JP2008231081A - Ketoprofen-containing external preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a patch which contains ketoprofen as an active ingredient and has an analgesic effect against the pain of rheumatoid arthritis. <P>SOLUTION: The ketoprofen-containing external preparation has an analgesic effect against the pain of rheumatoid arthritis and yields an intramascular and/or intratendinous ketoprofen concentration of ≥30 ng/g after administration. In particular, the ketoprofen-containing external preparation yields and keeps an intramascular and/or intratendinous ketoprofen concentration of ≥30 ng/g for at least 14 hr after administration. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an external preparation having an analgesic effect on pain of rheumatoid arthritis containing ketoprofen as an active ingredient.

Nonsteroidal anti-inflammatory analgesics are widely used for osteoarthritis, osteoarthritis, low back pain, etc. (Patent Document 1), and representative examples thereof include ketoprofen. In addition, a patch using ketoprofen as an active ingredient of an anti-inflammatory analgesic is known (Patent Documents 2 and 3).
However, a specific example of an external preparation having an analgesic effect on rheumatoid arthritis pain comprising a nonsteroidal anti-inflammatory analgesic as an active ingredient has not been known so far. This is because it is not clear how much rheumatoid arthritis treatment, especially topical preparations, should be transferred to the affected area through the skin, and as a result, it is difficult to develop external preparations effective for rheumatoid arthritis pain. It was partly because it was.

JP 2006-45099 A Japanese Patent No. 2816765 International Publication No. 2005/063215 Pamphlet

  The subject of this invention is providing the external preparation which has the analgesic effect with respect to the pain of rheumatoid arthritis which uses ketoprofen as an active ingredient newly.

  In the course of earnest research to solve the above problems, the present inventors maintain a concentration of anti-inflammatory analgesic in tissues such as muscles and tendons at a predetermined concentration or more, and the predetermined concentration is a drug that lasts for a long time As a result of further research, it was found that if the kinetics can be realized, it is effective in suppressing pain in rheumatoid arthritis, and the present invention was completed.

That is, the present invention relates to a ketoprofen-containing external preparation having an analgesic effect on rheumatoid arthritis pain, wherein the concentration of ketoprofen in muscle and / or tendon after administration reaches 30 ng / g or more.
Furthermore, the present invention relates to the above-mentioned ketoprofen-containing external preparation, wherein the concentration is 30 ng / g or more until at least 14 hours after administration after the intramuscular and / or tendon ketoprofen concentration reaches 30 ng / g or more.
The present invention also relates to the ketoprofen-containing external preparation described above, wherein the concentration of ketoprofen in muscle and / or tendon 1 hour after administration is 30 ng / g or more.
Furthermore, the present invention relates to the above-mentioned ketoprofen-containing external preparation, wherein the ketoprofen concentration in plasma does not exceed 500 ng / mL after administration.
Moreover, this invention relates to the said ketoprofen containing external preparation which is a patch.
Furthermore, the present invention relates to a ketoprofen-containing external preparation, which is a ketoprofen-containing external preparation and has the same bioavailability in the bioequivalence test as that of the above-mentioned ketoprofen-containing external preparation.

  The external preparation of the present invention has an effective effect on rheumatoid arthritis pain when administered to an affected area (application, sticking, spraying, etc.) and then an effective amount or more of ketoprofen reaches the muscle tissue or tendon. Furthermore, the external preparation of the present invention is safer because the systemic blood concentration is lower than that of the oral preparation, and it is a simpler and more compliant therapeutic agent for rheumatoid arthritis pain because it is an external preparation, particularly a patch. Can be provided.

Hereinafter, suitable implementation of the external preparation of the present invention will be described in detail.
From the viewpoint of the effect of suppressing rheumatoid arthritis, the external preparation of the present invention has a ketoprofen concentration of 30 ng / g or more, particularly 40 ng / g or more after administration, for example, 1 hour after administration, It is preferable to reach 50 ng / g or more. Furthermore, it is more preferable that the concentration is maintained at or above the predetermined concentration for at least 14 hours, particularly 20 hours or more after administration.

Similarly, the ketoprofen concentration in the tendon tissue preferably reaches 30 ng / g or more, particularly 50 ng / g or more, particularly 100 ng / g or more after administration, for example, 1 hour after administration. Furthermore, it is more preferable that the concentration is maintained at or above the predetermined concentration for at least 14 hours, particularly 20 hours or more after administration.
Moreover, the external preparation of the present invention does not exceed 500 ng / mL after administration of ketoprofen in plasma from the viewpoint of side effects and reduction of burden on the body, in particular, does not exceed 300 ng / mL, and in particular, 200 ng / mL. It is preferred not to exceed mL.

And the analgesic effect with respect to the pain of rheumatoid arthritis can be show | played as an external preparation by the density | concentration in the said structure | tissue and plasma of the ketoprofen.
The external preparation of the present invention may be in any dosage form as long as it is administered transdermally. For example, patches, liquids, lotions, creams, gels, ointments, liniments such as poultices or plasters. Agents, sprays and the like. In particular, a patch is preferred because it is convenient for supplying a sufficient amount of medicine for a long period of time.

The bases and formulation examples according to each dosage form of the external preparation of the present invention will be described below.
First, a patch such as a poultice or a plaster will be described. The patch of the present invention comprises a support, a base (a poultice base, a plaster base), and a release sheet, and the base and / or the support contains ketoprofen.

  As the poultice base used in the poultice, it is selected from those usually used, for example, thickener (polyacrylic acid soda, polyacrylic acid, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, polyvinyl methacrylate, etc. Synthetic water-soluble polymers, natural products such as gum arabic, starch, gelatin, methylcellulose, hydroxypropylcellulose, alginic acid, sodium alginate, ammonium alginate, sodium carboxymethylcellulose, etc., wetting agents (urea, glycerin, polyethylene glycol, propylene glycol) , Butylene glycol, sorbitol, etc.), fillers (kaolin, talc, bennite, epoxy resins, organic acids (citric acid, tartaric acid, maleic acid, maleic anhydride, succinic acid, etc.) , Calcium, magnesium, aluminum, etc.), water, solubilizers (propylene carbonate, crotamiton, diisopropyl adipate, etc.), anti-rash agents (diphenhydramine hydrochloride, chlorpheniramine maleate, glycyrrhizic acid, dexamethasone, betamethasone, fluocinolone acetanilide, etc. ), And other additives (salicylic acid, methyl salicylate, glycol salicylate, l-menthol, camphor, nonylic acid vanillylamide, red pepper extract, peppermint oil, Aison (registered trademark), etc.) and the like are selected. The poultice of the present invention can be obtained by blending ketoprofen into the poultice base formed by mixing various components.

  Next, a suitable production example (formulation example) of the poultice is shown. That is, first, 0.1 to 10 parts by weight of ketoprofen is mixed and dissolved in 0.5 to 8 parts by weight of a solubilizing agent to obtain a uniform mixture A. On the other hand, 5 to 20 parts by weight (preferably 10 to 15 parts by weight) of a thickener is mixed and dispersed in 5 to 40 parts by weight of a wetting agent and 10 to 80 parts by weight of water, and further 20 parts by weight or less of a filler is added. A uniform kneaded product B is obtained. Next, the mixture A is added to the kneaded product B and mixed to obtain a uniform kneaded product. The obtained kneaded material is spread-coated on a support by a usual method, and then a release sheet is stuck thereon to obtain the poultice of the present invention.

In addition, as a support body, a stretchable or non-stretchable support body can be used. Specifically, the support is made of woven fabric, non-woven fabric, polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, polyethylene terephthalate, polybutylene terephthalate, paper, aluminum sheet, or a composite material thereof. Etc. In particular, a polyester cloth made of polyethylene terephthalate or polybutylene terephthalate free from ketoprofen drug adsorption is preferred.
Examples of the release sheet include release paper that has been subjected to release treatment, cellophane, polyethylene, polypropylene, polyvinyl chloride, polyester, polyvinylidene chloride, and silicon processed paper.

  Next, the plaster agent will be described. The plaster base used for the plaster agent is selected from those usually used. For example, a polymer base (copolymer with a vinyl monomer such as methacrylic acid esters, acrylonitrile, vinyl acetate, vinyl propionate) is used. Acrylic composition which is a polymer, silicone resin, polyisoprene rubber, natural rubber, acrylic rubber, styrene-butadiene-styrene block copolymer, styrene-isoprene-styrene block copolymer, styrene-butadiene copolymer, poly Rubber polymers such as isoprene and polybutadiene), fats and oils or higher fatty acids (almond oil, olive oil, camellia oil, persic oil, peanut oil, olein oil, liquid paraffin, polybutene, etc.), tackifiers, fatty acid metal salts (undecylene) Zinc acid, stearic acid , Calcium stearate, aluminum stearate, magnesium stearate, sodium stearate, zinc palmitate, zinc myristate, magnesium myristate, sodium laurate, zinc laurate, etc., anti-rash agent, other additives (salicylic acid, salicylic acid) Methyl, salicylic acid glycol, l-menthol, camphor, nonylic acid vanillylamide, red pepper extract, peppermint oil, Azone (registered trademark), etc., and a plaster base formed by mixing various components selected from these The plaster agent of this invention can be obtained by mix | blending ketoprofen with.

  As the polymer base, a styrene-isoprene-styrene block copolymer having a low polarity is particularly preferable. When a styrene-isoprene-styrene block copolymer is used, the mass average molecular weight is preferably 100,000 to 300,000. For example, Kraton D-KX401CS or D-1107CU (manufactured by Shell Chemical Co., Ltd.), Califlex TR-1107, TR-1111, TR-1112, TR-1117 (manufactured by Shell Chemical Co., Ltd.), SIS-5000 or SIS-5002 (manufactured by Nippon Synthetic Rubber Co., Ltd.), Quintac 3530, 3421 or 3570C (Japan) Zeon Co., Ltd.) and Sorprene 428 (Philip Petroleum Co., Ltd.). One or more of these styrene-isoprene-styrene block copolymers can be blended in the base. In addition to the rubber-based polymer, polyisoprene rubber, polyisobutylene rubber, natural rubber, styrene-isoprene copolymer, styrene-isoprene-butadiene block copolymer, styrene-ethylene-propylene as synthetic rubber or natural rubber -You may mix | blend a styrene block copolymer etc.

  A preferable plaster base according to the present invention contains a rubber polymer such as a styrene-isoprene-styrene block copolymer, another rubber polymer such as polyisobutylene, a tackifier, and a plasticizer.

  As the tackifier, those having a softening point of 60 ° C. to 150 ° C. are preferable. For example, rosin ester, hydrogenated rosin ester, maleic acid-modified rosin ester, terpene resin, and petroleum resin can be used. Esters, terpene resins and petroleum resins are preferred, and a combination of hydrogenated rosin ester and terpene resin is most preferred. Specifically, ester gum A, AA-G, H, or HP (made by Arakawa Chemical Co., Ltd.), Harrier Star L, S, or P (made by Harima Kasei Co., Ltd.), Pine Crystal KE-100, or KE-311 (Arakawa Chemical Co., Ltd.), Hercolin D (Rika Hercules Co., Ltd.), Foral 85 or 105 (Rika Hercules Co., Ltd.), Stevelite Ester 7 or 10 (Rika Hercules Co., Ltd.), Pentaline 4820, or 4740 (Rika Hercules Co., Ltd.), Alcon P-85, or P-100 (Arakawa Chemical Co., Ltd.), Escorez 5300 (Exxon Chemical Co., Ltd.), Clearon K, M, or P, YS Resin PX1000, PX1150 or PX1250 (made by Yashara Chemical Co., Ltd.) It can be blended one or more of these in adhesive base material.

  The plasticizer preferably has a solution viscosity of 10 to 100 centistokes (40 ° C.), and examples thereof include almond oil, olive oil, camellia oil, persic oil, peanut oil, olefinic acid, and liquid paraffin. It can mix | blend with a seed | species or 2 or more types of adhesive bases.

  The plaster base may contain conventionally known fillers, antioxidants, solubilizers and the like. As the filler, for example, zinc oxide, aluminum oxide, titanium dioxide, calcium carbonate, synthetic aluminum silicate, silicas, magnesium oxide, stearic acid metal salts and the like are used. As the antioxidant, for example, ascorbic acid, tocopherol acetate, natural vitamin E, dibutylhydroxytoluene, propyl gallate and the like are used. As the solubilizer, for example, oleic acid, benzyl alcohol, isopropyl myristate, crotamiton, oleyl alcohol, eucalyptus oil, limonene, isopulegol, diisopropyl adipate, diethyl sebacate or other oil refiners are used. Moreover, surfactant, fats and oils, a higher fatty acid, a flavoring agent, etc. can be contained as needed. Furthermore, skin irritants (counteriritant) such as L-menthol, camphor, peppermint oil, pepper extract, capsaicin, benzyl nicotinate, methyl salicylate, glycol salicylate, etc. can be appropriately blended as necessary.

  Next, a suitable production example (formulation example) of a plaster agent is shown. That is, first, in the case of producing by a hot melt method, first, 5 to 40 parts by weight of the polymer base, 20 to 70 parts by weight of the fat or higher fatty acid at 120 to 160 ° C. using a mixer such as a kneader or a mixer. Then, 10 to 40 parts by weight of the tackifier and 0.1 to 10 parts by weight of the fatty acid metal salt are heated and mixed, and then 0.1 to 10 parts by weight of ketoprofen is added and mixed. The obtained mixture is directly spread on a support, or on a paper, film, etc. that has been subjected to a release treatment, and after being spread, the desired support is covered and transferred by pressure. Also good. On the other hand, in the case of manufacturing by the solvent method, the above components were dissolved in a solvent such as toluene, hexane, methylene chloride using a mixer such as an explosion-proof mixer, and the resulting solution was subjected to a release treatment. After spreading on paper, film, etc., the solvent is distilled off with a drier, and then a pressure transfer is performed with the desired support covered. The plaster agent of the present invention is obtained by applying a release sheet on the spread coating on the support.

Specifically, the support is made of woven fabric, non-woven fabric, polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, polyethylene terephthalate, polybutylene terephthalate, paper, aluminum sheet, or a composite material thereof. Etc. In particular, a polyester cloth made of polyethylene terephthalate or polybutylene terephthalate free from ketoprofen drug adsorption is preferred.
Examples of the release sheet include release paper that has been subjected to release treatment, cellophane, polyethylene, polypropylene, polyvinyl chloride, polyester, polyvinylidene chloride, and silicon processed paper.

  Next, the ointment will be described. The ointment base used in the ointment is selected from those usually used, for example, higher fatty acids or their esters (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, Myristic acid ester, palmitic acid ester, diethyl sebacate, hexyl laurate, cetyl isooctanoate, etc., waxes (eg, whale wax, beeswax, cecilene, etc.), surfactants (polyoxyethylene alkyl ether phosphate, etc.), high grade Alcohol (cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oil (dimethylpolysiloxane, methylphenylpolysiloxane, glycol methylpolysiloxane, silicone glycol polymer, etc.), hydrocarbons (hydrophilic petrolatum, white petrolatum, Lanolin, liquid paraffin, etc.), water, absorption promoters (propylene carbonate, diisopropyl adipate, crotamiton, Azone (registered trademark), etc.), moisturizers (glycerin, propylene glycol, butylene glycol, sorbitol, etc.), anti-rash agents, etc. Additives such as salicylic acid, methyl salicylate, glycol salicylate, l-menthol, camphor, mint oil, etc., etc., and blending ketoprofen with an ointment base made by mixing various components selected from these Thus, the ointment of the present invention can be obtained.

  Next, a suitable production example (formulation example) of an ointment will be shown. That is, first, 5 to 15 parts by weight of a higher fatty acid ester, 1 to 10 parts by weight of a surfactant and 0.1 to 10 parts by weight of ketoprofen are mixed at room temperature or under heating, and 4 to 10 parts by weight of waxes and 50 hydrocarbons. Add ~ 90 parts by weight, heat and maintain at 50-100 ° C. After all the components become a transparent solution, mix uniformly with a homomixer. Then, the ointment of the present invention is obtained by lowering the resulting mixture to room temperature while stirring.

  Next, the gel agent will be described. The gel base used for the gel is selected from those usually used. For example, lower alcohol (ethanol, isopropanol, etc.), water, gelling agent (carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, Methyl cellulose, ethyl cellulose, carboxymethyl cellulose, propylene glycol alginate, etc.), neutralizer (triethanolamine, diisopropanolamine, sodium hydroxide, etc.), surfactant (sorbitan sesquioleate, sorbitan trioleate, sorbitan monooleate) Sorbitan monostearate, sorbitan monolaurate, polyethylene glycol monostearate, polyoxyethylene nonylphenyl ether, polyoxyethylene cetyl acetate , Polyoxyethylene lauryl ether, etc.), absorption accelerators (propylene carbonate, diethyl sepacate, diisopropyl adipate, crotamiton, Aison (registered trademark), propylene glycol, etc.), solubilizers (lower alcohols such as ethanol and isopropanol, cetyl alcohol) , Stearyl alcohol, batyl alcohol, behenyl alcohol, oleyl alcohol, hexadecyl alcohol, octyldodecanol and other higher alcohols, isopropyl myristate, octyldodecyl myristate, cetyl myristate, myristyl myristate, diethyl sebacate, diisopropyl sebacate, adipine Diisopropyl acid, oleyl oleate, hexyl laurate, cetyl isooctanoate, medium chain fatty acid triglyceride, pro Fatty acid esters such as lenglycol fatty acid esters, N-methyl-2-pyrrolidone, triacetin, benzyl alcohol, lanolin alcohol, l-menthyl glyceryl ether, etc.), glycols (glycerin, propylene glycol, polyethylene glycol, polypropylene glycol, sorbitol, 1 , 3-butylene glycol, dipropylene glycol, etc.), anti-rash agent, and other additives (salicylic acid, methyl salicylate, glycol salicylate, l-menthol, camphor, mint oil, etc.) and the like are selected. The gel agent of the present invention can be obtained by blending ketoprofen with a gel base obtained by mixing various components.

  Next, one suitable manufacturing method (formulation example) of a gel is shown. That is, first, 0.5 to 5 parts by weight of a gelling agent is added to 55 parts by weight or less of water and swollen to obtain a swollen material A. On the other hand, 0.1 to 10 parts by weight of ketoprofen is dissolved or suspended in 0.1 to 10 parts by weight of a solubilizer, and further dissolved in a mixture of 40 parts by weight or less of glycols and 60 parts by weight or less of lower alcohol. Object B is obtained. Next, after adding the dissolved material B to the swollen material A, the neutralizing agent is added to adjust the pH value to be 4 to 7, whereby the gel agent of the present invention is obtained.

  Next, the cream will be described. The cream base used in the cream is selected from those usually used, for example, higher fatty acid esters (adipic acid ester, myristic acid ester, palmitic acid ester, diethyl sebacate, hexyl laurate, isooctanoic acid Cetyl, etc.), lower alcohols (ethanol, isopropanol, etc.), carbohydrates (liquid paraffin, squalane, etc.), polyhydric alcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, 2-octyl) Dodecanol, etc.), emulsifiers (polyoxyethylene alkyl ethers, fatty acid esters, polyethylene glycol fatty acid esters, etc.), preservatives (paraoxybenzoic acid esters, etc.), absorption promoters (propylene carbonate, diethyl ether) Kate, diisopropyl adipate, crotamiton, Azone (registered trademark), propylene glycol, etc.), anti-rash agent, other additives (salicylic acid, methyl salicylate, glycol salicylate, l-menthol, camphor, mint oil, etc.), etc. The cream of the present invention can be obtained by blending ketoprofen with a cream base obtained by mixing various components selected from these.

  In addition, in order to obtain a gel cream having intermediate properties between a cream and a gel, a gelling agent (carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose is added to the above cream. , Propylene glycol alginate, etc.), and neutralizing agents (triethanolamine, diisopropanolamine, sodium hydroxide, etc.) are added, and the pH is adjusted to 4-8 (preferably 5-6.5). The gel cream of the invention can be obtained.

  Next, a preferred production example (formulation example) of a gel cream will be shown. That is, first, 0.1 to 10 parts by weight of ketoprofen is dissolved in a mixture of 25 parts by weight or less of a higher fatty acid ester and 40 parts by weight or less of a lower alcohol, and 0.5 parts by weight or less of an antiseptic and 5 parts by weight or less of an emulsifier are added. To obtain mixture A. On the other hand, a swelling agent B is obtained by adding a gelling agent to water so as to have a concentration of 0.5 to 5 parts by weight to swell. Next, after adding the swollen material B to the mixture A and uniformly emulsifying with a homomixer, a neutralizing agent is added to the obtained emulsion to adjust the pH value to 4 to 8, thereby The gel cream of the invention is obtained.

  Next, the liniment is described. The liniment base used in the liniment is selected from those commonly used. For example, alcohols (monohydric alcohols such as ethanol, propanol and isopropanol, polyvalent glycols such as polyethylene glycol, propylene glycol and butylene glycol) Alcohol, etc.) 10-70 parts by weight, fatty acid ester (adipic acid, sebacic acid, various esters of myristic acid, etc.) 60 parts by weight or less, surfactant (polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, etc.) 10 weight The liniment of the present invention can be obtained by blending 0.1 to 10 parts by weight of ketoprofen with such a liniment base. In the liniment, if necessary, a neutralizing agent for adjusting pH or a viscosity imparting agent such as methylcellulose, a rash prevention agent, and other additives (salicylic acid, methyl salicylate, glycol salicylate, l-menthol, camphor, Peppermint oil, pepper extract, nonyl acid vanillylamide, crotamiton, Azone (registered trademark), propylene carbonate, diisopropyl adipate, etc.) may be blended.

  As mentioned above, although the suitable embodiment of the base according to each dosage form of the external preparation of the present invention and a prescription example was described, the dosage form and the prescription example are not limited to these, and the blending order of each component is particularly It is not limited. For example, the aerosol agent of the present invention can be obtained by substituting 0.1 to 10 parts by weight of a medicinal component in a conventionally known aerosol formulation.

  Moreover, in the external preparation of this invention, in addition to the said prescription, antioxidant, UVA blocker, UVB blocker, etc. may be further mix | blended. As the antioxidant, tert-butylhydroxyanisole, di-tert-butylhydroxytoluene, thymol, phenol derivatives such as propyl gallate, tocopherol and its ester derivatives, ascorbic acid and its ester derivatives are preferable. Such antioxidant may be used individually by 1 type, and may be used in combination of 2 or more type. The blending amount is not particularly limited, but is preferably 0 to 10% by weight, and more preferably 0 to 5% by weight based on the total amount of the preparation.

  The UVA blocking agent is an inorganic UVA blocking agent or an organic UVA blocking agent such as a dibenzoylmethane derivative, a benzophenone derivative, a cinnamic acid derivative, a camphor derivative, a benzotriazole derivative, an amino acid compound, or a benzoyl pinacolone derivative. May be. Inorganic UVA blocking agents include zinc oxide, dibenzoylmethane derivatives as 4-tert-butyl-4′-methoxydibenzoylmethane, and benzophenone derivatives as 2- (4-diethylamino-2-hydroxybenzoyl) benzoic acid. Examples of the acid n-hexyl ester, cinnamic acid derivative and esters thereof include 4-hydroxy-3-methoxycinnamic acid such as 4-hydroxy-3-methoxycinnamic acid and 4-hydroxy-3-methoxycinnamic acid isostearyl. Branched alkyl esters of acids, camphor derivatives as terephthalylidene-3,3′-diccamphor-10,10′-disulfonic acid, and benzotriazole derivatives as 2- (2H-benzotriazol-2-yl) -4-methyl-6- [2-methyl-3- [1,3,3,3-teto Methyl-1-[(trimethylsilyl) oxy] disiloxanyl] propyl] phenol, dimethoxybenzylidenedioxoimidazolidinepropionic acid 2-hexyl ester as an amino acid compound, and 1- (3,4-dimethoxyphenyl) as a benzoylpinacolone derivative ) -4,4-dimethyl-1,3-pentanedione is preferred respectively. The blending amount of the UVA blocking agent is not particularly limited, but is, for example, 0.01 to 20% by weight, preferably 0.5 to 20% by weight, more preferably 1 to 15% by weight based on the total amount of the preparation. %, More preferably 2 to 10% by mass.

  The UVB blocker is a benzophenone derivative, cinnamic acid derivative, camphor derivative, amino acid compound, benzoyl pinacolone derivative, etc., and the benzophenone derivative is 2- (4-diethylamino-2-hydroxybenzoyl) ) Benzoic acid n-hexyl ester, cinnamic acid derivatives and esters thereof include 4-hydroxy-3-methoxy such as 4-hydroxy-3-methoxycinnamic acid and 4-hydroxy-3-methoxycinnamic acid isostearyl. Cinnamic acid branched chain alkyl esters, camphor derivatives include terephthalylidene-3,3′-diccamphor-10,10′-disulfonic acid, and amino acid compounds include dimethoxybenzylidene dioxoimidazolidinepropionic acid 2- Hexyl ester, benzoy The pinacolone derivative, 1- (3,4-dimethoxyphenyl) -4,4-dimethyl-1,3-pentanedione is preferable, respectively. The blending amount of the UVB blocking agent is not particularly limited, but is, for example, 0.01 to 20% by weight, preferably 0.5 to 20% by weight, more preferably 1 to 15% by weight based on the total amount of the preparation. %, More preferably 2 to 10% by mass.

  The ketoprofen-containing external preparation of the present invention includes the above-described external preparation that maintains the ketoprofen concentration in tissues such as muscles and tendons at a predetermined concentration or more, and a ketoprofen-containing external preparation that has the same bioavailability in a bioequivalence test. included. A bioequivalence test here is bioequivalent, ie, bioavailability (the rate and amount of unchanged or active metabolites entering the systemic blood or the rate and amount of reaching the site of action). This refers to a test for determining whether or not they are equivalent. Specifically, whether or not the bioavailability is equivalent is described in, for example, No. 1124005 of the Dietary Diet Review dated November 24, 2006 (2006). , The bioequivalence test described in the “Guidelines for Bioequivalence Tests for Generic Drugs” and “Guidelines for Bioequivalence Tests for Generic Drugs for Topical Skin Application” established by the Ministry of Health, Labor and Welfare in Japan Can be determined.

For example, in the “Guidelines for Bioequivalence Testing of Generic Drugs”, when the crossover method is performed in principle and blood is used as a collected body fluid, AUC _t (AUC up to the final sampling time t) is used in a single-dose test. (Area under blood concentration-time curve)) and Cmax (maximum blood concentration) are used as bioequivalence determination parameters. When F (relative absorption rate of the test preparation relative to the reference preparation (aqueous solution or intravenous administration)) can be calculated by deconvolution, F can be used instead of AUC. For reference parameter, AUC _∞ (infinity AUC up to the time), tmax (in maximum blood concentration arrival time or maximum urinary excretion rate arrival time), MRT (mean residence time), the like kel (elimination rate constant) . When urine is used as a collected body fluid, Ae _t (cumulative urinary excretion up to the final sampling time t), Ae _τ (cumulative urinary excretion within one administration interval (τ) after reaching a steady state) , Ae _∞ (cumulative urinary excretion up to infinite time), Umax (maximum urinary excretion rate) and U _τ (urinary excretion rate at τ time after administration in steady state) are _expressed as AUC _t and AUC _τ (steady state) Used as parameters to replace AUC),） _{∞ ∞} , Cmax and C _τ (blood concentration at τ time after administration in steady state) after reaching the state.

  The “Bioequivalence Test Guidelines for Generic Drugs for Topical Skin Application Formulations” 1. Skin pharmacokinetic test (equivalence evaluation parameter: drug recovery amount in the steady state, average drug concentration in stratum corneum or drug concentration in stratum corneum) 2. Pharmacological test (equivalence evaluation parameter: AUEC (whitening intensity after preparation removal—area under the time curve)) 3. Residual amount test (equivalence evaluation parameter: amount of drug distributed from the preparation to the skin) 4. Pharmacokinetic test (equivalence evaluation parameter: blood concentration in AUC or steady state), 5. Clinical trial (with clinical effect as index), 6. In vitro efficacy test (in vitro efficacy is used as an index), When assessing the bioequivalence of topical skin preparations, such as animal studies (indicating pharmacological reactions that occur on the skin surface of animals as a result of application of the preparations) You can select the test method.

Each test method as described above is appropriately selected, and the bioequivalence determination parameters of the obtained test preparation and standard preparation are statistically processed. When the test preparation and the standard preparation are within a predetermined range, For example, in the above-mentioned “Guidelines for Bioequivalence Testing of Generic Drugs”, the bioequivalent tolerance range is a test when AUC and Cmax are lognormally distributed. 90% confidence interval for the difference between the mean values of the logarithmic values of the bioequivalence determination parameters of the test formulation and the standard formulation, which is 0.80 to 1.25 when expressed as the population average ratio of the formulation and standard formulation parameters Is in the range of log (0.80) to log (1.25), the test formulation and the standard formulation are determined to be bioequivalent. In the “Bioequivalence Test Guidelines for Generic Drugs for Topical Skin Formulations” described above, when the equivalence evaluation parameter can be regarded as a lognormal distribution, When expressed as the population average ratio of the parameters of the standard formulation, 0.80 to 1.25 for drugs with strong action, 0.70 to 1.43 for drugs with strong action, and the equivalence evaluation parameter is normal. When the distribution is considered to be distributed, when the difference between the population mean of the parameters of the test product and the standard product is expressed as the ratio to the population mean of the standard product, it is -0.20 to +0.20 for drugs with strong action, other than those with strong action -0.30 to +0.30 for pharmaceuticals of When an evaluation is conducted in an efficacy test or a clinical trial, an appropriate tolerance can be set according to the characteristics of the drug.
The bioequivalence tests described in these guidelines are well known to those skilled in the art.
EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples. In the examples, “parts” means all parts by weight.

Example 1
Styrene-isoprene-styrene block copolymer 25.0 parts Liquid paraffin (softener) 55.0 parts Rosin ester derivative 18.0 parts Ketoprofen 2.0 parts A patch was prepared according to the above formulation. That is, using a kneader as a mixer, heat-mix the styrene-isoprene-styrene block copolymer, softener and rosin ester derivative at 120-160 ° C., then add and mix ketoprofen, and directly spread on a polyester cloth (PET). And then cut to the desired size.

(Tissue and plasma ketoprofen concentration measurement test)
Patients undergoing anterior cruciate ligament reconstruction (37 cases) were divided into the following 6 groups and administered with ketoprofen. After a predetermined time, the half-tendon-like muscle tendon as a material for transplantation was removed, and the concentration of ketoprofen in unnecessary tissues (muscles and tendons) and in plasma was measured.
(1) Group: One hour patch group (7 cases)
(2) Group: 6-hour patch group (6 cases)
(3) Group: Patch 14-hour patch group (6 cases)
(4) Group: 20-hour patch group (2 cases)
(5) Group: Oral administration group (6 cases)
(6) Group: Control group (10 cases)

  In the groups (1) to (4), two patches (Example 1) (7 cm × 10 cm) of the present invention were affixed on the semi-tendon-like muscles so as to coincide with each other. The group (5) orally administered ketoprofen sustained release capsule (Ordis SR150 (Abbott Japan Co., Ltd.)) 14 hours before the start of surgery, and the group (6) was not administered any drug.

(Quantitative method for ketoprofen)
The plasma stored at −20 ° C. and ketoprofen concentration in each tissue were measured by HPLC by LC-MS-MS (Liquid chromatography coupled with mass spectrometry).
(result)
Table 1 shows the concentration (average value) of ketoprofen in each tissue and plasma in groups (1) to (4).

The concentration of ketoprofen in the tissue of the 14-hour patch group (group (3)) of the present invention was comparable to that of the oral drug administration group (group (5)). The plasma ketoprofen concentration in the) group was 196 ng / mL, about 1/17 of the (5) group (3365 ng / mL) (FIG. 1).
The ratio of the tissue ketoprofen concentration to the plasma ketoprofen concentration in the 14-hour patch group (group (3)) of the present invention was about 15 to 20 times that of the oral preparation group (group (5)). (Table 2).

In the groups (1) to (4), changes in the tissue and plasma ketoprofen concentrations over time increased more rapidly in the tissue than in the plasma. The concentration in the tissue quickly became the same level as that in the oral administration group (group (5)) 1 hour after the application, and was maintained until 20 hours after the application (FIG. 2).
The patch of the present invention is fast-acting and can maintain the same effect as an oral preparation for a long time. The patch of the present invention has a low systemic blood concentration and is safer than an oral preparation. In the patch of the present invention, it was suggested that ketoprofen was directly transferred from the application position to the tissue immediately below.

(Inhibition of joint pain in patients with rheumatoid arthritis)
The patch of the present invention (Example 1) (7 cm × 10 cm) is applied to 300 patients with rheumatoid arthritis with persistent pain on the wrist, once a day (one per time) to one test site. ), The superiority of the joint pain improvement effect was verified by a placebo-controlled randomized double-blind method with the rate of change in pain VAS by the patient as the primary endpoint.
(result)
A significant effect was observed in the patch of the present invention.

  From the above results, the external preparation of the present invention that achieves a ketoprofen concentration of a predetermined concentration or more in the tissue for a certain period after administration, and the external preparation that realizes such a ketoprofen concentration has an effect of suppressing rheumatoid arthritis pain Was found.

It is the graph compared with the case where the oral agent is administered about the ketoprofen density | concentration in each structure | tissue and plasma 14 hours after sticking the patch of this invention. It is a graph which shows the time-dependent change of the ketoprofen density | concentration in each structure | tissue and plasma at the time of sticking the patch of this invention.

Claims (6)

  A ketoprofen-containing external preparation having an analgesic effect on pain of rheumatoid arthritis, wherein the concentration of ketoprofen in muscle and / or tendon after administration reaches 30 ng / g or more.   The ketoprofen-containing external preparation according to claim 1, wherein the concentration is 30 ng / g or more until at least 14 hours after the concentration of ketoprofen in muscle and / or tendon reaches 30 ng / g or more.   The ketoprofen-containing external preparation according to claim 1 or 2, wherein the concentration of ketoprofen in muscle and / or tendon 1 hour after administration is 30 ng / g or more.   The ketoprofen-containing external preparation according to any one of claims 1 to 3, wherein the concentration of ketoprofen in plasma does not exceed 500 ng / mL after administration.   The ketoprofen-containing external preparation according to any one of claims 1 to 4, which is a patch.   It is a ketoprofen-containing external preparation, wherein the ketoprofen-containing external preparation according to any one of claims 1 to 5 has the same bioavailability in a bioequivalence test.

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