WO2017126488A1 - Psoriasis treatment composition and treatment method - Google Patents

Psoriasis treatment composition and treatment method Download PDF

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Publication number
WO2017126488A1
WO2017126488A1 PCT/JP2017/001331 JP2017001331W WO2017126488A1 WO 2017126488 A1 WO2017126488 A1 WO 2017126488A1 JP 2017001331 W JP2017001331 W JP 2017001331W WO 2017126488 A1 WO2017126488 A1 WO 2017126488A1
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Prior art keywords
dermatitis
self
emulsifying composition
day
group
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PCT/JP2017/001331
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French (fr)
Japanese (ja)
Inventor
秀生 兼廣
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持田製薬株式会社
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Publication of WO2017126488A1 publication Critical patent/WO2017126488A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers

Definitions

  • the present invention relates to ⁇ 3 polyunsaturated fatty acids or their pharmaceutically acceptable salts, or their pharmaceutically acceptable esters, for the prevention and / or treatment of autoimmune skin diseases or inflammatory skin diseases. Or a pharmaceutically acceptable amide thereof, or a pharmaceutically acceptable phospholipid thereof as an active ingredient, and a self-emulsifying composition characterized by further containing an emulsifier.
  • the present invention also relates to a method for preventing and / or treating autoimmune skin disease or inflammatory skin disease using the self-emulsifying composition.
  • autoimmune skin diseases or inflammatory skin diseases Many treatments are provided for autoimmune skin diseases or inflammatory skin diseases, but current treatments are satisfactory for all patients due to, for example, serious side effects or insufficient therapeutic effects. It does not necessarily provide the results that should be done.
  • one exemplary autoimmune skin disease that requires good therapy is psoriasis.
  • Psoriasis is a T-cell-mediated systemic inflammatory skin disease that occurs in about 2-3% of the population, and is a disease that cannot be cured completely after repeated exacerbations and remissions. About patients suffering from this disease Has a significant impact on the quality of life.
  • the existing therapeutic agents for psoriasis are, for example, active vitamin D3 derivatives, steroids and combinations thereof as external preparations in Japan, cyclosporine, etretinate, apremilast and steroids as oral preparations, and secukinumab, ustekinumab, adalimumab as injections, There are anti-inflammatory cytokine antibodies such as infliximab, brodalumab, and ixekizumab.
  • ⁇ 3 polyunsaturated fatty acids hereinafter referred to as ⁇ 3 PUFA
  • EPA-E ethyl icosapentate
  • DHA-E docosahexaenoic acid ethyl ester
  • Non-patent Document 6 Reported that no efficacy was observed even after daily oral administration for 4 months (Non-patent Document 6), or about 18% of a triglyceride ester of icosapentoic acid (hereinafter referred to as EPA) and docosahexaenoic acid (hereinafter referred to as DHA).
  • EPA icosapentoic acid
  • DHA docosahexaenoic acid
  • the maximum efficacy of 18 mg / day MaxEPA containing about 12% of the triglyceride ester is as follows: It reported that it was no because there is (non-patent document 7).
  • Patent Document 1 Although an idea of an oral preparation for treating psoriasis containing a fatty acid mixture containing EPA-E or DHA-E and vitamin D has been reported, there is no description showing that it is actually effective (Patent Document 1). ), ⁇ 3 PUFA or their pharmaceutically acceptable esters have not yet been evaluated consistently for the prevention and / or treatment effect of psoriasis.
  • Self-emulsifying compositions containing ⁇ 3 PUFA or their pharmaceutically acceptable esters and an emulsifier are known.
  • a self-emulsifying composition with a low content of ethanol self-emulsifying property containing ⁇ 3 PUFA and a hydrophilic lipophilic balance (hereinafter referred to as HLB) 10 or more
  • HLB hydrophilic lipophilic balance
  • Self-emulsifying compositions containing a fatty acid oil mixture containing at least 75% by weight of eicosapentaenoic acid and docosahexaenoic acid and at least one surfactant have been reported (Patent Documents 8 to 10).
  • a self-emulsifying composition has been reported that contains ⁇ 3 PUFA and a surfactant to form an emulsion having a median particle size of about 100 nm to about 3 ⁇ m in contact with an aqueous liquid (Patent Document 11).
  • Patent Documents 2 to 8 describe that these self-emulsifying compositions have good absorbability when orally administered. However, there is no description of using these self-emulsifying compositions for the prevention and / or treatment of autoimmune skin diseases or inflammatory skin diseases.
  • autoimmune skin diseases such as psoriasis or inflammatory skin diseases
  • a composition for preventing and / or treating autoimmune skin diseases such as psoriasis or inflammatory skin diseases, which has a high preventive and / or therapeutic effect.
  • a composition for the prevention and / or treatment of autoimmune skin diseases or inflammatory skin diseases such as psoriasis that shortens the period of exacerbation and / or extends the period of remission or inactivity.
  • a composition for preventing and / or treating autoimmune skin diseases such as psoriasis or inflammatory skin diseases with few side effects is desired.
  • compositions for preventing and / or treating autoimmune skin diseases such as psoriasis or inflammatory skin diseases that reduces the frequency of administration and reduces the burden of patients on medication.
  • a composition for preventing and / or treating autoimmune skin diseases such as psoriasis or inflammatory skin diseases, which reduces the time taken for medication and reduces the burden of medication.
  • a composition for preventing and / or treating autoimmune skin diseases such as psoriasis or inflammatory skin diseases that reduces the cost of medication and reduces the burden of medication.
  • compositions for preventing and / or treating autoimmune skin diseases such as psoriasis or inflammatory skin diseases that solve at least one are desired. It is an object of the present invention to provide a self-emulsifying composition that improves at least one of the above properties. Furthermore, the present invention provides a method for preventing and / or treating autoimmune skin diseases such as psoriasis or inflammatory skin diseases using the self-emulsifying composition, which improves at least one of the above properties. It is a problem.
  • the first aspect of the present invention is the following self-emulsifying composition.
  • (1) For the prevention and / or treatment of autoimmune skin disease or inflammatory skin disease, characterized by intermittent oral administration every at least one period selected from the group consisting of 2 days to 1 month A self-emulsifying composition comprising ⁇ 3 PUFAs as an active ingredient and further containing an emulsifier.
  • (2) The self-emulsifying composition as described in (1) above, which is intermittently orally administered every at least one period selected from the group consisting of 2 days to 3 weeks.
  • (3) The self-emulsifying composition as described in (1) above, wherein the composition is intermittently orally administered every at least one period selected from the group consisting of 2 days to 2 weeks.
  • the self-emulsifying composition as described in (1) above wherein the composition is intermittently orally administered every at least one period selected from the group consisting of 2 days to 1 week.
  • the self-emulsifying composition as described in (1) above which is intermittently orally administered every 2 days, 3 days, 4 days, 5 days, 6 days or 1 week.
  • the self-emulsifying composition as described in (1) above which is intermittently orally administered every 10 days.
  • the self-emulsifying composition according to the above (1) which is intermittently orally administered every 20 days.
  • the self-emulsifying composition according to (1) above which is intermittently orally administered every 3 weeks.
  • the self-emulsifying composition as described in (1) above which is intermittently orally administered every 4 weeks or every month.
  • (11) characterized by being intermittently orally administered two days a week (eg, Monday and Thursday, Monday and Friday, Tuesday and Friday, Tuesday and Saturday, Wednesday and Saturday, Wednesday and Sunday, Thursday and Sunday), The self-emulsifying composition as described in (1) above.
  • intermittent administration refers to, for example, intermittent administration every two days, when the first day is administered, the next administration is performed two days later.
  • intermittent administration refers to, for example, intermittent administration every two days, when the first day is administered, the next administration is performed two days later.
  • every X days the period is calculated in days, and it is administered on the first day, and the next dose is administered on the X day.
  • the period is calculated in weeks, and it is administered on the first day, and the next dose is administered after Y weeks.
  • it is administered on the first day, the next day after Z months (for example, if the first day administration is 10 days, 10 days after Z month, and the first day administration is 29 to 31 days, the same day after Z months)
  • the administration interval is one week or more, the administration day can be shifted back and forth from the regular interval.
  • 1 week before and after 1 week 2 days before and 2 weeks, 2 days before and after 3 weeks, 3 days before and after 3 weeks, 4 days before and after 4 weeks, 5 days after 5 weeks
  • days and 6-week intervals it is 6 days before and after, and in the case of 7-week intervals, it is 1 week before and after, but is not limited thereto.
  • ⁇ 3 PUFAs are EPA, DHA, docosapentaenoic acid (hereinafter referred to as DPA), ⁇ -linolenic acid (hereinafter referred to as ALA), their pharmaceutically acceptable salts, and their pharmaceutically acceptable Any one of the above (1) to (12), which is at least one selected from the group consisting of pharmaceutically acceptable esters, pharmaceutically acceptable amides thereof, and pharmaceutically acceptable phospholipids thereof.
  • Autoimmune skin disease or inflammatory skin disease is psoriasis and analogies (including psoriasis vulgaris (including severe cases), psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, limbic limb dermatitis, Herpes zoster, Reiter's syndrome, trichomes psoriasis, etc.), ichthyosis group (common ichthyosis, blistered congenital ichthyosis-like erythroderma, non-bullous congenital ichthyosis-like erythroderma), palm Keratosis, Darier's disease, palmoplantar pustulosis, erythematous erythematosus, erythematous keratosis, dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis
  • Autoimmune skin disease or inflammatory skin disease is psoriasis and analogies (including psoriasis vulgaris (including severe cases), arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, limbic limb dermatitis, Herpes zoster, Reiter syndrome, prickly psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, autosensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, oil Leaky dermatitis, progressive palmokeratosis, other finger dermatitis, dermatitis of the auricle and ear canal, dermatitis around the nasal vestibule and nasal wing, generalized exfoliative dermatitis, congestive dermatitis, limited And at least one selected from the group consisting of Behcet's disease, preferably psoriasis
  • Psoriasis and analogies including psoriasis vulgaris (including severe cases), psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, limbic limb dermatitis, pustular impetigo, Reiter's syndrome, drops Psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic dermatitis, progressive palmar keratin , Other finger dermatitis, auricular and ear canal dermatitis, nasal vestibular and nasal wing dermatitis, generalized exfoliative dermatitis, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat Cyclosporine, etretinate, triamcinolone, hydrocortisone, cortis
  • Psoriasis and analogies including psoriasis vulgaris (including severe cases), arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, limbic limb dermatitis, herpes zoster, Reiter's syndrome, drops Psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic dermatitis, progressive palmar keratin , Other finger dermatitis, auricular and ear canal dermatitis, nasal vestibular and nasal wing dermatitis, generalized exfoliative dermatitis, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat Cyclosporine, etretinate, methotrexate, triamcinolone, hydro
  • intermittent oral administration is carried out every at least one period selected from the group consisting of 2 to 7 days.
  • the administration interval is increased by 1 day or 2 days for at least one period selected from the group consisting of weeks to 1 month, and selected from the group consisting of 1 week to 1 month in the remission period or inactive period.
  • the self-emulsifying composition according to any one of (1) to (33), which is intermittently orally administered every at least one period.
  • the self-emulsifying composition is a) 50 to 95% by weight of the total amount of ⁇ 3 PUFAs, b) 3 to 40 parts by weight of lecithin with respect to 100 parts by weight of ⁇ 3 PUFAs, c) From 10 to 50 parts by mass of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, and polyoxyethylene polyoxypropylene glycol per 100 parts by mass of ⁇ 3 PUFAs At least one emulsifier selected from the group consisting of: d) The self-emulsifying composition according to any one of (1) to (37) above, wherein the ethanol content is 4% by mass or less of the total amount.
  • the self-emulsifying composition is a) 50 to 95% by mass of ⁇ 3 PUFAs based on the total amount of the composition, b) at least one selected from the group consisting of sucrose laurate, sucrose myristic ester, sucrose palmitate, sucrose stearate and sucrose oleate in an amount of 4 to 20% by weight of the total amount.
  • An emulsifier wherein one HLB is 10 or more sucrose fatty acid esters, c) ⁇ 3PUFA, a pharmaceutically acceptable salt thereof, 5 to 30 parts by mass of glycerin with respect to 100 parts by mass of at least one compound selected from the group consisting of ethyl ester and triglyceride ester, and d) the content of ethanol
  • the self-emulsifying composition as described in any one of (1) to (37) above, which is 4% by mass or less of the total amount.
  • the self-emulsifying composition is an international publication WO2010 / 134614, an international publication WO2015 / 008848, an international publication WO2015 / 008849, an international publication WO2016 / 117057, an international publication WO2016 / 117621, an international publication.
  • the self milk according to any one of (1) to (37) above, which is at least one self emulsifying composition selected from Composition.
  • the second aspect of the present invention is the following method for preventing and / or treating autoimmune skin disease or inflammatory skin disease.
  • a self-emulsifying composition comprising ⁇ 3PUFAs as an active ingredient and an emulsifier for a patient in need of prevention and / or treatment of an autoimmune skin disease or inflammatory skin disease.
  • a method for preventing and / or treating autoimmune skin disease or inflammatory skin disease comprising intermittently orally administering at least one period selected from the group consisting of days to 1 month.
  • the self-emulsifying composition is administered 3 days a week (eg Monday and Wednesday and Friday, Monday and Wednesday and Saturday, Monday and Thursday and Saturday, Tuesday and Thursday and Saturday, Tuesday and Thursday and Sunday, Tuesday and Friday and The prevention and / or treatment method according to (42) above, characterized by intermittent oral administration on Sunday, Wednesday and Friday and Sunday.
  • ⁇ 3 PUFAs are EPA, DHA, DPA, ALA, their pharmaceutically acceptable salts, their pharmaceutically acceptable esters, their pharmaceutically acceptable amides, their pharmaceutical
  • a self-emulsifying composition that is at least one selected from the group consisting of phospholipids that are acceptable above is orally administered.
  • Autoimmune skin disease or inflammatory skin disease is psoriasis and analogies (psoriasis vulgaris (including severe cases), arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, limbic limb dermatitis, Herpes zoster, Reiter's syndrome, trichomes psoriasis, etc.), ichthyosis group (common ichthyosis, blistering congenital ichthyosis-like erythroderma, non-bullous congenital ichthyosis-like erythroderma), palm Keratosis, Darier's disease, palmoplantar pustulosis, erythematous erythematosus, erythematous keratosis, dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis,
  • Autoimmune skin disease or inflammatory skin disease is psoriasis and analogies (including psoriasis vulgaris (including severe cases), arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, limbic limb dermatitis, Herpes zoster, Reiter syndrome, prickly psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, autosensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, oil Leaky dermatitis, progressive palmokeratosis, other finger dermatitis, dermatitis of the auricle and ear canal, dermatitis around the nasal vestibule and nasal wing, generalized exfoliative dermatitis, congestive dermatitis, limited And at least one selected from the group consisting of Behcet's disease, preferably psoria
  • Psoriasis and analogies including psoriasis vulgaris (including severe cases), arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, limbic limb dermatitis, herpes zoster, Reiter's syndrome, drops Psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic dermatitis, progressive palmar keratin , Other finger dermatitis, auricular and ear canal dermatitis, nasal vestibular and nasal wing dermatitis, generalized exfoliative dermatitis, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat Cyclosporine, etretinate, methotrexate, triamcinolone, hydro
  • the self-emulsifying composition further comprising, as an active ingredient, at least one selected from the group consisting of cyclosporine, etretinate, apremilast, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone and betamazone, (42) The prevention and / or treatment method according to any one of (71).
  • Psoriasis and analogies including psoriasis vulgaris (including severe cases), psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, limbic limb dermatitis, pustular impetigo, Reiter's syndrome, drops Psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic dermatitis, progressive palmar keratin , Other finger dermatitis, auricular and ear canal dermatitis, nasal vestibular and nasal wing dermatitis, generalized exfoliative dermatitis, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat Cyclosporine, etretinate, methotrexate, triamcinolone, hydrocort
  • intermittent oral administration is performed at least every period selected from the group consisting of 2 to 7 days.
  • the administration interval is increased by 1 day or 2 days for at least one period selected from the group consisting of weeks to 1 month, and selected from the group consisting of 1 week to 1 month in the remission period or inactive period.
  • the prevention and / or treatment method according to 1.
  • At least one emulsifier selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol and sucrose fatty acid ester
  • the self-emulsifying composition is a) 50 to 95% by mass of ⁇ 3 PUFAs in a total amount, b) 3 to 40 parts by weight of lecithin with respect to 100 parts by weight of ⁇ 3 PUFAs, c) From 10 to 50 parts by mass of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, and polyoxyethylene polyoxypropylene glycol per 100 parts by mass of ⁇ 3 PUFAs At least one emulsifier selected from the group consisting of: d) The prophylaxis and / or treatment method according to any one of (42) to (78) above, wherein the ethanol content is 4% by mass or less of the total amount.
  • the self-emulsifying composition is a) 50 to 95% by mass of ⁇ 3 PUFAs based on the total amount of the composition, b) at least one selected from the group consisting of sucrose laurate, sucrose myristic ester, sucrose palmitate, sucrose stearate and sucrose oleate in an amount of 4 to 20% by weight of the total amount.
  • An emulsifier wherein one HLB is 10 or more sucrose fatty acid esters, c) ⁇ 3PUFA, a pharmaceutically acceptable salt thereof, 5 to 30 parts by mass of glycerin with respect to 100 parts by mass of at least one compound selected from the group consisting of ethyl ester and triglyceride ester, and d) the content of ethanol
  • the prevention and / or treatment method according to any one of (42) to (78) above, wherein the total amount is 4% by mass or less.
  • the self-emulsifying composition is an international publication WO2010 / 134614 pamphlet, an international publication WO2015 / 008848 pamphlet, an international publication WO2015 / 008849 pamphlet, an international publication WO2016 / 117570 pamphlet, an international publication WO2016 / 117621 pamphlet, an international publication. From the prevention and / or treatment methods described in the published WO2016 / 117629 pamphlet, the internationally published WO2010 / 103402 pamphlet, the internationally published WO2010 / 103404 pamphlet, the internationally published WO2010 / 119319 pamphlet and the internationally published WO2011 / 047259 pamphlet. (42) to (42), wherein the composition is at least one self-emulsifying composition selected from the group consisting of Prevention and / or treatment method according to any one of 8).
  • the third aspect of the present invention is the following method for preventing and / or treating autoimmune skin disease or inflammatory skin disease.
  • the fourth aspect of the present invention is the following method for preventing and / or treating autoimmune skin disease or inflammatory skin disease.
  • a self-emulsifying composition containing ⁇ 3PUFAs as an active ingredient and an emulsifier for a patient in need of prevention and / or treatment of autoimmune skin disease or inflammatory skin disease In the exacerbation period, intermittent oral administration is performed every at least one period selected from the group consisting of 2 to 7 days, and when improvement of symptoms is observed, at least one selected from the group consisting of 1 week to 1 month The administration interval is increased by 1 day or 2 days for each period, and is administered at least one period selected from the group consisting of 1 week to 1 month in the remission period or inactivity period, A method for preventing and / or treating autoimmune skin disease or inflammatory skin disease.
  • a fifth aspect of the present invention is characterized in that it contains ⁇ 3PUFA as an active ingredient and further contains an emulsifier for use in the prevention and / or treatment of the following autoimmune skin diseases or inflammatory skin diseases. It is a self-emulsifying composition.
  • ⁇ 3 PUFAs intermittently orally administered every at least one period selected from the group consisting of 2 days to 1 month for use in the prevention and / or treatment of autoimmune skin disease or inflammatory skin disease Is a self-emulsifying composition characterized by further containing an emulsifier.
  • ⁇ 3 PUFAs are EPA, DHA, DPA, ALA, their pharmaceutically acceptable salts, their pharmaceutically acceptable esters, their pharmaceutically acceptable amides, their pharmaceutical
  • Autoimmune skin disease or inflammatory skin disease is psoriasis and analogies (including psoriasis vulgaris (including severe cases), psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, acrotic limb dermatitis, Herpes zoster, Reiter's syndrome, trichomes psoriasis, etc.), ichthyosis group (common ichthyosis, blistering congenital ichthyosis-like erythroderma, non-bullous congenital ichthyosis-like erythroderma), palm Keratosis, Darier's disease, palmoplantar pustulosis, erythematous erythematosus, erythematous keratosis, dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic
  • Autoimmune skin disease or inflammatory skin disease is psoriasis and analogies (including psoriasis vulgaris (including severe cases), arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, acrotic limb dermatitis, Herpes zoster, Reiter syndrome, prickly psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, autosensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, oil Leaky dermatitis, progressive palmokeratosis, other finger dermatitis, dermatitis of the auricle and ear canal, dermatitis around the nasal vestibule and nasal wing, generalized exfoliative dermatitis, congestive dermatitis, limited And at least one selected from the group consisting of Behcet's disease, preferably ps,
  • Psoriasis and analogies psoriasis vulgaris (including severe cases), psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, peptic limb dermatitis, pustular impetigo, Reiter's syndrome, drops Psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic dermatitis, progressive palmar keratin , Other finger dermatitis, auricular and ear canal dermatitis, nasal vestibular and nasal wing dermatitis, generalized exfoliative dermatitis, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat Cyclosporine, etretinate, methotrexate, triamcinolone, hydrocort
  • the self-emulsifying composition further contains at least one selected from the group consisting of cyclosporine, etretinate, apremilast, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone and betamethasone as an active ingredient.
  • the self-emulsifying composition according to any one of the above (87) to (117).
  • Psoriasis and symptoms psoriasis vulgaris (including severe cases), psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, limbic limb dermatitis, herpes zoster, Reiter's syndrome, drops Psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic dermatitis, progressive palmar keratin , Other finger dermatitis, auricular and ear canal dermatitis, nasal vestibular and nasal wing dermatitis, generalized exfoliative dermatitis, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat Cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone
  • intermittent oral administration is carried out every at least one period selected from the group consisting of 2 to 7 days.
  • the administration interval is increased by 1 day or 2 days for at least one period selected from the group consisting of weeks to 1 month, and selected from the group consisting of 1 week to 1 month in the remission period or inactive period.
  • the self-emulsifying composition according to any one of (87) to (120), which is intermittently orally administered every at least one period.
  • At least one emulsifier selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol and sucrose fatty acid ester
  • the self-emulsifying composition is a) 50 to 95% by mass of the total amount of ⁇ 3 PUFAs, b) 3 to 40 parts by weight of lecithin with respect to 100 parts by weight of ⁇ 3 PUFAs, c) From 10 to 50 parts by mass of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, and polyoxyethylene polyoxypropylene glycol per 100 parts by mass of ⁇ 3 PUFAs At least one emulsifier selected from the group consisting of: d) The self-emulsifying composition according to any one of (87) to (124), wherein the ethanol content is 4% by mass or less of the total amount
  • the self-emulsifying composition is a) 50 to 95% by mass of ⁇ 3 PUFAs based on the total amount of the composition, b) at least one selected from the group consisting of sucrose laurate, sucrose myristic ester, sucrose palmitate, sucrose stearate and sucrose oleate in an amount of 4 to 20% by weight of the total amount.
  • An emulsifier wherein one HLB is 10 or more sucrose fatty acid esters, c) ⁇ 3PUFA, a pharmaceutically acceptable salt thereof, 5 to 30 parts by mass of glycerin with respect to 100 parts by mass of at least one compound selected from the group consisting of ethyl ester and triglyceride ester, and d) the content of ethanol
  • the self-emulsifying composition as described in any one of (87) to (124) above, which is 4% by mass or less of the total amount.
  • the self-emulsifying composition is an international publication WO2010 / 134614 pamphlet, an international publication WO2015 / 008848 pamphlet, an international publication WO2015 / 008849 pamphlet, an international publication WO2016 / 117057 pamphlet, an international publication WO2016 / 117621 pamphlet, an international publication.
  • the self-emulsifying composition of the present invention can be administered orally in specific usages / doses, such as intermittent administration, combined use with existing therapeutic agents, sequential administration, and administration differently between an exacerbation period and a remission period or inactive period.
  • Self-emulsifying compositions that improve at least one of the following properties can be provided.
  • High preventive and / or therapeutic effect shortens the period of exacerbation and / or prolongs the period of remission or inactivity, reduces side effects, reduces the frequency of administration, reduces patient burden, and reduces the time taken And / or reduce the cost of medication, reduce the burden of medication, and reduce the frequency and / or dose of existing medication by using it in combination with existing treatments (efficacy, side effects and patients)
  • the method for preventing and / or treating autoimmune skin disease or inflammatory skin disease of the present invention can improve at least one of the above properties.
  • the “autoimmune skin disease or inflammatory skin disease” used in the present invention includes a skin disease that develops due to or accompanies autoimmune failure or a skin disease that accompanies inflammation.
  • psoriasis and analogies including psoriasis vulgaris (including severe cases), psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, epidural limb dermatitis, pustular impetigo, Reiter's syndrome, prickly psoriasis ), Ichthyosis group (common ichthyosis, blistering congenital ichthyosis-like erythroderma, non-bullous congenital ichthyosis-like erythroderma), palmokeratosis, Darier's disease, palmoplantar pustulosis, Pore erythema, erythematous keratosis, dermatitis group (contact p
  • the EPA / AA ratio in serum or plasma is, for example, less than 1.5, less than 1.4, less than 1.3, less than 1.2. Less than 1, less than 1.0, less than 0.9, less than 0.8, less than 0.75, less than 0.7, less than 0.65, less than 0.6, less than 0.55, less than 0.5, Contains less than 45, less than 0.4, less than 0.35, less than 0.3, less than 0.25, less than 0.2, less than 0.15, less than 0.1, less than 0.05, or less than 0.01 Preferably less than 1.0, more preferably less than 0.75, even more preferably less than 0.7, even more preferably less than 0.5, especially preferably less than 0.4, even more preferably less than 0.3, Most preferred are patients with less than 0.1, but are not limited thereto.
  • ⁇ 3 PUFAs used in the present invention means pharmaceutically acceptable salts, esters, amides and phospholipids of ⁇ 3PUFA and / or ⁇ 3PUFA which are free fatty acids such as EPA, DHA, DPA, ALA, Or any other form that leads to metabolism of ⁇ 3 PUFA or uptake of ⁇ 3 PUFA into blood, lymph, body fluid, cells, tissues or organs.
  • EPAs”, “DHAs”, “DPAs”, and “ALAs” refer to each free fatty acid and / or pharmaceutically acceptable salts, esters, amides of each free fatty acid.
  • Pharmaceutically acceptable salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids, and the like. It is not limited.
  • metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt.
  • the salt with an organic base include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, triamine.
  • the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, N-acetylcysteine, etc.
  • Salt with organic carboxylic acid salt with organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, gluta Acid addition salts with acidic amino acids such as phosphate and the like.
  • Preferable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine
  • preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned.
  • the compound which made the amino acid ion-bond between the above-mentioned 2 molecules of ⁇ 3 PUFA amino acid salt described in the pamphlet of International Publication WO2015 / 195491 with divalent metal ions such as magnesium ion, calcium ion, and zinc ion may also be included.
  • pharmaceutically acceptable salts are preferred.
  • an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt)
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • esters examples include alkyl esters such as methyl ester, ethyl ester, n-propyl ester and i-propyl ester, and monoglyceride ester, diglyceride ester and triglyceride ester (hereinafter referred to as TG ester). Including but not limited to glyceride esters.
  • a compound in which ⁇ 3PUFA is ester-bonded at any one of positions 1 to 3 and in the case of diglyceride ester, a compound in which ⁇ 3PUFA is ester-bonded to any one of positions 1 to 3 and ⁇ 3PUFA are in position 1 and A compound having an ester bond at two positions of the 2-position or the 1-position and the 3-position, and, in the case of a TG ester, a compound having an ester bond at any one of the 1- to 3-positions of the ⁇ 3 PUFA, And a compound in which ⁇ 3PUFA is ester-bonded at three positions of the 1st to 3rd positions.
  • amides include, but are not limited to, amides such as carboxylic acid amides, sulfonamides and phosphoric acid amides.
  • the pharmaceutically acceptable phospholipids include, but are not limited to, compounds in which at least one ⁇ 3 PUFA is bound to phospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol and phosphatidylinositol. Desirable examples are free acids, ethyl esters, TG esters, phospholipids, etc. Free acids and ethyl esters are more desirable.
  • desirable examples include EPA, EPA-E, EPA TG ester, DHA, DHA-E, DHA TG ester, DPA, DPA ethyl ester (hereinafter referred to as DPA-E), DPA TG ester, ALA, ALA ethyl ester (hereinafter referred to as ALA-E) and ALA TG ester, etc. are included, such as EPA, EPA-E, DHA, DHA-E, DPA, DPA-E, ALA and ALA-E.
  • DPA-E DPA ethyl ester
  • ALA-E ALA ethyl ester
  • ALA-E ALA ethyl ester
  • ⁇ 3 PUFA may contain ⁇ 3 PUFA other than those described above.
  • HTA hexadecatrienoic acid
  • ETE eicosatrienoic acid
  • SDA stearidonic acid
  • ETA eicosatetraenoic acid
  • heneicosapentaene examples include acid (HPA), tetracosapentaenoic acid (TPA) or tetracosahexaenoic acid (THA) or pharmaceutically acceptable salts, esters, amides and phospholipids thereof.
  • the content of these ⁇ 3 PUFAs is low, and more desirably less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, and 25% by weight. Less than, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, and more preferably less than 1% by weight.
  • EPA-E as referred to in the present invention is an ethyl ester (CAS registration number: 86227-47-6) of icosapentic acid (CAS registration number: 10417-94-4) belonging to ⁇ 3 PUFA.
  • the natural product means one extracted from a natural oil containing icosapentic acids by a known method, one that has been roughly purified, or one that has been further refined.
  • Semi-synthetic products include icosapentic acids produced by microorganisms and the like, and those obtained by subjecting the icosapentic acids or natural icosapentic acids to chemical treatments such as esterification and transesterification. In the present invention, as EPA-E, one of these can be used alone, or two or more can be used in combination.
  • the purity of the raw material EPA-E used in the self-emulsifying composition of the present invention is not particularly limited.
  • the content of EPA-E in the total fatty acids of the self-emulsifying composition is 20% by mass or more and 25% by mass. Or more, 30% by mass or more, 35% by mass or more, preferably 40% by mass or more, 45% by mass or more, 50% by mass or more, 55% by mass or more, 60% by mass or more, 65% by mass or more, more preferably 70% by mass.
  • the EPA has a high purity, for example, the EPA content ratio in all fatty acids is preferably 40% by mass or more, more preferably 60% by mass or more, still more preferably 70% by mass or more, and 80% by mass. % Or more is more preferred, 90% or more is more preferred, 96.5% or more is particularly preferred, and 98% or more is most preferred.
  • the content of EPA-E in the total fatty acids of the self-emulsifying composition is 40% by mass or more, 41% by mass or more, 42% by mass or more, 43% by mass or more, 44% by mass or more, 45% by mass or more, 46% by mass or more, 47% by mass or more, 48% by mass or more, 49% by mass or more, 50% by mass or more, 51% by mass or more, 52% by mass or more, 53% by mass or more, 54% by mass or more, 55% by mass or more, 56% or more, 57% or more, 58% or more, 59% or more, 60% or more, 61% or more, 62% or more, 63% or more, 64% or more, 65% or more, 66% or more, 67% or more, 68% or more, 69% or more, 70% or more, 71% or more, 72% or more, 73% or more, 74% or more, 75% or more, 76% by mass or more, 77% by mass or less 78% by mass, 79% by mass or
  • EPA-E is a purity of EPA that is substantially free of DHA or, for example, less than 1.0% by weight, preferably less than 0.5% by weight, more preferably less than 0.2% by weight. That is, it is desirable that the purity of EPA-E is higher.
  • a composition containing EPA-E and DHA-E (for example, a mass ratio of EPA-E to DHA-E is 10: 1 to 1:
  • Other fatty acids or esters thereof or triglycerides, more specifically, ⁇ 3 PUFA ethyl ester) or a composition containing EPA and DHA (for example, a mass ratio of EPA to DHA of 10: 1 to 1:10).
  • compositions of the present invention may also include EPAs and DPA, or EPAs, DPA and HPA, or EPAs, DPA and TPA, or EPAs, DPA, HPA, and TPA.
  • DPA ratios are 99: 1 to 1:99, 90: 1 to 1:90, 60: 1 to 1:60, 40: 1 to 1:40, 30: 1 to 1:30, 20 1 to 1:20, 10: 1 to 1:10, 5: 1 to 1: 5, and 2: 1 to 1: 2.
  • the composition of the present invention comprises EPAs, DHAs and DPA, or EPAs, DHAs, DPA and HPA, or EPAs, DHAs, DPA and TPA, or EPAs, DHAs, DPA, HPA And TPA.
  • DPA ratios are 1: 100 or less, 1:95 or less, 1:90 or less, 1:80 or less, 1:70 or less, 1:60 or less, 1:50 or less, 1:40 or less, 1: 30 or less, 1:20 or less, 1:10 or less, 1: 5 or less, 1: 2 or less, 1: 1 or less, 2: 1 or less, 5: 1 or less, 10: 1 or less, 20: 1 or less, 50: 1 or less, and 100: 1 or less.
  • the self-emulsifying composition of the present invention includes ⁇ 6 polyunsaturated fatty acids such as AA, linoleic acid, ⁇ -linolenic acid and dihomo- ⁇ -linolenic acid, pharmaceutically acceptable salts and esters thereof. May contain amides or phospholipids.
  • the content of ⁇ 6 polyunsaturated fatty acid in all fatty acids is desirably low, and more desirably less than 10% by mass, less than 9% by mass, less than 8% by mass, less than 7% by mass, less than 6% by mass, 5% Less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, more preferably less than 0.2% by weight.
  • the content of AA and their pharmaceutically acceptable salts, esters, amides or phospholipids (hereinafter referred to as AA) with respect to the total fatty acid content is desirably low, more desirably 5 masses.
  • the aspect is more preferably less than 0.05% by mass, and most desirably an embodiment substantially free of AA's.
  • the content of ⁇ 3 PUFAs or EPAs when the total amount of the self-emulsifying composition is 100% by mass is 50 to 90% by mass, preferably 60 to 86% by mass, and more preferably 65%. -80% by mass, more preferably 70-80% by mass.
  • the content of ⁇ 3 PUFAs or EPAs with the total amount of the self-emulsifying composition being 100% by mass is 50% by mass, 51% by mass, 52% by mass, 53% by mass.
  • EPA-E is a soft capsule (trade name Epadale: manufactured by Mochida Pharmaceutical Co., Ltd.) containing high-purity EPA-E (96.5% by mass or more) that can be obtained as a therapeutic agent for ASO and hyperlipidemia in Japan.
  • EPA-E-containing soft capsule trade name VASCEPA: amarin
  • VASCEPA amarin
  • composition under development such as Epanova TM (Omthera, AstraZeneca) or MAT9001 (Matinas Biopharma) containing ⁇ 3 PUFA free acid, or a magnesium bis-liginate bis-EPA dihydrate described in WO2015 / 195491 Bis-lysinate bis-DHA dihydrate, magnesium bis-lysinate bis-DPA dihydrate and the like may be used.
  • the “self-emulsifying composition” used in the present invention is a composition that easily disperses and self-emulsifies when in contact with an aqueous solution, and is disclosed in International Publication WO2010 / 134614, International Publication WO2015 / 008848, International Publication WO2015 / 008849 pamphlet, International publication WO2016 / 117057 pamphlet, International publication WO2016 / 117621 pamphlet, International publication WO2016 / 117629 pamphlet, International publication WO2010 / 103402 pamphlet, International publication WO2010 / 103404 pamphlet, International publication WO2010 / 119319 pamphlet and international publication WO2011 / 047259 pamphlet.
  • the self-emulsifying composition described in Examples 1 to 13 of International Publication WO2010 / 134614 the self-emulsifying composition described in Examples 1 to 11 of International Publication WO2015 / 008848, and International Publication WO2015 / Self-emulsifying composition described in pamphlet Examples 1 to 17 of No.
  • the “emulsifier” used in the present invention is a compound that has a hydrophilic group part and a lipophilic group part, and has an action of creating a uniform state by working at the boundary surface of water and oil that are not originally mixed. is there.
  • international publication WO2010 / 134614 pamphlet international publication WO2015 / 008848 pamphlet, international publication WO2015 / 008849 pamphlet, international publication WO2016 / 117757 pamphlet, international publication WO2016 / 117621 pamphlet, international publication WO2016 / 117629 pamphlet
  • the emulsifier described in the international publication WO2010 / 103402 pamphlet, the international publication WO2010 / 103404 pamphlet, the international publication WO2010 / 119319 pamphlet, and the international publication WO2011 / 047259 pamphlet is included.
  • polyoxyethylene hydrogenated castor oil polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, etc.
  • HLB used in the present invention is a substance that has no hydrophilic group and has only a lipophilic group as HLB0, and a substance that does not have a lipophilic group and has only a hydrophilic group as HLB20.
  • An emulsifier having both lipophilicity and hydrophilicity takes a value in between.
  • the emulsifier contained in the self-emulsifying composition of the present invention preferably has an HLB of 10 or more, more preferably 11 or more, and still more preferably 12 or more.
  • polyoxyethylene hydrogenated castor oil is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil obtained by adding hydrogen to castor oil.
  • Various compounds are commercially available depending on the average degree of polymerization of ethylene oxide.
  • examples include, but are not limited to, hydrogenated castor oil (NIKKOLOHCO-100, Nikko Chemicals), and preferably polyoxyethylene (60) hydrogenated castor oil.
  • one of these can be used alone or in combination of two or more.
  • the term “polyoxyethylene hydrogenated castor oil” is used in the sense of including all of the above compounds unless otherwise specified.
  • polyoxyethylene sorbitan fatty acid ester is a polyoxyethylene ether of a fatty acid ester in which a part of hydroxyl groups of anhydrous sorbitol is esterified with a fatty acid.
  • Various compounds are commercially available depending on the fatty acid to be esterified.
  • polyoxyethylene (20) sorbitan monolaurate NIKKOL TL-10, polysorbate 20, Tween 20
  • polyoxyethylene (20) sorbitan monopalmitate NIKKOL TP
  • polysorbate 40 Tween 40
  • polyoxyethylene (20) sorbitan monostearate NIKKOL TS-10MV
  • polysorbate 60 Tween 60
  • polyoxyethylene sorbitan tristearate
  • polysorbate 65 Polyoxyethylene (20) sorbitan monoisostearate (NIKKOL TI-10V)
  • polyoxyethylene (20) sorbitan monooleate NIK
  • OL TO-10MV polysorbate 80, Tween 80
  • polyoxyethylene (20) sorbitan trioleate NIKKOL TO-30V, polysorbate 85) and the like
  • polyoxyethylene castor oil is a compound obtained by addition polymerization of castor oil with ethylene oxide.
  • Various compounds are commercially available depending on the average number of moles of ethylene oxide added.
  • NIKKOL CO-3 Nikko Chemicals
  • NIKKOL CO-10 Nikko Chemicals
  • EMALEX C-20 Japanese emulsion
  • EMALEX C-30 Japanese emulsion
  • Kolliphor EL BASF
  • polyoxyl 35 castor oil with 35 added moles, average added mole
  • EMALEX C-40 Japanese emulsion
  • EMALEX C-50 Japanese emulsion
  • Kolliphor EL is preferable, but is not limited thereto
  • polyethylene glycol fatty acid ester is a fatty acid ester of polyethylene glycol, which is a fatty acid polymerized with ethylene oxide.
  • Commercial products include various compounds that differ in esterified fatty acids. Examples include polyethylene glycol monolaurate (NIKKOL MYL-10, Nikko Chemicals Co., Ltd.), polyethylene glycol monostearate (NIKKOL MYS-10V, MYS-25V, MYS-40V, NYS-45V, and MYS- 55V, Nikko Chemicals Co., Ltd., polyethylene glycol monooleate (NIKKOL MYO-6 and MYO-10, Nikko Chemicals Co., Ltd.), Polyethylene glycol distearate (NIKKOL CDS-Colks Cok.
  • polyethylene glycol diisostearate Nikko Chemicals Co., Ltd.
  • polyethylene glycol diisostearate Nikko Chemicals Co., Ltd.
  • polyoxyethylene polyoxypropylene glycol is a compound prepared by adding polymerization of ethylene oxide to polypropylene glycol, and is a polymerized propylene oxide.
  • Commercial products include various compounds that differ in the average degree of polymerization of propylene oxide and ethylene oxide.
  • Examples include polyoxyethylene (3) polyoxypropylene (17) glycol (Adeka Pluronic L-31, ADEKA), polyoxyethylene (20) polyoxypropylene (20) glycol (Adeka Pluronic L-44, ADEKA), Polyoxyethylene (42) polyoxypropylene (67) glycol (Adeka Pluronic P-123, ADEKA), polyoxyethylene (54) polyoxypropylene (39) glycol (Newdet PE-85, Sanyo Chemical Industries, Ltd.), Polyoxyethylene (105) Polyoxypropylene (5) Glycol (PEP101, Sanyo Chemical Industries, L d.), polyoxyethylene (120) polyoxypropylene (40) glycol (Adeka Pluronic F-87, ADEKA), polyoxyethylene (160) polyoxypropylene (30) glycol (Adeka Pluronic F-68, ADEKA), There are polyoxyethylene (196) polyoxypropylene (67) glycol (Lutrol F127, BASF Japan), polyoxyethylene (200) polyoxypropylene (70
  • “sucrose fatty acid ester” is an ester of sugar and fatty acid.
  • Commercial products include various compounds that differ in the type of esterified fatty acid and the degree of esterification. Examples include Surfhope SE PHARMA J-1216 (Mitsubishi-Kagaku Foods Corporation), which contains 95% lauric acid in fatty acids, and SurfoSE PHARMA J-14gosfisChosfisChosfisChisFo-ChosfisChisFo-Chosfis-Chosfis-Chosfis-Chos-Fo (Chi-Fo-S-Chus-Fo-S-Chors-Ko-Fo-S-Fo-S-Chos-Fo-C-Fo-S-Chos-Fos ), Surfhope SE PHARMA J-1615 and J-1616 (Mitsubishi-Kagaku Foods Corporation) containing 80% palmitic acid in the fatty acid, J-1811, J-1815 and J-1815 containing 70% ste
  • sorbitan fatty acid ester is obtained by esterifying the hydroxyl group of anhydrous sorbitol with a fatty acid.
  • Various compounds are commercially available depending on the fatty acid to be esterified.
  • sorbitan monolaurate (Span20, NIKKOL SL-10, nonion LP-20R), sorbitan monostearate (NIKKOL SS-10MV), sorbitan monooleate (Span80 , NIKKOL SO-10V), sorbitan monopalmitate (Span40, NIKKOL SP-10V), sorbitan trioleate (NIKKOL SO-30) and sorbitan sesquioleate (Span83, NIKKOL SO-15MV, nonionic OP-83R)
  • sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, and more preferably sorbitan monolaurate is used. Although it is shown, but are not limited to. Moreover
  • glycolin fatty acid ester is an ester of fatty acid and glycerin or polyglycerin and its derivatives (glycerin fatty acid ester, glycerin acetic acid fatty acid ester, glycerin lactic acid fatty acid ester, glycerin citric acid fatty acid ester, glycerin succinic acid fatty acid ester, glycerin. Diacetyl tartaric acid fatty acid ester, glycerin acetic acid ester, polyglycerin fatty acid ester and polyglycerin condensed ricinoleic acid ester).
  • glyceryl monooleate PECEOL
  • NIKKOL MGS-F50SEV MGS-AMV
  • MGS-BMV decaglyceryl monooleate
  • NIKKOL Decaglyn 1-OV decaglyceryl monooleate
  • Poem J-0381V decaglyceryl monolaurate
  • NIKKOL Decaglyn 1-L decaglyceryl trioleate
  • NIKKOL Decaglyn 3-OV decaglyceryl pentaoleate
  • NIKKOL monodecylglycolate NIKKOL Tetraglyn 1-OV
  • glyceryl monooleate decaglyceryl monooleate
  • glyceryl monostearate preferably glyceryl monooleate, decaglyceryl monooleate, glyceryl monostearate
  • the decaglyceryl monooleate is illustrative and not limited thereto.
  • the total content of the emulsifier in the self-emulsifying composition of the present invention is not particularly limited, but usually 1 to 40% by mass, 1 to 35% by mass, 1 to 30% by mass when the total amount of the self-emulsifying composition is 100% by mass. %, 1 to 27% by weight, preferably 3 to 27% by weight, more preferably 5 to 27% by weight, still more preferably 5 to 24% by weight, and still more preferably 10 to 20% by weight. Is preferably 27 mass%, more preferably 10-27 mass%, and even more preferably 12-24 mass%. Further, it is 5 to 45 parts by mass, preferably 10 to 45 parts by mass, more preferably 15 to 35 parts by mass, and particularly preferably 15 to 25 parts by mass with respect to 100 parts by mass of the ⁇ 3 PUFAs.
  • the self-emulsifying composition of the present invention may contain a small amount of water. By including water in the composition, the compatibility of the self-emulsifying composition is improved, and no polyhydric alcohol or ethanol is required. Therefore, the appearance is clear even without polyhydric alcohol or ethanol, and the self-emulsifying composition No separation or white turbidity.
  • Water is preferably 0.5 to 6% by mass, more preferably 0.5 to 4% by mass, even more preferably 0.5 to 3% by mass, when the total amount of the self-emulsifying composition is 100% by mass. . Most preferably, it is 1 to 3% by mass. Or 0.5 to 3 mass% is preferable, and 0.5 to 1.5 mass% is more preferable.
  • lecithin is a kind of glycerophospholipid, soy lecithin, enzyme-degraded soybean lecithin, hydrogenated soybean lecithin, soybean phospholipid, purified soybean phospholipid, hydrogenated soybean phospholipid, egg yolk lecithin, egg yolk phospholipid.
  • soybean lecithin is exemplified, and more preferably, soybean lecithin is exemplified, but not limited thereto. Moreover, one of these can be used alone or in combination of two or more.
  • lecithin is used in the meaning including all the glycerophospholipids as described above.
  • Various products such as purified soybean lecithin (Nisshin Oilio), purified egg yolk lecithin (Asahi Kasei Pharma), egg yolk lecithin PL-100M (Kupie) are commercially available.
  • Soy lecithin is, for example, Basis LP-20B (Nisshin Oil), Lipoid S45, S20 (lipoid), and enzymatically decomposed lecithin is various, such as Basis LP-20E (Nisshin Oil), Phospholipon RLPC20 (lipoid). Products are commercially available and can be obtained and used.
  • the content of lecithin added to the self-emulsifying composition of the present invention is not particularly limited, but is preferably 0.5 to 40 parts by weight, preferably 1 to 40 parts by weight, based on 100 parts by weight of EPA-E. Part is preferable, 3 to 40 parts by weight is preferable, 3 to 30 parts by weight is more preferable, 3 to 25 parts by weight is further preferable, 3 to 20 parts by weight, 3.2 to 17 parts by weight, and 3.5 to 15 parts by weight are preferable. Part to 3.7 to 17 parts by mass is particularly preferred. Alternatively, it is preferably 3 to 15 parts by mass, more preferably 3 to 12 parts by mass, and even more preferably 3 to 10 parts by mass. Most preferred is 5 to 10 parts by mass.
  • Lecithin is preferably 2.1 to 36% by mass, more preferably 2.1 to 20% by mass, and even more preferably 2.1 to 15% by mass, when the total amount of the self-emulsifying composition is 100% by mass. .
  • it is preferably 0.5 to 30% by mass, more preferably 1 to 25% by mass, further preferably 1 to 20% by mass, and particularly preferably 2 to 15% by mass. .
  • the content is 2.1 to 10% by mass.
  • Lecithin is preferably 10 to 75% by mass, and 11 to 60% by mass when the total content of emulsifiers in the self-emulsifying composition (lecithin is not included in the emulsifiers defined in the present invention) is 100% by mass. More preferred is 20 to 55% by mass.
  • lecithin is preferably 5 to 50% by mass, more preferably 6 to 40% by mass, and even more preferably 7 to 30% by mass, when the total content of emulsifiers in the self-emulsifying composition is 100% by mass. Most preferably, it is 8 to 30% by mass.
  • Lecithin is preferably 10 to 150 parts by weight, more preferably 20 to 120 parts by weight, and more preferably 40 to 90 parts by weight, when the total content of polyoxyethylene sorbitan fatty acid ester in the self-emulsifying composition is 100 parts by weight. Further preferred. Most preferred is 50 to 70 parts by mass.
  • lecithin is preferably 10 to 100 parts by weight, more preferably 15 to 80 parts by weight, and more preferably 15 to 60 parts by weight when the total content of polyoxyethylene sorbitan fatty acid ester in the self-emulsifying composition is 100 parts by weight. Part is more preferred. Most preferred is 15 to 40 parts by mass.
  • polyhydric alcohol is a polyol compound having a structure in which one hydroxy group is substituted for two or more carbon atoms of a chain aliphatic hydrocarbon or a cycloaliphatic hydrocarbon.
  • dihydric alcohols such as ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butylene glycol, tetramethylene glycol, 1,3-butylene glycol, 2,3-butylene glycol and pentamethylene glycol, glycerin, trimethyl
  • dihydric alcohols such as ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butylene glycol, tetramethylene glycol, 1,3-butylene glycol, 2,3-butylene glycol and pentamethylene glycol, glycerin, trimethyl
  • examples thereof include methylolpropane and trivalent alcohols such as 1,2,6-hexanetriol, polyhydric alcohol polymers such as diethylene glycol, dipropylene glycol triethylene
  • Glycerol includes, but is not limited to, concentrated glycerin.
  • the polyhydric alcohol is used in the meaning including all the polyol compounds as described above unless otherwise specified.
  • the content of the polyhydric alcohol added to the self-emulsifying composition of the present invention is preferably within a range in which the capsule is not deformed when the capsule is filled with the self-emulsifying composition. For example, when the entire self-emulsifying composition is 100% by mass, it is preferable that the composition does not contain more than 4% by mass of polyhydric alcohol.
  • the content of the polyhydric alcohol in the composition is preferably 4% by mass or less, more preferably 3% by mass or less, further preferably 2% by mass or less, and particularly preferably 1% by mass or less. Most preferred is 0% by weight.
  • the ethanol contained in the self-emulsifying composition of the present invention preferably has a range that does not cause a change in quality during the encapsulation production process, distribution and storage, and does not cause a denaturation of the capsule contents.
  • a range that does not exceed the record of drug use is desirable.
  • the entire self-emulsifying composition is 100% by mass, it is preferable that no more than 4% by mass of ethanol is contained in the composition.
  • the content of ethanol in the composition is preferably 4% by mass or less, more preferably 3% by mass or less, further preferably 2% by mass or less, and particularly preferably 1% by mass or less. Most preferred is 0% by weight.
  • the self-emulsifying composition contains ethanol and a polyhydric alcohol
  • the total amount of the self-emulsifying composition is 100% by mass
  • the total content in the self-emulsifying composition is more than 4% by mass of ethanol and polyvalent alcohol. It is preferable not to contain alcohol.
  • a preferred embodiment is substantially free of ethanol and polyhydric alcohol.
  • the total amount of ethanol and polyhydric alcohol in the composition is preferably 4% by mass or less, more preferably 3% by mass or less, further preferably 2% by mass or less, and particularly preferably 1% by mass or less. Most preferred is 0% by mass or less.
  • the self-emulsifying composition of the present invention can be encapsulated.
  • a hard capsule or a soft capsule can be selected, and a soft capsule is preferable.
  • the form of the soft capsule is not necessarily limited, but is preferably a rotary soft capsule or a seamless capsule.
  • the self-emulsifying composition of the present invention is solid, it can be made into solid preparations such as tablets, powders, granules and powders.
  • the composition of the capsule film is not necessarily limited.
  • main components include gelatin, carrageenan, pectin, pullulan, sodium alginate, starch, hypromellose, hydroxypropylcellulose, and various known components.
  • gelatin is preferable.
  • the gelatin is not limited, and known gelatins such as acid-treated gelatin, alkali-treated gelatin, amphoteric gelatin, and chemically modified gelatin can be used, and one or more of these can be used. Preferred is acid-treated gelatin or alkali-treated gelatin.
  • gelatin Although the origin of gelatin is not necessarily limited, for example, cow bone, cow skin, pig bone, pig skin, fish scale, fish skin, preferably cow bone, cow skin, pig bone, pig skin.
  • examples of “gelatin” include those normally used in the manufacture of soft capsules, for example, pharmaceutical gelatin (gelatin and purified gelatin) defined by the 16th revision Japanese Pharmacopoeia. Two or more types of gelatin may be used in combination.
  • the capsule film may contain a plasticizer and the like.
  • plasticizer to be blended in the capsule film
  • polyhydric alcohols such as glycerin (eg, concentrated glycerin), ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol Sugar alcohols such as sorbitol, mannitol, and xylitol are preferred.
  • glycerin and sorbitol are preferable. It is also preferable to use a combination of glycerin and sorbitol.
  • the mass ratio of glycerin and sorbitol is preferably used in the range of 1: 5 to 5: 1, and more preferably in the range of 1: 3 to 3: 1.
  • the capsule film solution preferably contains gelatin and a plasticizer in a weight ratio of 10: 1 to 1:10. It is more preferable to contain in the range of: 1.
  • the weight ratio of the capsule film solution to the capsule contents is usually 10: 1 to 1:10, preferably 3: 1 to 1:10.
  • plasticizers such as amino acids, citric acid, glycerin, sorbitol, trehalose, preservatives, coloring agents such as pigments and titanium oxide, organic acids, etc. Can be added.
  • composition for capsule film can be produced by mixing and dissolving gelatin and a plasticizer and, if necessary, various additives in water at room temperature or under heating.
  • Capsules containing the self-emulsifying composition of the present invention as a content liquid preferably have a hardness immediately after production and do not decrease in hardness due to storage.
  • the decrease in hardness not only deforms the capsule but also becomes brittle, so the capsule breaks and the content liquid flows out, which is not preferable in terms of quality.
  • the presence or absence of softening of the capsule can be confirmed by measuring the hardness with a general hardness meter.
  • the capsule of the present invention has a hardness immediately after production of 18 kgf or more, preferably 20 kgf or more, more preferably 22 kgf or more.
  • it is desirable that the hardness does not substantially decrease when stored in a sealed aluminum package at 40 ° C.
  • the hardness does not decrease more than 6 kgf, and the hardness after storage at 40 ° C. for one week.
  • the capsule hardness can be measured by an existing general-purpose hardness tester for soft solids (for example, Jeromat II (M & K Corporation)), and 1 kgf is converted to about 9.81 Newtons (N).
  • the hardness immediately after production is 100%, the hardness when stored in a sealed aluminum package at 40 ° C. for 1 week is maintained at 60% or more, preferably 70% or more, more preferably 80% or more. More preferably, the hardness of 85% or more, particularly preferably 90% or more is maintained.
  • “intermittent administration” is an administration mode in which there are days that are not administered instead of daily administration. For example, preferably administered every at least one period selected from the group consisting of 2 days to 3 months, administered every at least one period selected from the group consisting of 2 days to 12 weeks, and from 2 days to 10 weeks Administered at least one period selected from the group consisting of, administered at least one period selected from the group consisting of 2 days to 2 months, and at least one period selected from the group consisting of 2 days to 8 weeks Dosed every time, administered every at least one period selected from the group consisting of 2 days to 1 month, administered every at least one period selected from the group consisting of 2 days to 4 weeks, from 2 days to 3 weeks Administered at least one period selected from the group consisting of, administered every at least one period selected from the group consisting of 2 days to 20 days, at least one selected from the group consisting of 2 days to 2 weeks Administration every period, administration every at least one period selected from the group consisting of 2 days to 10 days, and administration every
  • 2 days a week eg Monday and Thursday, Monday and Friday, Tuesday and Friday, Tuesday and Saturday, Wednesday and Saturday, Wednesday and Sunday, Thursday and Sunday
  • 3 days a week eg Monday and Wednesday and Friday, Monday and Wednesday and Saturday, Monday and Thursday and Saturday, Tuesday and Thursday and Saturday, Tuesday and Thursday and Sunday, Tuesday and Friday and Sunday, Wednesday and Friday and Sunday
  • 2 days a month eg, 1 day and 15 days, 5 days and 20 days, 10 days and 25 days, 10 days and 30 days (but the last day in February)
  • 3 days a month eg, 1st and 11th days and 21st, 5th, 15th and 25th, 10th, 20th and 30th (but last day in February)
  • 4 per month Day administration eg, 1st to 4th Monday, 1st to 4th Tuesday, 1st to 4th Wednesday, 1st to 4th Thursday, 1st to 4th Friday, 1st to 4th Saturday, 1st to 4th
  • the administration day can be shifted back and forth from the regular interval.
  • 1 week before and after 1 week 2 days before and 2 weeks, 2 days before and after 3 weeks, 3 days before and after 3 weeks, 4 days before and after 4 weeks, 5 days after 5 weeks
  • days and 6-week intervals it is 6 days before and after
  • 7-week intervals it is 1 week before and after, but is not limited thereto.
  • the interval between intermittent administrations of the self-emulsifying composition of the present invention can be appropriately adjusted according to the severity of symptoms, body weight, age, and other factors so as to be suitable for realizing the intended effect.
  • the intermittent administration interval can be lengthened when the symptom is improved, and the intermittent administration interval can be shortened when the symptom is worsened. Further, the intermittent administration interval can be adjusted while monitoring the concentration and / or EPA / AA ratio of ⁇ 3PUFA, EPA, DHA, DPA or ALA in blood, plasma or serum.
  • the daily dosage of the self-emulsifying composition of the present invention is, for example, 0.1-20 g / day, 0.3-15 g / day, 0.5-10 g / day, 1-9 g / day, 1-8 g / day.
  • a lower daily dose is preferable, and it is preferably 10 g or less per day, 9 g or less per day, 8 g or less per day, preferably 7 g or less per day, more preferably 6 g or less per day. More preferably, it is 5 g or less per day, particularly preferably 4 g or less per day, more preferably 3 g or less per day, and most preferably 2 g or less per day.
  • the daily dosage of the self-emulsifying composition of the present invention can be appropriately adjusted depending on the severity of symptoms, weight, age, and other factors. For example, if the symptoms improve, the daily dose can be decreased, and if the symptoms worsen, the daily dose can be increased. In addition, the daily dose can be adjusted while monitoring the concentration and / or EPA / AA ratio of ⁇ 3PUFA, EPA, DHA, DPA or ALA in blood, plasma or serum. Furthermore, the intermittent dosing interval and the daily dose of the self-emulsifying composition of the present invention can be combined and adjusted appropriately depending on the severity of symptoms, weight, age, and other factors.
  • the frequency of administration of the self-emulsifying composition of the present invention per day is, for example, 1 to 10 times a day, 1 to 6 times a day, 1 to 3 times a day, 1 to 2 times a day, once a day, etc.
  • a day twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, ten times a day
  • it is 3 times or less per day, preferably 2 times or less per day, more preferably once a day.
  • count of administration can also be adjusted for every administration day for a patient's convenience.
  • the self-emulsifying composition of the present invention exhibits excellent absorbency even on an empty stomach. Therefore, the self-emulsifying composition of the present invention can be administered at any timing convenient for the patient.
  • “Combination” as used in the present invention refers to an embodiment in which the effect and / or action of another drug is present in the patient's body while the self-emulsifying composition of the present invention is administered.
  • both the self-emulsifying composition of the present invention and the concomitant drug are simultaneously present in the patient's body, eg, in the patient's blood.
  • the concomitant drug is administered within 24 hours after administration of the self-emulsifying composition of the invention.
  • the combination according to the present invention is generally assumed as long as the self-emulsifying composition of the present invention and the concomitant drug are used in combination, and is not particularly limited.
  • Exemplary embodiments include, for example: (1) administration of a compounding composition containing an active ingredient of a concomitant drug in the self-emulsifying composition of the present invention, (2) The self-emulsifying composition of the present invention and the concomitant drug are prepared separately, and both are administered, and from the same administration route with or without the kit of the combination of the self-emulsifying composition of the present invention and the concomitant drug Simultaneous administration of these self-emulsifying composition of the present invention and a concomitant drug, (3) The self-emulsifying composition of the invention and the concomitant drug are prepared separately, and both are administered from the same administration route with or without the kit of the combination of the self-emulsifying composition of the present invention and the concomitant drug.
  • the self-emulsifying composition of the present invention and the concomitant drug are administered at different timings with a time lag, (4)
  • the self-emulsifying composition of the invention and the concomitant drug are prepared separately, and both are administered, and different administration routes (different depending on whether or not there is a kit of the combination of the self-emulsifying composition and concomitant drug of the present invention Administration of these self-emulsifying composition of the present invention and a concomitant drug from the same patient from the same place), (5)
  • the self-emulsifying composition of the invention and the concomitant drug are prepared separately, and both are administered, and different administration routes (different depending on whether or not there is a kit of the combination of the self-emulsifying composition and concomitant drug of the present invention Administration of the self-emulsifying composition of the present invention and the concomitant drug at different timings with a time lag, and the like, but is not limited thereto.
  • the combination agent of the present invention is collectively abbreviated as the combination agent of the present invention.
  • the self-emulsifying composition of the present invention and the concomitant drug can be administered in this order or in the reverse order.
  • the self-emulsifying composition of the present invention and the concomitant drug may be intentionally used at various timings and administration intervals for various purposes.
  • the time difference varies depending on the active ingredient, dosage form, and administration method to be administered in combination.
  • the self-emulsifying composition of the present invention is administered within 1 minute to 1 day, more preferably within 1 minute to 12 hours, and even more preferably within 1 minute to 6 hours.
  • the compound of the present invention is administered first, it is within 1 minute to 7 days after administration of the compound of the present invention, preferably within 1 minute to 1 day, more preferably within 1 minute to 6 hours, and even more preferably 1
  • a method of administering a concomitant drug within minutes to 1 hour can be mentioned. As long as side effects do not become a problem, any concomitant drugs can be used in any dosage and dosage.
  • the daily dose as a concomitant drug varies depending on the administration subject, administration route, target disease, symptoms and the like.
  • the self-emulsifying composition of the present invention is used in combination with a concomitant drug, one or both doses can be reduced within a safe range in consideration of additive or synergistic effects.
  • the combination mode of the self-emulsifying composition of the present invention and the concomitant drug can be appropriately adjusted depending on the severity of symptoms, body weight, age, and other factors.
  • oral cyclosporine, etretinate, apremilast, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone or betamazone can be administered daily, and the self-emulsifying composition of the present invention can be administered intermittently as described above. .
  • Topical maxacalcitol, maxacalcitol and betamethasone butyrate propionate, calcipotriol, calcipotriol and betamethasone dipropionate, tacalcitol hydrate, hydrocortisone acetate Betamethasone acetate or diflorazone acetate is applied daily, and the self-emulsifying composition of the present invention can be intermittently administered as described above.
  • Injectable secukinumab is administered subcutaneously for the first time, one week later, two weeks later, three weeks later, four weeks later, and thereafter subcutaneously administered at intervals of 4 weeks.
  • the self-emulsifying composition of the present invention is intermittent as described above. Can be administered.
  • Ustekinumab is administered subcutaneously after the first 4 weeks, and thereafter administered at 12-week intervals, and the self-emulsifying composition of the present invention can be intermittently administered as described above.
  • Adalimumab is subcutaneously administered once every two weeks after the initial administration, and the self-emulsifying composition of the present invention can be intermittently administered as described above.
  • Infliximab is administered 2 and 6 weeks after the first intravenous infusion, and thereafter administered at intervals of 6 to 8 weeks.
  • the self-emulsifying composition of the present invention can be intermittently administered as described above.
  • Brodalumab is administered subcutaneously for the first time, one week later, two weeks later, and thereafter subcutaneously administered at intervals of two weeks, and the self-emulsifying composition of the present invention can be intermittently administered as described above.
  • Ixekizumab is subcutaneously administered for the first time, and is subcutaneously administered every 2 weeks from 2 weeks to 12 weeks, and thereafter subcutaneously administered at intervals of 4 weeks.
  • the self-emulsifying composition of the present invention is intermittently administered as described above. Can be administered.
  • the preventive and / or therapeutic effect is improved by the combined use, and the dose of the concomitant drug can be decreased, or the administration interval of the concomitant drug can be lengthened.
  • the intermittent dosing interval and daily dose of the self-emulsifying composition of the present invention can be combined and adjusted appropriately depending on the severity of symptoms, weight, age, and other factors.
  • the concentration and / or EPA / AA ratio of ⁇ 3PUFA, EPA, DHA, DPA, or ALA in blood, plasma, or serum it is used in combination by adjusting the intermittent dosing interval and daily dose.
  • “sequential administration” is an embodiment in which the self-emulsifying composition of the present invention and an existing therapeutic agent are used in combination or alternately.
  • autoimmune or inflammatory skin diseases for example, cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone, betamethasone, maxacalcitol, calcipotriol, tacalcitol hydrate , Hydrocortisone acetate, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildrakizumab, brodalumab, guselcoumab, dupirumumab, nemorizumab, rituximab,
  • the mode in which the self-emulsifying composition of the present invention is used in combination or alternately with an existing therapeutic agent can be appropriately adjusted depending on the severity of symptoms, weight, age, and other factors.
  • the intermittent dosing interval and daily dose of the self-emulsifying composition of the present invention can be combined and adjusted appropriately depending on the severity of symptoms, weight, age, and other factors.
  • the existing intermittently administered dose and daily dose are adjusted in combination. Can be used in combination with or alternately with these therapeutic agents.
  • the concomitant drug or its metabolite in blood, plasma or serum is used in combination with the self-emulsifying composition of the present invention by adjusting the administration interval and daily dose of the concomitant drug in combination. Alternatively, they can be administered alternately.
  • Nonsteroidal anti-inflammatory drugs I
  • Classic NSAIDs arcofenac, aceclofenac, sulindac, tolmethine, etodolac, fenoprofen, thiaprofenic acid, meclofenamic acid, meloxicam, teoxicam, lornoxicam, nabumetone, acetaminophen, phenacetin, ethenamide, sulpyrine, antipyrine, antipyrine Mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, fructophenine, piroxi
  • I Nonsteroidal anti-inflammatory drugs
  • cyclooxygenase inhibitors COX-1 selective inhibitors, COX-2 selective inhibitors, etc.: salicylic acid derivatives (eg, celecoxib, aspirin), etoroxib, valdecoxib, diclofenac, indomethacin, loxoprofen, etc.
  • salicylic acid derivatives eg, celecoxib, aspirin
  • etoroxib etoroxib
  • valdecoxib valdecoxib
  • diclofenac indomethacin
  • loxoprofen etc.
  • Nitric Oxide Free NSAIDs (2) Disease-modifying anti-rheumatic drugs (DMARDs)
  • Gold formulation Auranofin et al.
  • Penicillamine D-penicillamine
  • Amino salicylic acid preparation Sulfasalazine, mesalamine, olsalazine, balsalazide.
  • Antimalarial drugs chloroquine and the like.
  • Pyrimidine synthesis inhibitors leflunomide and the like.
  • Anti-cytokine drugs protein preparations
  • TNF inhibitors etanercept, infliximab, adalimumab, sertolizumab Pegor, golimumab, PASSTNF- ⁇ , soluble TNF- ⁇ receptor, TNF- ⁇ binding protein, anti-TNF- ⁇ Antibodies etc.
  • Interleukin-1 inhibitor Anakinra (interleukin-1 receptor antagonist), soluble interleukin-1 receptor and the like.
  • Interleukin-6 inhibitor Tocilizumab (anti-interleukin-6 receptor antibody), anti-interleukin-6 antibody and the like.
  • Interleukin-10 inhibitor anti-interleukin-10 receptor antibody, anti-interleukin-10 antibody and the like.
  • Interleukin-12 / 23 inhibitor ustekinumab, briakinumab, guselcumab, BI65506 (anti-interleukin-12 / 23 antibody) and the like.
  • Interleukin-17 inhibitor secukinumab, ixekizumab (anti-interleukin-17A antibody), brotalumab (anti-interleukin-17 receptor A antibody) and the like.
  • Interleukin-4 inhibitor Dupilumab (anti-interleukin-4 receptor a antibody), anti-interleukin-4 antibody and the like.
  • Interleukin-31 inhibitor Nemorizumab (anti-interleukin-31 receptor A antibody), anti-interleukin-31 antibody and the like.
  • MAPK inhibitor BMS-582949 and the like.
  • Gene regulators inhibitors of molecules related to signal transduction such as NF- ⁇ , NF- ⁇ B, IKK-1, IKK-2, AP-1.
  • Nrf2 activators such as sulforaphane, dimethylfumaric acid, bardoxolone methyl, curcumin, resveratrol, catechin, epigallocatechin gallate, glycated hesperidin, hesperidin, hesperetin.
  • Cytokine production inhibitors iguratimod, tetomilast and the like.
  • TNF- ⁇ converting enzyme inhibitor v) Interleukin-1 ⁇ converting enzyme inhibitor: VX-765 and the like.
  • Interleukin-6 antagonist HMPL-004 and the like.
  • Interleukin-8 inhibitor IL-8 antagonist, CXCR1 & CXCR2 antagonist, reparexin and the like.
  • Chemokine antagonists CCR9 antagonists (CCX-282, CCX-025), MCP-1 antagonists and the like.
  • Interleukin-2 receptor antagonist Denileukine, Diftitox, etc.
  • Therapeutic vaccines TNF- ⁇ vaccine and the like.
  • Gene therapy drug gene therapy for the purpose of enhancing the expression of genes having anti-inflammatory activity such as interleukin-4, interleukin-10, soluble interleukin-1 receptor, soluble TNF- ⁇ receptor medicine.
  • Antisense compound ISIS 104838 and the like.
  • JAK inhibitors tofacitinib, ruxolitinib, varicitinib and the like. (4) Integrin inhibitors Natalizumab, vedolizumab, AJM300, TRK-170, E-6007, etc.
  • Immunomodulatory drugs immunosuppressive drugs
  • Steroid drugs Dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, cortisone acetate, hydrocortisone, diflorazone, clobetasol, fluorochrome Beclomethasone propionate, estriol, etc.
  • Angiotensin converting enzyme inhibitor enalapril, captopril, ramipril, lisinopril, cilazapril, perindopril and the like.
  • Angiotensin II receptor antagonist candesartan, cilexetil, valsartan, irbesartan, olmesartan, eprosartan and the like.
  • Diuretics Hydrochlorothiazide, spironolactone, furosemide, indapamide, bendrofluazide, cyclopenthiazide and the like.
  • Cardiotonic drugs Digoxin, dobutamine and the like.
  • (11) ⁇ receptor antagonist carvedilol, metoprolol, atenolol and the like.
  • Ca channel antagonist nifedipine, cilnidipine, amlodipine, diltiazem, verapamil and the like.
  • Antiplatelet drugs anticoagulants heparin, aspirin, warfarin and the like.
  • Contraceptive agent (i) Sex hormone or derivative thereof: progesterone or derivative thereof (progesterone, 17 ⁇ -hydroxyprogesterone, medroxyprogesterone, medroxyprogesterone acetate, norethisterone, norethisterone enanthate, norethindrone, norethindrone acetate, norethinodrel, levo Norgestrel, Norgestrel, Ethinodiol diacetate, Desogestrel, Norgestimate, Guestden, Progestin, Etnogestrel, Drospirenone, Dienogest, Trimegestone, Nestrone, Chromazinone acetate, Mifepristone, Nomegestrol acetate, Org-30659, TX-525, EMM-310525) Or progesterone or its derivative and follicular hormone or its derivative , Estradiol benzoate, estradiol cypionate, estradiol di
  • T cell inhibitor Inosine monophosphate dehydrogenase (IMPDH) inhibitor: Mycophenolate mofetil and the like.
  • Adhesion molecule inhibitors ISIS 2302, selectin inhibitors, ELAM-1, VCAM-1, ICAM-1, etc.
  • Thalidomide v) Cathepsin inhibitor
  • MMPs Matrix metalloprotease
  • Glucose-6-phosphate dehydrogenase inhibitor (viii) Dihydrorotate dehydrogenase (DHODH) inhibitor (ix) Phosphodiesterase IV (PDE IV) inhibitor: apremilast, roflumilast, CG-1088 and the like.
  • Phospholipase A2 inhibitor (xi) iNOS inhibitor: VAS-203 and the like.
  • iii Microtubule stimulant: paclitaxel and the like.
  • Microtable inhibitor Rheumacon and the like.
  • MHC class II antagonist (xv) Prostacyclin agonist: iloprost and the like.
  • CD4 antagonist zanolimumab and the like.
  • CD23 antagonist CD23 antagonist
  • LTB4 receptor antagonist DW-1305 and the like.
  • 5-lipoxygenase inhibitor zileuton and the like.
  • Cholinesterase inhibitor galantamine and the like.
  • tyrosine kinase inhibitor Tyk2 inhibitor (WO20101422752) and the like.
  • Calepsin B inhibitor xxiii) Adenosine deaminase inhibitor: Pentostatin and the like.
  • CD52 inhibitor alemtuzumab and the like.
  • Vitamin A derivatives etretinate and the like.
  • Vitamin D derivatives maxacalcitol, calcipotriol, tacalcitol hydrate and the like.
  • Selective histamine 1 receptor antagonists epinastine hydrochloride, olopatadine hydrochloride and the like.
  • Antifungal drugs antibiotics: ketoconazole, miconazole, isconazole, bifonazole, ranoconazole, luliconazole, clotrimazole, terbinafine, butenafine, neticonazole, tetracycline, gentamicin, clindamycin, chloramphenicol, fradiomycin and the like.
  • the self-emulsifying composition of the present invention can be formulated by arbitrarily combining with pharmaceutically acceptable additives.
  • excipients eg lactose, sucrose, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch
  • binders eg celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC))
  • Crystalline cellulose saccharides (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol, polyvinyl alcohol (PVA) )
  • Lubricant eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose
  • disintegrant eg; starches (corn starch, potato starch), carboxymethyl starch sodium, car
  • ⁇ 3 PUFAs are highly unsaturated, for example, butylhydroxytoluene, butylhydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable quinones, astaxanthins, and ⁇ -tocopherols
  • an effective amount of at least one oil-soluble antioxidant selected from is incorporated into the composition.
  • the ⁇ 3 PUFAs are solid, it is desirable that an effective amount of at least one water-soluble antioxidant selected from ascorbic acid, glutathione, and lipoic acid is incorporated into the composition.
  • the storage temperature is desirably room temperature and it is desirable to avoid freezing storage as it can lead to loss of self-emulsifying properties, dispersibility of the composition, or emulsion stability.
  • the self-emulsifying composition comprising EPA compounds of the present invention, the above Epadel (R), Lovaza TM, Omacor TM, Lotriga TM or and commercial EPA such compositions such Vascepa TM,, Epanova TM (Omthera , Astrazeneca) Alternatively, it can be made using an EPA-like composition under development such as MAT9001 (Matinas Biopharma).
  • Self-emulsifying compositions containing EPAs are in tablet, capsule, powder or solid oral dosage form, in liquid form, in soft gel capsule or other capsule form, or other dosages suitable and convenient for administration In the form, it is administered to the patient in need.
  • composition also includes pharmaceutically acceptable excipients known to those skilled in the art, including surfactants, oils, co-solvents, or such excipients and stabilizers, emulsifiers. , Preservatives, solubilizers, and / or combinations with other inert pharmaceutical ingredients known to those skilled in the art for the formulation of pharmaceutical compositions.
  • Examples of various dosage forms include tablets, capsules, granules, powders, pills, liquids, spirits, suspensions, extracts, elixirs, and the like.
  • the auricle and back were visually observed under anesthesia, and the degree of dorsal skin findings (erythema, infiltration, scale) was 0 to 4 (0: none, 1: mild) (2: moderate, 3: high, 4: extremely high), and the total score (0-12) is calculated using a psoriasis severity index (PSI), and the auricular thickness is measured using a micrometer. taking measurement. The thickness of the auricle is evaluated by calculating the daily transition and the difference between the initial measurement and the final measurement.
  • PSI psoriasis severity index
  • the dorsal skin is removed using a biopsy trepan (BIOPSY PUNCH) with a 6 mm diameter circular auricular skin tissue and scalpel.
  • the auricular skin tissue and the back skin tissue are cut in half and used for pathological tissue evaluation, protein expression evaluation of various cytokines, and mRNA expression evaluation.
  • EPA-E daily administration group EPA-E 500 mg / kg is orally administered using a gastric sonde from the day before the application of Beserna cream to the final application day.
  • EPA-E or EPA-E self-emulsifying composition is orally administered every 3 days from the day before the application of Beserna cream using a stomach tube so that the EPA-E is 1500 mg / kg.
  • EPA-E or EPA-E self-emulsifying composition was orally administered using a gastric sonde to give 3500 mg / kg as EPA-E on the day before and one week after the application of Beserna cream. To do.
  • the Beselna cream application group showed macroscopically swelling of the auricle and back and increased back PSI, increased auricular thickness over time, and histopathologically the auricle And psoriasis-like dermatitis with epidermal thickening on the back is confirmed.
  • the EPA-E daily administration group, the EPA-E self-emulsification composition every 3 days administration group, and the EPA-E self-emulsification composition every week administration group suppressed the swelling of the auricle and back, and the back PSI.
  • At least one of the effects of suppressing the increase in the auricle, the daily increase in the thickness of the auricle, and the suppression of the thickening of the epidermis and the epidermis in the histopathology are high in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsifying composition every week administration group.
  • interleukin (IL) -1, IL-2, IL-4, IL-5, IL-6, IL-10 in the auricular and dorsal skin tissues in the beselna cream application group At least one protein expression and / or mRNA expression of IL-12, IL-17, IL-22, IL-23, IL-27, IL-36 and TNF- ⁇ is increased,
  • the EPA-E daily administration group, the EPA-E self-emulsifying composition every 3 days administration group, and the EPA-E self-emulsifying composition every week administration group suppressed the increase in at least one of these,
  • the inhibitory effect is high in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsifying composition every week administration group.
  • side effects such as loose stool or diarrhea are observed depending on the individual, but in the EPA-E self-emulsifying composition
  • mice IL-23 intraauricular intradermic administration psoriasis model mouse test The test described in Journal of Investigative Dermatology, 131, 1110-1118, 2011 is appropriately modified and tested.
  • Mouse recombinant IL-23 (R & D systems, Minneapolis, Cat. No. 1887-ML / CF) 500 ng / 10 ⁇ L in the auricular skin of 6-8 week-old male BALB / c mice (Charles River, Yokohama, Japan)
  • Phosphate buffered saline is intradermally administered once a day for 5-7 days under isoflurane anesthesia.
  • phosphate buffered saline is administered in the same manner instead of IL-23.
  • the auricle Before each intradermal administration and 6 hours after the administration, the auricle is visually observed under anesthesia, and the auricle thickness is measured using a micrometer. The thickness of the auricle is evaluated by calculating the daily transition and the difference between the initial measurement and the final measurement. After the final measurement of the pinna thickness, the pinna is removed, and a circular pinna skin tissue having a diameter of 6 mm centering on the intradermal administration site is collected using a biopsy trepan (BIOPSY PUNCH). The auricular skin tissue is cut in half and used for pathological tissue evaluation or protein expression evaluation and mRNA expression evaluation of various cytokines.
  • EPA-E daily administration group EPA-E 500 mg / kg is orally administered using a stomach tube in the EPA-E daily administration group from the day before the administration of IL23 to the final application day.
  • EPA-E or EPA-E self-emulsifying composition is orally administered every 2 days from the day before IL23 administration using a gastric sonde so that each EPA-E is 1000 mg / kg.
  • EPA-E or the EPA-E self-emulsifying composition is orally administered using a gastric sonde every 2000 days from the day before IL23 administration so that the EPA-E is 2000 mg / kg.
  • the IL23-administered group showed macroscopic swelling of the auricle, increased auricular thickness over time, and histopathologically psoriasis-like with epidermal thickening It is confirmed that dermatitis is induced.
  • the EPA-E daily administration group, the EPA-E self-emulsification composition every 2 days administration group, and the EPA-E self-emulsification composition every 4 days administration group suppresses the swelling of the auricle, At least one of the suppression effects of histological increase and the suppression of histopathological epidermis thickening was confirmed, and the degree of psoriasis-like dermatitis was confirmed to be small.
  • the group administered every 2 days and the group administered every 4 days in the EPA-E self-emulsifying composition In the group administered every 2 days and the group administered every 4 days in the EPA-E self-emulsifying composition.
  • IL23 administration group compared to the control group, interleukin (IL) -1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12 in the auricular skin tissue, Expression of at least one protein of IL-17, IL-22, IL-23, IL-27, IL-36, and TNF- ⁇ and / or mRNA expression is increased, and EPA- is compared to the IL23 administration group.
  • IL interleukin
  • the EPA-E self-emulsifying composition every 2 days administration group, and the EPA-E self-emulsifying composition every 4 days administration group the increase in at least one of these was suppressed, and these inhibitory effects were EPA-E High in the self-emulsifying composition every 2 days and in the EPA-E self-emulsifying composition every 4 days.
  • side effects such as loose stool or diarrhea are observed depending on the individual, but in the EPA-E self-emulsifying composition administration group, no side effects to be noted are observed.
  • Experimental example 3 Treatment test for patients with exacerbation of psoriasis vulgaris Patients diagnosed with psoriasis vulgaris in exacerbations were divided into 5 groups (15 in each group), and 900 mg of olive oil was orally administered to the control group twice daily
  • the Epadale S daily administration group was orally administered with Epadale S® 900 (containing EPA-E 900 mg) twice a day, and the EPA-E self-emulsifying composition daily administration group, EPA-E self-emulsifying composition
  • the EPA-E self-emulsifying composition and the EPA-E self-emulsifying composition weekly administration group each had a EPA-E self-emulsifying composition of 1 g, 3 g and 5 g as EPA-E.
  • psoriasis status is assessed using the psoriasis area and severity index (PASI) before the start of treatment and every 2 weeks after the start of treatment, and a PASI score for each patient and an average PASI score for each group are calculated.
  • PASI psoriasis area and severity index
  • the degree of skin symptom (erythema, infiltration / thickness, scale) for each part of the head, upper limbs, trunk and lower limbs is 0 to 4 (0: none, 1: mild, 2: moderate, 3: advanced) 4: very high) and total.
  • the lesion range (lesion area relative to the body surface area) is 0 to 6 (0: none, less than 1: 10%, 2: 10% or more but less than 30%, 3: 30% or more and less than 50%, 4) : 50% or more and less than 70%, 5: 70% or more and less than 90%, 6: 90% or more).
  • the average PASI score in any group other than the control group decreases after the start of treatment.
  • the degree or rate of decrease in the average PASI score is equally and greatest in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsifying composition every week administration group.
  • the EPA-E self-emulsifying composition daily administration group and the Epadale S daily administration group are in this order.
  • the period until remission is the shortest in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsification composition every week administration group.
  • the EPA-E self-emulsifying composition daily administration group, the Epadale S daily administration group and the control group are in this order.
  • Each patient's PASI score improves additively or synergistically in combination with existing therapeutics.
  • the dose of the existing therapeutic agent can be reduced, or the administration period of the existing therapeutic agent can be shortened, and the occurrence of side effects of the existing therapeutic agent can be suppressed or the burden of taking can be reduced.
  • the effect of reducing the dose or shortening the administration period of the existing therapeutic agent is the same and greatest in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsifying composition every week administration group, followed by EPA-E self-emulsification This is the order of the daily composition group and the Epadale S daily group.
  • Experimental example 4 Prevention / treatment test for patients with psoriasis vulgaris remission period Patients with psoriasis diagnosed with psoriasis in remission with a PASI score of less than 12 were divided into 4 groups (20 people in each group). Olive oil 900 mg was orally administered twice daily, and Epadale S daily administration group was orally administered Epadale S 900 (containing EPA-E 900 mg) twice daily, and EPA-E self-emulsifying composition was administered daily. Group and EPA-E self-emulsifying composition weekly administration group are orally administered once a day on each dosing day so that the EPA-E self-emulsifying composition is 1 g and 5 g as EPA-E, respectively. .
  • EPA-E administration continues until the patient reaches an exacerbation period, during which no existing psoriasis treatment is administered.
  • the PASI score is evaluated using PASI every two weeks after the start of treatment, and a PASI score for each patient is calculated. When the PASI score is 12 or more, it is judged that the ashamed period has been reached.
  • the period from the start of prevention / treatment to the exacerbation period is the longest in the EPA-E self-emulsifying composition administered every week group.
  • the EPA-E self-emulsifying composition daily administration group, the Epadale S daily administration group, and the control group are in this order. It is possible to prevent exacerbation without using an existing therapeutic drug in the remission period, to eliminate the side effects and medication burden of the existing therapeutic drug, and to extend the remission period.
  • Experimental Example 5 Treatment test for patients with atopic dermatitis exacerbation The patients diagnosed with atopic dermatitis in the exacerbation period were divided into 5 groups (15 in each group), and 900 mg of olive oil was administered daily to the control group.
  • Epadale S® 900 (containing EPA-E 900 mg) was orally administered twice daily to the Epadale S daily administration group, and the EPA-E self-emulsifying composition daily administration group, EPA-E self The emulsion composition every 3 days administration group and the EPA-E self-emulsification composition weekly administration group had EPA-E self-emulsification composition at 1 g, 3 g and 5 g as EPA-E, respectively. Orally once daily.
  • the average SCORAD or EASI score decreases in any group other than the control group after initiation of treatment.
  • the degree or rate of average SCORAD or EASI score reduction is equally and greatest in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsifying composition every week administration group.
  • the EPA-E self-emulsifying composition daily administration group and the Epadale S daily administration group are in this order.
  • the period until remission is the shortest in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsification composition every week administration group.
  • the EPA-E self-emulsifying composition daily administration group, the Epadale S daily administration group and the control group are in this order.
  • Each patient's SCORAD or EASI score improves additively or synergistically in combination with existing therapeutics.
  • the dose of the existing therapeutic agent can be reduced, or the administration period of the existing therapeutic agent can be shortened, and the occurrence of side effects of the existing therapeutic agent can be suppressed or the burden of taking can be reduced.
  • the effect of reducing the dose or shortening the administration period of the existing therapeutic agent is the same and greatest in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsification composition every week administration group.
  • the EPA-E self-emulsifying composition daily administration group and the Epadale S daily administration group are in this order.
  • EPA-E administration continues until the patient reaches an exacerbation period, during which no existing atopic dermatitis treatment is administered.
  • the condition of atopic dermatitis is evaluated using SCORAD or EASI every 2 weeks after the start of treatment, and the SCORAD or EASI score for each patient is calculated. When the SCORAD score is 15 or more or the EASI score is 12 or more, it is determined that the ashamed period has been reached.
  • the period from the start of prevention / treatment to the exacerbation period is the longest in the EPA-E self-emulsifying composition administered every week group.
  • the EPA-E self-emulsifying composition daily administration group, the Epadale S daily administration group, and the control group are in this order. It is possible to prevent exacerbation without using an existing therapeutic drug in the remission period, to eliminate the side effects and medication burden of the existing therapeutic drug, and to extend the remission period.
  • Experimental Example 7 Treatment test for patients with Behcet's disease (exacerbation) stage Five groups of patients diagnosed with Behcet's disease in the active (exacerbation) stage with oral aphthous ulcer and / or skin / genital ulcer symptoms Divided into 10 groups in each group, olive oil 900 mg was orally administered twice daily to the control group, and Epadale S® 900 (containing EPA-E 900 mg) was administered to the Epadale S daily administration group 2 times a day.
  • EPA-E self-emulsifying composition daily administration group EPA-E self-emulsifying composition daily administration group and EPA-E self-emulsifying composition weekly administration group include EPA-E self-emulsifying composition Are orally administered once a day on each day of administration to give 1 g, 3 g and 5 g as EPA-E. Administration is continued until the patient reaches an inactive period, and existing Behcet's disease therapeutic agents may be administered at the discretion of the doctor, or may be reduced in dosage, extended administration intervals, or withdrawn due to symptom improvement. Assess the status of Behcet's disease using activity scores for oral aphthous and / or vulvar ulcer symptoms before the start of treatment and every 2 weeks after the start of treatment.
  • the activity score is calculated as follows. Score 0: no symptoms Score 1: Of the last 4 weeks, symptoms were present in less than 2 weeks, Score 2: Of the last 4 weeks, symptoms were present for more than 2 weeks, Score 3: Symptoms were present in most of the last 4 weeks. When the score before the start of treatment improves by 1 or more and the score becomes less than 2, it is determined that the inactive period has been reached. Further, a case where score 0 continues for one year or more is determined as a fixed (remission) period.
  • the average activity score in any group other than the control group decreases after the start of treatment.
  • the degree or rate of decrease in average activity score is equally and greatest in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsifying composition every week administration group.
  • the EPA-E self-emulsifying composition daily administration group and the Epadale S daily administration group are in this order.
  • the period leading to the inactive period and / or the fixed (remission) period is equally short in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsifying composition every week administration group.
  • the EPA-E self-emulsifying composition daily administration group, the Epadale S daily administration group, and the control group are in this order.
  • Each patient's activity score improves additively or synergistically in combination with existing therapeutics.
  • the dose of the existing therapeutic agent can be reduced, or the administration period of the existing therapeutic agent can be shortened, and the occurrence of side effects of the existing therapeutic agent can be suppressed or the burden of taking can be reduced.
  • the effect of reducing the dose or shortening the administration period of the existing therapeutic agent is the same and greatest in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsification composition every week administration group.
  • the EPA-E self-emulsifying composition daily administration group and the Epadale S daily administration group are in this order.
  • Experimental Example 8 Prevention and treatment test for patients with non-active stage of Behcet's disease Four groups of patients diagnosed with Behcet's disease in the non-active stage with activity scores of oral aphthous ulcer and / or skin / genital ulcer less than 2 Divided into 10 groups in each group, olive oil 900 mg was orally administered twice daily to the control group, and Epadale S® 900 (containing EPA-E 900 mg) was administered to the Epadale S daily administration group 2 times a day.
  • the EPA-E self-emulsifying composition daily administration group and the EPA-E self-emulsifying composition weekly administration group the EPA-E self-emulsifying composition is 1 g and 5 g as EPA-E, respectively.
  • EPA-E administration continues until the patient reaches an active (exacerbation) period, during which time no existing Behcet's disease treatment is administered.
  • the state of Behcet's disease is evaluated every 2 weeks after the start of treatment, and the activity score of each patient is calculated. When the activity score is 2 or more, it is determined that the activity (exacerbation) period has been reached.
  • the period from the start of prevention / treatment to the active (exacerbation) period is the longest in the EPA-E self-emulsifying composition administered every week.
  • the EPA-E self-emulsifying composition daily administration group, the Epadale S daily administration group, and the control group are in this order. It is possible to prevent an active (exacerbation) period without using an existing therapeutic agent in an inactive period, to eliminate side effects and medication burdens of the existing therapeutic drug, and to extend the inactive period.

Abstract

The present invention provides a self-emulsifying composition for the prevention and treatment of autoimmune skin diseases or inflammatory skin diseases such as psoriasis, the self-emulsifying composition being orally administered with a specific dosage regimen, such as intermittent administration, combination-sequential administration with an existing therapeutic agent or performing administration differently in the increment phase and the remission or non-active phase. The self-emulsifying composition comprises as an active ingredient ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts thereof, pharmaceutically acceptable esters thereof, pharmaceutically acceptable amides thereof, or pharmaceutically acceptable phospholipids thereof, and further comprises an emulsifier.

Description

乾癬治療用組成物および治療方法Psoriasis treatment composition and treatment method
　本発明は、自己免疫性皮膚疾患または炎症性皮膚疾患予防および／または治療のための、ω３多価不飽和脂肪酸又はそれらの製薬学上許容しうる塩類、又はそれらの製薬学上許容しうるエステル類、又はそれらの製薬学上許容しうるアミド類、又はそれらの製薬学上許容しうるリン脂質類を有効成分として含有し、さらに乳化剤を含有することを特徴とする自己乳化組成物に関する。また、本発明は、該自己乳化組成物を用いた自己免疫性皮膚疾患または炎症性皮膚疾患予防および／または治療方法に関する。 The present invention relates to ω3 polyunsaturated fatty acids or their pharmaceutically acceptable salts, or their pharmaceutically acceptable esters, for the prevention and / or treatment of autoimmune skin diseases or inflammatory skin diseases. Or a pharmaceutically acceptable amide thereof, or a pharmaceutically acceptable phospholipid thereof as an active ingredient, and a self-emulsifying composition characterized by further containing an emulsifier. The present invention also relates to a method for preventing and / or treating autoimmune skin disease or inflammatory skin disease using the self-emulsifying composition.
　自己免疫性皮膚疾患または炎症性皮膚疾患では、多くの治療薬が提供されているが、現在の治療薬は、例えば、重篤な副作用又は不十分な治療効果のため全ての患者に対して満足すべき結果を必ずしも提供していない。例えば、良好な療法を必要とする１つの例示的な自己免疫性皮膚疾患は乾癬である。乾癬は、人口の約２～３％で発症するＴ細胞媒介性の全身性炎症性皮膚疾患であり、増悪期と寛解期を繰り返して完治が困難な疾患であり、この病気に罹った患者についての生活の質に対して重大な影響を与えている。 Many treatments are provided for autoimmune skin diseases or inflammatory skin diseases, but current treatments are satisfactory for all patients due to, for example, serious side effects or insufficient therapeutic effects. It does not necessarily provide the results that should be done. For example, one exemplary autoimmune skin disease that requires good therapy is psoriasis. Psoriasis is a T-cell-mediated systemic inflammatory skin disease that occurs in about 2-3% of the population, and is a disease that cannot be cured completely after repeated exacerbations and remissions. About patients suffering from this disease Has a significant impact on the quality of life.
　種々の治療薬が乾癬を治療する試みにおいて開発されてきたが、有効性、副作用および患者の服薬負担（頻回服薬・服薬にかかる時間、費用）等の点において必ずしも満足すべき治療薬がない状況にある。乾癬に対する既存治療剤は、例えば日本では、外用剤として活性型ビタミンＤ３誘導体、ステロイドおよびこれらの配合剤が、経口剤としてシクロスポリン、エトレチナート、アプレミラストおよびステロイドが、また注射剤としてセクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、ブロダルマブ、イキセキズマブ等の抗炎症性サイトカイン抗体がある。しかしながら、外用剤は有効性が必ずしも十分ではなく、全身の患部に塗布する煩雑性および着服時の不快感があり、また、ステロイドには皮膚委縮や紫斑の副作用および使用中止後の急性憎悪がある。経口剤のシクロスポリンには腎障害や血圧上昇の副作用があり、エトレチナートには催奇形性や骨発育障害の副作用がありアメリカおよびカナダでは販売中止になっており、アプレミラストは非臨床試験において胚・胎児毒性を有することが示されたため妊婦、妊娠している可能性のある女性への投与は禁忌とされており、ステロイドには臓器障害性の副作用および使用中止後の急性憎悪がある。抗炎症性サイトカイン抗体注射剤は、肺炎や肺結核等の感染増悪リスク等の副作用や頻回服薬の時間的・費用的負担等の課題がある。 Various therapeutic agents have been developed in an attempt to treat psoriasis, but there are not necessarily satisfactory therapeutic agents in terms of efficacy, side effects and patient burden (time and cost required for frequent medications) Is in the situation. The existing therapeutic agents for psoriasis are, for example, active vitamin D3 derivatives, steroids and combinations thereof as external preparations in Japan, cyclosporine, etretinate, apremilast and steroids as oral preparations, and secukinumab, ustekinumab, adalimumab as injections, There are anti-inflammatory cytokine antibodies such as infliximab, brodalumab, and ixekizumab. However, the effectiveness of external preparations is not always sufficient, and there are complexities to apply to the affected area and discomfort at the time of wearing, and steroids have side effects of skin atrophy and purpura and acute hatred after discontinuation of use . Oral cyclosporine has side effects such as kidney damage and increased blood pressure, etretinate has side effects of teratogenicity and bone growth disorder, and has been discontinued in the US and Canada. It has been shown to be toxic and is contraindicated in pregnant and potentially pregnant women, and steroids have side effects of organ damage and acute aversion after discontinuation of use. Anti-inflammatory cytokine antibody injections have problems such as side effects such as infection exacerbation risk such as pneumonia and pulmonary tuberculosis, and time and cost burden of frequent medication.
　ω３多価不飽和脂肪酸（以下、ω３ＰＵＦＡと記す）又はそれらの製薬学上許容しうるエステル類を乾癬患者に毎日経口投与した臨床試験報告がされているが、有効とする報告および無効とする報告の両方がある。イコサペント酸エチル（以下、ＥＰＡ－Ｅと記す）（エパデール）１．８ｇ／日、２．７ｇ／日または３．６ｇ／日を乾癬患者に４週間～１２ヶ月間毎日経口投与すると症状が改善したとする報告（非特許文献１～５）がある一方、ＥＰＡ-Ｅ５１％およびドコサヘキサエン酸エチルエステル（以下、ＤＨＡ－Ｅと記す）３２％を含有するω３ＰＵＦＡエチルエステル（Ｋ８５）６ｇ／日を乾癬患者に４ヶ月間毎日経口投与しても有効性は認められなかったとする報告（非特許文献６）、あるいはイコサペント酸（以下、ＥＰＡと記す）のトリグリセリドエステル約１８％およびドコサヘキサエン酸（以下、ＤＨＡと記す）のトリグリセリドエステル約１２％を含有するＭａｘＥＰＡ１８ｇ／日を乾癬患者に８週間毎日経口投与しても有効性は認められなかったとする報告（非特許文献７）がある。また、ＥＰＡ－ＥやＤＨＡ－Ｅを含有する脂肪酸混合物とビタミンＤとを含有する乾癬治療用経口製剤のアイデアが報告されているが、実際に有効であることを示す記載はなく（特許文献１）、ω３ＰＵＦＡ又はそれらの製薬学上許容しうるエステル類の乾癬予防および／または治療効果に関しては未だに一定した評価が得られていない。 There have been clinical trial reports of daily oral administration of ω3 polyunsaturated fatty acids (hereinafter referred to as ω3 PUFA) or their pharmaceutically acceptable esters to patients with psoriasis. There are both. Symptoms improved by daily oral administration of ethyl icosapentate (hereinafter referred to as EPA-E) (Epadale) 1.8 g / day, 2.7 g / day or 3.6 g / day to patients with psoriasis for 4 to 12 months On the other hand, patients with psoriasis received ω3 PUFA ethyl ester (K85) 6 g / day containing 51% EPA-E and 32% docosahexaenoic acid ethyl ester (hereinafter referred to as DHA-E). Reported that no efficacy was observed even after daily oral administration for 4 months (Non-patent Document 6), or about 18% of a triglyceride ester of icosapentoic acid (hereinafter referred to as EPA) and docosahexaenoic acid (hereinafter referred to as DHA). The maximum efficacy of 18 mg / day MaxEPA containing about 12% of the triglyceride ester is as follows: It reported that it was no because there is (non-patent document 7). Moreover, although an idea of an oral preparation for treating psoriasis containing a fatty acid mixture containing EPA-E or DHA-E and vitamin D has been reported, there is no description showing that it is actually effective (Patent Document 1). ), Ω3 PUFA or their pharmaceutically acceptable esters have not yet been evaluated consistently for the prevention and / or treatment effect of psoriasis.
　ω３ＰＵＦＡ又はそれらの製薬学上許容しうるエステル類をおよび乳化剤を含有する自己乳化組成物が知られている。例えば、エタノールの含量が少ない自己乳化組成物として、ω３ＰＵＦＡと親水性親油性バランス（以下、ＨＬＢと記す）１０以上の乳化剤とを含有する自己乳化性、空腹時における経口吸収性・吸収速度が良好な自己乳化組成物が報告されている（特許文献２～７）。脂肪酸油混合物の少なくとも７５重量％のエイコサペンタエン酸とドコサヘキサエン酸とを含む脂肪酸油混合物と少なくとも一種の界面活性剤とを含む自己乳化組成物が報告されている（特許文献８～１０）。ω３ＰＵＦＡと界面活性剤とを含み水性液体と接触して約１００ｎｍ～約３μｍの中央粒子サイズを有するエマルションを形成する自己乳化組成物が報告されている（特許文献１１）。
　特許文献２～８には、これらの自己乳化組成物は経口投与した際の吸収性が良いことが記載されている。しかしながら、これらの自己乳化組成物を自己免疫性皮膚疾患または炎症性皮膚疾患の予防および／または治療に使用することの記載はない。 Self-emulsifying compositions containing ω3 PUFA or their pharmaceutically acceptable esters and an emulsifier are known. For example, as a self-emulsifying composition with a low content of ethanol, self-emulsifying property containing ω3 PUFA and a hydrophilic lipophilic balance (hereinafter referred to as HLB) 10 or more, good oral absorption and absorption speed on an empty stomach Self-emulsifying compositions have been reported (Patent Documents 2 to 7). Self-emulsifying compositions containing a fatty acid oil mixture containing at least 75% by weight of eicosapentaenoic acid and docosahexaenoic acid and at least one surfactant have been reported (Patent Documents 8 to 10). A self-emulsifying composition has been reported that contains ω3 PUFA and a surfactant to form an emulsion having a median particle size of about 100 nm to about 3 μm in contact with an aqueous liquid (Patent Document 11).
Patent Documents 2 to 8 describe that these self-emulsifying compositions have good absorbability when orally administered. However, there is no description of using these self-emulsifying compositions for the prevention and / or treatment of autoimmune skin diseases or inflammatory skin diseases.
国際公開ＷＯ２０１３／１５０３８４号パンフレットInternational Publication WO2013 / 150384 Pamphlet 国際公開ＷＯ２０１０／１３４６１４号パンフレットInternational publication WO2010 / 134614 pamphlet 国際公開ＷＯ２０１５／００８８４８号パンフレットInternational Publication WO2015 / 008848 Pamphlet 国際公開ＷＯ２０１５／００８８４９号パンフレットInternational Publication WO2015 / 008849 Pamphlet 国際公開ＷＯ２０１６／１１７０５７号パンフレットInternational Publication WO2016 / 117057 Pamphlet 国際公開ＷＯ２０１６／１１７６２１号パンフレットInternational Publication WO2016 / 117621 Pamphlet 国際公開ＷＯ２０１６／１１７６２９号パンフレットInternational Publication WO2016 / 117629 Pamphlet 国際公開ＷＯ２０１０／１０３４０２号パンフレットInternational Publication WO2010 / 103402 Pamphlet 国際公開ＷＯ２０１０／１０３４０４号パンフレットInternational Publication WO2010 / 103404 Pamphlet 国際公開ＷＯ２０１０／１１９３１９号パンフレットInternational Publication WO2010 / 119319 Pamphlet 国際公開ＷＯ２０１１／０４７２５９号パンフレットInternational Publication WO2011 / 047259 Pamphlet
　上述した自己免疫性皮膚疾患または炎症性皮膚疾患、特に乾癬における薬物療法において、種々の薬物が利用可能となっているが、その治療満足度は低い。
　予防および／または治療効果が高い、乾癬等の自己免疫性皮膚疾患または炎症性皮膚疾患予防および／または治療用組成物が望まれている。
　憎悪期を短縮および／または寛解期または非活動期を延長する、乾癬等の自己免疫性皮膚疾患または炎症性皮膚疾患予防および／または治療用組成物が望まれている。
　副作用が少ない、乾癬等の自己免疫性皮膚疾患または炎症性皮膚疾患予防および／または治療用組成物が望まれている。
　投与頻度を減少させ患者の服薬負担を軽減させる、乾癬等の自己免疫性皮膚疾患または炎症性皮膚疾患予防および／または治療用組成物が望まれている。
　服薬にかかる時間を減少させ患者の服薬負担を軽減させる、乾癬等の自己免疫性皮膚疾患または炎症性皮膚疾患予防および／または治療用組成物が望まれている。
　服薬にかかる費用を減少させ患者の服薬負担を軽減させる、乾癬等の自己免疫性皮膚疾患または炎症性皮膚疾患予防および／または治療用組成物が望まれている。
　併用することにより既存治療薬の投与頻度および／または投与量を減少させて既存治療薬が有する課題（有効性、副作用および患者の服薬負担（頻回服薬・服薬にかかる時間、費用）等）の少なくとも1つを解決する、乾癬等の自己免疫性皮膚疾患または炎症性皮膚疾患予防および／または治療用組成物が望まれている。
　上記の性質のうち少なくとも１つ以上を改善する自己乳化組成物を提供することが本発明の課題である。
　さらに、上記の性質のうち少なくとも１つ以上を改善する、当該自己乳化組成物を用いた、乾癬等の自己免疫性皮膚疾患または炎症性皮膚疾患予防および／または治療方法を提供することが本発明の課題である。 Various drugs are available in the above-described autoimmune skin disease or inflammatory skin disease, particularly in the drug therapy for psoriasis, but the treatment satisfaction is low.
There is a demand for a composition for preventing and / or treating autoimmune skin diseases such as psoriasis or inflammatory skin diseases, which has a high preventive and / or therapeutic effect.
What is desired is a composition for the prevention and / or treatment of autoimmune skin diseases or inflammatory skin diseases such as psoriasis that shortens the period of exacerbation and / or extends the period of remission or inactivity.
A composition for preventing and / or treating autoimmune skin diseases such as psoriasis or inflammatory skin diseases with few side effects is desired.
There is a need for a composition for preventing and / or treating autoimmune skin diseases such as psoriasis or inflammatory skin diseases that reduces the frequency of administration and reduces the burden of patients on medication.
There is a demand for a composition for preventing and / or treating autoimmune skin diseases such as psoriasis or inflammatory skin diseases, which reduces the time taken for medication and reduces the burden of medication.
There is a demand for a composition for preventing and / or treating autoimmune skin diseases such as psoriasis or inflammatory skin diseases that reduces the cost of medication and reduces the burden of medication.
Reduce the administration frequency and / or dose of existing treatments by using them in combination, and the problems that existing treatments have (effectiveness, side effects and patient medication burden (time and cost required for frequent medications)) Compositions for preventing and / or treating autoimmune skin diseases such as psoriasis or inflammatory skin diseases that solve at least one are desired.
It is an object of the present invention to provide a self-emulsifying composition that improves at least one of the above properties.
Furthermore, the present invention provides a method for preventing and / or treating autoimmune skin diseases such as psoriasis or inflammatory skin diseases using the self-emulsifying composition, which improves at least one of the above properties. It is a problem.
　本発明者らは、上記の課題を解決すべく鋭意研究を重ねてた結果、間欠投与、既存治療薬との併用・シークエンシャル投与および憎悪期と寛解期または非活動期で異なる投与を行う等の特定の用法・用量で経口投与される、ω３ＰＵＦＡ又はそれらの製薬学上許容しうる塩類、又はそれらの製薬学上許容しうるエステル類、又はそれらの製薬学上許容しうるアミド類、又はそれらの製薬学上許容しうるリン脂質類（以下、これらを総称してω３ＰＵＦＡ類と記すことがある）を有効成分として含有し、さらに乳化剤を含有する自己乳化組成物を用いることにより、自己免疫性皮膚疾患または炎症性皮膚疾患に対して上記課題のうち少なくとも１つ以上を改善する、乾癬等の自己免疫性皮膚疾患または炎症性皮膚疾患予防および／または治療用組成物、および当該自己乳化組成物を用いた乾癬等の自己免疫性皮膚疾患または炎症性皮膚疾患予防および／または治療方法を提供することが可能となることを見出し、本発明を完成させた。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have conducted intermittent administration, combined use with existing therapeutic agents / sequential administration, and administration differently in an aversion period and a remission period or inactive period, etc. Ω3 PUFA or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide thereof, or those which are orally administered at a specific usage / dose of By using a self-emulsifying composition containing pharmaceutically acceptable phospholipids (hereinafter sometimes collectively referred to as ω3 PUFAs) as an active ingredient and further containing an emulsifier, For the prevention and / or treatment of autoimmune skin diseases or inflammatory skin diseases such as psoriasis, which improves at least one of the above problems for skin diseases or inflammatory skin diseases It has been found that it is possible to provide a composition and a method for preventing and / or treating autoimmune skin diseases such as psoriasis or inflammatory skin diseases using the self-emulsifying composition, and completed the present invention.
　すなわち、本発明の第一の態様は以下の自己乳化組成物である。
（１）２日～１ヶ月からなる群から選択される少なくとも１つの期間毎に間欠経口投与されることを特徴とする、自己免疫性皮膚疾患または炎症性皮膚疾患予防および／または治療のためのω３ＰＵＦＡ類を有効成分として含有し、さらに乳化剤を含有することを特徴とする自己乳化組成物。
（２）２日～３週間からなる群から選択される少なくとも１つの期間毎に間欠経口投与されることを特徴とする、上記（１）に記載の自己乳化組成物。
（３）２日～２週間からなる群から選択される少なくとも１つの期間毎に間欠経口投与されることを特徴とする、上記（１）に記載の自己乳化組成物。
（４）２日～１週間からなる群から選択される少なくとも１つの期間毎に間欠経口投与されることを特徴とする、上記（１）に記載の自己乳化組成物。
（５）２日、３日、４日、５日、６日または１週間毎に間欠経口投与されることを特徴とする、上記（１）に記載の自己乳化組成物。
（６）１０日毎に間欠経口投与されることを特徴とする、上記（１）に記載の自己乳化組成物。
（７）２週間毎に間欠経口投与されることを特徴とする、上記（１）に記載の自己乳化組成物。
（８）２０日毎に間欠経口投与されることを特徴とする、上記（１）に記載の自己乳化組成物。
（９）３週間毎に間欠経口投与されることを特徴とする、上記（１）に記載の自己乳化組成物。
（１０）４週間または１ヶ月間毎に間欠経口投与されることを特徴とする、上記（１）に記載の自己乳化組成物。
（１１）１週間に２日（例えば、月曜日および木曜日、月曜日および金曜日、火曜日および金曜日、火曜日および土曜日、水曜日および土曜日、水曜日および日曜日、木曜日および日曜日）間欠経口投与されることを特徴とする、上記（１）に記載の自己乳化組成物。
（１２）１週間に３日（例えば、月曜日と水曜日および金曜日、月曜日と水曜日および土曜日、月曜日と木曜日および土曜日、火曜日と木曜日および土曜日、火曜日と木曜日および日曜日、火曜日と金曜日および日曜日、水曜日と金曜日および日曜日）間欠経口投与されることを特徴とする、上記（１）に記載の自己乳化組成物。
（間欠投与）
　なお、本明細書で間欠投与とは、例えば２日毎の間欠投与とは、初日投与した場合その２日後に次の投与を行うことをいう。Ｘ日毎と記載した場合は日で期間を計算し、初日投与し、次回はそのＸ日後に投与する。Ｙ週毎と記載した場合は週で期間を計算し、初日投与し、次回はそのＹ週後に投与する。Ｚヶ月毎と記載した場合は、初日投与し、次回はそのＺヶ月後（例えば、初日投与が１０日の場合はＺヶ月後の１０日、また初日投与が２９ないし３１日でＺヶ月後に同日がない場合はＺヶ月後の末日）に投与することを意味する。
　また、投与間隔が１週間以上の場合は、投与日を等間隔から前後にずらすこともできる。例えば、１週間間隔の場合は前後１日、２週間間隔の場合は前後２日、３週間間隔の場合は前後３日、４週間間隔の場合は前後４日、５週間間隔の場合は前後５日、６週間間隔の場合は前後６日、７週間間隔の場合は前後１週間等であるが、これらに限定されない。 That is, the first aspect of the present invention is the following self-emulsifying composition.
(1) For the prevention and / or treatment of autoimmune skin disease or inflammatory skin disease, characterized by intermittent oral administration every at least one period selected from the group consisting of 2 days to 1 month A self-emulsifying composition comprising ω3 PUFAs as an active ingredient and further containing an emulsifier.
(2) The self-emulsifying composition as described in (1) above, which is intermittently orally administered every at least one period selected from the group consisting of 2 days to 3 weeks.
(3) The self-emulsifying composition as described in (1) above, wherein the composition is intermittently orally administered every at least one period selected from the group consisting of 2 days to 2 weeks.
(4) The self-emulsifying composition as described in (1) above, wherein the composition is intermittently orally administered every at least one period selected from the group consisting of 2 days to 1 week.
(5) The self-emulsifying composition as described in (1) above, which is intermittently orally administered every 2 days, 3 days, 4 days, 5 days, 6 days or 1 week.
(6) The self-emulsifying composition as described in (1) above, which is intermittently orally administered every 10 days.
(7) The self-emulsifying composition as described in (1) above, which is intermittently orally administered every two weeks.
(8) The self-emulsifying composition according to the above (1), which is intermittently orally administered every 20 days.
(9) The self-emulsifying composition according to (1) above, which is intermittently orally administered every 3 weeks.
(10) The self-emulsifying composition as described in (1) above, which is intermittently orally administered every 4 weeks or every month.
(11) characterized by being intermittently orally administered two days a week (eg, Monday and Thursday, Monday and Friday, Tuesday and Friday, Tuesday and Saturday, Wednesday and Saturday, Wednesday and Sunday, Thursday and Sunday), The self-emulsifying composition as described in (1) above.
(12) 3 days a week (eg, Monday and Wednesday and Friday, Monday and Wednesday and Saturday, Monday and Thursday and Saturday, Tuesday and Thursday and Saturday, Tuesday and Thursday and Sunday, Tuesday and Friday and Sunday, Wednesday and Friday) And Sunday) intermittent self-emulsification composition according to (1) above, characterized by being intermittently orally administered.
(Intermittent administration)
In the present specification, intermittent administration refers to, for example, intermittent administration every two days, when the first day is administered, the next administration is performed two days later. When it is described as every X days, the period is calculated in days, and it is administered on the first day, and the next dose is administered on the X day. When it is described as every Y weeks, the period is calculated in weeks, and it is administered on the first day, and the next dose is administered after Y weeks. When it is described as every Z months, it is administered on the first day, the next day after Z months (for example, if the first day administration is 10 days, 10 days after Z month, and the first day administration is 29 to 31 days, the same day after Z months) When there is no, it means that it is administered on the last day after Z months).
In addition, when the administration interval is one week or more, the administration day can be shifted back and forth from the regular interval. For example, 1 week before and after 1 week, 2 days before and 2 weeks, 2 days before and after 3 weeks, 3 days before and after 3 weeks, 4 days before and after 4 weeks, 5 days after 5 weeks In the case of days and 6-week intervals, it is 6 days before and after, and in the case of 7-week intervals, it is 1 week before and after, but is not limited thereto.
（１３）ω３ＰＵＦＡ類がＥＰＡ、ＤＨＡ、ドコサペンタエン酸（以下、ＤＰＡと記す）、αリノレン酸（以下、ＡＬＡと記す）、それらの製薬学上許容しうる塩類、それらの製薬学上許容しうるエステル類、それらの製薬学上許容しうるアミド類、それらの製薬学上許容しうるリン脂質類からなる群から選択される少なくとも１つである、上記（１）乃至（１２）のいずれかに記載の自己乳化組成物。
（１４）ω３ＰＵＦＡ類がＥＰＡまたはＥＰＡ－Ｅである、上記（１）乃至（１３）のいずれかに記載の自己乳化組成物。
（１５）全脂肪酸およびその誘導体中のＥＰＡおよびＥＰＡ－Ｅ含量比が４０質量％以上である、上記（１）乃至（１４）のいずれかに記載の自己乳化組成物。
（１６）全脂肪酸およびその誘導体中のＥＰＡおよびＥＰＡ－Ｅ含量比が８０質量％以上である、上記（１）乃至（１５）のいずれかに記載の自己乳化組成物。
（１７）全脂肪酸およびその誘導体中のＥＰＡおよびＥＰＡ－Ｅ含量比が９６．５質量％以上である、上記（１）乃至（１６）のいずれかに記載の自己乳化組成物。
（１８）自己乳化組成物の全量を１００質量％としたときのＥＰＡおよびＥＰＡ－Ｅの含量が５０質量％以上である、上記（１）乃至（１７）のいずれかに記載の自己乳化組成物。
（１９）自己乳化組成物の全量を１００質量％としたときのＥＰＡおよびＥＰＡ－Ｅの含量が６０質量％以上である、上記（１）乃至（１８）のいずれかに記載の自己乳化組成物。
（２０）自己乳化組成物の全量を１００質量％としたときのＥＰＡおよびＥＰＡ－Ｅの含量が７０質量％以上である、上記（１）乃至（１９）のいずれかに記載の自己乳化組成物。 (13) ω3 PUFAs are EPA, DHA, docosapentaenoic acid (hereinafter referred to as DPA), α-linolenic acid (hereinafter referred to as ALA), their pharmaceutically acceptable salts, and their pharmaceutically acceptable Any one of the above (1) to (12), which is at least one selected from the group consisting of pharmaceutically acceptable esters, pharmaceutically acceptable amides thereof, and pharmaceutically acceptable phospholipids thereof. The self-emulsifying composition described in 1.
(14) The self-emulsifying composition according to any one of (1) to (13) above, wherein the ω3 PUFAs are EPA or EPA-E.
(15) The self-emulsifying composition according to any one of (1) to (14) above, wherein the content ratio of EPA and EPA-E in all fatty acids and derivatives thereof is 40% by mass or more.
(16) The self-emulsifying composition according to any one of (1) to (15) above, wherein the content ratio of EPA and EPA-E in all fatty acids and derivatives thereof is 80% by mass or more.
(17) The self-emulsifying composition according to any one of (1) to (16) above, wherein the content ratio of EPA and EPA-E in all fatty acids and derivatives thereof is 96.5% by mass or more.
(18) The self-emulsifying composition according to any one of (1) to (17), wherein the content of EPA and EPA-E is 50% by mass or more when the total amount of the self-emulsifying composition is 100% by mass. .
(19) The self-emulsifying composition according to any one of (1) to (18), wherein the content of EPA and EPA-E is 60% by mass or more when the total amount of the self-emulsifying composition is 100% by mass. .
(20) The self-emulsifying composition according to any one of (1) to (19), wherein the content of EPA and EPA-E is 70% by mass or more when the total amount of the self-emulsifying composition is 100% by mass. .
（２１）ω３ＰＵＦＡ類０．５ｇ／日～１０ｇ／日で経口投与することを特徴とする、上記（１）乃至（２０）のいずれかに記載の自己乳化組成物。
（２２）ω３ＰＵＦＡ類１ｇ／日～８ｇ／日で経口投与することを特徴とする、上記（１）乃至（２１）のいずれかに記載の自己乳化組成物。
（２３）ω３ＰＵＦＡ類２ｇ／日～６ｇ／日で経口投与することを特徴とする、上記（１）乃至（２２）のいずれかに記載の自己乳化組成物。
（２４）ω３ＰＵＦＡ類４ｇ／日～６ｇ／日で経口投与することを特徴とする、上記（１）乃至（２３）のいずれかに記載の自己乳化組成物。 (21) The self-emulsifying composition as described in any one of (1) to (20) above, which is orally administered at 0.5 g / day to 10 g / day of ω3 PUFAs.
(22) The self-emulsifying composition as described in any one of (1) to (21) above, which is orally administered at 1 g / day to 8 g / day of ω3 PUFAs.
(23) The self-emulsifying composition as described in any of (1) to (22) above, which is orally administered at 2 g / day to 6 g / day of ω3 PUFAs.
(24) The self-emulsifying composition as described in any one of (1) to (23) above, which is orally administered at 4 g / day to 6 g / day of ω3 PUFAs.
（２５）自己免疫性皮膚疾患または炎症性皮膚疾患が乾癬及び類症（尋常性乾癬（重症例含む）、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、稽留性肢端皮膚炎、疱疹状膿痂疹、ライター症候群、滴状乾癬、等）、魚鱗癬群（尋常性魚鱗癬、水疱型先天性魚鱗癬様紅皮症、非水疱型先天性魚鱗癬様紅皮症）、掌蹠角化症、ダリエー病、掌蹠膿疱症、毛孔性紅色粃糠疹、紅斑性角化症、皮膚炎群（接触皮膚炎、貨幣状皮膚炎、自家感作性皮膚炎、アトピー性皮膚炎、ビダール苔癬、その他の神経皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、その他の手指の皮膚炎、耳介及び外耳道の皮膚炎、鼻前庭及び鼻翼周辺の皮膚炎、全身性剥脱性皮膚炎、うっ血性皮膚炎、限局性掻爬皮膚炎、口周囲皮膚炎、汗疱、花粉性皮膚炎等）、多発性硬化症、強皮症、エリテマトーデス（全身性及び慢性円板状）、ベーチェット病、および天疱瘡からなる群から選択される少なくとも１つである、上記（１）乃至（２４）のいずれかに記載の自己乳化組成物。
（２６）自己免疫性皮膚疾患または炎症性皮膚疾患が乾癬及び類症（尋常性乾癬（重症例含む）、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、稽留性肢端皮膚炎、疱疹状膿痂疹、ライター症候群、滴状乾癬）、皮膚炎群（接触皮膚炎、貨幣状皮膚炎、自家感作性皮膚炎、アトピー性皮膚炎、ビダール苔癬、その他の神経皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、その他の手指の皮膚炎、耳介及び外耳道の皮膚炎、鼻前庭及び鼻翼周辺の皮膚炎、全身性剥脱性皮膚炎、うっ血性皮膚炎、限局性掻爬皮膚炎、口周囲皮膚炎、汗疱、花粉性皮膚炎、等）およびベーチェット病からなる群から選択される少なくとも１つであり、好ましくは、乾癬及び類症、皮膚炎群およびベーチェット病からなる群から選択される少なくとも１つであり、より好ましくは尋常性乾癬、関節症性乾癬、膿疱性乾癬、アトピー性皮膚炎およびベーチェット病からなる群から選択される少なくとも１つである、上記（１）乃至（２５）のいずれかに記載の自己乳化組成物。
（２７）血清または血漿中のＥＰＡとアラキドン酸（以下、ＡＡと記す）との比率（以下、ＥＰＡ／ＡＡ比と記す）が０．４未満である自己免疫性皮膚疾患または炎症性皮膚疾患患者に投与するための、上記（１）乃至（２６）のいずれかに記載の自己乳化組成物。
（２８）血清または血漿中のＥＰＡ／ＡＡ比が０．１未満である自己免疫性皮膚疾患または炎症性皮膚疾患患者に投与するための、上記（１）乃至（２７）のいずれかに記載の自己乳化組成物。 (25) Autoimmune skin disease or inflammatory skin disease is psoriasis and analogies (including psoriasis vulgaris (including severe cases), psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, limbic limb dermatitis, Herpes zoster, Reiter's syndrome, trichomes psoriasis, etc.), ichthyosis group (common ichthyosis, blistered congenital ichthyosis-like erythroderma, non-bullous congenital ichthyosis-like erythroderma), palm Keratosis, Darier's disease, palmoplantar pustulosis, erythematous erythematosus, erythematous keratosis, dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic dermatitis, progressive palmokeratosis, other finger dermatitis, pinna and ear canal dermatitis, nasal vestibular and perinasal dermatitis, systemic Exfoliative dermatitis, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat blister, pollen dermatitis, etc.), multiple sclerosis, scleroderma , Lupus erythematosus (systemic and chronic discoid), Behcet's disease, and at least one selected from the group consisting of pemphigus, the (1) through self-emulsifying composition as described in any of (24).
(26) Autoimmune skin disease or inflammatory skin disease is psoriasis and analogies (including psoriasis vulgaris (including severe cases), arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, limbic limb dermatitis, Herpes zoster, Reiter syndrome, prickly psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, autosensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, oil Leaky dermatitis, progressive palmokeratosis, other finger dermatitis, dermatitis of the auricle and ear canal, dermatitis around the nasal vestibule and nasal wing, generalized exfoliative dermatitis, congestive dermatitis, limited And at least one selected from the group consisting of Behcet's disease, preferably psoriasis and symptoms, dermatitis group and Behcet's disease At least one selected from the group consisting of and more preferred Or at least one selected from the group consisting of psoriasis vulgaris, psoriatic arthritis, pustular psoriasis, atopic dermatitis, and Behcet's disease, or the self according to any one of (1) to (25) above Emulsified composition.
(27) Patients with an autoimmune skin disease or inflammatory skin disease in which the ratio of EPA to arachidonic acid (hereinafter referred to as AA) in serum or plasma (hereinafter referred to as EPA / AA ratio) is less than 0.4 The self-emulsifying composition according to any one of the above (1) to (26), wherein
(28) The method according to any one of (1) to (27) above, wherein the EPA / AA ratio in serum or plasma is administered to a patient having an autoimmune skin disease or inflammatory skin disease of less than 0.1. Self-emulsifying composition.
（２９）自己免疫性皮膚疾患または炎症性皮膚疾患の憎悪期にシクロスポリン、エトレチナート、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンテネルマブ、カナキヌマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラからなる群から選択される少なくとも１つの化合物と併用するための、上記（１）乃至（２８）のいずれかに記載の自己乳化組成物。
（３０）乾癬及び類症（尋常性乾癬（重症例含む）、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、稽留性肢端皮膚炎、疱疹状膿痂疹、ライター症候群、滴状乾癬）、皮膚炎群（接触皮膚炎、貨幣状皮膚炎、自家感作性皮膚炎、アトピー性皮膚炎、ビダール苔癬、その他の神経皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、その他の手指の皮膚炎、耳介及び外耳道の皮膚炎、鼻前庭及び鼻翼周辺の皮膚炎、全身性剥脱性皮膚炎、うっ血性皮膚炎、限局性掻爬皮膚炎、口周囲皮膚炎、汗疱、花粉性皮膚炎、等）およびベーチェット病からなる群から選択される少なくとも１つの自己免疫性皮膚疾患または炎症性皮膚疾患の憎悪期にシクロスポリン、エトレチナート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンテネルマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラからなる群から選択される少なくとも１つの化合物と併用するための、上記（１）乃至（２９）のいずれかに記載の自己乳化組成物。
（３１）さらにシクロスポリン、エトレチナート、アプレミラスト、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロンおよびベタメゾンからなる群から選択される少なくとも１つを有効成分として含有する、上記（１）乃至（３０）のいずれかに記載の自己乳化組成物。
（３２）自己免疫性皮膚疾患または炎症性皮膚疾患の寛解期または非活動期にシクロスポリン、エトレチナート、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンテネルマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラと併用せず単独で投与するための、上記（１）乃至（３０）のいずれかに記載の自己乳化組成物。
（３３）乾癬及び類症（尋常性乾癬（重症例含む）、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、稽留性肢端皮膚炎、疱疹状膿痂疹、ライター症候群、滴状乾癬）、皮膚炎群（接触皮膚炎、貨幣状皮膚炎、自家感作性皮膚炎、アトピー性皮膚炎、ビダール苔癬、その他の神経皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、その他の手指の皮膚炎、耳介及び外耳道の皮膚炎、鼻前庭及び鼻翼周辺の皮膚炎、全身性剥脱性皮膚炎、うっ血性皮膚炎、限局性掻爬皮膚炎、口周囲皮膚炎、汗疱、花粉性皮膚炎、等）およびベーチェット病からなる群から選択される少なくとも１つの自己免疫性皮膚疾患または炎症性皮膚疾患の寛解期または非活動期にシクロスポリン、エトレチナート、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンテネルマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラと併用せず単独で投与するための、上記（１）乃至（３０）のいずれかに記載の自己乳化組成物。 (29) Cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone, betamethasone, maxacalcitol, calcipotriol, tacalcitol hydrate during the exacerbation of autoimmune skin disease or inflammatory skin disease , Hydrocortisone acetate, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildrakizumab, brodalumab, guselcoumab, dupirumumab, nemorizumab, rituximab, rituximab, rituximab, rituximab, rituximab , Upadacitinib, emicizumab, facinuma , Pegpreranib, omalizumab, leslizumab, subtabumab, gantenerumab, canakinumab, etanercept, tofacitinib, salicylic acid / white petrolatum, splatastosyl, azelastine hydrochloride, fexofenadine hydrochloride, sodium cromoglycate, oxatomide, oxatomide Tacrolimus hydrate, tranilast, beclomethasone propionic acid, human immunoglobulin / histamine dihydrochloride, methylprednisolone, apremilast, pimecrolimus, AMG-0101, AMG-0103, sturbene hydroxide molecule, chrysabolol, nalflavine, doxorubicin, WBI-1001, Octenidine, oxymetazoline, nitric oxide, timapiplant, rosipitol acetate, Consisting of bamamide, febipiplant, omiganan, asimadoline, metflumin, DSXS-1411, selenexer, terbinafine, ellenbecestat, velvecestat, ranabecestat, fluticasone, beperminogen per plasmid, darcetrapib, abatacept, thalidomide, bosentan The self-emulsifying composition according to any one of the above (1) to (28), for use in combination with at least one compound selected from the group.
(30) Psoriasis and analogies (including psoriasis vulgaris (including severe cases), psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, limbic limb dermatitis, pustular impetigo, Reiter's syndrome, drops Psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic dermatitis, progressive palmar keratin , Other finger dermatitis, auricular and ear canal dermatitis, nasal vestibular and nasal wing dermatitis, generalized exfoliative dermatitis, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat Cyclosporine, etretinate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone during the exacerbation of at least one autoimmune or inflammatory skin disease selected from the group consisting of blisters, pollen dermatitis, etc.) and Behcet's disease Prednisolone, Betamethasone, Maxacalcitol, Calcipotriol, Tacalcitol hydrate, Hydrocortisone acetate, Betamethasone acetate, Diflorazone acetate, Sekukinumab, Ustekinumab, Adalimumab, Infliximab, Ixekizumab, Tiludakizumab, Bumadarumabumamu, Brodalumab Traloquinumab, rituximab, salitumab, resultizumab, resultizabbate Fe Sofenadine hydrochloride, sodium cromoglycate, oxatomide, clobetasone butyrate, bendazac, suprofen, tacrolimus hydrate, tranilast, beclomethasone propionic acid, human immunoglobulin / histamine dihydrochloride, methylprednisolone, apremilast, pimecrolimus, AMG-0101, AMG-0103, hydroxylated sterubene molecule, chrysabolol, nalfrafin, doxorubicin, WBI-1001, octenidine, oxymetazoline, nitric oxide, timapiplant, rosipitol acetate, cobamide, febipiplant, omiganane, asimadrine, metflumin, DSXS-1411, celinec Terbinafine, Ellen Bethestat, Belvecestat, Rana Bethestat, Fluticasone, Beper The self-emulsifying composition according to any one of (1) to (29) above, for use in combination with at least one compound selected from the group consisting of minogen par plasmid, dalcetrapib, abatacept, thalidomide, bosentan, deflazacoat and anakinra object.
(31) The above (1) to (30), further comprising at least one selected from the group consisting of cyclosporine, etretinate, apremilast, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone and betamazone as an active ingredient. The self-emulsifying composition according to any one of the above.
(32) Cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone, betamethone, maxacalcitol, calcipotriol, during remission or inactivity of autoimmune skin disease or inflammatory skin disease Tacalcitol hydrate, hydrocortisone acetate, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildrakizumab, brodalumab, gusselumab, dupirumumab, nemorizumab, tralotimumab, traloticumab Cantratinib, traloquinumab, upadacitinib, emicizuma , Facinumab, pegprelanib, omalizumab, reslizumab, subtabumab, gantenerumab, etanercept, tofacitinib, salicylic acid / white petrolatum, splatastosyl, azelastine hydrochloride, fexofenadine hydrochloride, sodium cromoglycate, oxatomide, oxatomide Tacrolimus hydrate, tranilast, beclomethasone propionic acid, human immunoglobulin / histamine dihydrochloride, methylprednisolone, apremilast, pimecrolimus, AMG-0101, AMG-0103, sturbene hydroxide molecule, chrysabolol, nalflavine, doxorubicin, WBI-1001, Octenidine, oxymetazoline, nitric oxide, timapiplant, rosipitol acetate, Bamamide, febipiplant, omiganan, asimadoline, metflumin, DSXS-1411, selenexer, terbinafine, ellenbecestat, velvecestat, ranavecestat, fluticasone, beperminogen per plasmid, darcetrapib, abatacept, talidfuran and bosentan The self-emulsifying composition according to any one of the above (1) to (30), which is administered alone without being administered.
(33) Psoriasis and analogies (including psoriasis vulgaris (including severe cases), arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, limbic limb dermatitis, herpes zoster, Reiter's syndrome, drops Psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic dermatitis, progressive palmar keratin , Other finger dermatitis, auricular and ear canal dermatitis, nasal vestibular and nasal wing dermatitis, generalized exfoliative dermatitis, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat Cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, during remission or inactivity of at least one autoimmune skin disease or inflammatory skin disease selected from the group consisting of blisters, pollen dermatitis, etc.) and Behcet's disease Corti Acetate, dexamethasone, prednisolone, betamethasone, maxacalcitol, calcipotriol, tacalcitol trihydrate, hydrocortisone acetate, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildrazumab, tildrazumab Guselumab, Dupilumab, Nemorizumab, Traloquinumab, Rituximab, Balicitinib, Salilumab, Masitinib, Ocrelizumab, Pekkantratinib, Traloquinumab, Upadacitinib, Emicizumab, Facinumab, Pegpremab Sil, azelastine hydrochloride, fexofenadine hydrochloride, sodium cromoglycate, oxatomide, clobetasone butyrate, bendazac, suprofen, tacrolimus hydrate, tranilast, beclomethasone propionate, human immunoglobulin / histamine dihydrochloride, methylprednisolone, Apremilast, pimecrolimus, AMG-0101, AMG-0103, hydroxylated sterubene molecule, chrysabolol, nalflaffin, doxorubicin, WBI-1001, octenidine, oxymetazoline, nitric oxide, timapiplant, rosipitol acetate, cobamide, febipiplant, omiganane, ashimad Metoflumin, DSXS-1411, Selnexer, Terbinafine, Ellenbecestat, Berbecestat, Ranabe The self-emulsifying composition according to any one of (1) to (30) above, wherein the composition is administered alone without being combined with cestat, fluticasone, beperminogen par plasmid, dalcetrapib, abatacept, thalidomide, bosentan, defrazacoat and anakinra .
（３４）自己免疫性皮膚疾患または炎症性皮膚疾患の増悪期には２～７日からなる群から選択される少なくとも１つの期間毎に間欠経口投与され、症状の改善がみられた場合は１週間～１ヶ月からなる群から選択される少なくとも１つの期間毎に投与間隔を１日または２日ずつ増加して、寛解期または非活動期には１週間～１ヶ月からなる群から選択される少なくとも１つの期間毎に間欠経口投与される、上記（１）乃至（３３）のいずれかに記載の自己乳化組成物。
（３５）自己免疫性皮膚疾患または炎症性皮膚疾患の増悪期には２～１０ｇ／日経口投与され、症状の改善がみられた場合は１週間～１ヶ月からなる群から選択される少なくとも１つの期間毎に投与量を０．５～１g／日ずつ減量して、寛解期または非活動期には０．５～４ ｇ／日経口投与される、上記（１）乃至（３３）のいずれかに記載の自己乳化組成物。 (34) In the period of exacerbation of autoimmune skin disease or inflammatory skin disease, intermittent oral administration is carried out every at least one period selected from the group consisting of 2 to 7 days. The administration interval is increased by 1 day or 2 days for at least one period selected from the group consisting of weeks to 1 month, and selected from the group consisting of 1 week to 1 month in the remission period or inactive period The self-emulsifying composition according to any one of (1) to (33), which is intermittently orally administered every at least one period.
(35) At least one selected from the group consisting of 2 to 10 g / day orally in the exacerbation phase of autoimmune skin disease or inflammatory skin disease, and 1 week to 1 month when improvement in symptoms is observed Any one of the above (1) to (33), wherein the dose is reduced by 0.5 to 1 g / day every one period and is orally administered at 0.5 to 4 g / day in the remission period or inactive period. A self-emulsifying composition according to claim 1.
（３６）乳化剤がポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンヒマシ油、ポリエチレングリコール脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコールおよびショ糖脂肪酸エステルからなる群から選ばれる少なくとも１つの乳化剤である、上記（１）乃至（３５）のいずれかに記載の自己乳化組成物。
（３７）ＨＬＢが１０以上の乳化剤である、上記（１）乃至（３６）のいずれかに記載の自己乳化組成物。
（３８）ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステルおよびポリオキシエチレンヒマシ油からなる群から選択される少なくとも２つを含有する、上記（１）乃至（３７）のいずれかに記載の自己乳化組成物。
（３９）自己乳化組成物が、ａ）合計量の５０～９５質量％のω３ＰＵＦＡ類、
ｂ）　ω３ＰＵＦＡ類１００質量部に対して３～４０質量部のレシチン、
ｃ）　ω３ＰＵＦＡ類１００質量部に対して１０～５０質量部のポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンヒマシ油、ポリエチレングリコール脂肪酸エステル、およびポリオキシエチレンポリオキシプロピレングリコールからなる群から選ばれる少なくとも１つの乳化剤、および、
ｄ）　エタノールの含量が合計量の４質量％以下であることを特徴とする、上記（１）乃至（３７）のいずれかに記載の自己乳化組成物。
（４０）自己乳化組成物が、ａ）組成物の合計量の５０～９５質量％のω３ＰＵＦＡ類、
ｂ）前記合計量の４～２０質量％の、ショ糖ラウリン酸エステル、ショ糖ミリスチン酸エステル、ショ糖パルミチン酸エステル、ショ糖ステアリン酸エステルおよびショ糖オレイン酸エステルからなる群から選ばれる少なくとも１つのＨＬＢが１０以上のショ糖脂肪酸エステルである乳化剤、
ｃ）ω３ＰＵＦＡ、その製薬学上許容しうる塩、エチルエステルおよびトリグリセリドエステルからなる群から選ばれる少なくとも１つの化合物１００質量部に対して５～３０質量部のグリセリン、および
ｄ）エタノールの含量が前記合計量の４質量％以下であることを特徴とする、上記（１）乃至（３７）のいずれかに記載の自己乳化組成物。
（４１）自己乳化組成物が、国際公開ＷＯ２０１０／１３４６１４号パンフレット、国際公開ＷＯ２０１５／００８８４８号パンフレット、国際公開ＷＯ２０１５／００８８４９号パンフレット、国際公開ＷＯ２０１６／１１７０５７号パンフレット、国際公開ＷＯ２０１６／１１７６２１号パンフレット、国際公開ＷＯ２０１６／１１７６２９号パンフレット、国際公開ＷＯ２０１０／１０３４０２号パンフレット、国際公開ＷＯ２０１０／１０３４０４号パンフレット、国際公開ＷＯ２０１０／１１９３１９号パンフレットおよび国際公開ＷＯ２０１１／０４７２５９号パンフレットに記載されている自己乳化組成物からなる群より選択される少なくとも１つの自己乳化組成物である、上記（１）乃至（３７）のいずれかに記載の自己乳化組成物。 (36) At least one selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol and sucrose fatty acid ester. The self-emulsifying composition according to any one of (1) to (35), which is one emulsifier.
(37) The self-emulsifying composition according to any one of (1) to (36), wherein HLB is an emulsifier having 10 or more.
(38) The polyoxyethylene hydrogenated castor oil, the polyoxyethylene sorbitan fatty acid ester, and at least two selected from the group consisting of polyoxyethylene castor oils, according to any one of (1) to (37) above Self-emulsifying composition.
(39) The self-emulsifying composition is a) 50 to 95% by weight of the total amount of ω3 PUFAs,
b) 3 to 40 parts by weight of lecithin with respect to 100 parts by weight of ω3 PUFAs,
c) From 10 to 50 parts by mass of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, and polyoxyethylene polyoxypropylene glycol per 100 parts by mass of ω3 PUFAs At least one emulsifier selected from the group consisting of:
d) The self-emulsifying composition according to any one of (1) to (37) above, wherein the ethanol content is 4% by mass or less of the total amount.
(40) The self-emulsifying composition is a) 50 to 95% by mass of ω3 PUFAs based on the total amount of the composition,
b) at least one selected from the group consisting of sucrose laurate, sucrose myristic ester, sucrose palmitate, sucrose stearate and sucrose oleate in an amount of 4 to 20% by weight of the total amount. An emulsifier wherein one HLB is 10 or more sucrose fatty acid esters,
c) ω3PUFA, a pharmaceutically acceptable salt thereof, 5 to 30 parts by mass of glycerin with respect to 100 parts by mass of at least one compound selected from the group consisting of ethyl ester and triglyceride ester, and d) the content of ethanol The self-emulsifying composition as described in any one of (1) to (37) above, which is 4% by mass or less of the total amount.
(41) The self-emulsifying composition is an international publication WO2010 / 134614, an international publication WO2015 / 008848, an international publication WO2015 / 008849, an international publication WO2016 / 117057, an international publication WO2016 / 117621, an international publication. Group consisting of self-emulsifying compositions described in published WO2016 / 117629 pamphlet, international published WO2010 / 103402 pamphlet, international published WO2010 / 103404 pamphlet, international published WO2010 / 119319 pamphlet and international published WO2011 / 047259 pamphlet. The self milk according to any one of (1) to (37) above, which is at least one self emulsifying composition selected from Composition.
　本発明の第二の態様は以下の自己免疫性皮膚疾患または炎症性皮膚疾患の予防および／または治療方法である。
（４２）自己免疫性皮膚疾患または炎症性皮膚疾患の予防および／または治療が必要な患者に、ω３ＰＵＦＡ類を有効成分として含有し、さらに乳化剤を含有することを特徴とする自己乳化組成物を２日～１ヶ月からなる群から選択される少なくとも１つの期間毎に間欠経口投与することを特徴とする、自己免疫性皮膚疾患または炎症性皮膚疾患の予防および／または治療方法。
（４３）自己乳化組成物を２日～３週間からなる群から選択される少なくとも１つの期間毎に間欠経口投与することを特徴とする、上記（４２）に記載の予防および／または治療方法。
（４４）自己乳化組成物を２日～２週間からなる群から選択される少なくとも１つの期間毎に間欠経口投与することを特徴とする、上記（４２）に記載の予防および／または治療方法。
（４５）自己乳化組成物を２日～１週間からなる群から選択される少なくとも１つの期間毎に間欠経口投与することを特徴とする、上記（４２）に記載の予防および／または治療方法。
（４６）自己乳化組成物を２日、３日、４日、５日、６日または１週間毎に間欠経口投与することを特徴とする、上記（４２）に記載の予防および／または治療方法。
（４７）自己乳化組成物を１０日毎に間欠経口投与することを特徴とする、上記（４２）に記載の予防および／または治療方法。
（４８）自己乳化組成物を２週間毎に間欠経口投与することを特徴とする、上記（４２）に記載の予防および／または治療方法。
（４９）自己乳化組成物を２０日毎に間欠経口投与することを特徴とする、上記（４２）に記載の予防および／または治療方法。
（５０）自己乳化組成物を３週間毎に間欠経口投与することを特徴とする、上記（４２）に記載の予防および／または治療方法。
（５１）自己乳化組成物を４週間または１ヶ月間毎に間欠経口投与することを特徴とする、上記（４２）に記載の予防および／または治療方法。
（５２）自己乳化組成物を１週間に（２日例えば、月曜日および木曜日、月曜日および金曜日、火曜日および金曜日、火曜日および土曜日、水曜日および土曜日、水曜日および日曜日、木曜日および日曜日）間欠経口投与することを特徴とする、上記（４２）に記載の予防および／または治療方法。
（５３）自己乳化組成物を１週間に３日（例えば、月曜日と水曜日および金曜日、月曜日と水曜日および土曜日、月曜日と木曜日および土曜日、火曜日と木曜日および土曜日、火曜日と木曜日および日曜日、火曜日と金曜日および日曜日、水曜日と金曜日および日曜日）間欠経口投与することを特徴とする、上記（４２）に記載の予防および／または治療方法。 The second aspect of the present invention is the following method for preventing and / or treating autoimmune skin disease or inflammatory skin disease.
(42) A self-emulsifying composition comprising ω3PUFAs as an active ingredient and an emulsifier for a patient in need of prevention and / or treatment of an autoimmune skin disease or inflammatory skin disease. A method for preventing and / or treating autoimmune skin disease or inflammatory skin disease, comprising intermittently orally administering at least one period selected from the group consisting of days to 1 month.
(43) The prophylaxis and / or treatment method according to the above (42), wherein the self-emulsifying composition is intermittently orally administered every at least one period selected from the group consisting of 2 days to 3 weeks.
(44) The prophylaxis and / or treatment method according to the above (42), wherein the self-emulsifying composition is intermittently orally administered every at least one period selected from the group consisting of 2 days to 2 weeks.
(45) The prophylaxis and / or treatment method according to the above (42), wherein the self-emulsifying composition is intermittently orally administered every at least one period selected from the group consisting of 2 days to 1 week.
(46) The prophylaxis and / or treatment method according to (42) above, wherein the self-emulsifying composition is intermittently orally administered every 2 days, 3 days, 4 days, 5 days, 6 days or 1 week. .
(47) The prophylaxis and / or treatment method according to (42) above, wherein the self-emulsifying composition is intermittently orally administered every 10 days.
(48) The prevention and / or treatment method according to (42) above, wherein the self-emulsifying composition is intermittently orally administered every two weeks.
(49) The prophylaxis and / or treatment method according to (42) above, wherein the self-emulsifying composition is intermittently orally administered every 20 days.
(50) The prevention and / or treatment method according to (42) above, wherein the self-emulsifying composition is intermittently orally administered every 3 weeks.
(51) The prophylaxis and / or treatment method according to (42) above, wherein the self-emulsifying composition is intermittently orally administered every 4 weeks or 1 month.
(52) intermittent oral administration of the self-emulsifying composition for one week (eg, 2 days Monday and Thursday, Monday and Friday, Tuesday and Friday, Tuesday and Saturday, Wednesday and Saturday, Wednesday and Sunday, Thursday and Sunday) The prevention and / or treatment method according to (42) above, characterized in.
(53) The self-emulsifying composition is administered 3 days a week (eg Monday and Wednesday and Friday, Monday and Wednesday and Saturday, Monday and Thursday and Saturday, Tuesday and Thursday and Saturday, Tuesday and Thursday and Sunday, Tuesday and Friday and The prevention and / or treatment method according to (42) above, characterized by intermittent oral administration on Sunday, Wednesday and Friday and Sunday.
（５４）ω３ＰＵＦＡ類がＥＰＡ、ＤＨＡ、ＤＰＡ、ＡＬＡ、それらの製薬学上許容しうる塩類、それらの製薬学上許容しうるエステル類、それらの製薬学上許容しうるアミド類、それらの製薬学上許容しうるリン脂質類からなる群から選択される少なくとも１つである自己乳化組成物を経口投与する、上記（４２）乃至（５３）のいずれかに記載の予防および／または治療方法。
（５５）ω３ＰＵＦＡ類がＥＰＡまたはＥＰＡ－Ｅである、上記（４２）乃至（５４）のいずれかに記載の予防および／または治療方法。
（５６）全脂肪酸およびその誘導体中のＥＰＡおよびＥＰＡ－Ｅ含量比が４０質量％以上である、上記（４２）乃至（５５）のいずれかに記載の予防および／または治療方法。
（５７）全脂肪酸およびその誘導体中のＥＰＡおよびＥＰＡ－Ｅ含量比が８０質量％以上である、上記（４２）乃至（５６）のいずれかに記載の予防および／または治療方法。
（５８）全脂肪酸およびその誘導体中のＥＰＡおよびＥＰＡ－Ｅ含量比が９６．５質量％以上である、上記（４２）乃至（５７）のいずれかに記載の予防および／または治療方法。
（５９）自己乳化組成物の全量を１００質量％としたときのＥＰＡおよびＥＰＡ－Ｅの含量が５０質量％以上である、上記（４２）乃至（５８）のいずれかに記載の予防および／または治療方法。
（６０）自己乳化組成物の全量を１００質量％としたときのＥＰＡおよびＥＰＡ－Ｅの含量が６０質量％以上である、上記（４２）乃至（５８）のいずれかに記載の予防および／または治療方法。
（６１）自己乳化組成物の全量を１００質量％としたときのＥＰＡおよびＥＰＡ－Ｅの含量が７０質量％以上である、上記（４２）乃至（６０）のいずれかに記載の予防および／または治療方法。 (54) ω3 PUFAs are EPA, DHA, DPA, ALA, their pharmaceutically acceptable salts, their pharmaceutically acceptable esters, their pharmaceutically acceptable amides, their pharmaceutical The prevention and / or treatment method according to any one of (42) to (53), wherein a self-emulsifying composition that is at least one selected from the group consisting of phospholipids that are acceptable above is orally administered.
(55) The prevention and / or treatment method according to any one of (42) to (54), wherein the ω3 PUFA is EPA or EPA-E.
(56) The prevention and / or treatment method according to any one of (42) to (55) above, wherein the content ratio of EPA and EPA-E in all fatty acids and derivatives thereof is 40% by mass or more.
(57) The prevention and / or treatment method according to any one of (42) to (56), wherein the content ratio of EPA and EPA-E in all fatty acids and derivatives thereof is 80% by mass or more.
(58) The prevention and / or treatment method according to any one of (42) to (57), wherein the content ratio of EPA and EPA-E in all fatty acids and derivatives thereof is 96.5% by mass or more.
(59) The prevention and / or prevention according to any one of (42) to (58) above, wherein the content of EPA and EPA-E is 50% by mass or more when the total amount of the self-emulsifying composition is 100% by mass. Method of treatment.
(60) The prevention and / or prevention according to any one of (42) to (58) above, wherein the content of EPA and EPA-E is 60% by mass or more when the total amount of the self-emulsifying composition is 100% by mass. Method of treatment.
(61) The prevention and / or prevention according to any one of (42) to (60) above, wherein the content of EPA and EPA-E is 70% by mass or more when the total amount of the self-emulsifying composition is 100% by mass. Method of treatment.
（６２）ω３ＰＵＦＡ類０．５ｇ／日～１０ｇ／日で経口投与することを特徴とする、上記（４２）乃至（６１）のいずれかに記載の予防および／または治療方法。
（６３）ω３ＰＵＦＡ類１ｇ／日～８ｇ／日で経口投与することを特徴とする、上記（４２）乃至（６２）のいずれかに記載の予防および／または治療方法。
（６４）ω３ＰＵＦＡ類２ｇ／日～６ｇ／日で経口投与することを特徴とする、上記（４２）乃至（６３）のいずれかに記載の予防および／または治療方法。
（６５）ω３ＰＵＦＡ類４ｇ／日～６ｇ／日で経口投与することを特徴とする、上記（４２）乃至（６４）のいずれかに記載の予防および／または治療方法。 (62) The prophylaxis and / or treatment method according to any one of (42) to (61) above, wherein the ω3PUFAs are orally administered at 0.5 g / day to 10 g / day.
(63) The method for prophylaxis and / or treatment according to any of (42) to (62) above, wherein the ω3 PUFAs are orally administered at 1 g / day to 8 g / day.
(64) The prophylaxis and / or treatment method according to any one of (42) to (63) above, wherein ω3PUFAs are orally administered at 2 g / day to 6 g / day.
(65) The prophylaxis and / or treatment method according to any one of (42) to (64) above, wherein the ω3PUFAs are orally administered at 4 g / day to 6 g / day.
（６６）自己免疫性皮膚疾患または炎症性皮膚疾患が乾癬及び類症（尋常性乾癬（重症例含む）、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、稽留性肢端皮膚炎、疱疹状膿痂疹、ライター症候群、滴状乾癬、等）、魚鱗癬群（尋常性魚鱗癬、水疱型先天性魚鱗癬様紅皮症、非水疱型先天性魚鱗癬様紅皮症）、掌蹠角化症、ダリエー病、掌蹠膿疱症、毛孔性紅色粃糠疹、紅斑性角化症、皮膚炎群（接触皮膚炎、貨幣状皮膚炎、自家感作性皮膚炎、アトピー性皮膚炎、ビダール苔癬、その他の神経皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、その他の手指の皮膚炎、耳介及び外耳道の皮膚炎、鼻前庭及び鼻翼周辺の皮膚炎、全身性剥脱性皮膚炎、うっ血性皮膚炎、限局性掻爬皮膚炎、口周囲皮膚炎、汗疱、花粉性皮膚炎、等）、多発性硬化症、強皮症、エリテマトーデス（全身性及び慢性円板状）、ベーチェット病、および天疱瘡からなる群から選択される少なくとも１つである、上記（４２）乃至（６５）のいずれかに記載の予防および／または治療方法。
（６７）自己免疫性皮膚疾患または炎症性皮膚疾患が乾癬及び類症（尋常性乾癬（重症例含む）、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、稽留性肢端皮膚炎、疱疹状膿痂疹、ライター症候群、滴状乾癬）、皮膚炎群（接触皮膚炎、貨幣状皮膚炎、自家感作性皮膚炎、アトピー性皮膚炎、ビダール苔癬、その他の神経皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、その他の手指の皮膚炎、耳介及び外耳道の皮膚炎、鼻前庭及び鼻翼周辺の皮膚炎、全身性剥脱性皮膚炎、うっ血性皮膚炎、限局性掻爬皮膚炎、口周囲皮膚炎、汗疱、花粉性皮膚炎、等）およびベーチェット病からなる群から選択される少なくとも１つであり、好ましくは、乾癬及び類症、皮膚炎群およびベーチェット病からなる群から選択される少なくとも１つであり、より好ましくは尋常性乾癬、関節症性乾癬、膿疱性乾癬、アトピー性皮膚炎およびベーチェット病からなる群から選択される少なくとも１つである、上記（４２）乃至（６６）のいずれかに記載の予防および／または治療方法。
（６８）血清または血漿中のＥＰＡ／ＡＡ比が０．４未満である自己免疫性皮膚疾患または炎症性皮膚疾患患者に投与するための、上記（４２）乃至（６７）のいずれかに記載の予防および／または治療方法。
（６９）血清または血漿中のＥＰＡ／ＡＡ比が０．１未満である自己免疫性皮膚疾患または炎症性皮膚疾患患者に投与するための、上記（４２）乃至（６８）のいずれかに記載の予防および／または治療方法。 (66) Autoimmune skin disease or inflammatory skin disease is psoriasis and analogies (psoriasis vulgaris (including severe cases), arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, limbic limb dermatitis, Herpes zoster, Reiter's syndrome, trichomes psoriasis, etc.), ichthyosis group (common ichthyosis, blistering congenital ichthyosis-like erythroderma, non-bullous congenital ichthyosis-like erythroderma), palm Keratosis, Darier's disease, palmoplantar pustulosis, erythematous erythematosus, erythematous keratosis, dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic dermatitis, progressive palmokeratosis, other finger dermatitis, pinna and ear canal dermatitis, nasal vestibular and perinasal dermatitis, systemic Exfoliative dermatitis, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat blister, pollen dermatitis, etc.), multiple sclerosis, strong Prophylaxis and / or lupus erythematosus (systemic and chronic discoid), Behcet's disease, and pemphigus, at least one selected from the above (42) to (65) Method of treatment.
(67) Autoimmune skin disease or inflammatory skin disease is psoriasis and analogies (including psoriasis vulgaris (including severe cases), arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, limbic limb dermatitis, Herpes zoster, Reiter syndrome, prickly psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, autosensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, oil Leaky dermatitis, progressive palmokeratosis, other finger dermatitis, dermatitis of the auricle and ear canal, dermatitis around the nasal vestibule and nasal wing, generalized exfoliative dermatitis, congestive dermatitis, limited And at least one selected from the group consisting of Behcet's disease, preferably psoriasis and symptoms, dermatitis group and Behcet's disease At least one selected from the group consisting of and more preferred Or prevention according to any one of (42) to (66) above, which is at least one selected from the group consisting of psoriasis vulgaris, arthritic psoriasis, pustular psoriasis, atopic dermatitis and Behcet's disease And / or treatment methods.
(68) The method according to any one of (42) to (67), wherein the EPA / AA ratio in serum or plasma is administered to a patient having an autoimmune skin disease or inflammatory skin disease that is less than 0.4. Prophylactic and / or therapeutic methods.
(69) The device according to any one of (42) to (68) above, which is administered to a patient with an autoimmune skin disease or inflammatory skin disease whose EPA / AA ratio in serum or plasma is less than 0.1 Prophylactic and / or therapeutic methods.
（７０）自己免疫性皮膚疾患または炎症性皮膚疾患の憎悪期にシクロスポリン、エトレチナート、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンテネルマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラからなる群から選択される少なくとも１つの化合物と併用投与する、上記（４２）乃至（６９）のいずれかに記載の予防および／または治療方法。
（７１）乾癬及び類症（尋常性乾癬（重症例含む）、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、稽留性肢端皮膚炎、疱疹状膿痂疹、ライター症候群、滴状乾癬）、皮膚炎群（接触皮膚炎、貨幣状皮膚炎、自家感作性皮膚炎、アトピー性皮膚炎、ビダール苔癬、その他の神経皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、その他の手指の皮膚炎、耳介及び外耳道の皮膚炎、鼻前庭及び鼻翼周辺の皮膚炎、全身性剥脱性皮膚炎、うっ血性皮膚炎、限局性掻爬皮膚炎、口周囲皮膚炎、汗疱、花粉性皮膚炎、等）およびベーチェット病からなる群から選択される少なくとも１つの自己免疫性皮膚疾患または炎症性皮膚疾患の憎悪期にシクロスポリン、エトレチナート、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンテネルマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラからなる群から選択される少なくとも１つの化合物と併用投与する、上記（４２）乃至（７０）のいずれかに記載の予防および／または治療方法。
（７２）さらにシクロスポリン、エトレチナート、アプレミラスト、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロンおよびベタメゾンからなる群から選択される少なくとも１つを有効成分として含有する自己乳化組成物を投与する、上記（４２）乃至（７１）のいずれかに記載の予防および／または治療方法。
（７３）自己免疫性皮膚疾患または炎症性皮膚疾患の寛解期または非活動期にシクロスポリン、エトレチナート、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンテネルマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラと併用せず単独で投与する、上記（４２）乃至（７１）のいずれかに記載の予防および／または治療方法。
（７４）乾癬及び類症（尋常性乾癬（重症例含む）、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、稽留性肢端皮膚炎、疱疹状膿痂疹、ライター症候群、滴状乾癬）、皮膚炎群（接触皮膚炎、貨幣状皮膚炎、自家感作性皮膚炎、アトピー性皮膚炎、ビダール苔癬、その他の神経皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、その他の手指の皮膚炎、耳介及び外耳道の皮膚炎、鼻前庭及び鼻翼周辺の皮膚炎、全身性剥脱性皮膚炎、うっ血性皮膚炎、限局性掻爬皮膚炎、口周囲皮膚炎、汗疱、花粉性皮膚炎、等）およびベーチェット病からなる群から選択される少なくとも１つの自己免疫性皮膚疾患または炎症性皮膚疾患の寛解期または非活動期にシクロスポリン、エトレチナート、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンテネルマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラと併用せず単独で投与する、上記（４２）乃至（７１）のいずれかに記載の予防および／または治療方法。 (70) Cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone, betamethasone, maxacalcitol, calcipotriol, tacalcitol hydrate during the exacerbation of autoimmune skin disease or inflammatory skin disease , Hydrocortisone acetate, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildrakizumab, brodalumab, guselcoumab, dupirumumab, nemorizumab, rituximab, rituximab, rituximab, rituximab, rituximab , Upadacitinib, emicizumab, facinuma , Pegprelanib, omalizumab, reslizumab, subtabumab, gantenerumab, etanercept, tofacitinib, salicylic acid / white petrolatum, splatastosyl, azelastine hydrochloride, fexofenadine hydrochloride, sodium cromoglycate, oxatomidopromus tacrolimus Japanese, tranilast, beclomethasone propionic acid, human immunoglobulin / histamine dihydrochloride, methylprednisolone, apremilast, pimecrolimus, AMG-0101, AMG-0103, sturbene hydroxide molecule, chrysabolol, narfrafin, doxorubicin, WBI-1001, octenidine, Oxymetazoline, nitric oxide, timapiplant, rosipitol acetate, cobamide, Bipiplant, Omiganan, Asimadoline, Metoflumine, DSXS-1411, Serinexer, Terbinafine, Ellenbecestat, Belvecestat, Ranabecestat, Fluticasone, Beperminogen per plasmid, Darcetrapib, Abatacept, Talidamide, Bosentan, Deflazacote The method for prevention and / or treatment according to any one of (42) to (69), wherein the method is administered in combination with at least one selected compound.
(71) Psoriasis and analogies (including psoriasis vulgaris (including severe cases), arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, limbic limb dermatitis, herpes zoster, Reiter's syndrome, drops Psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic dermatitis, progressive palmar keratin , Other finger dermatitis, auricular and ear canal dermatitis, nasal vestibular and nasal wing dermatitis, generalized exfoliative dermatitis, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat Cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, cortisone acetic acid ester during the exacerbation of at least one autoimmune skin disease or inflammatory skin disease selected from the group consisting of blisters, pollen dermatitis, etc.) and Behcet's disease , Dexamethasone, prednisolone, betamaison, maxacalcitol, calcipotriol, tacalcitol hydrate, hydrocortisone acetate, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildramazumab, tildramazumab , Nemorizumab, traloquinumab, rituximab, salistatib Tin hydrochloride, fexofenadine hydrochloride, sodium cromoglycate, oxatomide, clobetasone butyrate, bendazac, suprofen, tacrolimus hydrate, tranilast, beclomethasone propionic acid, human immunoglobulin / histamine dihydrochloride, methylprednisolone, apremilast, Pimecrolimus, AMG-0101, AMG-0103, hydroxylated sterubene molecule, chrysabolol, nalfrafin, doxorubicin, WBI-1001, octenidine, oxymetazoline, nitric oxide, timapiplant, rosipitol acetate, cobamide, febipiplant, omiganan, acimadrine, metflumin, DSXS-1411, Selnexer, Terbinafine, Ellen Bethestat, Belvecestat, Rana Bethestat, Fu The prevention according to any one of (42) to (70), wherein the prophylaxis is administered in combination with at least one compound selected from the group consisting of luticazone, beperminogen par plasmid, dalcetrapib, abatacept, thalidomide, bosentan, deflazacoat and anakinra And / or treatment methods.
(72) The self-emulsifying composition further comprising, as an active ingredient, at least one selected from the group consisting of cyclosporine, etretinate, apremilast, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone and betamazone, (42) The prevention and / or treatment method according to any one of (71).
(73) Cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone, betamethone, maxacalcitol, calcipotriol, during remission or inactivity of autoimmune skin disease or inflammatory skin disease Tacalcitol hydrate, hydrocortisone acetate, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildrakizumab, brodalumab, gusselumab, dupirumumab, nemorizumab, tralotimumab, traloticumab Cantratinib, traloquinumab, upadacitinib, emicizuma , Facinumab, pegprelanib, omalizumab, reslizumab, subtabumab, gantenerumab, etanercept, tofacitinib, salicylic acid / white petrolatum, splatastosyl, azelastine hydrochloride, fexofenadine hydrochloride, sodium cromoglycate, oxatomide, oxatomide Tacrolimus hydrate, tranilast, beclomethasone propionic acid, human immunoglobulin / histamine dihydrochloride, methylprednisolone, apremilast, pimecrolimus, AMG-0101, AMG-0103, sturbene hydroxide molecule, chrysabolol, nalflavine, doxorubicin, WBI-1001, Octenidine, oxymetazoline, nitric oxide, timapiplant, rosipitol acetate, Bamamide, febipiplant, omiganan, asimadoline, metflumin, DSXS-1411, selenexer, terbinafine, ellenbecestat, velvecestat, ranavecestat, fluticasone, beperminogen per plasmid, darcetrapib, abatacept, talidfuran and bosentan The method for prevention and / or treatment according to any one of (42) to (71), wherein the method is administered alone without any administration.
(74) Psoriasis and analogies (including psoriasis vulgaris (including severe cases), psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, limbic limb dermatitis, pustular impetigo, Reiter's syndrome, drops Psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic dermatitis, progressive palmar keratin , Other finger dermatitis, auricular and ear canal dermatitis, nasal vestibular and nasal wing dermatitis, generalized exfoliative dermatitis, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat Cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, during remission or inactivity of at least one autoimmune skin disease or inflammatory skin disease selected from the group consisting of blisters, pollen dermatitis, etc.) and Behcet's disease Corti Acetate, dexamethasone, prednisolone, betamethasone, maxacalcitol, calcipotriol, tacalcitol trihydrate, hydrocortisone acetate, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildrazumab, tildrazumab Guselumab, Dupilumab, Nemorizumab, Traloquinumab, Rituximab, Balicitinib, Salilumab, Masitinib, Ocrelizumab, Pekkantratinib, Traloquinumab, Upadacitinib, Emicizumab, Facinumab, Pegpremab Sil, azelastine hydrochloride, fexofenadine hydrochloride, sodium cromoglycate, oxatomide, clobetasone butyrate, bendazac, suprofen, tacrolimus hydrate, tranilast, beclomethasone propionate, human immunoglobulin / histamine dihydrochloride, methylprednisolone, Apremilast, pimecrolimus, AMG-0101, AMG-0103, hydroxylated sterubene molecule, chrysabolol, nalflaffin, doxorubicin, WBI-1001, octenidine, oxymetazoline, nitric oxide, timapiplant, rosipitol acetate, cobamide, febipiplant, omiganane, ashimad Metoflumin, DSXS-1411, Selnexer, Terbinafine, Ellenbecestat, Berbecestat, Ranabe The prophylactic and / or therapeutic method according to any one of (42) to (71), wherein the drug is administered alone without being combined with cestat, fluticasone, beperminogen par plasmid, dalcetrapib, abatacept, thalidomide, bosentan, defrazacoat and anakinra .
（７５）自己免疫性皮膚疾患または炎症性皮膚疾患の増悪期には２～７日からなる群から選択される少なくとも１つの期間毎に間欠経口投与し、症状の改善がみられた場合は１週間～１ヶ月からなる群から選択される少なくとも１つの期間毎に投与間隔を１日または２日ずつ増加して、寛解期または非活動期には１週間～１ヶ月からなる群から選択される少なくとも１つの期間毎に間欠経口投与する、上記（４２）乃至（７４）のいずれかに記載の予防および／または治療方法。
（７６）自己免疫性皮膚疾患または炎症性皮膚疾患の増悪期には２～１０ｇ／日経口投与し、症状の改善がみられた場合は１週間～１ヶ月からなる群から選択される少なくとも１つの期間毎に投与量を０．５～１g／日ずつ減量して、寛解期または非活動期には０．５～４ ｇ／日経口投与する、上記（４２）乃至（７４）のいずれかに記載の予防および／または治療方法。 (75) In the period of exacerbation of autoimmune skin disease or inflammatory skin disease, intermittent oral administration is performed at least every period selected from the group consisting of 2 to 7 days. The administration interval is increased by 1 day or 2 days for at least one period selected from the group consisting of weeks to 1 month, and selected from the group consisting of 1 week to 1 month in the remission period or inactive period The prevention and / or treatment method according to any one of (42) to (74), wherein intermittent oral administration is performed at least every one period.
(76) At least 1 selected from the group consisting of 2 to 10 g / day orally in the exacerbation phase of autoimmune skin disease or inflammatory skin disease, and 1 week to 1 month when improvement in symptoms is observed Any of the above (42) to (74), wherein the dose is reduced by 0.5 to 1 g / day every one period and orally administered at 0.5 to 4 g / day in the remission period or inactive period The prevention and / or treatment method according to 1.
（７７）乳化剤がポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンヒマシ油、ポリエチレングリコール脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコールおよびショ糖脂肪酸エステルからなる群から選ばれる少なくとも１つの乳化剤であることを特徴とする、上記（４２）乃至（７６）のいずれかに記載の予防および／または治療方法。
（７８）乳化剤がＨＬＢが１０以上の乳化剤であることを特徴とする、上記（４２）乃至（７７）のいずれかに記載の予防および／または治療方法。
（７９）ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステルおよびポリオキシエチレンヒマシ油からなる群から選択される少なくとも２つを含有することを特徴とする、上記（４２）乃至（７８）のいずれかに記載の予防および／または治療方法。
（８０）自己乳化組成物が、ａ）合計量の５０～９５質量％のω３ＰＵＦＡ類、
ｂ）　ω３ＰＵＦＡ類１００質量部に対して３～４０質量部のレシチン、
ｃ）　ω３ＰＵＦＡ類１００質量部に対して１０～５０質量部のポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンヒマシ油、ポリエチレングリコール脂肪酸エステル、およびポリオキシエチレンポリオキシプロピレングリコールからなる群から選ばれる少なくとも１つの乳化剤、および、
ｄ）　エタノールの含量が合計量の４質量％以下であることを特徴とする、上記（４２）乃至（７８）のいずれかに記載の予防および／または治療方法。
（８１）自己乳化組成物が、ａ）組成物の合計量の５０～９５質量％のω３ＰＵＦＡ類、
ｂ）前記合計量の４～２０質量％の、ショ糖ラウリン酸エステル、ショ糖ミリスチン酸エステル、ショ糖パルミチン酸エステル、ショ糖ステアリン酸エステルおよびショ糖オレイン酸エステルからなる群から選ばれる少なくとも１つのＨＬＢが１０以上のショ糖脂肪酸エステルである乳化剤、
ｃ）ω３ＰＵＦＡ、その製薬学上許容しうる塩、エチルエステルおよびトリグリセリドエステルからなる群から選ばれる少なくとも１つの化合物１００質量部に対して５～３０質量部のグリセリン、および
ｄ）エタノールの含量が前記合計量の４質量％以下であることを特徴とする、上記（４２）乃至（７８）のいずれかに記載の予防および／または治療方法。
（８２）自己乳化組成物が、国際公開ＷＯ２０１０／１３４６１４号パンフレット、国際公開ＷＯ２０１５／００８８４８号パンフレット、国際公開ＷＯ２０１５／００８８４９号パンフレット、国際公開ＷＯ２０１６／１１７０５７号パンフレット、国際公開ＷＯ２０１６／１１７６２１号パンフレット、国際公開ＷＯ２０１６／１１７６２９号パンフレット、国際公開ＷＯ２０１０／１０３４０２号パンフレット、国際公開ＷＯ２０１０／１０３４０４号パンフレット、国際公開ＷＯ２０１０／１１９３１９号パンフレットおよび国際公開ＷＯ２０１１／０４７２５９号パンフレットに記載されている予防および／または治療方法からなる群より選択される少なくとも１つの自己乳化組成物であることを特徴とする、上記（４２）乃至（７８）のいずれかに記載の予防および／または治療方法。 (77) At least one emulsifier selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol and sucrose fatty acid ester The prophylaxis and / or treatment method according to any one of (42) to (76) above, wherein the emulsifier is one emulsifier.
(78) The prevention and / or treatment method according to any one of (42) to (77), wherein the emulsifier is an emulsifier having an HLB of 10 or more.
(79) The above (42) to (78), comprising at least two selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil The prevention and / or treatment method according to any one of the above.
(80) The self-emulsifying composition is a) 50 to 95% by mass of ω3 PUFAs in a total amount,
b) 3 to 40 parts by weight of lecithin with respect to 100 parts by weight of ω3 PUFAs,
c) From 10 to 50 parts by mass of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, and polyoxyethylene polyoxypropylene glycol per 100 parts by mass of ω3 PUFAs At least one emulsifier selected from the group consisting of:
d) The prophylaxis and / or treatment method according to any one of (42) to (78) above, wherein the ethanol content is 4% by mass or less of the total amount.
(81) The self-emulsifying composition is a) 50 to 95% by mass of ω3 PUFAs based on the total amount of the composition,
b) at least one selected from the group consisting of sucrose laurate, sucrose myristic ester, sucrose palmitate, sucrose stearate and sucrose oleate in an amount of 4 to 20% by weight of the total amount. An emulsifier wherein one HLB is 10 or more sucrose fatty acid esters,
c) ω3PUFA, a pharmaceutically acceptable salt thereof, 5 to 30 parts by mass of glycerin with respect to 100 parts by mass of at least one compound selected from the group consisting of ethyl ester and triglyceride ester, and d) the content of ethanol The prevention and / or treatment method according to any one of (42) to (78) above, wherein the total amount is 4% by mass or less.
(82) The self-emulsifying composition is an international publication WO2010 / 134614 pamphlet, an international publication WO2015 / 008848 pamphlet, an international publication WO2015 / 008849 pamphlet, an international publication WO2016 / 117570 pamphlet, an international publication WO2016 / 117621 pamphlet, an international publication. From the prevention and / or treatment methods described in the published WO2016 / 117629 pamphlet, the internationally published WO2010 / 103402 pamphlet, the internationally published WO2010 / 103404 pamphlet, the internationally published WO2010 / 119319 pamphlet and the internationally published WO2011 / 047259 pamphlet. (42) to (42), wherein the composition is at least one self-emulsifying composition selected from the group consisting of Prevention and / or treatment method according to any one of 8).
　本発明の第三の態様は以下の自己免疫性皮膚疾患または炎症性皮膚疾患の予防および／または治療方法である。
（８３）自己免疫性皮膚疾患または炎症性皮膚疾患の予防および／または治療が必要な患者に、憎悪期にはシクロスポリン、エトレチナート、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンテネルマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラからなる群から選択される少なくとも１つの化合物と併用して、ω３ＰＵＦＡ類を有効成分として含有し、さらに乳化剤を含有することを特徴とする自己乳化組成物を２日～１ヶ月からなる群から選択される少なくとも１つの期間毎に間欠経口投与することを特徴とする、自己免疫性皮膚疾患または炎症性皮膚疾患の予防および／または治療方法。
（８４）自己免疫性皮膚疾患または炎症性皮膚疾患の予防および／または治療が必要な患者に、寛解期または非活動期にはシクロスポリン、エトレチナート、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンテネルマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラと併用しないでω３ＰＵＦＡ類を有効成分として含有し、さらに乳化剤を含有することを特徴とする自己乳化組成物を２日～１ヶ月からなる群から選択される少なくとも１つの期間毎に単独で間欠経口投与することを特徴とする、自己免疫性皮膚疾患または炎症性皮膚疾患の予防および／または治療方法。 The third aspect of the present invention is the following method for preventing and / or treating autoimmune skin disease or inflammatory skin disease.
(83) For patients in need of prevention and / or treatment of autoimmune skin disease or inflammatory skin disease, cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone, betamethasone, maxi in the exacerbation period Sacalcitol, calcipotriol, tacalcitol hydrate, hydrocortisone acetate, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildrakizumab, brodalumab, gusultumab, dupilizumab, neupirumab , Salilumab, masitinib, ocrelizumab, pekkantratinib, traloquinumab, Padacitinib, emicizumab, facinumab, pegprelanib, omalizumab, reslizumab, subtabumab, gantenerumab, etanercept, tofacitinib, salicylic acid / white petrolatum, suplatastosyl, azelastine hydrochloride, foxafenamid sodium clotodaginate hydrochloride , Suprofen, tacrolimus hydrate, tranilast, beclomethasone propionic acid, human immunoglobulin / histamine dihydrochloride, methylprednisolone, apremilast, pimecrolimus, AMG-0101, AMG-0103, hydroxylated steruben molecule, chrysabolol, nalflavine, doxorubicin, WBI -1001, octenidine, oxymetazoline, nitric oxide, timapi Rosiptol acetate, cobamide, cobamide, febipiplant, omiganane, asimadoline, metflumin, DSXS-1411, cerinexer, terbinafine, ellenbecestat, velvecestat, ranabecestat, fluticasone, beperminogen per plasmid, darcetrapibsentan, abatamide A self-emulsifying composition comprising ω3PUFAs as an active ingredient and further containing an emulsifier in combination with at least one compound selected from the group consisting of deflazacote and anakinra comprises 2 days to 1 month A method for preventing and / or treating autoimmune skin disease or inflammatory skin disease, comprising intermittently orally administering at least one period selected from a group.
(84) In patients in need of prevention and / or treatment of autoimmune skin disease or inflammatory skin disease, cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone in remission or inactivity , Betamethasone, maxacalcitol, calcipotriol, tacalcitol hydrate, hydrocortisone acetate, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildrakizumab, brodalumab, durumumab , Rituximab, Balicitinib, Salilumab, Masitinib, Ocrelizumab, Pekkantratinib, To Loquinumab, Upadacitinib, Emicizumab, Facinumab, Pegprelanib, Omalizumab, Reslizumab, Subtabumab, Gatenerumab, Etanercept, Tofacitinib, Salicylic acid / White petrolatum, Splatastostolic acid, Feloxacin hydrochloride salt Vendazac, suprofen, tacrolimus hydrate, tranilast, beclomethasone propionic acid, human immunoglobulin / histamine dihydrochloride, methylprednisolone, apremilast, pimecrolimus, AMG-0101, AMG-0103, hydroxylated sterubene molecule, chrysabolol, nalflaffin, doxorubicin , WBI-1001, octenidine, oxymetazoline, monoxide Elemental, timapiplant, rosipitol acetate, cobamide, febipiprant, omiganan, asimadoline, metflumin, DSXS-1411, celinexer, terbinafine, ellenbecestat, velvecestat, ranabescestat, fluticasone, beperminogenper plasmid, darcetrapideta At least one period selected from the group consisting of 2 days to 1 month containing a ω3PUFA as an active ingredient without being combined with bosentan, deflazacote and anakinra and further containing an emulsifier A method for preventing and / or treating autoimmune skin disease or inflammatory skin disease, which comprises intermittent oral administration alone.
　本発明の第四の態様は以下の自己免疫性皮膚疾患または炎症性皮膚疾患の予防および／または治療方法である。
（８５）自己免疫性皮膚疾患または炎症性皮膚疾患の予防および／または治療が必要な患者に、ω３ＰＵＦＡ類を有効成分として含有し、さらに乳化剤を含有することを特徴とする自己乳化組成物を、増悪期には２～７日からなる群から選択される少なくとも１つの期間毎に間欠経口投与し、症状の改善がみられた場合は１週間～１ヶ月からなる群から選択される少なくとも１つの期間毎に投与間隔を１日または２日ずつ増加して、寛解期または非活動期には１週間～１ヶ月からなる群から選択される少なくとも１つの期間毎に投与することを特徴とする、自己免疫性皮膚疾患または炎症性皮膚疾患の予防および／または治療方法。
（８６）自己免疫性皮膚疾患または炎症性皮膚疾患の増悪期には２～１０ｇ／日経口投与し、症状の改善がみられた場合は１週間～１ヶ月からなる群から選択される少なくとも１つの期間毎に投与量を０．５～１g／日ずつ減量して、寛解期または非活動期には０．５～４ ｇ／日経口投与される、上記（８５）に記載の予防および／または治療方法。 The fourth aspect of the present invention is the following method for preventing and / or treating autoimmune skin disease or inflammatory skin disease.
(85) A self-emulsifying composition containing ω3PUFAs as an active ingredient and an emulsifier for a patient in need of prevention and / or treatment of autoimmune skin disease or inflammatory skin disease, In the exacerbation period, intermittent oral administration is performed every at least one period selected from the group consisting of 2 to 7 days, and when improvement of symptoms is observed, at least one selected from the group consisting of 1 week to 1 month The administration interval is increased by 1 day or 2 days for each period, and is administered at least one period selected from the group consisting of 1 week to 1 month in the remission period or inactivity period, A method for preventing and / or treating autoimmune skin disease or inflammatory skin disease.
(86) Orally administered at 2 to 10 g / day during an exacerbation period of autoimmune skin disease or inflammatory skin disease, and when symptoms are improved, at least one selected from the group consisting of 1 week to 1 month The prophylactic and / or prophylaxis as described in (85) above, wherein the dose is reduced by 0.5 to 1 g / day every three periods and orally administered at 0.5 to 4 g / day in remission or inactivity. Or treatment method.
　本発明の第五の態様は以下の自己免疫性皮膚疾患または炎症性皮膚疾患の予防および／または治療に使用するための、ω３ＰＵＦＡ類を有効成分として含有し、さらに乳化剤を含有することを特徴とする自己乳化組成物である。
（８７）自己免疫性皮膚疾患または炎症性皮膚疾患の予防および／または治療に使用するための、２日～１ヶ月からなる群から選択される少なくとも１つの期間毎に間欠経口投与されるω３ＰＵＦＡ類を有効成分として含有し、さらに乳化剤を含有することを特徴とする自己乳化組成物。
（８８）２日～３週間からなる群から選択される少なくとも１つの期間毎に間欠経口投与される、上記（８７）に記載の自己乳化組成物。
（８９）２日～２週間からなる群から選択される少なくとも１つの期間毎に間欠経口投与される、上記（８７）に記載の自己乳化組成物。
（９０）２日～１週間からなる群から選択される少なくとも１つの期間毎に間欠経口投与される、上記（８７）に記載の自己乳化組成物。
（９１）２日、３日、４日、５日、６日または１週間毎に間欠経口投与される、上記（８７）に記載の自己乳化組成物。
（９２）１０日毎に間欠経口投与される、上記（８７）に記載の自己乳化組成物。
（９３）２週間毎に間欠経口投与される、上記（８７）に記載の自己乳化組成物。
（９４）２０日毎に間欠経口投与される、上記（８７）に記載の自己乳化組成物。
（９５）３週間毎に間欠経口投与される、上記（８７）に記載の自己乳化組成物。
（９６）４週間または１ヶ月間毎に間欠経口投与される、上記（８７）に記載の自己乳化組成物。
（９７）１週間に（２日例えば、月曜日および木曜日、月曜日および金曜日、火曜日および金曜日、火曜日および土曜日、水曜日および土曜日、水曜日および日曜日、木曜日および日曜日）間欠経口投与される、上記（８７）に記載の自己乳化組成物。
（９８）１週間に３日（例えば、月曜日と水曜日および金曜日、月曜日と水曜日および土曜日、月曜日と木曜日および土曜日、火曜日と木曜日および土曜日、火曜日と木曜日および日曜日、火曜日と金曜日および日曜日、水曜日と金曜日および日曜日）間欠経口投与される、上記（８７）乃至（９８）に記載の自己乳化組成物。 A fifth aspect of the present invention is characterized in that it contains ω3PUFA as an active ingredient and further contains an emulsifier for use in the prevention and / or treatment of the following autoimmune skin diseases or inflammatory skin diseases. It is a self-emulsifying composition.
(87) ω3 PUFAs intermittently orally administered every at least one period selected from the group consisting of 2 days to 1 month for use in the prevention and / or treatment of autoimmune skin disease or inflammatory skin disease Is a self-emulsifying composition characterized by further containing an emulsifier.
(88) The self-emulsifying composition according to the above (87), which is intermittently orally administered every at least one period selected from the group consisting of 2 days to 3 weeks.
(89) The self-emulsifying composition according to the above (87), which is intermittently orally administered every at least one period selected from the group consisting of 2 days to 2 weeks.
(90) The self-emulsifying composition according to the above (87), which is intermittently orally administered every at least one period selected from the group consisting of 2 days to 1 week.
(91) The self-emulsifying composition according to the above (87), which is intermittently orally administered every 2 days, 3 days, 4 days, 5 days, 6 days or 1 week.
(92) The self-emulsifying composition according to (87), which is intermittently orally administered every 10 days.
(93) The self-emulsifying composition according to (87), which is intermittently orally administered every two weeks.
(94) The self-emulsifying composition according to (87), which is intermittently orally administered every 20 days.
(95) The self-emulsifying composition according to (87), which is intermittently orally administered every 3 weeks.
(96) The self-emulsifying composition according to the above (87), which is intermittently orally administered every 4 weeks or every month.
(97) As described above (87), administered intermittently orally once a week (eg, 2 days Monday and Thursday, Monday and Friday, Tuesday and Friday, Tuesday and Saturday, Wednesday and Saturday, Wednesday and Sunday, Thursday and Sunday) The self-emulsifying composition as described.
(98) 3 days a week (eg, Monday and Wednesday and Friday, Monday and Wednesday and Saturday, Monday and Thursday and Saturday, Tuesday and Thursday and Saturday, Tuesday and Thursday and Sunday, Tuesday and Friday and Sunday, Wednesday and Friday) And Sunday) The self-emulsifying composition according to any one of (87) to (98), which is intermittently orally administered.
（１００）ω３ＰＵＦＡ類がＥＰＡ、ＤＨＡ、ＤＰＡ、ＡＬＡ、それらの製薬学上許容しうる塩類、それらの製薬学上許容しうるエステル類、それらの製薬学上許容しうるアミド類、それらの製薬学上許容しうるリン脂質類からなる群から選択される少なくとも１つである、上記（８７）乃至（９８）のいずれかに記載の自己乳化組成物。
（１０１）ω３ＰＵＦＡ類がＥＰＡまたはＥＰＡ－Ｅである、上記（８７）乃至（１００）のいずれかに記載の自己乳化組成物。
（１０２）全脂肪酸およびその誘導体中のＥＰＡおよびＥＰＡ－Ｅ含量比が４０質量％以上である、上記（８７）乃至（１０１）のいずれかに記載の自己乳化組成物。
（１０３）全脂肪酸およびその誘導体中のＥＰＡおよびＥＰＡ－Ｅ含量比が８０質量％以上である、上記（８７）乃至（１０２）のいずれかに記載の自己乳化組成物。
（１０４）全脂肪酸およびその誘導体中のＥＰＡおよびＥＰＡ－Ｅ含量比が９６．５質量％以上である、上記（８７）乃至（１０３）のいずれかに記載の自己乳化組成物。
（１０５）自己乳化組成物の全量を１００質量％としたときのＥＰＡおよびＥＰＡ－Ｅの含量が５０質量％以上である、上記（８７）乃至（１０４）のいずれかに記載の自己乳化組成物。
（１０６）自己乳化組成物の全量を１００質量％としたときのＥＰＡおよびＥＰＡ－Ｅの含量が６０質量％以上である、上記（８７）乃至（１０５）のいずれかに記載の自己乳化組成物。
（１０７）自己乳化組成物の全量を１００質量％としたときのＥＰＡおよびＥＰＡ－Ｅの含量が７０質量％以上である、上記（８７）乃至（１０６）のいずれかに記載の自己乳化組成物。 (100) ω3 PUFAs are EPA, DHA, DPA, ALA, their pharmaceutically acceptable salts, their pharmaceutically acceptable esters, their pharmaceutically acceptable amides, their pharmaceutical The self-emulsifying composition according to any one of (87) to (98), which is at least one selected from the group consisting of the above-acceptable phospholipids.
(101) The self-emulsifying composition according to any one of (87) to (100) above, wherein the ω3 PUFA is EPA or EPA-E.
(102) The self-emulsifying composition according to any one of (87) to (101), wherein the content ratio of EPA and EPA-E in all fatty acids and derivatives thereof is 40% by mass or more.
(103) The self-emulsifying composition according to any one of (87) to (102), wherein the content ratio of EPA and EPA-E in all fatty acids and derivatives thereof is 80% by mass or more.
(104) The self-emulsifying composition according to any one of (87) to (103), wherein the content ratio of EPA and EPA-E in all fatty acids and derivatives thereof is 96.5% by mass or more.
(105) The self-emulsifying composition according to any one of the above (87) to (104), wherein the content of EPA and EPA-E is 50% by mass or more when the total amount of the self-emulsifying composition is 100% by mass .
(106) The self-emulsifying composition according to any of (87) to (105), wherein the content of EPA and EPA-E is 60% by mass or more when the total amount of the self-emulsifying composition is 100% by mass. .
(107) The self-emulsifying composition according to any one of (87) to (106), wherein the content of EPA and EPA-E is 70% by mass or more when the total amount of the self-emulsifying composition is 100% by mass. .
（１０８）ω３ＰＵＦＡ類０．５ｇ／日～１０ｇ／日で経口投与することを特徴とする、上記（８７）乃至（１０７）のいずれかに記載の自己乳化組成物。
（１０９）ω３ＰＵＦＡ類１ｇ／日～８ｇ／日で経口投与することを特徴とする、上記（８７）乃至（１０８）のいずれかに記載の自己乳化組成物。
（１１０）ω３ＰＵＦＡ類２ｇ／日～６ｇ／日で経口投与することを特徴とする、上記（８７）乃至（１０９）のいずれかに記載の自己乳化組成物。
（１１１）ω３ＰＵＦＡ類４ｇ／日～６ｇ／日で経口投与することを特徴とする、上記（８７）乃至（１１０）のいずれかに記載の自己乳化組成物。 (108) The self-emulsifying composition as described in any of (87) to (107) above, which is orally administered at 0.5 g / day to 10 g / day of ω3 PUFAs.
(109) The self-emulsifying composition as described in any of (87) to (108) above, which is orally administered at 1 g / day to 8 g / day of ω3 PUFAs.
(110) The self-emulsifying composition as described in any of (87) to (109) above, which is orally administered at 2 g / day to 6 g / day of ω3 PUFAs.
(111) The self-emulsifying composition according to any one of (87) to (110) above, which is orally administered at 4 g / day to 6 g / day of ω3 PUFAs.
（１１２）自己免疫性皮膚疾患または炎症性皮膚疾患が乾癬及び類症（尋常性乾癬（重症例含む）、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、稽留性肢端皮膚炎、疱疹状膿痂疹、ライター症候群、滴状乾癬、等）、魚鱗癬群（尋常性魚鱗癬、水疱型先天性魚鱗癬様紅皮症、非水疱型先天性魚鱗癬様紅皮症）、掌蹠角化症、ダリエー病、掌蹠膿疱症、毛孔性紅色粃糠疹、紅斑性角化症、皮膚炎群（接触皮膚炎、貨幣状皮膚炎、自家感作性皮膚炎、アトピー性皮膚炎、ビダール苔癬、その他の神経皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、その他の手指の皮膚炎、耳介及び外耳道の皮膚炎、鼻前庭及び鼻翼周辺の皮膚炎、全身性剥脱性皮膚炎、うっ血性皮膚炎、限局性掻爬皮膚炎、口周囲皮膚炎、汗疱、花粉性皮膚炎、等）、多発性硬化症、強皮症、エリテマトーデス（全身性及び慢性円板状）、ベーチェット病、および天疱瘡からなる群から選択される少なくとも１つである、上記（８７）乃至（１１１）のいずれかに記載の自己乳化組成物。
（１１３）自己免疫性皮膚疾患または炎症性皮膚疾患が乾癬及び類症（尋常性乾癬（重症例含む）、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、稽留性肢端皮膚炎、疱疹状膿痂疹、ライター症候群、滴状乾癬）、皮膚炎群（接触皮膚炎、貨幣状皮膚炎、自家感作性皮膚炎、アトピー性皮膚炎、ビダール苔癬、その他の神経皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、その他の手指の皮膚炎、耳介及び外耳道の皮膚炎、鼻前庭及び鼻翼周辺の皮膚炎、全身性剥脱性皮膚炎、うっ血性皮膚炎、限局性掻爬皮膚炎、口周囲皮膚炎、汗疱、花粉性皮膚炎、等）およびベーチェット病からなる群から選択される少なくとも１つであり、好ましくは、乾癬及び類症、皮膚炎群およびベーチェット病からなる群から選択される少なくとも１つであり、より好ましくは尋常性乾癬、関節症性乾癬、膿疱性乾癬、アトピー性皮膚炎およびベーチェット病からなる群から選択される少なくとも１つである、上記（８７）乃至（１１２）のいずれかに記載の自己乳化組成物。
（１１４）血清または血漿中のＥＰＡ／ＡＡ比が０．４未満である自己免疫性皮膚疾患または炎症性皮膚疾患患者に投与するための、上記（８７）乃至（１１３）のいずれかに記載の自己乳化組成物。
（１１５）血清または血漿中のＥＰＡ／ＡＡ比が０．１未満である自己免疫性皮膚疾患または炎症性皮膚疾患患者に投与するための、上記（８７）乃至（１１４）のいずれかに記載の自己乳化組成物。 (112) Autoimmune skin disease or inflammatory skin disease is psoriasis and analogies (including psoriasis vulgaris (including severe cases), psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, acrotic limb dermatitis, Herpes zoster, Reiter's syndrome, trichomes psoriasis, etc.), ichthyosis group (common ichthyosis, blistering congenital ichthyosis-like erythroderma, non-bullous congenital ichthyosis-like erythroderma), palm Keratosis, Darier's disease, palmoplantar pustulosis, erythematous erythematosus, erythematous keratosis, dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic dermatitis, progressive palmokeratosis, other finger dermatitis, pinna and ear canal dermatitis, nasal vestibular and perinasal dermatitis, systemic Exfoliative dermatitis, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat blister, pollen dermatitis, etc.), multiple sclerosis, The self-emulsifying composition according to any one of (87) to (111) above, which is at least one selected from the group consisting of dermatosis, lupus erythematosus (systemic and chronic discoid), Behcet's disease, and pemphigus object.
(113) Autoimmune skin disease or inflammatory skin disease is psoriasis and analogies (including psoriasis vulgaris (including severe cases), arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, acrotic limb dermatitis, Herpes zoster, Reiter syndrome, prickly psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, autosensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, oil Leaky dermatitis, progressive palmokeratosis, other finger dermatitis, dermatitis of the auricle and ear canal, dermatitis around the nasal vestibule and nasal wing, generalized exfoliative dermatitis, congestive dermatitis, limited And at least one selected from the group consisting of Behcet's disease, preferably psoriasis and symptoms, dermatitis group and Behcet's disease At least one selected from the group consisting of Or at least one selected from the group consisting of psoriasis vulgaris, psoriatic arthritis, pustular psoriasis, atopic dermatitis and Behcet's disease, or the self according to any one of (87) to (112) above Emulsified composition.
(114) The method according to any one of (87) to (113) above, which is administered to a patient with an autoimmune skin disease or inflammatory skin disease whose EPA / AA ratio in serum or plasma is less than 0.4 Self-emulsifying composition.
(115) The administration according to any one of (87) to (114) above, wherein the EPA / AA ratio in serum or plasma is administered to a patient having an autoimmune skin disease or inflammatory skin disease of less than 0.1. Self-emulsifying composition.
（１１６）自己免疫性皮膚疾患または炎症性皮膚疾患の憎悪期にシクロスポリン、エトレチナート、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンテネルマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラからなる群から選択される少なくとも１つの化合物と併用する、上記（８７）乃至（１１５）のいずれかに記載の自己乳化組成物。
（１１７）乾癬及び類症（尋常性乾癬（重症例含む）、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、稽留性肢端皮膚炎、疱疹状膿痂疹、ライター症候群、滴状乾癬）、皮膚炎群（接触皮膚炎、貨幣状皮膚炎、自家感作性皮膚炎、アトピー性皮膚炎、ビダール苔癬、その他の神経皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、その他の手指の皮膚炎、耳介及び外耳道の皮膚炎、鼻前庭及び鼻翼周辺の皮膚炎、全身性剥脱性皮膚炎、うっ血性皮膚炎、限局性掻爬皮膚炎、口周囲皮膚炎、汗疱、花粉性皮膚炎、等）およびベーチェット病からなる群から選択される少なくとも１つの自己免疫性皮膚疾患または炎症性皮膚疾患の憎悪期にシクロスポリン、エトレチナート、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンテネルマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラからなる群から選択される少なくとも１つの化合物と併用する、上記（８７）乃至（１１６）のいずれかに記載の自己乳化組成物。
（１１８）自己乳化組成物がさらにシクロスポリン、エトレチナート、アプレミラスト、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロンおよびベタメゾンからなる群から選択される少なくとも１つを有効成分として含有することを特徴とする、上記（８７）乃至（１１７）のいずれかに記載の自己乳化組成物。
（１１９）自己免疫性皮膚疾患または炎症性皮膚疾患の寛解期または非活動期にシクロスポリン、エトレチナート、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンネレルマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラと併用せず単独で投与する、上記（８７）乃至（１１８）のいずれかに記載の自己乳化組成物。
（１２０）乾癬及び類症（尋常性乾癬（重症例含む）、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、稽留性肢端皮膚炎、疱疹状膿痂疹、ライター症候群、滴状乾癬）、皮膚炎群（接触皮膚炎、貨幣状皮膚炎、自家感作性皮膚炎、アトピー性皮膚炎、ビダール苔癬、その他の神経皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、その他の手指の皮膚炎、耳介及び外耳道の皮膚炎、鼻前庭及び鼻翼周辺の皮膚炎、全身性剥脱性皮膚炎、うっ血性皮膚炎、限局性掻爬皮膚炎、口周囲皮膚炎、汗疱、花粉性皮膚炎、等）およびベーチェット病からなる群から選択される少なくとも１つの自己免疫性皮膚疾患または炎症性皮膚疾患の寛解期または非活動期にシクロスポリン、エトレチナート、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンテネルマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラと併用せず単独で投与する、上記（８７）乃至（１１９）のいずれかに記載の自己乳化組成物。 (116) Cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone, betamethasone, maxacalcitol, calcipotriol, tacalcitol hydrate during the exacerbation of autoimmune skin disease or inflammatory skin disease , Hydrocortisone acetate, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildrakizumab, brodalumab, guselcoumab, dupirumumab, nemorizumab, rituximab, rituximab, rituximab, rituximab, rituximab , Upadacitinib, emicizumab, fasinu Bu, pegprelanib, omalizumab, leslizumab, subtabumab, gantenerumab, etanercept, tofacitinib, salicylic acid / white petrolatum, splatastosyl, azelastine hydrochloride, fexofenadine hydrochloride, sodium cromoglycate, oxatomidoprostazobic Hydrates, tranilast, beclomethasone propionic acid, human immunoglobulin / histamine dihydrochloride, methylprednisolone, apremilast, pimecrolimus, AMG-0101, AMG-0103, hydroxylated sterubene molecule, chrysabolol, nalfrafin, doxorubicin, WBI-1001, octenidine , Oxymetazoline, nitric oxide, timapiplant, rosipitol acetate, cobamide, From Epipiplant, Omiganan, Asimadoline, Metoflumine, DSXS-1411, Serinexer, Terbinafine, Ellenbecestat, Berbecestat, Ranabecestat, Fluticasone, Beperminogen Per Plasmid, Darcetrapib, Abatacept, Talidamide, Bosentan and Deflazaquina The self-emulsifying composition according to any one of (87) to (115), which is used in combination with at least one selected compound.
(117) Psoriasis and analogies (psoriasis vulgaris (including severe cases), psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, peptic limb dermatitis, pustular impetigo, Reiter's syndrome, drops Psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic dermatitis, progressive palmar keratin , Other finger dermatitis, auricular and ear canal dermatitis, nasal vestibular and nasal wing dermatitis, generalized exfoliative dermatitis, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat Cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, cortisone acetate es during the exacerbation of at least one autoimmune skin disease or inflammatory skin disease selected from the group consisting of blisters, pollen dermatitis, etc.) and Behcet's disease Dexamethasone, prednisolone, prednisolone, betamaison, maxacalcitol, calcipotriol, tacalcitol hydrate, hydrocortisone acetate, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildramazumab Dupirumab, nemorizumab, tralotinumab, rituximab, paripremab, remuximab, paripremab, rituximab, paripretumab Aze Stin hydrochloride, fexofenadine hydrochloride, sodium cromoglycate, oxatomide, clobetasone butyrate, bendazac, suprofen, tacrolimus hydrate, tranilast, beclomethasone propionic acid, human immunoglobulin / histamine dihydrochloride, methylprednisolone, apremilast, Pimecrolimus, AMG-0101, AMG-0103, hydroxylated sterubene molecule, chrysabolol, nalfrafin, doxorubicin, WBI-1001, octenidine, oxymetazoline, nitric oxide, timapiplant, rosipitol acetate, cobamide, febipiplant, omiganan, acimadrine, metflumin, DSXS-1411, Selnexer, Terbinafine, Ellen Bethestat, Belvecestat, Rana Bethestat, The self-emulsification according to any one of (87) to (116) above, which is used in combination with at least one compound selected from the group consisting of fluticasone, beperminogen par plasmid, darcetrapib, abatacept, thalidomide, bosentan, deflazacote and anakinra Composition.
(118) The self-emulsifying composition further contains at least one selected from the group consisting of cyclosporine, etretinate, apremilast, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone and betamethasone as an active ingredient. The self-emulsifying composition according to any one of the above (87) to (117).
(119) Cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone, betamethone, maxacalcitol, calcipotriol, during remission or inactivity of autoimmune skin disease or inflammatory skin disease Tacalcitol hydrate, hydrocortisone acetate, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildrakizumab, brodalumab, gusselumab, dupirumumab, nemorizumab, tralotimumab, traloticumab Cantratinib, traloquinumab, upadacitinib, emiciz Bufacinoumab, pegprelanib, omalizumab, reslizumab, subtabumab, gunnerelmab, etanercept, tofacitinib, salicylic acid / white petrolatum, suplatastosyl, azelastine hydrochloride, fexofenadine hydrochloride, sodium cromoglycate, oxatomide, oxatomide , Tacrolimus hydrate, tranilast, beclomethasone propionic acid, human immunoglobulin / histamine dihydrochloride, methylprednisolone, apremilast, pimecrolimus, AMG-0101, AMG-0103, hydroxylated sterubene molecule, chrysabolol, nalflaffin, doxorubicin, WBI-1001 , Octenidine, oxymetazoline, nitric oxide, timapiplant, rosiptol acetate Cobamide, febipiplant, omiganan, asimadoline, metflumin, DSXS-1411, selenexer, terbinafine, ellenbecestat, velvecestat, ranavecestat, fluticasone, beperminogen per plasmid, darcetrapib, abatacept, botanidan The self-emulsifying composition according to any one of (87) to (118), wherein the self-emulsifying composition is administered alone.
(120) Psoriasis and symptoms (psoriasis vulgaris (including severe cases), psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, limbic limb dermatitis, herpes zoster, Reiter's syndrome, drops Psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic dermatitis, progressive palmar keratin , Other finger dermatitis, auricular and ear canal dermatitis, nasal vestibular and nasal wing dermatitis, generalized exfoliative dermatitis, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat Cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, during remission or inactivity of at least one autoimmune skin disease or inflammatory skin disease selected from the group consisting of blisters, pollen dermatitis, etc.) and Behcet's disease Col Zon acetate, dexamethasone, prednisolone, betamethasone, maxacalcitol, calcipotriol, tacalcitol hydrate, hydrocortisone acetate, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildrazumab, tildrazumab Guselumab, Dupilumab, Nemorizumab, Traloquinumab, Rituximab, Balicitinib, Salilumab, Masitinib, Ocrelizumab, Pekkantratinib, Tralochinumab, Upadacitinib, Emicizumab, Facineumab, Pegpremab Tosyl, azelastine hydrochloride, fexofenadine hydrochloride, sodium cromoglycate, oxatomide, clobetasone butyrate, bendazac, suprofen, tacrolimus hydrate, tranilast, beclomethasone propionic acid, human immunoglobulin / histamine dihydrochloride, methylprednisolone, Apremilast, pimecrolimus, AMG-0101, AMG-0103, hydroxylated sterubene molecule, chrysabolol, nalflaffin, doxorubicin, WBI-1001, octenidine, oxymetazoline, nitric oxide, timapiplant, rosipitol acetate, cobamide, febipiplant, omiganane, asimadoline Metoflumin, DSXS-1411, Selnexer, Terbinafine, Ellenbecestat, Berbecestat, Rana 120. The self-emulsifying composition according to any one of the above (87) to (119), which is administered alone without being combined with becestat, fluticasone, beperminogen par plasmid, dalcetrapib, abatacept, thalidomide, bosentan, defrazacoat and anakinra.
（１２１）自己免疫性皮膚疾患または炎症性皮膚疾患の増悪期には２～７日からなる群から選択される少なくとも１つの期間毎に間欠経口投与し、症状の改善がみられた場合は１週間～１ヶ月からなる群から選択される少なくとも１つの期間毎に投与間隔を１日または２日ずつ増加して、寛解期または非活動期には１週間～１ヶ月からなる群から選択される少なくとも１つの期間毎に間欠経口投与する、上記（８７）乃至（１２０）のいずれかに記載の自己乳化組成物。
（１２２）自己免疫性皮膚疾患または炎症性皮膚疾患の増悪期には２～１０ｇ／日経口投与し、症状の改善がみられた場合は１週間～１ヶ月からなる群から選択される少なくとも１つの期間毎に投与量を０．５～１g／日ずつ減量して、寛解期または非活動期には０．５～４ ｇ／日経口投与する、上記（８７）乃至（１２１）のいずれかに記載の自己乳化組成物。 (121) In the period of exacerbation of autoimmune skin disease or inflammatory skin disease, intermittent oral administration is carried out every at least one period selected from the group consisting of 2 to 7 days. The administration interval is increased by 1 day or 2 days for at least one period selected from the group consisting of weeks to 1 month, and selected from the group consisting of 1 week to 1 month in the remission period or inactive period The self-emulsifying composition according to any one of (87) to (120), which is intermittently orally administered every at least one period.
(122) At least 1 selected from the group consisting of 2 to 10 g / day orally administered in the exacerbation phase of autoimmune skin disease or inflammatory skin disease, and 1 week to 1 month when improvement in symptoms is observed Any of the above (87) to (121), wherein the dose is reduced by 0.5 to 1 g / day every one period and orally administered at 0.5 to 4 g / day in the remission period or inactive period The self-emulsifying composition described in 1.
（１２３）乳化剤がポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンヒマシ油、ポリエチレングリコール脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコールおよびショ糖脂肪酸エステルからなる群から選ばれる少なくとも１つの乳化剤である、上記（８７）乃至（１２２）のいずれかに記載の自己乳化組成物。
（１２４）乳化剤がＨＬＢが１０以上の乳化剤である、上記（８７）乃至（１２３）のいずれかに記載の自己乳化組成物。
（１２５）ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステルおよびポリオキシエチレンヒマシ油からなる群から選択される少なくとも２つを含有する、上記（８７）乃至（１２４）のいずれかに記載の自己乳化組成物。
（１２６）自己乳化組成物が、ａ）合計量の５０～９５質量％のω３ＰＵＦＡ類、
ｂ）　ω３ＰＵＦＡ類１００質量部に対して３～４０質量部のレシチン、
ｃ）　ω３ＰＵＦＡ類１００質量部に対して１０～５０質量部のポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンヒマシ油、ポリエチレングリコール脂肪酸エステル、およびポリオキシエチレンポリオキシプロピレングリコールからなる群から選ばれる少なくとも１つの乳化剤、および、
ｄ）　エタノールの含量が合計量の４質量％以下であることを特徴とする、上記（８７）乃至（１２４）のいずれかに記載の自己乳化組成物。
（１２７）自己乳化組成物が、ａ）組成物の合計量の５０～９５質量％のω３ＰＵＦＡ類、
ｂ）前記合計量の４～２０質量％の、ショ糖ラウリン酸エステル、ショ糖ミリスチン酸エステル、ショ糖パルミチン酸エステル、ショ糖ステアリン酸エステルおよびショ糖オレイン酸エステルからなる群から選ばれる少なくとも１つのＨＬＢが１０以上のショ糖脂肪酸エステルである乳化剤、
ｃ）ω３ＰＵＦＡ、その製薬学上許容しうる塩、エチルエステルおよびトリグリセリドエステルからなる群から選ばれる少なくとも１つの化合物１００質量部に対して５～３０質量部のグリセリン、および
ｄ）エタノールの含量が前記合計量の４質量％以下であることを特徴とする、上記（８７）乃至（１２４）のいずれかに記載の自己乳化組成物。
（１２８）自己乳化組成物が、国際公開ＷＯ２０１０／１３４６１４号パンフレット、国際公開ＷＯ２０１５／００８８４８号パンフレット、国際公開ＷＯ２０１５／００８８４９号パンフレット、国際公開ＷＯ２０１６／１１７０５７号パンフレット、国際公開ＷＯ２０１６／１１７６２１号パンフレット、国際公開ＷＯ２０１６／１１７６２９号パンフレット、国際公開ＷＯ２０１０／１０３４０２号パンフレット、国際公開ＷＯ２０１０／１０３４０４号パンフレット、国際公開ＷＯ２０１０／１１９３１９号パンフレットおよび国際公開ＷＯ２０１１／０４７２５９号パンフレットに記載されている自己乳化組成物からなる群より選択される少なくとも１つの自己乳化組成物である、上記（８７）乃至（１２４）のいずれかに記載の自己乳化組成物。 (123) At least one emulsifier selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol and sucrose fatty acid ester The self-emulsifying composition according to any one of (87) to (122), which is one emulsifier.
(124) The self-emulsifying composition according to any one of (87) to (123), wherein the emulsifier is an emulsifier having an HLB of 10 or more.
(125) The at least two selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil, according to any one of (87) to (124) above Self-emulsifying composition.
(126) The self-emulsifying composition is a) 50 to 95% by mass of the total amount of ω3 PUFAs,
b) 3 to 40 parts by weight of lecithin with respect to 100 parts by weight of ω3 PUFAs,
c) From 10 to 50 parts by mass of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, and polyoxyethylene polyoxypropylene glycol per 100 parts by mass of ω3 PUFAs At least one emulsifier selected from the group consisting of:
d) The self-emulsifying composition according to any one of (87) to (124), wherein the ethanol content is 4% by mass or less of the total amount.
(127) The self-emulsifying composition is a) 50 to 95% by mass of ω3 PUFAs based on the total amount of the composition,
b) at least one selected from the group consisting of sucrose laurate, sucrose myristic ester, sucrose palmitate, sucrose stearate and sucrose oleate in an amount of 4 to 20% by weight of the total amount. An emulsifier wherein one HLB is 10 or more sucrose fatty acid esters,
c) ω3PUFA, a pharmaceutically acceptable salt thereof, 5 to 30 parts by mass of glycerin with respect to 100 parts by mass of at least one compound selected from the group consisting of ethyl ester and triglyceride ester, and d) the content of ethanol The self-emulsifying composition as described in any one of (87) to (124) above, which is 4% by mass or less of the total amount.
(128) The self-emulsifying composition is an international publication WO2010 / 134614 pamphlet, an international publication WO2015 / 008848 pamphlet, an international publication WO2015 / 008849 pamphlet, an international publication WO2016 / 117057 pamphlet, an international publication WO2016 / 117621 pamphlet, an international publication. Group consisting of self-emulsifying compositions described in published WO2016 / 117629 pamphlet, internationally published WO2010 / 103402 pamphlet, internationally published WO2010 / 103404 pamphlet, internationally published WO2010 / 119319 pamphlet and internationally published WO2011 / 047259 pamphlet. Any one of the above (87) to (124), which is at least one self-emulsifying composition selected from His own emulsion composition.
　本発明の自己乳化組成物は、間欠投与、既存治療薬との併用・シークエンシャル投与および憎悪期と寛解期または非活動期で異なる投与を行う等の特定の用法・用量で経口投与することで、下記の性質の少なくとも１つを改善する自己乳化組成物を提供することができる。
　予防および／または治療効果が高く、憎悪期を短縮および／または寛解期または非活動期を延長し、副作用が少なく、投与頻度を減少させ患者の服薬負担を軽減させ、服薬にかかる時間を減少させおよび／または服薬にかかる費用を減少させ患者の服薬負担を軽減させ、併用することにより既存治療薬の投与頻度および／または投与量を減少させて既存治療薬が有する課題（有効性、副作用および患者の服薬負担（頻回服薬・服薬にかかる時間、費用）等）の少なくとも1つを解決する。
　さらに、本発明の自己免疫性皮膚疾患または炎症性皮膚疾患の予防および／または治療方法は、上記の性質の少なくとも１つを改善することができる。 The self-emulsifying composition of the present invention can be administered orally in specific usages / doses, such as intermittent administration, combined use with existing therapeutic agents, sequential administration, and administration differently between an exacerbation period and a remission period or inactive period. Self-emulsifying compositions that improve at least one of the following properties can be provided.
High preventive and / or therapeutic effect, shortens the period of exacerbation and / or prolongs the period of remission or inactivity, reduces side effects, reduces the frequency of administration, reduces patient burden, and reduces the time taken And / or reduce the cost of medication, reduce the burden of medication, and reduce the frequency and / or dose of existing medication by using it in combination with existing treatments (efficacy, side effects and patients) To solve at least one of the burden of taking medications (such as frequent medications / time and cost)
Furthermore, the method for preventing and / or treating autoimmune skin disease or inflammatory skin disease of the present invention can improve at least one of the above properties.
　以下に本発明を詳細に記載する。
　本明細書で言及されるすべての特許文献および非特許文献は、個々のそれぞれの特許文献および非特許文献が、具体的および個別に参照により援用されるよう指示されたのと同じ程度に、参照により本明細書に援用される。
　本明細書で使用される「約」という単語は、特定の使用の文脈内で、記述される数値のプラスまたはマイナス５％、１０％あるいは１５％の範囲を指すことがある。例えば、約１０は９．５～１０．５、９～１１あるいは８．５～１１．５の範囲を指すことがある。
　「約」はまた、値の測定における典型的な誤差または不正確さを説明している。
　また、本明細書で使用される「数値」は、特定の使用の文脈内で、記述される数値の一桁下の数値を四捨五入した結果を指すことがある。例えば、１０は９．５～１０．４の範囲を指すことがある。 The present invention is described in detail below.
All patent and non-patent documents referred to herein are to the same extent as each individual patent and non-patent document was specifically and individually indicated to be incorporated by reference. Is incorporated herein by reference.
As used herein, the term “about” may refer to a range of plus or minus 5%, 10%, or 15% of the numerical value described, within the context of a particular use. For example, about 10 may refer to the range of 9.5 to 10.5, 9 to 11, or 8.5 to 11.5.
“About” also describes typical errors or inaccuracies in the measurement of values.
In addition, the “numerical value” used in the present specification may refer to a result obtained by rounding a numerical value that is one digit lower than the numerical value described within a specific usage context. For example, 10 may refer to the range of 9.5 to 10.4.
　本発明で使用される「自己免疫性皮膚疾患または炎症性皮膚疾患」とは、自己免疫不全を原因または伴って発症する皮膚疾患または炎症を伴なう皮膚疾患を含有する。例えば、乾癬及び類症（尋常性乾癬（重症例含む）、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、稽留性肢端皮膚炎、疱疹状膿痂疹、ライター症候群、滴状乾癬、等）、魚鱗癬群（尋常性魚鱗癬、水疱型先天性魚鱗癬様紅皮症、非水疱型先天性魚鱗癬様紅皮症）、掌蹠角化症、ダリエー病、掌蹠膿疱症、毛孔性紅色粃糠疹、紅斑性角化症、皮膚炎群（接触皮膚炎、貨幣状皮膚炎、自家感作性皮膚炎、アトピー性皮膚炎、ビダール苔癬、その他の神経皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、その他の手指の皮膚炎、耳介及び外耳道の皮膚炎、鼻前庭及び鼻翼周辺の皮膚炎、全身性剥脱性皮膚炎、うっ血性皮膚炎、限局性掻爬皮膚炎、口周囲皮膚炎、汗疱、花粉性皮膚炎、等）、多発性硬化症、強皮症、エリテマトーデス（全身性及び慢性円板状）、ベーチェット病、および天疱瘡等が挙げられ、好ましくは、乾癬及び類症、皮膚炎群およびベーチェット病が挙げられ、より好ましくは尋常性乾癬、関節症性乾癬、膿疱性乾癬、アトピー性皮膚炎およびベーチェット病の皮膚症状が挙げられるが、これらに限定されない。
　また、自己免疫性皮膚疾患または炎症性皮膚疾患患者のうち、血清または血漿中のＥＰＡ／ＡＡ比が、例えば１．５未満、１．４未満、１．３未満、１．２未満、１．１未満、１．０未満、０．９未満、０．８未満、０．７５未満、０．７未満、０．６５未満、０．６未満、０．５５未満、０．５未満、０．４５未満、０．４未満、０．３５未満、０．３未満、０．２５未満、０．２未満、０．１５未満０．１未満、０．０５未満または０．０１未満の患者が含有され、好ましくは１．０未満、より好ましくは０．７５未満、さらに好ましくは０．７未満、さらにより好ましくは０．５未満、とりわけ好ましくは０．４未満、いっそう好ましくは０．３未満、最も好ましくは０．１未満の患者であるが、これらに限定されない。 The “autoimmune skin disease or inflammatory skin disease” used in the present invention includes a skin disease that develops due to or accompanies autoimmune failure or a skin disease that accompanies inflammation. For example, psoriasis and analogies (including psoriasis vulgaris (including severe cases), psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, epidural limb dermatitis, pustular impetigo, Reiter's syndrome, prickly psoriasis ), Ichthyosis group (common ichthyosis, blistering congenital ichthyosis-like erythroderma, non-bullous congenital ichthyosis-like erythroderma), palmokeratosis, Darier's disease, palmoplantar pustulosis, Pore erythema, erythematous keratosis, dermatitis group (contact dermatitis, monetary dermatitis, autosensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrhea Dermatitis, progressive palmokeratosis, other finger dermatitis, dermatitis of the auricle and ear canal, dermatitis around the nasal vestibule and nasal wing, generalized exfoliative dermatitis, congestive dermatitis, localized Curettage dermatitis, perioral dermatitis, sweat blisters, pollen dermatitis, etc.), multiple sclerosis, scleroderma, lupus erythematosus (systemic and chronic circles) ), Behcet's disease, pemphigus, etc., preferably psoriasis and symptoms, dermatitis group and Behcet's disease, more preferably psoriasis vulgaris, arthritic psoriasis, pustular psoriasis, atopic Examples include, but are not limited to, dermatitis and skin symptoms of Behcet's disease.
Further, among patients with autoimmune skin diseases or inflammatory skin diseases, the EPA / AA ratio in serum or plasma is, for example, less than 1.5, less than 1.4, less than 1.3, less than 1.2. Less than 1, less than 1.0, less than 0.9, less than 0.8, less than 0.75, less than 0.7, less than 0.65, less than 0.6, less than 0.55, less than 0.5, Contains less than 45, less than 0.4, less than 0.35, less than 0.3, less than 0.25, less than 0.2, less than 0.15, less than 0.1, less than 0.05, or less than 0.01 Preferably less than 1.0, more preferably less than 0.75, even more preferably less than 0.7, even more preferably less than 0.5, especially preferably less than 0.4, even more preferably less than 0.3, Most preferred are patients with less than 0.1, but are not limited thereto.
　本発明で使用される「ω３ＰＵＦＡ類」とは、ＥＰＡ、ＤＨＡ、ＤＰＡ、ＡＬＡ等の遊離脂肪酸であるω３ＰＵＦＡおよび／またはω３ＰＵＦＡの製薬学上許容しうる塩類、エステル類、アミド類およびリン脂質類、またはω３ＰＵＦＡの代謝またはω３ＰＵＦＡの血液、リンパ液、体液、細胞、組織または臓器への取り込みにつながるその他のあらゆる形態を指す。同様に、「ＥＰＡ類」、「ＤＨＡ類」、「ＤＰＡ類」および「ＡＬＡ類」とは、各々の遊離脂肪酸および／または各々の遊離脂肪酸の製薬学上許容しうる塩類、エステル類、アミド類およびリン脂質類、または各々の遊離脂肪酸の代謝または各々の遊離脂肪酸の血液、リンパ液、体液、細胞、組織または臓器への取り込みにつながるその他のあらゆる形態を指す。
　製薬学上許容しうる塩類は、例えば金属塩、アンモニウム塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性、又は酸性アミノ酸との塩などを含むが、これらに限定されない。
　金属塩の好適な例としては、例えば、リチウム塩、ナトリウム塩、カリウム塩、セシウム塩などのアルカリ金属塩、カルシウム塩、マグネシウム塩、バリウム塩などのアルカリ土類金属塩、アルミニウム塩などが挙げられる。有機塩基との塩の好適な例としては、例えば、メチルアミン、エチルアミン、ｔ－ブチルアミン、ｔ－オクチルアミン、ジエチルアミン、トリメチルアミン、トリエチルアミン、シクロヘキシルアミン、ジシクロヘキシルアミン、ジベンジルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、ピペリジン、モルホリン、ピリジン、ピコリン、リシン、アルギニン、オルニチン、エチレンジアミン、Ｎ－メチルグルカミン、グルコサミン、フェニルグリシンアルキルエステル、グアニジン、２、６－ルチジン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、Ｎ、Ｎ'－ジベンジルエチレンジアミン等との塩が挙げられる。無機酸との塩の好適な例としては、例えば、塩酸、臭化水素酸、よう化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。有機酸との塩の好適な例としては、例えば、ギ酸、酢酸、トリフルオロ酢酸、プロピオン酸、酪酸、吉草酸、エナント酸、カプリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、乳酸、ソルビン酸、マンデル酸等の脂肪族モノカルボン酸等との塩、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、リンゴ酸、酒石酸等の脂肪族ジカルボン酸との塩、クエン酸等の脂肪族トリカルボン酸との塩、安息香酸、サリチル酸等の芳香族モノカルボン酸との塩、フタル酸等の芳香族ジカルボン酸の塩、桂皮酸、グリコール酸、ピルビン酸、オキシル酸、サリチル酸、Ｎ－アセチルシステイン等の有機カルボン酸との塩、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等の有機スルホン酸との塩、アスパラギン酸、グルタミン酸等の酸性アミノ酸類との酸付加塩が挙げられる。塩基性アミノ酸との塩の好適な例としては、例えば、アルギニン、リジン、オルニチンなどとの塩が挙げられ、酸性アミノ酸との塩の好適な例としては、例えば、アスパラギン酸、グルタミン酸などとの塩が挙げられる。また、国際公開ＷＯ２０１５／１９５４９１号パンフレットに記載された前述のω３ＰＵＦＡアミノ酸塩２分子をマグネシウムイオン、カルシウムイオン、亜鉛イオン等の２価金属イオンでアミノ酸間をイオン結合させた化合物も含み得る。例えば、マグネシウム　ビス－リジネート　ビス－ＥＰＡ　ジハイドレート、マグネシウム　ビス－リジネート　モノ－ＥＰＡ、マグネシウム　ビス－リジネート　ビス－ＤＨＡ　ジハイドレート、マグネシウム　ビス－リジネート　モノ－ＥＰＡ　モノ－ＤＨＡ　ジハイドレート、マグネシウム　ビス－リジネート　ビス－ＤＰＡ　ジハイドレート、等が挙げられるが、これらに限定されない。これらのうち、製薬学上許容しうる塩が好ましい。例えば、化合物内に酸性官能基を有する場合にはアルカリ金属塩（例、ナトリウム塩、カリウム塩など）、アルカリ土類金属塩（例、カルシウム塩、マグネシウム塩、バリウム塩など）などの無機塩、アンモニウム塩など、また、化合物内に塩基性官能基を有する場合には、例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸など無機酸との塩、又は酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、ｐ－トルエンスルホン酸などの有機酸との塩が挙げられる。
　製薬学上許容しうるエステル類は、例えばメチルエステル、エチルエステル、ｎ－プロピルエステル、ｉ－プロピルエステルなどのアルキルエステル、およびモノグリセリドエステル、ジグリセリドエステルおよびトリグリセリドエステル（以下、ＴＧエステルと記す）などのグリセリドエステルを含むが、これらに限定されない。モノグリセリドエステルの場合はω３ＰＵＦＡが１～３位のいずれか１箇所にエステル結合した化合物が、ジグリセリドエステルの場合はω３ＰＵＦＡが１～３位のいずれか１箇所にエステル結合した化合物およびω３ＰＵＦＡが１位および２位または１位および３位の２箇所にエステル結合した化合物が、およびＴＧエステルの場合はω３ＰＵＦＡが１～３位のいずれか１箇所にエステル結合した化合物、ω３ＰＵＦＡが１位および２位または１位および３位の２箇所にエステル結合した化合物およびがω３ＰＵＦＡが１位～３位の３箇所にエステル結合した化合物が含まれ得る。
　製薬学上許容しうるアミド類は、カルボン酸アミド、スルホンアミドおよびリン酸アミドなどのアミド類を含むが、これらに限定されない。
　製薬学上許容しうるリン脂質類は、例えばホスファチジルコリン、ホスファチジルエタノールアミン、ホスファチジルセリン、ホスファチジルグリセロールおよびホスファチジルイノシトールなどのリン脂質に少なくとも１つのω３ＰＵＦＡが結合した化合物を含むが、これらに限定されない。
　望ましい例は遊離酸、エチルエステル、ＴＧエステル、リン脂質類などであり、遊離酸およびエチルエステルがより望ましい。
　さらに具体的に言えば、望ましい例にはＥＰＡ、ＥＰＡ－Ｅ、ＥＰＡのＴＧエステル、ＤＨＡ、ＤＨＡ－Ｅ、ＤＨＡのＴＧエステル、ＤＰＡ、ＤＰＡエチルエステル（以下、ＤＰＡ－Ｅと記す）、ＤＰＡのＴＧエステル、ＡＬＡ、ＡＬＡエチルエステル（以下、ＡＬＡ－Ｅと記す）およびＡＬＡのＴＧエステルなどが含まれ、ＥＰＡ、ＥＰＡ－Ｅ、ＤＨＡ、ＤＨＡ－Ｅ、ＤＰＡ、ＤＰＡ－Ｅ、ＡＬＡおよびＡＬＡ－Ｅがより望ましく、ＥＰＡ、ＥＰＡ－Ｅ、ＤＨＡおよびＤＨＡ－Ｅが更に望ましく、ＥＰＡおよびＥＰＡ－Ｅが最も望ましい。
　また、ω３ＰＵＦＡは前記以外のω３ＰＵＦＡを含有する場合もあり、例えば、ヘキサデカトリエン酸（ＨＴＡ）、エイコサトリエン酸（ＥＴＥ）、ステアリドン酸（ＳＤＡ）、エイコサテトラエン酸（ＥＴＡ）、ヘネイコサペンタエン酸（ＨＰＡ）、テトラコサペンタエン酸（ＴＰＡ）またはテトラコサヘキサエン酸（ＴＨＡ）またはそれらの製薬学上許容しうる塩類、エステル類、アミド類およびリン脂質類などが挙げられる。ただし、これらのω３ＰＵＦＡの含有量は、低いほうが望ましく、より望ましくは重量比で６０％未満、５５％未満、５０％未満、４５％未満、４０％未満、３５％未満、３０％未満、２５％未満、２０％未満、１５％未満、１０％未満、５％未満、４％未満、３％未満、２％未満、さらに望ましくは重量比で１％未満である。 The “ω3 PUFAs” used in the present invention means pharmaceutically acceptable salts, esters, amides and phospholipids of ω3PUFA and / or ω3PUFA which are free fatty acids such as EPA, DHA, DPA, ALA, Or any other form that leads to metabolism of ω3 PUFA or uptake of ω3 PUFA into blood, lymph, body fluid, cells, tissues or organs. Similarly, “EPAs”, “DHAs”, “DPAs”, and “ALAs” refer to each free fatty acid and / or pharmaceutically acceptable salts, esters, amides of each free fatty acid. And phospholipids or any other form that leads to the metabolism of each free fatty acid or the uptake of each free fatty acid into blood, lymph, body fluids, cells, tissues or organs.
Pharmaceutically acceptable salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids, and the like. It is not limited.
Preferable examples of the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt. . Preferable examples of the salt with an organic base include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, triamine. Ethanolamine, piperidine, morpholine, pyridine, picoline, lysine, arginine, ornithine, ethylenediamine, N-methylglucamine, glucosamine, phenylglycine alkyl ester, guanidine, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, N And salts with N′-dibenzylethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, N-acetylcysteine, etc. Salt with organic carboxylic acid, salt with organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, gluta Acid addition salts with acidic amino acids such as phosphate and the like. Preferable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned. Moreover, the compound which made the amino acid ion-bond between the above-mentioned 2 molecules of ω3 PUFA amino acid salt described in the pamphlet of International Publication WO2015 / 195491 with divalent metal ions such as magnesium ion, calcium ion, and zinc ion may also be included. For example, magnesium bis-lysinate bis-EPA dihydrate, magnesium bis-liginate mono-EPA, magnesium bis-liginate bis-DHA dihydrate, magnesium bis-liginate mono-EPA mono-DHA dihydrate, magnesium bis-liginate bis-DPA dihydrate, etc. However, it is not limited to these. Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt), In the case where the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, Examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
Examples of pharmaceutically acceptable esters include alkyl esters such as methyl ester, ethyl ester, n-propyl ester and i-propyl ester, and monoglyceride ester, diglyceride ester and triglyceride ester (hereinafter referred to as TG ester). Including but not limited to glyceride esters. In the case of monoglyceride ester, a compound in which ω3PUFA is ester-bonded at any one of positions 1 to 3, and in the case of diglyceride ester, a compound in which ω3PUFA is ester-bonded to any one of positions 1 to 3 and ω3PUFA are in position 1 and A compound having an ester bond at two positions of the 2-position or the 1-position and the 3-position, and, in the case of a TG ester, a compound having an ester bond at any one of the 1- to 3-positions of the ω3 PUFA, And a compound in which ω3PUFA is ester-bonded at three positions of the 1st to 3rd positions.
Pharmaceutically acceptable amides include, but are not limited to, amides such as carboxylic acid amides, sulfonamides and phosphoric acid amides.
The pharmaceutically acceptable phospholipids include, but are not limited to, compounds in which at least one ω3 PUFA is bound to phospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol and phosphatidylinositol.
Desirable examples are free acids, ethyl esters, TG esters, phospholipids, etc. Free acids and ethyl esters are more desirable.
More specifically, desirable examples include EPA, EPA-E, EPA TG ester, DHA, DHA-E, DHA TG ester, DPA, DPA ethyl ester (hereinafter referred to as DPA-E), DPA TG ester, ALA, ALA ethyl ester (hereinafter referred to as ALA-E) and ALA TG ester, etc. are included, such as EPA, EPA-E, DHA, DHA-E, DPA, DPA-E, ALA and ALA-E. Are more desirable, EPA, EPA-E, DHA and DHA-E are more desirable, and EPA and EPA-E are most desirable.
In addition, ω3 PUFA may contain ω3 PUFA other than those described above. For example, hexadecatrienoic acid (HTA), eicosatrienoic acid (ETE), stearidonic acid (SDA), eicosatetraenoic acid (ETA), heneicosapentaene Examples include acid (HPA), tetracosapentaenoic acid (TPA) or tetracosahexaenoic acid (THA) or pharmaceutically acceptable salts, esters, amides and phospholipids thereof. However, it is desirable that the content of these ω3 PUFAs is low, and more desirably less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, and 25% by weight. Less than, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, and more preferably less than 1% by weight.
　本発明でいうところのＥＰＡ－Ｅとは、ω３ＰＵＦＡに属するイコサペント酸（ＣＡＳ登録番号：１０４１７－９４－４）のエチルエステル（ＣＡＳ登録番号：８６２２７－４７－６）であり、合成品、半合成品または天然品のいずれでもよく、これらを含有する天然油の形態でもよい。ここで、天然品とは、イコサペント酸類を含有する天然油から公知の方法によって抽出されたもの、粗精製されたもの、あるいはそれらを更に高度に精製したものを意味する。半合成品は、微生物などにより産生されたイコサペント酸類を含み、また該イコサペント酸類あるいは天然のイコサペント酸類にエステル化、エステル交換等の化学処理を施したものも含まれる。本発明では、ＥＰＡ－Ｅとして、これらのうちの１種を単独で、あるいは２種以上を組み合わせて用いることができる。 EPA-E as referred to in the present invention is an ethyl ester (CAS registration number: 86227-47-6) of icosapentic acid (CAS registration number: 10417-94-4) belonging to ω3 PUFA. Products or natural products, or in the form of natural oils containing these. Here, the natural product means one extracted from a natural oil containing icosapentic acids by a known method, one that has been roughly purified, or one that has been further refined. Semi-synthetic products include icosapentic acids produced by microorganisms and the like, and those obtained by subjecting the icosapentic acids or natural icosapentic acids to chemical treatments such as esterification and transesterification. In the present invention, as EPA-E, one of these can be used alone, or two or more can be used in combination.
　本発明の自己乳化組成物に用いる原料のＥＰＡ－Ｅの純度は特に限定されないが、通常、本自己乳化組成物の全脂肪酸類中のＥＰＡ－Ｅの含量として、２０質量％以上、２５質量％以上、３０質量％以上、３５質量％以上、好ましくは４０質量％以上、４５質量％以上、５０質量％以上、５５質量％以上、６０質量％以上、６５質量％以上、さらに好ましくは７０質量％以上、７５質量％以上、さらに好ましくは８０質量％以上、８５質量％以上、より好ましくは９０質量％以上、質量％以上、とりわけ好ましくは９６．５質量％以上のものがいっそう好ましく、最も好ましくは９８質量％以上である。ＥＰＡが高純度のもの、例えば、全脂肪酸類中のＥＰＡ類含有比が４０質量％以上のものが好ましく、６０質量％以上のものがより好ましく、７０質量％以上のものがさらに好ましく、８０質量％以上のものがいっそう好ましく、９０質量％以上のものがいっそう好ましく、９６．５質量％以上のものがとりわけ好ましく、９８質量％以上のものが最も好ましい。また、本自己乳化組成物の全脂肪酸類中のＥＰＡ－Ｅの含量として、４０質量％以上、４１質量％以上、４２質量％以上、４３質量％以上、４４質量％以上、４５質量％以上、４６質量％以上、４７質量％以上、４８質量％以上、４９質量％以上、５０質量％以上、５１質量％以上、５２質量％以上、５３質量％以上、５４質量％以上、５５質量％以上、５６質量％以上、５７質量％以上、５８質量％以上、５９質量％以上、６０質量％以上、６１質量％以上、６２質量％以上、６３質量％以上、６４質量％以上、６５質量％以上、６６質量％以上、６７質量％以上、６８質量％以上、６９質量％以上、７０質量％以上、７１質量％以上、７２質量％以上、７３質量％以上、７４質量％以上、７５質量％以上、７６質量％以上、７７質量％以上、７８質量％以上、７９質量％以上、８０質量％以上、８１質量％以上、８２質量％以上、８３質量％以上、８４質量％以上、８５質量％以上、８６質量％以上、８７質量％以上、８８質量％以上、８９質量％以上、９０質量％以上、９１質量％以上、９２質量％以上、９３質量％以上、９４質量％以上、９５質量％以上、９６質量％以上、９６．５質量％以上、９７質量％以上、９８質量％以上、９９質量％以上である。実質的にＤＨＡを全く含まないか、含んでいても例えば１．０質量％未満、好ましくは０．５質量％未満、より好ましくは０．２質量％未満であるＥＰＡの純度が最も好ましい。つまり、ＥＰＡ－Ｅの純度はより高いことが望ましい。 The purity of the raw material EPA-E used in the self-emulsifying composition of the present invention is not particularly limited. Usually, the content of EPA-E in the total fatty acids of the self-emulsifying composition is 20% by mass or more and 25% by mass. Or more, 30% by mass or more, 35% by mass or more, preferably 40% by mass or more, 45% by mass or more, 50% by mass or more, 55% by mass or more, 60% by mass or more, 65% by mass or more, more preferably 70% by mass. 75% by mass or more, more preferably 80% by mass or more, 85% by mass or more, more preferably 90% by mass or more, more preferably 9% by mass or more, and particularly preferably 96.5% by mass or more, and most preferably It is 98 mass% or more. The EPA has a high purity, for example, the EPA content ratio in all fatty acids is preferably 40% by mass or more, more preferably 60% by mass or more, still more preferably 70% by mass or more, and 80% by mass. % Or more is more preferred, 90% or more is more preferred, 96.5% or more is particularly preferred, and 98% or more is most preferred. Further, the content of EPA-E in the total fatty acids of the self-emulsifying composition is 40% by mass or more, 41% by mass or more, 42% by mass or more, 43% by mass or more, 44% by mass or more, 45% by mass or more, 46% by mass or more, 47% by mass or more, 48% by mass or more, 49% by mass or more, 50% by mass or more, 51% by mass or more, 52% by mass or more, 53% by mass or more, 54% by mass or more, 55% by mass or more, 56% or more, 57% or more, 58% or more, 59% or more, 60% or more, 61% or more, 62% or more, 63% or more, 64% or more, 65% or more, 66% or more, 67% or more, 68% or more, 69% or more, 70% or more, 71% or more, 72% or more, 73% or more, 74% or more, 75% or more, 76% by mass or more, 77% by mass or less 78% by mass, 79% by mass or more, 80% by mass or more, 81% by mass or more, 82% by mass or more, 83% by mass or more, 84% by mass or more, 85% by mass or more, 86% by mass or more, 87% by mass or more 88% by weight or more, 89% by weight or more, 90% by weight or more, 91% by weight or more, 92% by weight or more, 93% by weight or more, 94% by weight or more, 95% by weight or more, 96% by weight or more, 96.5% by weight % Or more, 97 mass% or more, 98 mass% or more, or 99 mass% or more. Most preferred is a purity of EPA that is substantially free of DHA or, for example, less than 1.0% by weight, preferably less than 0.5% by weight, more preferably less than 0.2% by weight. That is, it is desirable that the purity of EPA-E is higher.
　本発明の自己乳化組成物に用いる原料のＥＰＡ－Ｅに代えて、ＥＰＡ－ＥとＤＨＡ－Ｅとを含む組成物（例えばＥＰＡ－ＥとＤＨＡ－Ｅとの質量比が１０：１～１：１０、５：１～１：５、４：１～１：５または３：１～１：３の範囲内の混合組成物であるもの、あるいはまたその混合組成物にその混合物の質量より少ない質量の他の脂肪酸もしくはそのエステルもしくはトリグリセリド等を含み得るもの、より具体的にはω３ＰＵＦＡエチルエステル）あるいはＥＰＡとＤＨＡとを含む組成物（例えばＥＰＡとＤＨＡとの質量比が１０：１～１：１０、５：１～１：５、４：１～１：５または３：１～１：３の範囲内の混合組成物であるもの、あるいはまたその混合組成物にその混合物の質量より少ない質量の他の脂肪酸もしくはそのエステルもしくはトリグリセリド等を含み得るもの、より具体的にはω３ＰＵＦＡ）を使用することも可能である。
　また、本発明の前記組成物は、ＥＰＡ類およびＤＰＡ、またはＥＰＡ類、ＤＰＡおよびＨＰＡ、またはＥＰＡ類、ＤＰＡおよびＴＰＡ、またはＥＰＡ類、ＤＰＡ、ＨＰＡおよびＴＰＡを含む場合がある。望ましいＥＰＡ類：ＤＰＡの比は、９９：１～１：９９、９０：１～１：９０、６０：１～１：６０、４０：１～１：４０、３０：１～１：３０、２０：１～１：２０、１０：１～１：１０、５：１～１：５、および２：１～１：２である。
　また、本発明の前記組成物は、ＥＰＡ類、ＤＨＡ類およびＤＰＡ、またはＥＰＡ類、ＤＨＡ類、ＤＰＡおよびＨＰＡ、またはＥＰＡ類、ＤＨＡ類、ＤＰＡおよびＴＰＡ、またはＥＰＡ類、ＤＨＡ類、ＤＰＡ、ＨＰＡおよびＴＰＡを含む場合がある。望ましいＤＨＡ類：ＤＰＡ比は、１：１００以下、１：９５以下、１：９０以下、１：８０以下、１：７０以下、１：６０以下、１：５０以下、１：４０以下、１：３０以下、１：２０以下、１：１０以下、１：５以下、１：２以下、１：１以下、２：１以下、５：１以下、１０：１以下、２０：１以下、５０：１以下、および１００：１以下である。
　また、本発明の自己乳化組成物はω３ＰＵＦＡ類以外にＡＡ、リノール酸、γリノレン酸、ジホモ-γ-リノレン酸などのω６多価不飽和脂肪酸、それらの製薬学上許容しうる塩類、エステル類、アミド類またはリン脂質類を含有する場合もある。ただし、ω６多価不飽和脂肪酸の全脂肪酸類中の含有量は低いほうが望ましく、より望ましくは１０質量％未満、９質量％未満、８質量％未満、７質量％未満、６質量％未満、５質量％未満、４質量％未満、３質量％未満、２質量％未満、１質量％未満および０．５質量％未満、さらに望ましくは０．２質量％未満である。特に、ＡＡおよびそれらの製薬学上許容しうる塩類、エステル類、アミド類またはリン脂質類（以下、ＡＡ類と記す）の全脂肪酸含有量に対する含有量は、低いほうが望ましく、より望ましくは５質量％未満、４質量％未満、３質量％未満、２質量％未満、１質量％未満、０．５質量％未満、０．３質量％未満、０．２質量％未満、０．１質量％未満で、さらに望ましくは０．０５質量％未満、最も望ましくは、ＡＡ類を実質的に含まない態様がとくに好ましい。 Instead of the raw material EPA-E used in the self-emulsifying composition of the present invention, a composition containing EPA-E and DHA-E (for example, a mass ratio of EPA-E to DHA-E is 10: 1 to 1: A mixture composition in the range of 10, 5: 1 to 1: 5, 4: 1 to 1: 5 or 3: 1 to 1: 3, or also less than the weight of the mixture in the mixture composition Other fatty acids or esters thereof or triglycerides, more specifically, ω3 PUFA ethyl ester) or a composition containing EPA and DHA (for example, a mass ratio of EPA to DHA of 10: 1 to 1:10). 5: 1 to 1: 5, 4: 1 to 1: 5 or 3: 1 to 1: 3 in the mixed composition, or also in the mixed composition less than the weight of the mixture Other fatty acids or their Which may include le or triglycerides, and the like, and more specifically it is also possible to use ω3PUFA).
The compositions of the present invention may also include EPAs and DPA, or EPAs, DPA and HPA, or EPAs, DPA and TPA, or EPAs, DPA, HPA, and TPA. Desirable EPAs: DPA ratios are 99: 1 to 1:99, 90: 1 to 1:90, 60: 1 to 1:60, 40: 1 to 1:40, 30: 1 to 1:30, 20 1 to 1:20, 10: 1 to 1:10, 5: 1 to 1: 5, and 2: 1 to 1: 2.
Also, the composition of the present invention comprises EPAs, DHAs and DPA, or EPAs, DHAs, DPA and HPA, or EPAs, DHAs, DPA and TPA, or EPAs, DHAs, DPA, HPA And TPA. Desirable DHAs: DPA ratios are 1: 100 or less, 1:95 or less, 1:90 or less, 1:80 or less, 1:70 or less, 1:60 or less, 1:50 or less, 1:40 or less, 1: 30 or less, 1:20 or less, 1:10 or less, 1: 5 or less, 1: 2 or less, 1: 1 or less, 2: 1 or less, 5: 1 or less, 10: 1 or less, 20: 1 or less, 50: 1 or less, and 100: 1 or less.
In addition to ω3 PUFAs, the self-emulsifying composition of the present invention includes ω6 polyunsaturated fatty acids such as AA, linoleic acid, γ-linolenic acid and dihomo-γ-linolenic acid, pharmaceutically acceptable salts and esters thereof. May contain amides or phospholipids. However, the content of ω6 polyunsaturated fatty acid in all fatty acids is desirably low, and more desirably less than 10% by mass, less than 9% by mass, less than 8% by mass, less than 7% by mass, less than 6% by mass, 5% Less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, more preferably less than 0.2% by weight. In particular, the content of AA and their pharmaceutically acceptable salts, esters, amides or phospholipids (hereinafter referred to as AA) with respect to the total fatty acid content is desirably low, more desirably 5 masses. %, Less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.3%, less than 0.2%, less than 0.1% More desirably, the aspect is more preferably less than 0.05% by mass, and most desirably an embodiment substantially free of AA's.
　本発明の自己乳化組成物における、自己乳化組成物の全量を１００質量％としたときのω３ＰＵＦＡ類またはＥＰＡ類の含量は、５０～９０質量％、好ましくは６０～８６質量％、さらに好ましくは６５～８０質量％、より好ましくは７０～８０質量％である。
　また、本発明の自己乳化組成物における、自己乳化組成物の全量を１００質量％としたω３ＰＵＦＡ類またはＥＰＡ類の含量は、５０質量％以上、５１質量％以上、５２質量％以上、５３質量％以上、５４質量％以上、５５質量％以上、５６質量％以上、５７質量％以上、５８質量％以上、５９質量％以上、６０質量％以上、６１質量％以上、６２質量％以上、６３質量％以上、６４質量％以上、６５質量％以上、６６質量％以上、６７質量％以上、６８質量％以上、６９質量％以上、７０質量％以上、７１質量％以上、７２質量％以上、７３質量％以上、７４質量％以上、７５質量％以上、７６質量％以上、７７質量％以上、７８質量％以上、７９質量％以上、８０質量％以上、８１質量％以上、８２質量％以上、８３質量％以上、８４質量％以上、８５質量％以上、８６質量％以上、８７質量％以上、８８質量％以上、８９質量％以上または９０質量％以上、好ましくは５５質量％以上、より好ましくは６０質量％以上、さらに好ましくは６５質量％以上、いっそう好ましくは７０質量％以上、よりいっそう好ましくは７３質量％以上、とりわけ好ましくは７６質量％以上である。 In the self-emulsifying composition of the present invention, the content of ω3 PUFAs or EPAs when the total amount of the self-emulsifying composition is 100% by mass is 50 to 90% by mass, preferably 60 to 86% by mass, and more preferably 65%. -80% by mass, more preferably 70-80% by mass.
In the self-emulsifying composition of the present invention, the content of ω3 PUFAs or EPAs with the total amount of the self-emulsifying composition being 100% by mass is 50% by mass, 51% by mass, 52% by mass, 53% by mass. 54% by mass or more, 55% by mass or more, 56% by mass or more, 57% by mass or more, 58% by mass or more, 59% by mass or more, 60% by mass or more, 61% by mass or more, 62% by mass or more, 63% by mass Or more, 64 mass% or more, 65 mass% or more, 66 mass% or more, 67 mass% or more, 68 mass% or more, 69 mass% or more, 70 mass% or more, 71 mass% or more, 72 mass% or more, 73 mass% 74% by mass or more, 75% by mass or more, 76% by mass or more, 77% by mass or more, 78% by mass or more, 79% by mass or more, 80% by mass or more, 81% by mass or more, 82% by mass or more, 83% by mass 84 quality % Or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, or 90% or more, preferably 55% or more, more preferably 60% or more, and even more preferably. Is 65% by mass or more, more preferably 70% by mass or more, still more preferably 73% by mass or more, and particularly preferably 76% by mass or more.
　ω３ＰＵＦＡ類を含有する様々な市販製品があり、例えば、ＩｎｃｒｏｍｅｇａTM　ＤＨＡ２７、、ＩｎｃｒｏｍｅｇａTM　ＤＨＡ４６、、ＩｎｃｒｏｍｅｇａTM　ＤＨＡ７００Ｅ、、ＩｎｃｒｏｍｅｇａTM　ＤＨＡ７００ＴＧ、、ＩｎｃｒｏｍｅｇａTM　ＤＨＡ　５００ＴＧ、、ＩｎｃｒｏｍｅｇａTM　Ｅ４００２００、、ＩｎｃｒｏｍｅｇａTM　Ｅ４０３０、、ＩｎｃｒｏｍｅｇａTM　Ｅ４５２０、、ＩｎｃｒｏｍｅｇａTM　Ｅ４６０１８０、、ＩｎｃｒｏｍｅｇａTM　Ｅ５０２０、、ＩｎｃｒｏｍｅｇａTM　Ｅ５３０２００、、ＩｎｃｒｏｍｅｇａTM　Ｅ６８１４、、ＩｎｃｒｏｍｅｇａTM　Ｅ１０５０、、ＩｎｃｒｏｍｅｇａTM　Ｅ１０７０、、ＩｎｃｒｏｍｅｇａTM　Ｅ３３２２、、ＩｎｃｒｏｍｅｇａTM　Ｅ３５２５、、ＩｎｃｒｏｍｅｇａTM　Ｅ３８２６、、ＩｎｃｒｏｍｅｇａTM　Ｅ７０１０、、ＩｎｃｒｏｍｅｇａTM　ＥＰＡ５００ＥＥ、、ＩｎｃｒｏｍｅｇａTM　ＥＰＡ５００ＴＧ、、ＩｎｃｒｏｍｅｇａTM　ＥＰＡ７００Ｅ、、ＩｎｃｒｏｍｅｇａTM　ＴＧ０５２５、、ＩｎｃｒｏｍｅｇａTM　ＴＧ１０４０、、ＩｎｃｒｏｍｅｇａTM　ＴＧ１０５０、、ＩｎｃｒｏｍｅｇａTM　ＴＧ３３２２、、ＩｎｃｒｏｍｅｇａTM　ＴＧ３３２２ＳＲ、、ＩｎｃｒｏｍｅｇａTM　ＴＧ４０３０、、ＩｎｃｒｏｍｅｇａTM　ＴＧ６０１５、、ＩｎｃｒｏｍｅｇａTM　ＴＧ７０１０、、ＩｎｃｒｏｍｅｇａTM　ＴｒｉｏＥＥおよびＩｎｃｒｏｍｅｇａTM　Ｔｒｉｏ　ＥＥ　（Ｃｒｏｄａ　Ｉｎｔｅｒｎａｔｉｏｎａｌ　ＰＬＣ、、Ｙｏｒｋｓｈｉｒｅ、Ｅｎｇｌａｎｄ）、およびＥＰＡＸ６５００ＥＥ、ＥＰＡＸ６０１５ＴＧ、ＥＰＡＸ６０１５ＥＥ、ＥＰＡＸ６０００ＴＧ、ＥＰＡＸ６０００ＥＥ、ＥＰＡＸ６０００ＴＧＮ、ＥＰＡＸ６０００ＦＡ、ＥＰＡＸ５５００ＥＥ、ＥＰＡＸ５０００ＴＧ、ＥＰＡＸ４５１０ＴＧ、ＥＰＡＸ４０２０ＴＧ、ＥＰＡＸ４０２０ＥＥ、ＥＰＡＸ２０５０ＴＧ、ＥＰＡＸ７０１０ＥＥ、ＥＰＡＸ１０５０ＴＧ、ＥＰＡＸ１０５０ＴＧＮ、Ｋ８５ＴＧ、Ｋ８５ＥＥ、およびＫ８０ＥＥ　（ＦＭＣ　Ｃｏｒｐｏｒａｔｉｏｎ、Ｐｈｉｌａｄｅｌｐｈｉａ、Ｕ．Ｓ．Ａ．）、また、ＬｏｖａｚａTM（Ｇｌａｘｏ　ＳｍｉｔｈＫｌｉｎｅ、ＦＬ　ＵＳＡ）、Ｏｍａｃｏｒ　TM（Ｐｒｏｎｏｖａ　Ｂｉｏｐｈａｒｍａ　ＡＳＡ、Ｏｓｌｏ　Ｎｏｒｗａｙ）、ＬｏｔｒｉｇａTM（Ｔａｋｅｄａ　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｃｏ．、　Ｌｔｄ．、Ｏｓａｋａ　Ｊａｐａｎ）などがある。これらの製品を購入し、本発明の自己乳化組成物に使用してもよい。
　また、ＥＰＡ－Ｅは、日本において、ＡＳＯおよび高脂血症治療薬として入手可能な高純度ＥＰＡ－Ｅ（９６．５質量％以上）含有軟カプセル剤（商品名エパデール：持田製薬社製）や、米国において、重度高ＴＧ血症治療薬として入手可能な高純度ＥＰＡ－Ｅ含有軟カプセル剤（商品名ＶＡＳＣＥＰＡ：アマリン）の内容物を用いることができる。
　また、ω３ＰＵＦＡ遊離酸を含有する、ＥｐａｎｏｖａTM（Ｏｍｔｈｅｒａ、Ａｓｔｒａｚｅｎｅｃａ）またはＭＡＴ９００１（Ｍａｔｉｎａｓ　Ｂｉｏｐｈａｒｍａ）などの開発中の組成物、あるいはＷＯ２０１５／１９５４９１号パンフレットに記載されたマグネシウム　ビス－リジネート　ビス－ＥＰＡ　ジハイドレート、マグネシウム　ビス－リジネート　ビス－ＤＨＡ　ジハイドレート、マグネシウム　ビス－リジネート　ビス－ＤＰＡ　ジハイドレート等を使用してもよい。 There are a variety of commercial products containing ω3PUFA, such, Incromega TM DHA27,, Incromega TM DHA46,, Incromega TM DHA700E ,, Incromega TM DHA700TG ,, Incromega TM DHA 500TG ,, Incromega TM E400200,, Incromega TM E4030 ,, Incromega TM E4520,, Incromega TM E460180 ,, Incromega TM E5020,, Incromega TM E530200,, Incromega TM E6814,, Incromega TM E1050,, Incromega TM E1070,, Incromega TM E3322,, Incromega TM E3525,, Incromega TM E382 ,, Incromega TM E7010,, Incromega TM EPA500EE ,, Incromega TM EPA500TG ,, Incromega TM EPA700E ,, Incromega TM TG0525,, Incromega TM TG1040,, Incromega TM TG1050,, Incromega TM TG3322,, Incromega TM TG3322SR ,, Incromega TM TG4030 , Incromega ™ TG6015, Incromega ™ TG7010, Incromega ™ TrioEE and Incromega ™ Trio EE (Croda International PLC, Yorkshire, England), and EPAX6X EPAX6015EE, EPAX6000TG, EPAX6000EE, EPAX6000TGN, EPAX6000FA, EPAX5500EE, EPAX5000TG, EPAX4510TG, EPAX4020TG, EPAX4020EE, EPAX2050TG, EPAX7010EE, EPAX1050TG, EPAX1050TGN, K85TG, K85EE, and K80EE (FMC Corporation, Philadelphia, U.S.A.), Also, Lovaza ™ (Glaxo SmithKline, FL USA), Omacor ™ (Pronova Biopharma ASA, Oslo Norway), Lotriga ™ (Takeda Pharmaceutical Co. Ltd., Ltd. Osaka Japan). These products may be purchased and used in the self-emulsifying composition of the present invention.
EPA-E is a soft capsule (trade name Epadale: manufactured by Mochida Pharmaceutical Co., Ltd.) containing high-purity EPA-E (96.5% by mass or more) that can be obtained as a therapeutic agent for ASO and hyperlipidemia in Japan. In the United States, the contents of a high-purity EPA-E-containing soft capsule (trade name VASCEPA: amarin) that can be obtained as a therapeutic agent for severe hyperTGemia can be used.
Further, a composition under development such as Epanova ™ (Omthera, AstraZeneca) or MAT9001 (Matinas Biopharma) containing ω3 PUFA free acid, or a magnesium bis-liginate bis-EPA dihydrate described in WO2015 / 195491 Bis-lysinate bis-DHA dihydrate, magnesium bis-lysinate bis-DPA dihydrate and the like may be used.
　本発明で使用される「自己乳化組成物」とは、水溶液に接触した際に容易に分散・自己乳化する組成物であり、国際公開ＷＯ２０１０／１３４６１４号パンフレット、国際公開ＷＯ２０１５／００８８４８号パンフレット、国際公開ＷＯ２０１５／００８８４９号パンフレット、国際公開ＷＯ２０１６／１１７０５７号パンフレット、国際公開ＷＯ２０１６／１１７６２１号パンフレット、国際公開ＷＯ２０１６／１１７６２９号パンフレット、国際公開ＷＯ２０１０／１０３４０２号パンフレット、国際公開ＷＯ２０１０／１０３４０４号パンフレット、国際公開ＷＯ２０１０／１１９３１９号パンフレットおよび国際公開ＷＯ２０１１／０４７２５９号パンフレットに記載されている自己乳化組成物を含む。
　例えば、国際公開ＷＯ２０１０／１３４６１４号パンフレット実施例１～１３に記載されている自己乳化組成物、国際公開ＷＯ２０１５／００８８４８号パンフレット実施例１～１１に記載されている自己乳化組成物、国際公開ＷＯ２０１５／００８８４９号パンフレット実施例１～１７に記載されている自己乳化組成物、国際公開ＷＯ２０１６／１１７０５７号パンフレット実施例１～１１に記載されている自己乳化組成物、国際公開ＷＯ２０１６／１１７６２１号パンフレット実施例１～８に記載されている自己乳化組成物、国際公開ＷＯ２０１６／１１７６２９号パンフレット実施例１～１１および実施例３－１～３－２５２に記載されている自己乳化組成物、国際公開ＷＯ２０１０／１０３４０２号パンフレット実施例６４～６７に記載されている自己乳化組成物、国際公開ＷＯ２０１０／１０３４０４号パンフレット実施例７および８に記載されている自己乳化組成物、国際公開ＷＯ２０１０／１１９３１９号パンフレット実施例１、２、４、９および１０に記載されている自己乳化組成物および国際公開ＷＯ２０１１／０４７２５９号パンフレット実施例３および４に記載されている自己乳化組成物、ＧＳＫ２２１２８３６を含むが、これらに限定されない。 The “self-emulsifying composition” used in the present invention is a composition that easily disperses and self-emulsifies when in contact with an aqueous solution, and is disclosed in International Publication WO2010 / 134614, International Publication WO2015 / 008848, International Publication WO2015 / 008849 pamphlet, International publication WO2016 / 117057 pamphlet, International publication WO2016 / 117621 pamphlet, International publication WO2016 / 117629 pamphlet, International publication WO2010 / 103402 pamphlet, International publication WO2010 / 103404 pamphlet, International publication WO2010 / 119319 pamphlet and international publication WO2011 / 047259 pamphlet.
For example, the self-emulsifying composition described in Examples 1 to 13 of International Publication WO2010 / 134614, the self-emulsifying composition described in Examples 1 to 11 of International Publication WO2015 / 008848, and International Publication WO2015 / Self-emulsifying composition described in pamphlet Examples 1 to 17 of No. 008849, self-emulsifying composition described in pamphlet examples 1 to 11 of international publication WO2016 / 117057, pamphlet example 1 of international publication WO2016 / 117621 Self-emulsifying composition described in -8, self-emulsifying composition described in International Publication WO2016 / 117629, Examples 1 to 11 and Examples 3-1 to 3-252, International Publication WO2010 / 103402 Brochure examples 64-67 The self-emulsifying composition described, the self-emulsifying composition described in International Publication WO 2010/103404, Examples 7 and 8, and International Publication WO 2010/119319, Examples 1, 2, 4, 9 and 10 Including, but not limited to, the self-emulsifying composition described and the self-emulsifying composition described in International Publication WO2011 / 047259, Examples 3 and 4.
　本発明で使用される「乳化剤」とは、親水基部分と親油基部分を有し、水と油のような本来混じり合わないものの境界面で働いて均一な状態を作る作用を持つ化合物である。例えば、国際公開ＷＯ２０１０／１３４６１４号パンフレット、国際公開ＷＯ２０１５／００８８４８号パンフレット、国際公開ＷＯ２０１５／００８８４９号パンフレット、国際公開ＷＯ２０１６／１１７０５７号パンフレット、国際公開ＷＯ２０１６／１１７６２１号パンフレット、国際公開ＷＯ２０１６／１１７６２９号パンフレット、国際公開ＷＯ２０１０／１０３４０２号パンフレット、国際公開ＷＯ２０１０／１０３４０４号パンフレット、国際公開ＷＯ２０１０／１１９３１９号パンフレットおよび国際公開ＷＯ２０１１／０４７２５９号パンフレットに記載されている乳化剤を含む。例えば、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンヒマシ油、ポリエチレングリコール脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコール、ショ糖脂肪酸エステル、ソルビタン脂肪酸エステル、グリセリン脂肪酸エステル、等が挙げられるが、これらに限定されない。
　本発明で使用される「ＨＬＢ」とは、親水基を持たず親油基のみを持つ物質をＨＬＢ０とし、親油基をもたず親水基のみを持つ物質をＨＬＢ２０として等分したもので、親油性と親水性を併せ持っている乳化剤はその間の値をとることになる。本発明の自己乳化組成物に含有される乳化剤は、ＨＬＢが１０以上であることが好ましいが、より好ましくは１１以上、さらに好ましくは１２以上である。 The “emulsifier” used in the present invention is a compound that has a hydrophilic group part and a lipophilic group part, and has an action of creating a uniform state by working at the boundary surface of water and oil that are not originally mixed. is there. For example, international publication WO2010 / 134614 pamphlet, international publication WO2015 / 008848 pamphlet, international publication WO2015 / 008849 pamphlet, international publication WO2016 / 117757 pamphlet, international publication WO2016 / 117621 pamphlet, international publication WO2016 / 117629 pamphlet, The emulsifier described in the international publication WO2010 / 103402 pamphlet, the international publication WO2010 / 103404 pamphlet, the international publication WO2010 / 119319 pamphlet, and the international publication WO2011 / 047259 pamphlet is included. For example, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, etc. For example, but not limited to.
“HLB” used in the present invention is a substance that has no hydrophilic group and has only a lipophilic group as HLB0, and a substance that does not have a lipophilic group and has only a hydrophilic group as HLB20. An emulsifier having both lipophilicity and hydrophilicity takes a value in between. The emulsifier contained in the self-emulsifying composition of the present invention preferably has an HLB of 10 or more, more preferably 11 or more, and still more preferably 12 or more.
　本発明において、「ポリオキシエチレン硬化ヒマシ油」は、ヒマシ油に水素を添加した硬化ヒマシ油に酸化エチレンが付加重合した化合物である。酸化エチレンの平均重合度により種々の化合物が市販されており、例えば、ポリオキシエチレン（２０）硬化ヒマシ油（ＮＩＫＫＯＬ ＨＣＯ－２０、日光ケミカルズ）、ポリオキシエチレン（４０）硬化ヒマシ油（ＮＩＫＫＯＬ ＨＣＯ－４０、日光ケミカルズ）、ポリオキシエチレン（５０）硬化ヒマシ油（ＮＩＫＫＯＬ ＨＣＯ－５０、日光ケミカルズ）、ポリオキシエチレン（６０）硬化ヒマシ油（ＮＩＫＫＯＬ ＨＣＯ－６０、日光ケミカルズ）およびポリオキシエチレン（１００）硬化ヒマシ油（ＮＩＫＫＯＬ ＨＣＯ－１００、日光ケミカルズ）が例示され、好ましくはポリオキシエチレン（６０）硬化ヒマシ油が例示されるが、これらに限定されない。また、これらのうちの１種を単独で、あるいは２種以上を組み合わせて用いることもできる。本発明においてポリオキシエチレン硬化ヒマシ油とは、特に断らない限りは、上記のような化合物をすべて含む意味で用いられる。 In the present invention, “polyoxyethylene hydrogenated castor oil” is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil obtained by adding hydrogen to castor oil. Various compounds are commercially available depending on the average degree of polymerization of ethylene oxide. For example, polyoxyethylene (20) hydrogenated castor oil (NIKKOL HCO-20, Nikko Chemicals), polyoxyethylene (40) hydrogenated castor oil (NIKKOL HCO- 40, Nikko Chemicals), polyoxyethylene (50) hydrogenated castor oil (NIKKOL HCO-50, Nikko Chemicals), polyoxyethylene (60) hydrogenated castor oil (NIKKOL HCO-60, Nikko Chemicals) and polyoxyethylene (100) Examples include, but are not limited to, hydrogenated castor oil (NIKKOLＯHCO-100, Nikko Chemicals), and preferably polyoxyethylene (60) hydrogenated castor oil. Moreover, one of these can be used alone or in combination of two or more. In the present invention, the term “polyoxyethylene hydrogenated castor oil” is used in the sense of including all of the above compounds unless otherwise specified.
　本発明において、「ポリオキシエチレンソルビタン脂肪酸エステル」は無水ソルビトールの水酸基の一部が脂肪酸でエステル化された脂肪酸エステルのポリオキシエチレンエーテルである。エステル化する脂肪酸により種々の化合物が市販されており、例えば、モノラウリン酸ポリオキシエチレン（２０）ソルビタン（ＮＩＫＫＯＬ　ＴＬ－１０、ポリソルベート２０、Ｔｗｅｅｎ２０）、モノパルミチン酸ポリオキシエチレン（２０）ソルビタン（ＮＩＫＫＯＬ　ＴＰ－１０Ｖ、ポリソルベート４０、Ｔｗｅｅｎ４０）、モノステアリン酸ポリオキシエチレン（２０）ソルビタン（ＮＩＫＫＯＬ　ＴＳ－１０ＭＶ、ポリソルベート６０、Ｔｗｅｅｎ６０）、トリステアリン酸ポリオキシエチレン（２０）ソルビタン（ＮＩＫＫＯＬ　ＴＳ－３０Ｖ、ポリソルベート６５）、モノイソステアリン酸ポリオキシエチレン（２０）ソルビタン（ＮＩＫＫＯＬ　ＴＩ－１０Ｖ）、モノオレイン酸ポリオキシエチレン（２０）ソルビタン（ＮＩＫＫＯＬ　ＴＯ－１０ＭＶ、ポリソルベート８０、Ｔｗｅｅｎ８０）、トリオレイン酸ポリオキシエチレン（２０）ソルビタン（ＮＩＫＫＯＬ　ＴＯ－３０Ｖ、ポリソルベート８５）等が例示され、好ましくは、モノオレイン酸ポリオキシエチレン（２０）ソルビタン、トリオレイン酸ポリオキシエチレン（２０）ソルビタンが例示され、より好ましくは、モノオレイン酸ポリオキシエチレン（２０）ソルビタンが例示されるが、これらに限定されない。
　また、これらのうちの１種を単独で、あるいは２種以上を組み合わせて用いることもできる。本発明においてポリオキシエチレンソルビタン脂肪酸エステルとは上記のような化合物をすべて含む意味で用いられる。 In the present invention, “polyoxyethylene sorbitan fatty acid ester” is a polyoxyethylene ether of a fatty acid ester in which a part of hydroxyl groups of anhydrous sorbitol is esterified with a fatty acid. Various compounds are commercially available depending on the fatty acid to be esterified. For example, polyoxyethylene (20) sorbitan monolaurate (NIKKOL TL-10, polysorbate 20, Tween 20), polyoxyethylene (20) sorbitan monopalmitate (NIKKOL TP) -10V, polysorbate 40, Tween 40), polyoxyethylene (20) sorbitan monostearate (NIKKOL TS-10MV, polysorbate 60, Tween 60), polyoxyethylene (20) sorbitan tristearate (NIKKOL TS-30V, polysorbate 65) , Polyoxyethylene (20) sorbitan monoisostearate (NIKKOL TI-10V), polyoxyethylene (20) sorbitan monooleate (NIK) OL TO-10MV, polysorbate 80, Tween 80), polyoxyethylene (20) sorbitan trioleate (NIKKOL TO-30V, polysorbate 85) and the like, preferably polyoxyethylene (20) sorbitan monooleate, trio Polyoxyethylene (20) sorbitan oleate is exemplified, and more preferably, polyoxyethylene (20) sorbitan monooleate is exemplified, but not limited thereto.
Moreover, one of these can be used alone or in combination of two or more. In the present invention, the term “polyoxyethylene sorbitan fatty acid ester” is used in the sense of including all of the above compounds.
　本発明において、「ポリオキシエチレンヒマシ油」は、ヒマシ油に酸化エチレンが付加重合した化合物である。酸化エチレンの平均付加モル数により種々の化合物が市販されており、例えば、平均付加モル数３のＮＩＫＫＯＬ　ＣＯ－３（日光ケミカルズ）、平均付加モル数１０のＮＩＫＫＯＬ　ＣＯ－１０（日光ケミカルズ）、平均付加モル数２０のＥＭＡＬＥＸ　Ｃ－２０（日本エマルジョン）、平均付加モル数３０のＥＭＡＬＥＸ　Ｃ－３０（日本エマルジョン）、平均付加モル数３５のＫｏｌｌｉｐｈｏｒ　ＥＬ（ＢＡＳＦ）（ポリオキシル３５ヒマシ油）、平均付加モル数４０のＥＭＡＬＥＸ　Ｃ－４０（日本エマルジョン）および平均付加モル数５０のＥＭＡＬＥＸ　Ｃ－５０（日本エマルジョン）が例示され、好ましくはＫｏｌｌｉｐｈｏｒ　ＥＬであるが、これらに限定されない。また、これらのうちの１種を単独で、あるいは２種以上を組み合わせて用いることもできる。本発明においてポリオキシエチレンヒマシ油とは、特に断らない限りは、上記のような化合物をすべて含む意味で用いられる。 In the present invention, “polyoxyethylene castor oil” is a compound obtained by addition polymerization of castor oil with ethylene oxide. Various compounds are commercially available depending on the average number of moles of ethylene oxide added. For example, NIKKOL CO-3 (Nikko Chemicals) with an average number of added moles of 3, NIKKOL CO-10 (Nikko Chemicals) with an average number of added moles of 10 and an average EMALEX C-20 (Japanese emulsion) with 20 added moles, EMALEX C-30 (Japanese emulsion) with 30 added moles, Kolliphor EL (BASF) (polyoxyl 35 castor oil) with 35 added moles, average added mole For example, EMALEX C-40 (Japanese emulsion) having a number of 40 and EMALEX C-50 (Japanese emulsion) having an average added mole number of 50 are exemplified, and Kolliphor EL is preferable, but is not limited thereto. Moreover, one of these can be used alone or in combination of two or more. In the present invention, the term “polyoxyethylene castor oil” is used in the sense of including all the above compounds unless otherwise specified.
　本発明において、「ポリエチレングリコール脂肪酸エステル」は、ポリエチレングリコールの脂肪酸エステルであり、酸化エチレンで重合された脂肪酸である。市販製品には、エステル化された脂肪酸が異なる様々な化合物がある。例としては、ポリエチレングリコールモノラウレート（ＮＩＫＫＯＬ　ＭＹＬ－１０、Ｎｉｋｋｏ　Ｃｈｅｍｉｃａｌｓ　Ｃｏ．、　Ｌｔｄ．）、ポリエチレングリコールモノステアレート（ＮＩＫＫＯＬ　ＭＹＳ－１０Ｖ、ＭＹＳ－２５Ｖ、ＭＹＳ－４０Ｖ、ＮＹＳ－４５Ｖ、およびＭＹＳ－５５Ｖ、Ｎｉｋｋｏ　Ｃｈｅｍｉｃａｌｓ　Ｃｏ．、　Ｌｔｄ．）、ポリエチレングリコールモノオレエート（ＮＩＫＫＯＬ　ＭＹＯ－６およびＭＹＯ－１０、Ｎｉｋｋｏ　Ｃｈｅｍｉｃａｌｓ　Ｃｏ．、　Ｌｔｄ．）、ポリエチレングリコールジステアレート（ＮＩＫＫＯＬ　ＣＤＳ－６０００Ｐ、Ｎｉｋｋｏ　Ｃｈｅｍｉｃａｌｓ　Ｃｏ．、　Ｌｔｄ．）、およびポリエチレングリコールジイソステアレート（ＮＩＫＫＯＬ　ＣＤＩＳ－４００、Ｎｉｋｋｏ　Ｃｈｅｍｉｃａｌｓ　Ｃｏ．、　Ｌｔｄ．）などがあるが、これらに限定されない。また、これらのうちの１種を単独で、あるいは２種以上を組み合わせて用いることもできる。本発明においてポリエチレングリコール脂肪酸エステルとは、特に断らない限りは、上記のような化合物をすべて含む意味で用いられる。 In the present invention, “polyethylene glycol fatty acid ester” is a fatty acid ester of polyethylene glycol, which is a fatty acid polymerized with ethylene oxide. Commercial products include various compounds that differ in esterified fatty acids. Examples include polyethylene glycol monolaurate (NIKKOL MYL-10, Nikko Chemicals Co., Ltd.), polyethylene glycol monostearate (NIKKOL MYS-10V, MYS-25V, MYS-40V, NYS-45V, and MYS- 55V, Nikko Chemicals Co., Ltd., polyethylene glycol monooleate (NIKKOL MYO-6 and MYO-10, Nikko Chemicals Co., Ltd.), Polyethylene glycol distearate (NIKKOL CDS-Colks Cok. , Ltd.), and polyethylene glycol diisostearate (NIKKOL CDIS-400) Nikko Chemicals Co., Ltd.) there are such as, but not limited to. Moreover, one of these can be used alone or in combination of two or more. In the present invention, the term “polyethylene glycol fatty acid ester” is used in the meaning including all the above compounds unless otherwise specified.
　本発明において、「ポリオキシエチレンポリオキシプロピレングリコール」は、酸化エチレンのポリプロピレングリコールへの重合を加えることで調合される化合物であり、重合された酸化プロピレンである。市販製品には、酸化プロピレンと酸化エチレンの平均の重合程度が異なる様々な化合物がある。例としては、ポリオキシエチレン（３）ポリオキシプロピレン（１７）グリコール（Ａｄｅｋａ　Ｐｌｕｒｏｎｉｃ　Ｌ－３１、ＡＤＥＫＡ）、ポリオキシエチレン（２０）ポリオキシプロピレン（２０）グリコール（Ａｄｅｋａ　Ｐｌｕｒｏｎｉｃ　Ｌ－４４、ＡＤＥＫＡ）、ポリオキシエチレン（４２）ポリオキシプロピレン（６７）グリコール（Ａｄｅｋａ　Ｐｌｕｒｏｎｉｃ　Ｐ－１２３、ＡＤＥＫＡ）、ポリオキシエチレン（５４）ポリオキシプロピレン（３９）グリコール（Ｎｅｗｄｅｔ　ＰＥ－８５、Ｓａｎｙｏ　Ｃｈｅｍｉｃａｌ　Ｉｎｄｕｓｔｒｉｅｓ、　Ｌｔｄ．）、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコール（ＰＥＰ１０１、Ｓａｎｙｏ　Ｃｈｅｍｉｃａｌ　Ｉｎｄｕｓｔｒｉｅｓ、　Ｌｔｄ．）、ポリオキシエチレン（１２０）ポリオキシプロピレン（４０）グリコール（Ａｄｅｋａ　Ｐｌｕｒｏｎｉｃ　Ｆ－８７、ＡＤＥＫＡ）、ポリオキシエチレン（１６０）ポリオキシプロピレン（３０）グリコール（Ａｄｅｋａ　Ｐｌｕｒｏｎｉｃ　Ｆ－６８、ＡＤＥＫＡ）、ポリオキシエチレン（１９６）ポリオキシプロピレン（６７）グリコール（Ｌｕｔｒｏｌ　Ｆ１２７、ＢＡＳＦ　Ｊａｐａｎ）、およびポリオキシエチレン（２００）ポリオキシプロピレン（７０）グリコールなどがあり、望ましいものはポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコールであるが、これらに限定されない。また、これらのうちの１種を単独で、あるいは２種以上を組み合わせて用いることもできる。本発明においてポリオキシエチレンポリオキシプロピレングリコールとは、特に断らない限りは、上記のような化合物をすべて含む意味で用いられる。 In the present invention, “polyoxyethylene polyoxypropylene glycol” is a compound prepared by adding polymerization of ethylene oxide to polypropylene glycol, and is a polymerized propylene oxide. Commercial products include various compounds that differ in the average degree of polymerization of propylene oxide and ethylene oxide. Examples include polyoxyethylene (3) polyoxypropylene (17) glycol (Adeka Pluronic L-31, ADEKA), polyoxyethylene (20) polyoxypropylene (20) glycol (Adeka Pluronic L-44, ADEKA), Polyoxyethylene (42) polyoxypropylene (67) glycol (Adeka Pluronic P-123, ADEKA), polyoxyethylene (54) polyoxypropylene (39) glycol (Newdet PE-85, Sanyo Chemical Industries, Ltd.), Polyoxyethylene (105) Polyoxypropylene (5) Glycol (PEP101, Sanyo Chemical Industries, L d.), polyoxyethylene (120) polyoxypropylene (40) glycol (Adeka Pluronic F-87, ADEKA), polyoxyethylene (160) polyoxypropylene (30) glycol (Adeka Pluronic F-68, ADEKA), There are polyoxyethylene (196) polyoxypropylene (67) glycol (Lutrol F127, BASF Japan), polyoxyethylene (200) polyoxypropylene (70) glycol, etc., preferably polyoxyethylene (105) polyoxy Although it is propylene (5) glycol, it is not limited to these. Moreover, one of these can be used alone or in combination of two or more. In the present invention, the term “polyoxyethylene polyoxypropylene glycol” is used in the meaning including all the above compounds unless otherwise specified.
　本発明において、「ショ糖脂肪酸エステル」は、糖と脂肪酸のエステルである。市販製品には、エステル化された脂肪酸の種類とエステル化の程度が異なる様々な化合物がある。例としては、脂肪酸に９５％のラウリン酸を含有するＳｕｒｆｈｏｐｅ　ＳＥ　ＰＨＡＲＭＡ　Ｊ－１２１６（Ｍｉｔｓｕｂｉｓｈｉ－Ｋａｇａｋｕ　Ｆｏｏｄｓ　Ｃｏｒｐｏｒａｔｉｏｎ）、脂肪酸に９５％のミリスチン酸を含有するＳｕｒｆｈｏｐｅ　ＳＥ　ＰＨＡＲＭＡ　Ｊ－１４１６（Ｍｉｔｓｕｂｉｓｈｉ－Ｋａｇａｋｕ　Ｆｏｏｄｓ　Ｃｏｒｐｏｒａｔｉｏｎ）、脂肪酸に８０％のパルミチン酸を含有するＳｕｒｆｈｏｐｅ　ＳＥ　ＰＨＡＲＭＡ　Ｊ－１６１５およびＪ－１６１６（Ｍｉｔｓｕｂｉｓｈｉ－Ｋａｇａｋｕ　Ｆｏｏｄｓ　Ｃｏｒｐｏｒａｔｉｏｎ）、脂肪酸に７０％のステアリン酸を含有するＪ－１８１１、Ｊ－１８１５、およびＪ－１８１６（Ｍｉｔｓｕｂｉｓｈｉ－Ｋａｇａｋｕ　Fｏｏｄｓ　Ｃｏｒｐｏｒａｔｉｏｎ）、および脂肪酸に７０％のオレイン酸を含有するＳｕｒｆｈｏｐｅ　ＳＥ　ＰＨＡＲＭＡ　Ｊ－１７１５であるが、これらに限定されない。また、これらのうちの１種を単独で、あるいは２種以上を組み合わせて用いることもできる。本発明においてショ糖脂肪酸エステルとは、特に断らない限りは、上記のような化合物をすべて含む意味で用いられる。 In the present invention, “sucrose fatty acid ester” is an ester of sugar and fatty acid. Commercial products include various compounds that differ in the type of esterified fatty acid and the degree of esterification. Examples include Surfhope SE PHARMA J-1216 (Mitsubishi-Kagaku Foods Corporation), which contains 95% lauric acid in fatty acids, and SurfoSE PHARMA J-14gosfisChosfisChosfisChisFo-ChosfisChisFo-Chosfis-Chosfis-Chos-Fo (Chi-Fo-S-Chus-Fo-S-Chors-Ko-Fo-S-Fo-S-Chos-Fo-C-Fo-S-Chos-Fos ), Surfhope SE PHARMA J-1615 and J-1616 (Mitsubishi-Kagaku Foods Corporation) containing 80% palmitic acid in the fatty acid, J-1811, J-1815 and J-1815 containing 70% stearic acid in the fatty acid -1816 (Mitsubishi-Kagaku Foods Corpora ), and Surfhope SE PHARMA J-1715, which contains 70% oleic acid in the fatty acid, but is not limited thereto. Moreover, one of these can be used alone or in combination of two or more. In the present invention, the term “sucrose fatty acid ester” is used in the sense of including all of the above compounds unless otherwise specified.
　本発明において、「ソルビタン脂肪酸エステル」は、無水ソルビトールの水酸基を脂肪酸でエステル化したものである。エステル化する脂肪酸により種々の化合物が市販されており、例えば、モノラウリン酸ソルビタン（Ｓｐａｎ２０、ＮＩＫＫＯＬ　ＳＬ－１０、ノニオン　ＬＰ－２０Ｒ）、モノステアリン酸ソルビタン（ＮＩＫＫＯＬ　ＳＳ－１０ＭＶ）、モノオレイン酸ソルビタン（Ｓｐａｎ８０、ＮＩＫＫＯＬ　ＳＯ－１０Ｖ）、モノパルミチン酸ソルビタン（Ｓｐａｎ４０、ＮＩＫＫＯＬ　ＳＰ－１０Ｖ）、トリオレイン酸ソルビタン（ＮＩＫＫＯＬ　ＳＯ－３０）およびセスキオレイン酸ソルビタン（Ｓｐａｎ８３、ＮＩＫＫＯＬ　ＳＯ－１５ＭＶ、ノニオンＯＰ－８３Ｒ）が例示され、好ましくは、モノラウリン酸ソルビタン、モノオレイン酸ソルビタン、セスキオレイン酸ソルビタンが例示され、より好ましくは、モノラウリン酸ソルビタンが例示されるが、これらに限定されない。また、これらのうちの１種を単独で、あるいは２種以上を組み合わせて用いることもできる。本発明においてソルビタン脂肪酸エステルとは上記のような化合物をすべて含む意味で用いられる。 In the present invention, “sorbitan fatty acid ester” is obtained by esterifying the hydroxyl group of anhydrous sorbitol with a fatty acid. Various compounds are commercially available depending on the fatty acid to be esterified. For example, sorbitan monolaurate (Span20, NIKKOL SL-10, nonion LP-20R), sorbitan monostearate (NIKKOL SS-10MV), sorbitan monooleate (Span80 , NIKKOL SO-10V), sorbitan monopalmitate (Span40, NIKKOL SP-10V), sorbitan trioleate (NIKKOL SO-30) and sorbitan sesquioleate (Span83, NIKKOL SO-15MV, nonionic OP-83R) Preferably, sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, and more preferably sorbitan monolaurate is used. Although it is shown, but are not limited to. Moreover, one of these can be used alone or in combination of two or more. In the present invention, sorbitan fatty acid ester is used to mean all of the above compounds.
　本発明において、「グリセリン脂肪酸エステル」は、脂肪酸とグリセリン又はポリグリセリンのエステル及びその誘導体（グリセリン脂肪酸エステル、グリセリン酢酸脂肪酸エステル、グリセリン乳酸脂肪酸エステル、グリセリンクエン酸脂肪酸エステル、グリセリンコハク酸脂肪酸エステル、グリセリンジアセチル酒石酸脂肪酸エステル、グリセリン酢酸エステル、ポリグリセリン脂肪酸エステル及びポリグリセリン縮合リシノレイン酸エステルがある）である。
　種々の化合物が市販されており、例えば、モノオレイン酸グリセリル（ＰＥＣＥＯＬ）、モノステアリン酸グリセリル（ＮＩＫＫＯＬ　ＭＧＳ－Ｆ５０ＳＥＶ、ＭＧＳ－ＡＭＶ、ＭＧＳ－ＢＭＶ）、モノオレイン酸デカグリセリル（ＮＩＫＫＯＬ　Ｄｅｃａｇｌｙｎ　１－ＯＶ、ポエム　Ｊ－０３８１Ｖ）、モノラウリン酸デカグリセリル（ＮＩＫＫＯＬ　Ｄｅｃａｇｌｙｎ　１－Ｌ）、トリオレイン酸デカグリセリル（ＮＩＫＫＯＬ　Ｄｅｃａｇｌｙｎ　３－ＯＶ）、ペンタオレイン酸デカグリセリル（ＮＩＫＫＯＬ　Ｄｅｃａｇｌｙｎ　５－ＯＶ）、モノオレイン酸テトラグリセリル（ＮＩＫＫＯＬ　Ｔｅｔｒａｇｌｙｎ　１－ＯＶ）、が例示され、好ましくは、モノオレイン酸グリセリル、モノオレイン酸デカグリセリル、モノステアリン酸グリセリル、が例示され、より好ましくは、モノオレイン酸デカグリセリルが例示されるが、これらに限定されない。また、これらのうちの１種を単独で、あるいは２種以上を組み合わせて用いることもできる。本発明においてグリセリン脂肪酸エステルとは上記のような化合物をすべて含む意味で用いられる。 In the present invention, “glycerin fatty acid ester” is an ester of fatty acid and glycerin or polyglycerin and its derivatives (glycerin fatty acid ester, glycerin acetic acid fatty acid ester, glycerin lactic acid fatty acid ester, glycerin citric acid fatty acid ester, glycerin succinic acid fatty acid ester, glycerin. Diacetyl tartaric acid fatty acid ester, glycerin acetic acid ester, polyglycerin fatty acid ester and polyglycerin condensed ricinoleic acid ester).
Various compounds are commercially available, for example, glyceryl monooleate (PECEOL), glyceryl monostearate (NIKKOL MGS-F50SEV, MGS-AMV, MGS-BMV), decaglyceryl monooleate (NIKKOL Decaglyn 1-OV), Poem J-0381V), decaglyceryl monolaurate (NIKKOL Decaglyn 1-L), decaglyceryl trioleate (NIKKOL Decaglyn 3-OV), decaglyceryl pentaoleate (NIKKOL monodecylglycolate) NIKKOL Tetraglyn 1-OV), preferably glyceryl monooleate, decaglyceryl monooleate, glyceryl monostearate There are exemplified, more preferably, the decaglyceryl monooleate is illustrative and not limited thereto. Moreover, one of these can be used alone or in combination of two or more. In the present invention, glycerin fatty acid ester is used in the meaning including all the above compounds.
　本発明の自己乳化組成物における乳化剤の合計含量は特に限定されないが、通常、自己乳化組成物の全量を１００質量％としたとき、１～４０質量％、１～３５質量％、１～３０質量％、１～２７質量％であり、好ましくは３～２７質量％、より好ましくは５～２７質量％、さらに好ましくは５～２４質量％、いっそう好ましくは１０～２０質量％であり、また、８～２７質量％が好ましく、１０～２７質量％がより好ましく、１２～２４質量％がさらに好ましい。また、ω３ＰＵＦＡ類１００質量部に対して５～４５質量部、好ましくは１０～４５質量部、さらに好ましくは１５～３５質量部、とりわけ好ましくは１５～２５質量部である。 The total content of the emulsifier in the self-emulsifying composition of the present invention is not particularly limited, but usually 1 to 40% by mass, 1 to 35% by mass, 1 to 30% by mass when the total amount of the self-emulsifying composition is 100% by mass. %, 1 to 27% by weight, preferably 3 to 27% by weight, more preferably 5 to 27% by weight, still more preferably 5 to 24% by weight, and still more preferably 10 to 20% by weight. Is preferably 27 mass%, more preferably 10-27 mass%, and even more preferably 12-24 mass%. Further, it is 5 to 45 parts by mass, preferably 10 to 45 parts by mass, more preferably 15 to 35 parts by mass, and particularly preferably 15 to 25 parts by mass with respect to 100 parts by mass of the ω3 PUFAs.
　本発明の自己乳化組成物は少量の水を含んでいても良い。組成中に水を含むことにより、自己乳化組成物の相溶性が良好となり、多価アルコールやエタノールが不要となるため、多価アルコールやエタノールを含まなくても外観が澄明で、自己乳化組成物の分離や白濁を生じない。
　水は自己乳化組成物の全量を１００質量％としたとき、０．５～６質量％であることが好ましく、０．５～４質量％がより好ましく、０．５～３質量％がさらに好ましい。最も好ましくは１～３質量％である。または、０．５質量％以上３質量％未満が好ましく、０．５質量％以上１．５質量％未満がより好ましい。 The self-emulsifying composition of the present invention may contain a small amount of water. By including water in the composition, the compatibility of the self-emulsifying composition is improved, and no polyhydric alcohol or ethanol is required. Therefore, the appearance is clear even without polyhydric alcohol or ethanol, and the self-emulsifying composition No separation or white turbidity.
Water is preferably 0.5 to 6% by mass, more preferably 0.5 to 4% by mass, even more preferably 0.5 to 3% by mass, when the total amount of the self-emulsifying composition is 100% by mass. . Most preferably, it is 1 to 3% by mass. Or 0.5 to 3 mass% is preferable, and 0.5 to 1.5 mass% is more preferable.
　本発明において、「レシチン」はグリセロリン脂質の１種であり、大豆レシチン、酵素分解大豆レシチン、水素添加大豆レシチン、大豆リン脂質、精製大豆リン脂質、水素添加大豆リン脂質、卵黄レシチン、卵黄リン脂質、水素添加リン脂質、牛乳由来リン脂質、高純度合成リン脂質、不飽和リン脂質、リゾレシチン、リン脂質プレミックス、ホスファチジン酸、ホスファチジルエタノールアミン、ホスファチジルコリン（精製ホスファチジルコリンや精製卵黄ホスファチジルコリン、水素添加ホスファチジルコリン、ポリエンホスファチジルコリン、水素添加精製卵黄ホスファチジルコリン）、ホスファチジルセリン、ホスファチジルグリセロール（精製ホスファチジルグリセロールや精製卵黄ホスファチジルグリセロール、水素添加ホスファチジルグリセロール）、ホスファチジルイノシトール、カルジオリピン、α―グリセロホスホコリンおよび精製卵黄スフィンゴミエリン、が例示される。好ましくは、大豆レシチン、酵素分解大豆レシチン、水素添加大豆レシチンおよび卵黄レシチンが例示され、更に好ましくは大豆レシチンが例示されるが、これらに限定されない。また、これらのうちの１種を単独で、あるいは２種以上を組み合わせて用いることもできる。本発明においてレシチンとは、特に断らない限りは、上記のようなグリセロリン脂質をすべて含む意味で用いられる。
　精製大豆レシチン（日清オイリオ）、精製卵黄レシチン（旭化成ファーマ）、卵黄レシチンＰＬ－１００Ｍ（キューピー）などの種々の製品が市販されている。大豆レシチンは、例えば、ベイシスＬＰ－２０Ｂ（日清製油）、Ｌｉｐｏｉｄ　Ｓ４５、Ｓ２０（リポイド）などが、酵素分解レシチンは例えばベイシスＬＰ－２０Ｅ（日清製油）、Ｐｈｏｓｐｈｏｌｉｐｏｎ　ＲＬＰＣ２０（リポイド）などの種々の製品が市販されており、これらを入手して使用することもできる。 In the present invention, “lecithin” is a kind of glycerophospholipid, soy lecithin, enzyme-degraded soybean lecithin, hydrogenated soybean lecithin, soybean phospholipid, purified soybean phospholipid, hydrogenated soybean phospholipid, egg yolk lecithin, egg yolk phospholipid. , Hydrogenated phospholipid, milk-derived phospholipid, high-purity synthetic phospholipid, unsaturated phospholipid, lysolecithin, phospholipid premix, phosphatidic acid, phosphatidylethanolamine, phosphatidylcholine (purified phosphatidylcholine or purified egg yolk phosphatidylcholine, hydrogenated phosphatidylcholine, polyene Phosphatidylcholine, hydrogenated purified egg yolk phosphatidylcholine), phosphatidylserine, phosphatidylglycerol (purified phosphatidylglycerol and purified egg yolk phosphatidylglycerol, hydrogenated phosphatidylcholine) § Chi Jill glycerol), phosphatidylinositol, cardiolipin, alpha-glycerophosphocholine and purified egg yolk sphingomyelin, and the like. Preferably, soybean lecithin, enzyme-decomposed soybean lecithin, hydrogenated soybean lecithin and egg yolk lecithin are exemplified, and more preferably, soybean lecithin is exemplified, but not limited thereto. Moreover, one of these can be used alone or in combination of two or more. In the present invention, unless otherwise specified, lecithin is used in the meaning including all the glycerophospholipids as described above.
Various products such as purified soybean lecithin (Nisshin Oilio), purified egg yolk lecithin (Asahi Kasei Pharma), egg yolk lecithin PL-100M (Kupie) are commercially available. Soy lecithin is, for example, Basis LP-20B (Nisshin Oil), Lipoid S45, S20 (lipoid), and enzymatically decomposed lecithin is various, such as Basis LP-20E (Nisshin Oil), Phospholipon RLPC20 (lipoid). Products are commercially available and can be obtained and used.
　本発明の自己乳化組成物に添加するレシチンの含量は特に限定されないが、ＥＰＡ－Ｅ１００質量部に対して、０．５～４０質量部が好ましく、１～４０質量部が好ましく、２～４０質量部が好ましく、３～４０質量部が好ましく、３～３０質量部がより好ましく、３～２５質量部がさらに好ましく、３～２０質量部、３．２～１７質量部、３．５～１５質量部、３．７～１７質量部がとりわけ好ましい。あるいは、３～１５質量部が好ましく、３～１２質量部がより好ましく、３～１０質量部がさらに好ましい。最も好ましくは５～１０質量部である。
　レシチンは自己乳化組成物の全量を１００質量％としたとき、２．１～３６質量％であることが好ましく、２．１～２０質量％がより好ましく、２．１～１５質量％がさらに好ましい。あるいは、０．５～３０質量％であることが好ましく、１～２５質量％であることがより好ましく、１～２０質量％であることがさらに好ましく、２～１５質量％であることがとりわけ好ましい。最も好ましくは２．１～１０質量％である。
　レシチンは自己乳化組成物における乳化剤（レシチンは本発明で規定する乳化剤には算入しない）の合計含量を１００質量％としたとき、１０～７５質量％であることが好ましく、１１～６０質量％がより好ましく、２０～５５質量％がさらに好ましい。最も好ましくは２５～３５質量％である。あるいは、レシチンは自己乳化組成物における乳化剤の合計含量を１００質量％としたとき、５～５０質量％であることが好ましく、６～４０質量％がより好ましく、７～３０質量％がさらに好ましい。最も好ましくは８～３０質量％である。
　レシチンは自己乳化組成物におけるポリオキシエチレンソルビタン脂肪酸エステルの合計含量を１００質量部としたとき、１０～１５０質量部であることが好ましく、２０～１２０質量部がより好ましく、４０～９０質量部がさらに好ましい。最も好ましくは５０～７０質量部である。あるいは、レシチンは自己乳化組成物におけるポリオキシエチレンソルビタン脂肪酸エステルの合計含量を１００質量部としたとき、１０～１００質量部であることが好ましく、１５～８０質量部がより好ましく、１５～６０質量部がさらに好ましい。最も好ましくは１５～４０質量部である。 The content of lecithin added to the self-emulsifying composition of the present invention is not particularly limited, but is preferably 0.5 to 40 parts by weight, preferably 1 to 40 parts by weight, based on 100 parts by weight of EPA-E. Part is preferable, 3 to 40 parts by weight is preferable, 3 to 30 parts by weight is more preferable, 3 to 25 parts by weight is further preferable, 3 to 20 parts by weight, 3.2 to 17 parts by weight, and 3.5 to 15 parts by weight are preferable. Part to 3.7 to 17 parts by mass is particularly preferred. Alternatively, it is preferably 3 to 15 parts by mass, more preferably 3 to 12 parts by mass, and even more preferably 3 to 10 parts by mass. Most preferred is 5 to 10 parts by mass.
Lecithin is preferably 2.1 to 36% by mass, more preferably 2.1 to 20% by mass, and even more preferably 2.1 to 15% by mass, when the total amount of the self-emulsifying composition is 100% by mass. . Alternatively, it is preferably 0.5 to 30% by mass, more preferably 1 to 25% by mass, further preferably 1 to 20% by mass, and particularly preferably 2 to 15% by mass. . Most preferably, the content is 2.1 to 10% by mass.
Lecithin is preferably 10 to 75% by mass, and 11 to 60% by mass when the total content of emulsifiers in the self-emulsifying composition (lecithin is not included in the emulsifiers defined in the present invention) is 100% by mass. More preferred is 20 to 55% by mass. Most preferably, it is 25 to 35% by mass. Alternatively, lecithin is preferably 5 to 50% by mass, more preferably 6 to 40% by mass, and even more preferably 7 to 30% by mass, when the total content of emulsifiers in the self-emulsifying composition is 100% by mass. Most preferably, it is 8 to 30% by mass.
Lecithin is preferably 10 to 150 parts by weight, more preferably 20 to 120 parts by weight, and more preferably 40 to 90 parts by weight, when the total content of polyoxyethylene sorbitan fatty acid ester in the self-emulsifying composition is 100 parts by weight. Further preferred. Most preferred is 50 to 70 parts by mass. Alternatively, lecithin is preferably 10 to 100 parts by weight, more preferably 15 to 80 parts by weight, and more preferably 15 to 60 parts by weight when the total content of polyoxyethylene sorbitan fatty acid ester in the self-emulsifying composition is 100 parts by weight. Part is more preferred. Most preferred is 15 to 40 parts by mass.
　本発明において、「多価アルコール」は、鎖式脂肪族炭化水素または環式脂肪族炭化水素の２つ以上の炭素原子に１つずつヒドロキシ基が置換している構造を持つポリオール化合物である。例えば、エチレングリコール、プロピレングリコール、トリメチレングリコール、１、２－ブチレングリコール、テトラメチレングリコール、１、３－ブチレングリコール、２、３－ブチレングリコールおよびペンタメチレングリコール等の２価のアルコール、グリセリン、トリメチロールプロパンおよび１、２、６－ヘキサントリオール等の３価のアルコール、ジエチレングリコール、ジプロピレングリコールトリエチレングリコール、ポリエチレングリコール、ポリプロピレングリコール、ポリグリセリン等の多価アルコール重合体、等が例示され、好ましくはプロピレングリコールまたはグリセリンである。グリセリンには濃グリセリンも包含されるが、これらに限定されない。本発明において多価アルコールとは、特に断らない限りは、上記のようなポリオール化合物をすべて含む意味で用いられる。
　本発明の自己乳化組成物に添加する多価アルコールの含量は自己乳化組成物をカプセルに充填した場合に、カプセルを変形させない範囲が好ましい。例えば、自己乳化組成物全体を１００質量％としたとき、組成中に４質量％より多い多価アルコールを含まないことが好ましい。また、組成中の多価アルコールの含量が４質量％以下であることが好ましく、３質量％以下がより好ましく、２質量％以下がさらに好ましく、１質量％以下がとりわけ好ましい。最も好ましいのは０質量％である。 In the present invention, “polyhydric alcohol” is a polyol compound having a structure in which one hydroxy group is substituted for two or more carbon atoms of a chain aliphatic hydrocarbon or a cycloaliphatic hydrocarbon. For example, dihydric alcohols such as ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butylene glycol, tetramethylene glycol, 1,3-butylene glycol, 2,3-butylene glycol and pentamethylene glycol, glycerin, trimethyl Examples thereof include methylolpropane and trivalent alcohols such as 1,2,6-hexanetriol, polyhydric alcohol polymers such as diethylene glycol, dipropylene glycol triethylene glycol, polyethylene glycol, polypropylene glycol, and polyglycerin. Propylene glycol or glycerin. Glycerol includes, but is not limited to, concentrated glycerin. In the present invention, the polyhydric alcohol is used in the meaning including all the polyol compounds as described above unless otherwise specified.
The content of the polyhydric alcohol added to the self-emulsifying composition of the present invention is preferably within a range in which the capsule is not deformed when the capsule is filled with the self-emulsifying composition. For example, when the entire self-emulsifying composition is 100% by mass, it is preferable that the composition does not contain more than 4% by mass of polyhydric alcohol. The content of the polyhydric alcohol in the composition is preferably 4% by mass or less, more preferably 3% by mass or less, further preferably 2% by mass or less, and particularly preferably 1% by mass or less. Most preferred is 0% by weight.
　本発明の自己乳化組成物に含有されるエタノールはカプセル化製造工程や流通・保存中に品質変化を生じさせず、かつ、カプセル内容物の変性を生じさせない範囲が望ましく、また、１日投与量として医薬品使用実績を超えない範囲が望ましい。例えば、自己乳化組成物全体を１００質量％としたとき、組成中に４質量％より多いエタノールを含まないことが好ましい。また、組成中のエタノールの含量が４質量％以下であることが好ましく、３質量％以下がより好ましく、２質量％以下がさらに好ましく、１質量％以下がとりわけ好ましい。最も好ましいのは０質量％である。
　また、自己乳化組成物にエタノールと多価アルコールが含まれる場合には、自己乳化組成物全体を１００質量％としたとき、自己乳化組成物中に合計含量として４質量％より多いエタノール及び多価アルコールを含まないことが好ましい。好ましい態様としてはエタノール及び多価アルコールを実質的に含まない。また、組成中のエタノール及び多価アルコールの合計量が４質量％以下が好ましく、３質量％以下がより好ましく、２質量％以下がさらに好ましく、１質量％以下がとりわけ好ましい。最も好ましいのは０質量％以下である。 The ethanol contained in the self-emulsifying composition of the present invention preferably has a range that does not cause a change in quality during the encapsulation production process, distribution and storage, and does not cause a denaturation of the capsule contents. A range that does not exceed the record of drug use is desirable. For example, when the entire self-emulsifying composition is 100% by mass, it is preferable that no more than 4% by mass of ethanol is contained in the composition. Further, the content of ethanol in the composition is preferably 4% by mass or less, more preferably 3% by mass or less, further preferably 2% by mass or less, and particularly preferably 1% by mass or less. Most preferred is 0% by weight.
Further, when the self-emulsifying composition contains ethanol and a polyhydric alcohol, when the total amount of the self-emulsifying composition is 100% by mass, the total content in the self-emulsifying composition is more than 4% by mass of ethanol and polyvalent alcohol. It is preferable not to contain alcohol. A preferred embodiment is substantially free of ethanol and polyhydric alcohol. The total amount of ethanol and polyhydric alcohol in the composition is preferably 4% by mass or less, more preferably 3% by mass or less, further preferably 2% by mass or less, and particularly preferably 1% by mass or less. Most preferred is 0% by mass or less.
　本発明の自己乳化組成物はカプセルに封入することが出来る。カプセルは硬カプセルや軟カプセルが選択出来、好ましくは軟カプセルである。軟カプセルの形態は必ずしも限定されないが、好ましくはロータリー式軟カプセルまたはシームレスカプセルである。
　また、本発明の自己乳化組成物が固体の場合は、錠剤、粉末剤、顆粒剤、散剤などの固形製剤とすることが出来る。 The self-emulsifying composition of the present invention can be encapsulated. As the capsule, a hard capsule or a soft capsule can be selected, and a soft capsule is preferable. The form of the soft capsule is not necessarily limited, but is preferably a rotary soft capsule or a seamless capsule.
When the self-emulsifying composition of the present invention is solid, it can be made into solid preparations such as tablets, powders, granules and powders.
　本発明の軟カプセルにおいて、カプセル皮膜の組成は必ずしも限定されず、主要成分としては、例えば、ゼラチン、カラギーナン、ペクチン、プルラン、アルギン酸ナトリウム、デンプン、ヒプロメロース、ヒドロキシプロピルセルロース等、および種々の公知の成分が挙げられるが、好ましくはゼラチンである。ゼラチンとしては、制限はなく、酸処理ゼラチン、アルカリ処理ゼラチン、両性ゼラチン、化学修飾ゼラチン等、公知のゼラチンを用いることができ、これらの１種または２種以上を用いることができる。好ましくは、酸処理ゼラチンまたはアルカリ処理ゼラチンである。ゼラチンの由来は、必ずしも限定されないが、例えば、牛骨、牛皮、豚骨、豚皮、魚鱗、魚皮、好ましくは牛骨、牛皮、豚骨、豚皮、である。
　「ゼラチン」としては、軟カプセル剤の製造において通常使用されるもの、例えば、第１６改正日本薬局方で規定される医薬用ゼラチン（ゼラチンおよび精製ゼラチン）が挙げられる。ゼラチンは、２種以上を組合せて用いてもよい。カプセル皮膜はその他に可塑剤等を含有しうる。
　カプセル皮膜に配合する「可塑剤」としては、軟カプセル剤の製造において通常使用されるもの、例えば、グリセリン(例、濃グリセリン)、エチレングリコール、ポリエチレングリコール、プロピレングリコール、ポリプロピレングリコール等の多価アルコール、ソルビトール、マンニトール、キシリトール等の糖アルコールなどが好ましい。これらの可塑剤は、２種以上を組合せて用いてもよい。中でも、グリセリン、ソルビトールが好ましい。また、グリセリンとソルビトールとの組み合わせを使用することも好ましい。この場合、グリセリンとソルビトールとの質量比を、１：５～５：１の範囲で使用することが好ましく、１：３～３：１の範囲で使用することがより好ましい。
　本発明の軟カプセル剤、特にシームレスカプセルにおいて、カプセル皮膜液は、ゼラチンと可塑剤とを、その重量比において、１０：１～１：１０の範囲で含有することが好ましく、１０：１～１：１の範囲で含有することがより好ましい。
　カプセル皮膜液とカプセル内容物との重量比は、通常１０：１～１：１０で、好ましくは３：１～１：１０である。
　さらに、必要に応じて、カプセル皮膜に一般に用いられる各種添加剤、例えば、アミノ酸、クエン酸、グリセリン、ソルビトール、トレハロース、等の可塑剤、防腐剤、色素や酸化チタン等の着色剤、有機酸等を添加することができる。 In the soft capsule of the present invention, the composition of the capsule film is not necessarily limited. Examples of main components include gelatin, carrageenan, pectin, pullulan, sodium alginate, starch, hypromellose, hydroxypropylcellulose, and various known components. Among them, gelatin is preferable. The gelatin is not limited, and known gelatins such as acid-treated gelatin, alkali-treated gelatin, amphoteric gelatin, and chemically modified gelatin can be used, and one or more of these can be used. Preferred is acid-treated gelatin or alkali-treated gelatin. Although the origin of gelatin is not necessarily limited, for example, cow bone, cow skin, pig bone, pig skin, fish scale, fish skin, preferably cow bone, cow skin, pig bone, pig skin.
Examples of “gelatin” include those normally used in the manufacture of soft capsules, for example, pharmaceutical gelatin (gelatin and purified gelatin) defined by the 16th revision Japanese Pharmacopoeia. Two or more types of gelatin may be used in combination. In addition, the capsule film may contain a plasticizer and the like.
As the “plasticizer” to be blended in the capsule film, those usually used in the production of soft capsules, for example, polyhydric alcohols such as glycerin (eg, concentrated glycerin), ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol Sugar alcohols such as sorbitol, mannitol, and xylitol are preferred. These plasticizers may be used in combination of two or more. Of these, glycerin and sorbitol are preferable. It is also preferable to use a combination of glycerin and sorbitol. In this case, the mass ratio of glycerin and sorbitol is preferably used in the range of 1: 5 to 5: 1, and more preferably in the range of 1: 3 to 3: 1.
In the soft capsule of the present invention, particularly the seamless capsule, the capsule film solution preferably contains gelatin and a plasticizer in a weight ratio of 10: 1 to 1:10. It is more preferable to contain in the range of: 1.
The weight ratio of the capsule film solution to the capsule contents is usually 10: 1 to 1:10, preferably 3: 1 to 1:10.
Furthermore, as required, various additives generally used for capsule films, for example, plasticizers such as amino acids, citric acid, glycerin, sorbitol, trehalose, preservatives, coloring agents such as pigments and titanium oxide, organic acids, etc. Can be added.
　カプセル皮膜用組成物は、ゼラチンおよび可塑剤、さらに必要に応じて各種添加剤を、常温又は加温下で、水に混合溶解することで製造できる。 The composition for capsule film can be produced by mixing and dissolving gelatin and a plasticizer and, if necessary, various additives in water at room temperature or under heating.
　本発明の自己乳化組成物を内容液としたカプセルは、製造直後の硬度が良好であり、保存により硬度低下しないことが好ましい。硬度の低下はカプセルを変形させるだけでなく、脆くなるためカプセルが割れ、内容液が流出してしまうため品質上好ましくない。カプセルの軟化の有無は、一般的な硬度計により硬度を測定することで確認することが出来る。
　本発明のカプセルは、製造直後の硬度が１８ｋｇｆ以上、好ましくは２０ｋｇｆ以上、より好ましくは２２ｋｇｆ以上である。また、密封されたアルミ包装で４０℃１週間保管した場合に製造直後と比較して硬度が実質的に低下しない、あるいは硬度が６ｋｇｆ以上低下しないことが望ましく、４０℃１週間の保管後の硬度が１０ｋｇｆ以上、好ましくは１５ｋｇｆ以上、より好ましくは２０ｋｇｆ以上である。カプセル硬度は、既存汎用の軟質固体用硬さ試験機（例えば、ジェロマットII（エムアンドケー株式会社））で測定することができ、１ｋｇｆは約９．８１ニュートン（Ｎ）と換算される。
　また、製造直後の硬度を１００％とした時、密封されたアルミ包装で４０℃１週間保管した場合の硬度が６０％以上、好ましくは７０％以上、より好ましくは８０％以上維持される。さらに好ましくは８５％以上、とりわけ好ましくは９０％以上の硬度が維持される。 Capsules containing the self-emulsifying composition of the present invention as a content liquid preferably have a hardness immediately after production and do not decrease in hardness due to storage. The decrease in hardness not only deforms the capsule but also becomes brittle, so the capsule breaks and the content liquid flows out, which is not preferable in terms of quality. The presence or absence of softening of the capsule can be confirmed by measuring the hardness with a general hardness meter.
The capsule of the present invention has a hardness immediately after production of 18 kgf or more, preferably 20 kgf or more, more preferably 22 kgf or more. In addition, it is desirable that the hardness does not substantially decrease when stored in a sealed aluminum package at 40 ° C. for one week, or that the hardness does not decrease more than 6 kgf, and the hardness after storage at 40 ° C. for one week. Is 10 kgf or more, preferably 15 kgf or more, more preferably 20 kgf or more. The capsule hardness can be measured by an existing general-purpose hardness tester for soft solids (for example, Jeromat II (M & K Corporation)), and 1 kgf is converted to about 9.81 Newtons (N).
Further, when the hardness immediately after production is 100%, the hardness when stored in a sealed aluminum package at 40 ° C. for 1 week is maintained at 60% or more, preferably 70% or more, more preferably 80% or more. More preferably, the hardness of 85% or more, particularly preferably 90% or more is maintained.
　本発明において、「間欠投与」は毎日投与ではなく投与しない日が存在する投与態様である。例えば、好ましくは２日～３ヶ月からなる群から選択される少なくとも１つの期間毎に投与、２日～１２週間からなる群から選択される少なくとも１つの期間毎に投与、２日～１０週間からなる群から選択される少なくとも１つの期間毎に投与、２日～２ヶ月からなる群から選択される少なくとも１つの期間毎に投与、２日～８週間からなる群から選択される少なくとも１つの期間毎に投与、２日～１ヶ月からなる群から選択される少なくとも１つの期間毎に投与、２日～４週間からなる群から選択される少なくとも１つの期間毎に投与、２日～３週間からなる群から選択される少なくとも１つの期間毎に投与、２日～２０日からなる群から選択される少なくとも１つの期間毎に投与、２日～２週間からなる群から選択される少なくとも１つの期間毎に投与、２日～１０日からなる群から選択される少なくとも１つの期間毎に投与および２日～１週間からなる群から選択される少なくとも１つの期間毎に投与等が挙げられるが、これらに限定されない。
　また、２日毎、３日毎、４日毎、５日毎、６日毎、７日（１週間）毎、８日毎、９日毎、１０日毎、１１日毎、１２日毎、１３日毎、１４日（２週間）毎、１５日毎、１６日毎、１７日毎、１８日毎、１９日毎、２０日毎、２１日（３週間）毎、２２日毎、２３日毎、２４日毎、２５日毎、２６日毎、２７日毎、２８日（４週間）毎、２９日毎、３０日毎、３１日毎、３２日毎、３３日毎、３４日毎、３５日（５週間）毎、３６日毎、３７日毎、３８日毎、３９日毎、４０日毎、４１日毎、４２日（６週間）毎、４３日毎、４４日毎、４５日毎、４６日毎、４７日毎、４８日毎、４９日（７週間）毎、５０日毎、５１日毎、５２日毎、５３日毎、５４日毎、５５日毎、５６日（８週間）毎、５７日毎、５８日毎、５９日毎、６０日毎、６１日毎、６２日毎、６３日（９週間）毎、６４日毎、６５日毎、６６日毎、６７日毎、６８日毎、６９日毎、７０日（１０週間）毎、７１日毎、７２日毎、７３日毎、７４日毎、７５日毎、７６日毎、７７日（１１週間）毎、７８日毎、７９日毎、８０日毎、８１日毎、８２日毎、８３日毎、８４日（１２週間）毎、８５日毎、８６日毎、８７日毎、８８日毎、８９日毎、９０日毎、９１日（１３週間）毎および９２日毎、あるいは１ヶ月毎、２ヶ月毎および３ヶ月毎に投与等が挙げられるが、これらに限定されない。
　また、１週間に２日（例えば、月曜日および木曜日、月曜日および金曜日、火曜日および金曜日、火曜日および土曜日、水曜日および土曜日、水曜日および日曜日、木曜日および日曜日）投与、１週間に３日（例えば、月曜日と水曜日および金曜日、月曜日と水曜日および土曜日、月曜日と木曜日および土曜日、火曜日と木曜日および土曜日、火曜日と木曜日および日曜日、火曜日と金曜日および日曜日、水曜日と金曜日および日曜日）投与、1ヶ月に２日投与（例えば、１日および１５日、５日および２０日、１０日および２５日、１０日および３０日（ただし、２月は最終日））、１ヶ月に３日投与（例えば、１日と１１日および２１日、５日と１５日および２５日、１０日と２０日および３０日（ただし、２月は最終日））、１ヶ月に４日投与（例えば、第１～第４月曜日、第１～第４火曜日、第１～第４水曜日、第１～第４木曜日、第１～第４金曜日、第１～第４土曜日、第１～第４日曜日のように、第５曜日は投与しない）のように等間隔でない投与をすることもできるが、これらに限定されない。また、投与間隔が１週間以上の場合は、投与日を等間隔から前後にずらすこともできる。例えば、１週間間隔の場合は前後１日、２週間間隔の場合は前後２日、３週間間隔の場合は前後３日、４週間間隔の場合は前後４日、５週間間隔の場合は前後５日、６週間間隔の場合は前後６日、７週間間隔の場合は前後１週間等であるが、これらに限定されない。
　本発明の自己乳化組成物の間欠投与間隔は、症状の重症度、体重、年齢、およびその他の要因によって、意図する効果を実現させるのに適するように適切に調整することができる。例えば、症状が改善された場合は間欠投与間隔を長くし、症状が悪化した場合は間欠投与間隔を短くすることができる。また、血中、血漿中あるいは血清中のω３ＰＵＦＡ、ＥＰＡ、ＤＨＡ、ＤＰＡあるいはＡＬＡの濃度および／またはＥＰＡ／ＡＡ比をモニターしながら、間欠投与間隔を調整することができる。 In the present invention, “intermittent administration” is an administration mode in which there are days that are not administered instead of daily administration. For example, preferably administered every at least one period selected from the group consisting of 2 days to 3 months, administered every at least one period selected from the group consisting of 2 days to 12 weeks, and from 2 days to 10 weeks Administered at least one period selected from the group consisting of, administered at least one period selected from the group consisting of 2 days to 2 months, and at least one period selected from the group consisting of 2 days to 8 weeks Dosed every time, administered every at least one period selected from the group consisting of 2 days to 1 month, administered every at least one period selected from the group consisting of 2 days to 4 weeks, from 2 days to 3 weeks Administered at least one period selected from the group consisting of, administered every at least one period selected from the group consisting of 2 days to 20 days, at least one selected from the group consisting of 2 days to 2 weeks Administration every period, administration every at least one period selected from the group consisting of 2 days to 10 days, and administration every at least one period selected from the group consisting of 2 days to 1 week, etc. It is not limited to these.
Every 2 days, 3 days, 4 days, 5 days, 6 days, 7 days (1 week), 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days (2 weeks) Every 15 days, every 16 days, every 17 days, every 18 days, every 19 days, every 20 days, every 21 days (3 weeks), every 22 days, every 23 days, every 24 days, every 25 days, every 26 days, every 27 days, every 28 days (4 weeks) ), 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days (5 weeks), 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days ( 6 weeks), 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days (7 weeks), 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 Every day (8 weeks), every 57 days, every 58 days, every 59 days, every 60 days, every 61 days , 62 days, 63 days (9 weeks), 64 days, 65 days, 66 days, 67 days, 68 days, 69 days, 70 days (10 weeks), 71 days, 72 days, 73 days, 74 days, Every 75 days, 76 days, 77 days (11 weeks), 78 days, 79 days, 80 days, 81 days, 82 days, 83 days, 84 days (12 weeks), 85 days, 86 days, 87 days, 88 Examples include, but are not limited to, administration every day, every 89 days, every 90 days, every 91 days (13 weeks) and every 92 days, every month, every 2 months, and every 3 months.
Also administered 2 days a week (eg Monday and Thursday, Monday and Friday, Tuesday and Friday, Tuesday and Saturday, Wednesday and Saturday, Wednesday and Sunday, Thursday and Sunday), 3 days a week (eg Monday and Wednesday and Friday, Monday and Wednesday and Saturday, Monday and Thursday and Saturday, Tuesday and Thursday and Saturday, Tuesday and Thursday and Sunday, Tuesday and Friday and Sunday, Wednesday and Friday and Sunday), 2 days a month (eg, 1 day and 15 days, 5 days and 20 days, 10 days and 25 days, 10 days and 30 days (but the last day in February), 3 days a month (eg, 1st and 11th days and 21st, 5th, 15th and 25th, 10th, 20th and 30th (but last day in February)) 4 per month Day administration (eg, 1st to 4th Monday, 1st to 4th Tuesday, 1st to 4th Wednesday, 1st to 4th Thursday, 1st to 4th Friday, 1st to 4th Saturday, 1st to 4th It is also possible to administer at non-equal intervals, as in the case of the fourth Sunday (does not administer on the fifth day), but is not limited thereto. In addition, when the administration interval is one week or more, the administration day can be shifted back and forth from the regular interval. For example, 1 week before and after 1 week, 2 days before and 2 weeks, 2 days before and after 3 weeks, 3 days before and after 3 weeks, 4 days before and after 4 weeks, 5 days after 5 weeks In the case of days and 6-week intervals, it is 6 days before and after, and in the case of 7-week intervals, it is 1 week before and after, but is not limited thereto.
The interval between intermittent administrations of the self-emulsifying composition of the present invention can be appropriately adjusted according to the severity of symptoms, body weight, age, and other factors so as to be suitable for realizing the intended effect. For example, the intermittent administration interval can be lengthened when the symptom is improved, and the intermittent administration interval can be shortened when the symptom is worsened. Further, the intermittent administration interval can be adjusted while monitoring the concentration and / or EPA / AA ratio of ω3PUFA, EPA, DHA, DPA or ALA in blood, plasma or serum.
　本発明の自己乳化組成物の１日当たりの投与量は、例えば０．１～２０ｇ／日、０．３～１５ｇ／日、０．５～１０ｇ／日、１～９ｇ／日、１～８ｇ／日、１～７ｇ／日、１～６ｇ／日、１～５ｇ／日、１～４ｇ／日、１～３ｇ／日、１～２ｇ／日、２～１０ｇ／日、２～９ｇ／日、２～８ｇ／日、２～７ｇ／日、２～６ｇ／日、２～５ｇ／日、２～４ｇ／日、２～３ｇ／日、３～１０ｇ／日、３～９ｇ／日、３～８ｇ／日、３～７ｇ／日、３～６ｇ／日、３～５ｇ／日、３～４ｇ／日、４～１０ｇ／日、４～９ｇ／日、４～８ｇ／日、４～７ｇ／日、４～６ｇ／日、４～５ｇ／日、５～１０ｇ／日、５～９ｇ／日、５～８ｇ／日、５～７ｇ／日、５～６ｇ／日、６～１０ｇ／日、６～９ｇ／日、６～８ｇ／日、６～７ｇ／日、７～１０ｇ／日、７～９ｇ／日、７～８ｇ／日、８～１０ｇ／日、８～９ｇ／日および９～１０ｇ／日、等が挙げられるが、これらに限定されない。
　患者の服薬負担を軽減するためには、１日投与量は少ない方が好ましく、１日１０ｇ以下、１日９ｇ以下、１日８ｇ以下、好ましくは１日７ｇ以下、さらに好ましくは１日６ｇ以下、より好ましくは１日５ｇ以下、とりわけ好ましくは１日４ｇ以下、いっそう好ましくは１日３ｇ以下、最も好ましくは１日２ｇ以下である。
　また、０．１ｇ／日、０．２ｇ／日、０．３ｇ／日、０．４ｇ／日、０．５ｇ／日、０．６ｇ／日、０．７ｇ／日、０．８ｇ／日、０．９ｇ／日、１．０ｇ／日、１．０ｇ／日、１．１ｇ／日、１．２ｇ／日、１．３ｇ／日、１．４ｇ／日、１．５ｇ／日、１．６ｇ／日、１．７ｇ／日、１．８ｇ／日、１．９ｇ／日、２．０ｇ／日、２．１ｇ／日、２．２ｇ／日、２．３ｇ／日、２．４ｇ／日、２．５ｇ／日、２．６ｇ／日、２．７ｇ／日、２．８ｇ／日、２．９ｇ／日、３．０ｇ／日、３．１ｇ／日、３．２ｇ／日、３．３ｇ／日、３．４ｇ／日、３．５ｇ／日、３．６ｇ／日、３．７ｇ／日、３．８ｇ／日、３．９ｇ／日、４．０ｇ／日、４．１ｇ／日、４．２ｇ／日、４．３ｇ／日、４．４ｇ／日、４．５ｇ／日、４．６ｇ／日、４．７ｇ／日、４．８ｇ／日、４．９ｇ／日、５．０ｇ／日、５．１ｇ／日、５．２ｇ／日、５．３ｇ／日、５．４ｇ／日、５．５ｇ／日、５．６ｇ／日、５．７ｇ／日、５．８ｇ／日、５．９ｇ／日、６．０ｇ／日、６．１ｇ／日、６．２ｇ／日、６．３ｇ／日、６．４ｇ／日、６．５ｇ／日、６．６ｇ／日、６．７ｇ／日、６．８ｇ／日、６．９ｇ／日、７．０ｇ／日、７．１ｇ／日、７．２ｇ／日、７．３ｇ／日、７．４ｇ／日、７．５ｇ／日、７．６ｇ／日、７．７ｇ／日、７．８ｇ／日、７．９ｇ／日、８．０ｇ／日、８．１ｇ／日、８．２ｇ／日、８．３ｇ／日、８．４ｇ／日、８．５ｇ／日、８．６ｇ／日、８．７ｇ／日、８．８ｇ／日、８．９ｇ／日、９．０ｇ／日、９．１ｇ／日、９．２ｇ／日、９．３ｇ／日、９．４ｇ／日、９．５ｇ／日、９．６ｇ／日、９．７ｇ／日、９．８ｇ／日、９．９ｇ／日および１０．０ｇ／日などで投与することもできる。本発明の自己乳化組成物の１日当たりの投与量は、症状の重症度、体重、年齢、およびその他の要因によっては適切に調整することができる。例えば、症状が改善された場合は１日当たりの投与量投与量を減少し、症状が悪化した場合は１日当たりの投与量を増加することができる。また、血中、血漿中あるいは血清中のω３ＰＵＦＡ、ＥＰＡ、ＤＨＡ、ＤＰＡあるいはＡＬＡの濃度および／またはＥＰＡ／ＡＡ比をモニターしながら、１日当たりの投与量を調整することができる。
　さらに、本発明の自己乳化組成物の間欠投与間隔および１日当たりの投与量を組み合わせて、症状の重症度、体重、年齢、およびその他の要因によっては適切に調整することができる。例えば、症状が改善された場合は間欠投与間隔を長くし、かつ１日当たりの投与量投与量を減少し、症状が悪化した場合は間欠投与間隔を短くし、かつ１日当たりの投与量を増加することができる。また、血中、血漿中あるいは血清中のω３ＰＵＦＡ、ＥＰＡ、ＤＨＡ、ＤＰＡあるいはＡＬＡの濃度および／またはＥＰＡ／ＡＡ比をモニターしながら、間欠投与間隔および１日当たりの投与量を組み合わせて調整することができる。 The daily dosage of the self-emulsifying composition of the present invention is, for example, 0.1-20 g / day, 0.3-15 g / day, 0.5-10 g / day, 1-9 g / day, 1-8 g / day. 1-7 g / day, 1-6 g / day, 1-5 g / day, 1-4 g / day, 1-3 g / day, 1-2 g / day, 2-10 g / day, 2-9 g / day, 2-8 g / day, 2-7 g / day, 2-6 g / day, 2-5 g / day, 2-4 g / day, 2-3 g / day, 3-10 g / day, 3-9 g / day, 3- 8 g / day, 3-7 g / day, 3-6 g / day, 3-5 g / day, 3-4 g / day, 4-10 g / day, 4-9 g / day, 4-8 g / day, 4-7 g / day 4-6 g / day, 4-5 g / day, 5-10 g / day, 5-9 g / day, 5-8 g / day, 5-7 g / day, 5-6 g / day, 6-10 g / day, 6-9 g / day, 6-8 g / day, 6-7 g / day, 7-10 g / day , 7 ~ 9 g / day, 7 ~ 8 g / day, 8 ~ 10 g / day, 8 ~ 9 g / day and 9 ~ 10 g / day, and the like, without limitation.
In order to reduce the burden of patients on medication, a lower daily dose is preferable, and it is preferably 10 g or less per day, 9 g or less per day, 8 g or less per day, preferably 7 g or less per day, more preferably 6 g or less per day. More preferably, it is 5 g or less per day, particularly preferably 4 g or less per day, more preferably 3 g or less per day, and most preferably 2 g or less per day.
Also, 0.1 g / day, 0.2 g / day, 0.3 g / day, 0.4 g / day, 0.5 g / day, 0.6 g / day, 0.7 g / day, 0.8 g / day, 0.9 g / day, 1.0 g / day, 1.0 g / day, 1.1 g / day, 1.2 g / day, 1.3 g / day, 1.4 g / day, 1.5 g / day, 6 g / day, 1.7 g / day, 1.8 g / day, 1.9 g / day, 2.0 g / day, 2.1 g / day, 2.2 g / day, 2.3 g / day, 2.4 g / day Day, 2.5 g / day, 2.6 g / day, 2.7 g / day, 2.8 g / day, 2.9 g / day, 3.0 g / day, 3.1 g / day, 3.2 g / day, 3.3 g / day, 3.4 g / day, 3.5 g / day, 3.6 g / day, 3.7 g / day, 3.8 g / day, 3.9 g / day, 4.0 g / day, 4. 1 g / day, 4.2 g / day, 4.3 g / day, 4.4 g / day, 4.5 g / day, 4.6 g / day, 4 7 g / day, 4.8 g / day, 4.9 g / day, 5.0 g / day, 5.1 g / day, 5.2 g / day, 5.3 g / day, 5.4 g / day, 5.5 g / day Day, 5.6 g / day, 5.7 g / day, 5.8 g / day, 5.9 g / day, 6.0 g / day, 6.1 g / day, 6.2 g / day, 6.3 g / day, 6.4 g / day, 6.5 g / day, 6.6 g / day, 6.7 g / day, 6.8 g / day, 6.9 g / day, 7.0 g / day, 7.1 g / day, 7. 2 g / day, 7.3 g / day, 7.4 g / day, 7.5 g / day, 7.6 g / day, 7.7 g / day, 7.8 g / day, 7.9 g / day, 8.0 g / day Day, 8.1 g / day, 8.2 g / day, 8.3 g / day, 8.4 g / day, 8.5 g / day, 8.6 g / day, 8.7 g / day, 8.8 g / day, 8.9 g / day, 9.0 g / day, 9.1 g / day, 9.2 g / day, 9.3 g / day, 9.4 g / day , 9.5 g / day, 9.6 g / day, 9.7 g / day, 9.8 g / day, it can also be administered in such 9.9 g / day and 10.0 g / day. The daily dosage of the self-emulsifying composition of the present invention can be appropriately adjusted depending on the severity of symptoms, weight, age, and other factors. For example, if the symptoms improve, the daily dose can be decreased, and if the symptoms worsen, the daily dose can be increased. In addition, the daily dose can be adjusted while monitoring the concentration and / or EPA / AA ratio of ω3PUFA, EPA, DHA, DPA or ALA in blood, plasma or serum.
Furthermore, the intermittent dosing interval and the daily dose of the self-emulsifying composition of the present invention can be combined and adjusted appropriately depending on the severity of symptoms, weight, age, and other factors. For example, if symptoms improve, increase the intermittent dose interval and decrease the daily dose, and if symptoms worsen, shorten the intermittent dose interval and increase the daily dose. be able to. In addition, while monitoring the concentration and / or EPA / AA ratio of ω3PUFA, EPA, DHA, DPA or ALA in blood, plasma or serum, it is possible to adjust the combination of intermittent administration intervals and daily doses. it can.
　本発明の自己乳化組成物の１日当たりの投与回数は、例えば１日１～１０回、１日１～６回、１日１～３回および１日１～２回、１日１回等が挙げられるが、これらに限定されない。１日１回、１日２回、１日３回、１日４回、１日５回、１日６回、１日７回、１日８回、１日９回、１日１０回投与することもできるが、患者の服薬負担を軽減するためには、１日３回以下、好ましくは１日２回以下、より好ましくは１日１回である。また、患者の都合により、投与日ごとに投与回数を調整することもできる。
　本発明の自己乳化組成物は空腹時においても優れた吸収力を発揮する。そのため、本発明の自己乳化組成物は患者に都合が良い任意のタイミングで投与することができる。投与が各々の食事中、食直後、または食後以外の任意のタイミング、例えば、朝食前または朝食の直前、朝食と昼食の食間、昼食前または昼食の直前、昼食と夕食の食間、または夕食と就寝の間、就寝前または就寝の直前等に投与された場合でも、あるいは腸管の吸収力が低下した患者、例えば、高齢者、腸管疾患の患者、腸管の手術を受けた患者、末期癌患者、またはリパーゼ阻害剤を服用中の患者等の場合でも、または低服用量で使用する場合でも、意図する効果を得ることができる。
　本発明の自己乳化組成物の１日当たりの投与回数および投与タイミングは、１日投与量、症状の重症度、体重、年齢、およびその他の要因によっては適切に調整することができる。 The frequency of administration of the self-emulsifying composition of the present invention per day is, for example, 1 to 10 times a day, 1 to 6 times a day, 1 to 3 times a day, 1 to 2 times a day, once a day, etc. For example, but not limited to. Once a day, twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, ten times a day However, in order to reduce the burden of taking the patient, it is 3 times or less per day, preferably 2 times or less per day, more preferably once a day. Moreover, the frequency | count of administration can also be adjusted for every administration day for a patient's convenience.
The self-emulsifying composition of the present invention exhibits excellent absorbency even on an empty stomach. Therefore, the self-emulsifying composition of the present invention can be administered at any timing convenient for the patient. Administration during each meal, immediately after meals, or at any time other than after meals, for example, before or just before breakfast, between breakfast and lunch, before or just before lunch, between lunch and dinner, or dinner and sleep Patients who have been administered before or just before going to bed, or whose intestinal absorptivity has decreased, such as elderly people, patients with intestinal diseases, patients who have undergone intestinal surgery, patients with end-stage cancer, or The intended effect can be obtained even in the case of patients taking lipase inhibitors, etc. or when used at low doses.
The frequency and timing of administration of the self-emulsifying composition of the present invention can be appropriately adjusted depending on the daily dose, the severity of symptoms, body weight, age, and other factors.
　本発明で使用される「併用」とは、本発明の自己乳化組成物が投与されている間、別の薬の効果および／または作用が患者の体内に存在する実施形態を指している。いくつかの実施形態では、本発明の自己乳化組成物と併用薬物の両方が同時に患者の体内、例えば、患者の血液内に存在する。いくつかの実施形態では、前記併用薬物は本発明の自己乳化組成物の投与後２４時間以内に投与される。本発明による併用は、本発明の自己乳化組成物と併用薬物が組み合わせで使用される限り、一般的に想定されており、特に制限されない。例示的な実施形態は、例えば、
（１）本発明の自己乳化組成物に併用薬物の有効成分が含有されている配合組成物の投与、
（２）本発明の自己乳化組成物と併用薬物をそれぞれ別に準備することで両方を投与し、および本発明の自己乳化組成物と併用薬物の組み合わせのキットがあるまたはない条件で同じ投与経路からこれらの本発明の自己乳化組成物と併用薬物を同時に投与、
（３）発明の自己乳化組成物と併用薬物をそれぞれ別に準備することで両方を投与し、および本発明の自己乳化組成物と併用薬物の組み合わせのキットがあるまたはない条件で同じ投与経路からこれらの本発明の自己乳化組成物と併用薬物をタイムラグがある異なるタイミングで投与、
（４）発明の自己乳化組成物と併用薬物をそれぞれ別に準備することで両方を投与し、および本発明の自己乳化組成物と併用薬物の組み合わせのキットがあるまたはない条件で異なる投与経路（異なる箇所からの同じ患者）からこれらの本発明の自己乳化組成物と併用薬物を同時に投与、
（５）発明の自己乳化組成物と併用薬物をそれぞれ別に準備することで両方を投与し、および本発明の自己乳化組成物と併用薬物の組み合わせのキットがあるまたはない条件で異なる投与経路（異なる箇所からの同じ患者）からこれらの本発明の自己乳化組成物と併用薬物をタイムラグがある異なるタイミングで投与、等が挙げられるが、これらに限定されない。これらの投与形態をまとめて、本発明の併用剤と略記する。
　前記有効成分をタイムラグがある異なるタイミングで投与するとき、本発明の自己乳化組成物と併用薬物はこの順序、または逆の順序で投与することができる。本発明の自己乳化組成物と併用薬物は、様々な目的で意図的に異なるタイミングおよび投与間隔で使用してもよい。時間差をおいて投与する場合、時間差は併用投与する有効成分、剤形、及び投与方法により異なるが、例えば、併用薬物を先に投与する場合、併用薬物を投与した後１分～７日以内、好ましくは１分～１日以内、より好ましくは１分～１２時間以内、さらに好ましくは１分～６時間以内に本発明の自己乳化組成物を投与する方法が挙げられる。本発明の化合物を先に投与する場合、本発明の化合物を投与した後、１分～７日以内、好ましくは１分～1日以内、より好ましくは１分～６時間以内、さらに好ましくは１分～１時間以内に併用薬物を投与する方法が挙げられる。
　併用薬物は、副作用が問題とならなければ、どのような用法、用量を設定することも可能であるが、各々の併用薬物で定められた用法、用量を用いることが好ましい。併用薬物としての一日投与量は、投与対象、投与ルート、対象疾患、症状等によっても異なる。本発明の自己乳化組成物が併用薬物と組み合せて使用される場合には、相加あるいは相乗効果を考えて、いずれか一方あるいは両方の用量を安全な範囲内で低減できる。
　さらに、本発明の自己乳化組成物と併用薬物の併用態様は、症状の重症度、体重、年齢、およびその他の要因によっては適切に調整することができる。また、血中、血漿中あるいは血清中のω３ＰＵＦＡ、ＥＰＡ、ＤＨＡ、ＤＰＡあるいはＡＬＡの濃度および／またはＥＰＡ／ＡＡ比をモニターしながら、間欠投与間隔および１日当たりの投与量を組み合わせて調整して併用薬物と併用することができる。 “Combination” as used in the present invention refers to an embodiment in which the effect and / or action of another drug is present in the patient's body while the self-emulsifying composition of the present invention is administered. In some embodiments, both the self-emulsifying composition of the present invention and the concomitant drug are simultaneously present in the patient's body, eg, in the patient's blood. In some embodiments, the concomitant drug is administered within 24 hours after administration of the self-emulsifying composition of the invention. The combination according to the present invention is generally assumed as long as the self-emulsifying composition of the present invention and the concomitant drug are used in combination, and is not particularly limited. Exemplary embodiments include, for example:
(1) administration of a compounding composition containing an active ingredient of a concomitant drug in the self-emulsifying composition of the present invention,
(2) The self-emulsifying composition of the present invention and the concomitant drug are prepared separately, and both are administered, and from the same administration route with or without the kit of the combination of the self-emulsifying composition of the present invention and the concomitant drug Simultaneous administration of these self-emulsifying composition of the present invention and a concomitant drug,
(3) The self-emulsifying composition of the invention and the concomitant drug are prepared separately, and both are administered from the same administration route with or without the kit of the combination of the self-emulsifying composition of the present invention and the concomitant drug. The self-emulsifying composition of the present invention and the concomitant drug are administered at different timings with a time lag,
(4) The self-emulsifying composition of the invention and the concomitant drug are prepared separately, and both are administered, and different administration routes (different depending on whether or not there is a kit of the combination of the self-emulsifying composition and concomitant drug of the present invention Administration of these self-emulsifying composition of the present invention and a concomitant drug from the same patient from the same place),
(5) The self-emulsifying composition of the invention and the concomitant drug are prepared separately, and both are administered, and different administration routes (different depending on whether or not there is a kit of the combination of the self-emulsifying composition and concomitant drug of the present invention Administration of the self-emulsifying composition of the present invention and the concomitant drug at different timings with a time lag, and the like, but is not limited thereto. These administration forms are collectively abbreviated as the combination agent of the present invention.
When the active ingredients are administered at different timings with a time lag, the self-emulsifying composition of the present invention and the concomitant drug can be administered in this order or in the reverse order. The self-emulsifying composition of the present invention and the concomitant drug may be intentionally used at various timings and administration intervals for various purposes. When administered at a time difference, the time difference varies depending on the active ingredient, dosage form, and administration method to be administered in combination. For example, when administering the combination drug first, within 1 minute to 7 days after administration of the combination drug, Preferably, the self-emulsifying composition of the present invention is administered within 1 minute to 1 day, more preferably within 1 minute to 12 hours, and even more preferably within 1 minute to 6 hours. When the compound of the present invention is administered first, it is within 1 minute to 7 days after administration of the compound of the present invention, preferably within 1 minute to 1 day, more preferably within 1 minute to 6 hours, and even more preferably 1 A method of administering a concomitant drug within minutes to 1 hour can be mentioned.
As long as side effects do not become a problem, any concomitant drugs can be used in any dosage and dosage. However, it is preferable to use the dosage and dosage determined for each concomitant drug. The daily dose as a concomitant drug varies depending on the administration subject, administration route, target disease, symptoms and the like. When the self-emulsifying composition of the present invention is used in combination with a concomitant drug, one or both doses can be reduced within a safe range in consideration of additive or synergistic effects.
Furthermore, the combination mode of the self-emulsifying composition of the present invention and the concomitant drug can be appropriately adjusted depending on the severity of symptoms, body weight, age, and other factors. In addition, while monitoring the concentration and / or EPA / AA ratio of ω3PUFA, EPA, DHA, DPA, or ALA in blood, plasma, or serum, it is used in combination by adjusting the intermittent dosing interval and daily dose. Can be used in combination with drugs.
　例えば、経口剤のシクロスポリン、エトレチナート、アプレミラスト、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロンあるいはベタメゾンは毎日投与し、本発明の自己乳化組成物は前記の通り間欠的に投与することができる。外用剤のマキサカルシトール、マキサカルシトールとベタメタゾン酪酸エステルプロピオン酸エステルとの配合剤、カルシポトリオール、カルシポトリオールとベタメタゾンジプロピオン酸エステルとの配合剤、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステルあるいはジフロラゾン酢酸エステルは毎日塗布し、本発明の自己乳化組成物は前記の通り間欠的に投与することができる。注射剤のセクキヌマブは初回、１週後、２週後、３週後、４週後に皮下投与し、以降、４週間の間隔で皮下投与し、本発明の自己乳化組成物は前記の通り間欠的に投与することができる。ウステキヌマブは初回、４週後に皮下投与し、以降１２週間隔で投与し、本発明の自己乳化組成物は前記の通り間欠的に投与することができる。アダリムマブは初回投与後２週に１回皮下投与し、本発明の自己乳化組成物は前記の通り間欠的に投与することができる。インフリキシマブは初回点滴静注投与後２週および６週に投与し、以後６～８週間の間隔で投与し、本発明の自己乳化組成物は前記の通り間欠的に投与することができる。ブロダルマブは初回、１週後、２週後に皮下投与し、以降、２週間の間隔で皮下投与し、本発明の自己乳化組成物は前記の通り間欠的に投与することができる。イキセキズマブは初回に皮下投与し、２週後から１２週後までは２週間隔で皮下投与し、以降、４週間の間隔で皮下投与し、本発明の自己乳化組成物は前記の通り間欠的に投与することができる。
　また、併用により予防および／または治療効果が向上し、併用薬物の投与量を減少させる、あるいは併用薬物の投与間隔を長くすることもできる。さらに併用薬物の投与を止めることも可能である。さらに、本発明の自己乳化組成物の間欠投与間隔および１日投与量を組み合わせて、症状の重症度、体重、年齢、およびその他の要因によっては適切に調整することができる。また、血中、血漿中あるいは血清中のω３ＰＵＦＡ、ＥＰＡ、ＤＨＡ、ＤＰＡあるいはＡＬＡの濃度および／またはＥＰＡ／ＡＡ比をモニターしながら、間欠投与間隔および１日当たりの投与量を組み合わせて調整して併用薬物と併用することができる。 For example, oral cyclosporine, etretinate, apremilast, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone or betamazone can be administered daily, and the self-emulsifying composition of the present invention can be administered intermittently as described above. . Topical maxacalcitol, maxacalcitol and betamethasone butyrate propionate, calcipotriol, calcipotriol and betamethasone dipropionate, tacalcitol hydrate, hydrocortisone acetate Betamethasone acetate or diflorazone acetate is applied daily, and the self-emulsifying composition of the present invention can be intermittently administered as described above. Injectable secukinumab is administered subcutaneously for the first time, one week later, two weeks later, three weeks later, four weeks later, and thereafter subcutaneously administered at intervals of 4 weeks. The self-emulsifying composition of the present invention is intermittent as described above. Can be administered. Ustekinumab is administered subcutaneously after the first 4 weeks, and thereafter administered at 12-week intervals, and the self-emulsifying composition of the present invention can be intermittently administered as described above. Adalimumab is subcutaneously administered once every two weeks after the initial administration, and the self-emulsifying composition of the present invention can be intermittently administered as described above. Infliximab is administered 2 and 6 weeks after the first intravenous infusion, and thereafter administered at intervals of 6 to 8 weeks. The self-emulsifying composition of the present invention can be intermittently administered as described above. Brodalumab is administered subcutaneously for the first time, one week later, two weeks later, and thereafter subcutaneously administered at intervals of two weeks, and the self-emulsifying composition of the present invention can be intermittently administered as described above. Ixekizumab is subcutaneously administered for the first time, and is subcutaneously administered every 2 weeks from 2 weeks to 12 weeks, and thereafter subcutaneously administered at intervals of 4 weeks. The self-emulsifying composition of the present invention is intermittently administered as described above. Can be administered.
Moreover, the preventive and / or therapeutic effect is improved by the combined use, and the dose of the concomitant drug can be decreased, or the administration interval of the concomitant drug can be lengthened. It is also possible to stop administration of the concomitant drug. Furthermore, the intermittent dosing interval and daily dose of the self-emulsifying composition of the present invention can be combined and adjusted appropriately depending on the severity of symptoms, weight, age, and other factors. In addition, while monitoring the concentration and / or EPA / AA ratio of ω3PUFA, EPA, DHA, DPA, or ALA in blood, plasma, or serum, it is used in combination by adjusting the intermittent dosing interval and daily dose. Can be used in combination with drugs.
　本発明において、「シークエンシャル投与」は本発明の自己乳化組成物と既存の治療薬を併用あるいは交互に投与する態様である。自己免疫性皮膚疾患または炎症性皮膚疾患の憎悪期には、例えばシクロスポリン、エトレチナート、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンテネルマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラからなる群から選択される少なくとも１つの化合物を、本発明の自己乳化組成物を併用せずあるいは併用して投与し、寛解期または非活動期には、例えばシクロスポリン、エトレチナート、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンテネルマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラと併用しないで、本発明の自己乳化組成物を間欠経口投与する態様であるが、これらに限定されない。
　本発明の自己乳化組成物を既存の治療薬と併用あるいは交互に投与する態様は、症状の重症度、体重、年齢、およびその他の要因によっては適切に調整することができる。さらに、本発明の自己乳化組成物の間欠投与間隔および１日投与量を組み合わせて、症状の重症度、体重、年齢、およびその他の要因によっては適切に調整することができる。また、血中、血漿中あるいは血清中のω３ＰＵＦＡ、ＥＰＡ、ＤＨＡ、ＤＰＡあるいはＡＬＡの濃度および／またはＥＰＡ／ＡＡ比をモニターしながら、間欠投与間隔および１日当たりの投与量を組み合わせて調整して既存の治療薬と併用あるいは交互に投与することができる。また、血中、血漿中あるいは血清中の併用薬物あるいはその代謝物の濃度をモニターしながら、併用薬物の投与間隔および１日当たりの投与量を組み合わせて調整して本発明の自己乳化組成物と併用あるいは交互に投与することができる。 In the present invention, “sequential administration” is an embodiment in which the self-emulsifying composition of the present invention and an existing therapeutic agent are used in combination or alternately. For the exacerbations of autoimmune or inflammatory skin diseases, for example, cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, dexamethasone, prednisolone, betamethasone, maxacalcitol, calcipotriol, tacalcitol hydrate , Hydrocortisone acetate, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildrakizumab, brodalumab, guselcoumab, dupirumumab, nemorizumab, rituximab, rituximab, rituximab, rituximab, rituximab , Upadacitinib, emicizumab, fasinu Bu, pegprelanib, omalizumab, leslizumab, subtabumab, gantenerumab, etanercept, tofacitinib, salicylic acid / white petrolatum, splatastosyl, azelastine hydrochloride, fexofenadine hydrochloride, sodium cromoglycate, oxatomidoprostazobic Hydrates, tranilast, beclomethasone propionic acid, human immunoglobulin / histamine dihydrochloride, methylprednisolone, apremilast, pimecrolimus, AMG-0101, AMG-0103, hydroxylated sterubene molecule, chrysabolol, nalfrafin, doxorubicin, WBI-1001, octenidine , Oxymetazoline, nitric oxide, timapiplant, rosipitol acetate, cobamide, From Epipiplant, Omiganan, Asimadoline, Metoflumine, DSXS-1411, Serinexer, Terbinafine, Ellenbecestat, Berbecestat, Ranabecestat, Fluticasone, Beperminogen Per Plasmid, Darcetrapib, Abatacept, Talidamide, Bosentan and Deflazaquina At least one selected compound is administered without or in combination with the self-emulsifying composition of the present invention, and during remission or inactivity, for example, cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, cortisone acetate , Dexamethasone, prednisolone, betamazone, maxacalcitol, calcipotriol, tacalcitol hydrate, hydrocortisone acetic acid Esters, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildrakizumab, brodalumab, guselumab, dupirumab, nemorizumab, traloximab, rituximab, rituximab, rituximab, rituximab Emicizumab, facinumab, pegprelanib, omalizumab, resurizumab, subtabumab, gantenerumab, etanercept, tofacitinib, salicylic acid / white petrolatum, suplatastosyl, azelastine hydrochloride, fexofenadine hydrochloride, oxamomidic acid, oxatomidic acid, oxatomidic acid, oxatomidic acid , Tacrolimus hydrate, tranilast, beclomethasone propionic acid, human immunoglobulin / histamine dihydrochloride, methylprednisolone, apremilast, pimecrolimus, AMG-0101, AMG-0103, hydroxylated sterubene molecule, chrysabolol, nalflaffin, doxorubicin, WBI-1001 , Octenidine, oxymetazoline, nitric oxide, timapiplant, rosipitol acetate, cobamide, febipiplant, omiganan, asimadoline, metflumin, DSXS-1411, selenexer, terbinafine, elembescestat, velvecestat, ranbecestat, fluticasone perflunicazone Perplasmid, darcetrapib, abatacept, thalidomide, bosentan, deflazacote and anakinra Not mix, but a self-emulsifying composition of the present invention is an aspect of intermittently administered orally, but are not limited to.
The mode in which the self-emulsifying composition of the present invention is used in combination or alternately with an existing therapeutic agent can be appropriately adjusted depending on the severity of symptoms, weight, age, and other factors. Furthermore, the intermittent dosing interval and daily dose of the self-emulsifying composition of the present invention can be combined and adjusted appropriately depending on the severity of symptoms, weight, age, and other factors. In addition, while monitoring the concentration and / or EPA / AA ratio of ω3PUFA, EPA, DHA, DPA, or ALA in blood, plasma, or serum, the existing intermittently administered dose and daily dose are adjusted in combination. Can be used in combination with or alternately with these therapeutic agents. In addition, while monitoring the concentration of the concomitant drug or its metabolite in blood, plasma or serum, it is used in combination with the self-emulsifying composition of the present invention by adjusting the administration interval and daily dose of the concomitant drug in combination. Alternatively, they can be administered alternately.
　本発明において併用し得る薬物として、例えば以下の薬物を上げることができるが、これらに限定されない。
（１）非ステロイド性抗炎症薬（ＮＳＡＩＤｓ）
　（ｉ）Ｃｌａｓｓｉｃａｌ　ＮＳＡＩＤｓ：アルコフェナク、アセクロフェナク、スリンダク、トルメチン、エトドラク、フェノプロフェン、チアプロフェン酸、メクロフェナム酸、メロキシカム、テオキシカム、ロルノキシカム、ナブメトン、アセトアミノフェン、フェナセチン、エテンザミド、スルピリン、アンチピリン、ミグレニン、アスピリン、メフェナム酸、フルフェナム酸、ジクロフェナックナトリウム、ロキソプロフェンナトリウム、フェニルブタゾン、インドメタシン、イブプロフェン、ケトプロフェン、ナプロキセン、オキサプロジン、フルルビプロフェン、フェンブフェン、プラノプロフェン、フロクタフェニン、ピロキシカム、エピリゾール、塩酸チアラミド、ザルトプロフェン、メシル酸ガベキサート、メシル酸カモスタット、ウリナスタチン、コルヒチン、プロベネシド、スルフィンピラゾン、ベンズブロマロン、アロプリノール、金チオリンゴ酸ナトリウム、ヒアルロン酸ナトリウム、サリチル酸ナトリウム、塩酸モルヒネ、サリチル酸、アトロピン、スコポラミン、モルヒネ、ペチジン、レボルファノール、オキシモルフォン又はその塩等。
　（ｉｉ）シクロオキシゲナーゼ抑制薬（ＣＯＸ－１選択的阻害薬、ＣＯＸ－２選択的阻害薬等）：サリチル酸誘導体（例、セレコキシブ、アスピリン）、エトリコキシブ、バルデコキシブ、ジクロフェナック、インドメタシン、ロキソプロフェン等。
　（ｉｉｉ）Ｎｉｔｒｉｃ　ｏｘｉｄｅ遊離型　ＮＳＡＩＤｓ
（２）疾患修飾性抗リウマチ薬（ＤＭＡＲＤｓ）
　（ｉ）金製剤：Ａｕｒａｎｏｆｉｎ等。
　（ｉｉ）ペニシラミン：Ｄ－ペニシラミン
　（ｉｉｉ）アミノサルチル酸製剤：　スルファサラジン、メサラミン、オルサラジン、バルサラジド。
　（ｉｖ）抗マラリア薬：　クロロキン等。
　（ｖ）ピリミジン合成阻害薬：レフルノマイド等。
　（ｖｉ）プログラフ。 Examples of drugs that can be used in the present invention include, but are not limited to, the following drugs.
(1) Nonsteroidal anti-inflammatory drugs (NSAIDs)
(I) Classic NSAIDs: arcofenac, aceclofenac, sulindac, tolmethine, etodolac, fenoprofen, thiaprofenic acid, meclofenamic acid, meloxicam, teoxicam, lornoxicam, nabumetone, acetaminophen, phenacetin, ethenamide, sulpyrine, antipyrine, antipyrine Mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, fructophenine, piroxicam, epirizole, tiaramid hydrochloride, zaltoprofen, mesylic acid Gabexate, duck mesylate Stat, ulinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone, allopurinol, sodium gold thiomalate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, oxymorphone or Its salt.
(Ii) cyclooxygenase inhibitors (COX-1 selective inhibitors, COX-2 selective inhibitors, etc.): salicylic acid derivatives (eg, celecoxib, aspirin), etoroxib, valdecoxib, diclofenac, indomethacin, loxoprofen, etc.
(Iii) Nitric Oxide Free NSAIDs
(2) Disease-modifying anti-rheumatic drugs (DMARDs)
(I) Gold formulation: Auranofin et al.
(Ii) Penicillamine: D-penicillamine (iii) Amino salicylic acid preparation: Sulfasalazine, mesalamine, olsalazine, balsalazide.
(Iv) Antimalarial drugs: chloroquine and the like.
(V) Pyrimidine synthesis inhibitors: leflunomide and the like.
(Vi) Prograph.
（３）抗サイトカイン薬
（Ｉ）タンパク質製剤
　（ｉ）ＴＮＦ阻害薬：　エタネルセプト、インフリキシマブ、アダリムマブ、セルトリズマブ　ペゴール、ゴリムマブ、ＰＡＳＳＴＮＦ－α、可溶性ＴＮＦ－α受容体、ＴＮＦ－α結合蛋白、抗ＴＮＦ－α抗体等。
　（ｉｉ）インターロイキン－１阻害薬：アナキンラ（インターロイキン－１受容体拮抗薬）、可溶性インターロイキン－１受容体等。
　（ｉｉｉ）インターロイキン－６阻害薬：トシリズマブ（抗インターロイキン－６受容体抗体）、抗インターロイキン－６抗体等。
　（ｉｖ）インターロイキン－１０阻害薬：抗インターロイキン－１０受容体抗体、抗インターロイキン－１０抗体等。
　（ｖ）インターロイキン－１２／２３阻害薬：ウステキヌマブ、ブリアキヌマブ、グセルクマブ、ＢＩ６５５０６（抗インターロイキン－１２／２３抗体）等。
　（ｖｉ）インターロイキン－１７阻害薬：セクキヌマブ、イキセキズマブ（抗インターロイキン－１７Ａ抗体）、ブロタルマブ（抗インターロイキン－１７受容体Ａ抗体）等。
（ｖｉｉ）インターロイキン－４阻害薬：デュピルマブ（抗インターロイキン－４受容体ａ抗体）、抗インターロイキン－４抗体等。
（ｖｉｉｉ）インターロイキン－３１阻害薬：ネモリズマブ（抗インターロイキン－３１受容体Ａ抗体）、抗インターロイキン－３１抗体等。
（ＩＩ）非タンパク質製剤
　（ｉ）ＭＡＰＫ阻害薬：ＢＭＳ－５８２９４９等。
　（ｉｉ）遺伝子調節薬：ＮＦ－κ、ＮＦ－κＢ、ＩＫＫ－１、ＩＫＫ－２、ＡＰ－１等シグナル伝達に関係する分子の阻害薬等。スルフォラファン、ジメチルフマル酸、バルドキソロンメチル、クルクミン、レスベラトロール、カテキン、エピガロカテキンガレート、糖化ヘスペリジン、ヘスペリジン、ヘスペレチン等のＮｒｆ２活性化剤。
　（ｉｉｉ）サイトカイン産生抑制薬：イグラチモド、テトミラスト等。
　（ｉｖ）ＴＮＦ－α変換酵素阻害薬
　（ｖ）インターロイキン－１β変換酵素阻害薬：ＶＸ－７６５等。
　（ｖｉ）インターロイキン－６拮抗薬：ＨＭＰＬ－００４等。
　（ｖｉｉ）インターロイキン－８阻害薬：ＩＬ－８拮抗薬、ＣＸＣＲ１　＆　ＣＸＣＲ２拮抗薬、レパレキシン等。
　（ｖｉｉｉ）ケモカイン拮抗薬：ＣＣＲ９拮抗薬（ＣＣＸ－２８２、　ＣＣＸ－０２５）、ＭＣＰ－１拮抗薬等。
　（ｉｘ）インターロイキン－２受容体拮抗薬：デニロイキン、ディフチトックス等。
　（ｘ）Ｔｈｅｒａｐｅｕｔｉｃ　ｖａｃｃｉｎｅｓ：ＴＮＦ－αワクチン等。
　（ｘｉ）遺伝子治療薬：インターロイキン－４、インターロイキン－１０、可溶性インターロイキン－１受容体、可溶性ＴＮＦ－α受容体等抗炎症作用を有する遺伝子の発現を亢進させることを目的とした遺伝子治療薬。
　（ｘｉｉ）アンチセンス化合物：ＩＳＩＳ　１０４８３８等。
　（ｘｉｉｉ）ＪＡＫ阻害薬：トファシチニブ、ルキソリチニブ、バリシチニブ等。
（４）インテグリン阻害薬
　ナタリズマブ、ベドリズマブ、ＡＪＭ３００、ＴＲＫ－１７０、Ｅ－６００７等。 (3) Anti-cytokine drugs (I) protein preparations (i) TNF inhibitors: etanercept, infliximab, adalimumab, sertolizumab Pegor, golimumab, PASSTNF-α, soluble TNF-α receptor, TNF-α binding protein, anti-TNF-α Antibodies etc.
(Ii) Interleukin-1 inhibitor: Anakinra (interleukin-1 receptor antagonist), soluble interleukin-1 receptor and the like.
(Iii) Interleukin-6 inhibitor: Tocilizumab (anti-interleukin-6 receptor antibody), anti-interleukin-6 antibody and the like.
(Iv) Interleukin-10 inhibitor: anti-interleukin-10 receptor antibody, anti-interleukin-10 antibody and the like.
(V) Interleukin-12 / 23 inhibitor: ustekinumab, briakinumab, guselcumab, BI65506 (anti-interleukin-12 / 23 antibody) and the like.
(Vi) Interleukin-17 inhibitor: secukinumab, ixekizumab (anti-interleukin-17A antibody), brotalumab (anti-interleukin-17 receptor A antibody) and the like.
(Vii) Interleukin-4 inhibitor: Dupilumab (anti-interleukin-4 receptor a antibody), anti-interleukin-4 antibody and the like.
(Viii) Interleukin-31 inhibitor: Nemorizumab (anti-interleukin-31 receptor A antibody), anti-interleukin-31 antibody and the like.
(II) Non-protein preparation (i) MAPK inhibitor: BMS-582949 and the like.
(Ii) Gene regulators: inhibitors of molecules related to signal transduction such as NF-κ, NF-κB, IKK-1, IKK-2, AP-1. Nrf2 activators such as sulforaphane, dimethylfumaric acid, bardoxolone methyl, curcumin, resveratrol, catechin, epigallocatechin gallate, glycated hesperidin, hesperidin, hesperetin.
(Iii) Cytokine production inhibitors: iguratimod, tetomilast and the like.
(Iv) TNF-α converting enzyme inhibitor (v) Interleukin-1β converting enzyme inhibitor: VX-765 and the like.
(Vi) Interleukin-6 antagonist: HMPL-004 and the like.
(Vii) Interleukin-8 inhibitor: IL-8 antagonist, CXCR1 & CXCR2 antagonist, reparexin and the like.
(Viii) Chemokine antagonists: CCR9 antagonists (CCX-282, CCX-025), MCP-1 antagonists and the like.
(Ix) Interleukin-2 receptor antagonist: Denileukine, Diftitox, etc.
(X) Therapeutic vaccines: TNF-α vaccine and the like.
(Xi) Gene therapy drug: gene therapy for the purpose of enhancing the expression of genes having anti-inflammatory activity such as interleukin-4, interleukin-10, soluble interleukin-1 receptor, soluble TNF-α receptor medicine.
(Xii) Antisense compound: ISIS 104838 and the like.
(Xiii) JAK inhibitors: tofacitinib, ruxolitinib, varicitinib and the like.
(4) Integrin inhibitors Natalizumab, vedolizumab, AJM300, TRK-170, E-6007, etc.
（５）免疫調節薬（免疫抑制薬）
　メトトレキサート、シクロフォスファミド、ＭＸ－６８、アチプリモド、ディハイドロクロライド、ＢＭＳ－１８８６６７、ＣＫＤ－４６１、リメクソロン、シクロスポリン、タクロリムス、ピメクロリムス、グスペリムス、アザチオプリン、ミコフェノール酸モフェチル、抗リンパ血清、乾燥スルホ化免疫グロブリン、エリスロポイエチン、コロニー刺激因子、インターロイキン、インターフェロン等。
（６）ステロイド薬
　デキサメタゾン、ヘキセストロール、メチマゾール、ベタメタゾン、トリアムシノロン、トリアムシノロンアセトニド、フルオシノニド、フルオシノロンアセトニド、プレドニゾロン、メチルプレドニゾロン、酢酸コルチゾン、コルチゾン酢酸エステル、ヒドロコルチゾン、ジフロラゾン、クロベタゾール、フルオロメトロン、プロピオン酸ベクロメタゾン、エストリオール等。
（７）アンジオテンシン変換酵素阻害薬
　エナラプリル、カプトプリル、ラミプリル、リシノプリル、シラザプリル、ペリンドプリル等。
（８）アンジオテンシンＩＩ受容体拮抗薬
　カンデサルタン、シレキセチル、バルサルタン、イルベサルタン、オルメサルタン、エプロサルタン等。
（９）利尿薬
　ヒドロクロロチアジド、スピロノラクトン、フロセミド、インダパミド、ベンドロフルアジド、シクロペンチアジド等。
（１０）強心薬
　ジゴキシン、ドブタミン等。
（１１）β受容体拮抗薬
　カルベジロール、メトプロロール、アテノロール等。
（１２）Ｃａ感受性増強薬
　ＭＣＣ－１３５等。
（１３）Ｃａチャネル拮抗薬
　ニフェジピン、シルニジピン、アムロジピン、ジルチアゼム、ベラパミル等。
（１４）抗血小板薬、抗凝固薬
　ヘパリン、アスピリン、ワルファリン等。
（１５）ＨＭＧ－ＣｏＡ還元酵素阻害薬
　アトロバスタチン、ロスバスタチン、シンバスタチン、ピタバスタチン、フルバスタチン、プラバスタチン、ロバスタチン等。
（１６）避妊薬
　（ｉ）性ホルモン又はその誘導体：黄体ホルモン又はその誘導体（プロゲステロン、１７α－ヒドロキシプロゲステロン、メドロキシプロゲステロン、酢酸メドロキシプロゲステロン、ノルエチステロン、ノルエチステロンエナンタート、ノルエチンドロン、酢酸ノルエチンドロン、ノルエチノドレル、レボノルゲストレル、ノルゲストレル、二酢酸エチノジオール、デソゲストレル、ノルゲスチメート、ゲストデン、プロゲスチン、エトノゲストレル、ドロスピレノン、ジエノゲスト、トリメゲストン、ネストロン、酢酸クロマジノン、ミフェプリストン、酢酸ノメゲストロル、Ｏｒｇ－３０６５９、ＴＸ－５２５、ＥＭＭ－３１０５２５）あるいは黄体ホルモン又はその誘導体と卵胞ホルモン又はその誘導体（エストラジオール、安息香酸エストラジオール、エストラジオールシピオネート、エストラジオールジプロピオナート、エストラジオールエナンタート、エストラジオールヘキサヒドロベンゾアート、エストラジオールフェニルプロピオナート、エストラジオールウンデカノアート、吉草酸エストラジオール、エストロン、エチニルエストラジオール、メストラノール）との合剤等。
　（ｉｉ）抗卵胞ホルモン薬：　オルメロキシフェン、ミフェプリストン、Ｏｒｇ－３３６２８等。
　（ｉｉｉ）殺精子薬：ウシェルセル等。 (5) Immunomodulatory drugs (immunosuppressive drugs)
Methotrexate, cyclophosphamide, MX-68, atiprimod, dihydrochloride, BMS-188667, CKD-461, rimexolone, cyclosporine, tacrolimus, pimecrolimus, gusperimus, azathioprine, mycophenolate mofetil, anti-lymph serum, dry sulfonated immunity Globulin, erythropoietin, colony stimulating factor, interleukin, interferon, etc.
(6) Steroid drugs Dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, cortisone acetate, hydrocortisone, diflorazone, clobetasol, fluorochrome Beclomethasone propionate, estriol, etc.
(7) Angiotensin converting enzyme inhibitor enalapril, captopril, ramipril, lisinopril, cilazapril, perindopril and the like.
(8) Angiotensin II receptor antagonist candesartan, cilexetil, valsartan, irbesartan, olmesartan, eprosartan and the like.
(9) Diuretics Hydrochlorothiazide, spironolactone, furosemide, indapamide, bendrofluazide, cyclopenthiazide and the like.
(10) Cardiotonic drugs Digoxin, dobutamine and the like.
(11) β receptor antagonist carvedilol, metoprolol, atenolol and the like.
(12) Ca sensitivity enhancer MCC-135 and the like.
(13) Ca channel antagonist nifedipine, cilnidipine, amlodipine, diltiazem, verapamil and the like.
(14) Antiplatelet drugs, anticoagulants heparin, aspirin, warfarin and the like.
(15) HMG-CoA reductase inhibitor atorvastatin, rosuvastatin, simvastatin, pitavastatin, fluvastatin, pravastatin, lovastatin and the like.
(16) Contraceptive agent (i) Sex hormone or derivative thereof: progesterone or derivative thereof (progesterone, 17α-hydroxyprogesterone, medroxyprogesterone, medroxyprogesterone acetate, norethisterone, norethisterone enanthate, norethindrone, norethindrone acetate, norethinodrel, levo Norgestrel, Norgestrel, Ethinodiol diacetate, Desogestrel, Norgestimate, Guestden, Progestin, Etnogestrel, Drospirenone, Dienogest, Trimegestone, Nestrone, Chromazinone acetate, Mifepristone, Nomegestrol acetate, Org-30659, TX-525, EMM-310525) Or progesterone or its derivative and follicular hormone or its derivative , Estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate, estradiol hexahydrobenzoate, estradiol phenylpropionate, estradiol undecanoate, estradiol valerate, estrone, ethinyl estradiol, mestranol) Mixtures etc.
(Ii) Anti-follicular hormone drugs: olmeroxifene, mifepristone, Org-33628 and the like.
(Iii) Spermicide: Uchel cell and the like.
（１７）その他
　（ｉ）Ｔ細胞阻害薬
　（ｉｉ）イノシン一リン酸脱水素酵素（ＩＭＰＤＨ）阻害薬：マイコフェノレート　モフェチル等。
　（ｉｉｉ）接着分子阻害薬：ＩＳＩＳ　２３０２、セレクチン阻害薬、ＥＬＡＭ－１、ＶＣＡＭ－１、ＩＣＡＭ－１等。
　（ｉｖ）サリドマイド
　（ｖ）カテプシン阻害薬
　（ｖｉ）マトリックスメタロプロテアーゼ（ＭＭＰｓ）阻害薬：Ｖ－８５５４６等。
　（ｖｉｉ）グルコース－６－リン酸脱水素酵素阻害薬
　（ｖｉｉｉ）Ｄｉｈｙｄｒｏｏｒｏｔａｔｅ脱水素酵素（ＤＨＯＤＨ）阻害薬
　（ｉｘ）ホスホジエステラーゼＩＶ（ＰＤＥ　ＩＶ）阻害薬：アプレミラスト、ロフルミラスト、ＣＧ－１０８８等。
　（ｘ）ホスホリパーゼＡ２阻害薬
　（ｘｉ）ｉＮＯＳ阻害薬：ＶＡＳ－２０３等。
　（ｘｉｉ）Ｍｉｃｒｏｔｕｂｌｅ刺激薬：パクリタキセル等。
　（ｘｉｉｉ）Ｍｉｃｒｏｔｕｂｌｅ阻害薬：リューマコン等。
　（ｘｉｖ）ＭＨＣクラスＩＩ拮抗薬
　（ｘｖ）Ｐｒｏｓｔａｃｙｃｌｉｎ作働薬：イロプロスト等。
　（ｘｖｉ）ＣＤ４拮抗薬：ザノリムマブ等。
　（ｘｖｉｉ）ＣＤ２３拮抗薬
　（ｘｖｉｉｉ）ＬＴＢ４受容体拮抗薬：ＤＷ－１３０５等。
　（ｘｉｘ）５－リポキシゲナーゼ阻害薬：ジリュートン等。
　（ｘｘ）コリンエステラーゼ阻害薬：ガランタミン等。
　（ｘｘｉ）チロシンキナーゼ阻害薬：Ｔｙｋ２阻害薬（ＷＯ２０１０１４２７５２）等。
　（ｘｘｉｉ）カレプシンＢ阻害薬
　（ｘｘｉｉｉ）Ａｄｅｎｏｓｉｎｅ　ｄｅａｍｉｎａｓｅ阻害薬：ペントスタチン等。
　（ｘｘｉｖ）骨形成刺激薬
　（ｘｘｖ）ジペプチジルペプチダーゼ阻害薬
　（ｘｘｖｉ）コラーゲン作働薬
　（ｘｘｖｉｉ）Ｃａｐｓａｉｃｉｎクリーム
　（ｘｘｖｉｉｉ）ヒアルロン酸誘導体：シンビスク（ｈｙｌａｎ　Ｇ－Ｆ　２０）、オルソビスク等。
　（ｘｘｉｘ）硫酸グルコサミン
　（ｘｘｘ）アミプリローゼ
　（ｘｘｘｉ）ＣＤ－２０阻害薬：リツキシマブ、イブリツモマブ、トシツモマブ、オファツマブ等。
　（ｘｘｘｉｉ）ＢＡＦＦ阻害薬：ベリムマブ、タバルマブ、アタシセプト、Ａ－６２３等。
　（ｘｘｘｉｉｉ）ＣＤ５２阻害薬：アレムツズマブ等。
　（ｘｘｘｉｖ）ビタミンＡ誘導体：エトレチナート等。
　（ｘｘｘｖ）ビタミンＤ誘導体：マキサカルシトール、カルシポトリオール、タカルシトール水和物等。
　（ｘｘｘｖｉ）選択的ヒスタミン１受容体拮抗薬：エピナスチン塩酸塩、オロパタジン塩酸塩等。
　（ｘｘｘｖｉｉ）抗真菌薬、抗生物質：ケトコナゾール、ミコナゾール、イソコナゾール、ビホナゾール、ラノコナゾール、ルリコナゾール、クロトリマゾール、テルビナフィン、ブテナフィン、ネチコナゾール、テトラサイクリン、ゲンタマイシン、クリンダマイシン、クロラムフェニコール、フラジオマイシン等。 (17) Others (i) T cell inhibitor (ii) Inosine monophosphate dehydrogenase (IMPDH) inhibitor: Mycophenolate mofetil and the like.
(Iii) Adhesion molecule inhibitors: ISIS 2302, selectin inhibitors, ELAM-1, VCAM-1, ICAM-1, etc.
(Iv) Thalidomide (v) Cathepsin inhibitor (vi) Matrix metalloprotease (MMPs) inhibitor: V-85546 and the like.
(Vii) Glucose-6-phosphate dehydrogenase inhibitor (viii) Dihydrorotate dehydrogenase (DHODH) inhibitor (ix) Phosphodiesterase IV (PDE IV) inhibitor: apremilast, roflumilast, CG-1088 and the like.
(X) Phospholipase A2 inhibitor (xi) iNOS inhibitor: VAS-203 and the like.
(Xii) Microtubule stimulant: paclitaxel and the like.
(Xiii) Microtable inhibitor: Rheumacon and the like.
(Xiv) MHC class II antagonist (xv) Prostacyclin agonist: iloprost and the like.
(Xvi) CD4 antagonist: zanolimumab and the like.
(Xvii) CD23 antagonist (xviii) LTB4 receptor antagonist: DW-1305 and the like.
(Xix) 5-lipoxygenase inhibitor: zileuton and the like.
(Xx) Cholinesterase inhibitor: galantamine and the like.
(Xxi) tyrosine kinase inhibitor: Tyk2 inhibitor (WO20101422752) and the like.
(Xxii) Calepsin B inhibitor (xxiii) Adenosine deaminase inhibitor: Pentostatin and the like.
(Xxiv) Osteogenesis stimulating agent (xxv) Dipeptidyl peptidase inhibitor (xxvi) Collagen agonist (xxvii) Capsaicin cream (xxviii) Hyaluronic acid derivative: Synbisque (hylan GF 20), Orthobisque and the like.
(Xxix) Glucosamine sulfate (xxx) Amiprirose (xxx) CD-20 inhibitor: rituximab, ibritumomab, tositumomab, ofatumumab, etc.
(Xxxii) BAFF inhibitors: belimumab, tabalumab, atacicept, A-623 and the like.
(Xxxiii) CD52 inhibitor: alemtuzumab and the like.
(Xxxiv) Vitamin A derivatives: etretinate and the like.
(Xxxv) Vitamin D derivatives: maxacalcitol, calcipotriol, tacalcitol hydrate and the like.
(Xxxvi) Selective histamine 1 receptor antagonists: epinastine hydrochloride, olopatadine hydrochloride and the like.
(Xxxvii) Antifungal drugs, antibiotics: ketoconazole, miconazole, isconazole, bifonazole, ranoconazole, luliconazole, clotrimazole, terbinafine, butenafine, neticonazole, tetracycline, gentamicin, clindamycin, chloramphenicol, fradiomycin and the like.
　本発明の自己乳化組成物は、任意に製剤学上許容しうる添加剤と組み合わせて製剤をつくることができる。例えば、賦形剤(例；乳糖、白糖、マンニット、結晶セルロース、ケイ酸、トウモロコシデンプン、バレイショデンプン)、結合剤(例；セルロース類(ヒドロキシプロピルセルロース(ＨＰＣ)、ヒドロキシプロピルメチルセルロース(ＨＰＭＣ))、結晶セルロース、糖類(乳糖、マンニット、白糖、ソルビトール、エリスリトール、キシリトール、)、デンプン類(トウモロコシデンプン、バレイショデンプン)、α化デンプン、デキストリン、ポリビニルピロリドン(ＰＶＰ)、マクロゴール、ポリビニルアルコール(ＰＶＡ))、滑沢剤(例；ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、カルボキシメチルセルロース)、崩壊剤(例；デンプン類(トウモロコシデンプン、バレイショデンプン)、カルボキシメチルスターチナトリウム、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポピドン)、被膜剤(例；セルロース類(ヒドロキシプロピルセルロース(ＨＰＣ)、ヒドロキシプロピルメチルセルロース(ＨＰＭＣ)、アミノアルキルメタクリレートコポリマーＥ、メタクリル酸コポリマーＬＤ)、可塑剤(例；クエン酸トリエチル、マクロゴール)、隠蔽剤(例；酸化チタン)、着色剤、香味剤、防腐剤(例；塩化ベンザルコニウム、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、)、等張化剤(例；グリセリン、塩化ナトリウム、塩化カルシウム、マンニトール、ブドウ糖)、ｐＨ調節剤(例；水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、塩酸、硫酸、リン酸緩衝液などの緩衝液)、安定化剤(例；糖、糖アルコール、キサンタンガム)、分散剤、酸化防止剤(例；アスコルビン酸、ブチルヒドロキシアニソール(ＢＨＡ)、没食子酸プロピル、ｄｌ－α－トコフェロール)、緩衝剤、保存剤(例；パラベン、ベンジルアルコール、塩化ベンザルコニウム)、芳香剤(例；バニリン、ｌ－メントール、ローズ油)、溶解補助剤(例；ポリオキシエチレン硬化ヒマシ油、ポリソルベート８０、ポリエチレングリコール、リン脂質コレステロール、トリエタノールアミン)、吸収促進剤(例；グリコール酸ナトリウム、エデト酸ナトリウム、カプリン酸ナトリウム、アシルカルニチン類、リモネン)、ゲル化剤、懸濁化剤、又は乳化促進剤（例；１２～２２個の炭素原子を含む脂肪酸（ステアリン酸、オレイン酸、リノール酸、パルミチン酸、リノレン酸、ミリスチン酸、およびそれらの塩類など））、安定剤（例；ホスファチジン酸、アスコルビン酸、グリセリン、およびセタノール）、界面活性剤（例；ショ糖脂肪酸エステル、ソルビタン脂肪酸エステル、グリセリン脂肪酸エステル、ポリグリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンアルキルエーテル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレンアルキルフェニルエーテル、およびポリオキシエチレンポリオキシプロピレンアルキルエーテル（ＨＬＢが１０未満））、抗酸化剤としては、油溶性抗酸化剤（ブチルヒドロキシトルエン、ブチルヒドロキシアニソール、没食子酸プロピル、没食子酸プロピル、製薬学上許容しうるキノン、アスタキサンチン、およびα－トコフェロールなど）、水溶性抗酸化剤（アスコルビン酸（ビタミンＣ)、グルタチオン、リポ酸など）が挙げられるが、これらに限定されない。 The self-emulsifying composition of the present invention can be formulated by arbitrarily combining with pharmaceutically acceptable additives. For example, excipients (eg lactose, sucrose, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch), binders (eg celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC)) , Crystalline cellulose, saccharides (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol, polyvinyl alcohol (PVA) )), Lubricant (eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose), disintegrant (eg; starches (corn starch, potato starch), carboxymethyl starch sodium, carmelo , Carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg, celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), aminoalkyl methacrylate copolymer E, methacrylic acid copolymer LD)), Plasticizers (eg triethyl citrate, macrogol), masking agents (eg titanium oxide), colorants, flavoring agents, preservatives (eg benzalkonium chloride, ethyl paraoxybenzoate, propyl paraoxybenzoate), Isotonic agents (eg, glycerin, sodium chloride, calcium chloride, mannitol, glucose), pH regulators (eg, buffers such as sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, phosphate buffer) , Stabilizers (eg sugar, sugar alcohol, xanthan gum), dispersants Antioxidants (eg, ascorbic acid, butylhydroxyanisole (BHA), propyl gallate, dl-α-tocopherol), buffers, preservatives (eg, paraben, benzyl alcohol, benzalkonium chloride), fragrances (eg, Vanillin, l-menthol, rose oil), solubilizer (eg, polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol, phospholipid cholesterol, triethanolamine), absorption enhancer (eg, sodium glycolate, edet) Sodium acid, sodium caprate, acylcarnitines, limonene), gelling agent, suspending agent, or emulsifying accelerator (eg; fatty acids containing 12 to 22 carbon atoms (stearic acid, oleic acid, linoleic acid, Palmitic acid, linolenic acid, myristic acid, and their salts)), stabilizers Examples: phosphatidic acid, ascorbic acid, glycerin, and cetanol), surfactants (eg, sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene alkyl ether) , Polyoxyethylene fatty acid ester, polyoxyethylene alkylphenyl ether, and polyoxyethylene polyoxypropylene alkyl ether (HLB is less than 10)), as an antioxidant, oil-soluble antioxidant (butylhydroxytoluene, butylhydroxyanisole) , Propyl gallate, propyl gallate, pharmaceutically acceptable quinone, astaxanthin, and α-tocopherol), water-soluble antioxidants (ascorbic acid Tamine C), glutathione, lipoic acid and the like), but are not limited thereto.
　さらに具体的に言えば、ω３ＰＵＦＡ類は高度に不飽和であるので、例えば、ブチルヒドロキシトルエン、ブチルヒドロキシアニソール、没食子酸プロピル、没食子酸プロピル、製薬学上許容しうるキノン、アスタキサンチン、およびα‐トコフェロールから選択される少なくとも１つの油溶性抗酸化剤の有効な量が、前記組成物に組み込まれていることが望ましい。また、ω３ＰＵＦＡ類が固体の場合は、アスコルビン酸、グルタチオン、リポ酸から選択される少なくとも１つの水溶性抗酸化剤の有効な量が、前記組成物に組み込まれていることが望ましい。貯蔵温度は望ましくは室温であり、凍結貯蔵は自己乳化特性、前記組成物の分散性、または乳化安定性の喪失につながる可能性があるため、避けることが望ましい。 More specifically, since ω3 PUFAs are highly unsaturated, for example, butylhydroxytoluene, butylhydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable quinones, astaxanthins, and α-tocopherols Desirably, an effective amount of at least one oil-soluble antioxidant selected from is incorporated into the composition. When the ω3 PUFAs are solid, it is desirable that an effective amount of at least one water-soluble antioxidant selected from ascorbic acid, glutathione, and lipoic acid is incorporated into the composition. The storage temperature is desirably room temperature and it is desirable to avoid freezing storage as it can lead to loss of self-emulsifying properties, dispersibility of the composition, or emulsion stability.
　本発明のＥＰＡ類を含む自己乳化組成物には、上述のＥｐａｄｅｌ(R)、ＬｏｖａｚａTM、ＯｍａｃｏｒTM、ＬｏｔｒｉｇａTM、またはＶａｓｃｅｐａTMなどの市販のＥＰＡ類組成物や、ＥｐａｎｏｖａTM（Ｏｍｔｈｅｒａ、Ａｓｔｒａｚｅｎｅｃａ）またはＭＡＴ９００１（Ｍａｔｉｎａｓ　Ｂｉｏｐｈａｒｍａ）などの開発中のＥＰＡ類組成物を使用してつくることができる。ＥＰＡ類を含む自己乳化組成物は、錠剤、カプセル、粉末または固形の経口服用の形態で、液体の形態で、ソフトゲルカプセルまたはその他のカプセルの形態で、または投与に適切かつ便利なその他の服用形態で、必要とする患者に投与する。また、前記組成物は、同業者に既知の製薬学上許容しうる賦形剤を含むが、それには、界面活性剤、油、共溶剤、または、そのような賦形剤と安定剤、乳化剤、防腐剤、可溶化剤、および／または医薬組成物の製剤に関して同業者に既知のその他の不活性医薬成分との組み合わせが含まれる。 The self-emulsifying composition comprising EPA compounds of the present invention, the above Epadel (R), Lovaza TM, Omacor TM, Lotriga TM or and commercial EPA such compositions such Vascepa TM,, Epanova TM (Omthera , Astrazeneca) Alternatively, it can be made using an EPA-like composition under development such as MAT9001 (Matinas Biopharma). Self-emulsifying compositions containing EPAs are in tablet, capsule, powder or solid oral dosage form, in liquid form, in soft gel capsule or other capsule form, or other dosages suitable and convenient for administration In the form, it is administered to the patient in need. The composition also includes pharmaceutically acceptable excipients known to those skilled in the art, including surfactants, oils, co-solvents, or such excipients and stabilizers, emulsifiers. , Preservatives, solubilizers, and / or combinations with other inert pharmaceutical ingredients known to those skilled in the art for the formulation of pharmaceutical compositions.
　種々の剤形としては、例えば、錠剤、カプセル剤、顆粒剤、散剤、丸剤、液剤、酒精剤、懸濁剤、エキス剤、エリキシル剤等があげられる。 Examples of various dosage forms include tablets, capsules, granules, powders, pills, liquids, spirits, suspensions, extracts, elixirs, and the like.
　次に、本発明をさらに詳細に説明するために実施例をあげるが、これらの例は単なる実施であって、本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。 Next, examples will be given to describe the present invention in more detail. However, these examples are merely implementations, do not limit the present invention, and are changed without departing from the scope of the present invention. May be.
実験例１：イミキモド塗布乾癬モデルマウス試験
　Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｉｍｍｕｎｏｌｏｇｙ、　１８２、　５８３６－５８４５、　２００９に記載の方法を適宜改変して試験を行う。８－１１週齢の雄性ＢＡＬＢ／ｃマウス（日本チャールスリバー、横浜）の耳介および毛刈りした背部にベセルナクリーム５％（持田製薬、東京）を各々１２．５ｍｇ（イミキモド０．６２５ｍｇ）および６２．５ｍｇ（イミキモド３．１２５ｍｇ）をイソフルラン麻酔下、１日１回、５～８日間、均一に塗布する。対照群にはベセルナクリームに替えてワセリンクリーム（例えば、Ｖａｓｅｒｉｎ　Ｌａｎｅｔｔｅクリーム（Ｆａｇｒｏｎ、南ホラント））を同様に塗布する。各クリームの塗布前および塗布の２４時間後に麻酔下、耳介および背部を肉眼的に観察し、背部皮膚所見（紅斑、浸潤、鱗屑）の程度を各々０～４（０：なし、１：軽度、２：中等度、３：高度、４：極めて高度）にスコア化して合計スコア（０～１２）を算出するｐｓｏｒｉａｓｉｓ　ｓｅｖｅｒｉｔｙ　ｉｎｄｅｘ（ＰＳＩ）を用いて評価し、マイクロメーターを用いて耳介厚を測定する。耳介厚は経日的推移、および初回測定と最終測定の差を算出して評価する。
　各クリームの最終塗布の２４時間後に生検トレパン（ＢＩＯＰＳＹ　ＰＵＮＣＨ）を用いて直径６ｍｍの円形の耳介皮膚組織およびスカルぺルを用いて背部皮膚を摘出する。耳介皮膚組織および背部皮膚組織は半分に切り分け、病理組織評価、あるいは各種サイトカインのタンパク質発現評価およびｍＲＮＡ発現評価に用いる。
　なお、被験物質の投与は、ＥＰＡ－Ｅ毎日投与群では、ベセルナクリーム塗布前日より最終塗布日までＥＰＡ－Ｅ５００ｍｇ／ｋｇを胃ゾンデを用いて経口投与する。３日毎投与群では、ベセルナクリーム塗布前日より３日毎に、ＥＰＡ－ＥまたはＥＰＡ－Ｅ自己乳化組成物を、各々ＥＰＡ－Ｅとして１５００ｍｇ／ｋｇとなるように胃ゾンデを用いて経口投与する。また、１週間毎投与群では、ベセルナクリーム塗布前日および１週間後に、ＥＰＡ－ＥまたはＥＰＡ－Ｅ自己乳化組成物を、各々ＥＰＡ－Ｅとして３５００ｍｇ／ｋｇとなるように胃ゾンデを用いて経口投与する。 Experimental Example 1: Imiquimod-applied psoriasis model mouse test The test described in The Journal of Immunology, 182, 5836-5845, 2009 is performed with appropriate modifications. 8-11-week-old male BALB / c mice (Charles River, Japan) 12.5 mg (Imiquimod 0.625 mg) and 62% Beselna cream 5% (Mochida Pharmaceutical, Tokyo) on the auricle and shaved back, respectively, and 62 .5 mg (imiquimod 3.125 mg) is applied evenly once a day for 5-8 days under isoflurane anesthesia. Vaseline cream (for example, Vaserin Lanette cream (Facron, South Holland)) is similarly applied to the control group instead of Beserna cream. Before application of each cream and 24 hours after application, the auricle and back were visually observed under anesthesia, and the degree of dorsal skin findings (erythema, infiltration, scale) was 0 to 4 (0: none, 1: mild) (2: moderate, 3: high, 4: extremely high), and the total score (0-12) is calculated using a psoriasis severity index (PSI), and the auricular thickness is measured using a micrometer. taking measurement. The thickness of the auricle is evaluated by calculating the daily transition and the difference between the initial measurement and the final measurement.
Twenty-four hours after the final application of each cream, the dorsal skin is removed using a biopsy trepan (BIOPSY PUNCH) with a 6 mm diameter circular auricular skin tissue and scalpel. The auricular skin tissue and the back skin tissue are cut in half and used for pathological tissue evaluation, protein expression evaluation of various cytokines, and mRNA expression evaluation.
In the EPA-E daily administration group, EPA-E 500 mg / kg is orally administered using a gastric sonde from the day before the application of Beserna cream to the final application day. In the group administered every 3 days, EPA-E or EPA-E self-emulsifying composition is orally administered every 3 days from the day before the application of Beserna cream using a stomach tube so that the EPA-E is 1500 mg / kg. In addition, in the weekly administration group, EPA-E or EPA-E self-emulsifying composition was orally administered using a gastric sonde to give 3500 mg / kg as EPA-E on the day before and one week after the application of Beserna cream. To do.
　対照群に比してベセルナクリーム塗布群では肉眼的に耳介および背部の腫脹および背部ＰＳＩの増加が認められること、耳介厚が経日的に増加すること、および病理組織学的に耳介および背部に表皮肥厚を伴った乾癬様皮膚炎が誘導されることが確認される。ベセルナクリーム塗布群に比してＥＰＡ－Ｅ毎日投与群、ＥＰＡ－Ｅ自己乳化組成物３日毎投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群では耳介および背部の腫脹抑制、背部ＰＳＩの増加抑制、耳介厚の経日的増加抑制、および病理組織学的な耳介および背部の表皮肥厚抑制のうち少なくとも１つ以上の抑制効果が確認され、乾癬様皮膚炎の程度が軽いことが確認され、これらの抑制効果はＥＰＡ－Ｅ自己乳化組成物３日毎投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群で高い。
　また、対照群に比してベセルナクリーム塗布群では耳介および背部の皮膚組織でのインターロイキン（ＩＬ）－１、ＩＬ－２、ＩＬ－４、ＩＬ－５、ＩＬ－６、ＩＬ－１０、ＩＬ－１２、ＩＬ－１７、ＩＬ－２２、ＩＬ－２３、ＩＬ－２７、ＩＬ－３６およびＴＮＦ－αのうち少なくとも１つ以上のタンパク質発現および／またはｍＲＮＡ発現が増加し、ベセルナクリーム塗布群に比してＥＰＡ－Ｅ毎日投与群およびＥＰＡ－Ｅ自己乳化組成物３日毎投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群ではこれらのうち少なくとも１つ以上の増加が抑制され、これらの抑制効果はＥＰＡ－Ｅ自己乳化組成物３日毎投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群で高い。また、ＥＰＡ－Ｅ１週間毎投与群では、個体により軟便あるいは下痢の副作用が認められるが、ＥＰＡ－Ｅ自己乳化組成物投与群では特記すべき副作用は認められない。 Compared to the control group, the Beselna cream application group showed macroscopically swelling of the auricle and back and increased back PSI, increased auricular thickness over time, and histopathologically the auricle And psoriasis-like dermatitis with epidermal thickening on the back is confirmed. Compared to the Beserna cream application group, the EPA-E daily administration group, the EPA-E self-emulsification composition every 3 days administration group, and the EPA-E self-emulsification composition every week administration group suppressed the swelling of the auricle and back, and the back PSI. At least one of the effects of suppressing the increase in the auricle, the daily increase in the thickness of the auricle, and the suppression of the thickening of the epidermis and the epidermis in the histopathology. These inhibitory effects are high in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsifying composition every week administration group.
In addition, compared to the control group, interleukin (IL) -1, IL-2, IL-4, IL-5, IL-6, IL-10 in the auricular and dorsal skin tissues in the beselna cream application group, At least one protein expression and / or mRNA expression of IL-12, IL-17, IL-22, IL-23, IL-27, IL-36 and TNF-α is increased, In comparison, the EPA-E daily administration group, the EPA-E self-emulsifying composition every 3 days administration group, and the EPA-E self-emulsifying composition every week administration group suppressed the increase in at least one of these, The inhibitory effect is high in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsifying composition every week administration group. In addition, in the EPA-E weekly administration group, side effects such as loose stool or diarrhea are observed depending on the individual, but in the EPA-E self-emulsifying composition administration group, there are no notable side effects.
実験例２：ＩＬ－２３耳介皮内投与乾癬モデルマウス試験
　Ｊｏｕｒｎａｌ　ｏｆ　Ｉｎｖｅｓｔｉｇａｔｉｖｅ　Ｄｅｒｍａｔｏｌｏｇｙ、　１３１、　１１１０－１１１８、　２０１１に記載の方法を適宜改変して試験を行う。６－８週齢の雄性ＢＡＬＢ／ｃマウス（日本チャールスリバー、横浜）の耳介皮内にマウスリコンビナントＩＬ－２３（Ｒ＆Ｄ　ｓｙｓｔｅｍｓ、Ｍｉｎｎｅａｐｏｌｉｓ、　Ｃａｔ．Ｎｏ．１８８７－ＭＬ／ＣＦ）５００　ｎｇ／１０　μＬリン酸緩衝生理食塩水をイソフルラン麻酔下、１日１回、５～７日間、皮内投与する。対照群にはＩＬ－２３に替えてリン酸緩衝生理食塩水を同様に投与する。各皮内投与前および投与の６時間後に、麻酔下、耳介を肉眼的に観察し、マイクロメーターを用いて耳介厚を測定する。耳介厚は経日的推移、および初回測定と最終測定の差を算出して評価する。
　耳介厚の最終測定後に耳介を摘出し、生検トレパン（ＢＩＯＰＳＹ　ＰＵＮＣＨ）を用いて皮内投与部位を中心とする直径６　ｍｍの円形の耳介皮膚組織を採取する。耳介皮膚組織は半分に切り分け、病理組織評価、あるいは各種サイトカインのタンパク質発現評価およびｍＲＮＡ発現評価に用いる。
　なお、被験物質の投与は、ＥＰＡ－Ｅ毎日投与群では、ＩＬ２３投与前日より最終塗布日まで、ＥＰＡ－Ｅ５００ｍｇ／ｋｇを胃ゾンデを用いて経口投与する。２日毎投与群では、ＩＬ２３投与前日より２日毎に、ＥＰＡ－ＥまたはＥＰＡ－Ｅ自己乳化組成物を、各々ＥＰＡ－Ｅとして１０００ｍｇ／ｋｇとなるように胃ゾンデを用いて経口投与する。また、４日毎投与群では、ＩＬ２３投与前日より４日毎に、ＥＰＡ－ＥまたはＥＰＡ－Ｅ自己乳化組成物を、各々ＥＰＡ－Ｅとして２０００ｍｇ／ｋｇとなるように胃ゾンデを用いて経口投与する。 Experimental example 2: IL-23 intraauricular intradermic administration psoriasis model mouse test The test described in Journal of Investigative Dermatology, 131, 1110-1118, 2011 is appropriately modified and tested. Mouse recombinant IL-23 (R & D systems, Minneapolis, Cat. No. 1887-ML / CF) 500 ng / 10 μL in the auricular skin of 6-8 week-old male BALB / c mice (Charles River, Yokohama, Japan) Phosphate buffered saline is intradermally administered once a day for 5-7 days under isoflurane anesthesia. In the control group, phosphate buffered saline is administered in the same manner instead of IL-23. Before each intradermal administration and 6 hours after the administration, the auricle is visually observed under anesthesia, and the auricle thickness is measured using a micrometer. The thickness of the auricle is evaluated by calculating the daily transition and the difference between the initial measurement and the final measurement.
After the final measurement of the pinna thickness, the pinna is removed, and a circular pinna skin tissue having a diameter of 6 mm centering on the intradermal administration site is collected using a biopsy trepan (BIOPSY PUNCH). The auricular skin tissue is cut in half and used for pathological tissue evaluation or protein expression evaluation and mRNA expression evaluation of various cytokines.
In the EPA-E daily administration group, EPA-E 500 mg / kg is orally administered using a stomach tube in the EPA-E daily administration group from the day before the administration of IL23 to the final application day. In the 2-day administration group, EPA-E or EPA-E self-emulsifying composition is orally administered every 2 days from the day before IL23 administration using a gastric sonde so that each EPA-E is 1000 mg / kg. In the 4-day administration group, EPA-E or the EPA-E self-emulsifying composition is orally administered using a gastric sonde every 2000 days from the day before IL23 administration so that the EPA-E is 2000 mg / kg.
　対照群に比してＩＬ２３投与群では肉眼的に耳介の腫脹が認められること、耳介厚が経日的に増加すること、および病理組織学的に耳介に表皮肥厚を伴った乾癬様皮膚炎が誘導されることが確認される。ＩＬ２３投与群に比してＥＰＡ－Ｅ毎日投与群、ＥＰＡ－Ｅ自己乳化組成物２日毎投与群およびＥＰＡ－Ｅ自己乳化組成物４日毎投与群では耳介の腫脹抑制、耳介厚の経日的増加抑制、および病理組織学的な表皮肥厚抑制のうち少なくとも１つ以上の抑制効果が確認され、乾癬様皮膚炎の程度が軽いことが確認され、これらの抑制効果はＥＰＡ－Ｅ自己乳化組成物２日毎投与群およびＥＰＡ－Ｅ自己乳化組成物４日毎投与群で高い。
　また、対照群に比してＩＬ２３投与群では耳介皮膚組織でのインターロイキン（ＩＬ）－１、ＩＬ－２、ＩＬ－４、ＩＬ－５、ＩＬ－６、ＩＬ－１０、ＩＬ－１２、ＩＬ－１７、ＩＬ－２２、ＩＬ－２３、ＩＬ－２７、ＩＬ－３６およびＴＮＦ－αのうち少なくとも１つ以上のタンパク質発現および／またはｍＲＮＡ発現が増加し、ＩＬ２３投与群に比してＥＰＡ－Ｅ毎日投与群、ＥＰＡ－Ｅ自己乳化組成物２日毎投与群およびＥＰＡ－Ｅ自己乳化組成物４日毎投与群ではこれらのうち少なくとも１つ以上の増加が抑制され、これらの抑制効果はＥＰＡ－Ｅ自己乳化組成物２日毎投与群およびＥＰＡ－Ｅ自己乳化組成物４日毎投与群で高い。また、ＥＰＡ－Ｅ４日毎投与群では、個体により軟便あるいは下痢の副作用が認められるが、ＥＰＡ－Ｅ自己乳化組成物投与群では特記すべき副作用は認められない。 Compared with the control group, the IL23-administered group showed macroscopic swelling of the auricle, increased auricular thickness over time, and histopathologically psoriasis-like with epidermal thickening It is confirmed that dermatitis is induced. In comparison with the IL23 administration group, the EPA-E daily administration group, the EPA-E self-emulsification composition every 2 days administration group, and the EPA-E self-emulsification composition every 4 days administration group suppresses the swelling of the auricle, At least one of the suppression effects of histological increase and the suppression of histopathological epidermis thickening was confirmed, and the degree of psoriasis-like dermatitis was confirmed to be small. In the group administered every 2 days and the group administered every 4 days in the EPA-E self-emulsifying composition.
Further, in the IL23 administration group, compared to the control group, interleukin (IL) -1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12 in the auricular skin tissue, Expression of at least one protein of IL-17, IL-22, IL-23, IL-27, IL-36, and TNF-α and / or mRNA expression is increased, and EPA- is compared to the IL23 administration group. In the E daily administration group, the EPA-E self-emulsifying composition every 2 days administration group, and the EPA-E self-emulsifying composition every 4 days administration group, the increase in at least one of these was suppressed, and these inhibitory effects were EPA-E High in the self-emulsifying composition every 2 days and in the EPA-E self-emulsifying composition every 4 days. In addition, in the EPA-E 4-day administration group, side effects such as loose stool or diarrhea are observed depending on the individual, but in the EPA-E self-emulsifying composition administration group, no side effects to be noted are observed.
実験例３：尋常性乾癬増悪期患者の治療試験
　増悪期にある尋常性乾癬と診断された患者を５群（各群１５名）に分けて、対照群にはオリーブオイル９００ｍｇを毎日２回経口投与し、エパデールＳ毎日投与群には、エパデールＳ（登録商標）９００（ＥＰＡ－Ｅ９００ｍｇ含有）を１日２回経口投与し、ＥＰＡ－Ｅ自己乳化組成物毎日投与群、ＥＰＡ－Ｅ自己乳化組成物３日毎投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群には、ＥＰＡ－Ｅ自己乳化組成物を、各々ＥＰＡ－Ｅとして１ｇ、３ｇおよび５ｇとなるように、各投与日に１日１回経口投与する。投与は患者が寛解期に至るまで継続し、既存の乾癬治療薬は医者の判断により継続投与しても、症状の改善により減量、投与間隔の延長あるいは休薬してもよい。
　治療開始前および治療開始後２週間毎に、ｐｓｏｒｉａｓｉｓ　ａｒｅａ　ａｎｄ　ｓｅｖｅｒｉｔｙ　ｉｎｄｅｘ（ＰＡＳＩ）を用いて乾癬の状態を評価して、各患者のＰＡＳＩスコアおよび各群の平均ＰＡＳＩスコアを算出する。ＰＡＳＩの算出方法は、以下のとおりである。１）頭部、上肢、体幹および下肢の各部位別に皮膚症状（紅斑、浸潤・肥厚、鱗屑）の程度を各々０～４（０：なし、１：軽度、２：中等度、３：高度、４：極めて高度）にスコア化して合計する。２）各部位別に病巣範囲（体表面積に対する病変の面積）を各々０～６（０：なし、１：１０％未満、２：１０％以上３０％未満、３：３０％以上５０％未満、４：５０％以上７０％未満、５：７０％以上９０％未満、６：９０％以上）にスコア化する。３）各部位別に、１）の皮膚症状合計スコア×２）の病巣範囲スコア×部位別係数（頭部：０．１、上肢：０．２、体幹：０．３、下肢：０．４）を計算し、各部位の計算値の合計スコア（０～７２）をＰＡＳＩスコアとする。治療開始前のＰＡＳＩスコアが７５％以上改善して１２未満となった場合に寛解期に至ったと判断する。 Experimental example 3: Treatment test for patients with exacerbation of psoriasis vulgaris Patients diagnosed with psoriasis vulgaris in exacerbations were divided into 5 groups (15 in each group), and 900 mg of olive oil was orally administered to the control group twice daily The Epadale S daily administration group was orally administered with Epadale S® 900 (containing EPA-E 900 mg) twice a day, and the EPA-E self-emulsifying composition daily administration group, EPA-E self-emulsifying composition The EPA-E self-emulsifying composition and the EPA-E self-emulsifying composition weekly administration group each had a EPA-E self-emulsifying composition of 1 g, 3 g and 5 g as EPA-E. Oral administration once a day. Administration continues until the patient reaches remission, and existing treatments for psoriasis may be continued at the discretion of the doctor, or may be reduced, symptoms may be extended, or the drug may be withdrawn due to symptom improvement.
The psoriasis status is assessed using the psoriasis area and severity index (PASI) before the start of treatment and every 2 weeks after the start of treatment, and a PASI score for each patient and an average PASI score for each group are calculated. The PASI calculation method is as follows. 1) The degree of skin symptom (erythema, infiltration / thickness, scale) for each part of the head, upper limbs, trunk and lower limbs is 0 to 4 (0: none, 1: mild, 2: moderate, 3: advanced) 4: very high) and total. 2) The lesion range (lesion area relative to the body surface area) is 0 to 6 (0: none, less than 1: 10%, 2: 10% or more but less than 30%, 3: 30% or more and less than 50%, 4) : 50% or more and less than 70%, 5: 70% or more and less than 90%, 6: 90% or more). 3) For each region, 1) skin symptom total score × 2) lesion range score × regional coefficient (head: 0.1, upper limb: 0.2, trunk: 0.3, lower limb: 0.4 ) And the total score (0 to 72) of the calculated values for each part is taken as the PASI score. When the PASI score before the start of treatment improves by 75% or more and becomes less than 12, it is judged that the remission period has been reached.
　対照群に比べて、対照群以外のいずれの群も平均ＰＡＳＩスコアは治療開始後に低下する。平均ＰＡＳＩスコア低下の程度または速度は、ＥＰＡ－Ｅ自己乳化組成物３日毎投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群で同等で最も大きい。次いでＥＰＡ－Ｅ自己乳化組成物毎日投与群およびエパデールＳ毎日投与群の、この順番である。
　寛解期に至る期間は、ＥＰＡ－Ｅ自己乳化組成物３日毎投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群で同等で最も短い。次いでＥＰＡ－Ｅ自己乳化組成物毎日投与群、エパデールＳ毎日投与群および対照群の、この順番である。
　各患者のＰＡＳＩスコアは、既存治療薬との併用において相加または相乗的に改善される。また、併用した患者では既存治療薬の投与量を減少させることができ、または既存治療薬の投与期間を短くすることができ、既存治療薬の副作用発現が抑制されるまたは服用負担が軽減できる。既存治療薬の投与量減少または投与期間短縮効果は、ＥＰＡ－Ｅ自己乳化組成物３日毎投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群で同等で最も大きく、次いでＥＰＡ－Ｅ自己乳化組成物毎日投与群およびエパデールＳ毎日投与群の、この順番である。 Compared to the control group, the average PASI score in any group other than the control group decreases after the start of treatment. The degree or rate of decrease in the average PASI score is equally and greatest in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsifying composition every week administration group. The EPA-E self-emulsifying composition daily administration group and the Epadale S daily administration group are in this order.
The period until remission is the shortest in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsification composition every week administration group. Then, the EPA-E self-emulsifying composition daily administration group, the Epadale S daily administration group and the control group are in this order.
Each patient's PASI score improves additively or synergistically in combination with existing therapeutics. In addition, in the combined patient, the dose of the existing therapeutic agent can be reduced, or the administration period of the existing therapeutic agent can be shortened, and the occurrence of side effects of the existing therapeutic agent can be suppressed or the burden of taking can be reduced. The effect of reducing the dose or shortening the administration period of the existing therapeutic agent is the same and greatest in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsifying composition every week administration group, followed by EPA-E self-emulsification This is the order of the daily composition group and the Epadale S daily group.
実験例４：尋常性乾癬寛解期患者の予防・治療試験
　ＰＡＳＩスコアが１２未満の寛解期にある尋常性乾癬と診断された患者を４群（各群２０名）に分けて、対照群にはオリーブオイル９００ｍｇを毎日２回経口投与し、エパデールＳ毎日投与群には、エパデールＳ（登録商標）９００（ＥＰＡ－Ｅ９００ｍｇ含有）を１日２回経口投与し、ＥＰＡ－Ｅ自己乳化組成物毎日投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群には、ＥＰＡ－Ｅ自己乳化組成物を、各々ＥＰＡ－Ｅとして１ｇおよび５ｇとなるように、各投与日に１日１回経口投与する。ＥＰＡ－Ｅ投与は患者が増悪期に至るまで継続し、その間は既存の乾癬治療薬は投与しない。
　治療開始後２週間毎にＰＡＳＩを用いて乾癬の状態を評価して、各患者のＰＡＳＩスコアを算出する。ＰＡＳＩスコアが１２以上になった場合に憎悪期に至ったと判断する。 Experimental example 4: Prevention / treatment test for patients with psoriasis vulgaris remission period Patients with psoriasis diagnosed with psoriasis in remission with a PASI score of less than 12 were divided into 4 groups (20 people in each group). Olive oil 900 mg was orally administered twice daily, and Epadale S daily administration group was orally administered Epadale S 900 (containing EPA-E 900 mg) twice daily, and EPA-E self-emulsifying composition was administered daily. Group and EPA-E self-emulsifying composition weekly administration group are orally administered once a day on each dosing day so that the EPA-E self-emulsifying composition is 1 g and 5 g as EPA-E, respectively. . EPA-E administration continues until the patient reaches an exacerbation period, during which no existing psoriasis treatment is administered.
The PASI score is evaluated using PASI every two weeks after the start of treatment, and a PASI score for each patient is calculated. When the PASI score is 12 or more, it is judged that the hatred period has been reached.
　予防・治療開始から増悪期に至るまでの期間は、ＥＰＡ－Ｅ自己乳化組成物１週間毎投与群で最も長い。次いでＥＰＡ－Ｅ自己乳化組成物毎日投与群、エパデールＳ毎日投与群および対照群の、この順番である。寛解期において既存治療薬を使用せずに増悪を予防することができ、既存治療薬の副作用や服薬負担を解消し、かつ寛解期を延長することができる。 The period from the start of prevention / treatment to the exacerbation period is the longest in the EPA-E self-emulsifying composition administered every week group. The EPA-E self-emulsifying composition daily administration group, the Epadale S daily administration group, and the control group are in this order. It is possible to prevent exacerbation without using an existing therapeutic drug in the remission period, to eliminate the side effects and medication burden of the existing therapeutic drug, and to extend the remission period.
実験例５：アトピー性皮膚炎増悪期患者の治療試験
　増悪期にあるアトピー性皮膚炎と診断された患者を５群（各群１５名）に分けて、対照群にはオリーブオイル９００ｍｇを毎日２回経口投与し、エパデールＳ毎日投与群には、エパデールＳ（登録商標）９００（ＥＰＡ－Ｅ９００ｍｇ含有）を１日２回経口投与し、ＥＰＡ－Ｅ自己乳化組成物毎日投与群、ＥＰＡ－Ｅ自己乳化組成物３日毎投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群には、ＥＰＡ－Ｅ自己乳化組成物を、各々ＥＰＡ－Ｅとして１ｇ、３ｇおよび５ｇとなるように、各投与日に１日１回経口投与する。投与は患者が寛解期に至るまで継続し、既存のアトピー性皮膚炎治療薬は医者の判断により継続投与しても、症状の改善により減量、投与間隔の延長あるいは休薬してもよい。
　治療開始前および治療開始後２週間毎に、Ｅｕｒｏｐｅａｎ　Ｔａｓｋ　Ｆｏｒｃｅ　ｏｎ　Ａｔｏｐｉｃ　Ｄｅｒｍａｔｉｔｉｓ によるＳｅｖｅｒｉｔｙ　Ｓｃｏｒｉｎｇ　ｏｆ　Ａｔｏｐｉｃ　Ｄｅｒｍａｔｉｔｉｓ（ＳＣＯＲＡＤ、最高点数１０３ 点、Ｄｅｒｍａｔｏｌｏｇｙ，１９９３；１８６：２３―３１）または米国のＥｃｚｅｍａ　Ａｒｅａ　ａｎｄ　Ｓｅｖｅｒｉｔｙ　Ｉｎｄｅｘ（ＥＡＳＩ、最高点数７２ 点、Ｅｘｐ　Ｄｅｒｍａｔｏｌ，２００１；１０：１１―１８）を用いてアトピー性皮膚炎の状態を評価して、各患者のＳＣＯＲＡＤまたはＥＡＳＩスコアおよび各群の平均ＳＣＯＲＡＤまたはＥＡＳＩスコアを算出する。治療開始前のＳＣＯＲＡＤまたはＥＡＳＩスコアが５０％以上改善して、ＳＣＯＲＡＤスコアが１５未満またはＥＡＳＩスコアが１２未満となった場合に寛解期に至ったと判断する。 Experimental Example 5: Treatment test for patients with atopic dermatitis exacerbation The patients diagnosed with atopic dermatitis in the exacerbation period were divided into 5 groups (15 in each group), and 900 mg of olive oil was administered daily to the control group. Epadale S® 900 (containing EPA-E 900 mg) was orally administered twice daily to the Epadale S daily administration group, and the EPA-E self-emulsifying composition daily administration group, EPA-E self The emulsion composition every 3 days administration group and the EPA-E self-emulsification composition weekly administration group had EPA-E self-emulsification composition at 1 g, 3 g and 5 g as EPA-E, respectively. Orally once daily. Administration is continued until the patient reaches remission, and the existing atopic dermatitis therapeutic agent may be continuously administered according to the judgment of the doctor, or the dose may be reduced, the administration interval may be extended, or the drug may be withdrawn due to symptom improvement.
Severity Scoring of Atopic Dermatitis by European Task Force on Atomic Dermatitis (SCORAD, highest score of 103 points, Dermatology, 1993: 186a, United States, 1993; (EASI, maximum score 72 points, Exp Dermatol, 2001; 10: 11-18) was used to assess the status of atopic dermatitis, and each patient's SCORAD or EASI score and each group's average SCORAD or EASI score calculate. When the SCORAD or EASI score before the start of treatment improves by 50% or more and the SCORAD score is less than 15 or the EASI score is less than 12, it is determined that the remission period has been reached.
　対照群に比べて、対照群以外のいずれの群も平均ＳＣＯＲＡＤまたはＥＡＳＩスコアは治療開始後に低下する。平均ＳＣＯＲＡＤまたはＥＡＳＩスコア低下の程度または速度は、ＥＰＡ－Ｅ自己乳化組成物３日毎投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群で同等で最も大きい。次いでＥＰＡ－Ｅ自己乳化組成物毎日投与群およびエパデールＳ毎日投与群の、この順番である。
　寛解期に至る期間は、ＥＰＡ－Ｅ自己乳化組成物３日毎投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群で同等で最も短い。次いでＥＰＡ－Ｅ自己乳化組成物毎日投与群、エパデールＳ毎日投与群および対照群の、この順番である。
　各患者のＳＣＯＲＡＤまたはＥＡＳＩスコアは、既存治療薬との併用において相加または相乗的に改善される。また、併用した患者では既存治療薬の投与量を減少させることができ、または既存治療薬の投与期間を短くすることができ、既存治療薬の副作用発現が抑制されるまたは服用負担が軽減できる。既存治療薬の投与量減少または投与期間短縮効果は、ＥＰＡ－Ｅ自己乳化組成物３日毎投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群で同等で最も大きい。次いでＥＰＡ－Ｅ自己乳化組成物毎日投与群およびエパデールＳ毎日投与群の、この順番である。 Compared to the control group, the average SCORAD or EASI score decreases in any group other than the control group after initiation of treatment. The degree or rate of average SCORAD or EASI score reduction is equally and greatest in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsifying composition every week administration group. The EPA-E self-emulsifying composition daily administration group and the Epadale S daily administration group are in this order.
The period until remission is the shortest in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsification composition every week administration group. Then, the EPA-E self-emulsifying composition daily administration group, the Epadale S daily administration group and the control group are in this order.
Each patient's SCORAD or EASI score improves additively or synergistically in combination with existing therapeutics. In addition, in the combined patient, the dose of the existing therapeutic agent can be reduced, or the administration period of the existing therapeutic agent can be shortened, and the occurrence of side effects of the existing therapeutic agent can be suppressed or the burden of taking can be reduced. The effect of reducing the dose or shortening the administration period of the existing therapeutic agent is the same and greatest in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsification composition every week administration group. The EPA-E self-emulsifying composition daily administration group and the Epadale S daily administration group are in this order.
実験例６：アトピー性皮膚炎寛解期患者の予防・治療試験
　ＳＣＯＲＡＤスコアが１５未満またはＥＡＳＩスコアが１２未満の寛解期にあるアトピー性皮膚炎と診断された患者を４群（各群２０名）に分けて、対照群にはオリーブオイル９００ｍｇを毎日２回経口投与し、エパデールＳ毎日投与群には、エパデールＳ（登録商標）９００（ＥＰＡ－Ｅ９００ｍｇ含有）を１日２回経口投与し、ＥＰＡ－Ｅ自己乳化組成物毎日投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群には、ＥＰＡ－Ｅ自己乳化組成物を、各々ＥＰＡ－Ｅとして１ｇおよび５ｇとなるように、各投与日に１日１回経口投与する。ＥＰＡ－Ｅ投与は患者が増悪期に至るまで継続し、その間は既存のアトピー性皮膚炎治療薬は投与しない。
　治療開始後２週間毎にＳＣＯＲＡＤまたはＥＡＳＩを用いてアトピー性皮膚炎の状態を評価して、各患者のＳＣＯＲＡＤまたはＥＡＳＩスコアを算出する。ＳＣＯＲＡＤスコアが１５以上またはＥＡＳＩスコアが１２以上になった場合に憎悪期に至ったと判断する。 Experimental Example 6: Prophylactic / Treatment Test for Patients with Atopic Dermatitis Remission Period 4 groups (20 people in each group) diagnosed with atopic dermatitis in remission period with SCORAD score less than 15 or EASI score less than 12 In the control group, olive oil 900 mg was orally administered twice daily, and in the Epadale S daily administration group, Epadale S® 900 (containing EPA-E 900 mg) was orally administered twice daily. -E self-emulsifying composition daily administration group and EPA-E self-emulsifying composition weekly administration group include EPA-E self-emulsifying composition at 1 g and 5 g as EPA-E respectively. Orally once daily. EPA-E administration continues until the patient reaches an exacerbation period, during which no existing atopic dermatitis treatment is administered.
The condition of atopic dermatitis is evaluated using SCORAD or EASI every 2 weeks after the start of treatment, and the SCORAD or EASI score for each patient is calculated. When the SCORAD score is 15 or more or the EASI score is 12 or more, it is determined that the hatred period has been reached.
　予防・治療開始から増悪期に至るまでの期間は、ＥＰＡ－Ｅ自己乳化組成物１週間毎投与群で最も長い。次いでＥＰＡ－Ｅ自己乳化組成物毎日投与群、エパデールＳ毎日投与群および対照群の、この順番である。寛解期において既存治療薬を使用せずに増悪を予防することができ、既存治療薬の副作用や服薬負担を解消し、かつ寛解期を延長することができる。 The period from the start of prevention / treatment to the exacerbation period is the longest in the EPA-E self-emulsifying composition administered every week group. The EPA-E self-emulsifying composition daily administration group, the Epadale S daily administration group, and the control group are in this order. It is possible to prevent exacerbation without using an existing therapeutic drug in the remission period, to eliminate the side effects and medication burden of the existing therapeutic drug, and to extend the remission period.
実験例７：ベーチェット病活動（増悪）期患者の治療試験
　口腔内アフタ性潰瘍および／または皮膚・外陰部潰瘍症状を有し、活動（増悪）期にあるベーチェット病と診断された患者を５群（各群１０名）に分けて、対照群にはオリーブオイル９００ｍｇを毎日２回経口投与し、エパデールＳ毎日投与群には、エパデールＳ（登録商標）９００（ＥＰＡ－Ｅ９００ｍｇ含有）を１日２回経口投与し、ＥＰＡ－Ｅ自己乳化組成物毎日投与群、ＥＰＡ－Ｅ自己乳化組成物３日毎投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群には、ＥＰＡ－Ｅ自己乳化組成物を、各々ＥＰＡ－Ｅとして１ｇ、３ｇおよび５ｇとなるように、各投与日に１日１回経口投与する。投与は患者が非活動期に至るまで継続し、既存のベーチェット病治療薬は医者の判断により継続投与しても、症状の改善により減量、投与間隔の延長あるいは休薬してもよい。
　治療開始前および治療開始後２週間毎に、口腔内アフタ性潰瘍および／または皮膚・外陰部潰瘍症状について活動スコアを用いてベーチェット病の状態を評価して、各患者の活動スコアおよび各群の平均活動スコアを算出する。活動スコアの算出方法は、以下のとおりである。
スコア０：症状なし、
スコア１：最近の４週のうち症状が存在したのは２週未満である、
スコア２：最近の４週のうち症状が存在したのは２週以上である、
スコア３：最近の４週のうちほとんどに症状が存在した。
治療開始前のスコアが１以上改善して、スコアが２未満となった場合に非活動期に至ったと判断する。また、スコア０が１年間以上続いた場合を固定（寛解）期と判断する。 Experimental Example 7: Treatment test for patients with Behcet's disease (exacerbation) stage Five groups of patients diagnosed with Behcet's disease in the active (exacerbation) stage with oral aphthous ulcer and / or skin / genital ulcer symptoms Divided into 10 groups in each group, olive oil 900 mg was orally administered twice daily to the control group, and Epadale S® 900 (containing EPA-E 900 mg) was administered to the Epadale S daily administration group 2 times a day. EPA-E self-emulsifying composition daily administration group, EPA-E self-emulsifying composition daily administration group and EPA-E self-emulsifying composition weekly administration group include EPA-E self-emulsifying composition Are orally administered once a day on each day of administration to give 1 g, 3 g and 5 g as EPA-E. Administration is continued until the patient reaches an inactive period, and existing Behcet's disease therapeutic agents may be administered at the discretion of the doctor, or may be reduced in dosage, extended administration intervals, or withdrawn due to symptom improvement.
Assess the status of Behcet's disease using activity scores for oral aphthous and / or vulvar ulcer symptoms before the start of treatment and every 2 weeks after the start of treatment. Calculate the average activity score. The activity score is calculated as follows.
Score 0: no symptoms
Score 1: Of the last 4 weeks, symptoms were present in less than 2 weeks,
Score 2: Of the last 4 weeks, symptoms were present for more than 2 weeks,
Score 3: Symptoms were present in most of the last 4 weeks.
When the score before the start of treatment improves by 1 or more and the score becomes less than 2, it is determined that the inactive period has been reached. Further, a case where score 0 continues for one year or more is determined as a fixed (remission) period.
　対照群に比べて、対照群以外のいずれの群も平均活動スコアは治療開始後に低下する。平均活動スコア低下の程度または速度は、ＥＰＡ－Ｅ自己乳化組成物３日毎投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群で同等で最も大きい。次いでＥＰＡ－Ｅ自己乳化組成物毎日投与群およびエパデールＳ毎日投与群の、この順番である。
　非活動期および／または固定（寛解）期に至る期間は、ＥＰＡ－Ｅ自己乳化組成物３日毎投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群で同等で最も短い。次いでＥＰＡ－Ｅ自己乳化組成物毎日投与群およびエパデールＳ毎日投与群、対照群の、この順番である。
　各患者の活動スコアは、既存治療薬との併用において相加または相乗的に改善される。また、併用した患者では既存治療薬の投与量を減少させることができ、または既存治療薬の投与期間を短くすることができ、既存治療薬の副作用発現が抑制されるまたは服用負担が軽減できる。既存治療薬の投与量減少または投与期間短縮効果は、ＥＰＡ－Ｅ自己乳化組成物３日毎投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群で同等で最も大きい。次いでＥＰＡ－Ｅ自己乳化組成物毎日投与群およびエパデールＳ毎日投与群の、この順番である。 Compared to the control group, the average activity score in any group other than the control group decreases after the start of treatment. The degree or rate of decrease in average activity score is equally and greatest in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsifying composition every week administration group. The EPA-E self-emulsifying composition daily administration group and the Epadale S daily administration group are in this order.
The period leading to the inactive period and / or the fixed (remission) period is equally short in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsifying composition every week administration group. Then, the EPA-E self-emulsifying composition daily administration group, the Epadale S daily administration group, and the control group are in this order.
Each patient's activity score improves additively or synergistically in combination with existing therapeutics. In addition, in the combined patient, the dose of the existing therapeutic agent can be reduced, or the administration period of the existing therapeutic agent can be shortened, and the occurrence of side effects of the existing therapeutic agent can be suppressed or the burden of taking can be reduced. The effect of reducing the dose or shortening the administration period of the existing therapeutic agent is the same and greatest in the EPA-E self-emulsifying composition every 3 days administration group and the EPA-E self-emulsification composition every week administration group. The EPA-E self-emulsifying composition daily administration group and the Epadale S daily administration group are in this order.
実験例８：ベーチェット病非活動期患者の予防・治療試験
　口腔内アフタ性潰瘍および／または皮膚・外陰部潰瘍の活動スコアが２未満の非活動期にあるベーチェット病と診断された患者を４群（各群１０名）に分けて、対照群にはオリーブオイル９００ｍｇを毎日２回経口投与し、エパデールＳ毎日投与群には、エパデールＳ（登録商標）９００（ＥＰＡ－Ｅ９００ｍｇ含有）を１日２回経口投与し、ＥＰＡ－Ｅ自己乳化組成物毎日投与群およびＥＰＡ－Ｅ自己乳化組成物１週間毎投与群には、ＥＰＡ－Ｅ自己乳化組成物を、各々ＥＰＡ－Ｅとして１ｇおよび５ｇとなるように、各投与日に１日１回経口投与する。ＥＰＡ－Ｅ投与は患者が活動（増悪）期に至るまで継続し、その間は既存のベーチェット病治療薬は投与しない。
　治療開始後２週間毎にベーチェット病の状態を評価して、各患者の活動スコアを算出する。活動スコアが２以上になった場合に活動（増悪）期に至ったと判断する。 Experimental Example 8: Prevention and treatment test for patients with non-active stage of Behcet's disease Four groups of patients diagnosed with Behcet's disease in the non-active stage with activity scores of oral aphthous ulcer and / or skin / genital ulcer less than 2 Divided into 10 groups in each group, olive oil 900 mg was orally administered twice daily to the control group, and Epadale S® 900 (containing EPA-E 900 mg) was administered to the Epadale S daily administration group 2 times a day. In the EPA-E self-emulsifying composition daily administration group and the EPA-E self-emulsifying composition weekly administration group, the EPA-E self-emulsifying composition is 1 g and 5 g as EPA-E, respectively. Thus, it is orally administered once a day on each administration day. EPA-E administration continues until the patient reaches an active (exacerbation) period, during which time no existing Behcet's disease treatment is administered.
The state of Behcet's disease is evaluated every 2 weeks after the start of treatment, and the activity score of each patient is calculated. When the activity score is 2 or more, it is determined that the activity (exacerbation) period has been reached.
　予防・治療開始から活動（増悪）期に至るまでの期間は、ＥＰＡ－Ｅ自己乳化組成物１週間毎投与群で最も長い。次いでＥＰＡ－Ｅ自己乳化組成物毎日投与群、エパデールＳ毎日投与群および対照群の、この順番である。非活動期において既存治療薬を使用せずに活動（増悪）期に至ることを予防することができ、既存治療薬の副作用や服薬負担を解消し、かつ非活動期を延長することができる。 The period from the start of prevention / treatment to the active (exacerbation) period is the longest in the EPA-E self-emulsifying composition administered every week. The EPA-E self-emulsifying composition daily administration group, the Epadale S daily administration group, and the control group are in this order. It is possible to prevent an active (exacerbation) period without using an existing therapeutic agent in an inactive period, to eliminate side effects and medication burdens of the existing therapeutic drug, and to extend the inactive period.

Claims (13)

  1. 　２日～１ヶ月からなる群から選択される少なくとも１つの期間毎に間欠経口投与されることを特徴とする、自己免疫性皮膚疾患または炎症性皮膚疾患予防および／または治療のためのω３多価不飽和脂肪酸又はそれらの製薬学上許容しうる塩類、又はそれらの製薬学上許容しうるエステル類、又はそれらの製薬学上許容しうるアミド類、又はそれらの製薬学上許容しうるリン脂質類を有効成分として含有し、さらに乳化剤を含有する自己乳化組成物。 Ω3 multivalent for the prevention and / or treatment of autoimmune skin disease or inflammatory skin disease, characterized by being intermittently orally administered at least one period selected from the group consisting of 2 days to 1 month Unsaturated fatty acids or their pharmaceutically acceptable salts, or their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides, or their pharmaceutically acceptable phospholipids Is a self-emulsifying composition further containing an emulsifier.
  2. 　２日、３日、４日、５日、６日または１週間毎に間欠経口投与されることを特徴とする、請求項１に記載の自己乳化組成物。 2. The self-emulsifying composition according to claim 1, wherein the self-emulsifying composition is intermittently orally administered every 2 days, 3 days, 4 days, 5 days, 6 days or 1 week.
  3. 　１週間に２～３日間欠経口投与されることを特徴とする、請求項１に記載の自己乳化組成物。 2. The self-emulsifying composition according to claim 1, wherein the composition is intermittently orally administered for 2 to 3 days per week.
  4. 　イコサペント酸、ドコサヘキサエン酸、ドコサペンタエン酸、αリノレン酸、それらの製薬学上許容しうる塩類、それらの製薬学上許容しうるエステル類、それらの製薬学上許容しうるアミド類、それらの製薬学上許容しうるリン脂質類からなる群から選択される少なくとも１つを有効成分として含有する、請求項１乃至３のいずれか1項に記載の自己乳化組成物。 Eicosapentic acid, docosahexaenoic acid, docosapentaenoic acid, α-linolenic acid, their pharmaceutically acceptable salts, their pharmaceutically acceptable esters, their pharmaceutically acceptable amides, their pharmaceuticals The self-emulsifying composition according to any one of claims 1 to 3, comprising at least one selected from the group consisting of pharmaceutically acceptable phospholipids as an active ingredient.
  5. 　イコサペント酸またはイコサペント酸エチルエステルを有効成分として含有する、請求項１乃至４のいずれか1項に記載の自己乳化組成物。 The self-emulsifying composition according to any one of claims 1 to 4, comprising icosapentic acid or icosapentic acid ethyl ester as an active ingredient.
  6. 　自己乳化組成物の全量を１００質量％としたときのイコサペント酸またはイコサペント酸エチルエステルの含量が７０質量％以上である、請求項１乃至５のいずれか1項に記載の自己乳化組成物。 The self-emulsifying composition according to any one of claims 1 to 5, wherein the content of icosapentic acid or icosapentic acid ethyl ester is 70% by mass or more when the total amount of the self-emulsifying composition is 100% by mass.
  7. 　ω３多価不飽和脂肪酸又はそれらの製薬学上許容しうる塩類、又はそれらの製薬学上許容しうるエステル類、又はそれらの製薬学上許容しうるアミド類、又はそれらの製薬学上許容しうるリン脂質類を０．５ｇ／日～１０ｇ／日で経口投与することを特徴とする、請求項１乃至６のいずれか1項に記載の自己乳化組成物。 ω3 polyunsaturated fatty acids or their pharmaceutically acceptable salts, or their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides, or their pharmaceutically acceptable The self-emulsifying composition according to any one of claims 1 to 6, wherein phospholipids are orally administered at 0.5 g / day to 10 g / day.
  8. 　自己免疫性皮膚疾患または炎症性皮膚疾患が乾癬及び類症（尋常性乾癬（重症例含む）、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、稽留性肢端皮膚炎、疱疹状膿痂疹、ライター症候群、滴状乾癬、等）、魚鱗癬群（尋常性魚鱗癬、水疱型先天性魚鱗癬様紅皮症、非水疱型先天性魚鱗癬様紅皮症）、掌蹠角化症、ダリエー病、掌蹠膿疱症、毛孔性紅色粃糠疹、紅斑性角化症、皮膚炎群（接触皮膚炎、貨幣状皮膚炎、自家感作性皮膚炎、アトピー性皮膚炎、ビダール苔癬、その他の神経皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、その他の手指の皮膚炎、耳介及び外耳道の皮膚炎、鼻前庭及び鼻翼周辺の皮膚炎、全身性剥脱性皮膚炎、うっ血性皮膚炎、限局性掻爬皮膚炎、口周囲皮膚炎、汗疱、花粉性皮膚炎、等）、多発性硬化症、強皮症、エリテマトーデス（全身性及び慢性円板状）、ベーチェット病、および天疱瘡からなる群から選択される少なくとも１つである、請求項１乃至７のいずれか1項に記載の自己乳化組成物。 Autoimmune skin disease or inflammatory skin disease is psoriasis and analogies (including psoriasis vulgaris (including severe cases), arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, peculiar limb dermatitis, herpes zoster) Rash, Reiter's syndrome, trichomes psoriasis, etc.), ichthyosis group (common ichthyosis, blistered congenital ichthyosis-like erythroderma, non-bullous congenital ichthyosis-like erythroderma), palmokeratosis , Darier's disease, palmoplantar pustulosis, pore erythema, erythematous keratosis, dermatitis group (contact dermatitis, monetary dermatitis, self-sensitizing dermatitis, atopic dermatitis, Bidart lichen) Other neurodermatitis, seborrheic dermatitis, progressive palmokeratosis, other finger dermatitis, pinna and ear canal dermatitis, nasal vestibular and nasal dermatitis, generalized exfoliative skin Flame, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat blister, pollen dermatitis, etc.), multiple sclerosis, scleroderma, Ritematodesu (like systemic and chronic disc), Behcet's disease, and at least one selected from the group consisting of Pemphigus, self-emulsifying composition according to any one of claims 1 to 7.
  9. 　自己免疫性皮膚疾患または炎症性皮膚疾患が乾癬及び類症（尋常性乾癬（重症例含む）、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、稽留性肢端皮膚炎、疱疹状膿痂疹、ライター症候群、滴状乾癬）、皮膚炎群（接触皮膚炎、貨幣状皮膚炎、自家感作性皮膚炎、アトピー性皮膚炎、ビダール苔癬、その他の神経皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、その他の手指の皮膚炎、耳介及び外耳道の皮膚炎、鼻前庭及び鼻翼周辺の皮膚炎、全身性剥脱性皮膚炎、うっ血性皮膚炎、限局性掻爬皮膚炎、口周囲皮膚炎、汗疱、花粉性皮膚炎、等）およびベーチェット病からなる群から選択される少なくとも１つである、請求項１乃至８のいずれか1項に記載の自己乳化組成物。 Autoimmune skin disease or inflammatory skin disease is psoriasis and analogies (including psoriasis vulgaris (including severe cases), arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, peculiar limb dermatitis, herpes zoster) Urticaria, lighter syndrome, prickly psoriasis), dermatitis group (contact dermatitis, monetary dermatitis, autosensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic skin Inflammation, progressive palmokeratosis, other finger dermatitis, pinna and external auditory canal dermatitis, nasal vestibular and nasal dermatitis, generalized exfoliative dermatitis, congestive dermatitis, localized curettage skin The self-emulsifying composition according to any one of claims 1 to 8, wherein the composition is at least one selected from the group consisting of flame, perioral dermatitis, sweat blisters, pollen dermatitis, and the like) and Behcet's disease. .
  10. 　乾癬及び類症（尋常性乾癬（重症例含む）、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、稽留性肢端皮膚炎、疱疹状膿痂疹、ライター症候群、滴状乾癬）、皮膚炎群（接触皮膚炎、貨幣状皮膚炎、自家感作性皮膚炎、アトピー性皮膚炎、ビダール苔癬、その他の神経皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、その他の手指の皮膚炎、耳介及び外耳道の皮膚炎、鼻前庭及び鼻翼周辺の皮膚炎、全身性剥脱性皮膚炎、うっ血性皮膚炎、限局性掻爬皮膚炎、口周囲皮膚炎、汗疱、花粉性皮膚炎、等）およびベーチェット病からなる群から選択される少なくとも１つの自己免疫性皮膚疾患または炎症性皮膚疾患の憎悪期にシクロスポリン、エトレチナート、メトトレキサート、トリアムシノロン、ヒドロコルチゾン、コルチゾン酢酸エステル、デキサメタゾン、プレドニゾロン、ベタメゾン、マキサカルシトール、カルシポトリオール、タカルシトール水和物、ヒドロコルチゾン酢酸エステル、ベタメタゾン酢酸エステル、ジフロラゾン酢酸エステル、セクキヌマブ、ウステキヌマブ、アダリムマブ、インフリキシマブ、イキセキズマブ、チルドラキズマブ、ブロダルマブ、グセルクマブ、デュピルマブ、ネモリズマブ、トラロキヌマブ、リツキシマブ、バリシチニブ、サリルマブ、マシチニブ、オクレリズマブ、ペクカントラチニブ、トラロキヌマブ、ウパダシチニブ、エミシズマブ、ファシヌマブ、ペグプレラニブ、オマリズマブ、レスリズマブ、サプタブマブ、ガンテネルマブ、エタネルセプト、トファシチニブ、サリチル酸／白色ワセリン、スプラタストトシル、アゼラスチン塩酸塩、フェキソフェナジン塩酸塩、クロモグリク酸ナトリウム、オキサトミド、クロベタゾン酪酸エステル、ベンダザック、スプロフェン、タクロリムス水和物、トラニラスト、ベクロメタゾンプロピオン酸、人免疫グロブリン／ヒスタミン二塩酸塩、メチルプレドニゾロン、アプレミラスト、ピメクロリムス、ＡＭＧ－０１０１、ＡＭＧ－０１０３、水酸化ステルベン分子、クリサボロール、ナルフラフィン、ドキソルビシン、ＷＢＩ－１００１、オクテニジン、オキシメタゾリン、一酸化窒素、チマピプラント、酢酸ロシプトール、コバマミド、フェビピプラント、オミガナン、アシマドリン、メトフルミン、ＤＳＸＳ－１４１１、セリネクサー、テルビナフィン、エレンベセスタット、ベルベセスタット、ラナベセスタット、フルチカゾン、ベパーミノーゲンパープラスミド、ダルセトラピブ、アバタセプト、タリドミド、ボセンタン、デフラザコートおよびアナキンラからなる群から選択される少なくとも１つの化合物と併用するための、請求項１乃至９のいずれか1項に記載の自己乳化組成物。 Psoriasis and analogies (including psoriasis vulgaris (including severe cases), psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, limbic limb dermatitis, pustular impetigo, Reiter's syndrome, droplet psoriasis) Dermatitis group (Contact dermatitis, money dermatitis, self-sensitizing dermatitis, atopic dermatitis, Vidar lichen, other neurodermatitis, seborrheic dermatitis, progressive palmokeratosis, other Finger dermatitis, ear and ear canal dermatitis, nasal vestibular and nasal wing dermatitis, generalized exfoliative dermatitis, congestive dermatitis, localized curettage dermatitis, perioral dermatitis, sweat blisters, pollen Dermatitis, etc.) and at least one autoimmune skin disease or inflammatory skin disease selected from the group consisting of Behcet's disease, cyclosporine, etretinate, methotrexate, triamcinolone, hydrocortisone, cortisone acetate, Samethasone, prednisolone, betamethasone, maxacalcitol, calcipotriol, tacalcitol hydrate, hydrocortisone acetate, betamethasone acetate, diflorazone acetate, secukinumab, ustekinumab, adalimumab, infliximab, ixekizumab, tildrakizumab, brodalumab rubumarub Nemorizumab, Traloquinumab, Rituximab, Salitumab, Osalizumab, Espritumab, Rareximab, Salitumab, Osalizumab, Sacritumab Acid salt, fexofenadine hydrochloride, sodium cromoglycate, oxatomide, clobetasone butyrate, bendazac, suprofen, tacrolimus hydrate, tranilast, beclomethasone propionic acid, human immunoglobulin / histamine dihydrochloride, methylprednisolone, apremilast, pimecrolimus , AMG-0101, AMG-0103, hydroxylated sterubene molecule, chrysabolol, nalfrafin, doxorubicin, WBI-1001, octenidine, oxymetazoline, nitric oxide, timapiplant, rosipitol acetate, cobamide, febipiplant, omiganane, asimadoline, methfulmin, DSX -1411, selenexer, terbinafine, ellen becestat, velve cestat, ranbe cestat, flutica 10. The self according to any one of claims 1 to 9, for use in combination with at least one compound selected from the group consisting of zon, beperminogen par plasmid, dalcetrapib, abatacept, thalidomide, bosentan, deflazacoat and anakinra. Emulsified composition.
  11. 　自己免疫性皮膚疾患または炎症性皮膚疾患の増悪期には２～７日からなる群から選択される少なくとも１つの期間毎に間欠経口投与され、症状の改善がみられた場合は１週間～１ヶ月からなる群から選択される少なくとも１つの期間毎に投与間隔を１日または２日ずつ増加して、寛解期または非活動期には１週間～１ヶ月からなる群から選択される少なくとも１つの期間毎に間欠経口投与される、請求項１乃至１０のいずれか1項に記載の自己乳化組成物。 In the exacerbation phase of autoimmune skin disease or inflammatory skin disease, intermittent oral administration is performed at least every period selected from the group consisting of 2 to 7 days, and if improvement of symptoms is observed, 1 week to 1 At least one selected from the group consisting of 1 week to 1 month in remission or inactivity, increasing the dosing interval by one or two days for at least one period selected from the group consisting of months The self-emulsifying composition according to any one of claims 1 to 10, which is intermittently orally administered every period.
  12. 　自己免疫性皮膚疾患または炎症性皮膚疾患の増悪期には２～１０ｇ／日経口投与され、症状の改善がみられた場合は１週間～１ヶ月からなる群から選択される少なくとも１つの期間毎に投与量を０．５～１g／日ずつ減量して、寛解期または非活動期には０．５～４ ｇ／日経口投与される、請求項１乃至１１のいずれか1項に記載の自己乳化組成物。 At least one period selected from the group consisting of 1 week to 1 month when 2-10 g / day is orally administered in the exacerbation phase of autoimmune skin disease or inflammatory skin disease, and symptoms are improved 12. The method according to any one of claims 1 to 11, wherein the dose is reduced by 0.5 to 1 g / day and administered orally in a remission period or inactive period of 0.5 to 4 μg / day. Self-emulsifying composition.
  13. 　乳化剤がポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンヒマシ油、ポリエチレングリコール脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコールおよびショ糖脂肪酸エステルからなる群から選ばれる少なくとも１つの乳化剤である、請求項１乃至１２のいずれか1項に記載の自己乳化組成物。
          The emulsifier is at least one emulsifier selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol and sucrose fatty acid ester. The self-emulsifying composition according to any one of claims 1 to 12.
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US11365198B2 (en) 2015-10-16 2022-06-21 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US10981924B2 (en) 2015-10-16 2021-04-20 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US10981923B2 (en) 2015-10-16 2021-04-20 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[l,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US10995095B2 (en) 2015-10-16 2021-05-04 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carb oxamide and solid state forms thereof
US11186584B2 (en) 2015-10-16 2021-11-30 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US10344036B2 (en) 2015-10-16 2019-07-09 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-#a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-#carboxamide and solid state forms thereof
US11795175B2 (en) 2015-10-16 2023-10-24 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US11773105B2 (en) 2015-10-16 2023-10-03 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]- pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US11524964B2 (en) 2015-10-16 2022-12-13 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US11535625B2 (en) 2015-10-16 2022-12-27 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US11535626B2 (en) 2015-10-16 2022-12-27 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1 carboxamide and solid state forms thereof
US11787815B1 (en) 2015-10-16 2023-10-17 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US10202393B2 (en) 2015-10-16 2019-02-12 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-α]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US11767326B2 (en) 2015-10-16 2023-09-26 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US11512092B2 (en) 2015-10-16 2022-11-29 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US11773106B2 (en) 2015-10-16 2023-10-03 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US11780847B1 (en) 2015-10-16 2023-10-10 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1- carboxamide and solid state forms thereof
US11780848B2 (en) 2015-10-16 2023-10-10 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1- carboxamide and solid state forms thereof
CN112584855A (en) * 2018-06-14 2021-03-30 法国血液分割暨生化制品实验室 Combination of factor VII and anti-factor IX/X bispecific antibody
CN116019762A (en) * 2022-09-19 2023-04-28 厦门大学 Pharmaceutical composition for treating psoriasis, preparation method and application

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