Composition, pharmaceutical product, food product, and cosmetic product

Abstract

A composition containing a cis-xanthophyll derivative.

Description

TITLE OF INVENTION: COMPOSITION, PHARMACEUTICAL PRODUCT, FOOD PRODUCT, AND COSMETIC PRODUCT TECHNICAL FIELD

[0001] The present invention relates to a composition, a pharmaceutical product, a food product, and a cosmetic product. Priority is claimed on Japanese Patent Application No. 2024-033410, filed March 5, 2024, the content of which is incorporated herein by reference. BACKGROUND ART

[0002] Xanthophylls that occur widely in nature have a strong antioxidant effect and a variety of excellent effects and are thus in use in a wide range of applications such as health food products, cosmetic products, and food coloring. Xanthophylls refer to one class of carotenoids, and a lot of compounds, for example, lutein, zeaxanthin, P-cryptoxanthin, a-cryptoxanthin, capsanthin, capsorubin, and astaxanthin are known.

[0003] Xanthophylls have a structure including a polyene portion composed of conjugated double bonds in which a plurality of carbons continues, end groups having both ends thereof modified, and oxygen atoms such as an alcohol, a ketone, an epoxy, and a carboxylic acid in the molecule. Generally, xanthophylls occur in nature mainly in a trans form in which all double bonds are trans isomers. Recently, it has become clear that cis-xanthophylls are more favorable than trans-xanthophylls in terms of not only absorption or accumulation in bodies but also bioactive effects (an antioxidant effect, eye strain, an anti-cancer effect, an anti-obesity effect, a skin quality improvement effect, and the like), and the intake thereof has been attracting attention.

[0004] For example, Patent Document 1 describes an invention relating to a functional food product having an effect of relieving eye strain or the like such as cis-astaxanthin.

[0005] In addition, Patent Document 2 discloses a method for storing a cis-carotenoid in which a cis-carotenoid is stored in the presence of an antioxidant, an organic acid salt, or a vegetable oil or shark liver oil. Citation List Patent Document

[0006] Patent Document 1: PCT International Publication No. WO 2022 / 91995 Patent Document 2: Japanese Unexamined Patent Application, First Publication No. 2022-80682 SUMMARY OF INVENTION Technical Problem

[0007] In nature, some xanthophylls occur as cis-isomers, and the cis-isomer fraction is constant and stable in vivo; however, once extracted, cis-xanthophylls readily change and are unstable. That is, in the process of industrialization, cis-xanthophylls easily isomerize to trans-xanthophylls due to the influence of heat or the like during extraction or storage, and particularly, in a case where cis-xanthophylls and trans-xanthophylls coexist at room temperature or low temperatures that are preferable for distribution, since isomerization to trans-xanthophylls and decomposition significantly progress, it is difficult to stably maintain and store cis-xanthophylls three-dimensionally.

[0008] In conventional methods for storing a cis-carotenoid as in Patent Document 2, it cannot be said that stability is sufficient, and there is a desire for a composition enabling more stable and efficient intake of cis-xanthophylls.

[0009] The present invention has been made in view of the above-described circumstances, and an object of the present invention is to provide a composition containing a cis-xanthophyll derivative that does not easily allow isomerization to a trans-xanthophyll, has excellent storage stability, and enables the efficient intake of a cisxanthophyll. Solution to Problem

[0010] As a result of intensive studies on the above-described object, the present inventors found that in a case where a cis-xanthophyll has been turned into a cisxanthophyll derivative by substituting a part of the cis-xanthophyll with a different substituent, the cis-xanthophyll does not easily allow isomerization to a transxanthophyll and is stable and completed the present invention. In addition, the present inventors found that the use of a composition containing a specific cis-xanthophyll derivative enables more stable and efficient intake of cisxanthophylls. Furthermore, the present inventors found that when a specific amount of a cisxanthophyll derivative is made to coexist with a cis-xanthophyll that is unstable alone, isomerization of the cis-xanthophyll to a trans-xanthophyll is suppressed, and there is a storage stability improvement effect.

[0011] The present invention has the following aspects. [1] A composition containing: a cis-xanthophyll derivative. [2] The composition according to [1], further containing: a cis-xanthophyll, wherein a molar weight ratio between the cis-xanthophyll and the cis-xanthophyll derivative is 0.05 to 1000. [3] The composition according to [1] or [2], wherein the cis-xanthophyll derivative contains one or more cis-xanthophyll derivatives selected from the group consisting of a lipid ester of a cis-xanthophyll, a glycoside of a cis-xanthophyll, a fatty acid glycoside of a cis-xanthophyll, an aliphatic ether of a cis-xanthophyll, and a sulfate ester of a cis-xanthophyll. [4] The composition according to any one of [1] to [3], wherein the cisxanthophyll derivative contains a lipid ester of a cis-xanthophyll. [5] The composition according to any one of [1] to [4], wherein the cisxanthophyll derivative contains a lipid ester of a cis-xanthophyll and one or more fatty acids selected from the group consisting of palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, a-linolenic acid, y-linolenic acid, eicosapentaenoic acid, arachidonic acid, and docosahexaenoic acid. [6] The composition according to any one of [1] to [5], wherein the cisxanthophyll derivative contains one or more cis-xanthophyll derivatives selected from the group consisting of a cis-lutein derivative, a cis-zeaxanthin derivative, and a cisastaxanthin derivative. [7] The composition according to any one of [1] to [5], wherein the cis- xanthophyll derivative contains a cis-lutein derivative. [8] The composition according to any one of [1] to [5], wherein the cisxanthophyll derivative contains a cis-zeaxanthin derivative. [9] The composition according to any one of [1] to [5], wherein the cisxanthophyll derivative contains a cis-astaxanthin derivative.

[10] A pharmaceutical product containing: the composition according to any one of [1] to [9].

[11] A food product containing: the composition according to any one of [1] to [9].

[12] A cosmetic product containing: the composition according to any one of [1] to [9]. Advantageous Effects of Invention

[0012] According to the present invention, it is possible to provide a composition containing a cis-xanthophyll derivative that does not easily allow isomerization to a trans-xanthophyll, has excellent storage stability, and enables the efficient intake of a cisxanthophyll. BRIEF DESCRIPTION OF DRAWINGS

[0013] [FIG. 1] Chromatograms of M extracts. [FIG. 2] Chromatograms of M controls. [FIG. 3] Chromatograms of M extracts and M controls. [FIG. 4] Chromatograms of orange bell pepper extracts. [FIG. 5] Chromatograms of red bell pepper extracts. [FIG. 6] Chromatograms of persimmon extracts. [FIG. 7] Chromatograms of saffron extracts. DESCRIPTION OF EMBODIMENTS

[0014] Composition A composition of the present embodiment contains a cis-xanthophyll derivative.

[0015] Cis-Xanthophyll Derivative The cis-xanthophyll derivative is a compound obtained by substituting a part of a cis-xanthophyll with a different atom or substituent.

[0016] Examples of a xanthophyll in the cis-xanthophyll derivative include lutein, zeaxanthin, nostoxanthin, caloxanthin, P-cryptoxanthin, a-cryptoxanthin, zeinoxanthin, astaxanthin, adonixanthin, adonirubin, 3-hydroxyechinenone, 3’-hydroxyechinenone, capsanthin, capsorubin, cucurbitaxanthin A, violaxanthin, antheraxanthin, neoxanthin, fucoxanthin, fucoxanthinol, amarouciaxanthin A, diadinoxanthin, diazinoxanthin, rubixanthin, flavoxanthin, peridinin, siphonaxanthin, myxol, 4-ketomyxol, and apocarotenoids thereof such as P-apo-8’-carotenol, P-apo-8’-carotenic acid, paracentrone, abscisic acid, zaxinone, crocetin, crocin, bixin, retinol, and retinoic acid. Among these, lutein, zeaxanthin, or astaxanthin is preferable. That is, the composition of the present embodiment preferably contains one or more cis-xanthophyll derivatives selected from the group consisting of a cis-lutein derivative, a cis-zeaxanthin derivative, and a cisastaxanthin derivative.

[0017] The cis-lutein derivative is composed of a polyene chain composed of 10 conjugated double bonds and end groups (terminal groups) attached to both ends thereof. In the present specification, isomers including at least one cis-conjugated double bond among the 10 conjugated double bonds in the polyene chain will be referred to as cis-lutein, and isomers in which all of the 10 conjugated double bonds are transconjugated double bonds will be referred to as trans-lutein.

[0018] The cis-zeaxanthin derivative is composed of a polyene chain composed of 11 conjugated double bonds and end groups (terminal groups) attached to both ends thereof. In the present specification, isomers including at least one cis-conjugated double bond among the 11 conjugated double bonds in the polyene chain will be referred to as cis-zeaxanthins, and isomers in which all of the 11 conjugated double bonds are transconjugated double bonds will be referred to as trans-zeaxanthins.

[0019] The cis-astaxanthin derivative is composed of a conjugated system including a polyene chain composed of 11 conjugated double bonds and end groups (terminal groups) containing keto groups attached to both ends thereof. In the present specification, isomers including at least one cis-conjugated double bond among the 11 conjugated double bonds in the carbon polyene chain will be referred to as cis-astaxanthins, and isomers in which all of the 11 conjugated double bonds are trans-conjugated double bonds will be referred to as trans-astaxanthins.

[0020] cis-Xanthophylls can be produced by isomerizing trans-xanthophylls by methods publicly known through documents, and can be produced by, for example, a method described in Patent Document 3 or Document 1 (Japan Journal of Food Engineering, Vol. 21, No. 1, pp. 1 to 10, Mar. 2020). Specific examples thereof include a method in which a trans-xanthophyll is dissolved in an organic solvent (dichloromethane, chloroform, acetone, ethyl acetate, or the like), a vegetable oil (sesame oil, mustard oil, or the like), supercritical carbon dioxide, or the like and thermally treated, a method in which cis-isomerization catalysts such as isothiocyanates, polysulfides, and iodine are used, and the like.

[0021] Specific examples of the cis-xanthophyll derivative include a lipid ester of a cisxanthophyll, a glycoside of a cis-xanthophyll, a fatty acid glycoside of a cis-xanthophyll, an aliphatic ether of a cis-xanthophyll, a sulfate ester of a cis-xanthophyll, and the like.

[0022] • Lipid Ester of cis-Xanthophyll Examples of a lipid (fatty acid) in the lipid ester of a cis-xanthophyll include acetic acid, propionic acid, butyric acid, crotonic acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, myristoleic acid, pentadecylic acid, palmitic acid, sapienic acid, palmitoleic acid, margaric acid, pinolenic acid, stearic acid, sebaleic acid, oleic acid, linoleic acid, eleostearic acid, a-linolenic acid, y-linolenic acid, stearidonic acid, calendic acid, vaccenic acid, paullinic acid, elaidic acid, gadoleic acid, eicosenoic acid, arachidic acid, meadic acid, dihomo-y-linolenic acid, eicosatrienoic acid, eicosapentaenoic acid, arachidonic acid, behenic acid, erucic acid, docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, lignoceric acid, nervonic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, cerotic acid, montanic acid, melissic acid, and the like, preferable examples thereof include caprylic acid, capric acid, lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, a-linolenic acid, y-linolenic acid, stearidonic acid, calendic acid, vaccenic acid, paullinic acid, elaidic acid, eicosenoic acid, arachidic acid, dihomo-y- linolenic acid, eicosatrienoic acid, eicosapentaenoic acid, arachidonic acid, behenic acid, erucic acid, elaidic acid, docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, and the like, more preferable examples thereof include caprylic acid, capric acid, lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, a-linolenic acid, y-linolenic acid, dihomo-y-linolenic acid, elaidic acid, eicosapentaenoic acid, arachidonic acid, and docosahexaenoic acid, and still more preferable examples thereof include palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, a-linolenic acid, y-linolenic acid, eicosapentaenoic acid, arachidonic acid, elaidic acid, and docosahexaenoic acid.

[0023] The lipid ester of a cis-xanthophyll may be composed of a mixture of a plurality of lipid esters. In the mixture, the molar ratio of lipids to cis-xanthophylls is preferably 0.0001 to 4, more preferably 0.001 to 4, still more preferably 0.01 to 4, and particularly preferably 0.02 to 4. For example, the molar ratio of palmitic acid, stearic acid, elaidic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, and docosahexaenoic acid to the cisxanthophylls in the lipid ester mixture of the cis-xanthophylls is preferably 0.0001 to 4, more preferably 0.001 to 4, still more preferably 0.01 to 4, and particularly preferably 0.02 to 4.

[0024] • Glycoside of cis-Xanthophyll Examples of a glycoside in the glycoside of a cis-xanthophyll include glucose, xylose, arabinose, mannose, fucose, fructose, galactose, and polysaccharides containing these, preferable examples thereof include fucose and xylose, and more preferable examples thereof include glucose. The cis-xanthophyll glycoside is a mixture of a plurality of glycosides, and the molar ratio of fucose, xylose, lactose, and glucose, which are glycosides in the total weight, to cis-xanthophylls is preferably 0.001 to 600, more preferably 0.01 to 400, still more preferably 0.01 to 100, and particularly preferably 0.01 to 10.

[0026] • Fatty Acid Glycoside of cis-Xanthophyll Examples of a fatty acid glycoside in the fatty acid glycoside of a cisxanthophyll include glucose fatty acid esters and the like. As the cis-xanthophyll fatty acid glycoside, a mixture of a plurality of fatty acid glycosides can be used.

[0027] • Aliphatic Ether of cis-Xanthophyll Examples of the aliphatic ether of a cis-xanthophyll include generally known aliphatic ethers of a cis-xanthophyll. As the aliphatic ether of a cis-xanthophyll, a mixture of a plurality of aliphatic ethers can be used.

[0028] • Sulfate Ester of cis-Xanthophyll Examples of the sulfate ester of a cis-xanthophyll include generally known sulfate esters of a cis-xanthophyll. As the sulfate ester of a cis-xanthophyll, a mixture of a plurality of sulfate esters of a cis-xanthophyll can be used.

[0029] The cis-xanthophyll derivative has a cyclic group with one hydroxy group at any one of both terminals of the polyene chain composed of the conjugated double bonds and thus has one or two hydroxyl groups in the entire molecule. Therefore, as monoisomers, di-isomers, and mixtures thereof, monoesters, diesters, and mixtures thereof; monoglycosides, diglycosides, and mixtures thereof; monolipid glycosides, dilipid glycosides, and mixtures thereof; monoaliphatic ethers, dialiphatic ethers, and mixtures thereof; sulfate monoesters, sulfate diesters, and mixtures thereof can occur. In the present invention, any one of the mono-isomers, the di-isomers, and the mixtures thereof can be used. In the case of a mixture of a mono-isomer and a di-monomer, the mixing ratio therebetween (mono-isomer:di-isomer) in the mixture to be used is within a range of preferably 1:100 to 100:1, more preferably 1:50 to 50:1, still more preferably 1:25 to 25:1, particularly preferably 1:16 to 16:1, and most preferably 1:10 to 10:1. Regarding the mono-isomers, the di-isomers, and the mixtures thereof, it is possible to confirm the abundance fractions thereof by high-performance liquid chromatography (HPLC) or thin-layer chromatography (TLC).

[0030] The cis-xanthophyll derivative can be produced by converting a transxanthophyll to a lipid ester, a glycoside, a fatty acid glycoside, an aliphatic ether, or a sulfate ester and then isomerizing the lipid ester or the like by, for example, a method described in Document 1 described above. The isomerization of the trans-xanthophyll to the cis-xanthophyll can be confirmed by HPLC. In addition, as the trans-xanthophyll, a commercially available product can be used or a chemical synthetic product, a naturally derived xanthophyll, or a mixture thereof can be used.

[0031] For example, a cis-xanthophyll lipid ester can be produced by producing a trans xanthophyll lipid ester by a reaction between a trans-xanthophyll and a lipid and isomerizing the trans-xanthophyll lipid ester by the method described in Document 1 described above. The trans-xanthophyll can be produced by a generally known synthetic method or biological raw materials such as microalgae such as Haematococcus, yeast such as Phaffia rhodozyma, crustaceans of arthropods such as shrimp, krill, crabs, or Daphnia, and extracts thereof can be used.

[0032] For example, the cis-xanthophyll glycoside can be produced by producing a trans-xanthophyll glycoside by a reaction between a trans-xanthophyll and a glycoside and isomerizing the trans-xanthophyll glycoside by the method described in Document 1 described above.

[0033] For example, the cis-xanthophyll fatty acid glycoside can be produced by producing a trans-xanthophyll fatty acid glycoside by a reaction between a transxanthophyll and a fatty acid glycoside and isomerizing the trans-xanthophyll fatty acid glycoside by the method described in Document 1 described above.

[0034] For example, the cis-xanthophyll aliphatic ether can be produced by converting a trans-xanthophyll to a trans-xanthophyll aliphatic aliphatic ether by a generally known reaction and isomerizing the trans-xanthophyll aliphatic ether by the method described in Document 1 described above.

[0035] For example, the cis-xanthophyll sulfate ester can be produced by producing a trans-xanthophyll sulfate ester by a reaction between a trans-xanthophyll and a sulfated glycoside and isomerizing the trans-xanthophyll sulfate ester by the method described in Document 1 described above.

[0036] The composition of the present embodiment may contain a trans-xanthophyll derivative, but the proportion of the cis-xanthophyll derivative in all xanthophyll derivatives of the composition of the present embodiment is preferably 30% or more, more preferably 35% or more, still more preferably 40% or more, and particularly preferably 45% or more.

[0037] Arbitrary Components The composition of the present embodiment may contain arbitrary components other than the above-described cis-xanthophyll derivative. Examples of the arbitrary components include a cis-xanthophyll, an antioxidant, additives, and the like.

[0038] Cis-Xanthophyll The cis-xanthophyll is an unesterified form in which none of the hydroxyl groups and carboxylic acids in a xanthophyll are derivatized (esterified).

[0039] When a cis-xanthophyll derivative is made to coexist with a cis-xanthophyll, which is unstable alone, isomerization of the cis-xanthophyll to a trans-xanthophyll is suppressed, and storage stability can be improved.

[0040] In the composition of the present embodiment, the amount of the cisxanthophyll derivative relative to the amount of the cis-xanthophyll (molar ratio) is preferably 0.05 to 1000, more preferably 0.1 to 100, and still more preferably 1 to 10.

[0041] The composition of the present embodiment may contain a trans-xanthophyll. In a case where the composition of the present embodiment may contain a transxanthophyll, the amount of the trans-xanthophyll relative to the amount of the cisxanthophyll (molar ratio) is preferably 0.05 to 60, more preferably 0.05 to 40, and still more preferably 0.1 to 20.

[0042] Antioxidant Examples of the antioxidant include compounds having a phenolic hydroxyl group; amine-based compounds such as phenylenediamines like diphenyl-p-phenylenediamine or 4-amino-p-diphenylamine; ascorbic acid; oil-soluble derivatives of erythorbic acid. Specifically, examples of the compounds having a phenolic hydroxyl group include a guaiac resin; nordihydroguaiaretic acid (NDGA); gallic acid esters such as propyl gallate, butyl gallate, and octyl gallate; BHT (butylated hydroxytoluene); BHA (butylated hydroxyanisole); tocopherols (vitamin E; hereafter VE) such as mixed tocopherols; tocotrienols, bisphenols, and the like. Among these, tocopherols are preferable as the antioxidant.

[0043] Additives Examples of the additives include a solvent, a solubilizing agent, a lubricant, an emulsifier, a tonicity agent, a preservative, a surfactant, a pH adjuster, a buffer, an excipient, a sweetener or a flagrance, and the like.

[0044] • Solvent Examples of the solvent include monoglycerides, diglycerides, and triglycerides, and specific examples thereof include olive oil, camellia oil, macadamia nut oil, castor oil, avocado oil, evening primrose oil, turtle oil, corn oil, mink oil, rapeseed oil, egg yolk oil, sesame oil, peach kernel oil, wheat germ oil, sasanqua oil, linseed oil, safflower oil, cottonseed oil, perilla oil, soybean oil, peanut oil, tea seed oil, kaya oil, rice bran oil, tung oil, Japanese tung oil, jojoba oil, germ oil, glyceryl trioctanoate, glyceryl triisopalmitate, salad oil, safflower oil (benibana oil), palm oil, coconut oil, peanut oil, almond oil, hazelnut oil, walnut oil, grapeseed oil, and the like.

[0045] • Lubricant Examples of the lubricant include Acacia gum powder, cocoa butter, carnauba wax, carmellose calcium, carmellose sodium, caropeptide, hydrated silicon dioxide, dried aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, light liquid paraffin, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, sesame oil, wheat starch, white beeswax, magnesium oxide, dimethylpoly siloxane, potassium sodium tartrate, sucrose fatty acid esters, glycerin fatty acid esters, silicone resins, aluminum hydroxide gel, stearyl alcohol, stearic acid, aluminum stearate, calcium stearate, polyoxyl stearate, magnesium stearate, cetanol, gelatin, talc, magnesium carbonate, precipitated calcium carbonate, corn starch, lactose, hard fat, white sugar, potato starch, hydroxypropyl cellulose, fumaric acid, sodium stearyl fumarate, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, polysorbate, beeswax, magnesium aluminometasilicate, methylcellulose, Japan wax, glyceryl monostearate, sodium lauryl sulfate, calcium sulfate, magnesium sulfate, liquid paraffin, phosphoric acid, and the like.

[0046] • Solubilizing Agent Examples of the solubilizing agent include nonionic surfactants such as polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene monostearate, and polyoxyethylene hydrogenated castor oil, polyethylene glycol, and the like.

[0047] • Emulsifier Examples of the emulsifier include sucrose fatty acid esters, polysorbates, polyglycerol fatty acid esters, lecithin, lysolecithin, and the like.

[0048] • Tonicity Agent Examples of the tonicity agent include sugars such as sorbitol, glucose, and mannitol; polyhydric alcohols such as glycerin and propylene glycol; sodium chloride, and the like.

[0049] • Preservative Examples of the preservative include quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride; parahydroxybenzoic acid esters such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate; benzyl alcohol, phenethyl alcohol, sorbic acid and salts thereof, thimerosal, chlorobutanol, sodium dehydroacetate, and the like.

[0050] • Surfactant Examples of the surfactant include sucrose fatty acid esters, propylene glycol esters, glycerin fatty acid esters, sorbitan fatty acid esters, dextrin, reduced dextrin, and the like. • pH adjuster Examples of the pH adjuster include hydrochloric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and the like.

[0052] • Buffer Examples of the buffer include phosphate buffers, tartrate buffers, amino acids, and the like.

[0053] • Excipient Examples of the excipient include lactose, white sugar, mannitol, corn starch, crystalline cellulose, and the like.

[0054] Applications The composition of the present embodiment can be used in applications such as food products, beverages, functional food products, nutritional supplements, pharmaceutical products, quasi-pharmaceutical products, cosmetic products, veterinary pharmaceutical products, pet food, and feed or fish feed.

[0055] The amount of the cis-xanthophyll derivative and the cis-xanthophyll is preferably 0.5 to 40 mass%, more preferably 1 to 30 mass%, and still more preferably 5 to 20 mass% relative to the entire product.

[0056] The composition of the present embodiment can be made into an oily form, a powdery form, an emulsion form, and other forms by blending generally known additives according to the purpose thereof. Examples

[0057] Hereinafter, the present invention will be described in more detail with examples, comparative examples, and test examples, but the present invention is not limited thereto.

[0058] 1. Cis-Isomerization of Astaxanthin Derivative (Batch Type) A fatty acid ester of trans-astaxanthin was heated and rapidly cooled by the following procedure, thereby producing a fatty acid ester of cis-astaxanthin. As a raw material, 10 mass% of a Haematococcus algae color A containing a fatty acid ester of trans-astaxanthin in terms of unesterified-form astaxanthin (hereinafter also simply referred to as “Haematococcus algae color A”) was used. The remaining 90 mass% of the Haematococcus algae color A is a neutral fat such as a triglyceride or a diglyceride. The fatty acid ester of trans-astaxanthin in the Haematococcus algae color A is composed of Haematococcus algae-derived trans-astaxanthin and a fatty acid mixture (a mixture of palmitic acid, elaidic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, and the like). As a result of an analysis, it was possible to confirm that 99.9% or more of the fatty acid ester of trans-astaxanthin was an ester. The fatty acid ester of trans-astaxanthin is a fatty acid ester of trans-astaxanthin satisfying each standard of Non Patent Document A described below.

[0059] The fraction of each fatty acid constituting the fatty acid ester of trans astaxanthin is not analyzed. Incidentally, Non-Patent Documents B and C described below disclose the fraction of each fatty acid in the fatty acid ester of trans-astaxanthin produced using the same trans-astaxanthin and fatty acids. Therefore, the fraction of each fatty acid in the present fatty acid ester of trans-astaxanthin is also assumed to be the same as the fraction of each fatty acid in the fatty acid ester of trans-astaxanthin in Non-Patent Documents B and C. The fraction of each fatty acid in the fatty acid ester of trans-astaxanthin disclosed in Non-Patent Documents B and C is as follows: palmitic acid (15% to 35%), elaidic acid (10% to 20%), oleic acid (10% to 20%), linoleic acid (15% to 35%), linolenic acid (0.1% to 10%), arachidonic acid (1% or less), and eicosapentaenoic acid (1% or less).

[0060] Non-Patent Document A: According to the Union list of novel foods (Commission Implementing Regulation (EU) 2017 / 2470). Non-Patent Document B: Ruiz-Dominguez MC, Espinosa C, Paredes A, Palma J, Jaime C, Vilchez C, Cerezal P. Determining the Potential of Haematococcus pluvialis Oleoresin as a Rich Source of Antioxidants. Molecules. 2019 Nov 11; 24(22):4073. doi: 10.3390 / molecules24224073. PMID: 31717936; PMCID: PMC6891815. Non-Patent Document C: Mahadi, R.; Vahisan, L.P.S.; Ilhamsyah, D.P.A.; Kim, S.; Kim, B.; Lee, N.; Oh, Y.-K. Enhancement of Astaxanthin and Fatty Acid Production in Haematococcus pluvialis Using Strigolactone. Appl. Sci. 2022, 12, 1791.

[0061] Two grams of the Haematococcus algae color A was weighed in a glass container with a lid having a capacity of 9 mL (NWT-18; manufactured by Maruemu Corporation), the headspace was substituted with nitrogen, and the glass container was capped. After that, the Haematococcus algae color A was heated within a range of 100°C to 200°C for five to 60 minutes using an oil bath (SOS-183D; Sansho Co., Ltd.). After a reaction, the Haematococcus algae color A was rapidly cooled with ice and made into an isomerized specimen, and the isomerization efficiency was confirmed. The results will be shown in Table 1 below.

[0062] The amounts of the astaxanthin and the isomer were analyzed by high-performance liquid chromatography (HPLC) and calculated from peak areas thereof. • Conditions of normal-phase HPLC analysis of cis-astaxanthin-containing composition Device: High-performance liquid chromatograph Prominence system (SPD- M20A, manufactured by Shimadzu Corporation) Columns: Penomenex silica gel luna (2) (length: 150 mm x two columns, inner diameter: 4.6 mm, particle size: 5 pm, manufactured by Penomenex Inc.) Mobile phase: Hexane / ethyl acetate / acetone (volume fractions = 70:20:10) Flow rate: 1.2 mL / min Detection wavelength: 470 nm Column temperature: 40°C

[0063] [Table 1] Temperature Item Time (min) 5 10 15 30 60 100°C Fraction (%) trans 66.27 63.75 62.20 59.93 58.34 total cis 33.73 36.25 37.80 40.07 41.66 Residual rate (%) 100.07 102.95 102.76 100.55 99.23 120°C Fraction (%) trans 60.62 58.02 56.92 54.47 51.53 total cis 39.38 41.98 43.08 45.53 48.47 Residual rate (%) 93.51 94.84 94.39 93.83 92.58 140°C Fraction (%) trans 59.12 55.50 50.69 48.34 46.50 total cis 40.88 44.50 49.31 51.66 53.50 Residual rate (%) 94.67 93.91 94.20 92.81 90.47 160°C Fraction (%) trans 51.44 48.87 45.13 44.87 44.38 total cis 48.56 51.13 54.87 55.13 55.62 Residual rate (%) 97.23 95.61 94.23 87.19 81.72 180°C Fraction (%) trans 45.18 42.87 42.34 42.46 42.40 total cis 54.82 57.13 57.66 57.54 57.60 Residual rate (%) 94.69 89.43 86.22 70.83 58.34 200°C Fraction (%) trans 43.70 43.31 42.80 41.53 41.58 total cis 56.30 56.69 57.20 58.47 58.42 Residual rate (%) 83.76 74.79 59.47 38.47 17.97

[0064] As shown in Table 1, the isomerization efficiencies improved in a temperaturedependent manner, but decomposition was also promoted. However, under appropriate temperature conditions, isomerization was possible 5 within a short period of time while decomposition was suppressed. For example, within a range of 30 to 60 minutes at 140°C, 10 to 30 minutes at 160°C, and 5 to 15 minutes at 180°C, it was possible to improve the fraction of the cis isomer up to 50% or more while decomposition of an astaxanthin ester was suppressed (decomposition rate: 15% or less).

[0065] 10   2. Cis-Isomerization of Astaxanthin (Continuous Type) A Haematococcus algae color A was prepared to a concentration of 2% using medium-chain triglyceride and used as a sample. The samples were passed through dryers set to 160°C, 200°C, and 240°C using tubes having an inner diameter of 0.2 cm to perform isomerization reactions. The lengths of the tubes in the dryers were set to 15   79.62 cm, and the fluid volume was set to 2.5 mL The flow rates were set to five conditions of 0.5, 1.0, 2.5, 5.0, and 10.0 mL / min in studies (the isomerization reaction times of the specimens reached 5.0, 2.5, 1.0, 0.5, and 0.25 minutes). After the reactions, the samples were rapidly cooled with ice and made into isomerized specimens, and the isomerization efficiencies were confirmed. The results will be shown in Table 2 below.

[0066] [Table 2] Reaction time (min) 0.0 0.25 0.5 1.0 2.5 5.0 160°C Fraction (%) trans 69.72 64.01 51.84 47.00 44.11 49.47 total cis 30.28 35.99 48.16 53.00 55.89 50.53 Astaxanthin residual rate (%) 100.00 96.69 95.74 91.16 86.38 88.47 200°C Fraction (%) trans 69.11 57.86 43.42 41.16 40.22 44.39 total cis 30.89 42.14 56.58 58.84 59.78 55.61 Astaxanthin residual rate (%) 100.00 99.38 93.76 90.74 79.72 75.41 240°C Fraction (%) trans 69.72 58.48 43.12 41.05 41.97 42.04 total cis 30.28 41.52 56.88 58.95 58.03 57.96 Astaxanthin residual rate (%) 100.00 95.82 89.00 72.21 30.95 21.96 5

[0067] As shown in Table 2, it was possible to perform the isomerization reactions using the present device.

[0068] 3. Scale-Up Test of Cis-Isomerization 10            In order to study the industrial compatibility of an isomerization technique by heating, the influence of the test scale on the isomerization efficiency was investigated. Two grams of the Haematococcus algae color A and 25 g of the Haematococcus algae color A were weighed in a glass container with a lid having a capacity of 9 mL (NWT-18; manufactured by Maruemu Corporation) and a glass container with a lid having a 15 capacity of 110 mL (9-852-10; manufactured by AS One Corporation), respectively, the headspaces were substituted with nitrogen, and the glass containers were capped. These glass containers were heated at 180°C for 15 minutes using an oil bath (SOS-183D; Sansho Co., Ltd.) and then immediately cooled in icy water. The fractions of cisisomers of astaxanthin esters after treatments were 57.7% and 59.1% for the charged amounts of 2 g and 25 g, respectively, and no decreases in isomerization efficiency due to scale-up were observed.

[0069] 4. Studies on Production by Mixing of Astaxanthin Ester and Unesterified Form 4-1. Isomerization After Mixing of Astaxanthin Ester and Unesterified Form Two grams of a Haematococcus algae color A and 38 g of medium-chain triglyceride were mixed together to prepare an ester solution. 0.2 g of unesterified-form astaxanthin, 0.03 g of a mixed tocopherol, and 39.77 g of medium-chain triglyceride were dissolved in 20 mL of dichloromethane and ultrasonically treated for several seconds to be fully dissolved, thereby preparing an unesterified-form solution. The ester solution and the unesterified-form solution were mixed together in ratios of 10:0, 8:2, 5:5, 2:8, 1:9, and 0:10, 3.0 g of each mixture was added to a glass reaction tube, and an isomerization reaction was performed in an oil bath at 180°C for five minutes. After the reaction, the mixture was rapidly cooled with ice and stored at 30°C and 40°C for one week, and the fraction of a cis isomer and the astaxanthin residual rate were measured. The results will be shown in Table 3 below.

[0070] [Table 3] Ester: unesterified 10:0 8:2 5:5 2:8 1:9 0:10 Initial Fraction (%) trans 47.49 47.79 50.17 52.80 55.17 63.95 total cis 52.51 52.21 49.83 47.20 44.83 36.05 30°C Fraction (%) trans 50.02 50.32 52.11 54.77 57.79 56.66 total cis 49.98 49.68 47.89 45.23 42.21 43.34 Residual rate (%) 102.45 102.32 101.99 98.86 103.37 73.94 40°C Fraction (%) trans 50.98 51.23 53.54 56.44 59.65 61.57 total cis 49.02 48.77 46.46 43.56 40.35 38.43 Residua rate (%) 103.22 101.26 101.98 97.67 103.66 74.54

[0071] In the case of the unesterified-form solution alone, the results were that the astaxanthin residual rates significantly decreased. On the other hand, as the fraction of the ester increased, a tendency of the cis isomer becoming more stable was observed.

[0072] 4-2. In Case of Mixing Cis-Astaxanthin Ester and Unesterified-Form Cis-Astaxanthin Three grams of a Haematococcus algae color A was added to each of two glass reaction tubes, nitrogen was injected thereinto, and an isomerization reaction was performed in an oil bath at 180°C for five minutes. After the reaction, the glass reaction tube was rapidly cooled with ice, reactants were combined into one and mixed well, and a mixture was diluted with medium-chain triglyceride so that AX reached 0.5%, thereby preparing an ester solution. After a cis-isomerization reaction of unesterified-form astaxanthin, unesterified-form astaxanthin before isomerization was added thereto so that the contents of the previously prepared ester solution and a cis isomer became the same as each other and mixed. 28.80 mg of a mixture, 5.75 mg of a mixed tocopherol, and 5715.45 mg of medium-chain triglyceride were mixed together well and ultrasonically treated, thereby preparing an unesterified-form solution. The ester solution and the unesterified-form solution were mixed together in ratios of 10:0, 8:2, 5:5, 2:8, 1:9, and 0:10, each mixture was stored at 30°C and 40°C for one week, and the fraction of the cis isomer and the astaxanthin residual rate were measured. The results will be shown in Table 4 below. [Table 4] Ester: unesterified 10:0 8:2 5:5 2:8 1:9 0:10 Initial Fraction (%) trans 46.15 47.50 50.23 51.87 52.20 51.87 total cis 53.85 52.50 49.77 48.13 47.80 48.13 30°C Fraction (%) trans 48.06 52.56 58.15 65.80 69.33 73.20 total cis 51.94 47.44 41.85 34.20 30.67 26.80 Residua rate (%) 97.83 101.15 105.87 108.23 108.20 112.99 40°C Fraction (%) trans 49.02 54.15 61.72 72.90 79.09 84.33 total cis 50.98 45.85 38.28 27.10 20.91 15.67 Residua rate (%) 99.71 103.88 106.00 112.82 106.60 104.86

[0074] As shown in Table 4, as the fraction of the ester increased, a tendency of the cis isomer becoming more stable was observed. 5

[0075] 5. Production of Powder and Stability Test In order to make it easier to use cis-astaxanthin derivatives in a food product application, powder processing was studied. As a method for producing a powder, organic solvent-based spray drying was performed using a closed-loop spray dryer 10 (ADL311S; manufactured by Yamato Scientific Co., Ltd.). Ethanol was used as a solvent, and polyvinylpyrrolidone (PVP) or hydroxypropyl-P-cyclodextrin (HP-BC) was used as an excipient. A cis-astaxanthin derivative (a cis-astaxanthin derivative shown in Table 1 obtained by heating a Haematococcus algae color A at 140°C for 30 minutes and rapidly 15 cooling the Haematococcus algae color A (total cis: 51.66%)) was added to a solution obtained by dissolving the excipient in ethanol so that the concentration reached 0.1 mg / mL and fully dissolved. This solution was spray-dried at a flow rate of 5 mL / min to obtain a powder. As studies on spray drying, the inlet temperature and the concentration of the excipient under the following conditions were studied. Studies on inlet temperatures: 100°C, 120°C, and 140°C (excipient concentration: 10 mg / mL) Studies on excipient concentrations: 5, 10, and 20 mg / mL (temperature: 120°C) The results will be shown in Tables 5 and 6 below. It was found that regardless 5 of the excipients used, the cis-astaxanthin derivative was not isomerized to a transastaxanthin derivative and was stable in a spray drying spraying step.

[0076] [Table 5] Excipient: PVP Condition Inlet temperature Excipient concentration 100°C 120°C 140°C 5 mg / mL 20 mg / mL Fraction (%) trans 44.60 44.51 44.46 47.16 46.11 total cis 55.40 55.49 55.54 52.84 53.89 Recovery rate (%) 98.04 95.98 99.72 97.12 104.53 10

[0077] [Table 6] ixcipient: HP-BC Condition Inlet temperature Excipient concentration 100°C 120°C 140°C 5 mg / mL 20 mg / mL Fraction (%) trans 45.22 45.50 44.50 45.35 48.53 total cis 54.78 54.50 55.50 54.65 51.47 Recovery rate (%) 86.70 97.62 95.54 93.45 91.29 0078] Powders obtained under spraying conditions of an inlet temperature of 120°C 15 and an excipient concentration of 10 mg / mL were stored at 5°C, 30°C, and 40°C for one, three, and six weeks, and the fractions of cis isomers and the astaxanthin residual rates were measured. The results will be shown in Tables 7 and 8 below. [Table 7] ixcipient: PVP Period (weeks) 0 1 3 6 5°C Fraction (%) trans 44.87 44.40 45.02 45.01 total cis 55.13 55.60 54.98 54.99 Astaxanthin residual rate (%) 100.00 83.57 84.35 83.50 30°C Fraction (%) trans 44.87 49.50 51.11 51.79 total cis 55.13 50.50 48.89 48.21 Residual rate (%) 100.00 82.49 82.61 82.43 0080] [Table 8] ixcipient: HP-BC Period (weeks) 0 1 3 6 5°C Fraction (%) trans 45.76 45.13 45.48 45.23 total cis 54.24 54.87 54.52 54.77 Astaxanthin residual rate (%) 100.00 100.00 90.72 93.59 30°C Fraction (%) trans 45.76 48.44 50.66 50.55 total cis 54.24 51.56 49.34 49.45 Residual rate (%) 100.00 100.00 94.08 93.84 5

[0081] As shown in Tables 7 and 8, in terms of the astaxanthin residual rates, it was possible to obtain favorable results from all of the powders.

[0082] 6. Production of Emulsion and Stability Test 10            In order to further expand the applications of the cis-astaxanthin derivative (a cis-astaxanthin derivative shown in Table 1 obtained by heating a Haematococcus algae color A at 140°C for 30 minutes and rapidly cooling the Haematococcus algae color A (total cis: 51.66%)), emulsions were studied. One gram of the cis-astaxanthin derivative (the cis-astaxanthin derivative shown 15 in Table 1 obtained by heating a Haematococcus algae color A at 140°C for 30 minutes and rapidly cooling the Haematococcus algae color A (total cis: 51.66%)), 0.15 g of mixed tocopherol, 3.85 g of medium-chain triglyceride, and 5.0 g of a sucrose fatty acid ester were mixed together, thereby preparing an emulsion. DK ESTER-SS or Decaglyn 1-L was used as the sucrose fatty acid ester. The obtained emulsion was stored at 30°C for one week, and the fraction of the cis isomer and the astaxanthin residual rate were measured. The results will be shown below. The cis isomers exhibited favorable stability in all of the emulsions.

[0083] [Table 9] Period (weeks) 0 1 DK-ESTER SS Fraction (%) trans 45.13 48.43 total cis 54.87 51.57 Residual rate (%) 100.00 104.94 Decaglyn 1-L Fraction (%) trans 44.87 48.07 total cis 55.13 51.93 Residual rate (%) 100.00 113.39

[0084] 7. Studies on Cis-Isomerization of Lutein and Zeaxanthin Derivatives Fatty acid esters of trans-lutein and zeaxanthin were heated and rapidly cooled by the following procedure, thereby producing a fatty acid ester of a cis-lutein and zeaxanthin mixture. In order to study the cis-isomerization efficiency, unesterified-form trans-lutein and zeaxanthin were also used as comparison and contrast. As a raw material, a commercially available marigold extract supplement (lutein, Kyowa Hakko Bio Co., Ltd., hereinafter referred to as “M extract”) was used. The M extract contains 8 to 13 mg of trans-lutein per two capsules in terms of the unesterified-form as a main component and a fatty acid ester and also further contains a small amount of trans-zeaxanthin. In addition, it is also stated that 2000 pg of flcarotene and 120 mg of a bilberry (blueberry) extract have been blended thereinto. The rest is composed of edible olive oil and vitamin E-containing vegetable oil. Marigold oleoresin containing lutein and zeaxanthin (Katra Phytochem Pvt Ltd., India, hereinafter referred to as “M control”) was used as comparison and contrast. It is shown that the M control contains 20% of trans-lutein in terms of the unesterified-form as a main component and also further contain approximately 2% of trans-zeaxanthin in terms of the unesterified-form. The rest is composed of a neutral fat such as a triglyceride or a diglyceride. The composition of fatty acids constituting the fatty acid ester of lutein and zeaxanthin in marigold is assumed to be palmitic acid, stearic acid, myristic acid, and lauric acid based on Reference A. Two capsules as the M extract and 52.6 mg of the marigold oleoresin as the M control were weighed, respectively, and dissolved in 100 mL of methyl-tert-butyl ether (MTBE) containing 0.05% of butylated hydroxytoluene (BHT) as an antioxidant. After that, the M extract and the M control were washed with a saturated sodium sulfate aqueous solution several times. Particularly, the M extract was washed until the color of a water layer completely disappeared. Parts of the M extract and the M control were taken, dried under a nitrogen flow, then, dissolved again in MTBE, and analyzed by HPLC. A variety of conditions such as the gradient condition of HPLC were set as described below and in Table 10 with reference to Reference B. In the subsequent examples, the same HPLC conditions were employed unless particularly otherwise described. HPLC conditions HPLC system: LC-2030 (manufactured by Shimadzu Corporation) Detector: Photodiode array detector (300 to 700 nm) Column: YMC Carotenoid, length: 250 mm, inner diameter: 4.6 mm, particle size: 5 pm, manufactured by YMC Co., Ltd.) Mobile phase A: Methanol Mobile phase B: MTBE Mobile phase C: 1% Phosphoric acid: Flow rate: l.OmL / min Detection wavelength: 450 nm* Column temperature: 25°C Under the present conditions, chromatograms were corrected based on the highest peak.

[0085] [Table 10] Gradient condition of HPLC Time Mobile phase A Mobile phase B Mobile phase C 0 min 81% 15% 4% 10 min 81% 15% 4% 15 min 76% 20% 4% 23 min 66% 30% 4% 27 min 66% 30% 4% 40 min 16% 80% 4% 55 min 16% 80% 4%

[0086] The chromatograms of the marigold extract are shown in FIG. 1 and FIG. 2. Samples were identified from the retention times and the absorption spectra of the unesterified-form trans-lutein (maximum absorption: 445 nm) and the trans-zeaxanthin (maximum absorption: 450 nm). From the majority of carotenoids in the M extract, extremely small amounts of the unesterified-form trans-lutein and the trans-zeaxanthin were detected as in Reference B, but the majority thereof exhibited a complex peak shape as a mixture. Regarding the mixture, it is considered that P-carotene blended with the fatty acid esters of both (xanthophylls) had been combined into the mixture. On the other hand, the M control contained unesterified-form trans-lutein as a main component and also partially contained unesterified-form trans-zeaxanthin. In addition, peaks of extremely small amounts of cis-lutein and cis-zeaxanthin (xanthophylls) were observed.

[0087] Reference A Cantrill, et al., 82nd JECFA - Chemical and Technical Assessment (CTA), FAO 2016, URL: https: / / openknowledge.fao.org / server / api / core / bitstreams / 6faebbl6-6ba5-4791-9574-25690ell521d / content Reference B: Prado-Cabrero, Fur Food Res Technol (2016) 242: 599-608

[0088] Alkaline saponification One milliliter of an MTBE solution derived from each of the above-shown M extract and M control was taken in a brown glass centrifuge tube with a screw cap, 1 mL of 60% KOH / EtOH was added thereto, and the components were vigorously stirred. After the stirring, saponification was performed at 50°C for one hour. Immediately after the saponification, 3 mL of MTBE and 3 mL of a saturated sodium sulfate aqueous solution were added thereto, the components were vigorously stirred, then, centrifuged under conditions of 3000 rpm and 10 minutes, and confirmed to be separated into two layers, and 3 mL of an upper layer was taken, appropriately concentrated under a nitrogen flow, and subjected to HPLC. The HPLC results of the M extract and the M control were shown in FIGS. 1 and 2. When carotenes such as P-carotene, which are considered to have been blended into the supplement tablet, were excluded from FIGS. 1 and 2, similar chromatograms containing lutein as the main component and then containing zeaxanthin or an isomer thereof were shown. There were a larger number of cis isomers of xanthophylls in the M extract, and the ratio of the cis isomers of cisxanthophylls to all xanthophylls was 17.5%. The esterification rate of the M extract was assumed to be 99% or more. There were no significant differences in the chromatograms of the M control before and after cis-isomerization. However, an increase in the amount of the cis isomers, which was slight (an increase of approximately 0.1%), was observed.

[0089] Cis-isomerization treatment: A liquid MTBE extract derived from the M extract and the M control was fully dried under reduced pressure and dissolved in approximately 15 mL of commercially available MCT oil (Asahi Co., Ltd., Japan). A part of the obtained oil was transferred to a glass tube and warmed at 165 °C for 30 minutes under a nitrogen flow (30 L / h). The warmed specimen was reacted, then, immediately cooled with icy water, and then stored in a brown sample tube filled with nitrogen. One milliliter of each of the M extract and the M control after this heating was weighed, diluted with 9 mL of MTBE, and then subjected to the alkaline saponification shown in Paragraph

[0087] . The obtained specimen was appropriately concentrated under a nitrogen flow and subjected to HPLC. The HPLC results of the M extract and the M control were shown in FIG. 3, and a series of comparison results were shown in Table 11. In Table 11, “Total F-type xanthophyll” means total unesterified-form xanthophylls. [Table 11] Results of isomerization reactions of marigold-derived xanthophylls Raw material Reaction Carotenoid composition ratio (%) Cis-isomerization rate (%) Saponification Cis-isomerization Total cis-type F xanthophyll Trans F lutein Trans F zeaxanthin Ester type (M extract) N N 0.0% 0.21% 0.13% 0.2% Y N 14.5% 64.1% 4.3% 17.5% Y Y 15.7% 13.0% 0.9% 52.7% Unesterified form (M control) N N 1.5% 79.2% 19.2% 1.5% Y N 1.7% 79.1% 19.0% 1.7% Y Y 57.0% 38.6% 7.7% 55.2% From FIG. 3, no significant changes in the esters of the M extract on which the alkaline saponification had not been performed were observed before and after the cisisomerization. For the M extract (ester derivative) and the (unesterified-form) M control after the alkaline saponification, similar chromatograms were shown, and when FIGS. 1 and 2 were compared with each other, increases in a number of peaks, which were observed extremely slightly before the cis-isomerization treatment, were observed. In addition, decreases in the peaks of trans-lutein, which was the main component, were significant. For newly appearing peaks, the absorption maximum of UV / VIS shifted to lower wavelengths more than all of the trans-lutein and zeaxanthin by 5 to 10 nm, and maximum absorption dependent on the cis isomers appeared at near 315 to 330 nm, and these peaks were thus considered to be cis-lutein and cis-zeaxanthin. What was calculated from the total area value of these peaks was shown as “cis-xanthophyll” in Table 11. Table 11 shows that, while both were derived from different substances, the cis-xanthophyll cis isomer ratios of the M extract (ester derivative) and the M control (unesterified form) to all xanthophylls were 53% and 55%, respectively. When the results of the present studies were summarized, it was shown that regardless of the fact that the raw material form was different, that is, the unesterified form and the ester derivative, it was possible to highly efficiently obtain cis-lutein and cis-zeaxanthin by performing the cis-isomerization treatment.

[0092] 8. Studies on Cis-isomerization of Orange Bell Pepper-Derived Zeaxanthin Derivative Orange bell peppers are rich in zeaxanthin. Therefore, an attempt was made to synthesize cis-xanthophyll derivatives mainly containing zeaxanthin using orange bell peppers as a raw material. A commercially available orange bell pepper (product of Japan) was frozen, approximately 100 g of a flesh portion excluding a seed, a white portion, and a calyx was weighed, finely chopped, and then made into puree with a juicer. After that, the puree was fully added to 40 mL of EtOH and stirred well, 40 mL of methylene chloride was added thereto, and the components were further vigorously stirred and stored overnight in a refrigerator. After that, 40 mL of methylene chloride was added thereto, the components were stirred again, 150 mL of hexane was then added thereto, the components were vigorously stirred and then filtered with a tea strainer. A residue was washed with hexane several times, and a solution was collected. When the solution was left to stand for a while, a filtrate was separated into two layers. An upper layer was filtered using filter paper, then, transferred to a separating funnel, washed with saturated saline several times, and dried under reduced pressure with an evaporator. What had been dried was dissolved in 50 mL of MTBE. A part of the solution was taken and dried under a nitrogen flow, and an unsaponified specimen and an alkali-saponified specimen were analyzed by HPLC. In addition, as cis-isomerization, a liquid MTBE extract was dried under reduced pressure and then dissolved in approximately 15 mL of MCT, and heat-induced cis-isomerization was performed thereon by the same method as in Example 7. The alkaline saponification and the variety of conditions, such as the gradient condition, of the HPLC were set in the same manner as in Example 7. The results were shown in FIG. 4.

[0093] From the results of HPLC chromatograms shown in FIG. 4, it was shown that approximately 58% of coloring components contained were fatty acid ester derivatives of a variety of xanthophylls and carotenes. That is, in unsaponified specimens, as unesterified xanthophylls, trans-zeaxanthin (maximum absorption wavelength: 451 nm) was present as a main component, next, trans-lutein (maximum absorption wavelength: 445 nm or 471 nm) was present, and a peak that was assumed as a small amount of trans-P-cryptoxanthin (maximum absorption wavelength: 452 nm) or a small amount of cis-zeaxanthin (maximum absorption wavelength: 446 nm or 339 nm) was present. In addition, complex peaks that were eluted in the latter half were detected. It was found that some of these complex peaks were esters of carotenes and xanthophylls (all were composed mainly of trans-zeaxanthin, lutein, and P-cryptoxanthin) as a result of the alkaline saponification. When the alkaline saponification was performed after the cisisomerization, a number of peaks were confirmed around the peaks of unesterified zeaxanthin, unesterified lutein, and unesterified P-cryptoxanthin. The maximum absorptions of these peaks all shifted to lower wavelengths by 5 to 10 nm, maximum dependent on the cis isomer appeared at near 330 nm, and these peaks were thus considered to be cis-zeaxanthin, cis-lutein, and cis-P-cryptoxanthin. The same peak fluctuation was also observed for each part of the carotenes. When these were summarized, the ratio of the cis-isomers to the trans-xanthophylls was approximately 0.6%, but increased to approximately 48.6% by the cis-isomerization. Since the maximum absorptions of cis-peaks normally shift to lower wavelengths, it is considered that cis-xanthophylls are contained at a higher ratio than the original.

[0094] 9. Investigation of Cis-isomerization of Xanthophyll Derivatives Mainly Based on Capsanthin and Zeaxanthin Derived from Red Bell Peppers Red bell peppers are rich in capsanthin, capsorubin, and zeaxanthin, which are unique xanthophylls. Therefore, an attempt was made to synthesize cis-xanthophyll derivatives mainly containing these xanthophylls using red bell peppers as a raw material. A commercially available red bell pepper (product of Japan) was frozen, and 37 approximately 100 g of a flesh portion excluding a seed, a white portion, and a calyx was weighed, finely chopped, and then made into puree with a juicer. After that, the puree was fully added to 40 mL of EtOH and stirred well, 40 mL of methylene chloride was added thereto, and the components were further vigorously stirred and stored overnight in a refrigerator. After that, 40 mL of methylene chloride was added thereto, the components were stirred again, 150 mL of hexane was then added thereto, the components were vigorously stirred and then filtered with a tea strainer. As a result of washing a residue with hexane several times, a filtrate was separated into two layers. An upper layer was filtered using filter paper, then, transferred to a separating funnel, washed with saturated saline several times, and dried under reduced pressure with an evaporator. What had been dried was dissolved in 50 mL of MTBE. A part of the solution was taken and dried under a nitrogen flow, and an unsaponified specimen and an alkali-saponified specimen were analyzed by HPLC. In addition, as cis-isomerization, a liquid MTBE extract was dried under reduced pressure and then dissolved in approximately 15 mL of MCT, and heat-induced cis-isomerization was performed thereon by the same method as in Example 7. The alkaline saponification and the variety of conditions, such as the gradient condition, of the HPLC were set in the same manner as in Example 7. The results were shown in FIG. 5.

[0095] From the results of HPLC chromatograms shown in FIG. 5, it was shown that approximately 90% was fatty acid ester derivatives of a variety of xanthophylls and carotenes. That is, in unsaponified specimens, as unesterified xanthophylls, transcapsanthin (maximum absorption wavelength: 474 nm) was a main component, additionally, trans-zeaxanthin (maximum absorption wavelength: 451 nm), violaxanthin (maximum absorption wavelength: 428 nm or 478 nm), capsorubin (maximum absorption wavelength: 480 nm), and neoxanthin (maximum absorption wavelength: 423 nm or 447 nm) were contained in all of the unsaponified specimens, and additionally, a slight amount of what were assumed to be a cis-carotenoid of each was contained. In addition, components that were eluted in the latter half occupied the majority, and peaks with complex shapes were detected. It was found that some of these complex peaks were esters of carotenes and xanthophylls as a result of the alkaline saponification. When the alkaline saponification was performed after the cis-isomerization, in all cases, peaks of neoxanthin, violaxanthin, capsanthin, zeaxanthin, and P-cryptoxanthin appeared, and additionally, the number of unidentified peaks were confirmed. When cisisomerization was performed on extracts, and the conversion efficiencies by saponification were evaluated, since there were cases where inseparable smeared peaks were detected around neoxanthin, violaxanthin, capsanthin, zeaxanthin, and P-cryptoxanthin, the maximum absorptions of these peaks all shifted to lower wavelengths by 5 to 10 nm, and maximum dependent on the cis isomer appeared at near 330 nm, these peaks were considered to be mixtures of cis-capsanthin, zeaxanthin, and P-cryptoxanthin. In addition, the same peak fluctuation was also observed for each part of the carotenes. When these were summarized, it was considered that 68% or more of all of the xanthophylls in the composition turned into cis-xanthophylls. Since the maximum absorptions of cis-peaks normally shift to lower wavelengths, it is considered that cisxanthophylls are contained at a higher ratio than the original.

[0096] 9. Studies on Cis-isomerization of Persimmon-Derived P-Cryptoxanthin and Zeaxanthin Derivative Persimmons, like Satsuma mandarins, are rich in P-cryptoxanthin and zeaxanthin. Therefore, an attempt was made to synthesize cis-xanthophyll derivatives mainly containing P-cryptoxanthin using persimmons as a raw material. A commercially available persimmon (Fuyu persimmon, product of Japan) was frozen, and approximately 25 g of a flesh portion was weighed, finely chopped, and then made into puree with a juicer. After that, the puree was fully added to 40 mL of EtOH and stirred well, 40 mL of methylene chloride was added thereto, and the components were further vigorously stirred and stored overnight in a refrigerator. After that, 20 mL of a saturated sodium sulfate aqueous solution and 40 mL of methylene chloride were added thereto, the components were stirred again, 150 mL of hexane was then added thereto, and the components were vigorously stirred and then filtered with a tea strainer. A residue was washed with hexane several times, and a solution was collected. When the solution was left to stand for a while, a filtrate was separated into two layers. An upper layer was filtered using filter paper, then, transferred to a separating funnel, washed with saturated saline several times, and dried under reduced pressure with an evaporator. What had been dried was dissolved in 50 mL of MTBE. A part of the solution was taken and dried under a nitrogen flow, and an unsaponified specimen and an alkali-saponified specimen were analyzed by HPLC. In addition, as cis-isomerization, a liquid MTBE extract was dried under reduced pressure and then dissolved in approximately 15 mL of MCT, and heat-induced cis-isomerization was performed thereon by the same method as in Example 7. The alkaline saponification and the variety of conditions, such as the gradient condition, of the HPLC were set in the same manner as in Example 7. The results were shown in FIG. 6.

[0097] From the results of HPLC chromatograms shown in FIG. 6, it was shown that approximately 87% of coloring components contained were fatty acid ester derivatives of a variety of xanthophylls and carotenes. That is, in unsaponified specimens, as unesterified xanthophylls, trans-zeaxanthin (maximum absorption wavelength: 451 nm) was present as a main component, next, trans-lutein (maximum absorption wavelength: 445 nm) was present, and a peak that was assumed as a small amount of trans-P-cryptoxanthin (maximum absorption wavelength: 452 nm) or a small amount of cis-zeaxanthin was present. In addition, complex peaks that were eluted in the latter half were detected. It was found that some of these complex peaks were esters of carotenes and xanthophylls (all were composed mainly of trans-zeaxanthin, lutein, and P-cryptoxanthin) as a result of the alkaline saponification. When the alkaline saponification was performed after the cis-isomerization, the number of peaks were confirmed around the peaks of unesterified zeaxanthin, unesterified lutein, and unesterified P-cryptoxanthin. The maximum absorptions of these peaks all shifted to lower wavelengths by 5 to 10 nm, and maximum dependent on the cis isomer appeared at near 330 nm, and these peaks were thus considered to be cis-zeaxanthin, cis-lutein, and cis-P-cryptoxanthin. The same peak fluctuation was also observed for each part of the carotenes. When these were summarized, it was considered that approximately 57% of the xanthophylls in the composition turned into cis-xanthophylls. Since the maximum absorptions of cis-peaks normally shift to lower wavelengths, it is considered that cisxanthophylls are contained at a higher ratio than the original.

[0098] 11. Studies on Cis-isomerization of Saffron-Derived Crocins (Crocetin Glycosides) Approximately 1 g of commercially available saffron (product of Spain, House Foods Group Inc., Japan) was measured, 50 mL of MeOH was added thereto, the components were stirred well, 100 mL of chloroform was then added thereto, and the components were further vigorously stirred. This is referred to as a saffron extract. A part of this saffron extract was taken and dried under a nitrogen flow, dissolved in MTBE / MeOH (1:2), and analyzed by HPLC. In addition, similarly, another part was alkali-saponified. As a method, 1 mL of the liquid extract was taken in a glass centrifuge tube with a screw cap, 1 mL of 60% KOH / EtOH was added thereto, and the components were vigorously stirred. After the stirring, the components were treated at 50°C for one hour. Immediately after the treatment, 3 mL of MTBE, 3 mL of a saturated sodium sulfate aqueous solution, and 0.3 mL of phosphoric acid were added thereto, and the components were vigorously stirred and then centrifuged under conditions of 3000 rpm and 10 minutes. After the components were confirmed to be separated into two layers, 3 mL of an upper layer to which coloring had been fully transferred was taken, appropriately concentrated under a nitrogen flow, and subjected to HPLC. In addition, the remaining MTBE / MeOH (1:2) solution was dried under reduced pressure and dissolved in approximately 15 mL of MCT, and heat-induced cisisomerization was performed thereon by the same method as in Example 7. After a reaction, alkaline saponification was performed by the same method as for an unreacted material. A variety of conditions such as the gradient condition of HPLC were set according to Table 12 below. The results of HPLC were shown in FIG. 7. HPLC conditions HPLC system: LC-2030 (manufactured by Shimadzu Corporation) Detector: Photodiode array detector (300 to 700 nm) Column: YMC Carotenoid, length: 150 mm, inner diameter: 4.6 mm, particle size: 3 pm, manufactured by YMC Co., Ltd.) Mobile phase A: 1% Phosphoric acid Mobile phase B: Acetonitrile (AcN) Flow rate: l.OmL / min Detection wavelength: 420 nm** Column temperature: 30°C Under the present conditions, chromatograms were corrected based on the highest peak.

[0099] [Table 12] Gradient condition of HPLC Time Mobile phase A Mobile phase B 0 min 95% 5% 18 min 5% 95% 30 min 5% 95%

[0100] From the results of HPLC chromatograms shown in FIG. 7, in unsaponified specimens, a plurality of peaks were observed, but these were converted to trans-crocetin by the alkaline saponification. Therefore, it was suggested that almost all of the coloring components contained were trans-crocins, which are crocetin glycosides. That is, in saponified specimens, as unesterified xanthophylls, trans-crocetin (maximum absorption wavelengths: 427 nm or 451 nm) was present as a main component. When the alkaline saponification was performed after the cis-isomerization, the number of peaks were confirmed around the trans-crocetin. The maximum absorptions of these peaks all shifted to lower wavelengths by 5 to 20 nm, and these peaks were thus considered to be cis-crocetins. In particular, the maximum absorption of the peak immediately after all-trans-crocetin shifted to lower wavelengths by approximately 5 nm, and a peak unique to a cis-carotenoid was observed at 316 nm and was thus suggested to be 13-cis-crocetin. Therefore, this was considered to be a glycoside (crocin) and present in a cis form. When these were summarized, it was considered that approximately 49% of the crocins in the composition turned into cis-crocins. Since the maximum absorptions of cis-peaks normally shift to lower wavelengths, it is considered that cis-crocins are contained at a higher ratio than the original.

[0101] 5            Hitherto, preferable examples of the present invention have been described, but the present invention is not limited to these examples. Addition, omission, substitution, and other modifications of configurations are possible within the scope of the gist of the present invention. The present invention is not limited to the above description and is limited only by the scope of the attached claims. 10

Claims

1. A composition comprising:a cis-xanthophyll derivative.

2. The composition according to Claim 1, further comprising:a cis-xanthophyll,wherein a molar weight ratio between the cis-xanthophyll and the cisxanthophyll derivative is 0.05 to 1000.

3. The composition according to Claim 1,wherein the cis-xanthophyll derivative contains one or more cis-xanthophyll derivatives selected from the group consisting of a lipid ester of a cis-xanthophyll, a glycoside of a cis-xanthophyll, a fatty acid glycoside of a cis-xanthophyll, an aliphatic ether of a cis-xanthophyll, and a sulfate ester of a cis-xanthophyll.

4. The composition according to Claim 1,wherein the cis-xanthophyll derivative contains a lipid ester of a cis-xanthophyll.

5. The composition according to Claim 1,wherein the cis-xanthophyll derivative contains a lipid ester of a cis-xanthophyll and one or more fatty acids selected from the group consisting of palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, a-linolenic acid, y-linolenic acid, eicosapentaenoic acid, arachidonic acid, and docosahexaenoic acid.

6. The composition according to Claim 1,wherein the cis-xanthophyll derivative contains one or more cis-xanthophyll derivatives selected from the group consisting of a cis-lutein derivative, a cis-zeaxanthin derivative, and a cis-astaxanthin derivative.

7. The composition according to Claim 1,wherein the cis-xanthophyll derivative contains a cis-lutein derivative.

8. The composition according to Claim 1, wherein the cis-xanthophyll derivative contains a cis-zeaxanthin derivative.

9. The composition according to Claim 1, wherein the cis-xanthophyll derivative contains a cis-astaxanthin derivative.5

10. A pharmaceutical product comprising:the composition according to Claim 1.

11. A food product comprising:the composition according to Claim 1.

12. A cosmetic product comprising:10           the composition according to Claim 1.

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