JP2008241245A - Medicinal effect evaluation method of external medicine having analgesic effect with respect to pain of articular rheumatism - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicinal effect evaluation method of a new external medicine for articular rheumatism. <P>SOLUTION: In the medicinal effect evaluation method of the external medicine containing ketoprophene having the analgesic effect to the pain of articular rheumatism using the concentration of ketoprophene in muscle tissue and/or a tendon as an index, especially in a case that the concentration of ketoprophene in the muscle and/or tendon after administation reaches 30 ng/g or higher, the external medicine is evaluated to be effective for the analgesic effect to the pain of articular rheumatism. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for evaluating the efficacy of an external preparation having an analgesic effect on rheumatoid arthritis pain. In particular, the present invention relates to an external preparation having an analgesic effect on pain of rheumatoid arthritis containing ketoprofen as an active ingredient.

  Conventionally, as a method for evaluating the efficacy of a pharmaceutical preparation for rheumatoid arthritis, a method of quantifying clinical findings using the number of painful joints and the number of swollen joints as evaluation items, rheumatoid factor in blood, CRP (C-reactive protein), etc. A method is used as an indicator. In addition, it has been reported that an interleukin-1 receptor antagonist in urine is used as an index (Patent Document 1). The former method of quantifying the clinical findings is likely to cause variations in evaluation due to differences between observers and facilities, and the latter method that uses markers in blood or urine as an index selects the appropriate marker. There is no known method for determining the analgesic effect on rheumatoid arthritis pain in a short time, such as a long observation period is required for either method. It was.

Furthermore, a method for evaluating the efficacy of an external preparation having an analgesic effect on rheumatoid arthritis pain using the drug concentration in tissues such as muscles and tendons as an index has not been known so far.
Japanese Patent No. 3530239

  The subject of this invention is providing the medicinal-effect evaluation method of the external preparation which has the analgesic effect with respect to the pain of a new rheumatoid arthritis.

  In order to solve the above-mentioned problems, the present inventors have found that the pain suppression effect of rheumatoid arthritis depends on the drug concentration in tissues such as muscles and tendons, and further exerts such an effect. In other words, it has been found that this can be realized if the concentration is maintained at a predetermined concentration or higher, or if the predetermined concentration is maintained for a long time. As a result of further research based on these findings, the present invention has been completed.

That is, the present invention relates to a method for evaluating the efficacy of a ketoprofen-containing external preparation having an analgesic effect on rheumatoid arthritis pain, using the ketoprofen concentration in muscle tissue and / or tendon tissue as an index.
Furthermore, the present invention evaluates the efficacy as described above, wherein when the intramuscular and / or tendon ketoprofen concentration after administration reaches 30 ng / g or more, it is evaluated as having an analgesic effect on the pain of rheumatoid arthritis. Regarding the method.
The present invention also provides rheumatoid arthritis pain when the concentration of ketoprofen in muscle and / or tendon reaches 30 ng / g or more within 1 hour at the latest and the concentration is 30 ng / g or more until at least 14 hours after administration. It is related with the said medicinal-effect evaluation method evaluated that it is effective as having the analgesic effect with respect to.
Furthermore, this invention relates to the said medicinal efficacy evaluation method whose ketoprofen containing external preparation is a ketoprofen containing patch.
The present invention also relates to a ketoprofen-containing external preparation that has an analgesic effect on rheumatoid arthritis pain, which has been evaluated as effective by the above-described method for evaluating efficacy.
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.

  Since the method for evaluating drug efficacy of the present invention uses ketoprofen concentration in muscle tissue and / or tendon tissue as an index, it is more correlated with the state of drug delivery to the affected area, unlike using substances in blood or urine as an index. It is possible to accurately evaluate the efficacy of the drug. Moreover, since the preparation for external use is targeted, the increase in concentration in the tissue is fast, and simple evaluation can be performed in a short time. Thus, as a drug having an analgesic effect on rheumatoid arthritis pain, a topical preparation containing ketoprofen is expected to have a low concentration and high compliance (safety) compared to oral preparations, for example. When there is no appropriate drug efficacy evaluation method, the present invention has an extremely great significance of providing a very simple and accurate drug efficacy evaluation method for ketoprofen-containing external preparations.

Hereinafter, suitable implementation of the medicinal effect evaluation method of the present invention will be described in detail.
The method for evaluating the efficacy of an external preparation having an analgesic effect on rheumatoid arthritis pain according to the present invention is characterized by using as an index the ketoprofen concentration in muscle tissue and / or tendon tissue after administration of the external preparation.

The method for evaluating the efficacy of an external preparation having an analgesic effect on rheumatoid arthritis pain according to the present invention is performed, for example, by the following procedure.
a. A candidate topical preparation containing ketoprofen is administered to the subject group as an external preparation having an analgesic effect on rheumatoid arthritis pain.
b. From the subject group, muscle tissue, tendon tissue, and plasma are collected as samples after a certain time after administration.
c. Measure the ketoprofen concentration in each sample.
d. A candidate external preparation whose ketoprofen concentration in muscle and / or tendon has reached a predetermined concentration is evaluated as effective as having an analgesic effect on rheumatoid arthritis pain.

In addition to the above procedures a to d, the following procedures e and f may be arbitrarily combined to evaluate the drug efficacy.
e. When the concentration of ketoprofen in muscle and / or tendon reaches 30 ng / g or more and is at least 30 ng / g until at least 14 hours after administration, it is effective as having an analgesic effect on rheumatoid arthritis pain. And evaluate.
f. The topical agent evaluated as effective is administered to patients with rheumatoid arthritis and the pain suppression effect is confirmed.
By performing the above procedure e, it is possible to discriminate external preparations having sustained drug efficacy.

  When the ketoprofen concentration in muscle tissue reaches 30 ng / g or more after administration, for example, 1 hour after administration, it is evaluated as having an analgesic effect on rheumatoid arthritis pain. In particular, when it reaches 40 ng / g or more, especially 50 ng / g or more, it is evaluated that it is more effective. Furthermore, it is evaluated that the effectiveness of the external preparation is more effective when it is maintained at the predetermined concentration or more for at least 14 hours, particularly 20 hours or more after reaching the predetermined concentration.

  Similarly, when the ketoprofen concentration in the tendon tissue reaches 30 ng / g or more after administration, for example, 1 hour after administration, it is evaluated as having an analgesic effect on rheumatoid arthritis pain. In particular, when it reaches 50 ng / g or more, especially 100 ng / g or more, it is evaluated that it is more effective. Furthermore, it is evaluated that the effectiveness of the external preparation is more effective when it is maintained at the predetermined concentration or more for at least 14 hours, particularly 20 hours or more after reaching the predetermined concentration.

  Furthermore, if the ketoprofen concentration in plasma does not exceed 500 ng / mL after administration, side effects and burden on the body are evaluated to be reduced. In particular, if it does not exceed 300 ng / mL, and particularly does not exceed 200 ng / mL, it is evaluated that the burden is further reduced.

  The external preparation evaluated as effective by the above evaluation method is used as an external preparation having an analgesic effect on the pain of rheumatoid arthritis. And the external preparation used as the object of the medicinal effect evaluation method is not limited as long as it is transdermally administered. For example, patches, liquids, lotions, creams, gels, ointments such as poultices or plasters, Examples include liniments and sprays.

The bases and formulation examples according to each dosage form of the external preparation that can be the target of the medicinal effect evaluation method of the present invention will be described below.
First, a patch such as a poultice or a plaster will be described. The patch that can be the target of the method for evaluating the efficacy 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 (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. By blending ketoprofen with a poultice base formed by mixing various components, a poultice targeted for the method for evaluating the efficacy of the present invention can be obtained.

  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 and coated on a support by a usual method, and then a release sheet is stuck thereon to obtain a poultice targeted for the medicinal efficacy evaluation method 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 By adding ketoprofen to the mixture, a plaster agent that is an object of the method for evaluating the efficacy of the present invention can be obtained.

  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. By attaching a release sheet on the spread coating on the support, a plaster agent that is the subject of the method for evaluating the efficacy of the present invention can be obtained.

  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, an ointment that is a target of the medicinal effect evaluation method 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 which becomes the object of the medicinal effect evaluation method of the present invention is obtained by lowering the obtained 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. By blending ketoprofen with a gel base obtained by mixing various components, a gel agent that is the subject of the method for evaluating the efficacy of the present invention can be obtained.

  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. Subsequently, after adding the dissolved material B to the swollen material A, a neutralizing agent is added to adjust the pH value to 4 to 7, thereby obtaining a gel agent that is a target of the medicinal effect evaluation method of the present invention. It is done.

  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.) By blending ketoprofen with a cream base formed by mixing various components selected from these, a cream that is the subject of the method for evaluating the efficacy of the present invention can be obtained.

  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-like cream agent used as the object of the medicinal effect evaluation method 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 A gel cream that is the subject of the method for evaluating the efficacy 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 which becomes the object of the method for evaluating the efficacy 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 described above, the preferred embodiments of the base and the prescription examples according to each dosage form of the external preparation that is the target of the method for evaluating the efficacy of the present invention have been described, but the dosage forms and the prescription examples are not limited to these, The blending order of each component is not particularly limited. For example, in a conventionally known aerosol formulation, by substituting 0.1 to 10 parts by weight of the medicinal component with ketoprofen, it is possible to obtain an aerosol that is the target of the medicinal evaluation method of the present invention.

  Moreover, in the external preparation used as the object of the medicinal effect evaluation method of the present invention, an antioxidant, a UVA blocker, a UVB blocker and the like may be further blended in addition to the above prescription. 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 a ketoprofen-containing external preparation that is equivalent in the bioequivalence test to the external preparation evaluated as effective by the method for evaluating the efficacy of the external preparation having an analgesic effect on the pain of rheumatoid arthritis. Is 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 is a test for determining whether or not they are equivalent. Specifically, whether or not the bioavailability is equivalent is, for example, No. 1124005 issued on November 24, 2006 (2006). Bioequivalence described in “Guidelines for Bioequivalence Testing for Generic Drugs” and “Guidelines for Bioequivalence Testing for Generic Drugs for Topical Dermal Preparations” established by the Ministry of Health, Labor and Welfare in Japan It can be determined by testing.

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.

Formulation Example 1 (Patch)
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)
Ketoprofen was administered to the patients (31 cases) undergoing anterior cruciate ligament reconstruction in 5 groups. 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: Control group (10 cases)

  In the groups (1) to (4), two patches (formulation example 1) (7 cm × 10 cm) were affixed so as to coincide with the half-tendon-like muscles. (5) Group did not administer 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).

Table 2 shows the ratio of the ketoprofen concentration in the tissue to the plasma ketoprofen concentration in the 14-hour patch group (group (3)).

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 reached a concentration of 30 ng / g or more 1 hour after application, and was maintained until 20 hours after application (FIG. 1).
Formulation Example 1 (patch) is fast-acting and can maintain an analgesic effect for a long time. In addition, Formulation Example 1 has a low systemic blood concentration and is safer than when an oral preparation is used. In Formulation Example 1, it was suggested that ketoprofen was directly transferred from the attachment position to the tissue immediately below.

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

From the above results, it was found that an external preparation that achieves a ketoprofen concentration of a predetermined concentration or more in a tissue for a certain period after administration has an effect of suppressing rheumatoid arthritis pain.
Therefore, by using the ketoprofen concentration in tissues (particularly muscle tissue and tendon tissue) as an index, it is possible to select candidates for external preparations that can be ketoprofen-containing external preparations that have an analgesic effect on rheumatoid arthritis pain, and evaluate the drug efficacy It became possible.

It is a graph which shows a time-dependent change of the ketoprofen density | concentration in each structure | tissue and plasma at the time of sticking the formulation example 1 (patch).

Claims (6)

  A method for evaluating the efficacy of an external preparation containing ketoprofen having an analgesic effect on rheumatoid arthritis pain, using the ketoprofen concentration in muscle tissue and / or tendon tissue as an index.   The method for evaluating efficacy according to claim 1, wherein when the ketoprofen concentration in the muscle and / or tendon after administration reaches 30 ng / g or more, it is evaluated as effective as having an analgesic effect on rheumatoid arthritis pain. .   Has an analgesic effect on rheumatoid arthritis pain when the intramuscular and / or tendon ketoprofen concentration reaches 30 ng / g or more within 1 hour at the latest and is at least 30 ng / g until 14 hours after administration. The method for evaluating efficacy according to claim 2, wherein the method is evaluated as effective.   The medicinal efficacy evaluation method according to any one of claims 1 to 3, wherein the ketoprofen-containing external preparation is a ketoprofen-containing patch.   The ketoprofen containing external preparation which has the analgesic effect with respect to the pain of rheumatoid arthritis evaluated with the efficacy evaluation method in any one of Claims 1-4.   It is a ketoprofen-containing external preparation, wherein the ketoprofen-containing external preparation according to claim 5 has the same bioavailability in a bioequivalence test.

Images