Composition, pharmaceutical product, food product, and cosmetic product

Abstract

A composition containing a cis-xanthophyll derivative.

Description

Compositions, medicines, foods, cosmetics

[0001] The present invention relates to compositions, pharmaceuticals, foods, and cosmetics. This application claims priority to Japanese Patent Application No. 2024-033410, filed on March 5, 2024, the contents of which are incorporated herein by reference.

[0002] Xanthophylls, which are widely found in nature, have strong antioxidant properties and various other excellent effects, and are therefore used in a wide range of applications, including health foods, cosmetics, food coloring, etc. Xanthophylls are a type of carotenoid, and many compounds are known, including lutein, zeaxanthin, β-cryptoxanthin, α-cryptoxanthin, capsanthin, capsorubin, and astaxanthin.

[0003] Xanthophylls have a polyene moiety consisting of multiple consecutive conjugated double bonds, end groups modified at both ends, and oxygen atoms such as alcohols, ketones, epoxy groups, and carboxylic acids within the molecule. Naturally occurring xanthophylls generally exist primarily in the trans form, where all double bonds are trans. Recently, it has become clear that cis-xanthophylls are more readily absorbed and accumulated in the body than trans-xanthophylls, as well as possessing greater physiological activity (antioxidant effects, eye fatigue relief, anti-cancer effects, anti-obesity effects, skin quality improvement effects, etc.), and their intake has attracted attention.

[0004] For example, Patent Document 1 describes an invention relating to a functional food product containing cis-astaxanthin that has the effect of relieving eye fatigue.

[0005] Furthermore, Patent Document 2 discloses a method for storing cis-carotenoids, which is characterized by storing the cis-carotenoids in the presence of an antioxidant, an organic acid salt, or vegetable oil or shark liver oil.

[0006] International Publication No. 2022 / 91995 Japanese Patent Application Laid-Open No. 2022-80682

[0007] In nature, xanthophyll also exists partially as a cis isomer, and the cis isomer ratio is constant and stable in vivo, but once extracted, cis xanthophyll changes easily and is unstable. In other words, when industrialized, isomerization from cis to trans occurs easily due to the influence of heat during extraction and storage, and when cis and trans forms coexist at room temperature or low temperatures, which are favorable for distribution, isomerization to the trans form and decomposition progresses significantly, making it difficult to stably maintain and store the cis form.

[0008] Conventional methods for storing cis-carotenoids, such as those described in Patent Document 2, do not provide sufficient stability, and there is a demand for a composition that allows for more stable and efficient intake of cis-xanthophylls.

[0009] The present invention has been made in consideration of the above circumstances, and aims to provide a composition containing a cis-xanthophyll derivative that is inhibited from being isomerized to the trans-form, has excellent storage stability, and enables efficient intake of cis-xanthophyll.

[0010] As a result of intensive research into the above-mentioned problems, the present inventors have found that when cis-xanthophyll is converted into a cis-xanthophyll derivative by replacing a portion of the cis-xanthophyll with another substituent, it is less likely to be isomerized to the trans-isomer and is stable, thereby completing the present invention. Furthermore, they have found that by using a composition containing a specific cis-xanthophyll derivative, cis-xanthophyll can be ingested more stably and efficiently. Furthermore, they have found that by adding a specific amount of cis-xanthophyll derivative to cis-xanthophyll, which is unstable when used alone, the isomerization of cis-xanthophyll to the trans-isomer is suppressed, thereby improving storage stability.

[0011] The present invention has the following aspects. [1] A composition containing a cis-xanthophyll derivative. [2] The composition according to [1], further containing cis-xanthophyll, wherein the molar weight ratio of the cis-xanthophyll to the cis-xanthophyll derivative is 0.05 to 1,000. [3] The composition according to [1] or [2], wherein the cis-xanthophyll derivative comprises one or more cis-xanthophyll derivatives selected from the group consisting of a lipid ester of cis-xanthophyll, a glycoside of cis-xanthophyll, a fatty acid glycoside of cis-xanthophyll, an aliphatic ether of cis-xanthophyll, and a sulfate ester of cis-xanthophyll. [4] The composition according to any one of [1] to [3], wherein the cis-xanthophyll derivative comprises a lipid ester of cis-xanthophyll. [5] The composition according to any one of [1] to [4], wherein the cis-xanthophyll derivative comprises a lipid ester of cis-xanthophyll with one or more fatty acids selected from the group consisting of palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, eicosapentaenoic acid, arachidonic acid, and docosahexaenoic acid. [6] The composition according to any one of [1] to [5], wherein the cis-xanthophyll derivative comprises one or more cis-xanthophyll derivatives selected from the group consisting of cis-lutein derivatives, cis-zeaxanthin derivatives, and cis-astaxanthin derivatives. [7] The composition according to any one of [1] to [5], wherein the cis-xanthophyll derivative comprises a cis-lutein derivative. [8] The composition according to any one of [1] to [5], wherein the cis-xanthophyll derivative comprises a cis-zeaxanthin derivative. [9] The composition according to any one of [1] to [5], wherein the cis-xanthophyll derivative comprises a cis-astaxanthin derivative.

[10] A pharmaceutical comprising the composition according to any one of [1] to [9].

[11] A food comprising the composition according to any one of [1] to [9].

[12] A cosmetic comprising the composition according to any one of [1] to [9].

[0012] According to the present invention, it is possible to provide a composition containing a cis-xanthophyll derivative that is inhibited from being isomerized to the trans-form, has excellent storage stability, and allows efficient intake of cis-xanthophyll.

[0013] Chromatogram of M extract. Chromatogram of M control. Chromatogram of M extract and M control. Chromatogram of orange paprika extract. Chromatogram of red paprika extract. Chromatogram of persimmon extract. Chromatogram of saffron extract.

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

[0015] <Cis-Xanthophyll Derivative> A cis-xanthophyll derivative is a compound in which a part of a cis-xanthophyll is replaced with another atom or a substituent.

[0016] Examples of xanthophylls in cis-xanthophyll derivatives include lutein, zeaxanthin, nostoxanthin, caloxanthin, β-cryptoxanthin, α-cryptoxanthin, zeinoxanthin, astaxanthin, adonixanthin, adonirubin, 3-hydroxyechinenone, 3'-hydroxyechinenone, capsanthin, capsorubin, cucurbitaxanthin A, violaxanthin, antheraxanthin, neoxanthin, and furan. Examples of suitable carotenoids include coxanthin, fucoxanthinol, amarousiaxanthin A, diatoxanthin, diadinoxanthin, rubixanthin, flavoxanthin, peridin, siphonaxanthin, myxol, 4-ketomyxol, and their apocarotenoids, β-apo-8'-carotenol, β-apo-8'-carotenoic acid, paracentrone, abscisic acid, zaxinone, crocetin, crocin, bixin, retinol, and retinoic acid. Among these, lutein, zeaxanthin, or astaxanthin is preferred. That is, the composition of the present embodiment preferably contains one or more cis-xanthophyll derivatives selected from the group consisting of cis-lutein derivatives, cis-zeaxanthin derivatives, and cis-astaxanthin derivatives.

[0017] Cis-lutein is composed of a polyene chain consisting of 10 conjugated double bonds and end groups (terminal groups) attached to both ends. In this specification, an isomer in which at least one of the 10 conjugated double bonds in the polyene chain is in the cis form is referred to as cis-lutein, and an isomer in which all are in the trans form is referred to as trans-lutein.

[0018] Cis-zeaxanthin is composed of a polyene chain consisting of 11 conjugated double bonds and end groups (terminal groups) attached to both ends. In this specification, an isomer in which at least one of the 11 conjugated double bonds in the polyene chain is cis-type is referred to as cis-zeaxanthin, and an isomer in which all are trans-type is referred to as trans-zeaxanthin.

[0019] Cis-astaxanthin is composed of a conjugated system including a polyene chain consisting of 11 conjugated double bonds and end groups (terminal groups) containing keto groups attached to both ends. In this specification, an isomer in which at least one of the 11 conjugated double bonds in the carbon polyene chain is cis-type is referred to as cis-astaxanthin, and an isomer in which all are trans-type is referred to as trans-astaxanthin.

[0020] Cis-xanthophyll can be produced by isomerizing trans-xanthophyll using methods known in the literature, for example, the method described in Patent Document 3 or Document 1 (Journal of the Japanese Society of Food Science and Technology, Vol. 21, No. 1, pp. 1-10, March 2020). Specific examples include a method of dissolving trans-xanthophyll in an organic solvent (dichloromethane, chloroform, acetone, ethyl acetate, etc.), vegetable oil (sesame oil, mustard oil, etc.), supercritical carbon dioxide, etc., followed by heat treatment, and a method using a cis-isomerization catalyst such as isothiocyanates, polysulfides, or iodine.

[0021] Specific examples of cis-xanthophyll derivatives include lipid esters of cis-xanthophyll, glycosides of cis-xanthophyll, fatty acid glycosides of cis-xanthophyll, aliphatic ethers of cis-xanthophyll, and sulfate esters of cis-xanthophyll.

[0022] Lipid esters of cis-xanthophyll The lipids (fatty acids) in the lipid esters of cis-xanthophyll include acetic acid, propionic acid, butyric acid, crotonic acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelagolic 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, sebalaic acid, oleic acid, linoleic acid, eleostearic acid, α-linolenic acid, γ-linolenic acid, and sucralose. Examples of thearidonic acid include thearidonic acid, calendic acid, vaccenic acid, paulic acid, elaidic acid, gadoleic acid, eicosenoic acid, arachidic acid, mead acid, dihomogamma-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, and melissic acid, and preferably caprylic acid, capric acid, lauric acid, and melissic acid. Examples of the fatty acids include stearic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, stearidonic acid, calendic acid, vaccenic acid, paulic acid, elaidic acid, eicosenoic acid, arachidic acid, dihomogamma-linolenic acid, eicosatrienoic acid, eicosapentaenoic acid, arachidonic acid, behenic acid, erucic acid, elaidic acid, docosatetraenoic acid, docosapentaenoic acid, and docosahexaenoic acid, and more preferably caprylic acid, capric acid, and lanolin. Examples of the fatty acids include uric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, dihomogamma-linolenic acid, elaidic acid, eicosapentaenoic acid, arachidonic acid, and docosahexaenoic acid, and more preferred examples include palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, eicosapentaenoic acid, arachidonic acid, elaidic acid, and docosahexaenoic acid.

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

[0024] Cis-xanthophyll glycosides Examples of glycosides in cis-xanthophyll glycosides include glucose, xylose, arabinose, mannose, fucose, fructose, galactose, and polysaccharides containing these, preferably fucose and xylose, and more preferably glucose.

[0025] Cis-xanthophyll glycoside is a mixture of multiple glycosides, and the molar ratio of glycosides, i.e., fucose, xylose, lactose, and glucose, to cis-xanthophyll in the total weight of the mixture is preferably 0.001 to 600, more preferably 0.01 to 400, even more preferably 0.01 to 100, and particularly preferably 0.01 to 10.

[0026] Cis-xanthophyll fatty acid glycosides Examples of the fatty acid glycoside in cis-xanthophyll fatty acid glycosides include glucose fatty acid esters, etc. As the cis-xanthophyll fatty acid glycosides, a mixture of a plurality of fatty acid glycosides can be used.

[0027] Cis-xanthophyll aliphatic ethers Examples of cis-xanthophyll aliphatic ethers include those generally known in the art. The cis-xanthophyll aliphatic ether can also be a mixture of a plurality of aliphatic ethers.

[0028] Cis-xanthophyll sulfate esters include those generally known in the art. The cis-xanthophyll sulfate ester may be a mixture of a plurality of cis-xanthophyll sulfate esters.

[0029] Cis-xanthophyll derivatives have a cyclic group with one hydroxyl group at either end of a polyene chain consisting of conjugated double bonds, resulting in one to two hydroxyl groups per molecule. Therefore, the mono-, di-, and mixtures thereof may include monoesters, diesters, and mixtures thereof, monoglycosides, diglycosides, monolipid glycosides, dilipid glycosides, and mixtures thereof, monoaliphatic ethers, dialiphatic ethers, and mixtures thereof, sulfate monoesters, sulfate diesters, and mixtures thereof. The present invention can use any of the mono-, di-, and mixtures thereof. In the case of a mixture of the mono- and di-xanthophyll derivatives, the mixing ratio (mono-:di) is preferably 1:100 to 100:1, more preferably 1:50 to 50:1, even more preferably 1:25 to 25:1, particularly preferably 1:16 to 16:1, and most preferably 1:10 to 10:1. The ratio of the mono-, di- and mixtures thereof can be confirmed by high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0030] Cis-xanthophyll derivatives can be produced by converting trans-xanthophyll into lipid esters, glycosides, fatty acid glycosides, aliphatic ethers, or sulfate esters by a commonly known method, and then isomerizing the resulting product by, for example, the method described in the above-mentioned document 1. The isomerization from the trans-form to the cis-form can be confirmed by HPLC. Commercially available trans-xanthophylls can be used, including chemically synthesized products, xanthophylls derived from natural products, and mixtures thereof.

[0031] For example, cis-xanthophyll lipid ester can be produced by reacting trans-xanthophyll with a lipid to form a trans-xanthophyll lipid ester, followed by isomerization by the method described in the above-mentioned document 1. Trans-xanthophyll can be produced by a generally known synthetic method, or it can be produced from biological raw materials such as microalgae such as the green algae Haematococcus, yeasts such as the red yeast Phaffia, and the shells of arthropods such as shrimp, krill, crab, and daphnia, or extracts thereof.

[0032] For example, cis-xanthophyll glycoside can be produced by reacting trans-xanthophyll with a glycoside to form trans-xanthophyll glycoside, and then isomerizing it by the method described in the above-mentioned document 1.

[0033] For example, cis-xanthophyll fatty acid glycosides can be produced by reacting trans-xanthophyll with a fatty acid glycoside to form trans-xanthophyll fatty acid glycosides, and then isomerizing them by the method described in the above-mentioned document 1.

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

[0035] For example, cis-xanthophyll sulfate can be produced by reacting trans-xanthophyll with a sulfated glycoside to form trans-xanthophyll sulfate, and then isomerizing it by the method described in the above-mentioned document 1.

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

[0037] <Optional Components> The composition of the present embodiment may contain optional components other than the above-described cis-xanthophyll derivatives. Examples of the optional components include cis-xanthophyll, antioxidants, and additives.

[0038] <Cis-xanthophyll> Cis-xanthophyll is a free form in which none of the hydroxyl groups and carboxylic acids in xanthophyll have been derivatized, such as by esterification.

[0039] By allowing cis-xanthophyll, which is unstable when used alone, to coexist with a cis-xanthophyll derivative, isomerization of cis-xanthophyll to the trans isomer is suppressed, thereby improving storage stability.

[0040] In the composition of the present embodiment, the content (molar ratio) of the cis-xanthophyll derivative relative to the content of cis-xanthophyll is preferably 0.05-1,000, more preferably 0.1-100, and even more preferably 1-10.

[0041] The composition of the present embodiment may contain trans-xanthophyll. When the composition of the present embodiment contains trans-xanthophyll, the content (molar ratio) of trans-xanthophyll to the content of cis-xanthophyll is preferably 0.05 to 60, more preferably 0.05 to 40, and even more preferably 0.1 to 20.

[0042] <<Antioxidants>> Examples of antioxidants include compounds having a phenolic hydroxyl group; amine compounds such as phenylenediamines such as diphenyl-p-phenylenediamine and 4-amino-p-diphenylamine; ascorbic acid; and oil-soluble derivatives of erythorbic acid. Specific examples of compounds having a phenolic hydroxyl group include guaiac oil; nordihydroguaiaretic acid (NDGA); gallic acid esters such as propyl gallate, butyl gallate, and octyl gallate; BHT (butylhydroxytoluene); BHA (butylhydroxyanisole); tocopherols (vitamin E; hereinafter, VE) such as mixed tocopherol; tocotrienols; and bisphenols. Of the above, tocopherols are preferred as antioxidants.

[0043] <<Additives>> Examples of additives include solvents, solubilizers, lubricants, emulsifiers, isotonicity agents, preservatives, surfactants, pH adjusters, buffers, excipients, sweeteners, and flavors.

[0044] Solvents Examples of solvents include monoglycerides, diglycerides, and triglycerides, and specific examples 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, persic oil, wheat germ oil, camellia oil, linseed oil, safflower oil, cottonseed oil, perilla oil, soybean oil, peanut oil, tea seed oil, kaya oil, rice bran oil, Chinese tung oil, Japanese tung oil, jojoba oil, germ oil, glycerin trioctanoate, glycerin triisopalmiate, salad oil, safflower oil (carthamus oil), palm oil, coconut oil, peanut oil, almond oil, hazelnut oil, walnut oil, and grapeseed oil.

[0045] Lubricants Examples of lubricants include gum arabic, 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, hardened oil, synthetic aluminum silicate, sesame oil, wheat starch, white beeswax, magnesium oxide, dimethylpolysiloxane, potassium sodium tartrate, sucrose fatty acid ester, glycerin fatty acid ester, silicone resin, aluminum hydroxide gel, stearyl alcohol, stearic acid, aluminum stearate, and calcium stearate. Examples of suitable oleic acid surfactants include cellulose, 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, glycerin monostearate, sodium lauryl sulfate, calcium sulfate, magnesium sulfate, liquid paraffin, and phosphoric acid.

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

[0047] Emulsifiers Examples of emulsifiers include sucrose fatty acid esters, polysorbates, polyglycerin fatty acid esters, lecithin, and lysolecithin.

[0048] Isotonicity Agents Examples of isotonicity agents include sugars such as sorbitol, glucose, and mannitol; polyhydric alcohols such as glycerin and propylene glycol; and sodium chloride.

[0049] Preservatives Examples of preservatives 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, and sodium dehydroacetate.

[0050] Surfactants Examples of surfactants include sucrose fatty acid esters, propylene glycol esters, glycerin fatty acid esters, sorbitan fatty acid esters, dextrin, and reduced dextrin.

[0051] pH Adjusting Agent Examples of the pH adjusting agent include hydrochloric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogen carbonate.

[0052] Buffers Examples of buffers include phosphate buffers, tartrate buffers, and amino acids.

[0053] Excipients Examples of excipients include lactose, sucrose, mannitol, corn starch, and crystalline cellulose.

[0054] [Uses] The composition of the present embodiment can be used for applications such as foods, beverages, functional foods, nutritional supplements, pharmaceuticals, quasi-drugs, cosmetics, veterinary drugs, pet foods, feeds, and the like.

[0055] The content of the cis-xanthophyll derivative and cis-xanthophyll is preferably 0.5 to 40% by mass, more preferably 1 to 30% by mass, and even more preferably 5 to 20% by mass, based on the total mass of the product.

[0056] The composition of the present embodiment can be blended with commonly known additives depending on the purpose, and can be made into the form of oil, powder, emulsion, or the like.

[0057] The present invention will be described in more detail below with reference to examples, comparative examples and test examples, but the present invention is not limited to these.

[0058] 1. Cis-isomerization of astaxanthin derivatives (batch process) A fatty acid ester of trans-astaxanthin was produced by heating and rapidly cooling a fatty acid ester of trans-astaxanthin according to the following procedure. Haematococcus algae pigment A (hereinafter simply referred to as "Haematococcus algae pigment A") containing 10% by mass of trans-astaxanthin fatty acid ester, calculated as free astaxanthin, was used as the raw material. The remaining 90% by mass of Haematococcus algae pigment A is neutral fat such as triglycerides and diglycerides. The fatty acid ester of trans-astaxanthin in Haematococcus algae pigment A is composed of trans-astaxanthin derived from Haematococcus algae and a fatty acid mixture (a mixture of palmitic acid, elaidic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, etc.). Analysis of the trans-astaxanthin fatty acid ester confirmed that it was 99.9% or more of an ester. The trans-astaxanthin fatty acid ester satisfies the specifications of Non-Patent Document A below.

[0059] The ratios of each fatty acid constituting the fatty acid ester of trans-astaxanthin have not been analyzed. On the other hand, the following Non-Patent Documents B and C disclose the ratios of each fatty acid in a fatty acid ester of trans-astaxanthin produced using similar trans-astaxanthin and fatty acids. Therefore, the ratios of each fatty acid in the present trans-astaxanthin fatty acid ester are presumed to be similar to the ratios of each fatty acid in the fatty acid ester of trans-astaxanthin disclosed in Non-Patent Documents B and C. The ratios of each fatty acid in the fatty acid ester of trans-astaxanthin disclosed in Non-Patent Documents B and C are palmitic acid (15-35%), elaidic acid (10-20%), oleic acid (10-20%), linoleic acid (15-35%), linolenic acid (0.1-10%), arachidonic acid (up to 1%), and eicosapentaenoic acid (up to 1%).

[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, LPS; Ilhamsyah, DPA; 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] 2 g of Haematococcus algae pigment A was weighed into a 9 mL glass container with a cap (NWT-18; manufactured by Maruemu Co., Ltd.), the headspace was replaced with nitrogen, and the container was then capped. The Haematococcus algae pigment A was then heated for 5-60 minutes in the range of 100-200°C using an oil bath (SOS-183D; manufactured by Sansho Co., Ltd.). After the reaction, the sample was rapidly cooled on ice and used as an isomerization sample to confirm the isomerization efficiency. The results are shown in Table 1 below.

[0062] The amount of astaxanthin and its isomers were analyzed by high-performance liquid chromatography (HPLC) and calculated from the peak area. Conditions for normal-phase HPLC analysis of cis-astaxanthin-containing compositions: Apparatus: High-performance liquid chromatograph Prominence system (SPD-M20A, manufactured by Shimadzu Corporation); Column: Penomenex silica gel luna (2) (length: 150 mm x 2, inner diameter: 4.6 mm, particle size: 5 μm, manufactured by Penomenex); Mobile phase: hexane / ethyl acetate / acetone (volume ratio 70:20:10); Flow rate: 1.2 mL / min; Detection wavelength: 470 nm; Column temperature: 40°C.

[0063]

[0064] As shown in Table 1, the isomerization efficiency improved in a temperature-dependent manner, but decomposition was also promoted. However, under appropriate temperature conditions, isomerization was possible in a short period of time while suppressing decomposition. For example, at 140°C for 30-60 minutes, 160°C for 10-30 minutes, and 180°C for 5-15 minutes, the cis-astaxanthin ratio could be increased to 50% or more while suppressing decomposition of astaxanthin ester (decomposition rate of 15% or less).

[0065] 2. Cis-Isomerization of Astaxanthin (Continuous Method) Haematococcus algae pigment A was prepared at a 2% concentration using medium-chain fatty acid glycerides and used as a sample. The sample was subjected to isomerization reaction by passing it through a dryer set at 160, 200, or 240°C using a 0.2 cm inner diameter tube. The length of the tube in the dryer was 79.62 cm, and the liquid volume was 2.5 mL. Five flow rates were investigated: 0.5, 1.0, 2.5, 5.0, and 10.0 mL / min (isomerization reaction times for the sample were 5.0, 2.5, 1.0, 0.5, and 0.25 minutes). After the reaction, the sample was rapidly cooled with ice to prepare an isomerization sample, and the isomerization efficiency was confirmed. The results are shown in Table 2 below.

[0066]

[0067] As shown in Table 2, it was possible to carry out an isomerization reaction using this apparatus.

[0068] 3. Scale-up Test of Cis-Isomerization To investigate the industrial compatibility of this thermal isomerization technology, the effect of test scale on isomerization efficiency was investigated. 2 g and 25 g of Haematococcus algae pigment A were weighed into a 9 mL capped glass container (NWT-18; Maruemu Co., Ltd.) and a 110 mL capped glass container (9-852-10; AS ONE Corporation), respectively. The headspace was replaced with nitrogen and the container was then capped. These glass containers were heated at 180 °C for 15 minutes using an oil bath (SOS-183D; Sansho Co., Ltd.) and then immediately quenched in ice water. The cis-astaxanthin ester ratios after treatment were 57.7% and 59.1% for the 2 g and 25 g feed amounts, respectively, and no decrease in isomerization efficiency was observed due to scale-up.

[0069] 4. Investigation of Production Using a Mixture of Astaxanthin Ester and Free Form 4-1 Isomerization after Mixing Astaxanthin Ester and Free Form An ester solution was prepared by mixing 2 g of Haematococcus algae pigment A with 38 g of medium-chain fatty acid glyceride. 0.2 g of free astaxanthin, 0.03 g of mixed tocopherol, and 39.77 g of medium-chain fatty acid glyceride were dissolved in 20 mL of dichloromethane and sonicated for several seconds to completely dissolve the mixture, preparing a free form solution. The ester solution:free form solution was mixed in ratios of 10:0, 8:2, 5:5, 2:8, 1:9, and 0:10, and 3.0 g of each solution was added to a glass reaction tube and subjected to an isomerization reaction in an oil bath at 180°C for 5 minutes. After the reaction, the mixture was rapidly cooled on ice and stored at 30°C or 40°C for one week. The cis-form ratio and residual astaxanthin rate were measured. The results are shown in Table 3 below.

[0070]

[0071] When only the free form was used, the residual rate of astaxanthin was significantly reduced. On the other hand, the greater the proportion of esterified astaxanthin, the greater the stability of the cis form.

[0072] 4-2 Mixture of cis-astaxanthin ester and free-cis-astaxanthin 3.0 g of Haematococcus algae pigment A was added to each of two glass reaction tubes. After nitrogen was sealed inside, the mixture was subjected to an isomerization reaction in an oil bath at 180°C for 5 minutes. After the reaction, the mixture was rapidly cooled with ice, and the reaction mixture was combined and thoroughly mixed. The resulting mixture was diluted with medium-chain fatty acid glyceride to an AX content of 0.5% to prepare an ester solution. After the cis-isomerization reaction of free astaxanthin, pre-isomerized free astaxanthin was added and mixed to achieve an equivalent cis content to the previously prepared ester solution. The resulting mixture was thoroughly mixed with 28.80 mg of mixed tocopherol, 5.75 mg of medium-chain fatty acid glyceride, and 5715.45 mg of medium-chain fatty acid glyceride, and dispersed by sonication to prepare a free-cis solution. The ester solution and free astaxanthin solution were mixed in ratios of 10:0, 8:2, 5:5, 2:8, 1:9, and 0:10, and stored at 30°C and 40°C for one week, after which the cis-isomer ratio and residual astaxanthin rate were measured. The results are shown in Table 4 below.

[0073]

[0074] As shown in Table 4, the greater the proportion of esters, the higher the stability of the cis-isomer tended to be.

[0075] 5. Powder Production and Stability Testing To facilitate the use of cis-astaxanthin derivatives in food applications, powder processing was investigated. To produce the powder, organic solvent spray drying was performed using a closed spray dryer (ADL311S; Yamato Scientific). Ethanol was used as the solvent, and polyvinylpyrrolidone (PVP) or hydroxypropyl-β-cyclodextrin (HP-BC) was used as the excipient. A cis-astaxanthin derivative (shown in Table 1, obtained by heating Haematococcus algae pigment A at 140°C for 30 minutes and then rapidly cooling it, at a concentration of 0.1 mg / mL was added to a solution containing the excipient in ethanol, and the resulting solution was completely dissolved. This solution was spray-dried at a flow rate of 5 mL / min to obtain a powder. The inlet temperature and excipient concentration were investigated under the following conditions for spray drying. Inlet temperature study: 100°C, 120°C, 140°C (excipient concentration 10 mg / mL) Excipient concentration study: 5, 10, 20 mg / mL (temperature 120°C) The results are shown in Tables 5 and 6. It was found that whichever excipient was used was stable and did not undergo isomerization from cis to trans form during the spray-drying atomization process.

[0076]

[0077]

[0078] The powder obtained under spray conditions of an inlet temperature of 120°C and an excipient concentration of 10 mg / mL was stored at 5°C, 30°C, and 40°C for 1, 3, and 6 weeks, and the cis-isomer ratio and residual astaxanthin rate were measured. The results are shown in Tables 7 and 8 below.

[0079]

[0080]

[0081] As shown in Tables 7 and 8, good results were obtained for the astaxanthin residual rate in all cases.

[0082] 6. Production of Emulsion and Stability Testing To further expand the applications of the cis-astaxanthin derivative (the cis-astaxanthin derivative shown in Table 1 (total cis: 51.66%) obtained by heating Haematococcus algae pigment A at 140°C for 30 minutes and then quenching), an emulsion was investigated. An emulsion was prepared by mixing 1.0 g of the cis-astaxanthin derivative (the cis-astaxanthin derivative shown in Table 1 (total cis: 51.66%) obtained by heating Haematococcus algae pigment A at 140°C for 30 minutes and then quenching), 0.15 g of mixed tocopherol, 3.85 g of medium-chain fatty acid glyceride, and 5.0 g of sucrose fatty acid ester. DK Ester-SS or Decaglyn 1-L was used as the sucrose fatty acid ester. The resulting emulsions were stored at 30°C for one week, and the cis-isomer ratio and residual astaxanthin rate were measured. The results are shown below. In all emulsions, the cis-isomer showed good stability.

[0083]

[0084] 7. Cis-Isomerization of Lutein and Zeaxanthin Derivatives. Fatty acid esters of trans-lutein and zeaxanthin were heated and rapidly cooled as follows to produce a mixture of cis-lutein and zeaxanthin. Free trans-lutein and zeaxanthin were also used as a control to examine the efficiency of cis-isomerization. A commercially available marigold extract supplement (Lutein, Kirin Kyowa Hakko Bio Co., Ltd., hereafter referred to as "M Extract") was used as the raw material. M Extract contains 8-13 mg of trans-lutein per two tablets as a fatty acid ester, calculated as free form, as the main component, and also contains a small amount of trans-zeaxanthin. It is also listed as containing 2000 μg of β-carotene and 120 mg of bilberry (blueberry) extract. The remainder is comprised of edible olive oil and a vitamin E-containing vegetable oil. Marigold-derived oleoresin (Katra Phytochem Pvt Ltd., India; hereinafter referred to as "M Control") containing free lutein and zeaxanthin was used as a control for comparison. It has been shown that M Control contains 20% trans-lutein (free equivalent) as the main component, and also contains approximately 2% trans-zeaxanthin (free equivalent). The remainder is composed of neutral fats such as triglycerides and diglycerides. Based on Reference A, the fatty acid composition of the fatty acid esters of lutein and zeaxanthin in marigold is estimated to be palmitic acid, stearic acid, myristic acid, and lauric acid. Two capsules were used as the M extract and 52.6 mg of marigold-derived oleoresin as the M control, and each was dissolved in 100 mL of methyl-tert-butyl ether (MTBE) containing 0.05% dibutylhydroxytoluene (BHT) as an antioxidant. The solution was then washed several times with saturated aqueous sodium sulfate. The M extract, in particular, was washed until the aqueous layer was completely colorless. A portion of the solution was taken, dried under a nitrogen stream, redissolved in MTBE, and analyzed by HPLC. The HPLC gradient and other conditions were set with reference to Reference B and as shown in Table 10. The same HPLC conditions were used in the following examples unless otherwise noted.(HPLC conditions) HPLC system: LC-2030 (Shimadzu Corporation) Detector: Photodiode array detector (300-700 nm) Column: YMC Carotenoid, length: 250 mm, inner diameter: 4.6 mm, particle size: 5 μm, manufactured by YMC Mobile phase A: methanol Mobile phase B: MTBE Mobile phase C: 1% phosphoric acid Flow rate: 1.0 mL / min Detection wavelength: 450 nm. ＊ Column temperature: 25°C. Under these conditions, the chromatogram was corrected using the highest peak as the standard.

[0085]

[0086] Chromatograms of the marigold extract are shown in Figures 1 and 2. Sample assignment was based on retention time and the absorption spectra of free trans-lutein (maximum absorption at 445 nm) and trans-zeaxanthin (maximum absorption at 450 nm). As in Reference B, the majority of carotenoids in the M extract were free trans-lutein and trans-zeaxanthin, with very small amounts detected. However, the majority of the peaks showed complex shapes, likely representing a mixture of fatty acid esters of both (xanthophylls) and β-carotene. In contrast, the M control contained free trans-lutein as the major component, with some free trans-zeaxanthin present. Traces of cis-lutein and zeaxanthin (xanthophylls) peaks were also 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 / 6faebb16-6ba5-4791-9574-25690e11521d / content Reference B: Prado-Cabrero, Eur Food Res Technol (2016) 242:599-608

[0088] (Alkaline Saponification Treatment) 1 mL of the MTBE solution from the M extract and M control described above was placed in a brown glass screw centrifuge tube, and 1 mL of 60% KOH / EtOH was added and vigorously stirred. After stirring, the saponification treatment was carried out at 50°C for 1 hour. Immediately after treatment, 3 mL of MTBE and 3 mL of saturated aqueous sodium sulfate were added, vigorously stirred, and centrifuged at 3000 rpm for 10 minutes. After confirming separation into two layers, 3 mL of the upper layer was collected, appropriately concentrated under a nitrogen stream, and subjected to HPLC. The HPLC results for the M extract and M control are shown in Figures 1 and 2. Excluding carotenes such as β-carotene, which are believed to have been incorporated into the supplement tablets, Figures 1 and 2 show similar chromatograms, primarily containing lutein, followed by zeaxanthin and its isomers. The M extract contained more cis-isomers of xanthophylls, with the cis-isomer ratio of cis-xanthophylls to total xanthophylls being 17.5%. The esterification rate of the M extract was estimated to be over 99%. No significant difference was observed in the chromatograms of the M control before and after cis-conversion. However, a slight increase in cis-isomers (approximately 0.1%) was observed.

[0089] Cis-isomerization treatment: The entire MTBE extract from the M extract and M control was evaporated to dryness under reduced pressure and dissolved in approximately 15 mL of commercially available MCT oil (Asahi Co., Ltd., Japan). A portion of the resulting oil was transferred to a glass tube and heated at 165°C for 30 minutes under a nitrogen stream (30 L / h). The heated sample was immediately cooled in ice-cold water after the reaction, and then stored in an amber sample tube after filling with nitrogen. One mL of each of the heated M extract and M control was measured and diluted with 9 mL of MTBE. The alkaline saponification treatment described in paragraph

[0087] was then performed. The resulting samples were appropriately concentrated under a nitrogen stream and subjected to HPLC. The HPLC results for the M extract and M control are shown in Figure 3, and a series of comparative results are shown in Table 11. In Table 11, total F-xanthophylls refers to total free xanthophylls.

[0090]

[0091] As shown in Figure 3, the esters of the M extract that was not subjected to alkaline saponification did not change significantly before and after cis-isomerization. The M extract (ester derivative) and the M control (free form) after alkaline saponification also showed similar chromatograms. Compared to Figures 1 and 2, a slight increase in the number of peaks observed before cis-isomerization was observed. Furthermore, the peak for trans-lutein, the main component, was significantly reduced. The new peaks exhibited UV / VIS absorption maxima shifted 5 to 10 nm lower than all-trans-lutein and zeaxanthin, and a cis-isomer-dependent absorption maximum appeared around 315 to 330 nm. Therefore, these peaks were considered to be cis-lutein and cis-zeaxanthin. The values ​​calculated from the total area of ​​these peaks are designated as cis-xanthophylls in Table 11. As shown in Table 11, although the origins of both are different, the ratios of cis-xanthophyll cis-isomers to total xanthophyll in the M extract (ester derivative) and the M control (free form) were 53% and 55%, respectively. Summarizing the results of this study, it was shown that, despite the different raw material forms of the free form and ester derivative, it is possible to obtain cis-lutein and cis-zeaxanthin with high efficiency by carrying out this cis-conversion treatment method.

[0092] 8. Cis-isomerization study of zeaxanthin derivatives from orange peppers. Orange peppers are rich in zeaxanthin. Therefore, we attempted to synthesize cis-xanthophyll derivatives centered on zeaxanthin using orange peppers as a raw material. Commercially available orange peppers (orange, produced in Japan) were frozen, and approximately 100 g of the flesh, with the seeds, white part, and stem removed, was measured, shredded, and pureed in a juicer. The entire puree was then added with 40 mL of EtOH and stirred thoroughly. 40 mL of methylene chloride was then added, stirred vigorously, and stored in the refrigerator overnight. 40 mL of methylene chloride was then added, stirred again, and 150 mL of hexane was added. After vigorously stirring, the mixture was filtered through a tea strainer. The residue was washed several times with hexane and the solution was collected. After standing for a while, the filtrate separated into two layers. The upper layer was filtered using filter paper, transferred to a separatory funnel, washed several times with saturated saline, and evaporated to dryness under reduced pressure using an evaporator. The dried extract was dissolved in 50 mL of MTBE. A portion was taken and evaporated to dryness under a nitrogen stream, and then the unsaponified sample and the alkaline saponified sample were analyzed by HPLC. Furthermore, for cis-isomerization, the MTBE extract was evaporated to dryness under reduced pressure, dissolved in approximately 15 mL of MCT, and cis-isomerization by heating was carried out in the same manner as in Example 7. The alkaline saponification and HPLC gradient conditions were the same as in Example 7. The results are shown in Figure 4.

[0093] The HPLC chromatogram shown in Figure 4 indicates that approximately 58% of the pigment components contained in the sample were various xanthophyll fatty acid ester derivatives and carotenes. Specifically, in the unsaponified sample, trans-zeaxanthin (maximum absorption wavelength: 451 nm) was the main free xanthophyll, followed by trans-lutein (maximum absorption wavelengths: 445 nm and 471 nm), with small amounts of trans-β-cryptoxanthin (maximum absorption wavelength: 452 nm) and cis-zeaxanthin (maximum absorption wavelengths: 446 nm and 339 nm). Complex peaks eluting in the latter half of the sample were also detected. These complex peaks were found to be, in part, esters of carotenes and xanthophylls (mainly composed of trans-zeaxanthin, lutein, and β-cryptoxanthin) as a result of alkaline saponification. After cis-isomerization, alkaline saponification revealed numerous peaks around the peaks of free zeaxanthin, free lutein, and free β-cryptoxanthin. The absorption maxima of all these peaks shifted 5-10 nm toward lower wavelengths, and a cis-isomer-dependent maximum appeared around 330 nm, suggesting that these peaks represent cis-zeaxanthin, cis-lutein, and cis-β-cryptoxanthin. Similar peak variations were also observed for each of the carotene components. In summary, the ratio of cis-isomers to trans-xanthophylls was approximately 0.6%, but this increased to approximately 48.6% after cis-isomerization. Because the absorption maxima of cis-isomer peaks typically shift toward lower wavelengths, it is believed that the cis-xanthophylls are present at a higher ratio than this figure.

[0094] 9. Cis-isomerization study of xanthophyll derivatives based on capsanthin and zeaxanthin from red paprika. Red paprika is rich in the unique xanthophylls capsanthin, capsorubin, and zeaxanthin. Therefore, we attempted to synthesize cis-xanthophyll derivatives primarily composed of these xanthophylls using red paprika as a raw material. Commercially available red paprika (produced in Japan) was frozen, and approximately 100 g of the flesh, with the seeds, white part, and stem removed, was measured, shredded, and pureed in a juicer. The entire puree was then added to 40 mL of EtOH and stirred thoroughly. 40 mL of methylene chloride was then added, stirred vigorously, and stored in the refrigerator overnight. 40 mL of methylene chloride was then added, stirred again, and 150 mL of hexane was added. After stirring, the mixture was filtered through a tea strainer. The residue was washed several times with hexane, and the filtrate separated into two layers. The upper layer was filtered using filter paper, transferred to a separatory funnel, washed several times with saturated saline, and evaporated to dryness under reduced pressure using an evaporator. The dried extract was dissolved in 50 mL of MTBE. A portion was taken and evaporated to dryness under a nitrogen stream, and then the unsaponified sample and the alkaline saponified sample were analyzed by HPLC. Furthermore, for cis-isomerization, the MTBE extract was evaporated to dryness under reduced pressure, dissolved in approximately 15 mL of MCT, and cis-isomerization by heating was carried out in the same manner as in Example 7. The alkaline saponification and HPLC gradient conditions, among other conditions, were the same as in Example 7. The results are shown in Figure 5.

[0095] The HPLC chromatogram shown in Figure 5 indicates that approximately 90% of the xanthophylls were fatty acid ester derivatives and carotenes. In other words, the unsaponified sample contained trans-capsanthin (maximum absorption wavelength: 474 nm) as the main free xanthophylls, along with trans-zeaxanthin (maximum absorption wavelength: 451 nm), violaxanthin (maximum absorption wavelength: 428 nm, 478 nm), capsorubin (maximum absorption wavelength: 480 nm), and neoxanthin (maximum absorption wavelength: 423 nm, 447 nm), all of which were trans-formed. Small amounts of what are assumed to be cis-carotenoids were also present. Furthermore, the majority of the components eluted in the latter half of the sample were detected, and complex peaks were detected. These complex peaks were determined to be esters of carotenes and the aforementioned xanthophylls as a result of alkaline saponification. When alkaline saponification treatment was performed after cis-conversion treatment, peaks corresponding to trans-neoxanthin, violaxanthin, capsanthin, zeaxanthin, and β-cryptoxanthin appeared, along with numerous other unidentified peaks. When the extract was subjected to cis-conversion treatment and the conversion efficiency of the saponification treatment was evaluated, inseparable smear peaks were detected around neoxanthin, violaxanthin, capsanthin, zeaxanthin, and β-cryptoxanthin. The absorption maxima of these peaks shifted 5-10 nm toward lower wavelengths, and some peaks showed a cis-isomer-dependent maximum around 330 nm, suggesting a mixture of cis-capsanthin, zeaxanthin, and β-cryptoxanthin. Similar peak variations were also observed for each of the carotene fractions. In summary, it was estimated that more than 68% of the total xanthophylls in the composition were cis-xanthophylls. In addition, since the maximum absorption of the cis-xanthophyll peak usually shifts to the lower wavelength side, it is thought that the cis-xanthophyll content is higher than this figure.

[0096] 9. Cis-isomerization study of persimmon-derived β-cryptoxanthin and zeaxanthin derivatives. Persimmons, like Satsuma mandarins, are rich in β-cryptoxanthin and zeaxanthin. Therefore, we attempted to synthesize cis-xanthophyll derivatives, primarily β-cryptoxanthin, using persimmons as a raw material. Commercially available persimmons (Fuyu persimmons, produced in Japan) were frozen, and approximately 25 g of the peel was measured, shredded, and pureed in a juicer. The entire puree was then added to 40 mL of EtOH and stirred thoroughly. 40 mL of methylene chloride was then added, stirred vigorously, and stored in the refrigerator overnight. 20 mL of saturated aqueous sodium sulfate and 40 mL of methylene chloride were then added, stirred again, and 150 mL of hexane was added. After vigorously stirring, the mixture was filtered through a tea strainer. The residue was washed several times with hexane and the solution was collected. After standing for a while, the filtrate separated into two layers. The upper layer was filtered using filter paper, transferred to a separatory funnel, washed several times with saturated saline, and evaporated to dryness under reduced pressure using an evaporator. The dried extract was dissolved in 50 mL of MTBE. A portion was taken and evaporated to dryness under a nitrogen stream, and then the unsaponified sample and the alkaline saponified sample were analyzed by HPLC. Furthermore, for cis-isomerization, the MTBE extract was evaporated to dryness under reduced pressure, dissolved in approximately 15 mL of MCT, and cis-isomerization by heating was carried out in the same manner as in Example 7. The alkaline saponification and HPLC gradient conditions were the same as in Example 7. The results are shown in Figure 6.

[0097] The HPLC chromatogram shown in Figure 6 indicates that approximately 87% of the pigment components are various xanthophyll fatty acid ester derivatives and carotenes. In the unsaponified sample, trans-zeaxanthin (maximum absorption wavelength: 451 nm) was the predominant free xanthophyll, followed by trans-lutein (maximum absorption wavelength: 445 nm). Small amounts of trans-β-cryptoxanthin (maximum absorption wavelength: 452 nm) and small amounts of cis-zeaxanthin were also present. Complex peaks were also detected in the latter half of the sample. These complex peaks were found to be partly carotenes and xanthophylls esters (mainly composed of trans-zeaxanthin, lutein, and β-cryptoxanthin) after alkaline saponification. After alkaline saponification, numerous peaks were observed around the peaks of free zeaxanthin, free lutein, and free β-cryptoxanthin. The absorption maxima of all these peaks shifted 5-10 nm to the lower wavelength side, and a cis-isomer-dependent maximum appeared around 330 nm, indicating that they were cis-zeaxanthin, cis-lutein, and cis-β-cryptoxanthin. Similar peak variations were also observed for each of the carotene components. Taking these results together, it is believed that approximately 57% of the xanthophylls in the composition were cis-xanthophylls. Note that, because the absorption maxima of cis-type peaks usually shift to the lower wavelength side, it is believed that the cis-xanthophylls contained in the composition were higher than this figure.

[0098] 11. Study of cis-isomerization of crocins (crocetin glycosides) derived from saffron. Approximately 1 g of commercially available saffron (produced in Spain, House Foods, Japan) was weighed, 50 mL of MeOH was added, and the mixture was stirred thoroughly. 100 mL of chloroform was then added and further stirred vigorously. This was referred to as the saffron extract. A portion of the extract was taken, dried under a nitrogen stream, dissolved in MTBE / MeOH (1:2), and analyzed by HPLC. Similarly, a portion was subjected to alkaline saponification. To carry out the method, 1 mL of the above extract was placed in a glass screw centrifuge tube, and 1 mL of 60% KOH / EtOH was added and stirred vigorously. After stirring, the mixture was incubated at 50°C for 1 hour. Immediately after the treatment, 3 mL of MTBE, 3 mL of saturated aqueous sodium sulfate, and 0.3 mL of phosphoric acid were added, vigorously stirred, and centrifuged at 3,000 rpm for 10 minutes. After confirming separation into two layers, 3 mL of the upper layer, to which the dye had completely transferred, was collected, appropriately concentrated under a nitrogen stream, and subjected to HPLC. The remaining MTBE / MeOH (1:2) solution was evaporated to dryness under reduced pressure, dissolved in approximately 15 mL of MCT, and subjected to cis-isomerization by heating in the same manner as in Example 7. After the reaction, alkaline saponification was performed in the same manner as for the unreacted material. The HPLC gradient conditions and other conditions were as shown in Table 12 below. The HPLC results are shown in Figure 7. (HPLC conditions) HPLC system: LC-2030 (Shimadzu Corporation) Detector: Photodiode array detector (300-700 nm) Column: YMC Carotenoid, length: 150 mm, inner diameter: 4.6 mm, particle size: 3 μm, manufactured by YMC Mobile phase A: 1% phosphoric acid Mobile phase B: acetonitrile (AcN) Flow rate: 1.0 mL / min Detection wavelength: 420 nm ＊＊ Column temperature: 30°C. Under these conditions, the chromatogram was corrected using the highest peak as the standard.

[0099]

[0100] The HPLC chromatogram shown in Figure 7 revealed multiple peaks in the unsaponified sample, which were converted to trans-crocetin by alkaline saponification. This suggests that almost all of the pigments contained in the sample were trans-crocins, glycosides of crocetin. In other words, trans-crocetin (maximum absorption wavelengths: 427 nm, 451 nm) was present as the main free xanthophyll in the saponified sample. After cis-conversion, alkaline saponification revealed numerous peaks surrounding the trans-crocetin. These peaks were considered to represent cis-crocetin because their absorption maxima shifted 5 to 20 nm from trans-crocetin. In particular, the peak immediately following all-trans-crocetin exhibited an absorption maxima shifted approximately 5 nm toward the lower wavelength side, and a peak characteristic of cis-carotenoids was observed at 316 nm, suggesting that it was 13-cis-crocetin. These glycosides (crocins) were therefore considered to exist in the cis form. In summary, it is believed that cis-crocins accounted for approximately 49% of the crocins in the composition. However, since the cis-crocin peak usually has a maximum absorption shift to the lower wavelength side, it is believed that the cis-crocin content is higher than this figure.

[0101] Although the preferred embodiments of the present invention have been described above, the present invention is not limited to these embodiments. Addition, omission, substitution, and other modifications of the configuration are possible within the scope of the spirit of the present invention. The present invention is not limited by the above description, but is limited only by the scope of the appended claims.

Claims

1. Contains cis-xanthophyll derivatives and cis-xanthophyll, the content (molar ratio) of the cis-xanthophyll derivative relative to the content of the cis-xanthophyll is 0.05 to 1000; The composition comprises one or more cis-xanthophyll derivatives selected from the group consisting of lipid esters of cis-xanthophyll, glycosides of cis-xanthophyll, fatty acid glycosides of cis-xanthophyll, aliphatic ethers of cis-xanthophyll, and sulfate esters of cis-xanthophyll.

2. The composition according to claim 1, wherein the proportion of the cis-xanthophyll derivative in the total xanthophyll derivatives in the composition is 30% or more.

3. The composition according to claim 1, wherein the cis-xanthophyll derivative comprises a lipid ester of cis-xanthophyll.

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

5. The composition according to claim 1, wherein the cis-xanthophyll derivative comprises one or more cis-xanthophyll derivatives selected from the group consisting of cis-lutein derivatives, cis-zeaxanthin derivatives, and cis-astaxanthin derivatives.

6. The composition according to claim 1 , wherein the cis-xanthophyll derivative comprises a cis-lutein derivative.

7. The composition according to claim 1 , wherein the cis-xanthophyll derivative comprises a cis-zeaxanthin derivative.

8. The composition according to claim 1 , wherein the cis-xanthophyll derivative comprises a cis-astaxanthin derivative.

9. A pharmaceutical comprising the composition of claim 1.

10. A food product comprising the composition of claim 1.

11. A cosmetic product comprising the composition according to claim 1.