JP7061574B2 - Oral agent - Google Patents

Description

The present invention relates to an internal preparation.

Demand for oral preparations containing functional ingredients having various physiological activities is increasing as health foods. Oral preparations are required to be uniformly dispersed in water (dispersibility) so as to exert a stable effect when disintegrated in the body. When the functional component is a poorly soluble component, an emulsifier (for example, glycerin fatty acid ester) that can be used for food for dispersibility is used in combination (for example, Patent Documents 1 and 2).

Japanese Unexamined Patent Publication No. 2015-155384 Japanese Unexamined Patent Publication No. 2008-2455888

However, when the glycerin fatty acid ester is used as an emulsifier, the sparingly soluble component tends to reaggregate to form oil droplets after disintegration in a test solution assuming the inside of the stomach. In the oral preparation, it is necessary to suppress reaggregation in order for the preparation to be efficiently absorbed after disintegrating in the body (for example, in the stomach). An object of the present invention is to provide an internal preparation containing a poorly soluble component that can exhibit good dispersibility even in the digestive organs of the body.

The present invention provides the following [1] to [8].
[1] An oral preparation containing a component (A): a sparingly soluble component and a component (B): an organic acid monoglyceride.
[2] The agent according to [1], further comprising a component (C): a hydrophilic emulsifier having an HLB of 10 or more.
[3] The component (A) comprises at least one selected from the group consisting of lutein, capsanthin, zeaxanthin, β-cryptoxanthin, docosahexaenoic acid (hereinafter, also referred to as “DHA”), astaxanthin and β-carotene. The agent according to [1] or [2].
[4] In any one of [1] to [3], the component (B) contains at least one selected from the group consisting of citric acid monoglyceride, diacetyl tartaric acid monoglyceride, lactic acid monoglyceride, and succinic acid monoglyceride. The agent described.
[5] The agent according to any one of [1] to [4], further comprising a glycerin fatty acid ester or a polyglycerin fatty acid ester having an HLB of less than 10 (D).
[6] The agent according to any one of [1] to [5], which is a soft capsule.
[7] The agent according to [6], which has a content containing the component (A) and the component (B) and a film containing the content.
[8] Ingredient (A): a sparingly soluble ingredient, and ingredient (B): a step of preparing a content containing an organic acid monoglyceride, and
A method for producing a soft capsule, comprising a step of encapsulating the contents in a film substrate.

According to the present invention, by including the components (A) to (B), an internal preparation having good dispersibility between the component (A) and the component (B) is provided.

The oral preparation of the present invention contains the following component (A): a sparingly soluble component.

The poorly soluble component is a component that is insoluble or sparingly soluble in an aqueous solvent. Insoluble or sparingly soluble means, for example, that when a sample is dissolved in 100 g of water (20 ° C.), the solubility is usually less than 0.2 g / 100 g of water, preferably less than 0.1 g / 100 g of water. do.
The sparingly soluble components include, for example, fatty acids (n-3 fatty acids, etc.), carotenoids, ubiquinone (coenzyme Q10, etc.), fat-soluble vitamins (vitamin E (tocopherol, tocotrienol, etc.), vitamin K, sterol (squalane, etc.)). Can be mentioned. Of these, carotenoids and fatty acids are preferable. The origin of the sparingly soluble component is not particularly limited, and may be naturally derived from plants, animals, microorganisms, etc., artificially produced such as by chemical synthesis, or produced by biotechnology such as gene recombination. It may be a commercial product or a commercially available product.

Examples of the fatty acid include saturated fatty acid, unsaturated fatty acid, and polyunsaturated fatty acid (n-3 fatty acid, n-6 fatty acid, n-9 fatty acid), and polyunsaturated fatty acid is preferable. n-3 fatty acids are more preferable. The n-3 fatty acid is a fatty acid in which the carbon-carbon bond at the third position (n3 position, ω3 position) from the methyl end of the fatty acid is an unsaturated bond. The number of carbon atoms contained in the n-3 fatty acid is usually 15 or more, preferably 17 or more, and more preferably 19 or more. The upper limit of the number of carbon atoms is usually 30 or less, preferably 25 or less.

Examples of the n-3 fatty acid include docosahexaenoic acid (DHA, (4Z, 7Z, 10Z, 13Z, 16Z, 19Z) -docosa-4,7,10,13,16,19-hexaenoic acid) and docosapentaenoic acid. (DPA, all-cis-docosa-7,10,13,16,19-pentaenoic acid), α-linolenic acid, eicosatetraenoic acid (ETA, all-cis-8,11,14,17-eicosa) Tetraenoic acid), eicosapentaenoic acid (EPA, (5Z, 8Z, 11Z, 14Z, 17Z) -Icosa-5,8,11,14,17-pentaenoic acid). The n-3 fatty acid is preferably a component (functional component) capable of exerting a physiological function in the body of an organism, and more preferably DHA.

Many DHAs are derived from natural products such as animals (for example, fish) and microorganisms (for example, microorganisms belonging to the genus Schizochytrium), but the DHA is not limited thereto. DHA may be in the form of a pharmacologically acceptable salt.

DHA may be DHA as a free fatty acid or a derivative thereof. Examples of the derivative include triglyceride type DHA (TG-DHA) and phospholipid type DHA. TG-DHA is a compound in which triglycerol and DHA are ester-bonded. One or more molecules of DHA as a fatty acid can be bound to each triglycerol molecule. It is preferable that TG-DHA has two or more molecules of DHA bound to one molecule of triglycerol. The phospholipid type DHA is a compound in which DHA is bound to a phospholipid such as phosphatidylcholine and phosphatidylserine.

Carotenoids are usually contained as pigments in animals and plants and have a polyene structure consisting of a conjugated double bond system. The number of carbon atoms of the carotenoid is usually 20 or more, preferably 25 or more, more preferably 30 or more, and further preferably 40 or more. It is preferable that carotenoids can exert physiological functions (have functionality) in the body of an organism.

Examples of carotenoids include lutein (β, ε-carotene-3,3'-diol; C ₄₀ H ₅₆ O ₂ ), capsantin (all-trans-capsantin, (3R, 3'S, 5'R) -3, 3'-Dihydroxy-β, κ-carotene-6'-on; C ₄₀ H ₅₆ O ₃ ), Zeaxanthin (4- [18- (4-hydroxy-2,6,6-trimethyl-1-cyclohexenyl)- 3,7,12,16-tetramethyl-octadeca-1,3,5,7,9,11,13,15,17-nonaenyl] -3,5,5-trimethyl-3-cyclohexen-1-ol; C ₄₀ H ₅₆ O ₂ ), β-cryptoxanthin ((R) -3,5,5-trimethyl-4- [3,7,12,16-tetramethyl-18- (2,6,6-trimethylcyclohexyl) Sa-1-enyl) -octadeca-1,3,5,7,9,11,13,15,17-nonaenyl] -cyclohexa-3-enol; C ₄₀ H ₅₆ O), astaxanthin ((6S) -6 -Hydroxy-3-[(1E, 3E, 5E, 7E, 9E, 11E, 13E, 15E, 17E) -18-[(4S) -4-hydroxy-2,6,6-trimethyl-3-oxo-1) -Hydroxy] -3,7,12,16-Tetramethyloctadeca-1,3,5,7,9,11,13,15,17-Nonaenyl] -2,4,4-trimethyl-1-cyclohexa- 2-Enon; C ₄₀ H ₅₂ O ₄ ), fucoxanthin (Acetic acid [(1S, 3R) -3-hydroxy-4-[(3E, 5E, 7E, 9E, 11E, 13E, 15E) -18- [ (1S, 4S, 6R) -4-hydroxy-2,2,6-trimethyl-7-oxabiciclo [4.1.0] heptane-1-yl] -3,7,12,16-tetramethyl-17-oxooctadeca -1,3,5,7,9,11,13,15-octaenyllide] _-3,5,5 -trimethylcyclohesyl] ester; C 42H ₅₈ O ₆ ), violaxanthin ((1S, 4S, 6R) -1 -[(1E, 3E, 5E, 7E, 9E, 11E, 13E, 15E, 17E) -18-[(1S, 4S, 6R) -4-Hydroxy-2, 2,6-trimethyl-7-oxyclo [4] .1.0] heptan-1-y l] -3,7,12,16-tetramethyloctadeca-1,3,5,7,9,11,13,15,17-nonaenyl] -2,2,6-trimethyl-7-oxabiciclo [4.1. 0] heptan-4-ol; C ₄₀ H ₅₆ O ₄ ), actinio erythrrole ((3S, 3-primeS) -3,3-prime-Dihydroxy-2, 2-prime-dinor-beta, beta-carotene -4,4-prime-dione; C ₃₈ H ₄₈ O ₄ ), bixin ((2E, 4E, 6E, 8E, 10E, 12E, 14E, 16Z, 18E) -20-methoxy-4,8,13,17 -Tetramethyl-20-oxoicosa-2, 4,6,8,10,12,14,16,18-nonaenoic acid; C ₂₅ H ₃₀ O ₄ ), cantaxanthin (β, β-carotene-4,4'- Zeon; C ₄₀ H ₅₂ O ₂ ), apo-carotene ((2E, 4E, 6E, 8E, 10E, 12E, 14E, 16E) -2,6,11,15-tetramethyl-17- (2,6,6-trimethyl) -1-cyclohexenyl) heptadeca-2, 4, 6, 8, 10, 12, 14, 16- _octainal ; C 30H ₄₀ O), lycopene ((6E, 8E, 10E, 12E, 14E, 16E, 18E, 20E) , 22E, 24E, 26E) -2,6,10,14,19,23,27,31-octamethyldotoriacontene-2,6,8,10,12,14,16,18,20,22, 24,26,30-tridecaene; C ₄₀ H ₅₆ ), carotene (α-carotene, β-carotene, γ-carotene, δ-carotene, ε-carotene, etc.), including lutein, capsantin, zeaxanthin, β-crypt. Xanthin, astaxanthin and β-carotene are preferred.

Lutein is present in the chloroplasts of higher plants (spinach, kale, komatsuna, etc.). Capsanthin is present in plants such as paprika and capsicum. Zeaxanthin is present in plants (corn, etc.), egg yolks, and animal fats. β-Cryptoxanthin is present in plants such as Satsuma mandarin, physalis, orange, papaya and apple, dairy products such as egg yolk and butter, and animals such as cattle. Astaxanthin is present in crustaceans such as shrimp and crab, and fish such as salmon and red sea bream. However, each carotenoid is not limited to those derived from these. Each carotenoid may be in the form of a pharmacologically acceptable salt.

The component (A) may be one kind of sparingly soluble component or a combination of two or more kinds of sparingly soluble components. When the component (A) contains two or more carotenoids, it is preferable to include a combination of lutein and capsanthin, or a combination of lutein and capsanthin and zeaxanthin, and a combination of lutein and capsanthin or a combination of lutein and capsanthin and zeaxanthin. Is more preferable.

The content of the component (A) is usually 0.1% by mass or more, preferably 0.2% by mass or more, based on the total amount of the composition. The upper limit is usually 50% by mass or less, preferably 40% by mass or less. Therefore, the content of the component (A) is usually 0.1 to 50% by mass, preferably 0.2 to 40% by mass, based on the entire composition. As a result, the oral preparation of the present invention can efficiently exert the physiological function of the component (A) and can be an agent having an excellent balance of dispersibility. When the component (A) contains a carotenoid, the upper limit of the content of the carotenoid as the component (A) is 5.0% by mass or less, preferably 4.0% by mass or less, based on the total amount of the composition. Therefore, the content of the carotenoid as the component (A) is usually 0.1 to 5.0% by mass, preferably 0.2 to 4.0% by mass.

The oral preparation of the present invention contains the component (B): organic acid monoglyceride.

The organic acid monoglyceride (glycerin organic acid fatty acid monoester) is a compound obtained by esterifying the −OH group at the 3-position of the glycerin fatty acid monoester with an organic acid. The number of carbon atoms of the fatty acid contained in the organic acid monoglyceride is usually 8 or more, preferably 14 or more. The upper limit is usually 22 or less, preferably 18 or less. The number of carbon atoms is preferably 8 to 22, more preferably 8 to 18, and even more preferably 14 to 18. The fatty acid may be either an unsaturated fatty acid or a saturated fatty acid. Examples of fatty acids contained in the glycerin fatty acid ester include capric acid, pelargonic acid, capric acid, lauric acid, pentadecyl acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid and behen. Acids include capric acid, pelargonic acid, capric acid, lauric acid, pentadecylic acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid, preferably palmitic acid, margaric acid, stear. Acids and oleic acids are more preferred. Examples of the organic acid contained in the organic acid monoglyceride include oxycarboxylic acids such as tartaric acid, lactic acid, malic acid, citric acid and diacetyl tartaric acid; aliphatic saturated dicarboxylic acids such as succinic acid, oxalic acid, adipic acid and glutaric acid; acetic acid, Monocarboxylic acids composed of lower fatty acids such as propionic acid and butyric acid; aliphatic unsaturated dicarboxylic acids such as maleic acid and fumaric acid; and amino acids such as glycine and aspartic acid include oxycarboxylic acids and aliphatic saturated dicarboxylic acids. Acids are preferred, with diacetyl tartrate, lactic acid, citric acid and succinic acid being more preferred.

The HLB of the organic acid monoglyceride is not particularly limited, but is usually more than 5, preferably 5.5 or more, and more preferably 6.0 or more. The upper limit is usually less than 10, preferably 9.7 or less, and more preferably 9.5 or less. Therefore, it is usually more than 5 and less than 10, preferably 5.5 to 9.7, more preferably 6.0 to 9.5. Thereby, the dispersibility of the internal preparation of the present invention can be improved.

HLB (Hydrophile-Lipophile Balance) is an index of affinity between water and oil. Generally, the closer it is to 0, the higher the lipophilicity, and the closer it is to 20, the higher the hydrophilicity. The HLB in the present specification can be calculated by any one of the atlas method, the Griffin method, the Davis method, the upstream method and the like. Further, as a product, the value published by the manufacturer may be taken into consideration.

Examples of the organic acid monoglyceride include diacetyl tartrate monoglyceride (for example, diacetyl tartrate glycerin monostearate (HLB = 9.0)), lactic acid monoglyceride (eg, lactic acid monostearate glycerin (HLB = 7.5)), and citrate monoglyceride. (For example, glycerin monostearate citrate (HLB = 9.5), glycerin monooleate citrate (HLB = 7.0)), succinic acid monoglyceride (eg, glycerin monostearate succinate (HLB = 8.5)). )).

The component (B) may be one kind of organic acid monoglyceride or a combination of two or more kinds of organic acid monoglycerides.

The content of the component (B) is usually 0.1% by mass or more, preferably 0.3% by mass or more, and more preferably 0.5% by mass or more with respect to the total amount of the composition. The upper limit is usually 10.0% by mass or less, preferably 8.0% by mass or less, and more preferably 6.0% by mass or less. Thereby, the dispersibility of the agent of the present invention can be improved. Therefore, the content of the component (B) is usually 0.1 to 10.0% by mass, preferably 0.3 to 8.0% by mass, and more preferably 0.5 to 6% by mass with respect to the total amount of the composition. It is 0.0% by mass. As a result, the oral preparation of the present invention can efficiently exert the physiological function of the component (B) and can exhibit good dispersibility.

The oral preparation of the present invention may contain a hydrophilic emulsifier having a component (C): HLB of 10 or more, and is preferably contained. Thereby, the dispersibility of the internal preparation of the present invention can be further improved. The component (C) does not contain organic acid monoglyceride.

The hydrophilic emulsifier may be any emulsifier showing hydrophilicity. The HLB of the hydrophilic emulsifier is usually 10 or more, preferably 12 or more, more preferably 14 or more, still more preferably 15 or more. Thereby, the dispersibility of the component (A) and the component (B) in the internal preparation can be further improved. The upper limit of HLB is not particularly limited, but is usually 20 or less.

Examples of the emulsifier exhibiting hydrophilicity include nonionic surfactants. Examples of the nonionic surfactant include sucrose fatty acid ester, polyglycerin fatty acid ester, propylene glycol fatty acid ester, polyglycerin condensed ricinoleic acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, and sucrose fatty acid ester. Polyglycerin fatty acid ester, sorbitan fatty acid ester, and polyoxyethylene sorbitan fatty acid ester are preferable, and polyglycerin fatty acid ester, sorbitan fatty acid ester, and polyoxyethylene sorbitan fatty acid ester are more preferable.

The sucrose fatty acid ester is one in which a fatty acid is ester-bonded to at least one of the hydroxy groups of sucrose. When the sucrose fatty acid ester has two or more fatty acids, the respective fatty acids may be the same or different from each other. The number of carbon atoms of the fatty acid contained in the sucrose fatty acid ester is usually 8 or more, preferably 12 or more, and more preferably 14 or more. The upper limit is usually 22 or less, preferably 20 or less, and more preferably 16 or less. The number of carbon atoms is preferably 8 to 22, more preferably 12 to 20, and even more preferably 14 to 16. The fatty acid may be either an unsaturated fatty acid or a saturated fatty acid. Examples of fatty acids contained in sucrose fatty acid esters include capric acid, pelargonic acid, capric acid, lauric acid, pentadecyl acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and arachidonic acid. Examples include behenic acid, with lauric acid, pentadecylic acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid and linolenic acid being preferred, and palmitic acid, margaric acid and stearic acid being more preferred.

Examples of the sucrose fatty acid ester include sucrose dioleic acid ester, sucrose distearate, sucrose dipalmitic acid ester, sucrose dimyristic acid ester, sucrose dilauric acid ester, sucrose monooleic acid ester, and sucrose mono. Examples thereof include stearate ester, sucrose monopalmitic acid ester, sucrose monomyristin acid ester, and sucrose monolauric acid ester.

The polyglycerin fatty acid ester as the component (C) may be a polyglycerin fatty acid ester other than the polyglycerin fatty acid ester as the following component (D). The degree of polymerization of polyglycerin is usually 7 or more, preferably 8 or more. The upper limit is usually 15 or less, preferably 10 or less. The degree of polymerization of polyglycerin is preferably 7 to 15, and more preferably 8 to 10. When the polyglycerin fatty acid ester has two or more fatty acids, the respective fatty acids may be the same or different from each other. Preferred examples of fatty acids contained in polyglycerin fatty acid esters are capric acid, pelargonic acid, capric acid, lauric acid, pentadecic acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid and linolenic acid. , Palmitic acid, margaric acid, stearic acid are more preferred.

Examples of the polyglycerin fatty acid ester as the component (C) include polyglycerin oleic acid ester (for example, monooleic acid decaglycerin (HLB = 12 to 15.5), monooleic acid hexaglycerin (HLB = 11.6), and the like. Pentaglycerin monooleate (HLB = 13.0)), polyglycerin stearate ester (eg, decaglycerin monostearate (HLB = 12-13.4), decaglycerin tristearate (HLB = 10.0), Hexaglycerin monostearate (HLB = 11.6), decaglycerin distearate (HLB = 11.0), pentaglycerin monostearate (HLB = 13.0)), polyglycerin luminic acid ester (eg, decaglycerin mono) Palmitic acid ester (HLB = 13), hexaglycerin monopalmitic acid ester), polyglycerin myristic acid ester (eg, monomyristic acid pentaglycerin (HLB = 13.0), monomyristic acid decaglycerin (HLB = 14), poly Glyceric acid lauric acid ester (for example, monolauric acid decaglycerin (HLB = 14.7-16), monolauric acid hexaglycerin (HLB = 13.4), monolauric acid tetraglycerin (HLB = 10.4), monolauric acid pentaglycerin) (HLB = 14.0)), polyglycerin capricyl ester (eg, monocaprylic acid decaglycerin (HLB = 16.1)).

The sorbitan fatty acid ester is a fatty acid ester-bonded to at least one of the hydroxy groups of sorbitan. When the sorbitan fatty acid ester has two or more fatty acids, the respective fatty acids may be the same or different from each other. Preferred examples of the fatty acid contained in the sorbitan fatty acid ester are the same as those mentioned in the fatty acid contained in the sucrose fatty acid ester.

The polyoxyethylene sorbitan fatty acid ester is an ester bond of ethylene oxide to at least one of the hydroxy groups of the sorbitan fatty acid ester. Preferred examples of the sorbitan fatty acid ester are the same as described above. The number of moles of ethylene oxide added to the polyoxyethylene sorbitan fatty acid ester is usually 2 or more, preferably 4 or more, and more preferably 10 or more. The upper limit is usually 100 or less, preferably 50 or less, and more preferably 30 or less. The number of added moles is preferably 2 to 100, more preferably 4 to 50, and even more preferably 10 to 30.

Examples of the polyoxyethylene sorbitan fatty acid ester include polyoxyethylene monocaprylate sorbitan, polyoxyethylene monolaurate sorbitan (for example, polysorbate 20 (polyoxyethylene (20) monolaurate sorbitan (HLB = 16.7))), and poly. Oxyethylene monopalmitate sorbitan (HLB = 15.6), polyoxyethylene monostearate sorbitan (HLB = 14.9), polyoxyethylene sesquistearate sorbitan, polyoxyethylene tristearate sorbitan (HLB = 10.5) )), Polyoxyethylene isostearate sorbitan, polyoxyethylene sesquiisostearate sorbitan, polyoxyethylene sesquioleate sorbitan, polyoxyethylene monooleate sorbitan (for example, polysorbate 80 (polyoxyethylene (20) monooleate sorbitan () HLB = 15.7), polyoxyethylene trioleate sorbitan (eg, polysorbate 85 (polyoxyethylene (20) trioleate sorbitan (HLB = 11.0)), polyoxyethylene monolaurate sorbitan or poly). Sorbitane oxyethylene monooleate is preferred, with polysorbate 20 or polysorbate 80 being more preferred.

The component (C) may be one kind selected from hydrophilic emulsifiers or a combination of two or more kinds.

When the internal preparation contains the component (C), the content of the component (C) is usually 0.05% by mass or more, preferably 0.1% by mass or more, more preferably 0. It is 15% by mass or more, more preferably 0.3% by mass or more, and even more preferably 0.5% by mass or more. The upper limit is usually 4% by mass or less, preferably 3% by mass or less, and more preferably 2.5% by mass or less. Therefore, the content of the component (C) is usually 0.05 to 4% by mass, preferably 0.1 to 3% by mass, and more preferably 0.15 to 2.5% by mass with respect to the entire composition. , More preferably 0.3 to 2.5% by mass, and even more preferably 0.5 to 2.5% by mass. Thereby, the oral preparation of the present invention can improve the dispersibility and can be a preparation having no problem in safety as a food.

The oral preparation of the present invention may contain, and preferably contains, a component (D): a glycerin fatty acid ester or a polyglycerin fatty acid ester having an HLB of less than 10. Further, the component (D) may be a component (d1) having an HLB of 5 or less, or a component (d2) having an HLB of more than 5 and less than 10. Hereinafter, the component (d1) and the component (d2) will be described separately.

The HLB of the glycerin fatty acid ester or the polyglycerin fatty acid ester as the component (D) is usually less than 10, preferably 9.7 or less, and more preferably 9.3 or less. The lower limit is not particularly limited and is usually 0 or more.

A glycerin fatty acid ester is a fatty acid ester-bonded to at least one of the hydroxy groups of glycerin. When the glycerin fatty acid ester has two or more fatty acids, the respective fatty acids may be the same or different from each other. The number of carbon atoms of the fatty acid contained in the glycerin fatty acid ester is usually 8 or more, preferably 14 or more. The upper limit is usually 22 or less, preferably 18 or less. The number of carbon atoms is preferably 8 to 22, more preferably 8 to 18, and even more preferably 14 to 18. The fatty acid may be either an unsaturated fatty acid or a saturated fatty acid. Examples of fatty acids contained in the glycerin fatty acid ester include capric acid, pelargonic acid, capric acid, lauric acid, pentadecyl acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid and behen. Acids include capric acid, pelargonic acid, capric acid, lauric acid, pentadecylic acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid, preferably palmitic acid, margaric acid, stear. Acids are more preferred.

The polyglycerin fatty acid ester is a fatty acid esterified to at least one of the hydroxy groups of polyglycerin, which is a polymer of glycerin. The degree of polymerization of polyglycerin is usually 6 or less, preferably 5 or less, and more preferably 4 or less. The lower limit is usually 2 or more. The degree of polymerization of polyglycerin is preferably 2 to 6, more preferably 2 to 5, and even more preferably 2 to 4. When the polyglycerin fatty acid ester has two or more fatty acids, the respective fatty acids may be the same or different from each other. Preferred examples of the fatty acid contained in the polyglycerin fatty acid ester are the same as those mentioned in the fatty acid contained in the glycerin fatty acid ester.

The component (D) may be any of the following components (d1), component (d2), and a combination of the component (d1) and the component (d2), and the combination of the component (d1) and the component (d2). Is preferred:
Component (d1): A glycerin fatty acid ester or polyglycerin fatty acid ester component having an HLB of 5 or less.
Ingredient (d2): Glycerin fatty acid ester or polyglycerin fatty acid ester having an HLB of more than 5 and less than 10.

The HLB of the glycerin fatty acid ester and the polyglycerin fatty acid ester as the component (d1) is usually 5 or less, preferably 4.7 or less, and more preferably 4.5 or less. Thereby, the stability of the component (A) and the component (B) in the internal preparation can be improved. The lower limit of HLB is not particularly limited, but is usually 0 or more.

Examples of the glycerin fatty acid ester having an HLB of 5 or less include glycerin myristate (HLB = 3.5), glycerin monostearate (HLB = 4.3), glycerin distearate, and glycerin monostearate and glycerin distearate. Is preferable.

Examples of the polyglycerin fatty acid ester having an HLB of 5 or less include polyglycerin stearate ester (for example, decaglycerin decastearate (HLB = 3.0 to 3.8), hexaglycerin pentastearate (HLB = 4.5)). , Tetraglycerin tristearate (HLB = 4.6), decaglycerin pentastearate (HLB = 4.5), tetraglycerin pentastearate (HLB = 2.6), pentaglycerin hexastearate (HLB = 4.). 0), diglycerin monostearate (HLB = 5.0), hexaglycerin tristearate (HLB = 2.5)), polyglycerin oleic acid ester (eg, decaglycerin decaorainate (HLB = 3.0-3)). .3), decaglycerin pentaoleate (HLB = 4.5), hexaglycerin pentaoleate (HLB = 4.7), tetraglycerin pentaoleate (HLB = 2.9)), polyglycerin behenic acid ester (HLB = 2.9). For example, heptabechenic acid decaglycerin (HLB = 4.2), dodecavechenic acid decaglycerin (HLB = 2.5), tetrabechenic acid hexaglycerin), polyglycerin erucic acid ester (eg, octaerkaic acid decaglycerin (HLB = 3.7)). )).

The component (d1) may be one type selected from glycerin fatty acid esters and polyglycerin fatty acid esters having an HLB of 5 or less, or a combination of two or more types.

The oral preparation of the present invention may contain a component (d2): a glycerin fatty acid ester or a polyglycerin fatty acid ester having an HLB of more than 5 and less than 10. The oral preparation of the present invention preferably contains the component (d2) because it further improves the dispersibility. The HLB of the emulsifier as the component (d2) is more than 5, preferably 5.5 or more, and more preferably 6.0 or more. The upper limit is usually less than 10, preferably 9.7 or less, and more preferably 9.3 or less. Therefore, the HLB is usually more than 5 and less than 10, preferably 5.5 to 9.7, more preferably 6.0 to 9.3.

The glycerin fatty acid ester as the component (d2) may be any glycerin fatty acid ester other than the glycerin fatty acid ester as the component (C) and the component (d1). Preferred examples of the glycerin fatty acid ester are the same as those mentioned for the glycerin fatty acid ester as the component (C) and the component (d1).

Examples of the glycerin fatty acid ester as the component (d2) include caprylic acid monoglyceride (HLB = 7.2), lauric acid monoglyceride (HLB = 5.3), and capric acid monoglyceride (HLB = 6.5).

The polyglycerin fatty acid ester as the component (d2) may be any polyglycerin fatty acid ester other than the polyglycerin fatty acid ester as the component (C) and the component (d1). Preferred examples of the polyglycerin fatty acid ester are the same as those mentioned in the polyglycerin fatty acid ester as the component (C) and the component (d1).

Examples of the polyglycerin fatty acid ester as the component (d2) include polyglycerin stearate ester (for example, monostearate diglycerin (HLB = 7.0)) and mono-distearate diglycerin (monostearate diglycerin and distearic acid). Combination of diglycerin) (HLB = 6.5), hexaglycerin distearate (HLB = 9.6), hexaglycerin tristearate (HLB = 7.4), tetraglycerin monostearate (HLB = 6.0 ~) 8.4), Hexaglyceryl monostearate (HLB = 9.0)), Polyglycerin oleic acid ester (eg, mono-diglycerin monooleate (combination of diglycerin monooleate and diglycerin dioleate) (HLB =) 6.5), tetraglycerin monooleate (HLB = 8.8), pentaglycerin trioleate (HLB = 7.0), diglycerin monooleate (HLB = 7.3)), polyglycerin lauric acid ester (For example, monolauric acid diglycerin (HLB = 8.5)), polyglycerin myristic acid ester (for example, trimyristinate pentaglycerin (HLB = 8.0), monomyristic acid diglycerin (HLB = 7.7)). , Polyglycerin caprylic acid ester (for example, monocaprylic acid diglycerin (HLB = 8.7)), and mono-dioleate diglycerin is preferable.

The component (d2) may be one kind selected from glycerin fatty acid esters and polyglycerin fatty acid esters having an HLB of more than 5 and less than 10, or a combination of two or more kinds.

When the internal preparation contains the component (D), the content of the component (D) is usually 1% by mass or more, preferably 2% by mass or more, more preferably 3% by mass or more, based on the total amount of the composition. .. The upper limit is usually 40% by mass or less, preferably 30% by mass or less, and more preferably 20% by mass or less. Therefore, the content of the component (D) is usually 1 to 40% by mass, preferably 2 to 30% by mass, and more preferably 3 to 20% by mass with respect to the total amount of the composition. Thereby, the oral preparation of the present invention can improve the dispersibility and can be a preparation having no problem in safety as a food.

When the internal preparation contains the component (d1), the content of the component (d1) is usually 1% by mass or more, preferably 2% by mass or more, more preferably 3% by mass or more, and further, with respect to the total amount of the composition. It is preferably 4% by mass or more. The upper limit is usually 20% by mass or less, preferably 15% by mass or less, and more preferably 10% by mass or less. Therefore, the content of the component (d1) is usually 1 to 20% by mass, preferably 2 to 15% by mass, more preferably 3 to 10, still more preferably 4 to 10% by mass, based on the total amount of the composition. be. Thereby, the oral preparation of the present invention can improve the dispersibility and can be a preparation having no problem in safety as a food.

When the internal preparation contains the component (d2), the content of the component (d2) is usually 1% by mass or more, preferably 2% by mass or more, more preferably 3% by mass or more, based on the total amount of the composition. .. The upper limit is usually 20% by mass or less, preferably 18% by mass or less, and more preferably 15% by mass or less. Therefore, the content of the component (d2) is usually 1 to 20% by mass, preferably 2 to 18% by mass, and more preferably 3 to 15% by mass with respect to the total amount of the composition. Thereby, the oral preparation of the present invention can improve the dispersibility.

The ratio ((B) / (A)) (%) of the content of the component (B) to the content of the component (A) is preferably more than 0%, more preferably 10% or more. There is no particular upper limit, but it is usually 5000% or less, preferably 4000% or less.

The ratio of the content of the component (A) to the total content of the components (B) and (C) ((A) / ((B) + (C)) (%) is usually 5% or more. It is preferably 10% or more. There is no particular upper limit, but it is usually 5000% or less, preferably 4000% or less. Thereby, the oral preparation of the present invention can further improve the dispersibility as well as the stability. can.

The internal preparation may contain an emulsifier other than the component (E): components (A) to (D). Examples of the component (E) include:
Polysorbate fatty acid esters with an HLB of less than 5, such as sorbitan monostearate (HLB = 4.7), sorbitan sesquistearate (HLB = 4.2), sorbitan tristearate (HLB = 2.0), sesquiisostearic acid. Sorbitane (HLB = 4.5), sorbitan oleate (HLB = 4.3), sorbitan sesquioleate (HLB = 3.7), sorbitan trioleate (HLB = 2.0).
Sorbitan fatty acid esters with an HLB of 5 or more and less than 10, such as sorbitan monocaprylate, sorbitan monolaurate (HLB = 8.6), sorbitan isostearate (HLB = 8).

Examples of the pharmacologically acceptable salt in the present invention include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate; citrate, shu. Organic acid salts such as acid salts, acetates, formates, propionates, benzoates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates, or paratoluenesulfonates. Inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt; organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt, diisopropylammonium salt; arginine, aspartic acid, glutamate, etc. Amino acid salts can be mentioned.

The oral preparation of the present invention may further have a component other than the above and a pharmacologically acceptable base. Examples of pharmacologically acceptable bases include components that primarily ensure stability in storage and distribution (eg, storage stabilizers). In addition, one or two or more kinds of ingredients (preferably about 1 to 3 kinds, more preferably about 1 kind) selected from various ingredients constituting the target final product (for example, food and drink, pharmaceutical products, quasi-drugs). May be contained.

The pharmacologically acceptable base is not particularly limited as long as it does not impair the object of the present invention. For example, oily ingredients, excipients, disintegrants, binders, lubricants, coating agents, colorants, color formers, flavoring agents, flavoring agents, antioxidants, preservatives, flavoring agents, acidulants, sweetness. From among agents, fortifiers, vitamins, swelling agents, thickeners, and surfactants, those that do not impair the properties required for the formulation (eg, formulation stability) and are the final products (eg, pharmaceuticals, etc.). One or two or more types can be selected according to the dosage form of (non-pharmaceutical products, food and drink). Further, the pharmacologically acceptable base may be another component having an effect of suppressing nitric oxide production.

Examples of the oily component include fatty acid esters other than the components (A) to (D), edible fats and oils, hydrocarbons, higher fatty acids, and higher alcohols, and edible fats and oils are preferable. Examples of edible oils and fats include safflower oil, soybean oil, rapeseed oil, canola oil, flaxseed oil, mustard oil, walnut oil, sardine oil, rice oil, palm oil, palm kernel oil, grape oil, palm olein, palm oil, and cottonseed oil. , Sunflower oil, corn oil, sesame oil, olive oil, tongue oil, peanut oil, palm oil, camellia oil. The ratio of the total amount of the components (A) to (E) ((C) to (E) are arbitrary) to the total content of the oily component and the contents of the components (A) to (E) is usually It is 3% by mass or more, preferably 4% by mass or more. The upper limit is usually 90% by mass or less, preferably 80% by mass or less.

Examples of excipients include celluloses such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, crystalline cellulose, ethyl cellulose, low-substituted hydroxypropyl cellulose and pharmaceutically acceptable derivatives thereof; polyvinylpyrrolidone, partially saponified polyvinyl alcohol. Synthetic polymers such as gelatin, gum arabic powder, purulan, agar, alginic acid, sodium alginate, kitansan gum and other polysaccharides: ethanol, glycerin, isobutyl alcohol, isopropyl alcohol, butanol, propanol, 2-pentanol, 2-methylbutanol, etc. , 3-Methyl-2-butanol, 3-Methyl-2-butenol, 1-penten-3-ol and other lower alcohols; hydrogenated rapeseed oil alcohol, lauryl alcohol, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, lanolin Higher alcohols such as alcohols, octyldodecanols and other aliphatic higher alcohols; starches such as corn starch, potato starch, pregelatinized starch, hydroxypropyl starch and their pharmacologically acceptable derivatives; lactose, fructose, glucose , Sucrose, trehalose, palatinose, mannitol, sorbitol, erythritol, xylitol, reduced palatinose, powdered reduced malt sugar candy, martitol and other sugars and sugar alcohols; light anhydrous silicic acid, fine silicon oxide, fine silicon dioxide, titanium oxide, water Examples thereof include inorganic excipients such as aluminum oxide gel. The content of the excipient with respect to the total amount of the agent is preferably 0.01% by mass or more. The upper limit is preferably 70% by mass or less.

Examples of the disintegrant include crospovidone, carmellose calcium, croscarmellose sodium, low-degree-of-substitution hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, hydroxypropyl starch, and partially pregelatinized starch.

Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, dextrin, starch and pregelatinized starch.

Examples of the lubricant include calcium stearate, magnesium stearate, sucrose fatty acid esters other than the components (C) to (E), light anhydrous silicic acid, sodium stearyl fumarate, polyethylene glycol, talc, and stearic acid. .. The content of the lubricant with respect to the total amount of the agent is preferably 0.01% by mass or more. The upper limit is preferably 25% by mass or less.

Examples of the colorant include caramel color, turmeric color, orange color, cacao color, sugarcane color, marigold color, iron (III) oxide, titanium dioxide, safflower color, cutinashi color, and copper chlorophyll color.

Examples of the internal preparation of the present invention include agents used in the form of oral administration (for example, oral administration and sublingual administration). Among these, a less invasive administration form is preferable, and oral administration (oral administration) is more preferable.

The dosage form of the oral administration agent (oral preparation) or the oral administration composition (oral administration composition) is, for example, liquid (liquid), syrup (syrup), tablet (tablet, tablet), capsule (capsule). Agent), powder (granule, fine granule), soft capsule (soft capsule), solid, semi-liquid, cream, paste.

The target of administration of the oral preparation may be any animal including humans, and is usually human, but non-human animals (for example, mice, rats, hamsters, dogs, cats, sheep, goats, cows, pigs, monkeys, etc.) It may be a mammal).

The internal preparation of the present invention can be used as a food composition, a medicine, or a quasi-drug. Food compositions include, for example, beverages (soft beverages, carbonated beverages, nutritional beverages, powdered beverages, fruit beverages, dairy beverages, jelly beverages, etc.), confectionery (cookies, cakes, gums, candies, tablets, gummy, buns, sheep sardines, etc.) , Pudding, jelly, ice cream, sherbet, etc.), processed marine products (kamaboko, chikuwa, hampen, etc.), processed livestock products (hamburger, ham, sausage, wiener, cheese, butter, yogurt, cream, cheese, margarine, fermented Milk, etc.), soups (powdered soups, liquid soups, etc.), main foods (rice, noodles (dried noodles, raw noodles), bread, cereals, etc.), seasonings (mayonnaise, shortening, dressing, sauces, sauces, soy sauce, etc.) ).

The administration form of the oral preparation of the present invention is usually oral administration such as oral administration and sublingual administration.

The dosage form of the internal preparation of the present invention can be appropriately determined depending on whether it is a food or drink, a drug or a quasi-drug, and is not particularly limited. Examples of dosage forms for oral administration include liquid (liquid), syrup (syrup), tablets, capsules (capsules), powders (granule (granule), fine granules (powder)). , Soft capsule (soft capsule), solid (solid preparation), semi-liquid, cream, paste, and soft capsule (soft capsule) is preferable.

The method for producing the internal preparation is not particularly limited, and a conventional method may be followed based on the dosage form and use. As an example, the production method when the dosage form is a soft capsule is shown below.

First, the contents of the soft capsule are prepared. The component (B), the components (C) to (E) added as needed, and any component such as an oily component are heated and mixed, and then cooled. The heating is usually performed at 40 ° C. or higher, preferably 50 ° C. or higher, more preferably 55 ° C. or higher. Although there is no particular upper limit, it is usually 100 ° C. or lower, preferably 90 ° C. or lower, and more preferably 80 ° C. or lower. Therefore, heating is usually performed at 40 to 100 ° C, preferably 50 to 90 ° C, and more preferably 55 to 80 ° C. The mixing is preferably carried out so as to be uniform, and the mixture is stirred as necessary. The cooling temperature is usually 70 ° C. or lower, preferably 60 ° C. or lower, and more preferably 40 ° C. or lower, although it depends on the heating temperature. The lower limit is usually 20 ° C. or higher, preferably 22 ° C. or higher, and more preferably 25 ° C. or higher. Therefore, the cooling temperature is usually 20 to 70 ° C, preferably 22 to 60 ° C, and more preferably 25 to 40 ° C. After cooling, the component (A) is added and mixed (preferably made uniform, stirred if necessary) to obtain the contents of the soft capsule (hereinafter, also referred to as “content liquid”). Mixing (stirring mixing) is preferably performed mechanically. The apparatus is not particularly limited, and examples thereof include a high-speed stirrer such as a homomixer and a high-pressure homogenizer, and a high-pressure crusher.

Next, the obtained content liquid is included in the film base material. Examples of the inclusion method include a flat plate method and a rotary die method. Taking the latter as an example, it is assumed that a medicine tank, a gelatin melting tank, a filling machine capable of setting a die roll, and a tumbler dryer are used. Explain to.

The obtained content liquid is placed in a medicine tank and set in a predetermined position on the filling machine. Before putting it in the medicine tank, pretreatment such as emulsification or suspension of the content liquid may be performed as necessary.

A film substrate (for example, a polymer such as gelatin or starch), a plasticizer (for example, glycerin or sorbitol) and purified water are added to the gelatin melting tank, and the mixture is heated and dissolved (for example, about 80 ° C.). ) After that, perform the defoaming operation in the same tank to adjust the viscosity and use it as the undiluted film solution. Transfer the undiluted coating solution to a subdivision tank (usually heating (usually heating (50 to 55 ° C.)) while performing filtration, and set it in the predetermined position of the filling machine.

The prepared film stock solution and contents are set in a predetermined position of a filling machine, and a soft capsule is molded by a filling machine in which a predetermined die roll is set. The temperature of the filling chamber is usually adjusted to 20 to 30 ° C. The relative humidity of the filling chamber is usually maintained at 30-50%. Immediately after molding, the soft capsule is sent to a tumbler dryer connected to a filling machine, and while rotating, the shape is temporarily fixed and the moisture in the film is temporarily dried with clean air similar to the indoor conditions (usually about 1 to 4). time).

The soft capsules that have been encapsulated and temporarily dried are transferred to a tumbler dryer and dried. The temperature at the time of drying is usually 20 to 30 ° C., and the relative humidity is 30 to 50%. The drying time is usually 24-48 hours. Drying is performed, for example, until the water content at the time of filling is 30 to 40% and the water content is reduced to 6 to 8%.

After drying, the soft capsule may be polished with a tumbler for 2 minutes to 1 hour to finish the soft capsule, if necessary.

The oral preparation of the present invention includes foods such as health foods, functional foods, nutritional supplements, specified health foods, medical foods, sick foods, infant foods, nursing foods, and elderly foods. , Can be used as a drug or a non-pharmaceutical product.

Examples 1-46 and Comparative Examples 1-3
The contents of the soft capsules prepared with the compositions shown in Tables 1 to 7 were subjected to the following evaluation tests. Preparation of soft capsules was performed according to a conventional method. That is, after mixing each component as a content, each component as a film was coated to obtain a soft capsule.

<Dispersibility of content liquid>
In accordance with the disintegration test method of the general test method listed in the 16th revision of the Japanese Pharmacopoeia, the dispersibility in water when 6 soft capsules of each example and comparative example are disintegrated in the first solution of the disintegration test. Was visually observed. The results of visual observation were evaluated according to the following criteria.
A: There is no separation of the oily component containing the poorly soluble component, and the dispersibility in the disintegration test 1st liquid is uniform and good. C: Separation of oily components including poorly soluble components is observed and slightly dispersed in the first liquid of the disintegration test D: Most of the oily components including poorly soluble components are separated and the first disintegration test Does not disperse in liquid

The results of the evaluation test are shown in Tables 1-7. Information on the components used in each Example and Comparative Example is shown in Table 8.

The following is clear from Tables 1-7. In the comparative examples, the water dispersibility of the soft capsule content could not be evaluated, or the evaluation was D or C, but in most of the examples, the evaluation was B or higher. This indicates that the oral preparation of the present invention can exhibit good dispersibility.

Claims (8)

Ingredient (A): Contains at least one carotenoid selected from the group consisting of lutein, capsantine, zeaxanthin, β-cryptoxanthin, astaxanthin and β-carotene, or contains lutein, capsantine, zeaxanthin, β-cryptoxanthin, astaxanthin and A sparingly soluble component containing at least one carotenoid selected from the group consisting of β-carotene and docosahexaenoic acid, and component (B): diacetyl tartrate glycerin monostearate, glycerin lactic acid monostearate, monostearic citrate. Organic acid monoglycerides, including one or more selected from glycerin, glycerin monooleate citrate, glycerin monostearate succinate,
Soft capsules containing . Ingredient (C): The soft capsule according to claim 1, further comprising a hydrophilic emulsifier having an HLB of 10 or more. The soft capsule according to claim 2, wherein the component (C) contains one or more selected from polyglycerin fatty acid ester, sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester. The soft capsule according to any one of claims 1 to 3, wherein the content of the carotenoid as the component (A) is 0.1 to 5.0% by mass. Ingredient (D): The soft capsule according to any one of claims 1 to 4, further comprising a glycerin fatty acid ester or a polyglycerin fatty acid ester having an HLB of less than 10. The soft capsule according to claim 5, wherein the component (D) is the following component (d1), component (d2), or a combination of component (d1) and component (d2).
Component (d1): Glycerin fatty acid ester or polyglycerin fatty acid ester having an HLB of 5 or less.
Ingredient (d2): Glycerin fatty acid ester or polyglycerin fatty acid ester having an HLB of more than 5 and less than 10. The soft capsule according to claim 1 , further comprising a content containing the component (A) and the component (B) and a film containing the content. Ingredient (A): Contains at least one carotenoid selected from the group consisting of lutein, capsantine, zeaxanthin, β-cryptoxanthin, astaxanthin and β-carotene, or contains lutein, capsantine, zeaxanthin, β-cryptoxanthin, astaxanthin and A sparingly soluble component containing at least one carotenoid selected from the group consisting of β-carotene and docosahexaenoic acid, and component (B): diacetyl tartrate glycerin monostearate, glycerin lactic acid monostearate, monostearic citrate. Organic acid monoglycerides, including one or more selected from glycerin, glycerin monooleate citrate, glycerin monostearate succinate,
The process of preparing the contents including, as well as
A method for producing a soft capsule, comprising a step of encapsulating the contents in a film substrate.