterpene resins, cumarone-indene resins, petroleum-based resins, terpene phenol resins; liquid polybutene, mineral oil, liquid polyisoprene, liquid polyacrylate, etc. , A plasticizer, a filler antioxidant and the like.

When a patch is prepared as the external preparation for skin of the present invention, a support usually used for a patch is used as a support of the patch. Materials for such a support include cellulose acetate, ethyl cellulose, polyethylene terephthalate, vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride. , Aluminum and the like. These include, for example, a single-layer sheet (film) or a laminate of two or more sheets (laminate)
Used as a body. Materials other than aluminum may be used as a woven or nonwoven fabric.

The patch can be produced according to a conventional method. For example, in the case of an aqueous cataplasm, the above-mentioned components are kneaded to prepare a paste, which is applied to the support, and if necessary, a polyethylene film or the like. It is obtained by covering the facing. Further, for example, in the case of an acrylic, rubber, or silicone-based pressure-sensitive adhesive composition, a pressure-sensitive adhesive layer containing a drug and a surfactant is formed on the surface of the support to obtain a patch. In order to form the pressure-sensitive adhesive layer, various coating methods such as a solvent coating method, a hot melt coating method, and an electron beam emulsion coating method can be used.

Further, in the case of a liquid preparation such as an ointment or a lotion, a solvent, an oil component, glycols, a surfactant other than the above-mentioned nonionic surfactant, a water-soluble polymer compound and the like are mixed. Specifically, as a solvent, for example, water, ethanol, propyl alcohol, isopropyl alcohol, acetone, etc., and as an oil component, for example, lanolin, hydrogenated oil, lecithin, plastibase, liquid paraffin, beeswax, paraffin wax, micron Crystalline wax, silicone oil, etc., as glycols such as glycerin, propylene glycol, polyethylene glycol, polypropylene glycol, etc., as water-soluble polymer compounds such as carboxyvinyl polymer, sodium carboxymethylcellulose, polyvinyl alcohol Lumpur, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, can be blended polyacrylate.

When prepared as an ointment or liquid, it can be produced by a conventional method. In the case of an ointment, it can be prepared by, for example, adding the above-mentioned components to the above-mentioned solvent sequentially and kneading for an appropriate time. If so, for example, it can be prepared by sequentially adding and dissolving each of the above components to the above solvent.

In the case of a gel, a gelling agent such as carboxyvinyl polymer or glycerin monooleate can be added in addition to the optional components of the above liquid. For example, it can be prepared by sequentially adding and dissolving each of the above components other than the gelling agent to the above solvent, and then adding the gelling agent to cause gelation.

Further, other skin external preparations can be produced by a usual method using components according to the kind.

The external preparation for skin of the present invention has a formulation pH of 3.5 to 7.5, especially 4 to 6 in any form.
It is necessary to adjust. If the pH is too low or too high, skin irritation cannot be sufficiently reduced. Here, the pH of the preparation can be adjusted using ordinary amounts of pharmaceutically acceptable acidic compounds and alkaline compounds.

The amount and method of use of the external preparation for skin of the present invention are not particularly limited, and the external preparation for skin containing a normal non-steroidal anti-inflammatory agent may be used in accordance with the dosage form of the external preparation for skin. It can be used as well.

[0032]

According to the external preparation for skin of the present invention, the skin irritation at the time of application is alleviated, the applied warm feeling is enhanced, and the durability is improved. It can be used widely as a skin external preparation that not only excels in anti-inflammatory and analgesic effects, but also excels in usability and safety, as it can significantly improve the percutaneous absorbability of inflammatory agents and obtain long-lasting effects. Is what you can do.

[0033]

EXAMPLES Hereinafter, the present invention will be described in detail with reference to Examples, Experimental Examples and Comparative Examples, but the present invention is not limited to the following Examples.

Examples 1-33 and Comparative Examples 1-33 Using the components shown in Tables 1-6, lotions (Tables 1, 2), gels (Tables 3, 4), and patches were applied in the usual manner. Agents (Tables 5, 6) were prepared. The anti-inflammatory effect of each preparation was evaluated by the following method of measuring the edema-suppressing effect. The edema suppression rates are shown in Tables 1 to 6.

<Evaluation of edema-suppressing effect> Rats (Wistar strain, male, 5 weeks old) (10 rats per group) were applied to the right hind paw three times at a normal dose for each specimen (external preparation for skin). The control group was not subjected to sample application. Next, 1% carrageenin (λ Carrageenin, Minsei)
Rikagaku Co., Ltd. ) 0.1 ml of the solution was injected subcutaneously into the right hind paw to cause a fire.

Immediately after the inflammation, a volume measuring device (Ugo Ba)
The volume of the paw was measured with Sile. And after the fire
Measurements were made after 1, 2, 4, and 6 hours.
Tumor and inhibition rates were calculated. Edema rate E (%) = ｛(V_t-V₀) / V₀｝ × 100 V _t： Volume of paw at time t after carrageenin injection V ₀： Paw volume suppression rate immediately after carrageenin injection I (%) = ｛(E_c-E_t) / E_c｝ × 100 E_t: Edema rate at t hours after the sample application group E_c: Edema rate at time t in control group

[0037]

[Table 1]

[0038]

[Table 2]

[0039]

[Table 3]

[0040]

[Table 4]

[0041]

[Table 5]

[0042]

[Table 6]

According to the results shown in Tables 1 to 6, the external preparation for skin of the present invention was obtained by using two kinds of transdermal absorption enhancers in combination.
As compared with the comparative example in which one kind was used alone, it is recognized that all the non-steroidal anti-inflammatory agents and dosage forms are superior in the edema suppressing effect.

[Experimental Examples 1 to 22] Next, the effects on the percutaneous absorption and long-lasting effect of the non-steroidal anti-inflammatory agent when the warming sensation imparting substance is used alone or when two kinds are used in combination. In order to confirm the above, each of the components shown in Tables 7 and 8 was mixed and stirred by a Henschel mixer according to a conventional method.
22 patch bases were prepared. Place each base on non-woven fabric 100
g / m ^2, and the mixture was uniformly coated, and the polyethylene film was facing to produce a patch. For each patch, the blood concentration of the contained nonsteroidal anti-inflammatory drug was measured over time by the following measurement method, and the blood concentration
The blood concentration area (AUC) was determined from the transition time graph, and the time during which the blood concentration was maintained at 10 μg / ml or more was determined as an index of sustainability. Tables 7 and 8 show the results.
It is described together.

<Method for Measuring Blood Concentration of Nonsteroidal Anti-inflammatory Agent> Male Wistar rats (weight: 140-160)
g) Ten animals were subjected to the experiment as a group. Rats had their abdomen shaved the day before the experiment. On the day of the experiment, 3 × 5
After applying a patch having a size of cm, the animals were kept in individual cages. A total of 6, 1, 2, 3, 4, 6, 8 hours after application
At times, rat blood was collected under ether anesthesia. The collected blood was immediately centrifuged, and the plasma components were separated and subjected to high performance liquid chromatography analysis according to a conventional method. The blood concentration of each non-steroidal anti-inflammatory drug was calculated from a predetermined calibration curve, and the area under blood concentration (AUC) was calculated using blood concentration analysis software.

The time during which the blood concentration was maintained at 10 μg / ml or more was determined.

[0047]

[Table 7]

[0048]

[Table 8]

According to the results of Tables 7 and 8, the external preparation for skin of the present invention was obtained by using two kinds of warming substances in combination.
Compared with the case where one kind is blended alone, it is recognized that the percutaneous absorbability of the nonsteroidal anti-inflammatory agent is further improved and the long-lasting effect is also improved.

[Experimental Examples 23 to 110] Furthermore, in order to confirm the effects of the combined use of two percutaneous absorption enhancers on other preparations, the respective components shown in Tables 9 to 16 were used in a conventional manner. Creams (Tables 9 and 10), gels (Tables 11 and 12), lotions (Tables 13 and 14),
Ointments (Tables 15, 16) were prepared. The AUC of each nonsteroidal anti-inflammatory drug was determined in the same manner as in the above experimental example, except that the normal dose of each preparation was applied to rats so as to be in a range of about 3 × 5 cm. The results are shown in Tables 9 to 16.

[0051]

[Table 9]

[0052]

[Table 10]

[0053]

[Table 11]

[0054]

[Table 12]

[0055]

[Table 13]

[0056]

[Table 14]

[0057]

[Table 15]

[0058]

[Table 16]

[Examples 34 to 45 and Comparative Examples 34 to 4]
4] The components shown in Tables 17 and 18 were mixed and stirred by a Henschel mixer according to a conventional method to prepare the adhesive bases of Examples 34 to 45 and Comparative Examples 34 to 44. Each base is uniformly coated on the non-woven fabric so as to be 100 g / m ² ,
The polyethylene film was facing to produce a patch. Each patch was applied to the upper arm of 20 healthy persons (panels), and its skin irritation was evaluated by a closed patch test according to the following evaluation criteria for 24 hours. The evaluation points of each paneler were averaged to evaluate the skin irritation of the patch. It was used as an index of the effect of alleviating sex. The results are shown in Tables 17 and 18. <Evaluation criteria> 5: No skin irritation at all 4: Little skin irritation 3: Very little skin irritation 2: Some skin irritation 1: Some skin irritation

Next, each patch was applied to the shoulders of 20 healthy individuals (panelers), and 0.5, from the time of application of the patch to the skin.
The thermal sensation after 1, 2, 3, 4, and 5 hours was sensory-evaluated for each panelist based on the following evaluation criteria, and the evaluation points of each paneler were averaged for each time to evaluate the warmth of the patch The change over time was examined as an index of strength. The average value of the evaluation points for each time is described in Tables 19 and 20, and the change over time in the intensity of the warm feeling is shown in FIGS. <Evaluation Criteria> 0: No feeling of warmth 1: Feeling of warmth but extremely weak 2: Feeling of weak warmth 3: Feel warmth 4: Clearly feel warmth 5: Feel strong warmth 6: I feel too warm

[0061]

[Table 17]

[0062]

[Table 18]

[0063]

[Table 19]

[0064]

[Table 20]

[Examples 46 to 56 and Comparative Examples 45 to 5]
5) A cream was prepared by a conventional method using the components shown in Tables 21 and 22. A normal dose of each cream was applied to the upper arm of 20 healthy persons (panels), and skin irritation was evaluated in the same manner as described above. The results are shown in Tables 21 and 22. In addition, a normal dose of each cream was applied to the shoulders of 20 healthy persons (panelers), and the warmth was evaluated in the same manner as described above. The results are shown in Tables 23 and 24, and the change over time in the intensity of the warm feeling is shown in FIGS.

[0066]

[Table 21]

[0067]

[Table 22]

[0068]

[Table 23]

[0069]

[Table 24]

[Examples 57 to 67 and Comparative Examples 56 to 6]
6] A gel was prepared by a conventional method using the components shown in Tables 25 and 26. A normal dose of each gel was applied to the upper arm of 20 healthy persons (panels), and skin irritation was evaluated in the same manner as described above. The results are shown in Tables 25 and 26. In addition, a normal dose of each gel was applied to the shoulders of 20 healthy persons (panelers), and the warm feeling was evaluated in the same manner as described above. Table 27 shows the results.
5 and FIG. 6 show the change over time in the intensity of the warm feeling.

[0071]

[Table 25]

[0072]

[Table 26]

[0073]

[Table 27]

[0074]

[Table 28]

[Examples 68 to 78 and Comparative Examples 67 to 7]
7] A lotion was prepared by a conventional method using the components shown in Tables 29 and 30. A normal dose of each lotion was applied to the upper arm of 20 healthy persons (panels), and skin irritation was evaluated in the same manner as described above. The results are shown in Tables 29 and 30. In addition, a normal dose of each lotion was used for a healthy person.
The composition was applied to the shoulder of a name (paneler) and the warmth was evaluated in the same manner as described above. The results are shown in Tables 31 and 32, and the changes over time in the intensity of the warm feeling are shown in FIGS. 7 and 8.

[0076]

[Table 29]

[0077]

[Table 30]

[0078]

[Table 31]

[0079]

[Table 32]

[Examples 79 to 89 and Comparative Examples 78 to 8]
8] Ointments were prepared in the usual manner using the components shown in Tables 33 and 34. A normal dose of each ointment was applied to the upper arm of 20 healthy individuals (panels), and skin irritation was evaluated in the same manner as described above. The results are shown in Tables 33 and 34. In addition, a normal dose of each ointment was applied to the shoulders of 20 healthy persons (panels) and the warm feeling was evaluated in the same manner as described above. Table 35 shows the results.
And Table 36, and the change over time in the intensity of the warm feeling is shown in FIGS. 9 and 10.

[0081]

[Table 33]

[0082]

[Table 34]

[0083]

[Table 35]

[0084]

[Table 36]

[Brief description of the drawings]

FIG. 1 is a graph showing the change over time in the intensity of warmth of the patches of Examples 35 to 45.

FIG. 2 is a graph showing the change over time in the intensity of warmth of the patches of Comparative Examples 34 to 44.

FIG. 3 is a graph showing the change over time in the intensity of warmth of the creams of Examples 46 to 56.

FIG. 4 is a graph showing the change over time in the intensity of warmth of the creams of Comparative Examples 45 to 55.

FIG. 5 is a graph showing the change over time in the intensity of warmth of the gels of Examples 57 to 67.

FIG. 6 is a graph showing the time-dependent change in the intensity of warmth of the gels of Comparative Examples 56 to 66.

FIG. 7 is a graph showing the change over time in the intensity of warmth of the lotions of Examples 68 to 78.

FIG. 8 is a graph showing the change over time in the intensity of the warm feeling of the lotions of Comparative Examples 67 to 77.

FIG. 9 is a graph showing the change over time in the intensity of warmth of the ointments of Examples 79 to 89.

FIG. 10 is a graph showing the change over time in the intensity of warmth of the ointments of Comparative Examples 78 to 88.

Claims (1)

[Claims] 1. A composition comprising a non-steroidal anti-inflammatory agent, a warming-imparting substance and two or more transdermal absorption enhancers, wherein the amount of said warming-imparting substance is 0.00
An external preparation for skin, characterized in that the amount is from 0.1 to 5% by weight and the total amount of the transdermal absorption enhancer is from 0.1 to 10% by weight of the whole.