WO2019230230A1 - Composition pour le traitement ou la prévention de la dermatite atopique - Google Patents

Composition pour le traitement ou la prévention de la dermatite atopique Download PDF

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WO2019230230A1
WO2019230230A1 PCT/JP2019/016305 JP2019016305W WO2019230230A1 WO 2019230230 A1 WO2019230230 A1 WO 2019230230A1 JP 2019016305 W JP2019016305 W JP 2019016305W WO 2019230230 A1 WO2019230230 A1 WO 2019230230A1
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adrenergic receptor
atopic dermatitis
receptor agonist
antigen
selective
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PCT/JP2019/016305
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English (en)
Japanese (ja)
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芳樹 久保田
輝明 長澤
弥菜 新井
七子 長澤
葉子 山口
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株式会社ナノエッグ
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Priority to JP2020521781A priority Critical patent/JP7152051B2/ja
Publication of WO2019230230A1 publication Critical patent/WO2019230230A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • 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
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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    • 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
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G—PHYSICS
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    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing

Definitions

  • the present invention relates to a composition for treating or preventing atopic dermatitis.
  • Atopic dermatitis is dermatitis accompanied by urticaria, and allergic reaction caused by food (egg white, milk, soybean) or antigen (mite, dust, pollen, mold, etc.) is greatly involved.
  • Atopic dermatitis develops within a few months after birth and may recur, become severe, or become chronic after teenage.
  • a topical steroid preparation is listed as the first choice as a therapeutic agent.
  • a steroid agent can only suppress inflammation caused by atopic dermatitis. Cannot be treated directly.
  • side effects such as induction of skin infections due to suppression of the immune system on the skin surface may occur.
  • Non-patent Document 1 Filagrin deletion mutation has been reported as a cause of the onset of atopic dermatitis (Non-patent Document 2), but the detailed onset mechanism of atopic dermatitis has not been clarified, and an effective treatment method is also available. It was not established.
  • An object of the present invention is to provide a novel therapeutic agent that effectively treats atopic dermatitis.
  • ⁇ -adrenergic receptor agonists are unexpectedly effective in the treatment of atopic dermatitis, and have completed the present invention.
  • compositions for treating or preventing atopic dermatitis comprising a ⁇ -adrenergic receptor agonist.
  • the ⁇ adrenergic receptor agonist is selected from a selective ⁇ 1 adrenergic receptor agonist, a selective ⁇ 2 adrenergic receptor agonist, a selective ⁇ 3 adrenergic receptor agonist, and a non-selective ⁇ adrenergic receptor agonist.
  • composition according to item 1 wherein the composition is selected from the group consisting of: (Item 3)
  • the beta adrenergic receptor agonist is a selective beta 2-adrenergic receptor agonist, or a non-selective beta-adrenergic receptor agonist composition of claim 1.
  • the ⁇ -adrenergic receptor agonist is salbutamol, indacaterol, procaterol, salmeterol, clenbuterol, terbutaline, ritodrine, trimethoquinol, hexoprenalin, methoxyphenamine, fenoterol, bitolterol, metaproterenol, pyrbuterol, isoxpurin, alformoterol ,
  • a selective ⁇ 2 adrenergic receptor agonist selected from the group consisting of, bambuterol, formoterol, milveterol, olodaterol, birantelol, derivatives thereof, or pharmaceutically acceptable salts thereof, or solvates thereof Item 3.
  • the composition according to Item 2. (Item 5)
  • the ⁇ -adrenergic receptor agonist is a selective ⁇ selected from the group consisting of mirabegron, amibegron, CL-316,243, solabegron, derivatives thereof, or pharmaceutically acceptable salts thereof, or solvates thereof. 3.
  • Non-selective ⁇ -adrenergic receptor wherein the ⁇ -adrenergic receptor agonist is selected from the group consisting of isoproterenol (isoprenalin), derivatives thereof, or pharmaceutically acceptable salts thereof, or solvates thereof.
  • Item 3 The composition according to Item 2, which is a body agonist.
  • Item 8 A composition for treating or preventing atopic dermatitis, comprising a derivative of phenethylamine having ⁇ -adrenergic receptor agonist activity.
  • the phenethylamine derivative is: (1) having a hydroxy group at the ⁇ -position of the side chain of the phenyl group, (2) having no substituent other than hydrogen at the ⁇ -position of the side chain of the phenyl group, (3) Amino group is substituted or unsubstituted linear hydrocarbon group having 2 or more carbon atoms, substituted or unsubstituted branched hydrocarbon group, substituted or unsubstituted cyclic hydrocarbon group, and substitution Or at least one substituent selected from the group consisting of unsubstituted heterocyclic groups, (4) having a hydroxy group at the 4-position of the phenyl group,
  • the composition according to item 8 which has at least one of the following characteristics.
  • the ⁇ adrenergic agonist activity is selected from selective ⁇ 1 adrenergic agonist activity, selective ⁇ 2 adrenergic receptor agonist activity, selective ⁇ 3 adrenergic receptor agonist activity, and non-selective ⁇ adrenergic receptor agonist activity.
  • the beta adrenergic receptor agonist activity is a selective beta 2-adrenergic receptor agonist activity or non-selective beta-adrenergic receptor agonist activity, the composition according to any one of items 8-12.
  • a method of screening for a therapeutic agent for atopic dermatitis comprising: (A) providing a non-human animal in which atopic dermatitis is induced; (B) administering to the animal induced atopic dermatitis an amount of atopic dermatitis inducing agent sufficient to maintain atopic dermatitis and a test compound; (C) evaluating the improvement of the symptoms of atopic dermatitis by administration of the test compound.
  • a method for evaluating the therapeutic effect of a therapeutic agent for atopic dermatitis comprising: (A) providing a non-human animal in which atopic dermatitis is induced; (B) administering to the non-human animal induced by the atopic dermatitis an amount of the atopic dermatitis inducing agent sufficient to maintain the atopic dermatitis, and a therapeutic agent for the atopic dermatitis; (C) evaluating the improvement of the symptoms of atopic dermatitis by administration of the therapeutic agent for the atopic dermatitis.
  • the non-human animal in which the atopic dermatitis is induced is provided by administering a sufficient amount of an atopic dermatitis inducing substance to induce the atopic dermatitis.
  • Item 17. The method according to item 15 or 16, characterized.
  • (Item 18) The method according to any one of items 15 to 17, wherein the non-human animal is a mouse.
  • Item 20 Item 19.
  • the atopic dermatitis inducing substance is mite antigen, egg white antigen, milk antigen, wheat antigen, peanut antigen, soybean antigen, buckwheat antigen, sesame antigen, rice antigen, crustacean antigen, kiwi antigen, apple antigen, banana antigen, peach Antigen, tomato antigen, tuna antigen, salmon antigen, mackerel antigen, beef antigen, chicken antigen, pork antigen, cat antigen, insect antigen, pollen antigen, dog waste antigen, fungal antigen, bacterial antigen, latex, hapten and metal
  • (Item 23) The method according to any one of items 15-22, wherein the amount sufficient to maintain the atopic dermatitis is an amount less than an amount sufficient to induce the atopic dermatitis.
  • (Item 1A) A method of treating or preventing atopic dermatitis in a subject, comprising administering to the subject a ⁇ -adrenergic receptor agonist.
  • the ⁇ adrenergic receptor agonist is selected from a selective ⁇ 1 adrenergic receptor agonist, a selective ⁇ 2 adrenergic receptor agonist, a selective ⁇ 3 adrenergic receptor agonist, and a non-selective ⁇ adrenergic receptor agonist.
  • the method of item 1A selected from the group consisting of: (Item 3A) The method according to Item 1A, wherein the ⁇ adrenergic receptor agonist is a selective ⁇ 2 adrenergic receptor agonist or a non-selective ⁇ adrenergic receptor agonist.
  • the ⁇ -adrenergic receptor agonist is salbutamol, indacaterol, procaterol, salmeterol, clenbuterol, terbutaline, ritodrine, trimethoquinol, hexoprenalin, methoxyphenamine, fenoterol, bitolterol, metaproterenol, pyrbuterol, isoxpurin, alformoterol ,
  • a selective ⁇ 2 adrenergic receptor agonist selected from the group consisting of, bambuterol, formoterol, milveterol, olodaterol, birantelol, derivatives thereof, or pharmaceutically acceptable salts thereof, or solvates thereof.
  • the ⁇ -adrenergic receptor agonist is a selective ⁇ selected from the group consisting of mirabegron, amibegron, CL-316,243, solabegron, derivatives thereof, or pharmaceutically acceptable salts thereof, or solvates thereof.
  • the method according to item 2A which is a 3- adrenergic receptor agonist.
  • a selective ⁇ 1 adrenergic receptor selected from the group consisting of dobutamine, denopamine, xamoterol, derivatives thereof, or pharmaceutically acceptable salts thereof, or solvates thereof; The method of item 2A, which is an agonist.
  • Non-selective ⁇ -adrenergic receptor wherein the ⁇ -adrenergic receptor agonist is selected from the group consisting of isoproterenol (isoprenalin), derivatives thereof, or pharmaceutically acceptable salts thereof, or solvates thereof.
  • the method of item 2A which is a body agonist.
  • Item 8A A method for treating or preventing atopic dermatitis in a subject, comprising administering to the subject a derivative of phenethylamine having ⁇ -adrenergic receptor agonist activity.
  • the phenethylamine derivative is: (1) having a hydroxy group at the ⁇ -position of the side chain of the phenyl group, (2) having no substituent other than hydrogen at the ⁇ -position of the side chain of the phenyl group, (3) Amino group is substituted or unsubstituted linear hydrocarbon group having 2 or more carbon atoms, substituted or unsubstituted branched hydrocarbon group, substituted or unsubstituted cyclic hydrocarbon group, and substitution Or at least one substituent selected from the group consisting of unsubstituted heterocyclic groups, (4) having a hydroxy group at the 4-position of the phenyl group,
  • the method of item 8A having at least one of the following features: (Item 10A) Item 9.
  • the ⁇ adrenergic agonist activity is selected from selective ⁇ 1 adrenergic agonist activity, selective ⁇ 2 adrenergic receptor agonist activity, selective ⁇ 3 adrenergic receptor agonist activity, and non-selective ⁇ adrenergic receptor agonist activity.
  • the beta adrenergic receptor agonist activity is a selective beta 2-adrenergic receptor agonist activity or non-selective beta-adrenergic receptor agonist activity, A method according to any one of items 8A ⁇ 12A.
  • the ⁇ adrenergic receptor agonist is selected from a selective ⁇ 1 adrenergic receptor agonist, a selective ⁇ 2 adrenergic receptor agonist, a selective ⁇ 3 adrenergic receptor agonist, and a non-selective ⁇ adrenergic receptor agonist.
  • the ⁇ -adrenergic receptor agonist according to Item 1B selected from the group consisting of: (Item 3B) The ⁇ adrenergic receptor agonist according to Item 1B, wherein the ⁇ adrenergic receptor agonist is a selective ⁇ 2 adrenergic receptor agonist or a non-selective ⁇ adrenergic receptor agonist.
  • the ⁇ -adrenergic receptor agonist is salbutamol, indacaterol, procaterol, salmeterol, clenbuterol, terbutaline, ritodrine, trimethoquinol, hexoprenalin, methoxyphenamine, fenoterol, bitolterol, metaproterenol, pyrbuterol, isoxpurin, alformoterol ,
  • a selective ⁇ 2 adrenergic receptor agonist selected from the group consisting of, bambuterol, formoterol, milveterol, olodaterol, birantelol, derivatives thereof, or pharmaceutically acceptable salts thereof, or solvates thereof
  • the ⁇ -adrenergic receptor agonist according to Item 2B The ⁇ -adrenergic receptor agonist according to Item 2B.
  • the ⁇ -adrenergic receptor agonist is a selective ⁇ selected from the group consisting of mirabegron, amibegron, CL-316,243, solabegron, derivatives thereof, or pharmaceutically acceptable salts thereof, or solvates thereof.
  • the ⁇ -adrenergic receptor agonist according to Item 2B which is a 3- adrenergic receptor agonist.
  • a selective ⁇ 1 adrenergic receptor selected from the group consisting of dobutamine, denopamine, xamoterol, derivatives thereof, or pharmaceutically acceptable salts thereof, or solvates thereof;
  • the ⁇ -adrenergic receptor agonist according to Item 2B which is an agonist.
  • Non-selective ⁇ -adrenergic receptor wherein the ⁇ -adrenergic receptor agonist is selected from the group consisting of isoproterenol (isoprenalin), derivatives thereof, or pharmaceutically acceptable salts thereof, or solvates thereof.
  • the ⁇ -adrenergic receptor agonist according to Item 2B which is a body agonist.
  • Item 8B A derivative of phenethylamine having ⁇ -adrenergic receptor agonistic activity for treating or preventing atopic dermatitis.
  • the phenethylamine derivative is: (1) having a hydroxy group at the ⁇ -position of the side chain of the phenyl group, (2) having no substituent other than hydrogen at the ⁇ -position of the side chain of the phenyl group, (3) Amino group is substituted or unsubstituted linear hydrocarbon group having 2 or more carbon atoms, substituted or unsubstituted branched hydrocarbon group, substituted or unsubstituted cyclic hydrocarbon group, and substitution Or at least one substituent selected from the group consisting of unsubstituted heterocyclic groups, (4) having a hydroxy group at the 4-position of the phenyl group,
  • the derivative according to item 8B having at least one of the following characteristics: (Item 10B) Item 9.
  • the derivative according to Item 9B wherein the derivative of phenethylamine has at least two of the features (1) to (4).
  • (Item 11B) Item 9.
  • (Item 12B) Item 9.
  • the ⁇ adrenergic agonist activity is selected from selective ⁇ 1 adrenergic agonist activity, selective ⁇ 2 adrenergic receptor agonist activity, selective ⁇ 3 adrenergic receptor agonist activity, and non-selective ⁇ adrenergic receptor agonist activity.
  • Derivative according to any one of the beta-adrenergic receptor agonist activity is a selective beta 2-adrenergic receptor agonist activity or non-selective beta-adrenergic receptor agonist activity, items 8B ⁇ 12B.
  • the ⁇ adrenergic receptor agonist is selected from a selective ⁇ 1 adrenergic receptor agonist, a selective ⁇ 2 adrenergic receptor agonist, a selective ⁇ 3 adrenergic receptor agonist, and a non-selective ⁇ adrenergic receptor agonist.
  • ⁇ adrenergic receptor agonist is a selective ⁇ 2 adrenergic receptor agonist or a non-selective ⁇ adrenergic receptor agonist.
  • the ⁇ -adrenergic receptor agonist is salbutamol, indacaterol, procaterol, salmeterol, clenbuterol, terbutaline, ritodrine, trimethoquinol, hexoprenalin, methoxyphenamine, fenoterol, bitolterol, metaproterenol, pyrbuterol, isoxpurin, alformoterol ,
  • a selective ⁇ 2 adrenergic receptor agonist selected from the group consisting of, bambuterol, formoterol, milveterol, olodaterol, birantelol, derivatives thereof, or pharmaceutically acceptable salts thereof, or solvates thereof , Use according to Item 2C.
  • the ⁇ -adrenergic receptor agonist is a selective ⁇ selected from the group consisting of mirabegron, amibegron, CL-316,243, solabegron, derivatives thereof, or pharmaceutically acceptable salts thereof, or solvates thereof.
  • a selective ⁇ 1 adrenergic receptor selected from the group consisting of dobutamine, denopamine, xamoterol, derivatives thereof, or pharmaceutically acceptable salts thereof, or solvates thereof;
  • Non-selective ⁇ -adrenergic receptor wherein the ⁇ -adrenergic receptor agonist is selected from the group consisting of isoproterenol (isoprenalin), derivatives thereof, or pharmaceutically acceptable salts thereof, or solvates thereof.
  • the phenethylamine derivative is: (1) having a hydroxy group at the ⁇ -position of the side chain of the phenyl group, (2) having no substituent other than hydrogen at the ⁇ -position of the side chain of the phenyl group, (3) Amino group is substituted or unsubstituted linear hydrocarbon group having 2 or more carbon atoms, substituted or unsubstituted branched hydrocarbon group, substituted or unsubstituted cyclic hydrocarbon group, and substitution Or at least one substituent selected from the group consisting of unsubstituted heterocyclic groups, (4) having a hydroxy group at the 4-position of the phenyl group, Use according to item 8C, having at least one of the following characteristics: (Item 10C) Item 9.
  • the ⁇ adrenergic receptor agonist activity is selected from selective ⁇ 1 adrenergic receptor agonist activity, selective ⁇ 2 adrenergic receptor agonist activity, selective ⁇ 3 adrenergic receptor agonist activity, and non-selective ⁇ adrenergic receptor agonist activity.
  • the beta adrenergic receptor agonist activity is a selective beta 2-adrenergic receptor agonist activity or non-selective beta-adrenergic receptor agonist activity, Use according to any one of items 8C ⁇ 12C.
  • composition and method of the present invention can treat atopic dermatitis that has been difficult to treat effectively by providing an adrenergic receptor agonist as an active ingredient.
  • FIG. 1 shows the average amount of change in mouse body weight during the administration period of the test preparation in Example 1.
  • FIG. 2 shows the average amount of change in AD score during the administration period of the test preparation in Example 1.
  • FIG. 2A shows a comparison between the single agent administration group and the combination group, and
  • FIG. 2B shows only the single agent administration group.
  • FIG. 3 shows transdermal moisture transpiration (left) and stratum corneum moisture (right) on the last day of administration of the test preparation in Example 1.
  • FIG. 4 shows the epidermis thickness of AD-induced NC / Nga mice.
  • FIG. 5 shows the average amount of change in AD score of mice applied with a selective ⁇ -adrenergic receptor agonist.
  • FIG. 1 shows the average amount of change in mouse body weight during the administration period of the test preparation in Example 1.
  • FIG. 2A shows a comparison between the single agent administration group and the combination group
  • FIG. 2B shows only the single agent administration group.
  • FIG. 3 shows transdermal moisture transpiration (left
  • FIG. 6 shows AD scores before and after the test preparation (selective ⁇ -adrenergic receptor agonist) administration period.
  • FIG. 7 shows the auricular thickness after administration of the test preparation (selective ⁇ -adrenergic receptor agonist).
  • FIG. 8 shows a comparison of the structures of the test preparations.
  • FIG. 9 shows the epidermal thickness of AD-induced NC / Nga mice administered with the test preparation (selective ⁇ -adrenergic receptor agonist).
  • FIG. 10 shows the average amount of change in AD score of various test preparation non-administered (negative control) groups.
  • FIG. 11 shows changes in mouse body weight during the administration period of the test preparation in Example 3.
  • FIG. 12 shows the average change in AD score during the administration period of the test preparation in Example 3.
  • Atopic dermatitis is dermatitis associated with prurigo and is characterized by a chronic and repetitive course of repeated remission and ashamed. Many have allergic asthma, allergic rhinitis (hay fever), allergic conjunctivitis, etc. in the family and / or develop against the background of atopy, a predisposition to easily produce IgE antibodies.
  • ⁇ -adrenergic receptor as used herein, “ ⁇ -adrenergic receptor” belongs to subtype ⁇ of adrenergic receptor, and is a seven-fold membrane having catecholamines such as adrenaline and noradrenaline as ligands. Gs-coupled receptor with penetrating domain. ⁇ adrenergic receptors include ⁇ 1 adrenergic receptors, ⁇ 2 adrenergic receptors, and ⁇ 3 adrenergic receptors.
  • ⁇ -adrenergic receptor agonist means a substance having agonistic activity against ⁇ -adrenergic receptor (“ ⁇ -adrenergic receptor agonistic activity”), for example, catecholamines such as adrenaline and noradrenaline, and ⁇ -adrenergic receptor. On the other hand, it refers to a substance that exhibits the same action as adrenaline, noradrenaline and the like.
  • the “ ⁇ -adrenergic receptor agonist” only needs to have agonistic activity at least against ⁇ -adrenergic receptor, and may have agonistic activity against ⁇ -adrenergic receptor. , You do not have to.
  • a “ ⁇ -adrenergic receptor agonist” does not have activity to act on ⁇ -adrenergic and may have activity to act on ⁇ -adrenergic receptor.
  • Receptor agonists are referred to as “selective ⁇ -adrenergic receptor agonists”.
  • “Selective” means that the agonist activity of one receptor (eg, ⁇ 1 adrenergic receptor) is stronger than the agonist activity of other receptors (eg, ⁇ 2 and ⁇ 3 adrenergic receptors).
  • ⁇ -adrenergic receptor agonists are selective for two of the three ⁇ -adrenergic receptors (ie, agonist activity for two other receptors over agonist activity for one receptor) Is also strong).
  • Blocker interacts with a receptor to cause signal transduction through its receptor ligand (eg, a neurotransmitter such as adrenaline or a hormone). A substance that inhibits.
  • receptor ligand eg, a neurotransmitter such as adrenaline or a hormone.
  • “Inhibitor” refers to any substance that inhibits the action of a biomolecule (eg, adrenaline). As long as the action of the molecule in the living body can be inhibited, it may or may not directly interact with the biomolecule. Examples of inhibitors that do not directly interact with biomolecules include substances that act on an enzyme that synthesizes adrenaline and consequently indirectly inhibits the production of adrenaline.
  • a “derivative” as used herein is a compound whose core structure is the same as or very similar to that of the parent compound, but with modifications such as different functional groups or additional functional groups. Point to.
  • “derivative of phenethylamine” means a phenethylamine consisting of a phenyl group, a side chain, and an amino group:
  • the derivatives of phenethylamine are (1) having a hydroxy group at the ⁇ -position of the side chain of the phenyl group, (2) having no substituent other than hydrogen at the ⁇ -position of the side chain of the phenyl group, (3) Substituted or unsubstituted linear hydrocarbon groups having 2 or more carbon atoms, substituted or unsubstituted branched hydrocarbon groups, substituted or unsubstituted cyclic hydrocarbon groups, and substituted or unsubstituted heterocycles Having at least one substituent selected from the group consisting of groups, (4) having a hydroxy group at the 4-position of the phenyl group,
  • a phenethylamine derivative includes, for example, salbutamol, indacaterol, procaterol, salmeterol, clenbuterol, terbutaline, ritodrine, trimethoquinol, hexopre
  • Hydrocarbon group refers to any chemical group consisting of hydrogen and carbon.
  • the hydrocarbon group can be linear, branched or cyclic.
  • linear hydrocarbon group having 2 or more carbon atoms include linear (unbranched) ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and the like. It is not limited.
  • Examples of the “branched hydrocarbon group” include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, sec-hexyl and the like.
  • Examples of the “cyclic hydrocarbon group” include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Heterocyclic group refers to a monocyclic or polycyclic group in which at least one ring atom is a heteroatom selected from O, S and N.
  • heterocyclic group include pyridyl, furanyl, imidazolyl, indolyl, benzothiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, isopyrazolyl, pyrrolidinyl, benzoxazolyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl and the like. However, it is not limited to these.
  • the hydrocarbon group and heterocyclic group may or may not be substituted.
  • the substituent may be any group as long as a desired function is achieved, and examples thereof include, but are not limited to, an alkyl group, an aryl group, an araalkyl group, a cycloalkyl group, and an alkoxy group.
  • “Pharmaceutically acceptable salt” refers to an inorganic or organic acid addition salt of a compound that is pharmaceutically acceptable. These salts are used either during final isolation and purification of the compound, or by reacting the purified compound in its free base form separately with a suitable organic or inorganic acid, and so on. It can be prepared by isolating the salt formed. Such pharmaceutically acceptable salts are preferably low in toxicity.
  • Examples of the pharmaceutically acceptable basic salt of the compound used in the present invention include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; Salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, meglumine salt, diethanolamine salt, ethylenediamine salt, etc .; N, N-dibenzylethylenediamine, venetamine salt, etc.
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium salt and magnesium salt
  • ammonium salt Salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, meglumine salt, diethanolamine salt, ethylenediamine salt, etc .
  • N N-dibenzylethylenediamine, venetamine salt,
  • heterocyclic aromatic amine salts such as pyridine salt, picoline salt, quinoline salt, isoquinoline salt
  • tetramethylammonium salt such as pyridine salt, picoline salt, quinoline salt, isoquinoline salt
  • tetramethylammonium salt such as pyridine salt, picoline salt, quinoline salt, isoquino
  • Examples of the pharmaceutically acceptable acidic salt of the compound used in the present invention include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; Organic acid salts such as acetate, propionate, lactate, maleate, fumarate, tartrate, malate, citrate, ascorbate; methanesulfonate, isethionate, benzenesulfonate Examples thereof include salts, sulfonates such as p-toluenesulfonate, and acidic amino acids such as aspartate and glutamate.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate
  • Organic acid salts such as acetate, propionate, lactate, maleate, fumarate, tartrate, malate, citrate, ascorbate
  • Solidvate as used herein means a solvate of a compound used in the present invention or a pharmaceutically acceptable salt thereof, for example, a solvate with an organic solvent ( For example, alcohols (such as ethanol) and hydrates are included. When forming a hydrate, it may be coordinated with any number of water molecules. Examples of the hydrate include monohydrate, dihydrate and the like.
  • Subject refers to the subject of the composition or combination or method for treatment and prevention of the present invention, and the subject is a mammal (eg, human, mouse, rat, hamster, rabbit, cat). Dogs, cows, horses, sheep, monkeys, goats, pigs, etc.).
  • a sufficient amount to induce atopic dermatitis refers to an amount that results in an AD score of 6 or more, as used herein.
  • AD score is (1) redness / bleeding of the back, (2) crust / dryness of the back, (3) edema of the auricle, (4) auricle: tissue Refers to the score calculated according to the severity of each item of deficiency, and the AD score referred to in this specification is in accordance with the method described in the Biosta AD (Wako Pure Chemical) manual unless otherwise specified. This is the calculated score. Specifically, the score calculated according to the method described in the description of Biosta AD (Wako Pure Chemical Industries) is a score calculated based on the evaluation items described in Table 1 of Example 1.
  • an amount sufficient to maintain atopic dermatitis refers to an atopic dermatitis in a mouse that has induced atopic dermatitis, when no therapeutic agent for atopic dermatitis is administered. It refers to the amount of symptoms of dermatitis that do not become severe or alleviate.
  • an amount sufficient to maintain atopic dermatitis may be an amount that maintains within ⁇ 1 of the AD score when atopic dermatitis is induced.
  • the average change in AD score at the beginning of the week may be an amount that remains within ⁇ 0.5.
  • Test compound refers to any substance that can be a candidate for the treatment of atopic dermatitis.
  • Examples of the “test compound” include, but are not limited to, small molecule compounds, proteins, peptides, antibodies and the like.
  • the present invention provides a composition for treating or preventing atopic dermatitis comprising a beta adrenergic receptor agonist.
  • the ⁇ -adrenergic receptor agonist may further have an activity to activate the ⁇ -adrenergic receptor.
  • substances capable of operating both ⁇ -adrenergic receptor and ⁇ -receptor adrenaline include catecholamines (levodopa, dopamine, adrenaline, noradrenaline) and the like.
  • the beta adrenergic receptor agonist is a selective beta 1 adrenergic receptor agonist, a selective beta 2 adrenergic receptor agonist, a selective beta 3 adrenergic receptor agonist, and a non-selective beta adrenergic agonist. Selected from the group consisting of receptor agonists, preferably a selective ⁇ 2 adrenergic receptor agonist or a non-selective ⁇ adrenergic receptor agonist.
  • acetylcholine receptor blockers for example, hexetonium bromide (hereinafter referred to as Hexa) acting on nicotine-type acetylcholine receptor and its analogs, and scopolamine hydrobromide hydrous acid acting on muscarinic acetylcholine receptor
  • Hexa hexetonium bromide
  • scopolamine hydrobromide hydrous acid acting on muscarinic acetylcholine receptor It was revealed that a Japanese product (Scopolamine hydrohydrate trihydrate) is effective for atopic dermatitis (WO 2017/195833, which is incorporated herein by reference).
  • adrenaline and acetylcholine are known to suppress their activity via receptors at the respective terminals of parasympathetic nerve and sympathetic nerve, and either one dominantly conducts nerve transmission to the effector.
  • acetylcholine receptor blockers and ⁇ 2 AR ( ⁇ 2 adrenergic receptor) agonists are used for the purpose of relaxing bronchial smooth muscle.
  • ⁇ 2 AR ⁇ 2 adrenergic receptor
  • adrenergic receptor agonists / blockers affect atopic dermatitis.
  • the inventors have found that ⁇ -adrenergic receptor agonists are effective for atopic dermatitis, while ⁇ -adrenergic receptor blockers are not effective for atopic dermatitis. This result was surprising because an adrenergic receptor blocker was known to accelerate the recovery of the epidermal barrier (Grando et al., J Invest Dermatol. 2006 Sep; 126 (9): 1948-65). It was.
  • the selective ⁇ 2 adrenergic receptor agonist includes salbutamol, indacaterol, procaterol, salmeterol, clenbuterol, terbutaline, ritodrine, trimethoquinol, hexoprenalin, methoxyphenamine, fenoterol, bitolterol, meta Examples include, but are not limited to, proterenol, pyrbuterol, isoxsuprine, alformoterol, bambuterol, formoterol, milveterol, olodaterol, and birantrol.
  • non-selective ⁇ -adrenergic receptor agonists include, but are not limited to, isoproterenol (isoprenalin).
  • selective ⁇ 3 adrenergic receptor agonists include, but are not limited to, mirabegron, amibegron, CL-316,243, and sorabegron.
  • selective ⁇ 1 adrenergic receptor agonists include, but are not limited to dobutamine, denopamine, and xamoterol.
  • the ⁇ -adrenergic receptor agonist used in the composition for treating or preventing atopic dermatitis of the present invention includes a derivative of the above compound, a pharmaceutically acceptable salt thereof, or a solvent thereof. Japanese products can also be included.
  • the present invention provides a composition for treating or preventing atopic dermatitis comprising a derivative of phenethylamine having ⁇ -adrenergic receptor agonist activity.
  • the derivatives of phenethylamine are: (1) having a hydroxy group at the ⁇ -position of the side chain of the phenyl group, (2) having no substituent other than hydrogen at the ⁇ -position of the side chain of the phenyl group, (3) Amino group is substituted or unsubstituted linear hydrocarbon group having 2 or more carbon atoms, substituted or unsubstituted branched hydrocarbon group, substituted or unsubstituted cyclic hydrocarbon group, and substitution Or at least one substituent selected from the group consisting of unsubstituted heterocyclic groups, (4) having a hydroxy group at the 4-position of the phenyl group, May have at least one, at least two, at least three, or four features.
  • the derivative of phenethylamine has at least three of the above characteristics, and most preferably has all four of the above characteristics.
  • ⁇ -adrenergic receptor agonistic activity possessed by phenethylamine derivatives is selective ⁇ 1 adrenergic agonist activity, selective ⁇ 2 adrenergic receptor agonist activity, selective ⁇ 3 adrenergic receptor agonist activity, or non-selective ⁇ adrenergic receptor activity.
  • it is selective ⁇ 2 adrenergic agonist activity or non-selective ⁇ adrenergic receptor activity.
  • the present invention provides a composition or combination for treating or preventing atopic dermatitis comprising the ⁇ adrenergic receptor agonist and an inhibitor of acetylcholine.
  • the inhibitor of acetylcholine can be an inhibitor of muscarinic acetylcholine or an inhibitor of nicotinic acetylcholine.
  • the inhibitor of muscarinic acetylcholine can be an antagonist of a muscarinic acetylcholine receptor
  • the inhibitor of nicotinic acetylcholine can be an antagonist of a nicotinic acetylcholine receptor.
  • the beta adrenergic receptor agonist and the inhibitor of acetylcholine in the combination may be administered simultaneously or sequentially.
  • Inhibitors of muscarinic acetylcholine that can be used in the above combinations include trihexyphenidyl hydrochloride, butyl scopolamine bromide, pirenzepine hydrochloride hydrate, ipratropium bromide, oxitropium bromide, tiotropium bromide, atropine sulfate , Tropicamide, diphenhydramine hydrochloride, dicycloberine, oxybutynin hydrochloride, cyclopentrate hydrochloride, tolterodine tartrate, solifenacin succinate, diphenacin hydrobromide, mebevelin hydrochloride, procyclidine hydrochloride, acridinium bromide, propantelin bromide, scopolamine hydrobromide Salt hydrate, Methoscopolamine bromide, Mebenzolate bromide, Methaneterinium bromide, Orphenadrinoate, Homatropine bromide hydrogen salt
  • the present invention provides a method for treating or preventing atopic dermatitis in a subject, comprising the step of administering the ⁇ adrenergic receptor agonist to the subject.
  • ⁇ -adrenergic receptor agonists are described in detail above.
  • the present invention is a method of treating or preventing atopic dermatitis in a subject, comprising administering to the subject the beta adrenergic receptor agonist and the acetylcholine inhibitor.
  • ⁇ -adrenergic receptor agonists and inhibitors of acetylcholine are described in detail above.
  • the beta adrenergic receptor agonist and the inhibitor of acetylcholine may be administered simultaneously or sequentially.
  • the present invention provides the use of the ⁇ adrenergic receptor agonist in the manufacture of a medicament for treating or preventing atopic dermatitis in a subject.
  • ⁇ -adrenergic receptor agonists are described in detail above.
  • Inhibitors of nicotinic acetylcholine that can be used in the above combinations include kissamethonium chloride hydrate, decamethonium bromide, vecuronium bromide, pancuronium bromide, d-tubocurarine chloride hydrochloride hydrate, galamin triethiodide, mecamylamine hydrochloride , Trimethaphan cansylate, hexamethonium bromide, atracurium besylic acid, doxacurium chloride, mivacurium chloride, 18-methoxycoronaridine, dextromethorphan hydrobromide hydrate, methyl licacotinine, ⁇ -bungarotoxin , ⁇ -conotoxin G1, benzoquinonium, and bPiDDB, but are not limited to these.
  • the route of administration of a composition comprising a ⁇ -adrenergic receptor agonist includes topical application, transdermal administration, intradermal administration, subcutaneous administration, intravenous administration, oral administration, enteral administration, and pulmonary administration. Nasal administration, intraperitoneal administration, ear drop, eye drop, and the like, but are not limited thereto.
  • the composition is administered by topical application or transdermal administration.
  • Composition forms for topical or transdermal administration include ointments, dressings, solutions, emulsions, sprays, pastes, creams, lotions, gels, powders, oils, foams, and the like. It is not limited.
  • the content of ⁇ -adrenergic receptor agonist in a composition for topical application or transdermal administration depends on the type and toxicity of the ⁇ -adrenergic receptor agonist, the form of the composition, and the dose of those skilled in the art. It can be determined as appropriate.
  • the specific concentrations of ⁇ -adrenergic receptor agonist in the composition to be applied topically are shown below, but are not limited thereto.
  • the beta adrenergic receptor agonist in the topically applied composition is included at a concentration of about 0.001 to about 20% by weight. If the ⁇ -adrenergic receptor agonist content is too low, atopic dermatitis may not be sufficiently suppressed. If the ⁇ -adrenergic receptor agonist content is too high, toxicity may occur or the drug product May become difficult.
  • the composition for topical application or transdermal administration contains, in addition to the ⁇ -adrenergic receptor agonist, a drug capable of promoting percutaneous absorption and a base for external use capable of promoting percutaneous absorption.
  • a drug capable of promoting percutaneous absorption includes surfactants such as sodium lauryl sulfate and polyoxyethylene ether, alcohols such as oleyl alcohol, sorbitan esters such as sorbitan monolaurate, and cyclic monoesters such as l-menthol. Examples include terpenes and urea.
  • composition of the present invention may contain an anti-inflammatory agent, a steroid agent, an antihistamine, a preservative, an antioxidant, a wetting agent, vitamins and the like.
  • anti-inflammatory agent include, but are not limited to, glycyrrhetinic acid, dipotassium glycyrrhizinate, tranexamic acid, allantoin, and ⁇ -aminocaproic acid.
  • compositions of the invention can be administered by systemic administration, including but not limited to oral administration and intravenous administration.
  • systemic administration refers to a route of administration in which the administered compound can be distributed throughout the body and made available throughout the body.
  • the dosage forms for oral administration include solid or liquid dosage forms, specifically tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules), and syrups. Agents, emulsions, suspensions, and the like, but are not limited thereto.
  • Such dosage forms are produced by known methods and may contain carriers, diluents or excipients commonly used in the pharmaceutical field.
  • carriers and excipients for tablets include, but are not limited to, lactose, starch, sucrose, magnesium stearate, and the like.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and mixtures thereof.
  • Compositions suitable for injectable use according to the invention may be sterile aqueous solutions or dispersions or sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. It is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition.
  • the dose of an orally or intravenously administered ⁇ -adrenergic receptor agonist may vary depending on the subject of administration, the type of substance to be administered, the severity, the dosage form, etc.
  • the dose can be set as appropriate.
  • the present invention provides a method for treating or preventing atopic dermatitis in a subject, comprising the step of administering the ⁇ -adrenergic receptor agonist to the subject.
  • ⁇ -adrenergic receptor agonists are described in detail above.
  • the present invention provides the use of the ⁇ adrenergic receptor agonist in the manufacture of a medicament for treating or preventing atopic dermatitis in a subject.
  • ⁇ -adrenergic receptor agonists are described in detail above.
  • the present invention provides a method of screening for a therapeutic agent for atopic dermatitis.
  • the method comprises (a) providing a non-human animal in which atopic dermatitis has been induced, and (b) an amount sufficient to maintain atopic dermatitis in the animal in which atopic dermatitis has been induced. And a test compound, and (c) evaluating the improvement of the symptoms of atopic dermatitis by the administration of the test compound.
  • a non-human animal in which atopic dermatitis has been induced can be provided by administering an amount of an atopic dermatitis inducing agent sufficient to induce atopic dermatitis.
  • the method of the present invention may be a method for evaluating the therapeutic effect of a therapeutic agent for atopic dermatitis.
  • the non-human animal used in the method can be a mouse.
  • the mouse used in this method include, but are not limited to, NC / Nga, dd, ICR, BALB / c, C3H, DBA, C57BL, Hr ⁇ , and HR-1 mice.
  • the mouse used can be an NC / Nga mouse.
  • the atopic dermatitis inducing substance may be any substance capable of inducing atopic dermatitis in the non-human animal (for example, NC / Nga mouse), for example, mite antigen, egg white antigen, milk antigen, wheat Antigen, peanut antigen, soybean antigen, buckwheat antigen, sesame antigen, rice antigen, crustacean antigen, kiwi antigen, apple antigen, banana antigen, peach antigen, tomato antigen, tuna antigen, salmon antigen, mackerel antigen, beef antigen, chicken antigen , Pork antigen, cat skin antigen, insect antigen, pollen antigen, dog skin antigen, fungal antigen, bacterial antigen, latex, hapten, metal, but are not limited thereto.
  • the atopic dermatitis inducer used can be a tick antigen.
  • Step (a) is a step for providing a non-human animal in which atopic dermatitis is induced.
  • a non-human animal in which atopic dermatitis has been induced can be provided by administering an amount of an atopic dermatitis inducing agent sufficient to induce atopic dermatitis.
  • the administration period of the atopic dermatitis-inducing substance in step (a) is appropriately set by those skilled in the art. For example, it is about 1 week to about 5 weeks, preferably about 2 weeks to about 4 weeks. possible.
  • the period of administration of the atopic dermatitis inducing agent in step (a) can be about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, or about 5 weeks, but preferably 3 Week.
  • the frequency of administration of the atopic dermatitis inducer for inducing atopic dermatitis is once a day, once every two days, once every three days, once a week, twice a week, It can be three times a week, but is not limited to these.
  • a person skilled in the art can appropriately set the dose, administration period, and number of administrations of an atopic dermatitis inducer for inducing atopic dermatitis.
  • Step (b) is a step for administering a test compound to a non-human animal and evaluating the effect of treatment on atopic dermatitis.
  • An amount sufficient to maintain atopic dermatitis in step (b) does not aggravate or relieve the symptoms of atopic dermatitis if a therapeutic agent for atopic dermatitis is not administered.
  • the amount may be less than an amount sufficient to induce atopic dermatitis.
  • an amount sufficient to maintain atopic dermatitis is about 1/2, about 1/3, about 2/3, about 1 of the amount of atopic dermatitis inducing agent administered in step (a).
  • the amount is about one half of the amount of atopic dermatitis inducing agent administered in step (a).
  • the administration of the test compound in step (b) is typically once a day, but may be appropriately changed, and the dosage of the test compound may vary depending on the type of the test compound. If it is a trader, it can set appropriately considering toxicity, effectiveness, etc.
  • the breeding environment of the model animal in the method of the present invention can be appropriately set in order to achieve a predetermined AD score.
  • the flooring includes, but is not limited to, wood chips, paper chips, and corn coves in raising mice.
  • the flooring can be changed once, twice, three times, four times, five times, six times or seven times a week. In order to maintain atopic dermatitis, it is preferable to replace the flooring once a week.
  • the method of the present invention can also be used to confirm the effectiveness of the ⁇ -adrenergic receptor agonist or the phenethylamine derivative against atopic dermatitis.
  • the present invention provides a model animal for evaluating the effectiveness of a test compound against atopic dermatitis.
  • the model animal of the present invention can be used in the above screening method.
  • the model animal can be a mouse, including but not limited to NC / Nga, dd, ICR, BALB / c, C3H, DBA, C57BL, Hr ⁇ , HR-1 mice. .
  • NC / Nga mice are preferred because CD4 + T cells are more likely to be induced by Th2 cells important for atopic dermatitis induction.
  • Example 1 Analysis of AD therapeutic effect of ⁇ -adrenergic receptor agonist / blocker in AD model mice (NC / Nga)
  • the purpose of this example is to investigate the effects of ⁇ 2 AR agonists / blockers on AD.
  • the effect of combined use with anticholinergic drugs was also analyzed.
  • model mouse for atopic dermatitis A mouse (NC / Nga, 10 weeks old, male, Charles River, Japan) was used as a model animal for atopic dermatitis. Mite antigen (Biosta AD, Wako Pure Chemical Industries) was used to induce dermatitis. Model mice were prepared and scored according to the method described in the instructions attached to Biosta AD. Each of the four evaluation items was evaluated with 0 to 3 points, and the total score of each item was taken as the AD score. Table 1 below summarizes the scores for each evaluation item.
  • Test preparation Isoprenaline hydrochloride (Tokyo Chemical Industry) as a non-selective agonist of ⁇ -adrenergic receptor. Propranolol hydrochloride (Tokyo Chemical Industry) as a non-selective blocking agent. Procaterol hydrochloride hydrate (Wako Pure Chemical Industries) as a ⁇ 2 receptor selective agonist. ICI118551 hydrochloride was used as a ⁇ 2 receptor selective blocker, respectively. Hexamethonium bromide (Sigma-Aldrich) was used as an anti-acetylcholine drug. Table 2 shows the concentrations of the test preparations and their properties.
  • a preparation having a predetermined concentration of test preparation and 12 mM hexamethonium bromide dissolved therein was prepared, and the same amount as before was applied to each of the back and the auricle. This is a total of 5 times in the first week, once a day from Monday to Friday. In the second week, it was administered once a day from Monday to Thursday for a total of 4 times. On Monday and Thursday, the back was shaved and the dermatitis score was evaluated. On the last day of the test, transdermal transpiration moisture (TEWL), skin moisture (Corneometer), and epidermal thickness were measured.
  • TEWL transdermal transpiration moisture
  • Skin moisture Corneometer
  • epidermal thickness were measured.
  • FIG. 2A shows the average amount of change in the dermatitis score of all the administration groups
  • FIG. 2B shows the amount of change of only the single agent.
  • non-selective ⁇ agonist / blocking agents isoprenaline hydrochloride and propranolol hydrochloride used in this study have different activity for each subtype, and ⁇ 1 ⁇ 2 > ⁇ 3 in general. From these facts, it is presumed that ⁇ 1 AR and ⁇ 2 AR are involved in AD.
  • barrier function In AD, the barrier function of the skin is lowered. If the test substance normalizes epidermal differentiation, the barrier function is expected to improve. Therefore, transdermal moisture transpiration and stratum corneum moisture were measured as indicators of the barrier function. The respective measurement results on the final test day (11th day) are shown in FIG. Non-selective ⁇ -agonists and non-selective ⁇ -blockers showed improvement and exacerbation in AD score, respectively, but there was no significant difference in water transpiration compared to purified water administration group. A slight deterioration in transdermal water transpiration was observed in non-selective ⁇ agonists.
  • Adrenergic receptors are also involved in the regulation of the immune system. It has been reported that inflammation is suppressed by ⁇ 2 AR agonists, which is consistent with the action of isoprenaline hydrochloride (B pan ago). However, it is inconsistent with the results of procaterol hydrochloride hydrate (B2 ago). In addition, ⁇ 2 AR blockers are effective in skin barrier function and wound healing, contradicting the results of ICI 118551 hydrochloride (B2 ant) and propranolol hydrochloride (B-pan ant). From these results, it was suggested that different subtypes of ⁇ AR are involved in both immunity and epidermis in AD mice.
  • ⁇ AD patients show thickening of the epidermis due to inflammation. Therefore, the thickness of the epidermis layer was compared as an indicator of symptoms (FIG. 4). Skin tissue sections were stained with H & E, and the thickness of the epidermis layer was measured from a microscopic image. As compared with the non-treated group (Non-treated), a marked increase in the epidermal layer was observed in the negative purified water administration group (DW). The isoprenaline-administered group (B-pan ago) that showed improved scores in the AD score comparison showed a slight decrease in epidermal thickness. Procaterol (B2-ago), which showed a slight improvement in score, showed a marked reduction in skin thickness.
  • Example 2 Atopic dermatitis (AD) therapeutic effect analysis of selective ⁇ -adrenergic receptor agonist
  • AD selective ⁇ -adrenergic receptor agonist
  • model mouse for atopic dermatitis A mouse (NC / Nga, 10 weeks old, male, Charles River, Japan) was used as a model animal for atopic dermatitis. Mite antigen (Biosta AD, Wako Pure Chemical Industries) was used to induce dermatitis. Model mice were prepared and scored according to the method described in the instructions attached to Biosta AD.
  • Test preparation Dobutamine hydrochloride (Tokyo Kasei Kogyo) as a selective agonist of ⁇ 1 adrenergic receptor.
  • Salbutamol sulfate (Wako Pure Chemical Industries) as a short-acting selective agonist of ⁇ 2 adrenergic receptor.
  • ⁇ 2 of indacaterol maleate as an ultra-long-acting selective agonists (Tokyo Kasei Kogyo Co., Ltd.).
  • Mirabegron (Santa Cruz Biotechnology) was each used as a ⁇ 3 selective agonist.
  • a 50% aqueous ethanol solution was used as a solvent, and each was prepared so that the final concentration was 12 mM (Table 3).
  • TEWL transdermal transpiration moisture
  • Corneometer skin moisture
  • FIG. 6 shows a comparison of AD scores before and after the test preparation administration period.
  • the antigen was administered twice / week during the therapeutic agent application period.
  • the negative control solvent application group (Vehicle)
  • the ⁇ 3 selective agonist mirabegron (B3) showed a significant improvement in AD score compared to pre-dose.
  • Salbutamol sulfate (B2 SABA) showed a significant improvement in AD score immediately after the start of administration (FIG. 5).
  • Indacaterol maleate (B2 U-LABA) had the largest average change (improvement effect) on day 21 (FIG. 5).
  • the salbutamol sulfate (B2 SABA) showed a tendency to decrease the thickness of the auricle that had become thick due to AD induction. From these results, it was suggested that the ⁇ 2 receptor is greatly involved in the disease state.
  • the thickness of the epidermis layer was compared (FIG. 8). Skin tissue sections were stained with H & E, and the thickness of the epidermis layer was measured from a microscopic image. The group with increased skin thickness was only the dobutamine-administered group (B1-ago) as compared to the solvent-applied group (vehicle) as a negative target. In the salbutamol ⁇ B2-ago (SABA) ⁇ , indacaterol ⁇ B2-ago (ultra-LABA) ⁇ and mirabegron (B3-ago) administration groups, a decrease in epidermal thickness was observed. From these results, it was confirmed that agonists of ⁇ 2 and ⁇ 3 adrenergic receptors are effective for thickening of the epidermis layer.
  • FIG. 9 shows a structural comparison of the test preparations. The structural features common to the molecular structure of test preparations that showed therapeutic effects were defined as follows.
  • the administration conditions of the atopic dermatitis inducing substance in the negative control group during the administration period of the test preparation were examined. The results are shown in FIG. In this example, 100 mg biosta was applied twice a week (Monday / Thursday) during the atopic dermatitis induction period. During the test preparation administration period, 50 mg biosta, which is half of the dose in the atopic dermatitis induction period, was applied twice a week (Monday / Thursday), and as shown in FIG. 10 (Test 6), The AD score was maintained without significant fluctuations. For comparison, the following conditions in the test preparation administration period were tested. Test 1, Test 2 and 5: No antigen was applied.
  • AD score improvement Test 3: 100 mg biosta applied twice a week (Monday / Thursday). AD score worsened; Test 4: 100 mg biosta applied once a week (month) for the first 2 weeks. In the third week, 100 mg biosta was applied twice a week (month). Improved AD score. Under these conditions, some groups had improved AD scores despite not receiving the test preparation. Therefore, it is important to continuously administer the atopic dermatitis inducer during the administration period of the test preparation, and the dose is administered in an amount smaller than the induction period (for example, an amount of 1/2). It became clear that this was important.
  • Example 3 Atopic dermatitis therapeutic effect analysis of adrenaline
  • Examples 1 and 2 have shown the AD therapeutic effect of adrenaline ⁇ agonists. In this example, AD treatment effect by adrenaline was verified.
  • mice Preparation of model mice for atopic dermatitis: Mice (NC / Nga, 10 weeks old, male, Charles River, Japan) were used as model animals for atopic dermatitis. Mite antigen (Biosta AD, Wako Pure Chemical Industries) was used to induce dermatitis. Model mice were prepared and scored according to the method described in the instructions attached to Biosta AD. Test preparation: L-adrenaline hydrogen tartrate (Tokyo Chemical Industry, hereinafter adrenaline) dissolved in purified water at a specified concentration was used. A 1.2 mM adrenaline aqueous solution (1.2 mM Adrenaline), 6 mM (6 mM Adrenaline), and a solvent (purified water, vehicle) were used as test preparations.
  • L-adrenaline hydrogen tartrate Tokyo Chemical Industry, hereinafter adrenaline
  • Test method The test method described in Example 1 was followed. The test preparation was applied to the back and auricle of atopic dermatitis model mice at a frequency of once / day, 5 times / week (from Monday to Friday). This was administered 15 times in total for 3 weeks.
  • AD score decreased in both the 1, 2 and 6 mM adrenaline-administered groups as compared to the solvent group, but the AD score decreased more in the adrenaline-administered group than in the solvent group. From the above results, it was confirmed that adrenaline that activates both ⁇ -adrenergic receptor and ⁇ -adrenergic receptor, as well as ⁇ -adrenergic receptor agonist, has AD therapeutic effect.
  • Adrenaline has three features (1), (2) and (4) among the structural features determined in Example 2, and is consistent with the results of Example 2.
  • ⁇ -adrenergic receptor agonists show AD therapeutic effects regardless of whether they have ⁇ -adrenergic receptor agonist activity.
  • a composition or combination or method for effectively treating or preventing atopic dermatitis is provided.
  • Techniques that can be used in industries (pharmaceuticals, etc.) related to formulations and the like based on such techniques are provided.

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Abstract

La présente invention concerne une composition pour le traitement ou la prévention de la dermatite atopique. La présente invention concerne une composition pour le traitement ou la prévention de la dermatite atopique, la composition contenant un agoniste des récepteurs β-adrénergiques. Dans un mode de réalisation, l'agoniste des récepteurs β-adrénergiques est choisi dans le groupe constitué d'un agoniste sélectif des récepteurs β-1 adrénergiques, d'un agoniste sélectif des récepteurs β-2 adrénergiques, d'un agoniste sélectif des récepteurs β-3-adrénergiques et d'un agoniste non sélectif des récepteurs β-adrénergiques, mais l'agoniste des récepteurs β-adrénergiques est, de préférence, un agoniste sélectif des récepteurs β-2 adrénergiques ou un agoniste non sélectif des récepteurs β-adrénergiques.
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US11331322B1 (en) 2021-09-15 2022-05-17 Santen Pharmaceutical Co., Ltd. Medicament for preventing and/or treating dry eye
JP7076624B1 (ja) 2021-09-15 2022-05-27 参天製薬株式会社 ドライアイの予防及び／又は治療剤
WO2022174310A1 (fr) * 2021-02-22 2022-08-25 The University Of Sydney Compositions cicatrisantes
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022174310A1 (fr) * 2021-02-22 2022-08-25 The University Of Sydney Compositions cicatrisantes
WO2022174309A1 (fr) * 2021-02-22 2022-08-25 The University Of Sydney Procédés de cicatrisation
US11331322B1 (en) 2021-09-15 2022-05-17 Santen Pharmaceutical Co., Ltd. Medicament for preventing and/or treating dry eye
JP7076624B1 (ja) 2021-09-15 2022-05-27 参天製薬株式会社 ドライアイの予防及び／又は治療剤
WO2023042851A1 (fr) * 2021-09-15 2023-03-23 Santen Pharmaceutical Co., Ltd. Médicament pour la prévention et/ou le traitement de l'oeil sec
JP2023043126A (ja) * 2021-09-15 2023-03-28 参天製薬株式会社 ドライアイの予防及び／又は治療剤
US12005063B2 (en) 2021-09-15 2024-06-11 Santen Pharmaceutical Co., Ltd. Medicament for preventing and/or treating dry eye

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