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WO2017126488A1 - Composition de traitement du psoriasis et procédé de traitement - Google Patents

Composition de traitement du psoriasis et procédé de traitement 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
Prior art date
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PCT/JP2017/001331
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English (en)
Japanese (ja)
Inventor
秀生 兼廣
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Mochida Pharmaceutical Co Ltd
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Mochida Pharmaceutical Co Ltd
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Publication of WO2017126488A1 publication Critical patent/WO2017126488A1/fr
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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.

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Abstract

La présente invention concerne une composition auto-émulsifiante destinée à la prévention et au traitement de maladies auto-immunes de la peau ou de maladies inflammatoires de la peau telles que le psoriasis, la composition auto-émulsifiante étant administrée par voie orale suivant un régime posologique spécifique, tel qu'une administration intermittente, une administration combinatoire-séquentielle avec un agent thérapeutique existant, ou en procédant à l'administration d'une façon différente pendant la phase de progression et pendant la phase de rémission ou la phase non active. La composition auto-émulsifiante comprend comme principe actif des acides gras polyinsaturés ω3, des sels pharmaceutiquement acceptables de ces derniers, des esters pharmaceutiquement acceptables de ces derniers, des amides pharmaceutiquement acceptables de ces derniers ou des phospholipides pharmaceutiquement acceptables de ces derniers, et comprend en outre un émulsifiant.
PCT/JP2017/001331 2016-01-18 2017-01-17 Composition de traitement du psoriasis et procédé de traitement Ceased WO2017126488A1 (fr)

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CN116019762B (zh) * 2022-09-19 2024-06-07 厦门大学 一种用于治疗银屑病的药物组合物、制备方法和用途
CN116019762A (zh) * 2022-09-19 2023-04-28 厦门大学 一种用于治疗银屑病的药物组合物、制备方法和用途

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