WO2020116570A1 - External preparation for skin - Google Patents

External preparation for skin Download PDF

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Publication number
WO2020116570A1
WO2020116570A1 PCT/JP2019/047652 JP2019047652W WO2020116570A1 WO 2020116570 A1 WO2020116570 A1 WO 2020116570A1 JP 2019047652 W JP2019047652 W JP 2019047652W WO 2020116570 A1 WO2020116570 A1 WO 2020116570A1
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Prior art keywords
group
steroid
skin
resolvin
external preparation
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PCT/JP2019/047652
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French (fr)
Japanese (ja)
Inventor
健治 椛島
本田　哲也
雄宇 澤田
Original Assignee
一般財団法人リディアオリリー記念ピアス皮膚科学振興財団
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Priority to JP2020560012A priority Critical patent/JP7309215B2/en
Publication of WO2020116570A1 publication Critical patent/WO2020116570A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a skin external preparation.
  • Steroids have been widely used as pharmaceuticals since they have many actions such as anti-inflammatory, anti-allergic, or immunosuppression.
  • injections Steroid preparations having various dosage forms such as oral preparations, suppositories, and external preparations are known.
  • the widespread use of steroid preparations is due to the strong activity of steroids.
  • side effects also strongly appear in proportion to this activity. Therefore, clinically, steroids are currently used in consideration of their efficacy and side effects.
  • steroid external preparations used for the treatment of eczema are classified into 5 groups (group I: strongest, group II: very strong, group III: strong, group IV: medium, group V: weak) depending on the strength of anti-inflammatory action. Often classified into. Since the occurrence of side effects is almost parallel to the strength of drug efficacy, this classification is extremely useful when used in actual patients.
  • Patent Document 1 in the oil containing the long-chain ⁇ -3 polyunsaturated fatty acid extracted from organisms such as fish and crustaceans, a specific inflammation converging mediator (Specialized Proresolving Mediator: SPM) and It contains an SPM precursor, and the SPM contains Resolvin E1 (5S,12R,18R-trihydroxy-eicosa-6Z,8E,10E,14Z,16E-pentaenoic acid).
  • SPM Specific inflammation converging mediator
  • Resolvin E1 5S,12R,18R-trihydroxy-eicosa-6Z,8E,10E,14Z,16E-pentaenoic acid.
  • Patent Document 1 does not describe how much resolvin E1 exerts an anti-inflammatory effect on the skin.
  • the present invention has been made in view of the above-mentioned conventional state of the art, and an object thereof is to provide a skin external preparation. Further, a preferred object of the present invention is to provide an external preparation for skin having an excellent anti-inflammatory effect. Further, a preferred object of the present invention is to provide an external preparation for skin which has excellent anti-inflammatory effect, particularly excellent durability, and has few side effects.
  • the present inventors have conducted intensive studies to achieve the above-mentioned object, and as a result, by combining resolvin E1 and a steroid drug classified as a glucocorticoid receptor agonist, the anti-inflammatory effect of both is enhanced and , Found that sustainability is enhanced.
  • the steroid drug is classified as a V group (weak) in terms of classification, when used in combination with Resolvin E1, it has the same level as a steroid drug classified as a III group (strong). It has been found that a strong anti-inflammatory effect is obtained, and further, a decrease in the anti-inflammatory effect over time is suppressed, and a good anti-inflammatory effect lasts for a long time. Since steroids classified into group V (weak) have low side effects corresponding to the degree of drug efficacy, it can be said that it is desirable that the combination with resorbin E1 enhances the anti-inflammatory effect and maintains it.
  • the present invention has been completed by further research based on these findings, and has the following embodiments.
  • External preparation for skin An external preparation for skin which is a combination of resolvin E1 and a glucocorticoid receptor agonist.
  • I-2 A composition (combination drug) in which the combination of resolvin E1 and a glucocorticoid receptor agonist contains resolvin E1 and a glucocorticoid receptor agonist, or a preparation containing resolvin E1 (for example, skin
  • the external preparation for skin according to (I-1) which is a combination product (kit, set) of a preparation (external preparation) and a preparation containing a glucocorticoid receptor agonist (for example, external preparation for skin).
  • V group steroid drug a steroid drug classified into V group (weak)
  • IV group a steroid drug classified into IV group (medium)
  • An external preparation for skin which is a combination with a group IV steroid.
  • composition (combined preparation) containing the resolvin E1 and a group V steroid agent or a group IV steroid agent containing the resolvin E1 and a group V steroid agent or a group IV steroid agent, or resolvin E1 A combination product (kit, set) of a preparation containing (for example, a skin external preparation) and a preparation containing a group V steroid agent or a preparation containing a group IV steroid agent (for example, a skin external preparation), (I -3) External preparation for skin.
  • Group V steroid is selected from the group consisting of prednisolone, prednisolone acetate, fradiomycin sulfate, dexamethasone, hydrocortisone acetate, fludoxycortide, betamethasone, a mixture of betamethasone and chlordeniramine maleate, and hydrocortisone.
  • the at least one group IV steroid is at least one selected from the group consisting of valeric acid/prednisolone acetate, hydrocortisone butyrate, clobetasone butyrate, alclomethasone propionate, triamcinolone acetonide, and flumethasone pivalate.
  • the external preparation for skin according to I-3) or (I-4).
  • the glucocorticoid receptor agonist, or the group V or IV steroid is prednisolone, prednisolone acetate, valeric acid/prednisolone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, dexamethasone, betamethasone, betamethasone and malein.
  • the glucocorticoid receptor agonist or the V-group steroid is at least one selected from the group consisting of prednisolone and prednisolone acetate.
  • the external preparation for skin according to any one of items.
  • the resolvin E1 and the glucocorticoid receptor agonist or the steroid drug are used in a molar ratio of 1:1000 to 1:2, preferably 1:100 to 1:10, more preferably 1:50 to
  • (I-10) For treating or preventing at least one skin disease selected from the group consisting of eczema, dermatitis, psoriasis, prurigo group, palmoplantar pustulosis, pruritus cutis, erythema, and erythroderma
  • the external preparation for skin according to any one of (I-1) to (I-9), which is a pharmaceutical.
  • (II) Method of using external preparation for skin (II-1)
  • a step of applying an effective amount of the external preparation for skin according to any one of (I-1) to (I-10) above to the skin of mammals A method for reducing inflammation of the skin, comprising: (II-2)
  • the mammal has at least one skin disease selected from the group consisting of eczema, dermatitis, psoriasis, prurigo group, palmoplanter pustulosis, pruritus cutaneus, erythema, and erythroderma.
  • (II-1) which is an affected animal, and which has a step of applying an effective amount of the external preparation for skin according to any one of (I-1) to (I-10) to the affected area How to list.
  • (II-3) A combination of resolvin E1 and a glucocorticoid receptor agonist, or a combination of resolvin E1 and a group V or group IV steroid drug, which is used for the prevention or treatment of skin inflammation.
  • (II-4) Use for prevention or treatment of at least one skin disease selected from the group consisting of eczema, dermatitis, psoriasis, prurigo group, palmoplanter pustulosis, pruritus cutis, erythema, and erythroderma
  • Prophylactic or therapeutic agent for at least one skin disease selected from the group consisting of eczema, dermatitis, psoriasis, prurigo group, palmoplanter pustulosis, pruritus cutis, erythema, and erythroderma
  • An external preparation for skin comprising a combination of resolvin E1 which is one aspect of the present invention and a steroid drug classified as a glucocorticoid receptor agonist exhibits a high anti-inflammatory effect and is durable when used in combination. It is useful as an anti-inflammatory agent.
  • a skin external preparation comprising a combination of the resolvin E1 which is one embodiment of the present invention and a steroid agent (group V steroid agent or group IV steroid agent) classified into V group (weak) or IV group (medium) in classification. By including both, it is possible to obtain an anti-inflammatory effect equivalent to that of the class III (strong) steroid drug in terms of classification.
  • the external preparation for skin of the present invention can reduce the side effects that may occur due to the use of steroids. Therefore, the external preparation for skin is useful as an anti-inflammatory agent that exerts a high anti-inflammatory effect while suppressing the occurrence of side effects. Furthermore, the external preparation for skin which is a combination of Resolvin E1 and a group V or group IV steroid, preferably a group V steroid, has a long-lasting efficacy in addition to the above-mentioned effects, while suppressing the occurrence of side effects. It is also useful as a long-lasting anti-inflammatory agent that exerts a high anti-inflammatory effect.
  • External preparation for skin is an external preparation for skin obtained by combining resolvin E1 and a glucocorticoid receptor agonist.
  • Resolvin E1 is 5S,12R,18R-trihydroxy-eicosa-6Z,8E,10E,14Z,16E-pentaenoic acid, which is a compound known as a specific inflammatory converging mediator (SPM).
  • SPM specific inflammatory converging mediator
  • RvE1 can be produced according to a known production method, for example, the production method described in Ogawa N, Kobayashi Y. Tetrahedron lett. 2009; 50:6079-6082.
  • RvE1 is a natural component contained in oil containing long-chain ⁇ -3 polyunsaturated fatty acids extracted from fish, crustaceans, algae, or molluscs, It can also be extracted and isolated from an oil containing a polyunsaturated fatty acid (for example, Patent Document 1 described above).
  • the RvE1 used in the present invention may be a synthetic product or a naturally derived product as long as it has the effect. Further, it may be a purified product or a crudely purified product. Examples of the crude product include, but are not limited to, the aforementioned long-chain ⁇ -3 polyunsaturated fatty acid-containing oil, or its RvE1-containing fraction.
  • a glucocorticoid receptor agonist is a drug that exerts a medicinal effect including an anti-inflammatory action by binding to a glucocorticoid receptor.
  • Examples of the steroid drug classified as a glucocorticoid receptor agonist include, but are not limited to, the following (Nippon Pharmacologic Journal, Folia Pharmacol. Jpn. 128, 411-415, 2006).
  • Clobetasol propionate diftrazone acetate; mometasone furoate, betamethasone butyrate propionate, fluocinonide, betamethasone dipropionate, difluprednate, putesonide, amcinonide, diflucortron valerate, hydrocortisone butyrate propionate dexamethasone oxalate, dexamethasone valerate, , Betamethasone valerate, beclomethasone propionate, fluocinolone acetonide; prednisolone valerate acetate, triamcinolone acetonide, flumethasone pivalate, alclomethasone propionate, clobetasone butyrate hydrocortisone butyrate, dexamethasone; prednisolone, hydrocortisone acetate.
  • glucocorticoid receptor agonists compounds that are preferably classified as group V steroids or compounds that are classified as group IV steroids, and more preferably compounds that are classified as group V steroids.
  • These compounds have the advantage of low side effects, as described below, while their efficacy is relatively low or mild.
  • the combined use of RvE1 significantly enhances the drug effect (particularly the anti-inflammatory effect), and thus has an advantage that the benefit (merit) obtained by using RvE1 in combination is high.
  • the combined use of a compound classified as a V group or IV group steroid with RvE1 is also useful in that the durability of the anti-inflammatory effect is improved. That is, the external preparation for skin of this aspect is useful as a minimally invasive, persistent anti-inflammatory agent.
  • Examples of the glucocorticoid receptor agonist used in combination with RvE1 include preferably prednisolone and its salts, which are preferably classified into Group V. Among them, prednisolone acetate is preferable. By combining these, a long-lasting anti-inflammatory effect and/or a high side effect reducing effect can be obtained.
  • the ratio contained in the final preparation of RvE1 used in combination with the glucocorticoid receptor agonist is within a range in which the effect of the present invention is exerted. Although it is good, a range of 0.0001 to 0.1% by mass can be usually mentioned. It is preferably about 0.0005 to 0.01% by mass, and more preferably about 0.001 to 0.002% by mass. Further, the combination ratio of RvE1 and the glucocorticoid receptor agonist can be exemplified by a molar ratio in the range of 1:1000 to 1:2. It is preferably 1:100 to 1:10, more preferably 1:50 to 1:5.
  • Another aspect of the present invention is an external preparation for skin, which is a combination of RvE1 and a group V steroid or a group IV steroid.
  • the external preparation for skin of this embodiment contains RvE1 and a group V steroid agent or a group IV steroid agent to obtain an anti-inflammatory effect equivalent to that of a group III (strong) steroid agent (group III steroid agent).
  • group III strong
  • group III steroid agent group III steroid agent
  • group III steroid agent group III steroid agent
  • group V steroids and group IV steroids have fewer side effects than group III steroids, while suppressing and reducing side effects caused by the use of steroids, an anti-inflammatory effect equivalent to that of group III steroids can be obtained.
  • the external preparation for skin of this aspect is also useful in that the durability of the anti-inflammatory effect is better than that of the group III steroid. That is, the external preparation for skin of this aspect is useful as a minimally invasive, persistent anti-inflammatory agent.
  • the Group V steroids include, but are not limited to, prednisolone, prednisolone acetate, fradiomycin, dexamethasone sulfate, hydrocortisone, hydrocortisone acetate, fludoxycortide, betamethasone, and a mixture of betamethasone and chlordeniramine maleate. These can be used in combination with RvE1 either alone or in combination of two or more, and optionally in combination with a group IV steroid.
  • prednisolone and its salts are preferable because of their excellent anti-inflammatory effect persistence and large side effect reducing effect, and among them, prednisolone acetate is more preferable.
  • group IV steroids include, but are not limited to, valeric acid/prednisolone acetate, clobetasone butyrate, alclomethasone propionate, hydrocortisone butyrate, triamcinolone acetonide, and flumethasone pivalate. These can be used in combination with RvE1 alone or in combination of two or more, and optionally in combination with a Group V steroid.
  • the ratio contained in the final preparation of RvE1 used in combination with the steroid agent may be within the range that produces the effect of the present invention, Usually, the range of 0.0001 to 0.1 mass% can be mentioned. It is preferably about 0.0005 to 0.01% by mass, and more preferably about 0.001 to 0.002% by mass.
  • the combination ratio of RvE1 and the steroid agent can be exemplified in the range of 1:1000 to 1:2 as a molar ratio. It is preferably 1:100 to 1:10, more preferably 1:50 to 1:5.
  • “combination” means that the external preparation for skin of the present invention is (I) When RvE1 and a glucocorticoid receptor agonist or a group V or group IV steroid agent are contained in the same preparation in a mixed state (combined preparation), (Ii) A preparation containing RvE1 and a preparation containing a glucocorticoid receptor agonist or a group V or group IV steroid agent are packaged as separate preparations, and both are sold as a combination (kit).
  • a preparation containing RvE1 and a preparation containing a glucocorticoid receptor agonist or a group V or group IV steroid are each individual preparations, which are sold as one package in combination.
  • a formulation containing RvE1 and a formulation containing a glucocorticoid receptor agonist or a group V or group IV steroid are present in the market as separate formulations through separate distribution channels, It is used in the meaning including the case of being used in combination at the time of use.
  • the term “combination product” or “skin external preparation consisting of a combination” means that the administration of the preparation containing RvE1 to the skin of the subject (mammal) means that the drug is a glucocorticoid receptor agonist or group V or IV.
  • Administration of a preparation containing a group steroid agent may be carried out at different times, simultaneously or in parallel, and RvE1, a glucocorticoid receptor agonist or a group V or IV group steroid agent in a distribution stage including sales The form is not specifically asked.
  • both formulations are administered at the same time, it is preferable that the user or practitioner use the formulation containing RvE1 and the formulation containing a glucocorticoid receptor agonist or group V or group IV steroid at the time of use.
  • a method may be mentioned in which the compounded ingredients are mixed to prepare a compounded ingredient containing both, and the prepared compounded ingredient is applied to the skin of the subject.
  • the “formulation containing RvE1” as used herein means a preparation in which RvE1 is combined with other components
  • the “formulation containing a glucocorticoid receptor agonist” refers to a glucocorticoid receptor agonist other than It means a preparation in which components are combined
  • a preparation containing a group V or group IV steroid agent means a preparation in which a group V or group IV steroid agent is combined with another component.
  • These formulations include those in the form of external preparations for skin.
  • the other components include carriers or additives for pharmaceutical preparations that are usually used for external medicines.
  • the “combination product” is preferably the compounding agent described in (i) above.
  • the external preparation for skin includes an oily component, an aqueous component, an anti-inflammatory component other than RvE1, an anti-acne component, a whitening component, a preservative, a pH adjusting agent, and A sticking agent, a stabilizer and the like can be added as necessary.
  • oil component examples include cetostearyl alcohol, medium chain fatty acid triglyceride, polyoxyethylene hydrogenated castor oil, glycerin stearate, liquid paraffin, petrolatum, squalane, beeswax, palmitic acid and the like.
  • aqueous component examples include water, propylene glycol, glycerin, polyethylene glycol, 1,3-butylene glycol and the like.
  • anti-inflammatory component other than RvE1 examples include components derived from plants (for example, comfrey), allantoin, glycyrrhizic acid or derivatives thereof, tranexamic acid, zinc oxide, pyridoxine hydrochloride, tocopherol acetate, salicylic acid or derivatives thereof, ⁇ - Examples thereof include aminocaproic acid, pantothenyl alcohol, laurel extract, psyllium extract, quince extract, izayoi extract, and age extract.
  • the anti-acne component is a component effective against acne, and includes, for example, clindamycin, nadifloxacin, sulfur, isopropylmethylferrol, pionine (photosensitizer 201), allantoin, dipotassium glycyrrhizinate, pyridoxine hydrochloride, calamine, guaiazulene sulfone.
  • Antibacterial, antibacterial and anti-inflammatory components such as sodium acidate and stearyl glycyrrhetinate; components with chemical peeling effect such as glycolic acid, lactic acid, salicylic acid, macrogol salicylate, trichloroacetic acid, ascorbic acid, ascorbic acid glucoside, ascorbyl tetrahexyldecanoate, etc. Antioxidants and the like.
  • para-aminobenzoic acid derivatives As whitening ingredients, para-aminobenzoic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid compounds, benzotriazole derivatives, tetrazole derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives, camphor derivatives, furanic acid derivatives, pyrone derivatives, nucleic acid derivatives, allantoin Derivatives, nicotinic acid derivatives, vitamin C or its derivatives (vitamin C phosphate magnesium salt, vitamin C glucoside, etc.), vitamin D or its derivatives, vitamin E or its derivatives, kojic acid or its derivatives, oxybenzone, benzophenone, arbutin, Examples thereof include tranexamic acid, guaiazulene, shikonin, baicalin, baicalein, berberine, placenta extract, ellagic acid, and rucinol.
  • antiseptics examples include parabens and the like.
  • pH adjusters examples include phosphoric acid, citric acid, sodium hydroxide, potassium hydroxide, organic amines and the like.
  • thickener examples include crystalline cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxyvinyl polymer, acrylic acid-alkyl methacrylate copolymer, carmellose sodium, polyvinyl alcohol and the like.
  • stabilizer examples include tocopherol, BHT (dibutylhydroxytoluene), sodium edetate hydrate and the like.
  • the dosage form of the external preparation for skin of the present invention is not particularly limited. Examples of dosage forms include lotions, creams, gels, ointments and the like.
  • the external preparation for skin of the present invention can be prepared according to the usual method for producing an external preparation for skin (16th revised Japanese Pharmacopoeia Manual 2011, A126 to A149).
  • the external preparation for skin of the present invention exerts an anti-inflammatory effect by being applied to a subject's skin, specifically, mammalian skin, preferably human skin in an effective amount, and reduces inflammation in the skin. , Useful for healing and improvement.
  • the external preparation for skin of the present invention exerts an anti-inflammatory effect, so that eczema, dermatitis (including atopic dermatitis and the like), psoriasis, prurigo group, palmoplantar pustulosis, pruritus cutis, erythema. , And/or can be usefully used for treating or preventing skin diseases such as erythroderma.
  • the present invention is a method for reducing inflammation of the skin, which comprises a step of applying an effective amount of the external preparation for skin to the skin of mammals.
  • the mammal preferably includes a human.
  • the mammal also includes at least one skin disease selected from the group consisting of eczema, dermatitis, psoriasis, prurigo group, palmoplantar pustulosis, pruritus cutis, erythema, and erythroderma.
  • the number of applications (the number of applications) and the dose (the amount of application) to the affected area are not limited as long as the effects of the present invention are exhibited.
  • the effective daily amount that exerts an anti-inflammatory effect can be applied once or a plurality of times a day to the affected area.
  • the drugs used are as follows.
  • Vaseline Propeto (registered trademark), manufactured by Maruishi Pharmaceutical Co., Ltd.
  • Predonin eye ointment 0.25% prednisolone acetate ester-containing preparation, manufactured by Shionogi Pharmaceutical Co., Ltd.
  • RvE 1:1 mg RvE1 with ethanol 100 times Prepared by diluting (ethanol containing 1% RvE1)
  • Boala Ointment 0.12% dexamethasone valerate-containing preparation, manufactured by Maruho Co., Ltd.
  • predonin ophthalmic ointment is a steroid drug classified into Group V (weak), and Boala ointment is classified into Group III (strong) It is a steroid drug.
  • DNFB 1-Fluoro-2,4-dinitrobenzene
  • Sensitization induction was performed by applying 0.5% DNFB solution (25 ⁇ l) once to the abdomen of each group of mice (groups 1 to 5) with shaved abdomen and chest. ..

Abstract

As an external preparation for skin having an antiinflammatory effect, provided is a combination of resolvin E1 with a glucocorticoid receptor agonist or a combination of resolvin E1 with a steroid categorized as group V (weak) or a steroid categorized as group IV (medium).

Description

皮膚外用剤Topical skin
　本発明は、皮膚外用剤に関する。 The present invention relates to a skin external preparation.
　ステロイドは、抗炎症、抗アレルギー、または免疫抑制等の多くの作用を有していることから、従来より医薬品として広く用いられており、その使用目的、および作用部位等に応じて、注射剤、経口剤、坐剤、外用剤等の種々の剤型を有するステロイド製剤が知られている。このようにステロイド製剤が広範に使用されているのは、ステロイドが強い活性を有するためである。しかし、この活性に比例して副作用も強く発現する。このため、臨床上、ステロイドの使用にあたっては、常に薬効と副作用とを考慮しながら使用されているのが現状である。 Steroids have been widely used as pharmaceuticals since they have many actions such as anti-inflammatory, anti-allergic, or immunosuppression. Depending on the purpose of use and the site of action, injections, Steroid preparations having various dosage forms such as oral preparations, suppositories, and external preparations are known. The widespread use of steroid preparations is due to the strong activity of steroids. However, side effects also strongly appear in proportion to this activity. Therefore, clinically, steroids are currently used in consideration of their efficacy and side effects.
　例えば、湿疹の治療に使用されるステロイド外用剤は、抗炎症作用の強さにより５群（Ｉ群：strongest、ＩＩ群：very strong、ＩＩＩ群：strong、ＩＶ群：medium、Ｖ群：weak）に分類されることが多い。副作用の発現も薬効の強さとほぼ並行することから、この分類は実際の患者への使用に際して極めて有用である。 For example, steroid external preparations used for the treatment of eczema are classified into 5 groups (group I: strongest, group II: very strong, group III: strong, group IV: medium, group V: weak) depending on the strength of anti-inflammatory action. Often classified into. Since the occurrence of side effects is almost parallel to the strength of drug efficacy, this classification is extremely useful when used in actual patients.
　ところで、特許文献１には、魚類や甲殻類等の生物から抽出された長鎖ω－３多価不飽和脂肪酸を含有する油には、特異的炎症収束性メディエータ（Specialized Proresolving Mediator：ＳＰＭ）及びＳＰＭ前駆物質が含まれていること、および、ＳＰＭには、レゾルビンＥ１（５Ｓ，１２Ｒ，１８Ｒ－トリヒドロキシ－エイコサ－６Ｚ，８Ｅ，１０Ｅ，１４Ｚ，１６Ｅ－ペンタエン酸）が含まれていることが記載されている。しかしながら、特許文献１には、レゾルビンＥ１が皮膚に対してどの程度の抗炎症効果を奏するかについては記載されていない。 By the way, in patent document 1, in the oil containing the long-chain ω-3 polyunsaturated fatty acid extracted from organisms such as fish and crustaceans, a specific inflammation converging mediator (Specialized Proresolving Mediator: SPM) and It contains an SPM precursor, and the SPM contains Resolvin E1 (5S,12R,18R-trihydroxy-eicosa-6Z,8E,10E,14Z,16E-pentaenoic acid). Have been described. However, Patent Document 1 does not describe how much resolvin E1 exerts an anti-inflammatory effect on the skin.
特表２０１５－５２２５３５号公報Japanese Patent Publication No. 2015-522535
　本発明は、上記した従来技術の現状に鑑みてなされたものであり、皮膚外用剤を提供することを目的とする。また、本発明の好ましい目的は、抗炎症効果の持続性に優れた皮膚外用剤を提供することである。さらに本発明の好ましい目的は、優れた抗炎症効果、特に持続性に優れながらも、副作用の少ない皮膚外用剤を提供することである。 The present invention has been made in view of the above-mentioned conventional state of the art, and an object thereof is to provide a skin external preparation. Further, a preferred object of the present invention is to provide an external preparation for skin having an excellent anti-inflammatory effect. Further, a preferred object of the present invention is to provide an external preparation for skin which has excellent anti-inflammatory effect, particularly excellent durability, and has few side effects.
　本発明者らは、上記した目的を達成すべく鋭意研究を重ねた結果、レゾルビンＥ１とグルココルチコイド受容体作動薬に分類されるステロイド剤とを組み合わせることで、両者の抗炎症効果が増強するとともに、持続性が高まることを見出した。また、当該ステロイド剤は、分類上Ｖ群（weak）に分類されるステロイド剤であるにも関わらず、レゾルビンＥ１と併用することで、ＩＩＩ群（strong）に分類されるステロイド剤と同程度の強い抗炎症効果が得られること、さらに、抗炎症効果の経時的低下が抑制され、良好な抗炎症効果が長く持続することを見出した。Ｖ群（weak）に分類されるステロイド剤は、薬効の程度に相応して副作用も低いことから、レゾルビンＥ１と組み合わせることで抗炎症効果が上昇し、しかも持続することは望ましい効果といえる。 The present inventors have conducted intensive studies to achieve the above-mentioned object, and as a result, by combining resolvin E1 and a steroid drug classified as a glucocorticoid receptor agonist, the anti-inflammatory effect of both is enhanced and , Found that sustainability is enhanced. Further, although the steroid drug is classified as a V group (weak) in terms of classification, when used in combination with Resolvin E1, it has the same level as a steroid drug classified as a III group (strong). It has been found that a strong anti-inflammatory effect is obtained, and further, a decrease in the anti-inflammatory effect over time is suppressed, and a good anti-inflammatory effect lasts for a long time. Since steroids classified into group V (weak) have low side effects corresponding to the degree of drug efficacy, it can be said that it is desirable that the combination with resorbin E1 enhances the anti-inflammatory effect and maintains it.
　本発明は、これらの知見に基づいて、さらに研究を重ねて完成されたものであり、下記の実施形態を有するものである。 The present invention has been completed by further research based on these findings, and has the following embodiments.
（Ｉ）皮膚外用剤
（Ｉ－１）レゾルビンＥ１とグルココルチコイド受容体作動薬との組み合わせ物である皮膚外用剤。
（Ｉ－２）レゾルビンＥ１とグルココルチコイド受容体作動薬との組み合わせ物が、レゾルビンＥ１とグルココルチコイド受容体作動薬を含有する組成物（配合剤）、またはレゾルビンＥ１を含有する製剤（例えば、皮膚外用剤）とグルココルチコイド受容体作動薬を含有する製剤（例えば、皮膚外用剤）との組み合わせ製品（キット、セット）である、（Ｉ－１）に記載する皮膚外用剤。
（Ｉ－３）レゾルビンＥ１と、Ｖ群（weak）に分類されるステロイド剤（以下、単に「Ｖ群ステロイド剤」とも称する）またはＩＶ群（medium）に分類されるステロイド剤（以下、単に「ＩＶ群ステロイド剤」とも称する）との組み合わせ物である皮膚外用剤。
（Ｉ－４）レゾルビンＥ１とＶ群ステロイド剤またはＩＶ群ステロイド剤との組み合わせ物が、レゾルビンＥ１とＶ群ステロイド剤またはＩＶ群ステロイド剤とを含有する組成物（配合剤）、またはレゾルビンＥ１を含有する製剤（例えば、皮膚外用剤）と、Ｖ群ステロイド剤を含有する製剤またはＩＶ群ステロイド剤を含有する製剤（例えば、皮膚外用剤）との組み合わせ製品（キット、セット）である、（Ｉ－３）に記載する皮膚外用剤。
（Ｉ－５）Ｖ群ステロイド剤が、プレドニゾロン、酢酸プレドニゾロン、硫酸フラジオマイシン、デキサメサゾン、酢酸ヒドロコルチゾン、フルドキシコルチド、ベタメタゾン、ベタメタゾンとマレイン酸クロルデニラミンとの混合物、およびヒドロコルチゾンからなる群から選択される少なくとも１種であり、ＩＶ群ステロイド剤が、吉草酸・酢酸プレドニゾロン、酪酸ヒドロコルチゾン、酪酸クロベタゾン、プロピオン酸アルクロメタゾン、トリアムシノロンアセトニド、およびピバル酸フルメタゾンからなる群から選択される少なくとも１種である、（Ｉ－３）または（Ｉ－４）に記載する皮膚外用剤。
（Ｉ－６）前記グルココルチコイド受容体作動薬、または前記Ｖ群若しくはＩＶ群ステロイド剤が、プレドニゾロン、酢酸プレドニゾロン、吉草酸・酢酸プレドニゾロン、ヒドロコルチゾン、酢酸ヒドロコルチゾン、酪酸ヒドロコルチゾン、デキサメサゾン、ベタメタゾン、ベタメタゾン及びマレイン酸クロルデニラミンの混合物、酪酸クロベタゾン、プロピオン酸アルクロメタゾン、トリアムシノロンアセトニド、およびピバル酸フルメタゾンからなる群から選択される少なくとも１種である、（Ｉ－１）～（Ｉ－５）のいずれか一項に記載する皮膚外用剤。
（Ｉ－７）前記グルココルチコイド受容体作動薬または前記Ｖ群ステロイド剤が、プレドニゾロン、および酢酸プレドニゾロンからなる群から選択される少なくとも１種である、（Ｉ－１）～（Ｉ－５）のいずれか一項に記載する皮膚外用剤。
（Ｉ－８）　前記レゾルビンＥ１と前記グルココルチコイド受容体作動薬または前記ステロイド剤とを、モル比１：１０００～１：２、好ましくは１：１００～１：１０、より好ましくは１：５０～１：５の割合で組み合わせてなる、（Ｉ－１）～（Ｉ－７）のいずれか一項に記載する皮膚外用剤。
（Ｉ－９）抗炎症薬である（Ｉ－１）～（Ｉ－８）のいずれか一項に記載する皮膚外用剤。
（Ｉ－１０）湿疹、皮膚炎、乾癬、痒疹群、掌蹠膿疱症、皮膚掻痒症、紅斑症、および紅皮症からなる群より選択される少なくとも１種の皮膚疾患の治療又は予防用の医薬品である、（Ｉ－１）～（Ｉ－９）のいずれか一項に記載する皮膚外用剤。 (I) External preparation for skin (I-1) An external preparation for skin which is a combination of resolvin E1 and a glucocorticoid receptor agonist.
(I-2) A composition (combination drug) in which the combination of resolvin E1 and a glucocorticoid receptor agonist contains resolvin E1 and a glucocorticoid receptor agonist, or a preparation containing resolvin E1 (for example, skin The external preparation for skin according to (I-1), which is a combination product (kit, set) of a preparation (external preparation) and a preparation containing a glucocorticoid receptor agonist (for example, external preparation for skin).
(I-3) Resolvin E1 and a steroid drug classified into V group (weak) (hereinafter, also simply referred to as “V group steroid drug”) or a steroid drug classified into IV group (medium) (hereinafter, simply referred to as “ An external preparation for skin, which is a combination with a group IV steroid.
(I-4) A composition (combined preparation) containing the resolvin E1 and a group V steroid agent or a group IV steroid agent containing the resolvin E1 and a group V steroid agent or a group IV steroid agent, or resolvin E1 A combination product (kit, set) of a preparation containing (for example, a skin external preparation) and a preparation containing a group V steroid agent or a preparation containing a group IV steroid agent (for example, a skin external preparation), (I -3) External preparation for skin.
The (I-5) Group V steroid is selected from the group consisting of prednisolone, prednisolone acetate, fradiomycin sulfate, dexamethasone, hydrocortisone acetate, fludoxycortide, betamethasone, a mixture of betamethasone and chlordeniramine maleate, and hydrocortisone. The at least one group IV steroid is at least one selected from the group consisting of valeric acid/prednisolone acetate, hydrocortisone butyrate, clobetasone butyrate, alclomethasone propionate, triamcinolone acetonide, and flumethasone pivalate. The external preparation for skin according to I-3) or (I-4).
(I-6) The glucocorticoid receptor agonist, or the group V or IV steroid is prednisolone, prednisolone acetate, valeric acid/prednisolone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, dexamethasone, betamethasone, betamethasone and malein. The mixture of chlordeniramine acid, clobetasone butyrate, alclomethasone propionate, triamcinolone acetonide, and at least one selected from the group consisting of flumethasone pivalate, (I-1) to (I-5) Described external preparation for skin.
(I-7) The glucocorticoid receptor agonist or the V-group steroid is at least one selected from the group consisting of prednisolone and prednisolone acetate. (I-1) to (I-5) The external preparation for skin according to any one of items.
(I-8) The resolvin E1 and the glucocorticoid receptor agonist or the steroid drug are used in a molar ratio of 1:1000 to 1:2, preferably 1:100 to 1:10, more preferably 1:50 to The external preparation for skin according to any one of (I-1) to (I-7), which is combined in a ratio of 1:5.
(I-9) The external preparation for skin according to any one of (I-1) to (I-8), which is an anti-inflammatory drug.
(I-10) For treating or preventing at least one skin disease selected from the group consisting of eczema, dermatitis, psoriasis, prurigo group, palmoplantar pustulosis, pruritus cutis, erythema, and erythroderma The external preparation for skin according to any one of (I-1) to (I-9), which is a pharmaceutical.
（ＩＩ）皮膚外用剤の使用方法
（ＩＩ－１）前記（Ｉ－１）～（Ｉ－１０）のいずれか一項に記載する皮膚外用剤の有効量を、哺乳動物の皮膚に適用する工程を含む、当該皮膚の炎症を軽減する方法。
（ＩＩ－２）前記哺乳動物が、湿疹、皮膚炎、乾癬、痒疹群、掌蹠膿疱症、皮膚掻痒症、紅斑症、および紅皮症からなる群より選択される少なくとも１種の皮膚疾患に罹患した動物であり、前記（Ｉ－１）～（Ｉ－１０）のいずれか一項に記載する皮膚外用剤の有効量を、当該疾患患部に適用する工程を有する、（ＩＩ－１）に記載する方法。
（ＩＩ－３）皮膚炎症の予防または治療に使用される、レゾルビンＥ１とグルココルチコイド受容体作動薬との組み合わせ物、またはレゾルビンＥ１とＶ群またはＩＶ群ステロイド剤との組み合わせ物。
（ＩＩ－４）湿疹、皮膚炎、乾癬、痒疹群、掌蹠膿疱症、皮膚掻痒症、紅斑症、および紅皮症からなる群より選択される少なくとも１種の皮膚疾患の予防または治療に使用される、レゾルビンＥ１とグルココルチコイド受容体作動薬との組み合わせ物、またはレゾルビンＥ１とＶ群またはＩＶ群ステロイド剤との組み合わせ物。
（ＩＩ－５）抗炎症剤の製造のための、レゾルビンＥ１とグルココルチコイド受容体作動薬との組み合わせ物、またはレゾルビンＥ１とＶ群またはＩＶ群ステロイド剤との組み合わせ物の使用。
（ＩＩ－６）湿疹、皮膚炎、乾癬、痒疹群、掌蹠膿疱症、皮膚掻痒症、紅斑症、および紅皮症からなる群より選択される少なくとも１種の皮膚疾患の予防剤または治療剤の製造のための、レゾルビンＥ１とグルココルチコイド受容体作動薬との組み合わせ物、またはレゾルビンＥ１とＶ群またはＩＶ群ステロイド剤との組み合わせ物の使用。 (II) Method of using external preparation for skin (II-1) A step of applying an effective amount of the external preparation for skin according to any one of (I-1) to (I-10) above to the skin of mammals A method for reducing inflammation of the skin, comprising:
(II-2) The mammal has at least one skin disease selected from the group consisting of eczema, dermatitis, psoriasis, prurigo group, palmoplanter pustulosis, pruritus cutaneus, erythema, and erythroderma. In (II-1), which is an affected animal, and which has a step of applying an effective amount of the external preparation for skin according to any one of (I-1) to (I-10) to the affected area How to list.
(II-3) A combination of resolvin E1 and a glucocorticoid receptor agonist, or a combination of resolvin E1 and a group V or group IV steroid drug, which is used for the prevention or treatment of skin inflammation.
(II-4) Use for prevention or treatment of at least one skin disease selected from the group consisting of eczema, dermatitis, psoriasis, prurigo group, palmoplanter pustulosis, pruritus cutis, erythema, and erythroderma A combination of resolvin E1 and a glucocorticoid receptor agonist, or a combination of resolvin E1 and a group V or group IV steroid drug.
(II-5) Use of a combination of resolvin E1 and a glucocorticoid receptor agonist or a combination of resolvin E1 and a group V or group IV steroid drug for the production of an anti-inflammatory agent.
(II-6) Prophylactic or therapeutic agent for at least one skin disease selected from the group consisting of eczema, dermatitis, psoriasis, prurigo group, palmoplanter pustulosis, pruritus cutis, erythema, and erythroderma Use of a combination of Resolvin E1 and a glucocorticoid receptor agonist, or a combination of Resolvin E1 and a Group V or Group IV steroidal agent for the manufacture of:.
　本発明の一態様であるレゾルビンＥ１とグルココルチコイド受容体作動薬に分類されるステロイド剤とを組み合わせてなる皮膚外用剤は、両者を併用することで高い抗炎症効果を発揮するとともに持続性のある抗炎症剤として有用である。
　また本発明の一態様であるレゾルビンＥ１と、分類上Ｖ群（weak）又はＩＶ群（medium）に分類されるステロイド剤（Ｖ群ステロイド剤またはＩＶ群ステロイド剤）とを組み合わせてなる皮膚外用剤は、両者を含むことにより、分類上ＩＩＩ群（strong）のステロイド剤と同等の抗炎症効果を得ることができる。さらに、本発明の皮膚外用剤は、ステロイドの使用により起こり得る副作用を低減することができる。このため、当該皮膚外用剤は、副作用の発生を抑えながらも高い抗炎症効果を発揮する抗炎症剤として有用である。
　さらに、レゾルビンＥ１と、Ｖ群またはＩＶ群ステロイド剤、好ましくはＶ群ステロイド剤とを組み合わせてなる皮膚外用剤は、前記効果に加えて薬効持続性を有しており、副作用の発生を抑えながらも高い抗炎症効果を発揮する、持続性のある抗炎症剤として有用である。 An external preparation for skin comprising a combination of resolvin E1 which is one aspect of the present invention and a steroid drug classified as a glucocorticoid receptor agonist exhibits a high anti-inflammatory effect and is durable when used in combination. It is useful as an anti-inflammatory agent.
Further, a skin external preparation comprising a combination of the resolvin E1 which is one embodiment of the present invention and a steroid agent (group V steroid agent or group IV steroid agent) classified into V group (weak) or IV group (medium) in classification. By including both, it is possible to obtain an anti-inflammatory effect equivalent to that of the class III (strong) steroid drug in terms of classification. Furthermore, the external preparation for skin of the present invention can reduce the side effects that may occur due to the use of steroids. Therefore, the external preparation for skin is useful as an anti-inflammatory agent that exerts a high anti-inflammatory effect while suppressing the occurrence of side effects.
Furthermore, the external preparation for skin which is a combination of Resolvin E1 and a group V or group IV steroid, preferably a group V steroid, has a long-lasting efficacy in addition to the above-mentioned effects, while suppressing the occurrence of side effects. It is also useful as a long-lasting anti-inflammatory agent that exerts a high anti-inflammatory effect.
実験例で行った動物を用いた抗炎症効果の評価試験の結果を示すグラフである。It is a graph which shows the result of the evaluation test of the anti-inflammatory effect using the animal performed in the experimental example.
（Ｉ）皮膚外用剤
　本発明の一態様は、レゾルビンＥ１とグルココルチコイド受容体作動薬とを組み合わせてなる皮膚外用剤である。 (I) External preparation for skin One embodiment of the present invention is an external preparation for skin obtained by combining resolvin E1 and a glucocorticoid receptor agonist.
　レゾルビンＥ１（ＲｖＥ１）は、５Ｓ，１２Ｒ，１８Ｒ－トリヒドロキシ－エイコサ－６Ｚ，８Ｅ，１０Ｅ，１４Ｚ，１６Ｅ－ペンタエン酸であり、特異的炎症収束性メディエータ（ＳＰＭ）として公知の化合物である。ＲｖＥ１は、公知の製造方法、例えば、Ogawa N, Kobayashi Y. Tetrahedron lett. 2009;50:6079-6082に記載される製造方法に従って製造することができる。また、ＲｖＥ１は、魚類、甲殻類、藻類、または軟体動物から抽出される長鎖ω－３多価不飽和脂肪酸を含有する油に含まれている天然成分であり、当該長鎖ω－３多価不飽和脂肪酸含有油から抽出単離することもできる（例えば、前述する特許文献１）。 Resolvin E1 (RvE1) is 5S,12R,18R-trihydroxy-eicosa-6Z,8E,10E,14Z,16E-pentaenoic acid, which is a compound known as a specific inflammatory converging mediator (SPM). RvE1 can be produced according to a known production method, for example, the production method described in Ogawa N, Kobayashi Y. Tetrahedron lett. 2009; 50:6079-6082. RvE1 is a natural component contained in oil containing long-chain ω-3 polyunsaturated fatty acids extracted from fish, crustaceans, algae, or molluscs, It can also be extracted and isolated from an oil containing a polyunsaturated fatty acid (for example, Patent Document 1 described above).
　本発明で使用されるＲｖＥ１は、その効果を有することを限度として、合成品であっても、または天然由来のものであってもよい。また、精製物であっても、また粗精製物であってもよい。粗精製物としては、制限されないものの、例えば前記長鎖ω－３多価不飽和脂肪酸含有油、またはそのＲｖＥ１含有画分を挙げることができる。 The RvE1 used in the present invention may be a synthetic product or a naturally derived product as long as it has the effect. Further, it may be a purified product or a crudely purified product. Examples of the crude product include, but are not limited to, the aforementioned long-chain ω-3 polyunsaturated fatty acid-containing oil, or its RvE1-containing fraction.
　グルココルチコイド受容体作動薬とは、グルココルチコイド受容体に結合することで抗炎症作用を始めとする薬効を発揮する薬剤である。グルココルチコイド受容体作動薬に分類されるステロイド剤としては、制限されないものの、下記のものを例示することができる（日薬理誌 Folia Pharmacol. Jpn. 128, 411-415, 2006）。
　プロピオン酸クロベタゾール、酢酸ジフトラゾン；フランカルボン酸モメタゾン、酪酸プロピオン酸ベタメタゾン、フルオシノニド、ジプロピオン酸ベタメタゾン、ジフルプレドナート、プテソニド、アムシノニド、吉草酸ジフルコルトロン、酪酸プロピオン酸ヒドロコルチゾン；プロピオン酸デキサメタゾン、吉草酸デキサメタゾン、吉草酸ベタメタゾン、プロピオン酸ベクロメタゾン、フルオシノロンアセトニド；吉草酸酢酸プレドニゾロン、トリアムシノロンアセトニド、ピバル酸フルメタゾン、プロピオン酸アルクロメタゾン、酪酸クロベタゾン、酪酸ヒドロコルチゾン、デキサメタゾン；プレドニゾロン、酢酸ヒドロコルチゾン。 A glucocorticoid receptor agonist is a drug that exerts a medicinal effect including an anti-inflammatory action by binding to a glucocorticoid receptor. Examples of the steroid drug classified as a glucocorticoid receptor agonist include, but are not limited to, the following (Nippon Pharmacologic Journal, Folia Pharmacol. Jpn. 128, 411-415, 2006).
Clobetasol propionate, diftrazone acetate; mometasone furoate, betamethasone butyrate propionate, fluocinonide, betamethasone dipropionate, difluprednate, putesonide, amcinonide, diflucortron valerate, hydrocortisone butyrate propionate dexamethasone oxalate, dexamethasone valerate, , Betamethasone valerate, beclomethasone propionate, fluocinolone acetonide; prednisolone valerate acetate, triamcinolone acetonide, flumethasone pivalate, alclomethasone propionate, clobetasone butyrate hydrocortisone butyrate, dexamethasone; prednisolone, hydrocortisone acetate.
　これらのグルココルチコイド受容体作動薬のうち、好ましくはＶ群ステロイド剤に分類される化合物またはＩＶ群ステロイド剤に分類される化合物であり、より好ましくはＶ群ステロイド剤に分類される化合物である。これらの化合物は、後述するように、副作用が低いという長所を有する一方で、薬効は、比較的低いかマイルドである。しかし、ＲｖＥ１を併用することで当該薬効（特に抗炎症効果）が有意に増強されるため、ＲｖＥ１と併用することによって得られる利益（メリット）が高いという利点を有する。また後述するように、Ｖ群またはＩＶ群ステロイド剤に分類される化合物とＲｖＥ１とを併用することによって、抗炎症効果の持続性が向上する点でも有用である。つまり、この態様の皮膚外用剤は、低侵襲性の持続性抗炎症剤として有用である。 Among these glucocorticoid receptor agonists, compounds that are preferably classified as group V steroids or compounds that are classified as group IV steroids, and more preferably compounds that are classified as group V steroids. These compounds have the advantage of low side effects, as described below, while their efficacy is relatively low or mild. However, the combined use of RvE1 significantly enhances the drug effect (particularly the anti-inflammatory effect), and thus has an advantage that the benefit (merit) obtained by using RvE1 in combination is high. Further, as described later, the combined use of a compound classified as a V group or IV group steroid with RvE1 is also useful in that the durability of the anti-inflammatory effect is improved. That is, the external preparation for skin of this aspect is useful as a minimally invasive, persistent anti-inflammatory agent.
　ＲｖＥ１と併用するグルココルチコイド受容体作動薬として、好ましくはＶ群に分類されるプレドニゾロンおよびその塩が例示される。その中でも好ましくは酢酸プレドニゾロンである。これらを組み合わせることで、抗炎症効果の持続性、および／または高い副作用低減効果を得ることができる。 Examples of the glucocorticoid receptor agonist used in combination with RvE1 include preferably prednisolone and its salts, which are preferably classified into Group V. Among them, prednisolone acetate is preferable. By combining these, a long-lasting anti-inflammatory effect and/or a high side effect reducing effect can be obtained.
　ＲｖＥ１とグルココルチコイド受容体作動薬とを組み合わせてなる皮膚外用剤において、グルココルチコイド受容体作動薬と組み合わせて使用されるＲｖＥ１の最終製剤に含まれる割合として、本発明の効果を奏する範囲であればよいが、通常０．０００１～０．１質量％の範囲を挙げることができる。好ましくは０．０００５～０．０１質量％程度であり、より好ましくは０．００１～０．００２質量％程度である。また、ＲｖＥ１とグルココルチコイド受容体作動薬との組み合わせ比としては、モル比として１：１０００～１：２の範囲を例示することができる。好ましくは１：１００～１：１０であり、より好ましくは１：５０～１：５である。 In a skin external preparation comprising a combination of RvE1 and a glucocorticoid receptor agonist, the ratio contained in the final preparation of RvE1 used in combination with the glucocorticoid receptor agonist is within a range in which the effect of the present invention is exerted. Although it is good, a range of 0.0001 to 0.1% by mass can be usually mentioned. It is preferably about 0.0005 to 0.01% by mass, and more preferably about 0.001 to 0.002% by mass. Further, the combination ratio of RvE1 and the glucocorticoid receptor agonist can be exemplified by a molar ratio in the range of 1:1000 to 1:2. It is preferably 1:100 to 1:10, more preferably 1:50 to 1:5.
　本発明の他の一態様は、ＲｖＥ１と、Ｖ群ステロイド剤またはＩＶ群ステロイド剤とを組み合わせてなる皮膚外用剤である。 Another aspect of the present invention is an external preparation for skin, which is a combination of RvE1 and a group V steroid or a group IV steroid.
　この態様の皮膚外用剤は、ＲｖＥ１とＶ群ステロイド剤またはＩＶ群ステロイド剤とを含むことにより、分類上ＩＩＩ群（strong）のステロイド剤（ＩＩＩ群ステロイド剤）と同等の抗炎症効果を得ることが可能である。Ｖ群ステロイド剤およびＩＶ群ステロイド剤は、ＩＩＩ群ステロイド剤と比較して副作用が少ないため、ステロイドの使用により起こる副作用を抑制し低減しながら、ＩＩＩ群ステロイド剤と同等の抗炎症効果を得ることが可能である点で有用である。さらに、この態様の皮膚外用剤は、抗炎症効果の持続性がＩＩＩ群ステロイド剤と比較して良好である点でも有用である。つまり、この態様の皮膚外用剤は、低侵襲性の持続性抗炎症剤として有用である。 The external preparation for skin of this embodiment contains RvE1 and a group V steroid agent or a group IV steroid agent to obtain an anti-inflammatory effect equivalent to that of a group III (strong) steroid agent (group III steroid agent). Is possible. Since group V steroids and group IV steroids have fewer side effects than group III steroids, while suppressing and reducing side effects caused by the use of steroids, an anti-inflammatory effect equivalent to that of group III steroids can be obtained. Is useful in that it is possible. Furthermore, the external preparation for skin of this aspect is also useful in that the durability of the anti-inflammatory effect is better than that of the group III steroid. That is, the external preparation for skin of this aspect is useful as a minimally invasive, persistent anti-inflammatory agent.
　ここでＶ群ステロイド剤には、制限されないものの、プレドニゾロン、酢酸プレドニゾロン、硫酸フラジオマイシン、デキサメサゾン、ヒドロコルチゾン、酢酸ヒドロコルチゾン、フルドキシコルチド、ベタメタゾン、およびベタメタゾンとマレイン酸クロルデニラミンの混合物が含まれる。これらは一種または二種以上を組み合わせて、さらに必要に応じてＩＶ群ステロイド剤と組み合わせて、ＲｖＥ１と併用することができる。ＲｖＥ１と併用するＶ群ステロイド剤として、好ましくは抗炎症効果の持続性に優れ、また副作用低減効果が大きいことから、プレドニゾロンおよびその塩が好ましく、その中でも酢酸プレドニゾロンがより好ましい。 Here, the Group V steroids include, but are not limited to, prednisolone, prednisolone acetate, fradiomycin, dexamethasone sulfate, hydrocortisone, hydrocortisone acetate, fludoxycortide, betamethasone, and a mixture of betamethasone and chlordeniramine maleate. These can be used in combination with RvE1 either alone or in combination of two or more, and optionally in combination with a group IV steroid. As a V-group steroid used in combination with RvE1, prednisolone and its salts are preferable because of their excellent anti-inflammatory effect persistence and large side effect reducing effect, and among them, prednisolone acetate is more preferable.
　またＩＶ群ステロイド剤には、制限されないものの、吉草酸・酢酸プレドニゾロン、酪酸クロベタゾン、プロピオン酸アルクロメタゾン、酪酸ヒドロコルチゾン、トリアムシノロンアセトニド、及びピバル酸フルメタゾンが含まれる。これらは一種または二種以上を組み合わせて、さらに必要に応じてＶ群ステロイド剤と組み合わせて、ＲｖＥ１と併用することができる。 Also, group IV steroids include, but are not limited to, valeric acid/prednisolone acetate, clobetasone butyrate, alclomethasone propionate, hydrocortisone butyrate, triamcinolone acetonide, and flumethasone pivalate. These can be used in combination with RvE1 alone or in combination of two or more, and optionally in combination with a Group V steroid.
　ＲｖＥ１とＶ群またはＩＶ群ステロイド剤とを組み合わせてなる皮膚外用剤において、ステロイド剤と組み合わせて使用されるＲｖＥ１の最終製剤に含まれる割合として、本発明の効果を奏する範囲であればよいが、通常０．０００１～０．１質量％の範囲を挙げることができる。好ましくは０．０００５～０．０１質量％程度であり、より好ましくは０．００１～０．００２質量％程度である。また、ＲｖＥ１とステロイド剤との組み合わせ比としては、モル比として１：１０００～１：２の範囲を例示することができる。好ましくは１：１００～１：１０であり、より好ましくは１：５０～１：５である。 In the external preparation for skin, which is a combination of RvE1 and a group V or group IV steroid agent, the ratio contained in the final preparation of RvE1 used in combination with the steroid agent may be within the range that produces the effect of the present invention, Usually, the range of 0.0001 to 0.1 mass% can be mentioned. It is preferably about 0.0005 to 0.01% by mass, and more preferably about 0.001 to 0.002% by mass. In addition, the combination ratio of RvE1 and the steroid agent can be exemplified in the range of 1:1000 to 1:2 as a molar ratio. It is preferably 1:100 to 1:10, more preferably 1:50 to 1:5.
　本発明において「組み合わせ物」とは、本発明が対象とする皮膚外用剤が、
（ｉ）ＲｖＥ１と、グルココルチコイド受容体作動薬またはＶ群若しくはＩＶ群ステロイド剤とが同一製剤中に混合された態様で含まれている状態（配合剤）である場合、
（ｉｉ）ＲｖＥ１を含有する製剤と、グルココルチコイド受容体作動薬またはＶ群若しくはＩＶ群ステロイド剤を含有する製剤とが、おのおの別個の製剤として包装されており、両者が組み合わせ物（キット）として販売される場合、
（ｉｉｉ）ＲｖＥ１を含有する製剤と、グルココルチコイド受容体作動薬またはＶ群若しくはＩＶ群ステロイド剤を含有する製剤とが、おのおの個別の製剤であり、これらが組み合わせて一つの包装物として販売される場合、または
（ｉｖ）ＲｖＥ１を含有する製剤と、グルココルチコイド受容体作動薬またはＶ群若しくはＩＶ群ステロイド剤を含有する製剤とが、おのおの別個の製剤として、別個の流通経路で市場に存在し、使用時に組み合わせて使用される場合
を包含する意味で用いられる。 In the present invention, "combination" means that the external preparation for skin of the present invention is
(I) When RvE1 and a glucocorticoid receptor agonist or a group V or group IV steroid agent are contained in the same preparation in a mixed state (combined preparation),
(Ii) A preparation containing RvE1 and a preparation containing a glucocorticoid receptor agonist or a group V or group IV steroid agent are packaged as separate preparations, and both are sold as a combination (kit). If
(Iii) A preparation containing RvE1 and a preparation containing a glucocorticoid receptor agonist or a group V or group IV steroid are each individual preparations, which are sold as one package in combination. Or (iv) a formulation containing RvE1 and a formulation containing a glucocorticoid receptor agonist or a group V or group IV steroid are present in the market as separate formulations through separate distribution channels, It is used in the meaning including the case of being used in combination at the time of use.
　すなわち、本発明において「組み合わせ物」または「組み合わせてなる皮膚外用剤」とは、被験体（哺乳動物）の皮膚に対するＲｖＥ１を含有する製剤の投与が、グルココルチコイド受容体作動薬またはＶ群若しくはＩＶ群ステロイド剤を含有する製剤の投与と、異時、同時又は並行して行われる態様であればよく、販売を含む流通段階におけるＲｖＥ１、グルココルチコイド受容体作動薬またはＶ群若しくはＩＶ群ステロイド剤の形態を特に問うものではない。なお、両者の製剤を同時に投与する場合、好適には、用時に、使用者または施術者が、ＲｖＥ１を含有する製剤とグルココルチコイド受容体作動薬またはＶ群若しくはＩＶ群ステロイド剤を含有する製剤とを混ぜ合わせて両者を含む配合剤を調製し、調製した配合剤を被験体の皮膚に対して塗布する方法を挙げることができる。 That is, in the present invention, the term “combination product” or “skin external preparation consisting of a combination” means that the administration of the preparation containing RvE1 to the skin of the subject (mammal) means that the drug is a glucocorticoid receptor agonist or group V or IV. Administration of a preparation containing a group steroid agent may be carried out at different times, simultaneously or in parallel, and RvE1, a glucocorticoid receptor agonist or a group V or IV group steroid agent in a distribution stage including sales The form is not specifically asked. When both formulations are administered at the same time, it is preferable that the user or practitioner use the formulation containing RvE1 and the formulation containing a glucocorticoid receptor agonist or group V or group IV steroid at the time of use. A method may be mentioned in which the compounded ingredients are mixed to prepare a compounded ingredient containing both, and the prepared compounded ingredient is applied to the skin of the subject.
　また、ここで「ＲｖＥ１を含有する製剤」とはＲｖＥ１に他の成分を組み合わせた製剤を意味し、また「グルココルチコイド受容体作動薬を含有する製剤」とはグルココルチコイド受容体作動薬に他の成分を組み合わせた製剤を意味し、また「Ｖ群若しくはＩＶ群ステロイド剤を含有する製剤」とはＶ群若しくはＩＶ群ステロイド剤に他の成分を組み合わせた製剤を意味する。これらの製剤には、皮膚外用剤の形態を有する製剤が含まれる。ここで、他の成分としては、外用の医薬品に通常使用される製剤用の担体または添加剤が含まれる。 In addition, the “formulation containing RvE1” as used herein means a preparation in which RvE1 is combined with other components, and the “formulation containing a glucocorticoid receptor agonist” refers to a glucocorticoid receptor agonist other than It means a preparation in which components are combined, and "a preparation containing a group V or group IV steroid agent" means a preparation in which a group V or group IV steroid agent is combined with another component. These formulations include those in the form of external preparations for skin. Here, the other components include carriers or additives for pharmaceutical preparations that are usually used for external medicines.
　「組み合わせ物」として、好ましくは前記（ｉ）に記載する配合剤である。
　当該皮膚外用剤には、前述する有効成分のほかに、通常皮膚外用剤に用いられる油性成分、水性成分、ＲｖＥ１以外の抗炎症成分、抗ニキビ成分、美白成分、防腐剤、ｐＨ調整剤、増粘剤、安定化剤等を必要に応じて配合することができる。 The "combination product" is preferably the compounding agent described in (i) above.
In addition to the above-mentioned active ingredients, the external preparation for skin includes an oily component, an aqueous component, an anti-inflammatory component other than RvE1, an anti-acne component, a whitening component, a preservative, a pH adjusting agent, and A sticking agent, a stabilizer and the like can be added as necessary.
　油性成分としては、例えば、セトステアリルアルコール、中鎖脂肪酸トリグリセリド、ポリオキシエチレン硬化ヒマシ油、ステアリン酸グリセリン、流動パラフィン、ワセリン、スクワラン、ミツロウ、パルミチン酸等が挙げられる。 Examples of the oil component include cetostearyl alcohol, medium chain fatty acid triglyceride, polyoxyethylene hydrogenated castor oil, glycerin stearate, liquid paraffin, petrolatum, squalane, beeswax, palmitic acid and the like.
　水性成分としては、例えば、水、プロピレングリコール、グリセリン、ポリエチレングリコール、１，３－ブチレングリコール等が挙げられる。 Examples of the aqueous component include water, propylene glycol, glycerin, polyethylene glycol, 1,3-butylene glycol and the like.
　ＲｖＥ１以外の抗炎症成分としては、例えば、植物（例えば、コンフリー）に由来する成分、アラントイン、グリチルリチン酸又はその誘導体、トラネキサム酸、酸化亜鉛、塩酸ピリドキシン、酢酸トコフェロール、サリチル酸又はその誘導体、ε-アミノカプロン酸、パントテニルアルコール、オウレンエキス、オウバクエキス、ユキノシタエキス、イザヨイエキス、エイジツエキス等が挙げられる。 Examples of the anti-inflammatory component other than RvE1 include components derived from plants (for example, comfrey), allantoin, glycyrrhizic acid or derivatives thereof, tranexamic acid, zinc oxide, pyridoxine hydrochloride, tocopherol acetate, salicylic acid or derivatives thereof, ε- Examples thereof include aminocaproic acid, pantothenyl alcohol, laurel extract, psyllium extract, quince extract, izayoi extract, and age extract.
　抗ニキビ成分とはニキビに効果的な成分であり、例えば、クリンダマイシン、ナジフロキサシン、イオウ、イソプロピルメチルフェロール、ピオニン（感光素201号）、アラントイン、グリチルリチン酸ジカリウム、ピリドキシン塩酸塩、カラミン、グアイアズレンスルホン酸ナトリウム、グリチルレチン酸ステアリル等の殺菌、抗菌、抗炎症成分；グリコール酸、乳酸、サリチル酸、サリチル酸マクロゴール、トリクロロ酢酸等のケミカルピーリング効果のある成分、アスコルビン酸、アスコルビン酸グルコシド、テトラヘキシルデカン酸アスコルビル等の抗酸化剤等が挙げられる。 The anti-acne component is a component effective against acne, and includes, for example, clindamycin, nadifloxacin, sulfur, isopropylmethylferrol, pionine (photosensitizer 201), allantoin, dipotassium glycyrrhizinate, pyridoxine hydrochloride, calamine, guaiazulene sulfone. Antibacterial, antibacterial and anti-inflammatory components such as sodium acidate and stearyl glycyrrhetinate; components with chemical peeling effect such as glycolic acid, lactic acid, salicylic acid, macrogol salicylate, trichloroacetic acid, ascorbic acid, ascorbic acid glucoside, ascorbyl tetrahexyldecanoate, etc. Antioxidants and the like.
　美白成分としては、パラアミノ安息香酸誘導体、サリチル酸誘導体、クマリン誘導体、アミノ酸系化合物、ベンゾトリアゾール誘導体、テトラゾール誘導体、イミダゾリン誘導体、ピリミジン誘導体、ジオキサン誘導体、カンファー誘導体、フラン酸誘導体、ピロン誘導体、核酸誘導体、アラントイン誘導体、ニコチン酸誘導体、ビタミンＣ又はその誘導体（ビタミンＣリン酸エステルマグネシウム塩、ビタミンＣグルコシド等）、ビタミンＤ又はその誘導体、ビタミンＥ又はその誘導体、コウジ酸又はその誘導体、オキシベンゾン、ベンゾフェノン、アルブチン、トラネキサム酸、グアイアズレン、シコニン、バイカリン、バイカレイン、ベルベリン、胎盤エキス、エラグ酸、ルシノール等が挙げられる。 As whitening ingredients, para-aminobenzoic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid compounds, benzotriazole derivatives, tetrazole derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives, camphor derivatives, furanic acid derivatives, pyrone derivatives, nucleic acid derivatives, allantoin Derivatives, nicotinic acid derivatives, vitamin C or its derivatives (vitamin C phosphate magnesium salt, vitamin C glucoside, etc.), vitamin D or its derivatives, vitamin E or its derivatives, kojic acid or its derivatives, oxybenzone, benzophenone, arbutin, Examples thereof include tranexamic acid, guaiazulene, shikonin, baicalin, baicalein, berberine, placenta extract, ellagic acid, and rucinol.
　防腐剤としては、例えば、パラベン類等が挙げられる。 Examples of antiseptics include parabens and the like.
　ｐＨ調整剤としては、例えば、リン酸、クエン酸、水酸化ナトリウム、水酸化カリウム、有機アミン等が挙げられる。 Examples of pH adjusters include phosphoric acid, citric acid, sodium hydroxide, potassium hydroxide, organic amines and the like.
　増粘剤としては、例えば、結晶セルロース、メチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシビニルポリマー、アクリル酸－メタクリル酸アルキル共重合体、カルメロースナトリウム、ポリビニルアルコール等が挙げられる。 Examples of the thickener include crystalline cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxyvinyl polymer, acrylic acid-alkyl methacrylate copolymer, carmellose sodium, polyvinyl alcohol and the like.
　安定化剤としては、例えば、トコフェロール、ＢＨＴ（ジブチルヒドロキシトルエン）、エデト酸ナトリウム水和物等が挙げられる。 Examples of the stabilizer include tocopherol, BHT (dibutylhydroxytoluene), sodium edetate hydrate and the like.
　また、本発明の皮膚外用剤の剤形は、特に制限されない。剤形として、例えば、ローション、クリーム、ゲル、軟膏等が挙げられる。本発明の皮膚外用剤は、通常の皮膚外用剤の製造方法に準じて調製することができる（第１６改正日本薬局方解説書２０１１、Ａ１２６～Ａ１４９）。 The dosage form of the external preparation for skin of the present invention is not particularly limited. Examples of dosage forms include lotions, creams, gels, ointments and the like. The external preparation for skin of the present invention can be prepared according to the usual method for producing an external preparation for skin (16th revised Japanese Pharmacopoeia Manual 2011, A126 to A149).
　本発明の皮膚外用剤は、被験体の皮膚、具体的には哺乳動物の皮膚、好ましくはヒトの皮膚に有効量塗布して使用されることで抗炎症効果を発揮し、皮膚における炎症の緩和、治癒および改善に有用である。また、本発明の皮膚外用剤は、抗炎症効果を発揮することで、湿疹、皮膚炎（アトピー性皮膚炎等が含まれる）、乾癬、痒疹群、掌蹠膿疱症、皮膚掻痒症、紅斑症、および／または紅皮症等の皮膚疾患の治療又は予防に有用に使用することができる。 The external preparation for skin of the present invention exerts an anti-inflammatory effect by being applied to a subject's skin, specifically, mammalian skin, preferably human skin in an effective amount, and reduces inflammation in the skin. , Useful for healing and improvement. In addition, the external preparation for skin of the present invention exerts an anti-inflammatory effect, so that eczema, dermatitis (including atopic dermatitis and the like), psoriasis, prurigo group, palmoplantar pustulosis, pruritus cutis, erythema. , And/or can be usefully used for treating or preventing skin diseases such as erythroderma.
（II）皮膚外用剤の用途
　本発明は、前記皮膚外用剤の有効量を、哺乳動物の皮膚に適用する工程を含む、当該皮膚の炎症を軽減する方法である。当該哺乳動物としては好ましくはヒトが含まれる。また当該哺乳動物には、湿疹、皮膚炎、乾癬、痒疹群、掌蹠膿疱症、皮膚掻痒症、紅斑症、および紅皮症からなる群より選択される少なくとも１種の皮膚疾患に罹患した動物が含まれ、前記の皮膚外用剤の有効量を、当該疾患患部に適用する工程を有することで、当該皮膚疾患を有効に予防、緩和、治癒および改善することができる。 (II) Use of external preparation for skin The present invention is a method for reducing inflammation of the skin, which comprises a step of applying an effective amount of the external preparation for skin to the skin of mammals. The mammal preferably includes a human. The mammal also includes at least one skin disease selected from the group consisting of eczema, dermatitis, psoriasis, prurigo group, palmoplantar pustulosis, pruritus cutis, erythema, and erythroderma. By including the step of applying an effective amount of the external preparation for skin to the affected area of the disease, the skin disease can be effectively prevented, alleviated, cured and improved.
　患部への適用回数（塗布回数）、および投与量（塗布量）は、本発明の効果を奏することを限度として、制限されない。例えば、抗炎症効果を発揮する１日有効量を、１日に１回または複数回に分けて、疾患患部に塗布することができる。 The number of applications (the number of applications) and the dose (the amount of application) to the affected area are not limited as long as the effects of the present invention are exhibited. For example, the effective daily amount that exerts an anti-inflammatory effect can be applied once or a plurality of times a day to the affected area.
　以上、本明細書において、「含む」及び「含有する」の用語には、「からなる」及び「から実質的になる」という意味が含まれる。 As mentioned above, in this specification, the terms “including” and “containing” include the meanings of “consisting of” and “consisting essentially of”.
　以下、本発明の構成及び効果について、その理解を助けるために、実験例を用いて本発明を更に詳細に説明する。但し、本発明はかかる実験例によって何ら制限を受けるものではない。下記の実験は、特に言及する場合を除いて、室温（２５±５℃）及び大気圧条件下で実施した。なお、特に言及しない限り、以下に記載する「％」は「質量％」を意味する。 The present invention will be described in more detail below by using experimental examples in order to help understanding of the configuration and effects of the present invention. However, the present invention is not limited by such experimental examples. The experiments described below were performed under room temperature (25±5° C.) and atmospheric pressure conditions unless otherwise noted. In addition, "%" described below means "mass %" unless otherwise specified.
実験例１　動物を用いた抗炎症効果の評価試験
（１）実験動物
　約１５週齢のC57BL6／Nマウス（雌）を用い、下記の５群（ｎ＝４）に群分けした。
　１群：ワセリン塗布群（コントロール群）
　２群：プレドニン眼軟膏塗布群
　３群：レゾルビンＥ１（ＲｖＥ１）塗布群
　４群：ボアラ軟膏塗布群
　５群：「ＲｖＥ１＋プレドニン眼軟膏」塗布群 Experimental Example 1 Evaluation test of anti-inflammatory effect using animals (1) Experimental animals C57BL6/N mice (female) about 15 weeks old were used and divided into the following 5 groups (n=4).
Group 1: Vaseline application group (control group)
Group 2: Predonin ointment application group 3 Group: Resolvin E1 (RvE1) application group 4 Group: Boala ointment application group 5 Group: "RvE1 + prednin eye ointment" application group
（２）薬剤
　使用した薬剤は以下の通りである。
　（a）ワセリン：プロペト（登録商標）、丸石製薬株式会社製
　（b）プレドニン眼軟膏：0.25％プレドニゾロン酢酸エステル含有製剤、塩野義製薬株式会社製
　（c）ＲｖＥ１：1mgのRvE1をエタノールで１００倍に希釈して調製（1％RvE1含有エタノール）
　（d）ボアラ軟膏：0.12％デキサメタゾン吉草酸エステル含有製剤、マルホ株式会社製
　ここで、プレドニン眼軟膏はＶ群(weak)に分類されるステロイド剤であり、ボアラ軟膏はＩＩＩ群(strong)に分類されるステロイド剤である。 (2) Drugs The drugs used are as follows.
(A) Vaseline: Propeto (registered trademark), manufactured by Maruishi Pharmaceutical Co., Ltd. (b) Predonin eye ointment: 0.25% prednisolone acetate ester-containing preparation, manufactured by Shionogi Pharmaceutical Co., Ltd. (c) RvE 1:1 mg RvE1 with ethanol 100 times Prepared by diluting (ethanol containing 1% RvE1)
(D) Boala Ointment: 0.12% dexamethasone valerate-containing preparation, manufactured by Maruho Co., Ltd. Here, predonin ophthalmic ointment is a steroid drug classified into Group V (weak), and Boala ointment is classified into Group III (strong) It is a steroid drug.
　抗原として、１－フルオロ－２，４－ジニトロベンゼン（DNFB）（ナカライテスク株式会社製）を用いた。感作には、アセトンとオリーブ油との４：１（質量比）混合液に、０.５％となるようにＤＮＦＢを添加溶解して調製した０.５％ＤＮＦＢ液を使用した。惹起には、アセトンとオリーブ油との４：１（質量比）混合液に、０.３％となるようにＤＮＦＢを添加溶解して調製した０．３％ＤＮＦＢ液を使用した。 1-Fluoro-2,4-dinitrobenzene (DNFB) (manufactured by Nacalai Tesque, Inc.) was used as an antigen. For sensitization, a 0.5% DNFB solution prepared by adding and dissolving DNFB to a mixture of acetone and olive oil in a ratio of 4:1 (mass ratio) to 0.5% was used. For induction, a 0.3% DNFB solution prepared by adding and dissolving DNFB in a 4:1 (mass ratio) mixture of acetone and olive oil to a concentration of 0.3% was used.
（３）感作方法
　腹部及び胸部を剃毛した各群のマウス（１群～５群）の腹部に、０.５％ＤＮＦＢ液（25μl）を１回塗布することによって感作誘導を行った。 (3) Sensitization method Sensitization induction was performed by applying 0.5% DNFB solution (25 μl) once to the abdomen of each group of mice (groups 1 to 5) with shaved abdomen and chest. ..
（４）皮膚反応テスト
　上記の感作方法によりＤＮＦＢで感作した５日後に、各群のマウスの両耳介の裏表両面に、以下の試料１～５を塗布した。その１０分後に０．３％ＤＮＦＢ液（20μl）を同部位に塗布することによって、炎症を惹起した。なお、以下の試料１～５の分量は、片方の耳介への塗布量である。
１群／試料１：ワセリン（0.01g）
２群／試料２：プレドニン眼軟膏（0.01g）
３群／試料３：1％RvE1（20μl）
４群／試料４：ボアラ軟膏（0.01g）
５群／試料５：1％RvE1（20μl）＋プレドニン眼軟膏（0.01g） (4) Skin reaction test Five days after sensitizing with DNFB by the above sensitizing method, the following samples 1 to 5 were applied to both front and back surfaces of both auricles of mice in each group. 10 minutes later, inflammation was induced by applying 0.3% DNFB solution (20 μl) to the same site. The amounts of Samples 1 to 5 below are the amounts applied to one auricle.
1 group/Sample 1: Vaseline (0.01g)
Group 2/Sample 2: Predonin eye ointment (0.01g)
3 groups/Sample 3: 1% RvE1 (20 μl)
Group 4/Sample 4: Boala ointment (0.01g)
5 groups/Sample 5: 1% RvE1 (20 μl) + predonin eye ointment (0.01 g)
（５）評価
　炎症惹起前、惹起して２４時間及び４８時間後に、各群のマウスについて耳介皮膚の厚みを定圧厚さ測定器（シックネスゲージPG-20J、株式会社テクロック製）にて測定し、群毎に平均値を算出した。２４時間後又は４８時間後の平均値と惹起前の平均値との差を皮膚腫脹（μｍ）として求めた。結果を表１及び図１に示す。 (5) Evaluation The thickness of the auricle skin of each group of mice was measured with a constant pressure thickness measuring instrument (thickness gauge PG-20J, manufactured by Teclock Co., Ltd.) before and 24 hours and 48 hours after the inflammation was induced. The average value was calculated for each group. The difference between the average value after 24 hours or 48 hours and the average value before induction was determined as skin swelling (μm). The results are shown in Table 1 and FIG.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表１及び図１の惹起２４時間後の結果に示すように、RvE1は単独で使用すると、分類上Ｖ群（weak）に分類されるプレドニン眼軟膏より抗炎症効果が低いが、RvE1とプレドニン眼軟膏とを併用することにより、分類上ＩＩＩ群（strong）に分類されるボアラ軟膏と同等又はそれ以上の抗炎症効果が得られることがわかった。 As shown in Table 1 and the results after 24 hours of induction in FIG. 1, when RvE1 is used alone, the anti-inflammatory effect is lower than that of predonin eye ointment classified into V group (weak) in classification, but RvE1 and predonin eyes are less effective. It was found that when used in combination with an ointment, an anti-inflammatory effect equivalent to or higher than that of Boala ointment classified into Group III (strong) in classification was obtained.
　この結果から、プレドニン眼軟膏と同様に分類上ＩＶ群（medium）に分類されるステロイド剤を、RvE1と併用した場合にも、分類上ＩＩＩ群（strong）に分類されるステロイド剤と同等又はそれ以上の抗炎症効果が得られることが予想される。 From this result, when a steroid drug classified into the IV group (medium) in terms of taxonomy as in the case of predonin eye ointment is used in combination with RvE1, it is equal to or higher than the steroidal drug classified in category III (strong) in category It is expected that the above anti-inflammatory effect will be obtained.
　表１及び図１に示す皮膚腫脹の経時変化から、ボアラ軟膏は、惹起２４時間後には強い抗炎症効果を発揮するものの、時間が経過するにつれてその効果が低下する傾向が認められた。プレドニン眼軟膏も、抗炎症効果の程度は相違するものの、ボアラ軟膏と同様に、時間が経過するにつれてその効果が低下する傾向が認められた。これに対して、RvE1とプレドニン眼軟膏とを併用することにより、抗炎症効果の経時的低下が抑制され、強い抗炎症効果が持続することが確認された。この結果から、RvE1はステロイド剤と併用することで、ステロイド剤の抗炎症効果の経時的低下を抑制することができ、その結果、抗炎症効果を長く持続させることが可能になると考えられる。この抗炎症効果の持続性は、特に副作用の少ないＶ群（weak）に分類されるステロイド剤またはＩＶ群（medium）に分類されるステロイド剤に対して有用である。つまり、RvE1とＶ群（weak）またはＩＶ群（medium）に分類されるステロイド剤とを併用することで、副作用の発生を抑えながらも、分類上ＩＩＩ群（strong）に分類されるステロイド剤と同等又はそれ以上の抗炎症効果を長く持続させることが可能になると考えられる。 From the time course of skin swelling shown in Table 1 and FIG. 1, it was confirmed that although Boala ointment exerts a strong anti-inflammatory effect 24 hours after induction, the effect tends to decrease with time. Although the degree of the anti-inflammatory effect of prednin eye ointment was different, it was observed that the effect tended to decrease with the passage of time, like the boala ointment. On the other hand, it was confirmed that the combined use of RvE1 and predonin eye ointment suppresses the decrease in anti-inflammatory effect over time and maintains a strong anti-inflammatory effect. From these results, it is considered that, when RvE1 is used in combination with a steroid drug, it is possible to suppress a decrease in the anti-inflammatory effect of the steroid drug over time, and as a result, it is possible to maintain the anti-inflammatory effect for a long time. This persistence of the anti-inflammatory effect is particularly useful for steroid drugs classified into group V (weak) or steroid drugs classified into group IV (medium), which have few side effects. In other words, by using RvE1 in combination with a steroid drug classified into the V group (weak) or IV group (medium), it is possible to suppress the occurrence of side effects and It is thought that it becomes possible to sustain a comparable or higher anti-inflammatory effect for a long time.

Claims (15)

  1. 　レゾルビンＥ１とグルココルチコイド受容体作動薬との組み合わせ物である皮膚外用剤。 A skin external preparation which is a combination of resolvin E1 and a glucocorticoid receptor agonist.
  2. 　レゾルビンＥ１とグルココルチコイド受容体作動薬との組み合わせ物が、レゾルビンＥ１とグルココルチコイド受容体作動薬を含有する組成物、またはレゾルビンＥ１を含有する製品とグルココルチコイド受容体作動薬を含有する製品との組み合わせ製品である、請求項１に記載する皮膚外用剤。 A combination of a resolvin E1 and a glucocorticoid receptor agonist is a composition containing the resolvin E1 and a glucocorticoid receptor agonist, or a product containing the resolvin E1 and a product containing the glucocorticoid receptor agonist. The external preparation for skin according to claim 1, which is a combination product.
  3. 　レゾルビンＥ１と、Ｖ群（weak）に分類されるステロイド剤（Ｖ群ステロイド剤）またはＩＶ群（medium）に分類されるステロイド剤（ＩＶ群ステロイド剤）との組み合わせ物である皮膚外用剤。 A skin external preparation which is a combination of Resolvin E1 and a steroid drug classified into V group (weak) (group V steroid drug) or a steroid drug classified into group IV (medium) (group IV steroid drug).
  4. 　レゾルビンＥ１とＶ群ステロイド剤またはＩＶ群ステロイド剤との組み合わせ物が、レゾルビンＥ１とＶ群ステロイド剤またはＩＶ群ステロイド剤とを含有する組成物、またはレゾルビンＥ１を含有する製品と、Ｖ群ステロイド剤を含有する製品またはＩＶ群ステロイド剤を含有する製品との組み合わせ製品である、請求項３に記載する皮膚外用剤。 A composition comprising a combination of a resolvin E1 and a group V steroid or a group IV steroid, and a composition containing the resolvin E1 and a group V steroid or a group IV steroid, or a product containing the resolvin E1, and a group V steroid The external preparation for skin according to claim 3, which is a combination product with a product containing a steroid or a product containing a group IV steroid.
  5. 　前記Ｖ群ステロイド剤が、プレドニゾロン、酢酸プレドニゾロン、硫酸フラジオマイシン、デキサメサゾン、酢酸ヒドロコルチゾン、フルドキシコルチド、ベタメタゾン、ベタメタゾンとマレイン酸クロルデニラミンとの混合物、およびヒドロコルチゾンからなる群から選択される少なくとも１種であり、前記ＩＶ群ステロイド剤が、吉草酸・酢酸プレドニゾロン、酪酸ヒドロコルチゾン、酪酸クロベタゾン、プロピオン酸アルクロメタゾン、トリアムシノロンアセトニド、およびピバル酸フルメタゾンからなる群から選択される少なくとも１種である、請求項３または４に記載する皮膚外用剤。 The group V steroid is at least one selected from the group consisting of prednisolone, prednisolone acetate, fradiomycin sulfate, dexamethasone, hydrocortisone acetate, fludoxycortide, betamethasone, a mixture of betamethasone and chlordeniramine maleate, and hydrocortisone. The group IV steroidal agent is at least one selected from the group consisting of valeric acid/prednisolone acetate, hydrocortisone butyrate, clobetasone butyrate, alclomethasone propionate, triamcinolone acetonide, and flumethasone pivalate. The external preparation for skin according to item 4.
  6. 　前記グルココルチコイド受容体作動薬または前記Ｖ群若しくはＩＶ群ステロイド剤が、プレドニゾロン、酢酸プレドニゾロン、吉草酸・酢酸プレドニゾロン、ヒドロコルチゾン、酢酸ヒドロコルチゾン、酪酸ヒドロコルチゾン、デキサメサゾン、ベタメタゾン、ベタメタゾン及びマレイン酸クロルデニラミンの混合物、酪酸クロベタゾン、プロピオン酸アルクロメタゾン、トリアムシノロンアセトニド、およびピバル酸フルメタゾンからなる群から選択される少なくとも１種である、請求項１～５のいずれか一項に記載する皮膚外用剤。 The glucocorticoid receptor agonist or the group V or IV steroid is prednisolone, prednisolone acetate, valeric acid/prednisolone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, dexamethasone, betamethasone, a mixture of betamethasone and chlordeniramine maleate, butyric acid. The external skin preparation according to any one of claims 1 to 5, which is at least one selected from the group consisting of clobetasone, alclomethasone propionate, triamcinolone acetonide, and flumethasone pivalate.
  7. 　前記グルココルチコイド受容体作動薬または前記Ｖ群ステロイド剤が、プレドニゾロン、および酢酸プレドニゾロンからなる群から選択される少なくとも１種である、請求項１～５のいずれか一項に記載する皮膚外用剤。 The external preparation for skin according to any one of claims 1 to 5, wherein the glucocorticoid receptor agonist or the group V steroid is at least one selected from the group consisting of prednisolone and prednisolone acetate.
  8. 　前記レゾルビンＥ１と前記グルココルチコイド受容体作動薬または前記Ｖ群若しくはＩＶ群ステロイド剤とを、モル比１：１０００～１：２の割合で組み合わせてなる、請求項１～７のいずれか一項に記載する皮膚外用剤。 8. The resolvin E1 and the glucocorticoid receptor agonist or the group V or IV steroid agent are combined in a molar ratio of 1:1000 to 1:2. Described external preparation for skin.
  9. 　抗炎症薬である請求項１～８のいずれか一項に記載する皮膚外用剤。 The external preparation for skin according to any one of claims 1 to 8, which is an anti-inflammatory drug.
  10. 　湿疹、皮膚炎、乾癬、痒疹群、掌蹠膿疱症、皮膚掻痒症、紅斑症、および紅皮症からなる群より選択される少なくとも１種の皮膚疾患の治療又は予防用の医薬品である、請求項１～９のいずれか一項に記載する皮膚外用剤。 A medicinal product for treating or preventing at least one skin disease selected from the group consisting of eczema, dermatitis, psoriasis, prurigo group, palmoplanter pustulosis, pruritus cutis, erythema, and erythroderma. Item 10. The external preparation for skin according to any one of items 1 to 9.
  11. 　請求項１または３に記載する皮膚外用剤の有効量を、哺乳動物の皮膚に適用する工程を含む、当該皮膚の炎症を軽減する方法。 A method for reducing inflammation of the skin, which comprises a step of applying an effective amount of the external preparation for skin according to claim 1 or 3 to the skin of mammals.
  12. 　前記哺乳動物が、湿疹、皮膚炎、乾癬、痒疹群、掌蹠膿疱症、皮膚掻痒症、紅斑症、および紅皮症からなる群より選択される少なくとも１種の皮膚疾患に罹患した動物であり、前記請求項１または３に記載する皮膚外用剤の有効量を、当該疾患患部に適用する工程を有する、請求項１１に記載する方法。 The mammal is an animal suffering from at least one skin disease selected from the group consisting of eczema, dermatitis, psoriasis, prurigo group, palmoplantar pustulosis, pruritus cutis, erythema, and erythroderma. The method according to claim 11, further comprising the step of applying an effective amount of the external preparation for skin according to claim 1 or 3 to the affected area.
  13. 　湿疹、皮膚炎、乾癬、痒疹群、掌蹠膿疱症、皮膚掻痒症、紅斑症、および紅皮症からなる群より選択される少なくとも１種の皮膚疾患の予防または治療に使用される、レゾルビンＥ１とグルココルチコイド受容体作動薬との組み合わせ製剤、またはレゾルビンＥ１とＶ群またはＩＶ群ステロイド剤との組み合わせ製剤。 Resolvin E1 used for the prevention or treatment of at least one skin disease selected from the group consisting of eczema, dermatitis, psoriasis, prurigo group, palmoplanter pustulosis, pruritus cutis, erythema, and erythroderma And a glucocorticoid receptor agonist, or a combined preparation of resolvin E1 and a group V or group IV steroid.
  14. 　抗炎症剤の製造のための、レゾルビンＥ１とグルココルチコイド受容体作動薬との組み合わせ物、またはレゾルビンＥ１とＶ群またはＩＶ群ステロイド剤との組み合わせ物の使用。 Use of a combination of resolvin E1 and a glucocorticoid receptor agonist or a combination of resolvin E1 and a group V or group IV steroid drug for the production of an anti-inflammatory agent.
  15. 　湿疹、皮膚炎、乾癬、痒疹群、掌蹠膿疱症、皮膚掻痒症、紅斑症、および紅皮症からなる群より選択される少なくとも１種の皮膚疾患の予防剤または治療剤の製造のための、レゾルビンＥ１とグルココルチコイド受容体作動薬との組み合わせ物、またはレゾルビンＥ１とＶ群ステロイド剤との組み合わせ物の使用。 For the production of a prophylactic or therapeutic agent for at least one skin disease selected from the group consisting of eczema, dermatitis, psoriasis, prurigo group, palmoplantar pustulosis, pruritus cutis, erythema, and erythroderma , Use of a combination of Resolvin E1 and a glucocorticoid receptor agonist, or a combination of Resolvin E1 and a Group V steroid.
PCT/JP2019/047652 2018-12-05 2019-12-05 External preparation for skin WO2020116570A1 (en)

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Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ARITA, MAKOTO ET AL.: "Novel chemical mediators in the resolution of inflammation, Resorbin and protectin derived from omega-3 fatty acids", PROTEIN, NUCLEIC ACID AND ENZYME, vol. 52, no. 4, 2007, pages 348 - 354 *
KIM, T. ET AL.: "Omega-3 fatty acid-derived mediator, Resolvin E1, ameliorates 2, 4- dinitrofluorobenzene-induced atopic dermatitis in NC/Nga mice", INTERNATIONAL IMMUNOPHARMACOLOGY, vol. 14, no. 4, 2012, pages 384 - 391, XP055715330, ISSN: 1567-5769 *
SAWADA, Y. ET AL.: "Resolvin E1 attenuates murine psoriatic dermatitis", SCIENTIFIC REPORTS, vol. 8, no. 1, 8 August 2018 (2018-08-08), pages 11873, XP055715331, ISSN: 2045-2322, DOI: 10.1038/s41598-018-30373-1 *
WATANABE, TOSHIYUKI: "Treatment of atopic dermatitis with a new external medicine containing DHA/EPA", ALLERGY IN PRACTICE, vol. 27, no. 12, 2007, pages 972 - 975 *

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