Oral components

Abstract

The present invention provides an oral composition containing (A) a lipid-soluble substance and (B) crocin, which exhibits excellent stability against light and / or heat and excellent oral absorption. [Solution] Prepare an oral composition containing (A) a lipid-soluble substance and (B) an amphiphilic carotenoid, which form a complex in the composition.

Description

Technical Field

[0001] The present invention relates to an oral composition containing a fat-soluble substance and an amphiphilic carotenoid, which form a complex.

Background Art

[0002] It has been proposed that naturally occurring carotenoids such as lutein and zeaxanthin are used in foods including supplements due to their physiological activities (Patent Document 1).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] On the other hand, compositions containing fat-soluble substances such as these carotenoids are unstable and have a problem of low absorbability in the body.

[0005] Therefore, an object of the present invention is to provide an oral composition containing a fat-soluble substance having good stability and excellent absorbability in the body.

Means for Solving the Problems

[0006] As a result of intensive studies, the present inventors have surprisingly found that by including (B) an amphiphilic carotenoid in (A) a fat-soluble substance to form a complex, an oral composition having excellent absorbability in the body and high stability against light or heat can be obtained, and the present invention has been completed.

[0007] That is, the present invention provides the following oral composition. Item 1. An oral composition containing (A) a lipid-soluble substance and (B) an amphiphilic carotenoid, which form a complex within the composition. Section 2. The oral composition according to item 1, wherein the complex can be confirmed to form aggregates by electron microscopy observation. Section 3. The oral composition according to claim 1 or claim 2, wherein the content of component (A) is 0.0001 to 50% by mass. Section 4. An oral composition according to any one of items 1 to 3, wherein the content of component (B) is 0.01 to 85% by mass. Section 5. The oral composition according to items 1 to 4, wherein component (A) is a carotenoid, a polyphenol, or a vitamin. Section 6. The composition according to claim 5, wherein component (A) is one or more selected from the group consisting of lutein, zeaxanthin, capsanthin, canthaxanthin, fucoxanthin, violaxanthin, astaxanthin, quercetin, nobiletin, vitamin A, hesperidin, curcumin, luteolin, and lycopene. Claim 7. The composition according to any one of items 1 to 6, wherein the component (B) is a glycoside. Section 8. The composition according to item 7, wherein component (B) is crocin. Section 9. A method for improving the photo and / or thermal stability of a lipid-soluble substance (A) contained in a composition by coexisting with (B) an amphiphilic carotenoid in the composition (A). Section 10. A method for improving the oral absorption of (A) a lipid-soluble substance by coexisting (B) an amphiphilic carotenoid glycoside with (A) an oral composition containing the lipid-soluble substance. [Effects of the Invention]

[0008] The oral composition of the present invention contains a lipid-soluble substance and an amphiphilic carotenoid, and because they form a complex, it has good stability against light and / or heat, and its absorption into the body is improved.

Brief Description of Drawings

[0009] [Figure 1] Figure 1 is a transmission electron micrograph of the formulation of Example 1. [Figure 2] Figure 2 is a graph showing the oral absorbability of lutein in the formulation of Example 1. [Figure 3] Figure 3 is a graph showing the oral absorbability of lutein in the formulation of Example 4.

Modes for Carrying Out the Invention

[0010] [Oral Composition] The oral composition of the present invention contains (A) a fat-soluble substance and (B) an amphiphilic carotenoid, and is an oral composition in which (A) the fat-soluble substance and (B) the amphiphilic carotenoid form a complex in the composition.

[0011] ((A) Fat-soluble substance) In the present specification, the fat-soluble substance can be, for example, a compound having a π-conjugated system. Further, the fat-soluble substance preferably has a linear molecular structure. Here, when the component (A) is a compound having a π-conjugated system, the number of π can be 1 to 15. The number of π may also be 2 to 11.

[0012] In addition, the fat-soluble substance can be a compound having a LogP value greater than 0. When it is a compound having a LogP value greater than 0, the LogP value is preferably 0.1 to 20.

[0013] In addition, when the fat-soluble substance is solid, after being made into powder and put into a solvent, when vigorously shaken for 30 seconds at 20 ± 5°C, the amount of solvent capable of dissolving 1 g or 1 mL can be 30 mL or more. More preferably, it is 100 mL, and even more preferably 200 mL or more. The powder defined here is not particularly defined, but refers to those corresponding to the sieve degrees and powder degrees defined in the Japanese Pharmacopoeia.

[0014] The (A) component typically refers to one or more selected from the group consisting of polyphenols, carotenoids, and vitamins.

[0015] Examples of polyphenols include flavonoids such as catechin, anthocyanin, hesperidin, luteolin, quercetin, rutin, nobiletin, daidzein, genistin, etc.; phenylpropanoids such as lignan, chlorogenic acid, coumarin, eugenol, sesamin, magnolol, cinnamic acid, caffeic acid, coumaric acid, ferulic acid, etc.; curcuminoids such as curcumin, gingerol, etc.; stilbenoids such as resveratrol, etc.; ellagic acid, etc.

[0016] Specific examples of carotenoids include carotenes such as α-carotene, β-carotene, γ-carotene, lycopene, etc.; xanthophylls such as actinorhodin, canthaxanthin, capsorubin, astaxanthin, fucoxanthin, lutein, zeaxanthin, capsanthin, β-cryptoxanthin, violaxanthin, and their derivatives, etc.; apocarotenoids such as bixin, β-8’-apo-carotenal (apocarotenal), β-12’-apo-carotenal, and their derivatives, etc. Here, the derivatives in apocarotenoids may include ester compounds of bixin, β-8’-apo-carotenal (apocarotenal), β-12’-apo-carotenal, etc. with lower alcohols or higher alcohols.

[0017] Examples of vitamins include vitamin A, vitamin D, vitamin E, and vitamin K, etc.

[0018] In one aspect of the present invention, when using a carotenoid as the (A) component, one or more selected from the group consisting of lutein, lycopene, zeaxanthin, capsanthin, canthaxanthin, fucoxanthin, violaxanthin, and astaxanthin are more preferable.

[0019] Furthermore, these forms may include crystalline, amorphous, and nanoparticle forms. For example, lutein can be used as a composite material in various forms, such as crystalline lutein, amorphous lutein, and nanoparticle lutein. That is, crystalline lutein is preferred for improving the stability of the composition, but amorphous forms can also be used.

[0020] In one embodiment of the present invention, when polyphenols are used as component (A), one or more selected from the group consisting of hesperidin, curcumin, catechin, anthocyanin, luteolin, nobiletin, and quercetin are more preferable. Furthermore, these may take various forms such as crystalline, amorphous, or nanoparticle forms.

[0021] In one embodiment of the present invention, when a vitamin is used as component (A), one or more selected from the group consisting of vitamin A, vitamin D, and vitamin E are more preferable.

[0022] These substances may all be used individually, or two or more may be used in any combination.

[0023] The total content of component (A) in the oral composition of the present invention is preferably 0.0001% by mass or more, more preferably 0.001% by mass or more, and even more preferably 0.01% by mass or more, based on the total amount of the oral composition. It may also be, for example, 0.1% by mass or more, 1% by mass or more, 10% by mass, 20% by mass, or 30% by mass. It may also be, for example, 70% by mass or less, preferably 65% ​​by mass or less, more preferably 60% by mass or less, and even more preferably 55% by mass or less, and for example, 50% by mass or less.

[0024] The amount of component (A) in the oral composition of the present invention, expressed as a daily intake for humans, can be, for example, 0.1 mg to 3000 mg, preferably 0.15 mg to 2500 mg, and more preferably 0.2 mg to 2000 mg. It may also be 0.01 mg or more, 0.05 mg or more, 0.1 mg or more, 1 mg or more, 5 mg or more, 10 mg or more, 30 mg or more, 50 mg or more, 100 mg or more, or 3000 mg or less, 2000 mg or less, 1000 mg or less, 500 mg or less, 250 mg or less, or 200 mg or less.

[0025] If component (A) is lutein, the amount of component (A) included, expressed as the daily intake for humans, could be, for example, 0.1 mg to 200 mg, preferably 1 mg to 100 mg, and more preferably 5 mg to 50 mg or 5 to 20 mg. It could be 1 mg or more, 5 mg or more, 10 mg or more, 20 mg or more, 40 mg or more, 50 mg or more, 60 mg or more, 80 mg or more, or 100 mg or more, and could be 200 mg or less, 150 mg or less, 100 mg or less, 80 mg or less, 60 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, or 20 mg or less.

[0026] (A) When component (A) is zeaxanthin, the amount of component (A) included, expressed as a human daily intake, is, for example, 0.05 mg to 10 mg, preferably 0.1 mg to 6 mg, and more preferably 0.8 mg to 4 mg. It may be 0.1 mg or more, 0.5 mg or more, 1 mg or more, and 10 mg or less, 7 mg or less, or 5 mg or less.

[0027] If component (A) is luteolin, the amount of component (A) included, expressed as a human daily intake, could be, for example, 1 mg to 100 mg, preferably 5 mg to 50 mg, and more preferably 8 mg to 30 mg or 10 to 20 mg. It could be 1 mg or more, 3 mg or more, 5 mg or more, 10 mg or more, 12 mg or more, 15 mg or more, 18 mg or more, 20 mg or more, or 25 mg or more, and could be 100 mg or less, 90 mg or less, 80 mg or less, 70 mg or less, 60 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, or 20 mg or less.

[0028] If component (A) is curcumin, the amount of component (A) included, expressed as the daily intake for humans, could be, for example, 1 mg to 200 mg, preferably 10 mg to 150 mg, and more preferably 50 mg to 100 mg or 70 to 90 mg. It could be 10 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 55 mg or more, 65 mg or more, 70 mg or more, or 80 mg or more, and could be 200 mg or less, 180 mg or less, 150 mg or less, 130 mg or less, 120 mg or less, 110 mg or less, 100 mg or less, 90 mg or less, or 80 mg or less.

[0029] If component (A) is hesperidin, the amount of component (A) included, expressed as a human daily intake, could be, for example, 10 mg to 300 mg, preferably 20 mg to 250 mg, and more preferably 40 mg to 200 mg or 55 mg to 140 mg. It could be 10 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 60 mg or more, 80 mg or more, 100 mg or more, or 120 mg or more, and could be 300 mg or less, 280 mg or less, 250 mg or less, 230 mg or less, 200 mg or less, 180 mg or less, 150 mg or less, 100 mg or less, or 60 mg or less.

[0030] ((B) Amphipathic carotenoids) In this specification, the term "amphiphilic carotenoid" refers to a substance in which a hydrophilic group, such as a hydroxyl group or an amino group, is attached to a carotenoid. Typically, it refers to a substance in which a sugar component is glycosidically bonded to a carotenoid, forming an O-glycoside or C-glycoside. The number of sugar component bonds is not particularly limited, and sugar components may be attached to one or more locations on the carotenoid. Examples of carotenoids include carotenes such as α-carotene, β-carotene, γ-carotene, and lycopene; xanthophylls such as actinioerythritol, canthaxanthin, capsorbin, astaxanthin, fucoxanthin, lutein, zeaxanthin, capsanthin, β-cryptoxanthin, violaxanthin, and their derivatives; and apocarotenoids such as crocetin, mycolazicin, bixin, β-8'-apo-carotenal (apocarotenal), β-12'-apo-carotenal, and their derivatives. The sugar components bound to the carotenoids may be oligosaccharides such as monosaccharides, disaccharides, trisaccharides, and tetrasaccharides. While not limited to these, specific examples of such sugar components include monosaccharides such as glucose, rhamnose, apiose, glucuronic acid, and xylose; disaccharides such as genthiobiose, maltose, sucrose, lactose, glucuronosylglucuronic acid, and glucuronosylglucuronic acid; and trisaccharides such as gentiotriose, maltotriose, raffinose, panose, glucuronosylgenthiobiose, and glucosylgenthiobiose. Among these sugar components, glucose or genthiobiose is preferred, and genthiobiose is more preferred.

[0031] In one embodiment of the present invention, component (B) may be a natural pigment containing an amphiphilic carotenoid. While not limited to these, for example, gardenia yellow pigment or saffron pigment may be used. Rhodoping glycoside, myxol glycoside, or crocin may also be used. Crocin is particularly preferred as component (B) of the present invention, and gardenia pigment containing crocin may also be used as is.

[0032] The total content of component (B) in the oral composition of the present invention is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, and even more preferably 1% by mass or more, as the amount of amphiphilic carotenoid itself, relative to the total amount of the oral composition. For example, it may be 3% by mass or more, or for example, 95% by mass or less, preferably 93% by mass or less, more preferably 90% by mass or less, and even more preferably 87% by mass or less, and for example, 85% by mass or less. The total content of component (B) also varies depending on the component (A) that is blended, but in some cases it may be 5% by mass or more, 10% by mass or more, 20% by mass or more, 30% by mass or more, 50% by mass or more, and may also be 80% by mass or less, 70% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, and 20% by mass or less.

[0033] The dosage of the oral composition of the present invention is not particularly limited, but for example, the daily dose of component (B) can be 0.01 mg to 1000 mg, preferably 0.03 mg to 500 mg, more preferably 1 mg to 100 mg. It may also be 0.01 mg or more, 0.03 mg or more, 0.05 mg or more, 0.1 mg or more, 1 mg or more, 3000 mg or less, 1000 mg or less, 500 mg or less, 250 mg or less, or 100 mg or less. The daily dose of component (B) also varies depending on the component (A) that is included, but may be 5 mg or more, 10 mg or more, 20 mg or more, 30 mg or more, 50 mg or more, or 150 mg or less, 80 mg or less, 60 mg or less, 50 mg or less, or 40 mg or less.

[0034] (complex) In the oral composition of the present invention, (A) a lipid-soluble substance and (B) an amphiphilic carotenoid form a complex within the composition. The formation of the complex can be verified by electron microscopy, which confirms the formation of aggregates within the composition. Alternatively, the complex can be confirmed by nuclear magnetic resonance (NMR) under the same conditions. 1 This can be verified by observing whether a change (chemical shift) of 0.01δ / ppm or more, preferably 0.1δ / ppm or more, occurs in the HNMR value compared to before complex formation.

[0035] In the oral composition of the present invention, the ratio of parts by mass of component (A) to component (B) is preferably 0.1 to 100 parts by mass, more preferably 0.5 to 50 parts by mass, and even more preferably 1 to 10 parts by mass of component (B) per 1 part by mass of component (A). Component (B) may be 0.01 parts by mass or more, 0.1 parts by mass or more, 0.5 parts by mass or more, 1 part by mass or more, or 500 parts by mass or less, 200 parts by mass or less, 100 parts by mass or less, 80 parts by mass or less, 50 parts by mass or less, 25 parts by mass or less, or 10 parts by mass or less.

[0036] The composite may have a micelle-like structure with component (A) at the center and component (B) surrounding it. The particle size of the composite is not limited, but as measured by dynamic light scattering, it may be 10 to 500 nm, preferably 25 to 400 nm, and more preferably 25 to 300 nm. It may be 1 nm or more, 10 nm or more, 20 nm or more, 25 nm or more, 50 nm or more, 100 nm or more, and 1000 nm or less, 500 nm or less, 400 nm or less, 300 nm or less, or 200 nm or less.

[0037] (water) In the internal composition of the present invention, the water content is preferably such that the rate of change in mass (Tg value) measured by a thermogravimetric-differential thermal analyzer is 0 to 20%, more preferably 0 to 15%, and even more preferably 0 to 10%. When the water content is within this range, the effects of the present invention can be better exhibited.

[0038] The internally administered composition of the present invention preferably contains fats and oils such as animal and vegetable oils and synthetic oils, from the viewpoint of dispersibility and stability. Here, the fats and oils are not particularly limited, but include vegetable oils such as safflower oil, grape seed oil, sunflower oil, olive oil, corn oil, sesame oil, soybean oil, soybean germ oil, rapeseed oil, high oleic acid rapeseed oil, perilla oil, flaxseed oil, peanut oil, safflower oil, cottonseed oil, walnut oil, wheat germ oil, fish oil (EPA / DHA), palm oil, coconut oil, and cocoa butter; animal fats such as beef tallow, lard, chicken fat, milk fat, and algae oil; as well as synthetic oils such as diglycerides and medium-chain triglyceride fatty acids, fractionated oils, transesterified oils, and hydrogenated oils. Vegetable oils are considered preferred fats and oils, with safflower oil, grape seed oil, sunflower oil, olive oil, corn oil, sesame oil, soybean oil, rapeseed oil, and perilla oil being more preferred, and safflower oil, grape seed oil, sunflower oil, olive oil, and corn oil being even more preferred.

[0039] The amount of oil and fat included in the oral composition of the present invention, expressed as a human daily intake, can be, for example, 1 mg to 2000 mg, preferably 10 mg to 1000 mg, and more preferably 100 mg to 500 mg.

[0040] The oral composition of the present invention may contain other components suitable for the intended use of the oral composition of the present invention. Other components include components that are commonly known for their use. Long-chain fatty acids can be added to the oral composition of the present invention, and suitable long-chain fatty acids include, for example, α-linoleic acid, γ-linolenic acid, linoleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Fish oil can also be used as eicosapentaenoic acid and docosahexaenoic acid. Vitamin A, vitamin B (vitamin B 12 Vitamins such as vitamin C, vitamin D, and vitamin E, and minerals such as calcium, iron, manganese, and zinc can be added.

[0041] The formulation of the oral composition of the present invention is not particularly limited, as long as it contains component (A) and component (B) and forms a complex that can be taken orally. Specifically, examples include powders, fine granules, granular preparations, pills, capsules (including hard capsules and soft capsules), tablets [including uncoated tablets, sugar-coated tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, lozenges, film-coated tablets, etc.], dry syrups, liposomal preparations, etc. Among these, solid formulations are preferred from the viewpoint of further demonstrating the effects of the present invention and versatility, capsules are more preferred, and soft capsules are even more preferred.

[0042] The above-mentioned formulations can be prepared by adding excipients, and optionally binders, disintegrants, lubricants, colorants, flavoring agents, odorants, etc., to the above-mentioned composition according to conventional methods. As additives, those commonly used in the field may be used. For example, excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and silicic acid. Binders include ethanol, propanol, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, calcium phosphate, and polyvinylpyrrolidone. Disintegrants include dried starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate, and lactose. Lubricants include refined talc, stearate, borax, and polyethylene glycol. Flavoring agents include sucrose, orange peel, citric acid, and tartaric acid. Furthermore, emulsifiers, thickeners, sweeteners, acidulants, flavorings, amino acids, etc., can be added. Specifically, examples include sugars such as sucrose, isomerized sugar, glucose, fructose, palatinose, trehalose, lactose, and xylose; sugar alcohols such as sorbitol, xylitol, erythritol, lactitol, palatinose, reduced starch syrup, and reduced maltose syrup; high-intensity sweeteners such as aspartame, stevia, acesulfame potassium, and sucralose; emulsifiers such as sucrose fatty acid esters, glycerin fatty acid esters, and lecithin; thickeners (stabilizers) such as carrageenan, xanthan gum, guar gum, pectin, and locust bean gum; and acidulants such as citric acid, lactic acid, and malic acid.

[0043] Furthermore, the oral composition of the present invention may substantially contain or completely contain one or more of the above-mentioned additives.

[0044] (Containers, packaging, and contents) The container or packaging for the oral composition of the present invention is not particularly limited, as long as it is capable of containing the oral composition.

[0045] The oral composition of the present invention is preferable in that it can reduce the effects of light and heat, even when the oral composition is a solid dosage form and is stored in a manner in which differences in storage conditions between solid dosage forms are likely to occur (for example, when the solid dosage form is not individually packaged). Preferred packaging for the solid dosage form is aluminum pouch packaging, glass bottle packaging, or plastic bottle packaging. Examples of individual packaging include PTP packaging, SP packaging, pillow packaging, and stick packaging.

[0046] [Manufacturing method] The oral composition of the present invention can be produced by mixing component (A) and component (B) in a solvent and performing a solvent evaporation method or the like. A tetrahydrofuran aqueous mixture is preferably used as the solvent. Although not limited, crystalline lutein and crocin can be dissolved in a tetrahydrofuran aqueous mixture in equimolar amounts or in a fixed ratio, and then the solvent can be removed by distillation to obtain the formulation. Alternatively, component (A) and component (B) can be mixed in an aqueous solvent and produced by means of wet grinding or dispersion treatment. Water or an aqueous solution is preferably used as the aqueous solvent. Although not limited, a suspension of finely ground lutein can be obtained by dispersing crystalline lutein in an aqueous crocin solution and performing a bead mill treatment. Subsequently, a stable lutein / crocin complex powder can be obtained by drying the suspension.

[0047] (Application) Uses of the internally administered composition of the present invention include eye protection. More specifically, uses include increasing macular pigment in the retina to reduce blurring and haze, improving the ability to see clearly (contrast sensitivity), or protecting the eyes from light stimuli such as blue light.

[0048] (Dosage / Dosage) The timing of administration of the oral composition of the present invention is not particularly limited, but it is preferable to administer or ingest it orally 1 to 3 times a day, for example.

[0049] [Stability enhancer] The stability enhancer of the present invention is a stability enhancer for compositions containing lipophilic carotenoids, which contain amphiphilic carotenoids. Here, stability particularly includes stability after exposure to light or heat.

[0050] The types and amounts of each component in the above-mentioned stability enhancer, as well as other conditions, shall be in accordance with the contents described in the [Oral Composition] section above.

[0051] [Methods to improve stability] The present invention includes a method for improving the stability of a composition containing a lipid-soluble carotenoid, which involves coexisting with an amphiphilic carotenoid to form a complex.

[0052] The types and amounts of each component in the above method, the types and amounts of other components, and the form of the composition shall be in accordance with the contents described in the [Oral Composition] section above.

[0053] [Absorptive enhancer] The present invention provides an absorption enhancer for compositions containing amphiphilic carotenoids and lipid-soluble carotenoids. Here, improved absorption primarily refers to an increase in the blood concentration (e.g., plasma concentration) of the target component after oral ingestion. The types and amounts of each component in this method, the types and amounts of other components, and the form of the composition are as described in the section on [Oral Compositions] above.

[0054] [Methods to improve absorption in the body] Furthermore, the present invention includes a method for improving the bioavailability of lipid-soluble carotenoids, which involves coexisting lipid-soluble carotenoids and amphiphilic carotenoids to form a complex. Here, improved bioavailability mainly refers to an increase in the blood concentration (e.g., plasma concentration) of the target component after oral ingestion. The types and contents of each component in this method, the types and contents of other components, and the form of the composition are in accordance with the contents described in the [Oral Composition] section above. [Examples]

[0055] Next, the present invention will be specifically described with reference to examples and test cases, but the present invention is not limited to the following examples and test cases. Unless otherwise specified, the units of the amounts of each component in the table are in mass percent.

[0056] [Raw materials used] In the following test example, the materials were first prepared as follows. Crystalline lutein used in Examples 1-3: 3 mL of FloraGLO® lutein 20% SAF was mixed with 3 mL of n-hexane and stirred. The mixture was then centrifuged (1,250 × g, 5 min) and the supernatant was removed. These steps were repeated three times, and the resulting Crystalline LT was dried in a desiccator. Amorphous lutein was obtained by dissolving the above-mentioned crystalline lutein in THF and removing the solvent using an evaporator. The crystalline lutein used in Example 4 was added to 5 mL of n-hexane and mixed with 5 mL of Flora GLO® lutein 20% SAF. This mixture was centrifuged (1,250 × g, 5 min) and the supernatant was removed. This procedure was repeated three times, and the resulting Crystalline LT was dried in a desiccator for 2 days. Curcumin: Tokyo Chemical Industry Co., Ltd. Luteolin: Tokyo Chemical Industry Co., Ltd. Hesperidin: Tokyo Chemical Industry Co., Ltd. Crocin was prepared using Gardenia Yellow E10%5000 (manufactured by Zhongda Hengyuan). Moisture content was measured using a TG-DTA (thermogravimetric-differential thermal analyzer: HITACHI STA200RV) and confirmed by mass change. Approximately 5 mg was weighed, heated from room temperature to 100°C for 5 minutes, and then held for 10 minutes. The mass change (Tg value) (%) was then confirmed.

[0057] (Examples 1-3) As shown in the table below, crystalline lutein and crocin were dissolved in 50 mL of a 70% tetrahydrofuran aqueous mixture at molar ratios of 1:1, 1:5, and 1:10, respectively. [Table 1] Subsequently, the solvent was evaporated using an evaporator to prepare a formulation in which lutein and crocin were combined. The Tg value of Example 1 was 4.6%, and the Tg value of Example 3 was 3.8%. The particle size measured by dynamic light scattering and the resulting transmission electron microscope image of this formulation dispersed in water are shown in Figure 1. (Figure 1 represents the formulation of Example 1.)

[0058] (Example 4) A complex of nanoparticle-formed lutein and crocin (nLT / CR) was prepared. 100 mg of crystalline lutein (LT), 207 g of 0.1 mm diameter zirconia balls, and 46 mL of a 3.7 mg / mL aqueous solution of crocin (CR) were added to Apex LABO (Hiroshima Metal & Machinery, Hiroshima, Japan), and the mixture was operated at a tip speed of 8 m / s for 60 min. The resulting LT pulverized suspension was then freeze-dried in a freeze-dryer (FD-1000, Tokyo Rika Kiki Co., Ltd., Tokyo, Japan) to obtain nLT / CR.

[0059] (Examples 5-7) Luteolin and crocin (Example 5), curcumin and crocin (Example 6), and hesperidin and crocin (Example 7) were each dissolved in 50 mL of a 70% tetrahydrofuran aqueous mixture in a molar ratio of 1:5, and the solvent was evaporated using an evaporator to prepare the formulations of Examples 5 to 7.

[0060] [Test Example 1. Confirmation Test of the Photostability of the Composition] Crystalline lutein (Crystalline LT), amorphous lutein (Amorphous LT), the formulation from Example 1, and a DMSO solution (3 mg / mL, LT Solution) containing dissolved lutein were added to a 96-well microplate (manufactured by Asahi Glass Co., Ltd.) to a total lutein amount of 3 mg. A quartz lid was then placed on the plate, and simulated sunlight (250 W / m²) was generated using Atlas Suntest CPS+ (Atlas Material Technology LLC, Chicago, USA). 2 The samples were irradiated for 30, 60, 90, and 120 minutes. After irradiation, the samples were dissolved in 1 mL of DMSO, diluted 3000-fold with methanol, and the remaining amount of lutein was measured using HPLC / UV under the conditions shown below.

[0061] Column: Inertsil® ODS-4 (GL Sciences Inc., Tokyo, Japan) (Particle size: 3 μm, Column size: 4.6 × 150 mm) Column temperature: 40°C Mobile phase solution: A: Milli Q solution B: Methanol Isocratec program: A:B = 4:96 Flow rate: 1.0 mL / min Injection volume: 25 μL Detection: SPD-20A VP UV-VIS detector (Shimadzu, Kyoto, Japan) Wavelength: LT 445 nm Retention time: LT: Approx. 5.8 min

[0062] These results are shown in Table 2. [Table 2] Two hours after light irradiation, the amount of lutein remaining in amorphous lutein was 64%, but the lutein degradation in the formulation of Example 1 was very slight.

[0063] Similarly, the formulation from Example 5 was added to a 96-well microplate (manufactured by Asahi Glass Co., Ltd.) to a concentration of 3 mg of luteolin. A quartz lid was then placed over the plate, and simulated sunlight (250 W / m²) was generated using Atlas Suntest CPS+ (Atlas Material Technology LLC, Chicago, USA). 2 The sample was irradiated for 2 hours. The results are shown in Table 3. The data shows the mean ± standard error of the four experiments. Luteolin degradation in the formulation of Example 5 was suppressed compared to luteolin alone. [Table 3]

[0064] Separately, the formulation from Example 6 was added to a 96-well microplate (manufactured by Asahi Glass Co., Ltd.) to a curcumin content of 3 mg. Then, a quartz lid was placed on the plate, and simulated sunlight (750 W / m²) was generated using Atlas Suntest CPS+ (Atlas Material Technology LLC, Chicago, USA). 2 The sample was irradiated with ) for 1 hour. The results are shown in Table 4. The data shows the mean ± standard error of the four experiments. Curcumin degradation in the formulation of Example 6 was suppressed compared to curcumin alone. [Table 4]

[0065] [Test Example 2. Confirmation Test of Thermal Stability of Composition] Crystalline lutein (Crystalline LT), and the formulations from Examples 2 and 3 were stored at 60°C for 6, 12, and 24 hours. The stored formulations were dissolved in 1 mL of DMSO, diluted 3000-fold with methanol, and the remaining amount of lutein (%) was measured using HPLC / UV under the same conditions as in Test Example 1. [Table 5] After storage at 60°C for 24 hours, the remaining crystalline lutein was 24%, but in Examples 2 and 3, there was almost no decrease in lutein content throughout the 24 hours. From this, it was confirmed that the composition can improve stability regardless of the ratio of component (A) to component (B).

[0066] [Test Example 3. Pharmacokinetic Evaluation of the Composition] Laboratory animals Ten-week-old male Sprague-Dawley rats (manufactured by Nippon SLC Co., Ltd., weighing approximately 360g) were used as experimental animals. They were given free access to solid feed (manufactured by Oriental Yeast Co., Ltd.) and drinking water, and were housed at room temperature of 24±1℃, humidity of 55±5%, and under a 12-hour light-dark cycle. All animal experiments were conducted in accordance with the guidelines of the Shizuoka Prefectural University Laboratory Animal Ethics Committee.

[0067] Plasma concentration measurement Crystalline lutein (100 mg / kg), crystalline lutein (300 mg / kg), the formulation from Example 1 (lutein amount 50 mg / kg), and the formulation from Example 4 were orally administered to rats. At each time interval (1, 2, 4, 6, 8, 12, 24, and 48 hours), 400 μL of blood was collected from the tail vein of the rats and added to a tube containing heparin (100 units / mL). The obtained blood samples were centrifuged (10,000 × g, 10 min, 4°C) using a KUBOTA refrigerated centrifuge 3500 (manufactured by Kubota Shoji Co., Ltd.) to obtain plasma. To 100 μL of each plasma sample, 200 μL of methanol containing anthracene (1 μg / mL) as an internal standard and 900 μL of hexane were added, mixed, and then centrifuged (10,000 × g, 10 min, 4°C). The obtained supernatant was dried by blowing nitrogen gas onto it, and the resulting solid was dissolved in 100 μL of methanol to obtain the plasma sample. The plasma lutein concentration was measured using UHPLC / PDA under the same conditions as in Test Example 1.

[0068] To each 50 μL of plasma, 150 μL of MeOH / DMSO mixture (1:4 v / v) containing anthracene (1 μg / mL) as an internal standard was added, and the mixture was cooled on ice for 10 minutes, followed by centrifugation (10,000 × g, 10 min, 4°C). The resulting supernatant was filtered through a 0.2 μm filter to obtain the plasma sample, and the crocetin concentration in each plasma was measured using UHPLC / PDA under the conditions described below.

[0069] Column YMX-Triart C8 (Particle size: 1.9 μm; Column size: 2.1 mm × 75 mm) Column temperature 40°C Mobile phase A: Milli-Q containing 0.1% formic acid Solution B: 2-propanol The gradient program is constructed as follows: [Table 6]

[0070] Flow rate 0.25mL / min Injection volume 25μL Detection wavelength: SPD-10A VP UV-PDA detector (Shimadzu Corporation) 445 nm Retention time for crocetin: approximately 4.6 min

[0071] Oral administration of the formulation from Example 1 revealed good oral absorption of lutein and crocetin (Figure 2). Furthermore, it was found that lutein and crocetin in nanoparticle form (formulation from Example 4) also exhibited good oral absorption (Figure 3).

[0072] Examples of formulations are shown below. [Table 7] [Table 8] [Table 9]

Claims

1. An oral composition containing (A) a lipid-soluble substance and (B) an amphiphilic carotenoid, which form a complex within the composition.

2. The oral composition according to claim 1, wherein the complex can be confirmed to form an aggregate by electron microscope observation.

3. The oral composition according to claim 1, wherein the content of component (A) is 0.0001 to 50% by mass.

4. The oral composition according to claim 1, wherein the content of component (B) is 0.01 to 85% by mass.

5. The oral composition according to claim 1, wherein component (A) is a carotenoid, a polyphenol, or a vitamin.

6. The composition according to claim 5, wherein the component (A) is one or more selected from the group consisting of lutein, zeaxanthin, capsanthin, canthaxanthin, fucoxanthin, violaxanthin, astaxanthin, quercetin, nobiletin, vitamin A, hesperidin, curcumin, luteolin, and lycopene.

7. The composition according to any one of claims 1 to 6, wherein component (B) is a glycoside.

8. The composition according to claim 7, wherein component (B) is crocin.

9. A method for improving the photo and / or thermal stability of a lipid-soluble substance (A) contained in a composition by coexisting with (B) an amphiphilic carotenoid in the composition (A).

10. A method for improving the oral absorption of a lipid-soluble substance by coexisting with an amphiphilic carotenoid glycoside in an oral composition containing a lipid-soluble substance (A).

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