TW201513851A - Antiinflammatory drugs - Google Patents

Abstract

Provided is a dermatitis treatment agent for orally administration, and the dermatitis treatment agent contains a compound represented by the follow formula-X-C(CH3)=CH-CH=CH-C(CH3)=CH-CH=CH-CH=C(CH3)-CH=CH-CH=C(CH3)-Y-Z or the pharmaceutically acceptable salt thereof. In said formula, W is 4-hydroxyl-2,6,6-trimethyl-1-cyclohexenyl, etc., X and Y are vinylene, etc., Z is 4-hydroxyl-2,6,6-trimethyl-3-keto-1-cyclohexenyl, etc.

Description

Anti-inflammatory drug

The present invention relates to a dermatitis therapeutic agent for oral administration containing a xanthophyll compound having an anti-dermatitis effect. In particular, it is a dermatitis therapeutic agent and a functional food for oral administration containing adonixanthin or the like.

Carotenoids are useful natural pigments such as feed additives, food additives, cosmetic raw materials, and pharmaceuticals. Carotenoids include astaxanthin, canthaxanthin, zeaxanthin, beta-Cryptoxanthin, lycopene, beta-carotene (beta) -Carotene), Adonirubin, adonixanthin, Echinenone, Asteroidenone, and 3-Hydroxyechinenone.

Among them, astaxanthin is useful as a body color improving agent such as a carp, a carp, a real carp, or a feed additive such as a yolk color improving agent for poultry. Further, astaxanthin is known as a safe natural food additive, a health food raw material, and a cosmetic raw material, and has high industrial value. Calcein is expected to be used as a feed additive, a food additive, a cosmetic raw material, a pharmaceutical, etc., similarly to astaxanthin, by establishing an industrial manufacturing method. In addition, β-carotene is used as a feed additive, It is used as a food additive, a cosmetic raw material, a pharmaceutical, etc., and is used as a feed additive, a food additive, a cosmetics, etc., and a zeaxanthin is used as a food additive, a feed additive, a cosmetics raw material, etc.. In addition, lycopene, erionone, β-cryptoxanthin, hydroxycetanone, 3-hydroxycelerone and the like are also expected to be used as feed additives, food materials, cosmetic raw materials, and the like. Examples of the method for producing such carotenoids include a chemical synthesis method, a method of extracting from a natural product, a method of producing by a microorganism, and the like (for example, Patent Documents 1 and 2).

However, for carotenoids, especially marigolds, in addition to carbon atoms and hydrogen atoms in the molecule, a hetero atom represented by an oxygen atom is contained in the molecule, and the lutein compound belonging to the carotenoid has a biology. The role is still not fully understood.

On the other hand, the need to develop dermatitis, especially a therapeutic agent for atopic dermatitis, still exists. In other words, among the conventional therapeutic agents for atopic dermatitis, the steroid agent has an effect on the treatment of inflammation, but it has a strong side effect such as thinning of the skin, and it is difficult to use it for a long period of time. On the other hand, regarding the immunosuppressive agent, there is a problem that the immune system as a whole has an inhibitory effect, and it is easy to suffer from other diseases. In view of such conditions, it has been sought to develop a therapeutic agent having a therapeutic effect of inflammation and having few side effects.

[Advanced technical literature] [Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open Publication No. 2010-172293

[Patent Document 2] Japanese Patent Laid-Open Publication No. 2009-050237

The present invention has an object of providing a dermatitis therapeutic agent or a functional food for oral administration of a lutein compound having an anti-dermatitis effect.

In order to solve the above problems, the inventors of the present invention have conducted intensive studies and found that a specific lutein compound such as calendula yellow is administered orally, for the prevention and treatment of dermatitis, especially allergic dermatitis. Oral administration can effectively act and the like, thus completing the present invention.

In other words, the present invention is an orally allergic dermatitis therapeutic agent containing a lutein compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[In the formula (1), W represents a group represented by any one of the following formulae (2) to (4), and X represents a group represented by any one of the following formulae (5) to (8). Or W combined with W and X represents a group represented by the following formula (9), Y represents a group represented by any one of the following formulas (10) to (12), and Z represents a formula (13) below YZ represented by any one of (21) or YZ in combination with Y and Z represents a group represented by any one of the following formulae (22) to (24).

-CH=CH- (5)

-CH ₂ -CH ₂ - (8)

-CH=CH- (10)

-CH ₂ -CH ₂ - (12)

(here, in the general formulae (2) to (4) and (9), R ¹ and R ² are each independently the same or different, and represent a hydrogen atom; a C _1-20 alkyl group which may have a substituent a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; a C _3-22 cycloalkyl group which may have a substituent; a C _6-18 aryl group which may have a substituent; 5 to 20 membered heteroaryl groups which may have a substituent; 3 to 20 members of a non-aromatic heterocyclic group which may have a substituent; a glycosyl group which may have a substituent; a fluorenyl group which may have a substituent; -COR ³ ; -COOR ⁴ ; -CONR ⁵ R ⁶ ; -PO(OR ⁷ )(OR ⁸ ); or -SO ₂ R ⁹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁹ are each independently the same or Different, representing a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; C _{3 - which} may have a substituent _a cycloalkyl group; a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; or a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent, R ⁷ and R ⁸ each independently may be the same or different, represent a hydrogen atom; may have a substituent group of C _1-20 alkyl; may have Substituent of the C _2-20 alkenyl group; the group may have a substituent C _2-20 alkynyl; may have a C _3-22 cycloalkyl group substituted with the group; an optionally substituted aryl group of C _6-18; may have a substituent a 5- to 20-membered heteroaryl group; a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent; or a fluorenyl group which may have a substituent.

In the general formulae (13) to (15), R ¹⁰ , R ¹¹ and R ¹² are each independently the same or different and represent a hydrogen atom or -OQ ¹ , Q ¹ represents a hydrogen atom; C _{1 which} may have a substituent ₂₀ alkyl; C _2-20 alkenyl which may have a substituent; C _2-20 alkynyl which may have a substituent; C _3-22 cycloalkyl which may have a substituent; C _{6-18 which} may have a substituent An aryl group; a 5 to 20 membered heteroaryl group which may have a substituent; a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent; a saccharide group which may have a substituent; an fluorenyl group which may have a substituent; ¹⁶ ; -COOR ¹⁷ ; -CONR ¹⁸ R ¹⁹ ; -PO(OR ²⁰ )(OR ²¹ ); or -SO ₂ R ²² , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²² are each independently the same or Different, representing a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; C _{3 - which} may have a substituent _a cycloalkyl group; a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; or a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent, R ²⁰ and R ^{21 is} independently, may be the same or different, and represents a hydrogen atom; C which may have a substituent _1-20 alkyl; C _2-20 alkenyl which may have a substituent; C _2-20 alkynyl which may have a substituent; C _3-22 cycloalkyl which may have a substituent; C _{6 which} may have a substituent _{a -18} aryl group; a 5 to 20 membered heteroaryl group which may have a substituent; a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent; or a fluorenyl group which may have a substituent.

Further, in the general formulae (16), (18), (21) and (22), R ¹³ , R ¹⁴ and R ¹⁵ are each independently the same or different and each represents a hydrogen atom; and C _{1- which} may have a substituent ₂₀ alkyl; C _2-20 alkenyl which may have a substituent; C _2-20 alkynyl which may have a substituent; C _3-22 cycloalkyl which may have a substituent; C _{6-18 which} may have a substituent An aryl group; a 5 to 20 membered heteroaryl group which may have a substituent; a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent; a saccharide group which may have a substituent; an fluorenyl group which may have a substituent; ²³ ; -COOR ²⁴ ; -CONR ²⁵ R ²⁶ ; -PO(OR ²⁷ )(OR ²⁸ ); or -SO ₂ R ²⁹ , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ and R ²⁹ are each independently the same or Different, representing a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; C _{3 - which} may have a substituent _a cycloalkyl group; a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; or a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent, R ²⁷ and R ²⁸ each independently may be the same or different, represent a hydrogen atom; may have a substituent group of C _1-20 alkoxy ; C _2-20 alkenyl group may have a substituent group of; may have a substituent group of C _2-20 alkynyl group; an optionally substituted cycloalkyl group of C _3-22; may have a substituent group of C _6-18 aryl group; 5 to 20 membered heteroaryl groups which may have a substituent; 3 to 20 membered non-aromatic heterocyclic groups which may have a substituent; or a fluorenyl group which may have a substituent. )]

In the present invention, W may be represented by the formula (2) or (3).

Further, X may be represented by the formula (5), Y may be represented by the formula (10), and Z may be represented by any one of the formulae (13), (14) and (15).

Further, in the present invention, R ^{1 in the} formula (2) or (3) represents a hydrogen atom.

In the present invention, the lutein compound may be exemplified by at least one selected from the group consisting of, for example, zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, hydroxycapine, marigold, and lutein, and the like. A group of pharmaceutically acceptable salts.

Further, in the present invention, allergic dermatitis may include atopic dermatitis. Examples of dermatitis may be those caused by IgE.

Further, the present invention is a functional food containing the lutein compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof.

The definitions of the substituents in the general formula (1) and the formula (1) (W, X and W in combination with W and X, Y, Z and Y and Z in combination with Y) have the same meanings as described above.

The lutein compound contained in the functional food of the present invention may be at least one The species is selected from the group consisting of zeaxanthin, alpha-cryptoxanthin, beta-cryptoxanthin, hydroxycabinone, marigold, lutein, and such pharmaceutically acceptable salts.

Further, the present invention comprises at least one selected from the group consisting of zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, hydroxycabinone, marigold, lutein, and such pharmaceutically acceptable salts. A group of medical compositions for the treatment of atopic dermatitis.

According to the present invention, a dermatitis as an oral administration agent, particularly a therapeutic agent for allergic dermatitis, can be provided. In one embodiment of the present invention, the dermatitis therapeutic agent of the present invention has a decrease in the concentration dependence of the skin lesion score and/or the blood IgE concentration observed in the NC model mouse, and the blood IgE concentration is Causes of dermatitis, allergic dermatitis, especially the treatment of atopic dermatitis. Further, in another embodiment of the present invention, the dermatitis therapeutic agent of the present invention does not exhibit side effects of weight loss, and provides a therapeutic agent having less side effects.

Hereinafter, the present invention will be described in detail. The following embodiments are illustrative of the invention, and the invention is not limited to the embodiments. The present invention can be embodied in various forms without departing from the spirit thereof.

Further, the publications cited in the present specification are incorporated in this specification after the entire disclosure.

The present invention is based on the fact that a lutein compound such as marigold is administered orally and is effective for treating dermatitis in the treatment of NC mice. Therefore, the present invention provides a dermatitis therapeutic agent containing an anti-dermatitis effect lutein-like compound such as marigold. The dermatitis is, for example, allergic dermatitis, preferably atopic dermatitis.

1. Lutein with anti-dermatitis effect

In the present invention, "lutein" is not particularly limited to the treatment of dermatitis as long as it has an anti-inflammatory effect.

The lutein compound (hereinafter also referred to as "the lutein compound of the present invention") used as the orally-administered therapeutic agent of the present invention is represented by the following formula (1), and includes a pharmaceutically acceptable salt thereof.

In the formula (1), W represents a group represented by any one of the following formulae (2) to (4), and each of X represents a group represented by any one of the following formulae (5) to (8). Or W combined with W and X represents a group represented by the following formula (9), Y represents a group represented by any one of the following formulas (10) to (12), and each of Z represents the following formula (13) YZ represented by any one of (21) or YZ combined with Y represents a group represented by any one of the following general formulae (22) to (24).

-CH=CH- (5)

-CH ₂ -CH ₂ - (8)

-CH=CH- (10)

-CH ₂ -CH ₂ - (12)

Here, in the general formulae (2) to (4) and the general formula (9), R ¹ and R ² are each independently the same or different and each represents a hydrogen atom; a C _1-20 alkyl group which may have a substituent; C _2-20 alkenyl group which may have a substituent; C _2-20 alkynyl group which may have a substituent; C _3-22 cycloalkyl group which may have a substituent; C _6-18 aryl group which may have a substituent; 5 to 20 membered heteroaryl group having a substituent; 3 to 20 membered non-aromatic heterocyclic group which may have a substituent; a saccharide group which may have a substituent; an fluorenyl group which may have a substituent; -COR ³ ;-COOR ⁴ ; -CONR ⁵ R ⁶ ; -PO(OR ⁷ )(OR ⁸ ); or -SO ₂ R ⁹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁹ are each independently the same or different and represent hydrogen Atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; a C _3-22 cycloalkyl group which may have a substituent a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; or a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent, and R ⁷ and R ⁸ are each independently It may be the same or different, represent a hydrogen atom; may have a substituent group of C _1-20 alkyl; may have a substituent group C _2-20 alkenyl; C _2-20 alkynyl group may have the substituent group; cycloalkyl group may have a substituent group of _3-22 C; may have a substituent group of C _6-18 aryl group; the group may have a substituent 5 To 20 members of heteroaryl; 3 to 20 membered non-aromatic heterocyclic groups which may have a substituent; or an indenyl group which may have a substituent.

In the general formulae (13) to (15), R ¹⁰ , R ¹¹ and R ¹² are each independently the same or different and represent a hydrogen atom or -OQ ¹ , Q ¹ represents a hydrogen atom; C _{1 which} may have a substituent ₂₀ alkyl; C _2-20 alkenyl which may have a substituent; C _2-20 alkynyl which may have a substituent; C _3-22 cycloalkyl which may have a substituent; C _{6-18 which} may have a substituent An aryl group; a 5 to 20 membered heteroaryl group which may have a substituent; a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent; a saccharide group which may have a substituent; an fluorenyl group which may have a substituent; ¹⁶ ; -COOR ¹⁷ ; -CONR ¹⁸ R ¹⁹ ; -PO(OR ²⁰ )(OR ²¹ ); or -SO ₂ R ²² , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²² are each independently the same or Different, representing a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; C _{3 - which} may have a substituent _a cycloalkyl group; a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; or a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent, R ²⁰ and R ^{21 is} independently, may be the same or different, and represents a hydrogen atom; C which may have a substituent _1-20 alkyl; C _2-20 alkenyl which may have a substituent; C _2-20 alkynyl which may have a substituent; C _3-22 cycloalkyl which may have a substituent; C _{6 which} may have a substituent _{a -18} aryl group; a 5 to 20 membered heteroaryl group which may have a substituent; a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent; or a fluorenyl group which may have a substituent.

In the formulae (16), (18), (21) and (22), R ¹³ , R ¹⁴ and R ¹⁵ are each independently the same or different and represent a hydrogen atom; a C _1-20 alkane which may have a substituent C _2-20 alkenyl group which may have a substituent; C _2-20 alkynyl group which may have a substituent; C _3-22 cycloalkyl group which may have a substituent; C _6-18 aryl group which may have a substituent 5 to 20 membered heteroaryl groups which may have a substituent; 3 to 20 membered non-aromatic heterocyclic groups which may have a substituent; a sugar group which may have a substituent; a fluorenyl group which may have a substituent; -COR ²³ ; -COOR ²⁴ ; -CONR ²⁵ R ²⁶ ; -PO(OR ²⁷ )(OR ²⁸ ); or -SO ₂ R ²⁹ , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ and R ²⁹ are each independently the same or different, a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; a C _3-22 ring which may have a substituent An alkyl group; a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; or a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent, R ²⁷ and R ²⁸ each independently may be the same or different, represent a hydrogen atom; may have a substituent group of C _1-20 alkyl; C _2-20 alkenyl group having the substituent group; an optionally substituted alkynyl group of C _2-20; a cycloalkyl group having _3-22 C group of substituents; an optionally substituted aryl group of C _6-18; may have a 5 to 20 membered heteroaryl group of the substituent; a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent; or a fluorenyl group which may have a substituent.

Hereinafter, each of the lutein compounds represented by the formula (I) used in the present invention will be specifically described.

In the description of each group, for example, "C _1-20 " means that the number of carbon atoms is from 1 to 20 (C ₁ to C ₂₀ ), and unless otherwise specified, the number of carbon atoms of a straight chain, a branched chain or a cyclic group is shown. . The constituting carbon number includes the total number of carbon atoms of the group of the linear or branched group substituted with a cyclic group and the cyclic group substituted with a linear or branched group.

Therefore, for example, the chain group at the time of "C _1-20 " is a straight chain or a branched chain having a carbon number of 1 to 20. Further, the cyclic group is a cyclic group having 1 to 20 carbon atoms constituting the ring. The group having a chain group and a cyclic group is a group having a total carbon number of 1 to 20.

The representation of the number of other carbon atoms is also the same as above.

The "may have a substituent" means a plurality of substituents which may have one substituent or any combination at a substitutable moiety.

Examples of the substituent in the "substitutable group" include a halogen atom, a hydroxyl group, a thiol group, a nitro group, a cyano group, a decyl group, a carboxyl group, an amine group, a decyl group, a methanesulfonyl group, and a C _1-6 alkane. a group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a C _6-10 aryl group, a 5 to 10 membered heteroaryl group, a 3 to 10 membered non-aromatic heterocyclic group, C _1-6 alkoxy, C _1-6 alkylthio, C _3-8 cycloalkoxy, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _{2 -7} fluorenyl or C _2-7 alkoxycarbonyl and the like.

However, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5 to 10 membered heteroaryl, 3 to 10 members Non-aromatic heterocyclic group, C _1-6 alkoxy group, C _1-6 alkylthio group, C _3-8 cycloalkoxy group, mono-C _1-6 alkylamino group, di-C _1-6 The alkylamino group, the C _2-7 fluorenyl group and the C _2-7 alkoxycarbonyl group are each independently and may have 1 to 3 groups selected from the group of substituents described below. (Substituent group: halogen atom, hydroxyl group, thiol group, nitro group, cyano group, C _1-6 alkyl group, C _3-8 cycloalkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _6-10 aryl, 5 to 10 membered heteroaryl, 3 to 10 membered non-aromatic heterocyclic group, _C1-6 alkoxy group and _C1-6 alkylthio group.)

"Alkyl" means a straight or branched alkyl group. Examples of the "C _1-20 alkyl group" include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a second butyl group, a tert-butyl group, a pentyl group, an isopentyl group, and a neopentyl group. Base, third amyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl , 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2 -trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, 1-methyl Hexyl, octyl, 2-ethylhexyl, 1,1-dimethylhexyl, decyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl , hexadecyl, heptadecyl, octadecyl, 19-carbon, and 20-carbon.

"Alkenyl" means a straight, branched or cyclic alkenyl group. Examples of the "C _2-20 alkenyl group" include a vinyl group, an allyl group, an isopropenyl group, a 2-methylallyl group, a butenyl group, a pentenyl group, an isopentenyl group, a hexenyl group, and a 1-ring group. Propen-1-yl, 2-cyclopropen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopentene 1-yl, 1-cyclohexen-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclopentadien-1-yl, 2, 5-cyclohexadien-1-yl, heptenyl, octenyl, nonenyl, decenyl, 1-cyclohepten-1-yl, 1-cyclohexen-1-ylmethyl, 4 -methyl-1-cyclohexen-1-yl, 4,4-dimethyl-1-cyclohexen-1-yl, 3,3,5,5-tetramethyl-1-cyclohexene- 1-based and the like.

"Alkynyl" means a straight, branched or cyclic alkynyl group. Examples of the "C _2-20 alkynyl group" include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a butynyl group, a pentynyl group, a hexynyl group, a heptynyl group, an octynyl group, a decynyl group, and the like.癸 alkynyl and the like.

"Cycloalkyl" is a monocyclic or polycyclic saturated aliphatic hydrocarbon group. Examples of the "C _3-22 cycloalkyl group" include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, and a cyclopentylmethyl group. , 1-cyclopropylethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-methylcyclopropyl, cycloheptyl, cyclohexylmethyl, 2-cyclohexylethyl, 4 -methylcyclohexyl, 4,4-dimethylcyclohexyl, 3,3,5,5 tetramethylcyclohexyl, and the like.

"Aryl" is a monocyclic or condensed aryl group. Examples of the "C _6-18 aryl group" include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an anthracenyl group, a phenanthryl group, a fluorenyl group or the like or a (1-, 2-, 4- or 5-) indanyl group. a partially hydrogenated condensed aryl group such as a mercapto group or a tetrahydronaphthyl group. Here, the partially hydrogenated aryl group is a monovalent group capable of removing any hydrogen atom from a partially hydrogenated fused ring, and any one of a hydrogen atom of a fused ring aromatic ring moiety or a hydrogen atom of a hydrogenated moiety may be removed. . For example, a tetrahydronaphthyl group may be exemplified by 1,2,3,4-tetrahydronaphthalene (-1-yl,-2-yl,-3-yl,-4-yl,-5-yl,-6-yl) , -7-based, -8-yl) and the like.

The "5 to 20 membered heteroaryl group" is an aromatic cyclic group having 5 to 20 atoms constituting the ring and having 1 to 5 hetero atoms in the atom constituting the ring. "5 to The 20-membered heteroaryl group may, for example, be furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, furan Sulfhydryl, thiadiazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, fluorenyl, pteridinyl, quinolinyl, isoquinolinyl, naphthyl , quinoxalinyl, porphyrinyl, quinazolinyl, pyridazinyl, imidazopyridyl, imidazothiazolyl, imidazoxazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl , fluorenyl, isodecyl, carbazolyl, pyrrolopyridyl, thienopyridyl, furopyridinyl, benzothiadiazolyl, benzoxazolyl, pyridopyrimidinyl, benzo Furanyl, benzothienyl, thienofuranyl and the like.

The "3 to 20 member non-aromatic heterocyclic group" has 3 to 20 atoms constituting the ring, and the atom constituting the ring contains 1 to 2 hetero atoms, and the ring may have 1 to 2 double bonds in the ring. A monocyclic or polycyclic non-aromatic cyclic group which may contain from 1 to 3 ring groups of a carbonyl group, a sulfinyl group or a sulfonyl group. When a nitrogen atom is contained in the atom constituting the ring, a bonding bond may be extended from the nitrogen atom.

The "3 to 20 member non-aromatic heterocyclic group" may, for example, be azacyclopropyl, azetidinyl, epoxyethyl, oxetanyl, thiot-butyl, pyrrolidinyl or tetrahydrofuranyl. , tetrahydrothiophenyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl (oxetanyl), tetrahydrothiopyranyl, tetrahydrothiophenyl, six Hydropyrazinyl, dioxanyl, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl , oxadiazolyl, oxadiazolidinyl, morpholinyl, thiomorpholinyl, quinuclidinyl, oxetanyl and the like.

"Glycosyl" means a sugar residue such as a monosaccharide such as glucose, galactose, fructose or rhamnose, a saccharide such as sucrose, vetch, lactose, maltose or sucrose. The basis. Therefore, the glycosyl group may, for example, be a glucosyl group, a galactosyl group, a fructosyl group, a rhamnosyl group or the like. Further, any combination of the groups also includes a 1→2 bond, a 1→3 bond, and a 1→4 bond. The knot or 1→6 bond combines to form a disaccharide group.

"矽" is the base represented by -Si(R ³⁰ ) ₃ .

R ³⁰ each independently, which may be the same or different, represents a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; a C _3-22 cycloalkyl group which may have a substituent; a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; or a 3 to 20 member which may have a substituent Family heterocyclic group. The fluorenyl group is, for example, -SiH ₃ .

In the present invention, it is preferred that W is represented by the formula (2) or (3). Further, in another aspect of the invention, it is preferred that X is represented by the formula (5), Y is represented by the formula (10), and Z is represented by the formulae (13), (14) and (15). Any one of the presenters. Further, in another aspect of the present invention, it is preferred that W is represented by the general formula (2) or (3), X is represented by the general formula (5), Y is represented by the general formula (10), and Z is a general formula. Any one of (13), (14) and (15) is represented.

Further, in the present invention, it is more preferred that R ¹ in the formula (2) or (3) represents a hydrogen atom.

Examples of the lutein compound used in the present invention are shown below (Tables 1 to 5).

Among the above compounds, preferred lutein compounds include, for example, zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, hydroxycaalone, marigold, lutein, etc., among which marigold is preferred. Yellow matter. Calendula yellow is a precursor of astaxanthin in the carotenoid biosynthesis system, and astaxanthin is obtained by ketolizing the calendula. The therapeutic agent for oral dermatitis of the present invention can be used in combination with a lutein compound having an anti- dermatitis effect or a combination of a plurality of them, and is useful for the treatment of allergic dermatitis.

Hereinafter, the structural excerpts of zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, hydroxycaalone, marigold, and lutein are shown in Tables 1 to 5.

In the present invention, the lutein compound can be produced by a known method such as a chemical synthesis method or a method using a microorganism such as bacteria or yeast as long as it is the manufacturer. For example, when chemical synthesis is carried out, it can be produced by the method described in Pure & Appl. Chem., Vol 51, pp. 535-564 (1979). In addition, in the case of using bacteria, it is described in JP-A-2010-172293, JP-A-2005-087097, International Publication No. 2010/087400, International Publication No. 2010/044469, and JP-A-2001-352995. The method of manufacture. In addition, when the yeast is used, it can be produced by the method described in JP-A-H05-76347, JP-A-6-319531, and JP-A No. 8-214870.

Hereinafter, a method for producing calendula yellow is shown.

The bacterium used in the present invention is not particularly limited as long as it is a bacterium which can produce a lutein compound, and is preferably a genus Paracoccus, genus Sphingomonas, and Bacillus brevis. (Brevundimonas) is a genus of the genus Erythrobacter, and among them, a bacterium belonging to the genus Paracoccus is preferred. Among the bacteria belonging to the genus Paracoccus, Paracoccus carotinifaciens, Paracoccus marcusii, Paracoccus haeundaensis, and Paracoccus Zeaxanthinifaciens are more preferably used. Good use of carotenoid paracocci. Paracoccus Examples of the specific strain of the bacteria include the carotenoid paracoccus E-396 strain (FERM BP-4283) and the paracoccus bacterium A-581-1 strain (FERM BP-4671), and the variant strains can also be used in the present invention. Used in the invention.

Further, as the lutein-based compound-producing bacteria, a bacterium having high identity (identity) to the base sequence of the above E-396 strain is preferably used as the base sequence of the DNA corresponding to the 16S ribosomal RNA. Here, "high identity" means that the base sequence of the DNA corresponding to the 16S ribosomal RNA of the E-396 strain is preferably 95% or more, more preferably 96% or more, preferably the base sequence corresponding to the target bacteria. 97% or more, especially preferably 98% or more, preferably 99% or more. A bacterium having high identity with the base sequence of the strain E-396 was used. The nucleotide sequence of the DNA corresponding to the 16S ribosomal RNA of the E-396 strain is described, for example, in the Sequence Listing of International Publication No. 2010/044469.

The base sequence of the DNA corresponding to the 16S ribosomal RNA is a nucleotide sequence in which the U (uracil) in the 16S ribosomal RNA base sequence is substituted with T (thymine). Microbial taxonomy based on the identity of the base sequence of the 16S ribosomal RNA has become mainstream in recent years. In the past, the classification method of microorganisms has been based on the bacteriological properties such as kinetics, nutritional requirements, and assimilation of sugars, and microbial misclassification occurs when a shape change occurs through natural mutation. In this regard, since the base sequence of the 16S ribosomal RNA is genetically very stable, the classification based on its identity is superior to the previous classification.

The base sequence of the 16S ribosomal RNA of the carotenoid paracocci E-396 strain and the DSM 11574 strain, the paracoccus bacterium N-81106, and the Haeundae deputy, which produce bacteria for other lutein compounds. Cocci BC 74171 strain, The base sequence identity of the 16S ribosomal RNA of Paracoccus bacterium A-581-1 strain, Paracoval bacillus ATCC 21588 strain and Paracoccus PC-1 strain was 99.7%, 99.7%, 99.6%, respectively. 99.4%, 95.7%, and 95.4%, which are considered to be closely related to taxonomy. Therefore, these strains form a group as bacteria which produce lutein compounds. Therefore, these strains can be preferably used in the present invention to efficiently produce lutein-like compounds.

In the present invention, a mutant having improved productivity of a lutein compound can be used. Examples of the modified mutant strains include strains with high production of astaxanthin (Japanese Patent Laid-Open No. 2001-95500), strains of selective production of scutellaria (Japanese Patent Laid-Open No. 2003-304875), and zeaxanthin A strain which is produced in a large amount selectively with β-cryptoxanthin (Japanese Patent Laid-Open Publication No. 2005-87097), a strain selectively produced by lycopene (Japanese Patent Laid-Open No. 2005-87100), a strain which is improved in sedimentation property, and the like.

The improved mutant strain of the lutein compound can be obtained by mutation treatment and screening. The method of the mutation treatment is not particularly limited as long as it can induce the mutation. For example, a chemical method using a variant such as N-methyl-N'-nitro-N-nitroguanidine (NTG) or ethyl methanesulfonate (EMS), ultraviolet irradiation, and X-ray irradiation can be used. Methods, biological methods such as genetic recombination and transposition. The microorganism to be subjected to the variability treatment is not particularly limited, and it is preferred that the lutein compound produces a bacterium. Further, the mutant strain may be caused by a mutation caused by nature.

The screening method of the mutant strain is not particularly limited, and for example, a method of selecting a mutant strain of a colony in a color of a colony on an agar medium can be exemplified by cultivating a mutant strain in a test tube, a flask, a fermentation tank, or the like, and using the absorbance and the high speed. Analysis of carotenoid pigments such as liquid chromatographs and thin layer chromatography, and methods for selecting mutants of interest. The step of mutating and screening can be performed once, or for example by mutation The mutants can be obtained by screening and cultivating the mutants, and the mutants can be repeatedly manipulated and screened twice or more, and the mutants can be obtained by the mutation treatment and screening to obtain the productive modified strains.

Hereinafter, a method of producing the above-mentioned bacteria and producing a lutein compound in the present invention will be described.

(1) Method for producing bacterial cells

For example, according to the method of JP-A-2010-172293, a lutein compound is cultured to produce bacteria, and a cell (culture) is produced.

In the present invention, the medium for producing a lutein compound used in the bacterial culture can be used as long as it can grow a lutein-producing compound to produce a lutein compound, and preferably contains a carbon source, a nitrogen source, and an inorganic substance. A medium such as a salt and, if necessary, a vitamin.

Examples of the carbon source include sugars such as glucose, sucrose, lactose, fructose, trehalose, mannose, mannitol, and maltose, and organic acids such as acetic acid, fumaric acid, citric acid, propionic acid, malic acid, malonic acid, and pyruvic acid. Alcohols such as ethanol, propanol, butanol, pentanol, hexanol, isobutanol and glycerol, oils such as soybean oil, rice bran oil, olive oil, corn oil, sesame oil and linseed oil, etc. One or two or more kinds of these carbon sources are appropriately selected and used. Among them, glucose or sucrose is preferably used. The amount of the medium (starting medium) to be added before the culture may be appropriately adjusted depending on the kind of the carbon source. Usually, the medium is added in an amount of 1 to 100 g, preferably 2 to 50 g per 1 L. Further, the carbon source is not only added to the initial culture medium, but is preferably supplied sequentially or continuously during the cultivation.

Examples of the inorganic nitrogen source include ammonium salts such as ammonium nitrate, ammonium sulfate, ammonium chloride, and ammonium phosphate; and nitrates such as potassium nitrate; ammonia and urea, etc., and can be appropriately selected from these. One or two or more types are used. The amount of addition may be appropriately adjusted depending on the type of the nitrogen source, and is usually 0.1 g to 20 g, preferably 0.2 to 10 g, to 1 L of the medium.

The organic nitrogen source may, for example, be a corn steep liquor (including a filter treatment), a medicinal medium (pharmamedia), soybean meal, soybean meal, peanut meal, distillers soluble, dried yeast, sodium glutamate, or the like. One type or two or more types are appropriately selected from the above. The concentration to be added may be appropriately adjusted depending on the kind of the nitrogen source, and is usually from 0 to 80 g/L, preferably from 0 to 30 g/L. The inorganic nitrogen source and the organic nitrogen source are usually added to the starting medium, and may be supplied sequentially or continuously.

Examples of the inorganic salts include phosphates such as potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and disodium hydrogen phosphate; magnesium salts such as magnesium sulfate and magnesium chloride; iron salts such as iron sulfate and iron chloride; calcium chloride and carbonic acid. Calcium salts such as calcium, sodium salts such as sodium carbonate and sodium chloride, manganese salts such as manganese sulfate, cobalt salts such as cobalt chloride, copper salts such as copper sulfate, zinc salts such as zinc sulfate, sodium molybdate, etc. A nickel salt such as a molybdenum salt or a nickel sulfate such as a nickel sulfate or a selenium salt such as sodium selenate, or a boric acid or a potassium iodide may be used, and one or two or more kinds thereof may be appropriately selected. The amount of addition may be appropriately adjusted depending on the type of the inorganic salt, and is usually 0.0001 to 15 g for 1 L of the medium. The inorganic salts are usually added to the starting medium, and may be supplied sequentially or continuously.

Examples of the vitamins include cyanocobalamin, riboflavin, pantothenic acid, pyridoxine, thiamine, ascorbic acid, folic acid, nicotinic acid, p-aminobenzoic acid, biotin, inositol, choline, and the like. One or two or more types are appropriately selected and used. The addition ratio may be appropriately adjusted depending on the type of the vitamin, and is usually 0.001 to 1000 mg, preferably 0.01 to 100 mg, to 1 L of the medium. The vitamins are usually added to the starting medium, and may be supplied sequentially or continuously.

In the present invention, in order to suppress foaming of the culture, an antifoaming agent can be used. The type of the antifoaming agent may have a function of suppressing the occurrence of bubbles or eliminating the occurrence of bubbles, and the effect of inhibiting the production bacteria is small. For example, an alcohol-based antifoaming agent, a polyether-based antifoaming agent, an ester-based antifoaming agent, a fatty acid-based antifoaming agent, a fluorene-based antifoaming agent, a sulfonic acid-based antifoaming agent, and the like can be exemplified. The amount of addition may be appropriately adjusted depending on the type of the antifoaming agent, and is usually 0.01 g to 10 g for 1 L of the medium. Antifoaming agents are usually added to the starting medium before sterilization. Alternatively, it may be added continuously or intermittently during the cultivation.

The medium for producing a lutein compound used in the present invention can be used for culturing bacteria after sterilizing treatment. The sterilization treatment can be carried out as long as it is a manufacturer. For example, the medium in a suitable container can be heat sterilized by autoclaving. Alternatively, it can be sterilized by filtration through a sterile filter.

The initial pH of the medium for producing lutein compound used in the present invention is adjusted to 2 to 12, preferably 6 to 9, more preferably 6.5 to 8.0. It is also preferable to maintain the pH in the above range in the culture. The pH adjusting agent may, for example, be an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous sodium carbonate solution, an aqueous ammonia solution, an ammonia gas, an aqueous sulfuric acid solution or a mixture thereof.

In the present invention, the lutein compound-producing bacteria are inoculated in a medium for producing a lutein compound prepared as described above, and cultured under the predetermined conditions. The inoculum is cultured by using a test tube, a flask, a fermentation tank, or the like, and the strain is appropriately added, and the obtained culture is added to a medium for producing a lutein compound. The medium to be used for the inoculation culture is not particularly limited as long as the lutein-producing compound-producing bacteria can be well cultured.

The culture is carried out in a suitable culture vessel. The culture container can be appropriately selected depending on the culture capacity, and examples thereof include a test tube, a flask, a fermentation tank, and the like. The culture temperature is 15 to 80 ° C, preferably 20 to 35 ° C, more preferably 25 ° C to 32 ° C, usually The culture is carried out under aerobic conditions for 1 to 20 days, preferably 2 to 12 days, more preferably 3 to 9 days. The aerobic conditions include, for example, vibration culture or aeration agitation culture, and it is preferred to control the dissolved oxygen concentration within a certain range. The control of the dissolved oxygen concentration can be performed, for example, by changing the number of stirring revolutions, the amount of aeration, the internal pressure, and the like. The dissolved oxygen concentration is preferably controlled to be from 0.3 to 10 ppm, more preferably from 0.5 to 7 ppm, most preferably from 1 to 5 ppm.

(2) Remove the bacteria

Based on a known technique, only the medium component is removed from the culture of the cultured cell culture solution or the like, and then the cells are dried in a drum dryer. Drying method In addition to the drum dryer, a spray dryer, a granulating spray dryer, freeze drying, or the like can be used. Hereinafter, it is described in detail.

As described above, the culture obtained by culturing the lutein-like compound-producing bacteria separates the concentrate containing the lutein-like compound and the bacterial cell by centrifugation, filtration separation or decantation. The separation step can be carried out under acidic conditions (refer to JP-A-2010-172293). Here, in the present specification, the "culture" is any one of a culture supernatant, a cultured cell, or a bacterial cell disruption.

The culture may be subjected to a separation operation as it is, but in order to enhance the effect of removing unnecessary components, the culture is preferably diluted and separated with water. At this point, the pH of the culture can be adjusted prior to the addition of water or after the addition of water. Further, water may be added during the operations such as centrifugation, filtration separation, and decantation. The amount of water to be added for dilution is not limited, and is preferably from 0 to 10 times, more preferably from 0.5 to 3.0 times the volume of the culture. Further, between the completion of the culture and the separation, in order to kill the cultured microorganism, heat sterilization can be performed. The pH adjustment at this time can be before or after heat sterilization.

In the present invention, the method for separating lutein compounds is as long as it is The degradation-based separation method or the particle size-based separation method may preferably use centrifugal separation, filtration separation or decantation. These may be carried out separately or in combination of two or more. Further, the centrifugation was carried out once, and in order to recover the lutein compound remaining in the supernatant, the supernatant was again supplied to the centrifuge for separation, and the same kind of separation was repeated twice or more.

The centrifugal separator used in the centrifugal separation may be continuous or batchwise, and a continuous type is preferably used. The type of the centrifuge may be any type, and examples thereof include a cage type, a multi-chamber type, a decantation type, a disc type (nozzle type, a deslimation type), a tubular type, and a rotary type centrifugal separator. . The centrifugal acceleration may be any level as long as it is usually used in the separation of bacterial cells, and is preferably from 500 to 100,000 × g, more preferably from 1,000 to 50,000 × g.

The membrane filtration device used in the filtration separation may be of a static type or a crossflow type, and is preferably a lateral flow type which is easy to prevent clogging. The material of the film to be used may, for example, be a filter paper, a filter cloth, a chemical fiber, a ceramic, or the like. Further, diatomaceous earth or the like as a filter aid can also be used. Examples of the method for promoting the filtration force include a pressurized type, a reduced pressure type, a centrifugal filtration type, and a filter press type. The shape of the film may, for example, be a flat film, a hollow fiber membrane, or a tubular film. The pore diameter of the membrane is usually as long as it is suitable for separating bacteria, and is preferably from 0.001 μm to 100 μm, more preferably from 0.01 to 10 μm, still more preferably from 0.1 to 1 μm. It is better to use a precision filtration membrane or an ultrafiltration membrane to better use a precision filtration membrane.

The container used in the decantation may be any container, and for example, a usual cylindrical groove may be used. When the decantation method is used, the time during which the culture is allowed to stand is not particularly limited, and is preferably from 0.5 to 48 hours, more preferably from 1 to 24 hours.

The temperature of the culture to be separated can be as long as the temperature is usually carried out, and there is no special Further, it is preferably from 0 ° C to 90 ° C, more preferably from 2 ° C to 75 ° C, most preferably from 4 ° C to 60 ° C.

The precipitated concentrate obtained from the culture is a lutein compound and the cells are concentrated by the above separation step, that is, centrifugation, filtration separation, decantation or combination thereof. The precipitate concentrate is made into a viscosity and a water content suitable for the next step, and the separation speed, the separation strength, and the like are preferably appropriately adjusted. The recovery rate of the concentrate of the lutein compound in the separation step is affected by decomposition/degradation of the lutein compound, adhesion to the inner surface of the device, leakage to the supernatant, and the like, and is preferably 70 to 100. %, more preferably 80 to 100%, and most preferably 90 to 100%.

The obtained precipitate concentrate is dried to obtain a dried bacterial cell containing a lutein compound. The dried cells obtained by these operations can be used as a feed additive as they are. Further, the lutein compound is extracted from the dried cells and, if necessary, purified, and can be used for food, cosmetics, and feed. The precipitate concentrate can be produced without drying, and the lutein compound can be produced by extracting and recovering the lutein compound. The drying method is not particularly limited, and examples thereof include spray drying, flow drying, spray granulation drying, spray granulation flow drying, rotary drum drying, and freeze drying. Further, in the stage of the culture, the precipitation concentrate, or the dried cells, chemical treatment using an alkali reagent or a surfactant, and chemical treatment using superabsorbent or lipolytic enzyme, proteolytic enzyme or the like may be performed. One or more of physical treatments such as sound waves, pulverization, and heating.

(3) Extraction of lutein compounds from bacterial cells and (4) Purification of crude extracts from lutein compounds

The extraction is as follows, and may be carried out by a known technique as long as it is a manufacturer, and examples thereof include methods (i) to (iii), but are not limited to the methods.

(i) High-temperature ethanol extraction according to the method described in Japanese Patent No. 4969370.

(ii) The cells were placed in acetone at 50 ° C, suspended for 2 hours (or 6 hours at room temperature), and then filtered. Then, the solvent is removed and dried (known technique).

(iii) The cells were placed in a normal temperature chloroform solution, and suspended for 3 hours, followed by filtration. Then, the solvent is removed and dried (known technique).

When the lutein compound is extracted from the culture, the solvent used for the extraction and washing is not particularly limited, and examples thereof include lower alcohols such as methanol, ethanol, and isopropanol, acetone, tetrahydrofuran, methyl ethyl ketone, and A. Isobutyl ketone, dichloromethane, chloroform, dimethylformamide, dimethyl hydrazine, hexane, and the like.

The extract thus obtained can be used as a lutein compound as it is, or can be further purified. The method of isolating the cells or the like from the extract after the extraction operation is not particularly limited, and filtration, centrifugation, decantation, or the like can be used. The method of obtaining a precipitate of the lutein compound from the extract may, for example, be a method of precipitating the mixture, such as cooling, heating, concentration under reduced pressure, addition of a weak solvent, and addition of various salts such as an acid/base agent, alone or in combination. The precipitate of the lutein compound obtained can be suspended and stirred using a solvent such as a small amount of a lower alcohol if necessary. The method of washing is not particularly limited, and a practical method such as a method of filtering after suspension stirring or a method of passing liquid from above the precipitate may be mentioned.

When it is desired to prevent the oxidative decomposition of the lutein compound in the culture, the precipitate concentrate, the dried cells, the extract, the purified product, and the respective steps, it can be carried out under an inert gas atmosphere such as nitrogen. Also, you can choose to add antioxidants for pharmaceuticals or foods. These processes can also be combined. Further, in order to prevent the lutein compound from being photodegraded as much as possible, it can be carried out under the conditions of no light irradiation.

Precipitate concentrate, dried cells, extract obtained by the above operation Alternatively, the purified product may be used alone as a lutein compound, or may be used in combination at any ratio.

In the present invention, the lutein compound may be in the form of a pharmaceutically acceptable salt, and the salts are also included in the lutein compound of the present invention. In the present invention, the lutein compound also has a salt formed with an acid or a base. In the present invention, the pharmaceutically acceptable salt is not particularly limited as long as it is a lutein compound having an anti- dermatitis effect and a pharmaceutically acceptable salt. Specific examples thereof include hydrohalide salts (for example, hydrofluoric acid salts, hydrochloride salts, hydrobromide salts, hydroiodides, etc.), and inorganic acid salts (for example, sulfates, nitrates, perchlorates, and phosphoric acids). Salts, carbonates, bicarbonates, etc.), organic carboxylates (eg acetates, oxalates, maleates, tartrates, fumarates, citrates, etc.), organic sulfonates (eg A a sulfonate, a triflate, an ethanesulfonate, a besylate, a tosylate, a camphorsulfonate, etc., an amine acid salt (eg, aspartate, glutamate, etc.) And a quaternary amine salt, an alkali metal salt (for example, a sodium salt or a potassium salt), an alkaline earth metal salt (for example, a magnesium salt, a calcium salt, etc.), etc., but not limited thereto.

Further, in the present invention, the lutein compound may exist as an optical isomer, and these optical isomers are also included in the lutein compound of the present invention. The lutein compound contained in the present invention may also be a racemate.

Further, in the lutein compound having a hydroxyl group such as zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, hydroxycapine, marigold, lutein, etc., an ester with a fatty acid may be used. The form of the body or the glucoside bound to the sugar, the free form not bound to the compound, and the like. In the present invention, the lutein compound having an anti- dermatitis effect may exist in any form, and is preferably present as a free form.

2. Therapeutic agent for dermatitis

The dermatitis therapeutic agent (hereinafter also referred to as "the therapeutic agent of the present invention") of the oral administration agent of the present invention is an active ingredient containing the lutein compound of the present invention having an anti- dermatitis effect. In the therapeutic agent of the present invention, the lutein compound having anti- dermatitis effect is preferably zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, hydroxycaalone, marigold or lutein. Better for marigold yellow. The lutein-containing compound having an anti- dermatological action contained in the therapeutic agent of the present invention contains a pharmaceutically acceptable salt, an optical isomer, an ester or a glucoside, and the like.

The lutein compound contained in the therapeutic agent of the present invention has an effect of lowering blood IgE levels by oral administration. Therefore, the therapeutic agent of the present invention is effective for treating dermatitis or the like which is caused by IgE. Also, it is effective in dermatitis with pruritus. Since IgE is one of allergic diseases, the therapeutic agent of the present invention can be used as a therapeutic agent for allergic dermatitis for oral use. Further, as shown in the examples, the lutein compound contained in the therapeutic agent of the present invention can be calmed by dermal inflammation in NC mice by oral administration. The NC mouse is a model animal in which dermatitis is caused by the dust mite antigen. Since the symptoms of the dermatitis are similar to those of the atopic dermatitis, it is widely used as a model animal of atopic dermatitis. Therefore, the therapeutic agent of the present invention can be used as a therapeutic agent for atopic dermatitis for oral administration. In addition, it is effective not only for ectopicity, but also for improving the itching sensation caused by sensitive skin or dry skin or treating allergic symptoms.

In the present invention, "treatment" of dermatitis refers to prevention, inhibition, alleviation, delay of severe treatment, cessation or healing of dermatitis symptoms.

The lutein compound having an anti- dermatitis effect can also be used as an active ingredient of a dermatitis preventive agent. Therefore, a dermatitis prophylactic agent containing a lutein compound having an anti-dermatitis effect is also included in the present invention. In the present invention, the skin The "prevention" of inflammation is delay or prevention of dermatitis.

Judging whether it is effective for treating dermatitis can be determined by visual observation, skin lesion score, blood IgE concentration, pathological observation by HE staining, filling of cells by Giemsa staining, immunohistochemistry by CD4 The CD4 positive helper T cells were chemically calculated, F4/8-positive macrophages were calculated by F4/80 immunohistochemistry, IgE positive cells were calculated by IgE immunohistochemistry, and the like. As long as it is an operator, various methods based on a general method can be implemented.

The therapeutic agent of the present invention can be used as it is in the form of an anti- dermatological lutein compound, or can be formulated in combination with a carrier which is usually used for the preparation, a known pharmaceutically acceptable carrier or the like. Examples of such carriers include excipients, binders, disintegrators, lubricants, colorants, flavoring agents, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, and anti-corrosion agents. Oxidizing agents, preservatives, moisturizers, etc. The therapeutic agent of the present invention can also be provided as a formulated pharmaceutical composition. In other words, the pharmaceutical composition of the present invention is a pharmaceutical composition for treating allergic dermatitis containing the lutein compound of the present invention, and is preferably a pharmaceutical composition for treating atopic dermatitis.

Further, the administration form of the therapeutic agent of the present invention is oral administration. Therefore, the therapeutic agent of the present invention is an oral administration agent.

The dosage form to be formulated may, for example, be a tablet, a powder, a fine granule, a granule, a capsule, a syrup or the like which is used in the form of oral administration.

The therapeutic agent of the present invention contains a lutein compound having an anti- dermatitis action as an active ingredient. The effective administration amount of the lutein compound having anti- dermatitis effect depends on the degree of symptoms, the age of the patient, the sex, the body weight, the sensitivity difference, the administration method, the administration period, the administration interval, the administration period, and the preparation Nature, The type of the preparation, the type, and the active ingredient may vary, and may be appropriately set as long as it is the manufacturer. For example, for the total component amount of the therapeutic agent of the present invention, the content of the lutein compound having an anti- dermatitis effect is preferably 0.001 to 5.0% by weight, 0.01 to 5.0% by weight, more preferably 0.01 to 1.0% by weight. 0.05 to 1.0% by weight. Or an adult (weight 60 kg) may be administered in an amount of 0.01 to 500 mg, 0.1 to 500 mg, preferably 0.5 to 200 mg, more preferably 1 to 100 mg, most preferably 60 mg per day.

The present invention also provides a dermatitis treatment method characterized by administering an effective amount of a lutein compound having an anti-dermatitis effect to a patient. Further, in the present invention, a dermatitis oral therapeutic agent for use in the present invention, which has a dermatitis-resistant lutein compound, is also included. Here, the lutein compound having the above anti- dermatitis effect is preferably zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, hydroxycaalone, marigold yellow or lutein, more preferably Calendula yellow. Further, in another aspect of the present invention, the preferred lutein compound is lutein, and also includes optical isomers and modifications such as marigold. In the method of the present invention, the administration route and administration method of the lutein compound having an anti- dermatitis effect are not particularly limited, and the above-mentioned therapeutic agents of the present invention can be referred to.

3. Functional food

The functional food of the present invention is a lutein compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof, and can be used as a functional food (including supplements and health foods) because of its anti-inflammatory effect. use.

The form of the food of the present invention may, for example, be a supplement (a powder, a granule, a soft capsule, a hard capsule, a lozenge, a chewable tablet or a fast-disintegrating tablet), and may also be a beverage (tea, carbonated beverage, lactic acid beverage, Sports drinks, etc., snacks (gummy, jelly, chewing gum, chocolate, biscuits, candy, etc.), oil, fat food (Melico, Sauce, cream, cheese, margarine, etc., seasonings (ketchup, sauce, etc.), mobile food, dairy products (milk, yogurt, cheese, etc.), bread, noodles (wulong noodles, buckwheat, Ramen noodles, Italian noodles, fried noodles, broad noodles, plain noodles, cold noodles, rice noodles, etc.). However, it is not limited to these forms.

The functional food of the invention can be combined with various nutrients and various vitamins (vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin E, etc.), various minerals, dietary fiber, and plural. Saturated fatty acids, other nutrients (coenzyme Q10, carnitine, sesamin, alpha-lipoic acid, inositol, D-chiro-inositol, eric alcohol, phospholipid lysine, Stabilizers, sweeteners, tastes such as phospholipid 醯DHA, phospholipid 醯inositol, taurine, glucosamine, chondroitin sulfate, S-adenosylmethionine, etc.), dispersing agents, emulsifiers, etc. Ingredients (citric acid, malic acid, etc.), spices, royal jelly, propolis, mushroom (agaricus), and the like. Also, it can be blended with herbs such as mint, bergamot, chamomile, lavender, and thyme. Further, it may be blended with raw materials such as theaflavic acid, dehydroepiandrosterone, melatonin, and the like.

In the present invention, when the lutein compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof is used as a functional food or a supplement, the usage and amount thereof are not particularly limited, and can be suitably used for the above skin. The usage and dosage of the inflammatory therapeutic agent.

[Examples]

Hereinafter, the present invention will be described in detail based on the examples, but the present invention is not limited to the examples.

Hereinafter, examples of therapeutic agents for oral allergic dermatitis and health foods of the present invention will be described.

[Example 1]

For 50 mL of corn oil, 0.03 g of calendula yellow was suspended, and the mixture was stirred at 60 ° C under a nitrogen atmosphere to be dissolved, and then cooled to room temperature to obtain 50 mL of red marigold yellow/corn oil as a therapeutic agent for dermatitis.

[Embodiment 2]

For 50 mL of corn oil, 0.03 g of marigold was suspended, and the mixture was stirred at 60 ° C under a nitrogen atmosphere to be dissolved, and then cooled to room temperature to obtain 50 mL of red marigold/corn oil as a therapeutic agent for dermatitis.

[Example 3]

For corn oil 50mL, 0.03g of α-cryptoxanthin was suspended, and it was stirred at 60 ° C under nitrogen atmosphere to dissolve and then cooled to room temperature to obtain red α-cryptoxanthin/corn oil as a therapeutic agent for dermatitis. 50mL.

[Example 4]

For corn oil 50mL, suspend 0.03g of β-cryptoxanthin, stir under nitrogen atmosphere at 60 ° C to dissolve and then cool to room temperature, and obtain red β-cryptoxanthin/corn oil as a therapeutic agent for dermatitis. 50mL.

[Example 5]

For 50 mL of corn oil, 0.03 g of lutein was suspended, and the mixture was stirred at 60 ° C under a nitrogen atmosphere to be dissolved, and then cooled to room temperature to obtain 50 mL of red lutein/corn oil as a therapeutic agent for dermatitis.

[Embodiment 6]

For 50 mL of corn oil, 0.03 g of hydroxycelerone was suspended, and the mixture was stirred at 60 ° C under a nitrogen atmosphere to be dissolved, and then cooled to room temperature to obtain 50 mL of red hydroxycapine/corn oil as a therapeutic agent for dermatitis.

[Embodiment 7]

50 mL of olive oil was suspended, and 0.15 g of marigold was suspended in a nitrogen atmosphere, and the mixture was stirred at 60 ° C to be dissolved, and then cooled to room temperature to obtain 50 mL of red olive oil containing marigold as a therapeutic agent for dermatitis.

[Embodiment 8]

50 mL of canola oil was suspended, and 0.15 g of marigold was suspended in a nitrogen atmosphere, and the mixture was stirred at 60 ° C to be dissolved, and then cooled to room temperature to obtain 50 mL of canola flower containing marigold yellow as a healthy food.

[Embodiment 9]

50 mL of squalene was suspended, and 0.15 g of marigold was suspended in a nitrogen atmosphere, and the mixture was stirred at 60 ° C to be dissolved, and then cooled to room temperature to obtain 50 mL of squalene containing marigold yellow as a healthy food.

[Embodiment 10]

Calcium lactate 175mg, calcium glycerate phosphate 175mg, sodium bicarbonate 250mg, aspartate calcium 0.5mg, colloidal cerium oxide 12mg, corn starch 15mg, dextrose 10mg, maltodextrin 3mg, mannitol 6mg, pre 3 mg of gelatinized starch and 6 mg of calendula yellow were thoroughly mixed, and then ingot was obtained to obtain a 10 mg lozenge as a lozenge for health food.

[Example 11]

Calcium lactate 175mg, calcium glycerate phosphate 175mg, sodium bicarbonate 250mg, aspartate calcium 0.5mg, colloidal cerium oxide 12mg, corn starch 15mg, dextrose 10mg, maltodextrin 3mg, mannitol 6mg, pre 3 mg of gelatinized starch and 6 mg of zeaxanthin were thoroughly mixed and then ingot, and 10 mg of a tablet was obtained as a lozenge for health food.

[Embodiment 12]

175mg of calcium lactate, 175mg of calcium glycerate phosphate, 250mg of sodium bicarbonate, aspartic Calcium amide 0.5mg, colloidal cerium oxide 12mg, corn starch 15mg, dextrose 10mg, maltodextrin 3mg, mannitol 6mg, pregelatinized starch 3mg, β-cryptoxanthin 6mg completely mixed, then ingot, A 10 mg lozenge was obtained as a lozenge for health foods.

[Test example] <Method for Separation of Lutein Compounds in Paracoccus> (1) Production of concentrated dry solids from paracoccus

The lutein compound is cultured according to the prescribed method to produce bacteria. 100 g of the bacterial cells which removed a certain degree of the supernatant from the cultured culture by centrifugation were used in the extraction step. 500 mL of acetone was added to 100 g of the cells, and the mixture was allowed to stand at room temperature for 6 hours, and then separated into an extract (i) and a fungus (i). Another 500 mL of acetone was added to the cells (i), and the mixture was allowed to stand at room temperature for 6 hours, and then separated into an extract (ii) and a fungus (ii). Further, the same operation was carried out on the cells (ii) to obtain an extract (iii) and a fungus (iii). The extracts (i) to (iii) were mixed to obtain a total extract of about 1.5 L. After the whole extract obtained was concentrated in an evaporator until water and oil were separated, 100 mL of a hexane/chloroform 1:1 solution was added, and the mixture was separated into an organic solvent layer and an aqueous layer by a liquid separation operation. The organic solvent layer was concentrated by an evaporator at 40 ° C or lower to obtain a concentrated dry solid. When concentrating with an evaporator, if water remains, a small amount of ethanol may be added and azeotropically removed at 50 °C.

(2) Production of concentrated dry solids from dried cocci

In the same manner as in the above (1), only the medium components were removed from the cultured culture, and the cells were dried to obtain dried cells. To the obtained dried cells, water having a degree of wetting of the cells was added, and used for the extraction step (100 g). 500 mL of acetone was added, and the mixture was allowed to stand at room temperature for 6 hours, and then separated into an extract (iv) and a cell (iv). The bacterial cell (iv) was further added with 500 mL of acetone, and allowed to stand at room temperature for 6 hours, and then separated into an extract (v) and a bacterial cell (v). The extracts (iv) to (v) were mixed to obtain a whole extract. From the whole extract by the same as (1) above In this way, a concentrated dry solid product is obtained.

(3) Separation of lutein compounds from concentrated dry solids

The concentrated dry product was prepared by dissolving in tetrahydrofuran according to a prescribed method (JP2009-019935), and then preparing a lutein compound using a high-speed liquid chromatography apparatus (HPLC).

The column is used by connecting two Wakosil-II 5 SIL-100 (manufactured by Wako Pure Chemical Industries, Ltd.). The mobile phase was mixed with n-hexane:tetrahydrofuran:methanol (40:20:1) at a constant temperature around room temperature at 4 mL per minute.

The peak position of the lutein compound is confirmed in advance, and if necessary, peak separation is performed to prepare a lutein compound. The prepared lutein compounds can be separately prepared by HPLC under the same conditions.

The confirmation of the fine system was carried out by ¹ H-NMR and ¹³ C-NMR to obtain a purified lutein compound.

<Test Example 1> Test for the anti-atopic dermatitis effect of marigold in the NC mice

As a non-clinical test for the anti-dermatitis effect of Astragalus membranaceus (ADX), especially for the anti-atopic dermatitis effect, for NC mice suffering from atopic dermatitis, oral administration was carried out on the 28th. Calendula yellow, during which the changes in the lesions and side effects (weight loss) were studied by the examination described later.

(method) (1) Dosing solution (test substance)

Corn oil was added to the scutellaria baicalensis (ADX) powder, suspended, and three kinds of administration solutions each having a concentration of 0.0002 mg/mL, 0.02 mg/mL, and 0.2 mg/mL were prepared. Corn oil without hamster yellow was used as a negative control.

(2) Test system

Eight weeks old females were used in the experiment: 70 NC mice (NC/Nga Tnd Crlj system), Biostir was administered to NC mice as a dust mite antigen for atopic dermatitis. ) (registered trademark) AD (manufactured by Biosta). For these mice, based on the body weight, dermatitis score and total IgE amount measured before administration of the test substance, 32 were selected, and the average body weight and dermatitis scores of each group were determined by a completely random selection method. Divide into 4 groups as equally as possible. NC mice (no treatment mice) with unaffected atopic dermatitis were also administered as a completely negative control area. In the untreated mice, 10 were selected based on the body weight measured before the start of the test substance administration, and the average of each group was equally divided into 2 groups by using a completely random selection method of the computer.

(3) Group composition and investment

The amount of the substance to be administered, the concentration thereof, and the amount of the administration liquid per one day (one time) are shown in Table 6. The administration was carried out using a disposable syringe and a feeding needle (sonde) for 28 days (the first day from the start of the test substance administration).

(4) Inspection items

Body weight measurement: Body weight was measured once a week during the test.

Observation of lesions: before the administration of Biostata AD, Biosta AD was given 8th Before the test of the substance to be tested (the 15th day of the Biostita AD administration), the skin of the test substance was observed on the 8th, 15th, 22nd and 29th day. The observations were performed on the ear shell, the head, and the back of the neck, and the degree of symptoms was integrated with a slight 1 point, a moderate 2 points, and a severe 3 points, and the total points were evaluated. In addition, photo photography is performed while observing skin lesions.

Determination of the total amount of IgE in the blood: before the administration of Biostata AD, before the administration of the substance to be tested (the 16th day of the administration of Biostata AD) and the 15th day of the administration of the substance to be tested, via the anesthesia without anesthesia Blood was collected from the tail vein of the mouse. On the 29th day of the test substance administration, blood was collected from the abdominal aorta under anesthesia with haloane. The blood taken was centrifuged at 1,000 × g for 15 minutes at room temperature, and plasma was taken. For the total amount of IgE, a capture antibody: anti-mouse IgE antibody (rat monoclonal ab99571, manufactured by Abcam) was used, and antibody was detected: biotin-labeled anti-mouse IgE antibody (rat) Single plant ab11580, manufactured by Apkham Co., Ltd., was carried out by ELISA. Moreover, since IgE is added when an allergic reaction is caused, IgE (immunoglobulin) in blood becomes an indicator of whether or not an allergic reaction is caused.

Tissue weight measurement and tissue preservation: The spleen and lymph nodes were removed after blood collection under hail ethane anesthesia, and the weight was measured and fixed with 10% neutral buffered formalin. Thereafter, the skin of the neck and back was taken out, fixed with 10% neutral buffered formalin or frozen sections, embedded in a frozen tissue embedding agent (OCT compound), and then frozen and stored.

(5) Statistical methods

The measured values are expressed as mean ± standard error. The statistical analysis uses Excel 2003 and Excel 2004 (Microsoft (share) company), StatLight (registered trademark) (Yugus (share) company), the significant level is less than 5%.

(result) (1) skin lesion score

The average value and standard deviation of the skin lesion scores of each experimental group are shown in Table 7.

As shown in Table 7, the 0.2 mg/mL marigold yellow pigment administration group was compared with the control group at the initial stage to confirm that the amount of skin lesion score of the dose dependency was lowered.

(2) IgE

The IgE value in the blood after the 15th day of the administration and the end of the administration period in each group is shown in Table 8 as the relative value of the pre-administration value as 100. In Table 8, "carotenoid X" means marigold yellow.

In Table 8, on the 15th day of administration, compared with the control group, it was confirmed that all the marigolds were significantly changed in the blood concentration of IgE. On the 29th day after the end of the administration period, the difference was observed between the 0.2 mg/mL area of the marigold yellow flower and the control area. It was thus found that calendula yellow has an inhibitory effect on allergic reactions.

Further, regarding the no-treatment area, IgE was hardly observed because of atopic dermatitis.

(3) weight

The body weight was determined to determine the side effects of the test substance. The measurement results are shown in Table 9. Further, the results of weight loss from the start of the test are shown in Table 10.

From Tables 9 and 10, compared with the control area (corn oil administration area), the side effects of weight loss were not confirmed in the marigold administration area.

From the above results, it was confirmed that the administration of calendula yellow was effective in inhibiting or improving the symptoms of atopic dermatitis in NC mice. Under the conditions of the examples, the effect on skin lesion scores was observed in the initial stage of the concentration of 0.5 mg/mL of calendula yellow. In addition, since the concentration of IgE in the body is also lowered, it is confirmed that the effect of calendula yellow is inhibited by inflammation. The side effects of steroid reduction which is generally known as an anti-inflammatory drug have not occurred in the marigold administration area. Think of it A lutein compound having an anti- dermatological action such as a yellow flower can be utilized as a therapeutic agent for anti-dermatitis, particularly an anti-atopic dermatitis drug.

<Test Example 2> Skin histopathological examination using NC mice

Test Example 2 was carried out by using Hematoxylin-Eosin staining (HE staining) on the skin tissue of the control group (corn oil administration group) and the calendula yellow (ADX) administration group which were taken in Test Example 1. , Giemsa (Gimsa) staining, pathological examination of various immunostaining, the purpose of which is to review the anti-dermatitis effect of calendula yellow in histopathology based on the results.

In the present embodiment, the following items were studied. Each item will be detailed later.

. Take the neck and back skin to make frozen slices: 3 pieces × 16 pieces

(a) CD4 immunohistochemistry: calculation of CD4-positive helper T cells

(b) IgE immunohistochemistry: calculation of IgE positive cells

(c) F4/80 immunohistochemistry: calculation of F4/80 positive macrophages

. Making paraffin sections: 2 pieces × 16 pieces

(d) HE staining: pathological observation and evaluation

(e) Giemsa staining: calculating plump cells

(method) A. Hematoxylin-Eosin (H.E.) staining, Giemsa staining

(1) Subject skin tissue: The neck and back skin of NC mice to be taken in Test Example 1 was fixed with 10% neutral buffered formalin for histopathological examination. Specifically, in order to fix one half of the skin of the neck and back with 10% neutral buffered formalin, it was embedded in paraffin according to a usual method, and two pieces of paraffin sections having a thickness of about 3 μm were prepared. Paraffin sections were subjected to H.E. staining or Giemsa staining. Table 11 shows the group composition.

(2) Making specimens

The skin of the neck and back was cut out according to the usual method, embedded in paraffin, thinly cut, and stained with hematoxylin-eosin (H.E.) or Giemsa stain to prepare pathological tissue specimens.

(3) Observation project

Histopathological diagnosis was performed on H.E. stained specimens. The plump cells per 1 field of view (magnification: x 400) were measured for Giemsa stained specimens.

(4) Statistical analysis

A statistically significant difference between the control group (corn oil) and the marigold (ADX) group was determined, with significant levels set at 5% and 1%. All histopathological findings were statistically resolved by Wilcoxon assay (both sides) due to a certain degree of lesion.

B. Immunostaining (1) Subject skin tissue

The neck and back skin of NC mice taken in Test Example 1 was subjected to histopathological examination. Table 12 shows the group composition.

(2) Making specimens

One half of the central part of the skin of the neck and back was embedded in a frozen tissue embedding agent and then frozen and stored to prepare a frozen section having a thickness of about 6 μm. Freeze slice system for use

anti-CD4 (rat individual strain (GK1.5), sc-13573, Santa Cruz Biotechnology inc., ×200 dilution), anti-F4/80 (rat individual strain (3H21113), sc-71088, Santa Cruz Biotechnology Inc., x200 dilution) or immunohistochemical staining of mouse IgE antibody (FITC complex, A90-115F, Bethyl Laboratories Inc., x 2000 dilution). Specifically, anti-CD4 and anti-F4/80 were carried out by the ABC method (VECTASTAIN ABC Kit Elite, Code No. PK-6104, Vector Laboratories, Inc.), and the anti-IgE was carried out by a direct method.

(3) Observation project

For immunostained specimens, the number of positive cells that strongly expanded the 5-field was measured.

(4) Statistical analysis

For the number of positive cells in the immunostained specimen, in order to control the group and the ADX group 2 The Student t test was performed by confirming the dispersion to be uniform according to the F test. Significant levels were set at 5% and 1%.

(result) A. H.E. staining and Giemsa staining (1) Pathological observation

The results are shown in Table 13. In the corn oil (control) area, ADX-1 area and ADX-2 area, it was confirmed that the epidermis formed suede, hyperkeratosis, granular layer hypertrophy or epidermal hypertrophy, and cell infiltration and papilloma in the dermis and deep layers were confirmed. And phagocytic cells. Therefore, in these groups, it was confirmed that the contact with the genital dermatitis and its accompanying epidermal dysfunction caused by the chronic squatting action and the dermal papilloma of the dermis were confirmed. In the ADX groups, the frequency/degree of occurrence of these symptoms was reduced compared with the control group, but statistically no significant was observed.

As a result of HE staining, in the animal models of atopic dermatitis, the lesions (ulcer, epidermal hyperplasia, hyperkeratosis, inflammatory cell infiltration, and hair follicle atrophy) were generally confirmed, and the ADX group was confirmed to be improved compared with the control group. effect.

B. Immunostaining (1) Measuring immunostaining positive cells

When the corn oil of the control group (A-1) was set to 100, the relative values of the measurement results are shown in Table 15. Compared with the control group, the ADX (carotenoid X) group had no significant change in the number of CD4 positive cells, the number of F4/80 positive cells, and the number of IgE positive cells, and was low.

By comparing the immunostaining by HE staining and Giemsa staining with the control group, the ADX group confirmed the corresponding concentration, and its epidermal changes (smear formation, ulcer formation, hyperkeratosis, granular layer hypertrophy, epidermal hypertrophy) and dermal cell infiltration A tendency to reduce was observed.

From the results of immunostaining, it is considered that the concentration of the scutellaria, the epidermis formation, the ulcer formation, the hyperkeratosis, the granular layer hypertrophy, and the echinocytosis are reduced.

Based on the above results, it was confirmed by histopathological examination of the skin tissue that the calendula yellow was inhibited by oral administration and had an inhibitory effect on the atopic dermatitis symptoms of NC mice.

Claims (9)

A therapeutic agent for oral allergic dermatitis, which comprises a xanthophyll compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof [In the formula (1), W represents a group represented by any one of the following formulae (2) to (4), and X represents a group represented by any one of the following formulae (5) to (8). Or W combined with W and X represents a group represented by the following formula (9), Y represents a group represented by any one of the following formulas (10) to (12), and Z represents a formula (13) below YZ represented by any one of (21) or YZ combined with Y and Z represents a base represented by any one of the following general formulae (22) to (24) -CH=CH- (5) -CH ₂ -CH ₂ - (8) -CH=CH- (10) -CH ₂ -CH ₂ - (12) (here, in the general formulae (2) to (4) and (9), R ¹ and R ² are each independently the same or different, and represent a hydrogen atom; a C _1-20 alkyl group which may have a substituent a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; a C _3-22 cycloalkyl group which may have a substituent; a C _6-18 aryl group which may have a substituent; 5 to 20 membered heteroaryl groups which may have a substituent; 3 to 20 members of a non-aromatic heterocyclic group which may have a substituent; a glycosyl group which may have a substituent; a fluorenyl group which may have a substituent; -COR ³ ; -COOR ⁴ ; -CONR ⁵ R ⁶ ; -PO(OR ⁷ )(OR ⁸ ); or -SO ₂ R ⁹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁹ are each independently the same or Different, representing a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; C _{3 - which} may have a substituent _a cycloalkyl group; a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; or a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent, R ⁷ and R ⁸ each independently may be the same or different, represent a hydrogen atom; may have a substituent group of C _1-20 alkyl; may have Substituent of the C _2-20 alkenyl group; the group may have a substituent C _2-20 alkynyl; may have a C _3-22 cycloalkyl group substituted with the group; an optionally substituted aryl group of C _6-18; may have a substituent a 5 to 20 membered heteroaryl group; a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent; or a fluorenyl group which may have a substituent, in the formulae (13) to (15), R ¹⁰ , R ¹¹ and R ¹² are each independently the same or different and represent a hydrogen atom or -OQ ¹ , Q ¹ represents a hydrogen atom; a C _1-20 alkyl group which may have a substituent; and a C _2-20 alkenyl group which may have a substituent a C _2-20 alkynyl group which may have a substituent; a C _3-22 cycloalkyl group which may have a substituent; a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent a non-aromatic heterocyclic group which may have a substituent of 3 to 20 members; a saccharide group which may have a substituent; an fluorenyl group which may have a substituent; -COR ¹⁶ ; -COOR ¹⁷ ; -CONR ¹⁸ R ¹⁹ ;-PO ( OR ²⁰ )(OR ²¹ ); or -SO ₂ R ²² , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²² are each independently the same or different and represent a hydrogen atom; C _{1-20 which} may have a substituent alkyl; C _2-20 alkenyl group may have a substituent group of; may have a substituent group of C _2-20 alkynyl ; Cycloalkyl group may have a substituent group of _3-22 C; may have a substituent group of C _6-18 aryl group; a heteroaryl having a 5-20 aryl group substituents; or may have 3-20 substituents of non- The aromatic heterocyclic group, R ²⁰ and R ²¹ are each independently the same or different and represent a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; may have a substitution a C _2-20 alkynyl group; a C _3-22 cycloalkyl group which may have a substituent; a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; may have a substitution a 3 to 20 membered non-aromatic heterocyclic group; or a fluorenyl group which may have a substituent, and in the formulae (16), (18), (21) and (22), R ¹³ , R ¹⁴ and R ¹⁵ each independently, which may be the same or different, represents a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; a C _3-22 cycloalkyl group having a substituent; a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; 3 to 20 members of a non-aromatic impurity which may have a substituent a cyclyl group; a saccharide group which may have a substituent; ^{; -COR 23; -COOR 24; -CONR} 25 R 26; -PO (OR 27) (OR 28); or ^{_{-SO 2 R 29, R 23,}} R 24, R 25, R 26 and R ²⁹ are each independently, The same or different, representing a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; may have a substituent a C _3-22 cycloalkyl group; a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; or a 3 to 20 member non-aromatic heterocyclic group which may have a substituent, R ²⁷ and R ²⁸ are each independently the same or different and represent a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; and a C _{2-20 which} may have a substituent Alkynyl; C _3-22 cycloalkyl group which may have a substituent; C _6-18 aryl group which may have a substituent; 5 to 20 membered heteroaryl group which may have a substituent; 3 to 20 members which may have a substituent a non-aromatic heterocyclic group; or a fluorenyl group which may have a substituent)]. The therapeutic agent according to claim 1, wherein the W is represented by the formula (2) or (3). The therapeutic agent according to claim 2, wherein X is represented by the formula (5), Y is represented by the formula (10), and Z is a formula (13), (14) and (15) Any one of them is represented. The therapeutic agent according to claim 2, wherein the therapeutic agent is in the formula (2) or (3), and R ¹ represents a hydrogen atom. The therapeutic agent according to any one of claims 1 to 4, wherein the lutein compound is at least one selected from the group consisting of zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, A group of hydroxycapineketone, marigold, lutein, and such pharmaceutically acceptable salts. The therapeutic agent according to any one of claims 1 to 5, wherein the allergic dermatitis is atopic dermatitis. The therapeutic agent according to any one of claims 1 to 6, wherein the dermatitis is caused by IgE. A functional food comprising a lutein compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof [In the general formula (1), W represents a group represented by any one of the following general formulae (2) to (4), and each of X represents any one of the following general formulae (5) to (8). The group W or W combined with X represents a group represented by the following formula (9), and Y represents a group represented by any one of the following formulas (10) to (12), and each of Z represents the following formula (13). YZ represented by any one of (21) or YZ combined with Y and Z represents a base represented by any one of the following general formulae (22) to (24), -CH=CH- (5) -CH ₂ -CH ₂ - (8) -CH=CH- (10) -CH ₂ -CH ₂ - (12) (here, in the general formulae (2) to (4) and (9), R ¹ and R ² are each independently the same or different, and represent a hydrogen atom; a C _1-20 alkyl group which may have a substituent a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; a C _3-22 cycloalkyl group which may have a substituent; a C _6-18 aryl group which may have a substituent; 5 to 20 membered heteroaryl groups which may have a substituent; 3 to 20 membered non-aromatic heterocyclic groups which may have a substituent; a saccharide group which may have a substituent; an fluorenyl group which may have a substituent; -COR ³ ;- COOR ⁴ ; -CONR ⁵ R ⁶ ; -PO(OR ⁷ )(OR ⁸ ); or -SO ₂ R ⁹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁹ are each independently the same or different, a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; a C _3-22 naphthene which may have a substituent a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; or a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent, and each of R ⁷ and R ⁸ Independent, identical or different, representing a hydrogen atom; a C _1-20 alkyl group which may have a substituent; may have a substituent C _2-20 alkenyl; C _2-20 alkynyl group which may have a substituent; C _3-22 cycloalkyl group which may have a substituent; C _6-18 aryl group which may have a substituent; 5 which may have a substituent a 20-membered heteroaryl group; a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent; or a fluorenyl group which may have a substituent, in the formulae (13) to (15), R ¹⁰ and R ¹¹ and R ¹² each independently, may be the same or different, and represents a hydrogen atom or -OQ ¹ , Q ¹ represents a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group of a substituent; a C _3-22 cycloalkyl group which may have a substituent; a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; a 3 to 20 membered non-aromatic heterocyclic group of a substituent; a saccharide group which may have a substituent; an fluorenyl group which may have a substituent; -COR ¹⁶ ; -COOR ¹⁷ ; -CONR ¹⁸ R ¹⁹ ; -PO(OR ²⁰ ) (OR ²¹ ); or -SO ₂ R ²² , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²² are each independently the same or different and represent a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; a C _3-22 cycloalkyl group having a substituent; a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; or a 3 to 20 member non-aromatic group which may have a substituent The heterocyclic group, R ²⁰ and R ²¹ are each independently the same or different and represent a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; may have a substituent a C _2-20 alkynyl group; a C _3-22 cycloalkyl group which may have a substituent; a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; may have a substituent 3 to 20 members of a non-aromatic heterocyclic group; or a thiol group which may have a substituent, and in the formulae (16), (18), (21) and (22), R ¹³ , R ¹⁴ and R ¹⁵ are each independently , which may be the same or different, represent a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; may have a substituent a C _3-22 cycloalkyl group; a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; a 3 to 20 member non-aromatic heterocyclic group which may have a substituent; a glycosyl group which may have a substituent; an indenyl group which may have a substituent; -COR ²³ ;- COOR ²⁴ ; -CONR ²⁵ R ²⁶ ; -PO(OR ²⁷ )(OR ²⁸ ); or -SO ₂ R ²⁹ , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ and R ²⁹ are each independently the same or different, a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; a C _3-22 naphthene which may have a substituent a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; or a 3 to 20 membered non-aromatic heterocyclic group which may have a substituent, and each of R ²⁷ and R ²⁸ Independent, identical or different, represents a hydrogen atom; a C _1-20 alkyl group which may have a substituent; a C _2-20 alkenyl group which may have a substituent; a C _2-20 alkynyl group which may have a substituent; may have a substitution a C _3-22 cycloalkyl group; a C _6-18 aryl group which may have a substituent; a 5 to 20 membered heteroaryl group which may have a substituent; and a 3 to 20 member non-aromatic heterocyclic group which may have a substituent Or may have a substituent thiol)]. The functional food according to claim 8, wherein the lutein compound is at least one selected from the group consisting of zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, hydroxycapine, and marigold And lutein and these pharmaceutically acceptable salts Grouped into groups.