WO2018101269A1 - Oral agent - Google Patents

Oral agent Download PDF

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Publication number
WO2018101269A1
WO2018101269A1 PCT/JP2017/042649 JP2017042649W WO2018101269A1 WO 2018101269 A1 WO2018101269 A1 WO 2018101269A1 JP 2017042649 W JP2017042649 W JP 2017042649W WO 2018101269 A1 WO2018101269 A1 WO 2018101269A1
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WO
WIPO (PCT)
Prior art keywords
component
acid
fatty acid
hlb
less
Prior art date
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PCT/JP2017/042649
Other languages
French (fr)
Japanese (ja)
Inventor
大輔 金島
菅藤　寿裕
あゆみ 松野
宏彰 山鹿
洋一 折原
Original Assignee
ライオン株式会社
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Application filed by ライオン株式会社 filed Critical ライオン株式会社
Priority to KR1020197004344A priority Critical patent/KR20190089149A/en
Priority to CN201780071061.9A priority patent/CN109963558A/en
Priority to JP2018554163A priority patent/JP7133471B2/en
Publication of WO2018101269A1 publication Critical patent/WO2018101269A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • the present invention relates to an internal medicine.
  • Oily components such as n-3 fatty acids such as docosahexaenoic acid and carotenoids have various physiological activities, and therefore, there is an increasing demand for dosage forms such as soft capsules as health foods.
  • dosage forms such as soft capsules as health foods.
  • n-3 fatty acids such as docosahexaenoic acid and carotenoids
  • the stability of the content of the soft capsule cannot be maintained, and the components contained in the content tend to be separated.
  • a method using a wax-based emulsifier or beeswax having a high thickening effect has been developed.
  • this method has a problem that the dispersibility of the contents in water is poor in the disintegration test.
  • Patent Documents 1 and 2 As a method for improving the dispersibility of the contents in water, a method of solubilizing with an emulsifier having a high HLB value is generally used (for example, Patent Documents 1 and 2). On the other hand, a method of dispersing a hardly oil-soluble powder with an emulsifier having a relatively low HLB value has been proposed (Patent Document 3).
  • An object of the present invention is to provide an internal preparation that can exhibit a good balance between dispersibility and stability in an internal preparation containing two or more oily components.
  • the present invention provides the following [1] to [10].
  • Component (A) n-3 fatty acid
  • Component (B) a crystalline oily component
  • component (C) an internal preparation containing a glycerin fatty acid ester or polyglycerin fatty acid ester having an HLB of 5 or less.
  • Component (D) The agent according to [1], further comprising a hydrophilic emulsifier having an HLB of 10 or more.
  • Component (E) The agent according to [1] or [2], further comprising an emulsifier having an HLB of more than 5 and less than 10.
  • the component (B) according to any one of [1] to [3], wherein the component (B) includes at least one selected from the group consisting of lutein, capsanthin, zeaxanthin, ⁇ -cryptoxanthin, and astaxanthin.
  • Agent [5] The agent according to any one of [1] to [4], wherein the content of component (B) is 0.2% by mass or more based on the total amount of the composition.
  • [6] The agent according to any one of [1] to [5], wherein the content of component (A) is 60% by mass or less based on the total amount of the composition.
  • component (A) is docosahexaenoic acid.
  • an internal preparation that can exhibit the dispersibility and stability of the components (A) and (B) in a balanced manner is provided.
  • the internal preparation of the present invention contains the following component (A): n-3 fatty acid.
  • the n-3 fatty acid is a fatty acid having an unsaturated bond at the third (n3-position, ⁇ 3-position) carbon-carbon bond from the methyl end of the fatty acid.
  • the origin of the n-3 fatty acid is not particularly limited, and may be naturally derived from plants, animals, microorganisms, etc., may be artificially produced such as chemical synthesis, or biotechnology such as genetic recombination It may be manufactured by or a commercially available product.
  • the number of carbon atoms contained in the 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, and preferably 25 or less.
  • n-3 fatty acids include docosahexaenoic acid (DHA, (4Z, 7Z, 10Z, 13Z, 16Z, 19Z) -docosa-4,7,10,13,16,19-hexaenoic acid), docosapentaenoic acid (DPA, all-cis-docosa-7,10,13,16,19-pentaenoic acid), ⁇ -linolenic acid, eicosatetraenoic acid (ETA, all-cis-8,11,14,17-eicosa) Tetraenoic acid) and 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 physiological functions in the body of an organism, and more preferably DHA.
  • DHA is often derived from natural products such as animals (for example, fish) and microorganisms (for example, Schizophytrium genus microorganisms), but 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.
  • 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. DHA as one or more fatty acids per molecule of triglycerol can bind.
  • TG-DHA preferably has two or more DHA molecules 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.
  • Component (A) may be a single n-3 fatty acid or a combination of two or more n-3 fatty acids.
  • the content of the component (A) is usually 15% by mass or more, preferably 18% by mass, more preferably 20% by mass or more, and further preferably 25% by mass or more with respect to the total amount of the composition.
  • the upper limit is usually 65% by mass or less, preferably 60% by mass or less, more preferably 55% by mass or less, and still more preferably 50% by mass or less.
  • the internal preparation of this invention can become an agent excellent in balance of stability and a dispersibility.
  • the content of the component (A) is usually 15 to 65% by mass, preferably 15 to 60% by mass, more preferably 18 to 55% by mass, and further preferably 20 to 55% by mass with respect to the entire composition. %, Even more preferably 25 to 50% by weight.
  • the internal preparation of this invention can exhibit the physiological function of a component (A) efficiently, and can become an agent excellent in balance of stability and a dispersibility.
  • the internal preparation of the present invention contains component (B): a crystalline oily component.
  • Crystalline oily component means a component that is crystalline and insoluble in water. Insoluble in water means, for example, when the sample is dissolved in 100 g of water (20 ° C.), the solubility is less than 0.1 g / 100 g of water.
  • the crystalline oily component does not contain n-3 fatty acids.
  • the origin of the crystalline oily component is not particularly limited, and it may be naturally derived from plants, animals, microorganisms, etc., may be artificially produced such as chemical synthesis, or by biotechnology such as genetic recombination. What was manufactured may be sufficient and a commercial item may be sufficient.
  • the crystalline oily component examples include carotenoids, ubiquinones (such as coenzyme Q10), fat-soluble vitamins (such as vitamin E (such as tocopherol and tocotrienol)), vitamin K, and sterols (such as squalane), and carotenoids are preferred.
  • Carotenoids are usually contained as pigments in animals and plants and have a polyene structure consisting of conjugated double bonds.
  • the carotenoid preferably contains an oxygen atom, and more preferably contains a hydroxyl group (—OH).
  • the number of carbon atoms in 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 the carotenoid can exhibit a physiological function (has functionality) in the body of an organism.
  • carotenoids examples include lutein ( ⁇ , ⁇ -carotene-3,3′-diol; C 40 H 56 O 2 ), capsanthin (all-trans-capsanthin, (3R, 3 ′S, 5′R) -3, 3′-dihydroxy- ⁇ , ⁇ -carotene-6′-one; 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 ), ⁇ -cryptoxanthin ((R) -3,5,5-trimethyl-4- [3,7,12,16-tetramethyl-18- (2,6,6-trimethylcyclohexene) Sa-1-e Le) -
  • 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 (such as corn), egg yolk, and animal fat.
  • ⁇ -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 cows.
  • Astaxanthin is present in crustaceans such as shrimps and crabs, and fish such as salmon and red sea bream.
  • each carotenoid is not limited to those derived from these. Each carotenoid may be in the form of a pharmacologically acceptable salt.
  • Component (B) may be one type of crystalline oily component or a combination of two or more types of crystalline oily components.
  • component (B) contains two or more kinds of carotenoids, it preferably contains a combination of lutein and capsanthin, a combination of lutein, capsanthin and zeaxanthin, and a combination of lutein and capsanthin or a combination of lutein, capsanthin and zeaxanthin. More preferred.
  • the content of the component (B) is usually 0.01% by mass or more, preferably 0.1% by mass or more, more preferably 0.2% by mass or more with respect to the total amount of the composition.
  • the internal preparation of this invention can exhibit the physiological function of a component (B) efficiently.
  • the upper limit is usually 10% by mass or less, preferably 8% by mass or less, more preferably 4% by mass or less, and still more preferably 3% by mass or less.
  • the stability of the internal preparation of the present invention can be improved, and the internal preparation of the present invention can be an agent having an excellent balance between stability and dispersibility.
  • the content of component (B) is usually 0.01 to 10% by weight, preferably 0.1 to 8% by weight, more preferably 0.2 to 4% by weight, based on the entire composition.
  • the content is preferably 0.2 to 3% by mass.
  • the internal preparation of the present invention contains component (C): glycerin fatty acid ester or polyglycerin fatty acid ester having an HLB of 5 or less.
  • the HLB of glycerin fatty acid ester and polyglycerin fatty acid ester as component (C) is usually 5 or less, preferably 4.7 or less, more preferably 4.5 or less. Thereby, the stability of the component (A) and the component (B) in the internal medicine can be improved.
  • the minimum of HLB is not specifically limited, Usually, it is 0 or more. Therefore, the HLB of component (C) is usually 0 to 5, preferably 0 to 4.7, more preferably 0 to 4.5.
  • HLB Hydrophilicity
  • Glycerin fatty acid ester is a fatty acid ester-bonded to at least one of the hydroxyl groups of glycerin.
  • each fatty acid may be the same as 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 still more preferably 14 to 18.
  • the fatty acid may be either an unsaturated fatty acid or a saturated fatty acid.
  • fatty acids possessed by glycerin fatty acid esters include caprylic acid, pelargonic acid, capric acid, lauric acid, pentadecylic acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, and behenic acid.
  • Acid erucic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, pentadecylic acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid are preferred, palmitic acid, margarine Acid and stearic acid are more preferable.
  • Polyglycerin fatty acid ester is a fatty acid esterified with at least one of the hydroxyl groups of polyglycerol which is a polymer of glycerin.
  • the degree of polymerization of polyglycerol is usually 6 or less, preferably 5 or less, more preferably 4 or less.
  • the lower limit is usually 2 or more.
  • the degree of polymerization of polyglycerol is preferably 2 to 6, more preferably 2 to 5, and still more preferably 2 to 4.
  • each fatty acid may be the same as or different from each other.
  • the preferable example of the fatty acid which polyglycerin fatty acid ester has it is the same as that of mentioning about the fatty acid which glycerin fatty acid ester has.
  • the component (C) may be one kind selected from glycerin fatty acid ester and polyglycerin fatty acid ester having an HLB of 5 or less, or a combination of two or more kinds, but preferably contains at least a glycerin fatty acid ester having an HLB of 5 or less. More preferably, the HLB is 5 or less glycerin fatty acid ester.
  • the content of the component (C) is usually 1% by mass or more, preferably 2% by mass or more, more preferably 3% by mass or more, and further preferably 4% by mass or more with respect to the total amount of the composition.
  • the upper limit is usually 20% by mass or less, preferably 15% by mass or less, more preferably 10% by mass or less, and still more preferably 8% by mass or less. Therefore, the content of the component (C) is usually 1 to 20% by mass, preferably 2 to 15% by mass, more preferably 3 to 10% by mass, and further preferably 4 to 8% by mass with respect to the entire composition. %is there.
  • the internal use preparation of this invention can improve stability, and can be made into an agent which does not have a problem also in the safety
  • the internal preparation of the present invention may contain a component (D): a hydrophilic emulsifier having an HLB of 10 or more, and preferably contains a component (D).
  • a component (D) a hydrophilic emulsifier having an HLB of 10 or more, and preferably contains a component (D).
  • the hydrophilic emulsifier may be an emulsifier exhibiting hydrophilicity
  • the HLB is usually 10 or more, preferably 12 or more, more preferably 14 or more, and further preferably 15 or more.
  • stability of the component (A) and component (B) in an internal use can be improved more.
  • the upper limit of HLB is not specifically limited, Usually, it is 20 or less. Therefore, the HLB of component (D) is usually 10 to 20, preferably 12 to 20, more preferably 14 to 20, and still more preferably 15 to 20.
  • hydrophilic emulsifiers include nonionic surfactants.
  • Nonionic surfactants include sucrose fatty acid ester, polyglycerin fatty acid ester, organic acid monoglyceride, propylene glycol fatty acid ester, polyglycerin condensed ricinoleic acid ester, sorbitan fatty acid ester, and polyoxyethylene sorbitan fatty acid ester.
  • Sugar fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are preferred, and polyglycerin fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are more preferred.
  • Sucrose fatty acid ester is a fatty acid ester-bonded to at least one of the hydroxy groups of sucrose.
  • each fatty acid may be the same as 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, more preferably 14 or more.
  • the upper limit is usually 22 or less, preferably 20 or less, more preferably 16 or less.
  • the number of carbon atoms is preferably 8 to 22, more preferably 12 to 20, and still more preferably 14 to 16.
  • the fatty acid may be either an unsaturated fatty acid or a saturated fatty acid.
  • fatty acids possessed by sucrose fatty acid esters include caprylic acid, pelargonic acid, capric acid, lauric acid, pentadecylic acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, Examples include behenic acid and erucic acid, lauric acid, pentadecylic acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, and linolenic acid are preferable, and palmitic acid, margaric acid, and stearic acid are more preferable.
  • sucrose fatty acid esters examples include sucrose dioleate, sucrose distearate, sucrose dipalmitate, sucrose dimyristate, sucrose dilaurate, sucrose monooleate, sucrose mono Examples include stearic acid ester, sucrose monopalmitic acid ester, sucrose monomyristic acid ester, and sucrose monolauric acid ester.
  • the polyglycerin fatty acid ester as the component (D) may be any polyglycerin fatty acid ester other than the polyglycerin fatty acid ester as the component (C).
  • the degree of polymerization of polyglycerol 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 polyglycerol is preferably 7 to 15, and more preferably 8 to 10.
  • each fatty acid may be the same as or different from each other.
  • the preferable example of the fatty acid which polyglycerin fatty acid ester has it is the same as that of the fatty acid which glycerin fatty acid ester as a component (C) has.
  • Sorbitan fatty acid ester is a fatty acid ester-bonded to at least one of the hydroxy groups of sorbitan.
  • each fatty acid may be the same as or different from each other.
  • Preferable examples of the fatty acid that the sorbitan fatty acid ester has are the same as those mentioned for the fatty acid that the sucrose fatty acid ester has.
  • Polyoxyethylene sorbitan fatty acid ester is one in which ethylene oxide is ester-bonded to at least one of the hydroxy groups of 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, more preferably 10 or more.
  • the upper limit is usually 100 or less, preferably 50 or less, more preferably 30 or less.
  • the added mole number is preferably 2 to 100, more preferably 4 to 50, and still more preferably 10 to 30.
  • Component (D) may be one type selected from hydrophilic emulsifiers, or a combination of two or more types.
  • the content of the component (D) is usually 0.1% by mass or more, preferably 0.2% by mass or more, more preferably 0. It is 3% by mass or more, more preferably 0.5% by mass or more.
  • the upper limit is usually 5% by mass or less, preferably 3% by mass or less, more preferably 2.5% by mass or less, and further preferably 2% by mass or less. Therefore, the content of component (D) is usually 0.1 to 5% by mass, preferably 0.2 to 3% by mass, more preferably 0.3 to 2.5% by mass, based on the entire composition. More preferably, it is 0.5 to 2% by mass.
  • the internal preparation of this invention is excellent in balance of stability and dispersibility, and can be made into an agent which does not have a problem also in the safety as a foodstuff.
  • the internal preparation of the present invention may contain an emulsifier having an ingredient (E): HLB of more than 5 and less than 10, and preferably contains an ingredient (E).
  • an emulsifier having an ingredient (E): HLB of more than 5 and less than 10, and preferably contains an ingredient (E).
  • the HLB of the emulsifier as the component (E) exceeds 5, preferably 5.5 or more, more preferably 6.0 or more.
  • the upper limit is usually less than 10, preferably 9.7 or less, more preferably 9.3 or less.
  • the HLB is usually more than 5 and less than 10, preferably 5.5 to 9.7, more preferably 6.0 to 9.3.
  • Component (E) may be an emulsifier having an HLB exceeding 5 and less than 10, but from the group consisting of glycerin fatty acid ester, polyglycerin fatty acid ester, organic acid monoglyceride, sorbitan fatty acid ester, and polyoxyethylene sorbitan fatty acid ester. It is preferable that at least one selected.
  • the glycerin fatty acid ester as the component (E) may be a glycerin fatty acid ester other than the glycerin fatty acid ester as the component (C) and the component (D).
  • glycerol fatty acid ester it is the same as that of mentioning in the glycerol fatty acid ester as a component (C) and a component (D).
  • the polyglycerin fatty acid ester as the component (E) may be any polyglycerin fatty acid ester other than the polyglycerin fatty acid ester as the component (C) and the component (D).
  • a polyglycerol fatty acid ester it is the same as that of mentioning in the polyglycerol fatty acid ester as a component (C) and a component (D).
  • Organic acid monoglyceride is a compound in which the —OH group at the 3-position of glycerin fatty acid monoester is esterified 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 still more preferably 14 to 18.
  • the fatty acid may be either an unsaturated fatty acid or a saturated fatty acid.
  • fatty acids possessed by glycerin fatty acid esters include caprylic acid, pelargonic acid, capric acid, lauric acid, pentadecylic acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, and behenic acid.
  • acids such as caprylic acid, pelargonic acid, capric acid, lauric acid, pentadecylic acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, and linolenic acid, and palmitic acid, margaric acid, stearin Acid is more preferred.
  • Examples of the organic acid that the organic acid monoglyceride has include oxycarboxylic acids such as tartaric acid, lactic acid, malic acid, citric acid, and diacetyltartaric acid; aliphatic saturated dicarboxylic acids such as succinic acid, oxalic acid, adipic acid, and glutaric 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; oxycarboxylic acids and aliphatic saturated dicarboxylic acids An acid is preferable, and diacetyltartaric acid, lactic acid, citric acid, and succinic acid are more preferable.
  • oxycarboxylic acids such as tartaric acid, lactic acid, malic acid, citric acid, and diacetyltartaric acid
  • citric acid monoglyceride For example,
  • the sorbitan fatty acid ester as the component (E) may be a sorbitan fatty acid ester other than the sorbitan fatty acid ester as the component (D).
  • sorbitan fatty acid ester it is the same as that of mentioning in the glycerol fatty acid ester as a component (D).
  • Component (E) may be one type selected from glycerin fatty acid esters having an HLB exceeding 5 and less than 10, or a combination of two or more.
  • the content of the component (E) is usually 0.5% by mass or more, preferably 1% by mass or more, more preferably 2% by mass or more based on the total amount of the composition. More preferably, it is 3% by mass or more, and still more preferably 4% by mass or more.
  • the upper limit is usually 20% by mass or less, preferably 18% by mass or less, more preferably 15% by mass or less, and still more preferably 10% by mass or less. Therefore, the content of component (E) is usually 0.5 to 20% by mass, preferably 1 to 18% by mass, more preferably 2 to 15% by mass, and further preferably 3 to It is 10% by mass, and more preferably 4 to 10% by mass.
  • the agent of this invention can improve the stability and / or dispersibility of an internal use agent.
  • the ratio of the content of the component (B) to the content of the component (A) ((B) / (A)) (%) is preferably more than 0%, more preferably 0.5% or more. Although there is no upper limit in particular, it is usually 10.0% or less.
  • the ratio ((C) / ((A) + (B)) (%) of the content of component (C) to the total content of component (A) and component (B) is usually 3% or more.
  • the upper limit is not particularly limited, but is usually 40% or less, preferably 30% or less, whereby the stability of the internal use can be further improved.
  • the ratio of the content of the component (B) to the total content of the component (C) and the component (D) ((B) / ((C) + (D)) ( %) Is usually at least 3%, preferably at least 4%, although there is no particular upper limit, it is usually at most 70%, preferably at most 60%, more preferably at most 50%.
  • the stability and / or dispersibility of the component (A) and the component (B) in the internal medicine can be further improved.
  • the ratio of the content of the component (D) to the content of the component (C) ((D) / (C)) (%) is usually 70% or less, 60% Or less, more preferably 50% or less, still more preferably 40% or less, and even more preferably 30% or less. There is no particular lower limit, usually exceeding 0%, preferably 5% or more, more preferably 8% or more, and even more preferably 10% or more. Thereby, the stability and / or dispersibility of the component (A) and the component (B) in the internal medicine can be further improved.
  • the ratio of the content of component (D) to the total content of component (C) and component (E) ((D) / ((C) + (E))) (%) is preferably 40% or less, and more preferably 30% or less. There is no particular lower limit, and it is usually sufficient to exceed 0%. Thereby, the stability and / or dispersibility of the component (A) and the component (B) in the internal medicine can be further improved.
  • the internal preparation may contain an emulsifier other than Component (F): Components (A) to (E).
  • Examples of the pharmacologically acceptable salt in the present invention include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate and phosphate; Organic acid salts such as acid salts, acetate salts, formates, propionates, benzoates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates, paratoluenesulfonates; Inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt; organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt; amino acids such as arginine, aspartic acid and glutamic acid Salt.
  • inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate and phosphate
  • the internal preparation of the present invention may further have components other than those described above and a pharmacologically acceptable base.
  • a pharmacologically acceptable base is a component that mainly ensures stability in storage and distribution (for example, a storage stabilizer).
  • one or two or more types of components preferably about 1 to 3 types, more preferably about 1 type selected from various components constituting the target final product (for example, foods and drinks, pharmaceuticals, quasi drugs, etc.) ) May be contained.
  • the pharmacologically acceptable base is not particularly limited as long as the object of the present invention is not impaired.
  • strengthening agents, vitamins, swelling agents, thickeners, surfactants, etc. which do not impair various properties required for the formulation (eg, formulation stability) 1 type, or 2 or more types can be selected according to the dosage form.
  • the pharmacologically acceptable base may be another component having an inhibitory effect on nitric oxide production.
  • oils and fats examples include fatty acid esters other than components (A) to (F), edible oils and fats, hydrocarbons, higher fatty acids, and higher alcohols, and edible oils and fats are preferred.
  • fatty acid esters other than components (A) to (F) include fatty acid esters other than components (A) to (F), edible oils and fats, hydrocarbons, higher fatty acids, and higher alcohols, and edible oils and fats are preferred.
  • the ratio of the total amount of components (A) to (F) (components (D) to (F) is optional) to the total amount of oil component and components (A) to (F) 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.
  • excipient examples include cellulose such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, crystalline cellulose, ethylcellulose, low-substituted hydroxypropylcellulose, and pharmacologically acceptable derivatives thereof; polyvinylpyrrolidone, partially saponified polyvinyl alcohol Synthetic polymers such as gelatin, gum arabic powder, pullulan, agar, alginic acid, sodium alginate, chitansan gum, etc .; ethanol, glycerin, isobutyl alcohol, isopropyl alcohol, butanol, propanol, 2-pentanol, 2-methylbutanol Lower alcohols such as 3-methyl-2-butanol, 3-methyl-2-butenol, 1-penten-3-ol; hydrogenated rapeseed oil alcohol, laur Higher alcohols such as alcohol, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, lanolin alcohol, octyl
  • disintegrant examples include crospovidone, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, hydroxypropyl starch, and partially pregelatinized starch.
  • binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, dextrin, starch, and pregelatinized starch.
  • the lubricant examples include calcium stearate, magnesium stearate, sucrose fatty acid esters other than component (D) and component (E), light anhydrous silicic acid, sodium stearyl fumarate, polyethylene glycol, talc, and stearic acid. It is done.
  • 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.
  • colorant examples include caramel dye, turmeric dye, orange dye, cacao dye, red pepper dye, marigold dye, iron (III) oxide, titanium dioxide, safflower dye, gardenia dye, and copper chlorophyll dye.
  • Examples of the internal preparation of the present invention include agents used in oral administration forms (for example, oral administration, sublingual administration). Among these, a less invasive dosage form is preferable, and oral administration (internal use) is more preferable.
  • Examples of the dosage form of the oral administration agent (internal use) or the composition for oral administration (composition for internal use) include, for example, liquid (solution), syrup (syrup), tablet (tablet, tablet), capsule (capsule) Agent), powder (granule, fine granule), soft capsule (soft capsule), solid, semi-liquid, cream, and paste.
  • the administration target of the internal preparation may be an animal including a human, and is usually a human, but an animal other than a human (eg, mouse, rat, hamster, dog, cat, sheep, goat, cow, pig, monkey, etc. Mammals).
  • the internal preparation of the present invention can be used as a food composition, medicine, or quasi drug.
  • food compositions include beverages (soft drinks, carbonated drinks, nutritional drinks, powdered drinks, fruit drinks, milk drinks, jelly drinks, etc.), confectionery (cookies, cakes, gums, candies, tablets, gummies, buns, sheep candy) , Pudding, jelly, ice cream, sherbet, etc.), processed fishery products (kamaboko, chikuwa, hanpen, etc.), processed livestock products (hamburg, ham, sausage, winner, cheese, butter, yogurt, fresh cream, cheese, margarine, fermentation Milk, etc.), soup (powder soup, liquid soup, etc.), staple foods (rice, noodles (dried noodles, raw noodles), bread, cereals, etc.), seasonings (mayonnaise, shortening, dressing, sauce, sauce, soy sauce, etc.) ).
  • the dosage form of the internal preparation of the present invention is usually oral administration such as buccal administration and sublingual administration.
  • the dosage form of the internal preparation of the present invention can be determined as appropriate depending on whether it is a food or drink, a drug, or a quasi drug, and is not particularly limited.
  • dosage forms for oral administration are liquid (liquid), syrup (syrup), tablet, capsule (capsule), powder (granular (granule), fine (powder)) , Soft capsules (soft capsules), solids (solid preparations), semi-liquids, creams, and pastes, with soft capsules (soft capsules) being preferred.
  • the method for producing the internal preparation is not particularly limited, and may be followed according to a conventional method based on the dosage form and use. As an example, a production method when the dosage form is a soft capsule is shown below.
  • 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, more preferably 80 ° C. or lower. Therefore, the heating is usually performed at 40 to 100 ° C., preferably 50 to 90 ° C., more preferably 55 to 80 ° C.
  • the mixing is preferably performed so as to be uniform, and stirred as necessary.
  • the cooling temperature is usually 70 ° C.
  • the cooling temperature is usually 20 to 70 ° C., preferably 22 to 60 ° C., more preferably 25 to 40 ° C.
  • component (B) is added and mixed (preferably so as to be uniform, and stirred as necessary) to obtain the contents of the soft capsule (hereinafter also referred to as “content liquid”).
  • Content liquid contains the contents of the soft capsule (hereinafter also referred to as “content liquid”).
  • 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 pulverizer.
  • the obtained content liquid is included in the coating substrate.
  • the inclusion method include a flat plate method and a rotary die method. The latter is taken as an example, assuming that a medicine tank and a gelatin melting tank are provided, and a filling machine capable of setting a die roll and a tumbler dryer are used. Explained.
  • a film substrate for example, a polymer such as gelatin or starch
  • a plasticizer for example, glycerin, sorbitol, etc.
  • purified water or the like
  • a small tank usually warming (50 to 55 ° C)
  • the drying temperature is usually 20 to 30 ° C. and the relative humidity is 30 to 50%.
  • the drying time is usually 24 to 48 hours. For example, when the water content at the time of filling is 30 to 40%, the drying is performed until the water content decreases to 6 to 8%.
  • the dried soft capsules may be polished with a tumbler for 2 minutes to 1 hour, if necessary, to finish the soft capsules.
  • the oral preparations of the present invention are foods such as health foods, functional foods, dietary supplements (supplements), foods for specified health use, medical foods, foods for the sick, foods for infants, foods for nursing care, foods for the elderly, etc. It can be used as a medicine or quasi-drug.
  • Examples 1 to 46 and Comparative Examples 1 to 3 The contents of soft capsules prepared with the compositions described in Tables 1 to 7 were subjected to the following evaluation tests.
  • the soft capsule was prepared according to a conventional method. That is, after mixing each component as the contents, each component as a film was coated to obtain a soft capsule.
  • One of the evaluation of separation of the soft capsule content liquid and the evaluation of dispersibility in water in each of the examples and comparative examples is that one is B or more and the other is C or more, or both are C or more. It can be evaluated that it is suitable as a formulation by the above.
  • Tables 1-7 The results of the evaluation test are shown in Tables 1-7.
  • Table 8 shows information on the components used in each example and comparative example.

Abstract

The purpose of the present invention is to provide: an oral agent including two or more oily components, wherein the oral agent is capable of exhibiting a good balance between dispersibility and stability; and a method for producing a soft capsule agent. The present invention is: an oral agent including component (A): an n-3 fatty acid such as docosahexaenoic acid, component (B): a crystalline oily component such as lutein, capsanthin, zeaxanthin, β-cryptoxanthin, and astaxanthin, and component (C): a glycerin fatty acid ester or polyglycerin fatty acid ester having an HLB of 5 or lower; and a method for producing a soft capsule agent.

Description

内服剤Internal use
　本発明は、内服剤に関する。 The present invention relates to an internal medicine.
　ドコサヘキサエン酸等のｎ－３系脂肪酸、カロテノイド等の油性成分は、様々な生理活性を有することから健康食品としてソフトカプセル剤等の剤形での需要が高まっている。しかし、ドコサヘキサエン酸とカロテノイドをソフトカプセル剤に高含量配合すると、ソフトカプセル剤の内容物の安定性が保てずに、内容物に含まれる成分の分離が生じやすくなる。
　このような内容物に含まれる成分の分離を抑制するために、増粘効果の高いワックス系乳化剤やミツロウ等を使用する方法が開発されている。しかし、この方法では、崩壊試験において、内容物の水への分散性が悪いという課題が生じた。 Oily components such as n-3 fatty acids such as docosahexaenoic acid and carotenoids have various physiological activities, and therefore, there is an increasing demand for dosage forms such as soft capsules as health foods. However, when a high content of docosahexaenoic acid and carotenoid is blended in the soft capsule, the stability of the content of the soft capsule cannot be maintained, and the components contained in the content tend to be separated.
In order to suppress separation of components contained in such contents, a method using a wax-based emulsifier or beeswax having a high thickening effect has been developed. However, this method has a problem that the dispersibility of the contents in water is poor in the disintegration test.
　内容物の水への分散性を向上させる方法としては、高ＨＬＢ値の乳化剤で可溶化する方法が一般的である（例えば、特許文献１～２）。一方、難油溶性粉末を比較的低いＨＬＢ値の乳化剤で分散させる方法が提案されている（特許文献３）。 As a method for improving the dispersibility of the contents in water, a method of solubilizing with an emulsifier having a high HLB value is generally used (for example, Patent Documents 1 and 2). On the other hand, a method of dispersing a hardly oil-soluble powder with an emulsifier having a relatively low HLB value has been proposed (Patent Document 3).
特許第５８７８６３８号公報Japanese Patent No. 5878638 特許第５８８１８３８号公報Japanese Patent No. 5881838 特開２０１５－１５５３８４号公報JP-A-2015-155384
　しかしながら、一般に油性成分の分散性を高めるために高ＨＬＢ値の乳化剤を用いると、各成分が分離しやすくなる傾向にあり、従来の方法では分散性と安定性の両方をバランスよく発揮させることが難しい。本発明は、２種以上の油性成分を含む内服剤において、分散性と安定性とをバランスよく発揮できる内服剤の提供を目的とする。 However, in general, when an emulsifier having a high HLB value is used to increase the dispersibility of the oil component, each component tends to be separated, and the conventional method can exhibit both dispersibility and stability in a balanced manner. difficult. An object of the present invention is to provide an internal preparation that can exhibit a good balance between dispersibility and stability in an internal preparation containing two or more oily components.
　本発明は以下の〔１〕～〔１０〕を提供する。
〔１〕成分（Ａ）：ｎ－３系脂肪酸、
　成分（Ｂ）：結晶性油性成分、及び
　成分（Ｃ）：ＨＬＢが５以下の、グリセリン脂肪酸エステル又はポリグリセリン脂肪酸エステル、を含む内服剤。
〔２〕成分（Ｄ）：ＨＬＢが１０以上の親水性乳化剤をさらに含む、〔１〕に記載の剤。
〔３〕成分（Ｅ）：ＨＬＢが５を超えて１０未満の乳化剤をさらに含む、〔１〕又は〔２〕に記載の剤。
〔４〕成分（Ｂ）が、ルテイン、カプサンチン、ゼアキサンチン、β-クリプトキサンチン、及びアスタキサンチンからなる群より選択される少なくとも１つを含む、〔１〕～〔３〕のいずれか１項に記載の剤。
〔５〕成分（Ｂ）の含有量が、組成物全量に対し０．２質量％以上である、〔１〕～〔４〕のいずれか１項に記載の剤。
〔６〕成分（Ａ）の含有量が、組成物全量に対し６０質量％以下である、〔１〕～〔５〕のいずれか１項に記載の剤。
〔７〕成分（Ａ）がドコサヘキサエン酸である、〔１〕～〔６〕のいずれか１項に記載の剤。
〔８〕ソフトカプセル剤である、〔１〕～〔７〕のいずれか１項に記載の剤。
〔９〕成分（Ａ）～（Ｃ）を含む内容物と、内容物を包含する皮膜とを有する、〔８〕に記載の剤。
〔１０〕成分（Ａ）：ｎ－３系脂肪酸、
　成分（Ｂ）：結晶性油性成分、及び
　成分（Ｃ）：ＨＬＢが５以下のグリセリン脂肪酸エステル又はポリグリセリン脂肪酸エステル、を含む内容物を調製すること、並びに、内容物を皮膜基材で包含することを有する、ソフトカプセル剤の製造方法。 The present invention provides the following [1] to [10].
[1] Component (A): n-3 fatty acid,
Component (B): a crystalline oily component, and component (C): an internal preparation containing a glycerin fatty acid ester or polyglycerin fatty acid ester having an HLB of 5 or less.
[2] Component (D): The agent according to [1], further comprising a hydrophilic emulsifier having an HLB of 10 or more.
[3] Component (E): The agent according to [1] or [2], further comprising an emulsifier having an HLB of more than 5 and less than 10.
[4] The component (B) according to any one of [1] to [3], wherein the component (B) includes at least one selected from the group consisting of lutein, capsanthin, zeaxanthin, β-cryptoxanthin, and astaxanthin. Agent.
[5] The agent according to any one of [1] to [4], wherein the content of component (B) is 0.2% by mass or more based on the total amount of the composition.
[6] The agent according to any one of [1] to [5], wherein the content of component (A) is 60% by mass or less based on the total amount of the composition.
[7] The agent according to any one of [1] to [6], wherein component (A) is docosahexaenoic acid.
[8] The agent according to any one of [1] to [7], which is a soft capsule.
[9] The agent according to [8], comprising a content containing components (A) to (C) and a film containing the content.
[10] Component (A): n-3 fatty acid,
Ingredient (B): crystalline oily ingredient, and ingredient (C): preparing a content containing glycerin fatty acid ester or polyglycerin fatty acid ester having an HLB of 5 or less, and including the content in a coating substrate A method for producing a soft capsule.
　本発明によれば、成分（Ａ）～（Ｃ）を含むことにより、成分（Ａ）と成分（Ｂ）の分散性と安定性をバランスよく発揮できる内服剤が提供される。 According to the present invention, by including the components (A) to (C), an internal preparation that can exhibit the dispersibility and stability of the components (A) and (B) in a balanced manner is provided.
　本発明の内服剤は、以下の成分（Ａ）：ｎ－３系脂肪酸を含む。 The internal preparation of the present invention contains the following component (A): n-3 fatty acid.
　ｎ－３系脂肪酸とは、脂肪酸のメチル末端から３番目（ｎ３位、ω３位）の炭素－炭素結合が不飽和結合である脂肪酸である。ｎ－３系脂肪酸の由来は特に限定されず、植物、動物、微生物等の天然由来であってもよいし、化学合成等人工的に製造されたものでもよいし、遺伝子組換え等のバイオテクノロジーにより製造されたものでもよいし、市販品でもよい。脂肪酸が有する炭素原子数は、通常は１５以上であり、１７以上が好ましく、１９以上がより好ましい。炭素原子数の上限は、通常は３０以下であればよく、２５以下が好ましい。 The n-3 fatty acid is a fatty acid having an unsaturated bond at the third (n3-position, ω3-position) carbon-carbon bond from the methyl end of the fatty acid. The origin of the n-3 fatty acid is not particularly limited, and may be naturally derived from plants, animals, microorganisms, etc., may be artificially produced such as chemical synthesis, or biotechnology such as genetic recombination It may be manufactured by or a commercially available product. The number of carbon atoms contained in the 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, and preferably 25 or less.
　ｎ－３系脂肪酸としては例えば、ドコサヘキサエン酸（ＤＨＡ、（４Ｚ，７Ｚ，１０Ｚ，１３Ｚ，１６Ｚ，１９Ｚ）－ドコサ－４，７，１０，１３，１６，１９－ヘキサエン酸）、ドコサペンタエン酸（ＤＰＡ、ａｌｌ－ｃｉｓ－ドコサ－７，１０，１３，１６，１９－ペンタエン酸）、α－リノレン酸、エイコサテトラエン酸（ＥＴＡ、ａｌｌ－ｃｉｓ－８，１１，１４，１７－エイコサテトラエン酸）、エイコサペンタエン酸（ＥＰＡ、(５Ｚ，８Ｚ，１１Ｚ，１４Ｚ，１７Ｚ)－イコサ－５，８，１１，１４，１７－ペンタエン酸）が挙げられる。ｎ－３系脂肪酸は、生物の体内で生理機能を発揮し得る成分（機能性成分）が好ましく、ＤＨＡがより好ましい。 Examples of n-3 fatty acids include docosahexaenoic acid (DHA, (4Z, 7Z, 10Z, 13Z, 16Z, 19Z) -docosa-4,7,10,13,16,19-hexaenoic acid), 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) and 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 physiological functions in the body of an organism, and more preferably DHA.
　ＤＨＡは、動物（例えば、魚類）、微生物（例えば、Ｓｃｈｉｚｏｃｈｙｔｒｉｕｍ属微生物）等天然物に由来するものが多いが、これに限定されない。ＤＨＡは、薬理学的に許容される塩の形態であってもよい。 DHA is often derived from natural products such as animals (for example, fish) and microorganisms (for example, Schizophytrium genus microorganisms), but is not limited thereto. DHA may be in the form of a pharmacologically acceptable salt.
　ＤＨＡは、遊離脂肪酸としてのＤＨＡ、又はその誘導体でよい。誘導体としては、トリグリセリド型ＤＨＡ（ＴＧ－ＤＨＡ）、リン脂質型ＤＨＡが例示される。ＴＧ－ＤＨＡとは、トリグリセロールとＤＨＡがエステル結合している化合物である。トリグリセロール１分子あたり１分子以上の脂肪酸としてのＤＨＡが結合することができる。ＴＧ－ＤＨＡは、トリグリセロール１分子あたり２分子以上のＤＨＡが結合していることが好ましい。リン脂質型のＤＨＡとは、ホスファチジルコリン、ホスファチジルセリン等のリン脂質にＤＨＡが結合している化合物である。 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. DHA as one or more fatty acids per molecule of triglycerol can bind. TG-DHA preferably has two or more DHA molecules 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.
　成分（Ａ）は、１種類のｎ－３系脂肪酸でもよいし、２種以上のｎ－３系脂肪酸の組み合わせでもよい。 Component (A) may be a single n-3 fatty acid or a combination of two or more n-3 fatty acids.
　成分（Ａ）の含有量は、組成物全量に対して、通常は１５質量％以上、好ましくは１８質量％、より好ましくは２０質量％以上、さらに好ましくは２５質量％以上である。これにより、本発明の内服剤が成分（Ａ）の生理機能を効率よく発揮し得る。上限は、通常は６５質量％以下、好ましくは６０質量％以下、より好ましくは５５質量％以下、さらに好ましくは５０質量％以下である。これにより、本発明の内服剤が安定性及び分散性のバランスに優れた剤となり得る。従って、成分（Ａ）の含有量は、組成物全体に対して、通常は１５～６５質量％、好ましくは１５～６０質量％、より好ましくは１８～５５質量％、さらに好ましくは２０～５５質量％、さらにより好ましくは２５～５０質量％である。これにより、本発明の内服剤は、成分（Ａ）の生理機能を効率よく発揮することができ、かつ、安定性及び分散性のバランスに優れた剤となり得る。 The content of the component (A) is usually 15% by mass or more, preferably 18% by mass, more preferably 20% by mass or more, and further preferably 25% by mass or more with respect to the total amount of the composition. Thereby, the internal preparation of this invention can exhibit the physiological function of a component (A) efficiently. The upper limit is usually 65% by mass or less, preferably 60% by mass or less, more preferably 55% by mass or less, and still more preferably 50% by mass or less. Thereby, the internal preparation of this invention can become an agent excellent in balance of stability and a dispersibility. Therefore, the content of the component (A) is usually 15 to 65% by mass, preferably 15 to 60% by mass, more preferably 18 to 55% by mass, and further preferably 20 to 55% by mass with respect to the entire composition. %, Even more preferably 25 to 50% by weight. Thereby, the internal preparation of this invention can exhibit the physiological function of a component (A) efficiently, and can become an agent excellent in balance of stability and a dispersibility.
　本発明の内服剤は、成分（Ｂ）：結晶性油性成分を含む。 The internal preparation of the present invention contains component (B): a crystalline oily component.
　結晶性油性成分は、結晶性を有し、かつ水に不溶な成分を意味する。水に不溶であることは、例えば、サンプルを水（２０℃）１００ｇに溶解したときに、溶解度が０．１ｇ／水１００ｇ未満であることを意味する。なお、結晶性油性成分には、ｎ－３系脂肪酸は含まれない。 Crystalline oily component means a component that is crystalline and insoluble in water. Insoluble in water means, for example, when the sample is dissolved in 100 g of water (20 ° C.), the solubility is less than 0.1 g / 100 g of water. The crystalline oily component does not contain n-3 fatty acids.
　結晶性油性成分の由来は特に限定されず、植物、動物、微生物等の天然由来であってもよいし、化学合成等人工的に製造されたものでもよいし、遺伝子組換え等のバイオテクノロジーにより製造されたものでもよいし、市販品でもよい。 The origin of the crystalline oily component is not particularly limited, and it may be naturally derived from plants, animals, microorganisms, etc., may be artificially produced such as chemical synthesis, or by biotechnology such as genetic recombination. What was manufactured may be sufficient and a commercial item may be sufficient.
　結晶性油性成分としては、例えば、カロテノイド、ユビキノン（コエンザイムＱ１０など）、脂溶性ビタミン（ビタミンＥ（トコフェロール、トコトリエノールなど）、ビタミンＫ、ステロール（スクワランなど）など）が挙げられ、カロテノイドが好ましい。カロテノイドは通常、動植物に色素として含まれ、共役二重結合からなるポリエン構造を有する。カロテノイドは、酸素原子を含むものが好ましく、水酸基（－ＯＨ）を含むものがより好ましい。カロテノイドの炭素原子数は、通常は２０以上であり、好ましくは２５以上であり、より好ましくは３０以上であり、更に好ましくは４０以上である。カロテノイドは、生物の体内で生理機能を発揮し得る（機能性を有する）ことが好ましい。 Examples of the crystalline oily component include carotenoids, ubiquinones (such as coenzyme Q10), fat-soluble vitamins (such as vitamin E (such as tocopherol and tocotrienol)), vitamin K, and sterols (such as squalane), and carotenoids are preferred. Carotenoids are usually contained as pigments in animals and plants and have a polyene structure consisting of conjugated double bonds. The carotenoid preferably contains an oxygen atom, and more preferably contains a hydroxyl group (—OH). The number of carbon atoms in 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 the carotenoid can exhibit a physiological function (has functionality) in the body of an organism.
　カロテノイドとしては例えば、ルテイン（β，ε－カロテン－３，３’－ジオール；Ｃ４０Ｈ５６Ｏ２）、カプサンチン（ａｌｌ－ｔｒａｎｓ－カプサンチン、（３Ｒ，３’Ｓ，５’Ｒ）－３，３’－ジヒドロキシ－β，κ－カロテン－６’－オン；Ｃ４０Ｈ５６Ｏ３）、ゼアキサンチン（４－［１８－（４－ヒドロキシ－２，６，６－トリメチル－１－シクロヘキセニル）－３，７，１２，１６－テトラメチル－オクタデカ－１，３，５，７，９，１１，１３，１５，１７－ノナエニル］－３，５，５－トリメチル－３－シクロヘキセン－１－オール；Ｃ４０Ｈ５６Ｏ２）、β－クリプトキサンチン（（Ｒ）－３，５，５－トリメチル－４－［３，７，１２，１６－テトラメチル－１８－（２，６，６－トリメチルシクロヘキサ－１－エニル）－オクタデカ－１，３，５，７，９，１１，１３，１５，１７－ノナエニル］－シクロヘキサ－３－エノール；Ｃ４０Ｈ５６Ｏ）、アスタキサンチン（（６Ｓ）－６－ヒドロキシ－３－［（１Ｅ，３Ｅ，５Ｅ，７Ｅ，９Ｅ，１１Ｅ，１３Ｅ，１５Ｅ，１７Ｅ）－１８－［（４Ｓ）－４－ヒドロキシ－２，６，６－トリメチル－３－オキソ－１－シクロヘキシル］－３，７，１２，１６－テトラメチルオクタデカ－１，３，５，７，９，１１，１３，１５，１７－ノナエニル］－２，４，４－トリメチル－１－シクロヘキサ－２－エノン；Ｃ４０Ｈ５２Ｏ４）、フコキサンチン（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－ｏｘａｂｉｃｙｃｌｏ〔４．１．０〕ｈｅｐｔａｎｅ－１－ｙｌ］－３，７，１２，１６－ｔｅｔｒａｍｅｔｈｙｌ－１７－ｏｘｏｏｃｔａｄｅｃａ－１，３，５，７，９，１１，１３，１５－ｏｃｔａｅｎｙｌｉｄｅｎｅ］－３，５，５－ｔｒｉｍｅｔｈｙｌｃｙｃｌｏｈｅｘｙｌ］ｅｓｔｅｒ；Ｃ４２Ｈ５８Ｏ６）、ビオラキサンチン（（１Ｓ，４Ｓ，６Ｒ）－１－［（１Ｅ，３Ｅ，５Ｅ，７Ｅ，９Ｅ，１１Ｅ，１３Ｅ，１５Ｅ，１７Ｅ）－１８－［（１Ｓ，４Ｓ，６Ｒ）－４－Ｈｙｄｒｏｘｙ－２，２，６－ｔｒｉｍｅｔｈｙｌ－７－ｏｘａｂｉｃｙｃｌｏ［４．１．０］ｈｅｐｔａｎ－１－ｙｌ］－３，７，１２，１６－ｔｅｔｒａｍｅｔｈｙｌｏｃｔａｄｅｃａ－１，３，５，７，９，１１，１３，１５，１７－ｎｏｎａｅｎｙｌ］－２，２，６－ｔｒｉｍｅｔｈｙｌ－７－ｏｘａｂｉｃｙｃｌｏ［４．１．０］ｈｅｐｔａｎ－４－ｏｌ；Ｃ４０Ｈ５６Ｏ４）、アクチニオエリスロール（（３Ｓ，３－ｐｒｉｍｅＳ）－３，３－ｐｒｉｍｅ－Ｄｉｈｙｄｒｏｘｙ－２，２－ｐｒｉｍｅ－ｄｉｎｏｒ－ｂｅｔａ，ｂｅｔａ－ｃａｒｏｔｅｎｅ－４，４－ｐｒｉｍｅ－ｄｉｏｎｅ；Ｃ３８Ｈ４８Ｏ４）、ビキシン（（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；Ｃ２５Ｈ３０Ｏ４）、カンタキサンチン（β，β－カロテン－４，４’－ジオン；Ｃ４０Ｈ５２Ｏ２）、アポカロテナール（（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－ｏｃｔａｅｎａｌ；Ｃ３０Ｈ４０Ｏ）、リコピン（（６Ｅ，８Ｅ，１０Ｅ，１２Ｅ，１４Ｅ，１６Ｅ，１８Ｅ，２０Ｅ，２２Ｅ，２４Ｅ，２６Ｅ）－２，６，１０，１４，１９，２３，２７，３１－オクタメチルドトリアコンタ－２，６，８，１０，１２，１４，１６，１８，２０，２２，２４，２６，３０－トリデカエン；Ｃ４０Ｈ５６）が挙げられ、ルテイン、カプサンチン、ゼアキサンチン、β－クリプトキサンチン、アスタキサンチンが好ましい。 Examples of carotenoids include lutein (β, ε-carotene-3,3′-diol; C 40 H 56 O 2 ), capsanthin (all-trans-capsanthin, (3R, 3 ′S, 5′R) -3, 3′-dihydroxy-β, κ-carotene-6′-one; 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-trimethylcyclohexene) Sa-1-e Le) - octadeca -1,3,5,7,9,11,13,15,17- Nonaeniru] - cyclohex-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-cyclohexyl]- 3,7,12,16-tetramethyloctadeca-1,3,5,7,9,11,13,15,17-nonaenyl] -2,4,4-trimethyl-1-cyclohex-2-enone; 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-oxabiccyclo [4.1.0] heptane-1-yl] -3,7,12,16-tetramethyl-17-oxooctadeca-1,3 , 5,7,9,11,13,15-octaenylidene] -3,5,5-trimethylcyclohexyl ] ester; C 42 H 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-oxabicclo [4.1.0. ] Heptan-1-yl] -3,7,12,16-tetramethylocta eca-1,3,5,7,9,11,13,15,17-nonaenyl] -2,2,6- trimethyl-7-oxabicyclo [4.1.0] heptan-4-ol; C 40 H 56 O 4 ), actinioerythrol ((3S, 3-primeS) -3,3-prime-Dihydroxy-2,2-prime-dinor-beta, beta-caroten-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 ), canthaxanthin (β, β-carotene-4,4′-dione; C 40 H 52 O 2 ), apocarotenal ((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-octaeal; C 30 H 40 O), Lycopene ((6E, 8E, 10E, 12E, 14E, 16E, 18E, 20E, 22E, 24E, 26E) -2,6,10,14,19,23,27,31-octamethyldotriacont-2, 6,8,10,12,14,16,18,20,22,24,26,30- Toridekaen; C 40 H 56) can be mentioned, Rutei , Capsanthin, zeaxanthin, beta-cryptoxanthin, astaxanthin is preferred.
　ルテインは、高等植物（ホウレンソウ、ケール、コマツナなど）の葉緑体に存在する。カプサンチンは、パプリカ、トウガラシなどの植物に存在する。ゼアキサンチンは、植物（トウモロコシ等）、卵黄、動物性脂肪に存在する。β－クリプトキサンチンは、ウンシュウミカン、ホオズキ、オレンジ、パパイヤ、リンゴ等の植物、卵黄、バター等の乳製品、ウシ等の動物に存在する。アスタキサンチンは、エビ、カニ等の甲殻類、サケ、マダイ等の魚類に存在する。しかし各カロテノイドは、これらに由来するものに限定されない。カロテノイドは、それぞれ薬理学的に許容される塩の形態であってもよい。 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 (such as corn), egg yolk, and animal fat. 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 cows. Astaxanthin is present in crustaceans such as shrimps and crabs, 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.
　成分（Ｂ）は、１種類の結晶性油性成分でもよいし、２種以上の結晶性油性成分の組み合わせでもよい。成分（Ｂ）が２種以上のカロテノイドを含む場合、ルテインとカプサンチンの組み合わせ、ルテインとカプサンチンとゼアキサンチンの組み合わせを含むことが好ましく、ルテインとカプサンチンの組み合わせ又はルテインとカプサンチンとゼアキサンチンの組み合わせであることがより好ましい。 Component (B) may be one type of crystalline oily component or a combination of two or more types of crystalline oily components. When component (B) contains two or more kinds of carotenoids, it preferably contains a combination of lutein and capsanthin, a combination of lutein, capsanthin and zeaxanthin, and a combination of lutein and capsanthin or a combination of lutein, capsanthin and zeaxanthin. More preferred.
　成分（Ｂ）の含有量は、組成物全量に対して、通常は０．０１質量％以上、好ましくは０．１質量％以上、より好ましくは０．２質量％以上である。これにより、本発明の内服剤が成分（Ｂ）の生理機能を効率よく発揮し得る。上限は、通常は１０質量％以下、好ましくは８質量％以下、より好ましくは４質量％以下、さらに好ましくは３質量％以下である。これにより、本発明の内服剤の安定性を向上させることができ、本発明の内服剤が安定性及び分散性のバランスに優れた剤となり得る。従って、成分（Ｂ）の含有量は、組成物全体に対して、通常は０．０１～１０質量％、好ましくは０．１～８質量％、より好ましくは０．２～４質量％、さらに好ましくは０．２～３質量％である。これにより、本発明の内服剤は、成分（Ｂ）の生理機能を効率よく発揮することができ、かつ、安定性及び分散性のバランスに優れた剤となり得る。 The content of the component (B) is usually 0.01% by mass or more, preferably 0.1% by mass or more, more preferably 0.2% by mass or more with respect to the total amount of the composition. Thereby, the internal preparation of this invention can exhibit the physiological function of a component (B) efficiently. The upper limit is usually 10% by mass or less, preferably 8% by mass or less, more preferably 4% by mass or less, and still more preferably 3% by mass or less. Thereby, the stability of the internal preparation of the present invention can be improved, and the internal preparation of the present invention can be an agent having an excellent balance between stability and dispersibility. Therefore, the content of component (B) is usually 0.01 to 10% by weight, preferably 0.1 to 8% by weight, more preferably 0.2 to 4% by weight, based on the entire composition. The content is preferably 0.2 to 3% by mass. Thereby, the internal preparation of this invention can exhibit the physiological function of a component (B) efficiently, and can become an agent excellent in balance of stability and a dispersibility.
　本発明の内服剤は、成分（Ｃ）：ＨＬＢが５以下の、グリセリン脂肪酸エステル、又はポリグリセリン脂肪酸エステルを含む。 The internal preparation of the present invention contains component (C): glycerin fatty acid ester or polyglycerin fatty acid ester having an HLB of 5 or less.
　成分（Ｃ）としての、グリセリン脂肪酸エステル及びポリグリセリン脂肪酸エステルのＨＬＢは、通常５以下、好ましくは４．７以下、より好ましくは４．５以下である。これにより、内服剤における成分（Ａ）及び成分（Ｂ）の安定性を向上させることができる。ＨＬＢの下限は特に限定されないが、通常は０以上である。従って、成分（Ｃ）のＨＬＢは通常０～５、好ましくは０～４．７、より好ましくは０～４．５である。 The HLB of glycerin fatty acid ester and polyglycerin fatty acid ester as component (C) is usually 5 or less, preferably 4.7 or less, more preferably 4.5 or less. Thereby, the stability of the component (A) and the component (B) in the internal medicine can be improved. Although the minimum of HLB is not specifically limited, Usually, it is 0 or more. Therefore, the HLB of component (C) is usually 0 to 5, preferably 0 to 4.7, more preferably 0 to 4.5.
　ＨＬＢ（Ｈｙｄｒｏｐｈｉｌｅ－Ｌｉｐｏｐｈｉｌｅ　Ｂａｌａｎｃｅ）は、水と油への親和性の指標であり、一般に０に近いほど親油性が高く、２０に近いほど親水性が高くなる。本明細書中のＨＬＢは、アトラス法、グリフィン法、デイビス法、川上法等のいずれかにより算出することができる。また、製品として、メーカーが公表している値を参酌してもよい。 HLB (Hydrophile-Lipophile Balance) is an index of affinity for water and oil. Generally, the closer to 0, the higher the lipophilicity, and the closer to 20, the higher the hydrophilicity. The HLB in this specification can be calculated by any of the Atlas method, the Griffin method, the Davis method, the Kawakami method, and the like. In addition, the value published by the manufacturer may be taken into consideration as the product.
　グリセリン脂肪酸エステルは、グリセリンのヒドロキシ基のうち少なくとも１つに脂肪酸がエステル結合したものである。グリセリン脂肪酸エステルが２以上の脂肪酸を有する場合、それぞれの脂肪酸は互いに同一でもよいし異なってもよい。グリセリン脂肪酸エステルが有する脂肪酸の炭素原子数は、通常は８以上、好ましくは１４以上である。上限は通常２２以下、好ましくは１８以下である。炭素原子数は８～２２が好ましく、８～１８がより好ましく、１４～１８がさらに好ましい。脂肪酸は、不飽和脂肪酸及び飽和脂肪酸のいずれでもよい。グリセリン脂肪酸エステルが有する脂肪酸としては例えば、カプリル酸、ペラルゴン酸、カプリン酸、ラウリン酸、ペンタデシル酸、ミリスチン酸、パルミチン酸、マルガリン酸、ステアリン酸、オレイン酸、リノール酸、リノレン酸、アラキドン酸、ベヘン酸、エルカ酸が挙げられ、カプリル酸、ペラルゴン酸、カプリン酸、ラウリン酸、ペンタデシル酸、ミリスチン酸、パルミチン酸、マルガリン酸、ステアリン酸、オレイン酸、リノール酸、リノレン酸が好ましく、パルミチン酸、マルガリン酸、ステアリン酸がより好ましい。 Glycerin fatty acid ester is a fatty acid ester-bonded to at least one of the hydroxyl groups of glycerin. When the glycerin fatty acid ester has two or more fatty acids, each fatty acid may be the same as 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 still more preferably 14 to 18. The fatty acid may be either an unsaturated fatty acid or a saturated fatty acid. Examples of fatty acids possessed by glycerin fatty acid esters include caprylic acid, pelargonic acid, capric acid, lauric acid, pentadecylic acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, and behenic acid. Acid, erucic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, pentadecylic acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid are preferred, palmitic acid, margarine Acid and stearic acid are more preferable.
　ポリグリセリン脂肪酸エステルは、グリセリンの重合体であるポリグリセリンのヒドロキシ基のうち少なくとも１つ以上に脂肪酸がエステル化したものである。ポリグリセリンの重合度は、通常は６以下、好ましくは５以下、より好ましくは４以下である。下限は通常２以上である。ポリグリセリンの重合度は、２～６が好ましく、２～５がより好ましく、２～４がさらに好ましい。ポリグリセリン脂肪酸エステルが２以上の脂肪酸を有する場合、それぞれの脂肪酸は互いに同一でもよいし異なってもよい。ポリグリセリン脂肪酸エステルが有する脂肪酸の好ましい例については、グリセリン脂肪酸エステルが有する脂肪酸にて挙げたのと同様である。 Polyglycerin fatty acid ester is a fatty acid esterified with at least one of the hydroxyl groups of polyglycerol which is a polymer of glycerin. The degree of polymerization of polyglycerol is usually 6 or less, preferably 5 or less, more preferably 4 or less. The lower limit is usually 2 or more. The degree of polymerization of polyglycerol is preferably 2 to 6, more preferably 2 to 5, and still more preferably 2 to 4. When the polyglycerin fatty acid ester has two or more fatty acids, each fatty acid may be the same as or different from each other. About the preferable example of the fatty acid which polyglycerin fatty acid ester has, it is the same as that of mentioning about the fatty acid which glycerin fatty acid ester has.
　ＨＬＢが５以下のグリセリン脂肪酸エステルとしては例えば、ミリスチン酸グリセリン（ＨＬＢ＝３．５）、モノステアリン酸グリセリン（ＨＬＢ＝４．３）、ジステアリン酸グリセリンが挙げられ、モノステアリン酸グリセリン及びジステアリン酸グリセリンが好ましく、モノステアリン酸グリセリンがより好ましい。 Examples of the glycerin fatty acid ester having an HLB of 5 or less include glyceryl myristate (HLB = 3.5), glyceryl monostearate (HLB = 4.3), glyceryl distearate, glyceryl monostearate and glyceryl distearate. Is preferred, and glyceryl monostearate is more preferred.
　ＨＬＢが５以下のポリグリセリン脂肪酸エステルとしては例えば、ポリグリセリンステアリン酸エステル（例えば、デカステアリン酸デカグリセリン（ＨＬＢ＝３．０～３．８）、ペンタステアリン酸ヘキサグリセリン（ＨＬＢ＝４．５）、トリステアリン酸テトラグリセリン（ＨＬＢ＝４．６）、ペンタステアリン酸デカグリセリン（ＨＬＢ＝４．５）、ペンタステアリン酸テトラグリセリン（ＨＬＢ＝２．６）、ヘキサステアリン酸ペンタグリセリン（ＨＬＢ＝４．０）、モノステアリン酸ジグリセリン（ＨＬＢ＝５．０）、トリステアリン酸テトラグリセリン、トリステアリン酸ヘキサグリセリン（ＨＬＢ＝２．５））、ポリグリセリンオレイン酸エステル（例えば、デカオレイン酸デカグリセリン（ＨＬＢ＝３．０～３．３）、ペンタオレイン酸デカグリセリン（ＨＬＢ＝４．５）、ペンタオレイン酸ヘキサグリセリン（ＨＬＢ＝４．７）、ペンタオレイン酸テトラグリセリン（ＨＬＢ＝２．９））、ポリグリセリンベヘン酸エステル（例えば、ヘプタベヘン酸デカグリセリン（ＨＬＢ＝４．２）、ドデカベヘン酸デカグリセリン（ＨＬＢ＝２．５）、テトラベヘン酸ヘキサグリセリン）、ポリグリセリンエルカ酸エステル（例えば、オクタエルカ酸デカグリセリン（ＨＬＢ＝３．７））が挙げられる。 Examples of polyglycerin fatty acid esters having an HLB of 5 or less include polyglycerin stearic acid esters (for example, decastearic acid decaglycerin (HLB = 3.0 to 3.8), pentastearic acid hexaglycerin (HLB = 4.5) , Tetraglyceryl tristearate (HLB = 4.6), decaglycerol pentastearate (HLB = 4.5), tetraglyceryl pentastearate (HLB = 2.6), pentaglycerin hexastearate (HLB = 4. 0), diglyceryl monostearate (HLB = 5.0), tetraglyceryl tristearate, hexaglyceryl tristearate (HLB = 2.5)), polyglycerin oleate (for example, dekaleic acid decaglycerin (HLB) = 3.0-3.3) Taoleic acid decaglycerin (HLB = 4.5), pentaoleic acid hexaglycerin (HLB = 4.7), pentaoleic acid tetraglycerin (HLB = 2.9)), polyglycerin behenate (eg, heptabehenate deca Examples include glycerin (HLB = 4.2), decabehenic acid decaglycerin (HLB = 2.5), tetrabehenic acid hexaglycerin, and polyglycerin erucic acid ester (for example, octaerucic acid decaglycerin (HLB = 3.7)). .
　成分（Ｃ）は、ＨＬＢが５以下の、グリセリン脂肪酸エステル及びポリグリセリン脂肪酸エステルから選ばれる１種類、又は２種類以上の組み合わせでもよいが、少なくともＨＬＢが５以下のグリセリン脂肪酸エステルを含むことが好ましく、ＨＬＢが５以下のグリセリン脂肪酸エステルであることがより好ましい。 The component (C) may be one kind selected from glycerin fatty acid ester and polyglycerin fatty acid ester having an HLB of 5 or less, or a combination of two or more kinds, but preferably contains at least a glycerin fatty acid ester having an HLB of 5 or less. More preferably, the HLB is 5 or less glycerin fatty acid ester.
　成分（Ｃ）の含有量は、組成物全量に対して、通常は１質量％以上、好ましくは２質量％以上、より好ましくは３質量％以上、さらに好ましくは４質量％以上である。上限は、通常は２０質量％以下、好ましくは１５質量％以下、より好ましくは１０質量％以下、さらに好ましくは８質量％以下である。従って、成分（Ｃ）の含有量は、組成物全体に対して、通常は１～２０質量％、好ましくは２～１５質量％、より好ましくは３～１０質量％、さらに好ましくは４～８質量％ある。これにより、本発明の内服剤は、安定性を向上させることができ、食品としての安全性にも問題の無い剤とし得る。 The content of the component (C) is usually 1% by mass or more, preferably 2% by mass or more, more preferably 3% by mass or more, and further preferably 4% by mass or more with respect to the total amount of the composition. The upper limit is usually 20% by mass or less, preferably 15% by mass or less, more preferably 10% by mass or less, and still more preferably 8% by mass or less. Therefore, the content of the component (C) is usually 1 to 20% by mass, preferably 2 to 15% by mass, more preferably 3 to 10% by mass, and further preferably 4 to 8% by mass with respect to the entire composition. %is there. Thereby, the internal use preparation of this invention can improve stability, and can be made into an agent which does not have a problem also in the safety | security as a foodstuff.
　本発明の内服剤は、成分（Ｄ）：ＨＬＢが１０以上の親水性乳化剤を含んでもよく、成分（Ｄ）を含むことが好ましい。これにより、成分（Ａ）及び成分（Ｂ）の分散性をより向上させることができる。 The internal preparation of the present invention may contain a component (D): a hydrophilic emulsifier having an HLB of 10 or more, and preferably contains a component (D). Thereby, the dispersibility of a component (A) and a component (B) can be improved more.
　親水性乳化剤は、親水性を示す乳化剤であればよく、ＨＬＢが通常は１０以上、好ましくは１２以上、より好ましくは１４以上、更に好ましくは１５以上である。これにより、内服剤における成分（Ａ）及び成分（Ｂ）の安定性をより向上させることができる。ＨＬＢの上限は特に限定されないが、通常は２０以下である。従って、成分（Ｄ）のＨＬＢは通常１０～２０、好ましくは１２～２０、より好ましくは１４～２０、さらに好ましくは１５～２０である。 The hydrophilic emulsifier may be an emulsifier exhibiting hydrophilicity, and the HLB is usually 10 or more, preferably 12 or more, more preferably 14 or more, and further preferably 15 or more. Thereby, stability of the component (A) and component (B) in an internal use can be improved more. Although the upper limit of HLB is not specifically limited, Usually, it is 20 or less. Therefore, the HLB of component (D) is usually 10 to 20, preferably 12 to 20, more preferably 14 to 20, and still more preferably 15 to 20.
　親水性を示す乳化剤としては例えば、非イオン性界面活性剤が挙げられる。非イオン性界面活性剤としては、ショ糖脂肪酸エステル、ポリグリセリン脂肪酸エステル、有機酸モノグリセリド、プロピレングリコール脂肪酸エステル、ポリグリセリン縮合リシノレイン酸エステル、ソルビタン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステルが挙げられ、ショ糖脂肪酸エステル、ポリグリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステルが好ましく、ポリグリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステルがより好ましい。 Examples of hydrophilic emulsifiers include nonionic surfactants. Nonionic surfactants include sucrose fatty acid ester, polyglycerin fatty acid ester, organic acid monoglyceride, propylene glycol fatty acid ester, polyglycerin condensed ricinoleic acid ester, sorbitan fatty acid ester, and polyoxyethylene sorbitan fatty acid ester. Sugar fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are preferred, and polyglycerin fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are more preferred.
　ショ糖脂肪酸エステルは、ショ糖のヒドロキシ基のうち少なくとも１つに脂肪酸がエステル結合したものである。ショ糖脂肪酸エステルが２以上の脂肪酸を有する場合、それぞれの脂肪酸は互いに同一でもよいし異なってもよい。ショ糖脂肪酸エステルが有する脂肪酸の炭素原子数は、通常は８以上、好ましくは１２以上、より好ましくは１４以上である。上限は通常２２以下、好ましくは２０以下、より好ましくは１６以下である。炭素原子数は８～２２が好ましく、１２～２０がより好ましく、１４～１６がさらに好ましい。脂肪酸は、不飽和脂肪酸および飽和脂肪酸のいずれでもよい。ショ糖脂肪酸エステルが有する脂肪酸としては例えば、カプリル酸、ペラルゴン酸、カプリン酸、ラウリン酸、ペンタデシル酸、ミリスチン酸、パルミチン酸、マルガリン酸、ステアリン酸、オレイン酸、リノール酸、リノレン酸、アラキドン酸、ベヘン酸、エルカ酸が挙げられ、ラウリン酸、ペンタデシル酸、ミリスチン酸、パルミチン酸、マルガリン酸、ステアリン酸、オレイン酸、リノール酸、リノレン酸が好ましく、パルミチン酸、マルガリン酸、ステアリン酸がより好ましい。 Sucrose fatty acid ester is a fatty acid ester-bonded to at least one of the hydroxy groups of sucrose. When the sucrose fatty acid ester has two or more fatty acids, each fatty acid may be the same as 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, more preferably 14 or more. The upper limit is usually 22 or less, preferably 20 or less, more preferably 16 or less. The number of carbon atoms is preferably 8 to 22, more preferably 12 to 20, and still more preferably 14 to 16. The fatty acid may be either an unsaturated fatty acid or a saturated fatty acid. Examples of fatty acids possessed by sucrose fatty acid esters include caprylic acid, pelargonic acid, capric acid, lauric acid, pentadecylic acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, Examples include behenic acid and erucic acid, lauric acid, pentadecylic acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, and linolenic acid are preferable, and palmitic acid, margaric acid, and stearic acid are more preferable.
　ショ糖脂肪酸エステルとしては例えば、ショ糖ジオレイン酸エステル、ショ糖ジステアリン酸エステル、ショ糖ジパルミチン酸エステル、ショ糖ジミリスチン酸エステル、ショ糖ジラウリン酸エステル、ショ糖モノオレイン酸エステル、ショ糖モノステアリン酸エステル、ショ糖モノパルミチン酸エステル、ショ糖モノミリスチン酸エステル、ショ糖モノラウリン酸エステルが挙げられる。 Examples of sucrose fatty acid esters include sucrose dioleate, sucrose distearate, sucrose dipalmitate, sucrose dimyristate, sucrose dilaurate, sucrose monooleate, sucrose mono Examples include stearic acid ester, sucrose monopalmitic acid ester, sucrose monomyristic acid ester, and sucrose monolauric acid ester.
　成分（Ｄ）としてのポリグリセリン脂肪酸エステルは、成分（Ｃ）としてのポリグリセリン脂肪酸エステル以外のポリグリセリン脂肪酸エステルであればよい。ポリグリセリンの重合度は、通常は７以上、好ましくは８以上である。上限は通常１５以下、好ましくは１０以下である。ポリグリセリンの重合度は、７～１５が好ましく、８～１０がより好ましい。ポリグリセリン脂肪酸エステルが２以上の脂肪酸を有する場合、それぞれの脂肪酸は互いに同一でもよいし異なってもよい。ポリグリセリン脂肪酸エステルが有する脂肪酸の好ましい例については、成分（Ｃ）としてのグリセリン脂肪酸エステルが有する脂肪酸にて挙げたのと同様である。 The polyglycerin fatty acid ester as the component (D) may be any polyglycerin fatty acid ester other than the polyglycerin fatty acid ester as the component (C). The degree of polymerization of polyglycerol 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 polyglycerol is preferably 7 to 15, and more preferably 8 to 10. When the polyglycerin fatty acid ester has two or more fatty acids, each fatty acid may be the same as or different from each other. About the preferable example of the fatty acid which polyglycerin fatty acid ester has, it is the same as that of the fatty acid which glycerin fatty acid ester as a component (C) has.
　成分（Ｄ）としてのポリグリセリン脂肪酸エステルとしては例えば、ポリグリセリンオレイン酸エステル（例えば、モノオレイン酸デカグリセリン（ＨＬＢ＝１２～１５．５）、モノオレイン酸ヘキサグリセリン（ＨＬＢ＝１１．６）、モノオレイン酸ペンタグリセリン（ＨＬＢ＝１３．０））、ポリグリセリンステアリン酸エステル（例えば、モノステアリン酸デカグリセリン（ＨＬＢ＝１２～１３．４）、トリステアリン酸デカグリセリン（ＨＬＢ＝１０．０）、モノステアリン酸ヘキサグリセリン（ＨＬＢ＝１１．６）、ジステアリン酸デカグリセリン（ＨＬＢ＝１１．０）、モノステアリン酸ペンタグリセリン（ＨＬＢ＝１３．０））、ポリグリセリンパルミチン酸エステル（例えば、デカグリセリンモノパルミチン酸エステル（ＨＬＢ＝１３）、ヘキサグリセリンモノパルミチン酸エステル）、ポリグリセリンミリスチン酸エステル（例えば、モノミリスチン酸ペンタグリセリン（ＨＬＢ＝１３．０）、モノミリスチン酸デカグリセリン（ＨＬＢ＝１４）、ポリグリセリン酸ラウリン酸エステル（例えば、モノラウリン酸デカグリセリン（ＨＬＢ＝１４．７～１６）、モノラウリン酸ヘキサグリセリン（ＨＬＢ＝１３．４）、モノラウリン酸テトラグリセリン（ＨＬＢ＝１０．４）、モノラウリン酸ペンタグリセリン（ＨＬＢ＝１４．０））、ポリグリセリンカプリル酸エステル（例えば、モノカプリル酸デカグリセリン（ＨＬＢ＝１６．１））が挙げられる。 Examples of the polyglycerol fatty acid ester as the component (D) include polyglycerol oleate (for example, decaglycerol monooleate (HLB = 12-15.5), hexaglycerol monooleate (HLB = 11.6), Monooleic acid pentaglycerin (HLB = 13.0)), polyglycerin stearic acid ester (for example, monostearic acid decaglycerin (HLB = 12-13.4), tristearic acid decaglycerin (HLB = 10.0), Hexaglycerol monostearate (HLB = 11.6), decaglycerol distearate (HLB = 11.0), pentaglycerol monostearate (HLB = 13.0), polyglycerol palmitate ester (for example, decaglycerol mono Palmitic acid ester ( LB = 13), hexaglycerin monopalmitate), polyglyceryl myristate (eg, pentaglycerin monomyristate (HLB = 13.0), decaglycerin monomyristate (HLB = 14), polylauric acid lauric acid Esters (for example, decaglycerol monolaurate (HLB = 14.7-16), hexaglycerol monolaurate (HLB = 13.4), tetraglycerol monolaurate (HLB = 10.4), pentaglycerol monolaurate (HLB = 14) 0.0)), polyglycerin caprylic acid ester (for example, monocaprylic acid decaglycerin (HLB = 16.1)).
　ソルビタン脂肪酸エステルは、ソルビタンのヒドロキシ基のうち少なくとも１つに脂肪酸がエステル結合したものである。ソルビタン脂肪酸エステルが２以上の脂肪酸を有する場合、それぞれの脂肪酸は互いに同一でもよいし異なってもよい。ソルビタン脂肪酸エステルが有する脂肪酸の好ましい例は、ショ糖脂肪酸エステルが有する脂肪酸で挙げたのと同様である。 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, each fatty acid may be the same as or different from each other. Preferable examples of the fatty acid that the sorbitan fatty acid ester has are the same as those mentioned for the fatty acid that the sucrose fatty acid ester has.
　ポリオキシエチレンソルビタン脂肪酸エステルは、ソルビタン脂肪酸エステルのヒドロキシ基のうち少なくとも１つにエチレンオキサイドがエステル結合したものである。ソルビタン脂肪酸エステルの好ましい例については、上述したのと同様である。ポリオキシエチレンソルビタン脂肪酸エステルが有するエチレンオキサイドの付加モル数は、通常は２以上、好ましくは４以上、更に好ましくは１０以上である。上限は、通常は１００以下、好ましくは５０以下、より好ましくは３０以下である。付加モル数は２～１００が好ましく、４～５０がより好ましく、１０～３０が更に好ましい。 Polyoxyethylene sorbitan fatty acid ester is one in which ethylene oxide is ester-bonded to at least one of the hydroxy groups of 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, more preferably 10 or more. The upper limit is usually 100 or less, preferably 50 or less, more preferably 30 or less. The added mole number is preferably 2 to 100, more preferably 4 to 50, and still more preferably 10 to 30.
　ポリオキシエチレンソルビタン脂肪酸エステルとしては例えば、ポリオキシエチレンモノカプリル酸ソルビタン、ポリオキシエチレンモノラウリン酸ソルビタン（例えば、ポリソルベート２０（ポリオキシエチレン（２０）モノラウリン酸ソルビタン（ＨＬＢ＝１６．７）））、ポリオキシエチレンモノパルミチン酸ソルビタン（例えば、ポリソルベート４０（ポリオキシエチレン（２０）モノパルミチン酸ソルビタン（ＨＬＢ＝１５．６）））、ポリオキシエチレンモノステアリン酸ソルビタン（ＨＬＢ＝１４．９）、ポリオキシエチレンセスキステアリン酸ソルビタン、ポリオキシエチレントリステアリン酸ソルビタン（例えば、ポリソルベート６５（ポリオキシエチレン（２０）トリステアリン酸ソルビタン（ＨＬＢ＝１０．５）））、ポリオキシエチレンイソステアリン酸ソルビタン、ポリオキシエチレンセスキイソステアリン酸ソルビタン、ポリオキシエチレンオレイン酸ソルビタン、ポリオキシエチレンセスキオレイン酸ソルビタン、ポリオキシエチレンモノオレイン酸ソルビタン（例えば、ポリソルベート８０（ポリオキシエチレン（２０）モノオレイン酸ソルビタン（ＨＬＢ＝１５．７）））、ポリオキシエチレントリオレイン酸ソルビタン（例えば、ポリソルベート８５（ポリオキシエチレン（２０）トリオレイン酸ソルビタン（ＨＬＢ＝１１．０）））が挙げられ、ポリオキシエチレンモノラウリン酸ソルビタン又はポリオキシエチレンモノオレイン酸ソルビタンが好ましく、ポリソルベート２０又はポリソルベート８０がより好ましい。 Examples of polyoxyethylene sorbitan fatty acid esters include sorbitan polyoxyethylene monocaprylate, sorbitan polyoxyethylene monolaurate (for example, polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate (HLB = 16.7))), poly Sorbitan oxyethylene monopalmitate (for example, polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate (HLB = 15.6))), polyoxyethylene monostearate sorbitan (HLB = 14.9), polyoxyethylene Sorbitan sesquistearate, polyoxyethylene tristearate (eg, polysorbate 65 (polyoxyethylene (20) sorbitan tristearate (HLB = 10.5)) Sorbitan polyoxyethylene isostearate, sorbitan polyoxyethylene sesquiisostearate, sorbitan polyoxyethylene oleate, sorbitan polyoxyethylene sesquioleate, sorbitan polyoxyethylene monooleate (for example, polysorbate 80 (polyoxyethylene (20) Sorbitan monooleate (HLB = 15.7))), polyoxyethylene trioleate sorbitan (for example, polysorbate 85 (polyoxyethylene (20) sorbitan trioleate (HLB = 11.0))), Polyoxyethylene monolaurate sorbitan or sorbitan polyoxyethylene monooleate is preferred, and polysorbate 20 or polysorbate 80 is more preferred.
　成分（Ｄ）は、親水性乳化剤から選ばれる１種類、又は２種類以上の組み合わせでもよい。 Component (D) may be one type selected from hydrophilic emulsifiers, or a combination of two or more types.
　内服剤が成分（Ｄ）を含む場合の成分（Ｄ）の含有量は、組成物全量に対して、通常は０．１質量％以上、好ましくは０．２質量％以上、より好ましくは０．３質量％以上、さらに好ましくは０．５質量％以上である。上限は、通常は５質量％以下、好ましくは３質量％以下、より好ましくは２．５質量％以下、さらに好ましくは２質量％以下である。従って、成分（Ｄ）の含有量は、組成物全体に対して、通常は０．１～５質量％、好ましくは０．２～３質量％、より好ましくは０．３～２．５質量％、さらに好ましくは０．５～２質量％である。これにより、本発明の内服剤は、安定性及び分散性のバランスに優れ、食品としての安全性にも問題の無い剤とし得る。 When the internal preparation contains the component (D), the content of the component (D) is usually 0.1% by mass or more, preferably 0.2% by mass or more, more preferably 0. It is 3% by mass or more, more preferably 0.5% by mass or more. The upper limit is usually 5% by mass or less, preferably 3% by mass or less, more preferably 2.5% by mass or less, and further preferably 2% by mass or less. Therefore, the content of component (D) is usually 0.1 to 5% by mass, preferably 0.2 to 3% by mass, more preferably 0.3 to 2.5% by mass, based on the entire composition. More preferably, it is 0.5 to 2% by mass. Thereby, the internal preparation of this invention is excellent in balance of stability and dispersibility, and can be made into an agent which does not have a problem also in the safety as a foodstuff.
　本発明の内服剤は、成分（Ｅ）：ＨＬＢが５を超えて１０未満の乳化剤を含んでもよく、成分（Ｅ）を含むことが好ましい。これにより、内服剤の安定性及び／又は分散性を向上させることができる。 The internal preparation of the present invention may contain an emulsifier having an ingredient (E): HLB of more than 5 and less than 10, and preferably contains an ingredient (E). Thereby, the stability and / or dispersibility of the internal medicine can be improved.
　成分（Ｅ）としての、乳化剤のＨＬＢは、５を超えており、好ましくは５．５以上、より好ましくは６．０以上である。上限は、通常は１０未満、好ましくは９．７以下、より好ましくは９．３以下である。従って、ＨＬＢは通常５を超えて１０未満、好ましくは５．５～９．７、より好ましくは６．０～９．３である。これにより、内服剤における成分（Ａ）及び成分（Ｂ）の安定性及び／又は分散性をより向上させることができる。 The HLB of the emulsifier as the component (E) exceeds 5, preferably 5.5 or more, more preferably 6.0 or more. The upper limit is usually less than 10, preferably 9.7 or less, more preferably 9.3 or less. Accordingly, the HLB is usually more than 5 and less than 10, preferably 5.5 to 9.7, more preferably 6.0 to 9.3. Thereby, the stability and / or dispersibility of the component (A) and the component (B) in the internal medicine can be further improved.
　成分（Ｅ）は、ＨＬＢが５を超えて１０未満の乳化剤であればよいが、グリセリン脂肪酸エステル、ポリグリセリン脂肪酸エステル、有機酸モノグリセリド、ソルビタン脂肪酸エステル、及びポリオキシエチレンソルビタン脂肪酸エステルからなる群より選ばれる少なくとも１つであることが好ましい。 Component (E) may be an emulsifier having an HLB exceeding 5 and less than 10, but from the group consisting of glycerin fatty acid ester, polyglycerin fatty acid ester, organic acid monoglyceride, sorbitan fatty acid ester, and polyoxyethylene sorbitan fatty acid ester. It is preferable that at least one selected.
　成分（Ｅ）としてのグリセリン脂肪酸エステルは、成分（Ｃ）及び成分（Ｄ）としてのグリセリン脂肪酸エステル以外のグリセリン脂肪酸エステルであればよい。グリセリン脂肪酸エステルの好ましい例については、成分（Ｃ）及び成分（Ｄ）としてのグリセリン脂肪酸エステルにて挙げたのと同様である。 The glycerin fatty acid ester as the component (E) may be a glycerin fatty acid ester other than the glycerin fatty acid ester as the component (C) and the component (D). About the preferable example of glycerol fatty acid ester, it is the same as that of mentioning in the glycerol fatty acid ester as a component (C) and a component (D).
　成分（Ｅ）としてのグリセリン脂肪酸エステルとしては例えば、カプリル酸モノグリセリド（ＨＬＢ＝７．２）、ラウリン酸モノグリセリド（ＨＬＢ＝５．３）、カプリン酸モノグリセリド（ＨＬＢ＝６．５）が挙げられる。 Examples of the glycerin fatty acid ester as the component (E) include caprylic acid monoglyceride (HLB = 7.2), lauric acid monoglyceride (HLB = 5.3), and capric acid monoglyceride (HLB = 6.5).
　成分（Ｅ）としてのポリグリセリン脂肪酸エステルは、成分（Ｃ）及び成分（Ｄ）としてのポリグリセリン脂肪酸エステル以外のポリグリセリン脂肪酸エステルであればよい。ポリグリセリン脂肪酸エステルの好ましい例については、成分（Ｃ）及び成分（Ｄ）としてのポリグリセリン脂肪酸エステルにて挙げたのと同様である。 The polyglycerin fatty acid ester as the component (E) may be any polyglycerin fatty acid ester other than the polyglycerin fatty acid ester as the component (C) and the component (D). About the preferable example of a polyglycerol fatty acid ester, it is the same as that of mentioning in the polyglycerol fatty acid ester as a component (C) and a component (D).
　成分（Ｅ）としてのポリグリセリン脂肪酸エステルとしては例えば、ポリグリセリンステアリン酸エステル（例えば、モノステアリン酸ジグリセリン（ＨＬＢ＝７．０）、モノ・ジステアリン酸ジグリセリン（モノステアリン酸ジグリセリンとジステアリン酸ジグリセリンの組み合わせ）（ＨＬＢ＝６．５）、ジステアリン酸ヘキサグリセリン（ＨＬＢ＝９．６）、トリステアリン酸ヘキサグリセリン（ＨＬＢ＝７．４）、モノステアリン酸テトラグリセリン（ＨＬＢ＝６．０～８．４）、モノステアリン酸ヘキサグリセリン（ＨＬＢ＝９．０））、ポリグリセリンオレイン酸エステル（例えば、モノ・ジオレイン酸ジグリセリン（モノオレイン酸ジグリセリンとジオレイン酸ジグリセリンの組み合わせ）（ＨＬＢ＝６．５）、モノオレイン酸テトラグリセリン（ＨＬＢ＝８．８）、トリオレイン酸ペンタグリセリン（ＨＬＢ＝７．０）、モノオレイン酸ジグリセリン（ＨＬＢ＝７．３））、ポリグリセリンラウリン酸エステル（例えば、モノラウリン酸ジグリセリン（ＨＬＢ＝８．５））、ポリグリセリンミリスチン酸エステル（例えば、トリミリスチン酸ペンタグリセリン（ＨＬＢ＝８．０）、モノミリスチン酸ジグリセリン（ＨＬＢ＝７．７））、ポリグリセリンカプリル酸エステル（例えば、モノカプリル酸ジグリセリン（ＨＬＢ＝８．７））、ジアセチル酒石酸モノステアリン酸グリセリン（ＨＬＢ＝９．０）が挙げられ、ポリグリセリンオレイン酸エステルが好ましく、モノ・ジオレイン酸ジグリセリンがより好ましい。 Examples of the polyglycerol fatty acid ester as the component (E) include polyglycerol stearic acid esters (for example, diglyceryl monostearate (HLB = 7.0), diglyceryl monostearate (diglyceryl monostearate and distearic acid). Combination of diglycerin) (HLB = 6.5), hexaglyceryl distearate (HLB = 9.6), hexaglyceryl tristearate (HLB = 7.4), tetraglyceryl monostearate (HLB = 6.0 to 8.4), hexaglycerin monostearate (HLB = 9.0)), polyglycerin oleate (eg, diglyceryl monooleate (combination of diglycerin monooleate and diglycerin dioleate) (HLB = 6.5) Monoolei Acid tetraglycerin (HLB = 8.8), trioleic acid pentaglycerin (HLB = 7.0), monooleic acid diglycerin (HLB = 7.3)), polyglycerin lauric acid ester (for example, monolauric acid diglycerin) (HLB = 8.5)), polyglycerin myristic acid ester (for example, trimyristic acid pentaglycerin (HLB = 8.0), monomyristic acid diglycerin (HLB = 7.7)), polyglycerin caprylic acid ester ( For example, diglyceryl monocaprylate (HLB = 8.7)), diacetyltartaric acid monostearate glycerin (HLB = 9.0), polyglycerin oleate is preferable, and mono-dioleic acid diglycerin is more preferable. .
　有機酸モノグリセリド（グリセリン有機酸脂肪酸モノエステル）は、グリセリン脂肪酸モノエステルの３位の－ＯＨ基を有機酸でエステル化した化合物である。有機酸モノグリセリドが有する脂肪酸の炭素原子数は、通常は８以上、好ましくは１４以上である。上限は通常２２以下、好ましくは１８以下である。炭素原子数は８～２２が好ましく、８～１８がより好ましく、１４～１８がさらに好ましい。脂肪酸は、不飽和脂肪酸及び飽和脂肪酸のいずれでもよい。グリセリン脂肪酸エステルが有する脂肪酸としては例えば、カプリル酸、ペラルゴン酸、カプリン酸、ラウリン酸、ペンタデシル酸、ミリスチン酸、パルミチン酸、マルガリン酸、ステアリン酸、オレイン酸、リノール酸、リノレン酸、アラキドン酸、ベヘン酸が挙げられ、カプリル酸、ペラルゴン酸、カプリン酸、ラウリン酸、ペンタデシル酸、ミリスチン酸、パルミチン酸、マルガリン酸、ステアリン酸、オレイン酸、リノール酸、リノレン酸が好ましく、パルミチン酸、マルガリン酸、ステアリン酸がより好ましい。有機酸モノグリセリドが有する有機酸としては例えば、酒石酸、乳酸、リンゴ酸、クエン酸、ジアセチル酒石酸等のオキシカルボン酸；コハク酸、シュウ酸、アジピン酸、グルタル酸等の脂肪族飽和ジカルボン酸；酢酸、プロピオン酸、酪酸等の低級脂肪酸で構成されるモノカルボン酸；マレイン酸、フマル酸等の脂肪族不飽和ジカルボン酸；及びグリシン、アスパラギン酸等のアミノ酸が挙げられ、オキシカルボン酸、脂肪族飽和ジカルボン酸が好ましく、ジアセチル酒石酸、乳酸、クエン酸、コハク酸がより好ましい。 Organic acid monoglyceride (glycerin organic acid fatty acid monoester) is a compound in which the —OH group at the 3-position of glycerin fatty acid monoester is esterified 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 still more preferably 14 to 18. The fatty acid may be either an unsaturated fatty acid or a saturated fatty acid. Examples of fatty acids possessed by glycerin fatty acid esters include caprylic acid, pelargonic acid, capric acid, lauric acid, pentadecylic acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, and behenic acid. Examples include acids such as caprylic acid, pelargonic acid, capric acid, lauric acid, pentadecylic acid, myristic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, and linolenic acid, and palmitic acid, margaric acid, stearin Acid is more preferred. Examples of the organic acid that the organic acid monoglyceride has include oxycarboxylic acids such as tartaric acid, lactic acid, malic acid, citric acid, and diacetyltartaric acid; aliphatic saturated dicarboxylic acids such as succinic acid, oxalic acid, adipic acid, and glutaric 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; oxycarboxylic acids and aliphatic saturated dicarboxylic acids An acid is preferable, and diacetyltartaric acid, lactic acid, citric acid, and succinic acid are more preferable.
　有機酸モノグリセリドとしては例えば、ジアセチル酒石酸モノグリセリド（例えば、ジアセチル酒石酸モノステアリン酸グリセリン（ＨＬＢ＝９．０））、乳酸モノグリセリド（例えば、乳酸モノステアリン酸グリセリン（ＨＬＢ＝７．５））、クエン酸モノグリセリド（例えば、クエン酸モノステアリン酸グリセリン（ＨＬＢ＝９．５）、クエン酸モノオレイン酸グリセリン（ＨＬＢ＝７．０））、コハク酸モノグリセリド（例えば、コハク酸モノステアリン酸グリセリン（ＨＬＢ＝８．５））が挙げられる。 Examples of the organic acid monoglyceride include diacetyltartaric acid monoglyceride (eg, diacetyltartaric acid monostearate glycerin (HLB = 9.0)), lactic acid monoglyceride (eg, lactic acid monostearate glycerin (HLB = 7.5)), citric acid monoglyceride (For example, glyceryl monostearate (HLB = 9.5), glyceryl monooleate (HLB = 7.0)), succinic monoglyceride (for example, glyceryl monostearate (HLB = 8.5)) )).
　成分（Ｅ）としてのソルビタン脂肪酸エステルは、成分（Ｄ）としてのソルビタン脂肪酸エステル以外のソルビタン脂肪酸エステルであればよい。ソルビタン脂肪酸エステルの好ましい例については、成分（Ｄ）としてのグリセリン脂肪酸エステルにて挙げたのと同様である。 The sorbitan fatty acid ester as the component (E) may be a sorbitan fatty acid ester other than the sorbitan fatty acid ester as the component (D). About the preferable example of sorbitan fatty acid ester, it is the same as that of mentioning in the glycerol fatty acid ester as a component (D).
　成分（Ｅ）としてのソルビタン脂肪酸エステルとしては例えば、モノカプリル酸ソルビタン、モノラウリン酸ソルビタン（ＨＬＢ＝８．６）、イソステアリン酸ソルビタン（ＨＬＢ＝８）等が挙げられる。 Examples of the sorbitan fatty acid ester as component (E) include sorbitan monocaprylate, sorbitan monolaurate (HLB = 8.6), sorbitan isostearate (HLB = 8), and the like.
　成分（Ｅ）は、ＨＬＢが５を超えて１０未満のグリセリン脂肪酸エステルから選ばれる１種類、又は２種類以上の組み合わせでもよい。 Component (E) may be one type selected from glycerin fatty acid esters having an HLB exceeding 5 and less than 10, or a combination of two or more.
　内服剤が成分（Ｅ）を含む場合の成分（Ｅ）の含有量は、組成物全量に対して、通常は０．５質量％以上、好ましくは１質量％以上、より好ましくは２質量％以上、さらに好ましくは３質量％以上、さらにより好ましくは４質量％以上である。上限は、通常は２０質量％以下、好ましくは１８質量％以下、より好ましくは１５質量％以下、さらに好ましくは１０質量％以下である。従って、成分（Ｅ）の含有量は、組成物全体に対して、通常は０．５～２０質量％、好ましくは１～１８質量％、より好ましくは２～１５質量％、さらに好ましくは３～１０質量％、さらにより好ましくは４～１０質量％である。これにより、本発明の剤は、内服剤の安定性及び／又は分散性を向上させることができる。 When the internal preparation contains the component (E), the content of the component (E) is usually 0.5% by mass or more, preferably 1% by mass or more, more preferably 2% by mass or more based on the total amount of the composition. More preferably, it is 3% by mass or more, and still more preferably 4% by mass or more. The upper limit is usually 20% by mass or less, preferably 18% by mass or less, more preferably 15% by mass or less, and still more preferably 10% by mass or less. Therefore, the content of component (E) is usually 0.5 to 20% by mass, preferably 1 to 18% by mass, more preferably 2 to 15% by mass, and further preferably 3 to It is 10% by mass, and more preferably 4 to 10% by mass. Thereby, the agent of this invention can improve the stability and / or dispersibility of an internal use agent.
　成分（Ａ）の含有量に対する成分（Ｂ）の含有量の比率（（Ｂ）／（Ａ））（％）は、０％を超えることが好ましく、０．５％以上がより好ましい。上限は特にないが、通常は１０．０％以下である。 The ratio of the content of the component (B) to the content of the component (A) ((B) / (A)) (%) is preferably more than 0%, more preferably 0.5% or more. Although there is no upper limit in particular, it is usually 10.0% or less.
　成分（Ａ）と成分（Ｂ）の含有量の合計に対する成分（Ｃ）の含有量の比率（（Ｃ）／（（Ａ）＋（Ｂ））（％）は、通常は３％以上であり、好ましくは５％以上である。上限は特にないが、通常は４０％以下、好ましくは３０％以下である。これにより、内服剤の安定性をより向上させることができる。 The ratio ((C) / ((A) + (B)) (%) of the content of component (C) to the total content of component (A) and component (B) is usually 3% or more. The upper limit is not particularly limited, but is usually 40% or less, preferably 30% or less, whereby the stability of the internal use can be further improved.
　内服剤が成分（Ｄ）を含む場合、成分（Ｃ）と成分（Ｄ）の含有量の合計に対する成分（Ｂ）の含有量の比率（（Ｂ）／（（Ｃ）＋（Ｄ））（％）は、通常は３％以上であり、好ましくは４％以上である。上限は特にないが、通常は７０％以下、好ましくは６０％以下であり、より好ましくは５０％以下である。これにより、内服剤における成分（Ａ）及び成分（Ｂ）の安定性及び／又は分散性をより向上させることができる。 When the internal preparation contains the component (D), the ratio of the content of the component (B) to the total content of the component (C) and the component (D) ((B) / ((C) + (D)) ( %) Is usually at least 3%, preferably at least 4%, although there is no particular upper limit, it is usually at most 70%, preferably at most 60%, more preferably at most 50%. Thus, the stability and / or dispersibility of the component (A) and the component (B) in the internal medicine can be further improved.
　内服剤が成分（Ｄ）を含む場合、成分（Ｃ）の含有量に対する成分（Ｄ）の含有量の比率（（Ｄ）／（Ｃ））（％）は、通常は７０％以下、６０％以下が好ましく、５０％以下がより好ましく、４０％以下がさらに好ましく、３０％以下がさらにより好ましい。下限は特になく通常は０％を超えており、好ましくは５％以上であり、より好ましくは８％以上であり、さらに好ましくは１０％以上である。これにより、内服剤における成分（Ａ）及び成分（Ｂ）の安定性及び／又は分散性をより向上させることができる。 When the internal preparation contains the component (D), the ratio of the content of the component (D) to the content of the component (C) ((D) / (C)) (%) is usually 70% or less, 60% Or less, more preferably 50% or less, still more preferably 40% or less, and even more preferably 30% or less. There is no particular lower limit, usually exceeding 0%, preferably 5% or more, more preferably 8% or more, and even more preferably 10% or more. Thereby, the stability and / or dispersibility of the component (A) and the component (B) in the internal medicine can be further improved.
　内服剤が成分（Ｄ）及び成分（Ｅ）を含む場合、成分（Ｃ）と成分（Ｅ）の含有量の合計に対する成分（Ｄ）の含有量の比率（（Ｄ）／（（Ｃ）＋（Ｅ）））（％）は、４０％以下が好ましく、３０％以下がより好ましい。下限は特になく通常は０％を超えていればよい。これにより、内服剤における成分（Ａ）及び成分（Ｂ）の安定性及び／又は分散性をより向上させることができる。 When the internal preparation contains component (D) and component (E), the ratio of the content of component (D) to the total content of component (C) and component (E) ((D) / ((C) + (E))) (%) is preferably 40% or less, and more preferably 30% or less. There is no particular lower limit, and it is usually sufficient to exceed 0%. Thereby, the stability and / or dispersibility of the component (A) and the component (B) in the internal medicine can be further improved.
　内服剤は、成分（Ｆ）：成分（Ａ）～（Ｅ）以外の乳化剤を含んでもよい。成分（Ｆ）としては例えば、以下のものが挙げられる：
　ＨＬＢが５以下のソルビタン脂肪酸エステル、例えば、モノステアリン酸ソルビタン（ＨＬＢ＝４．７）、セスキステアリン酸ソルビタン（ＨＬＢ＝４．２）、トリステアリン酸ソルビタン（ＨＬＢ＝２．０）、セスキイソステアリン酸ソルビタン（ＨＬＢ＝４．５）、オレイン酸ソルビタン（ＨＬＢ＝４．３）、セスキオレイン酸ソルビタン（ＨＬＢ＝３．７）、トリオレイン酸ソルビタン（ＨＬＢ＝２．０）。 The internal preparation may contain an emulsifier other than Component (F): Components (A) to (E). Examples of component (F) include the following:
Sorbitan fatty acid esters having an HLB of 5 or less, such as sorbitan monostearate (HLB = 4.7), sorbitan sesquistearate (HLB = 4.2), sorbitan tristearate (HLB = 2.0), sesquiisostearic acid Sorbitan (HLB = 4.5), sorbitan oleate (HLB = 4.3), sorbitan sesquioleate (HLB = 3.7), sorbitan trioleate (HLB = 2.0).
　本発明において薬理学的に許容される塩としては、例えば、塩酸塩、臭化水素酸塩、硫酸塩、ヨウ化水素酸塩、硝酸塩、リン酸塩等の無機酸塩；クエン酸塩、シュウ酸塩、酢酸塩、ギ酸塩、プロピオン酸塩、安息香酸塩、トリフルオロ酢酸塩、マレイン酸塩、酒石酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、パラトルエンスルホン酸塩等の有機酸塩；ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、アンモニウム塩等の無機塩基塩；トリエチルアンモニウム塩、トリエタノールアンモニウム塩、ピリジニウム塩、ジイソプロピルアンモニウム塩等の有機塩基塩；アルギニン、アスパラギン酸、グルタミン酸などのアミノ酸塩が挙げられる。 Examples of the pharmacologically acceptable salt in the present invention include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate and phosphate; Organic acid salts such as acid salts, acetate salts, formates, propionates, benzoates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates, paratoluenesulfonates; Inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt; organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt; amino acids such as arginine, aspartic acid and glutamic acid Salt.
　本発明の内服剤は、上記以外の成分と、薬理学的に許容される基剤をさらに有していてもよい。薬理学的に許容される基剤の一例としては、主に貯蔵及び流通における安定性を確保する成分（例えば保存安定剤など）が挙げられる。その他、目的の最終製品（例えば、飲食品、医薬品、医薬部外品など）を構成する諸成分から選ばれる１又は２種類以上の成分（好ましくは１～３種類程度、より好ましくは１種類程度）を含有していてもよい。 The internal preparation of the present invention may further have components other than those described above and a pharmacologically acceptable base. An example of a pharmacologically acceptable base is a component that mainly ensures stability in storage and distribution (for example, a storage stabilizer). In addition, one or two or more types of components (preferably about 1 to 3 types, more preferably about 1 type) selected from various components constituting the target final product (for example, foods and drinks, pharmaceuticals, quasi drugs, etc.) ) May be contained.
　薬理学的に許容される基剤は、本発明の目的を損なわない限り、特に限定されない。例えば、油性成分、賦形剤、崩壊剤、結合剤、滑沢剤、コーティング剤、着色剤、発色剤、矯味剤、着香剤、酸化防止剤、防腐剤、呈味剤、酸味剤、甘味剤、強化剤、ビタミン剤、膨張剤、増粘剤、界面活性剤などの中から、製剤に必要な諸特性（例えば、製剤安定性）を損なわないものであって、最終製品（例えば、医薬品、医薬部外品、飲食品）の剤形に応じたものを１種又は２種以上選択することができる。また、薬理学的に許容される基剤は、一酸化窒素産生抑制効果を有する他の成分であってもよい。 The pharmacologically acceptable base is not particularly limited as long as the object of the present invention is not impaired. For example, oily ingredients, excipients, disintegrants, binders, lubricants, coating agents, colorants, coloring agents, flavoring agents, flavoring agents, antioxidants, preservatives, flavoring agents, sour agents, sweetness Among the preparations, strengthening agents, vitamins, swelling agents, thickeners, surfactants, etc., which do not impair various properties required for the formulation (eg, formulation stability) 1 type, or 2 or more types can be selected according to the dosage form. In addition, the pharmacologically acceptable base may be another component having an inhibitory effect on nitric oxide production.
　油性成分としては、例えば、成分（Ａ）～（Ｆ）以外の脂肪酸エステル、食用油脂、炭化水素、高級脂肪酸、高級アルコールが挙げられ、食用油脂が好ましい。食用油脂としては例えば、サフラワー油、大豆油、菜種油、キャノーラ油、アマニ油、芥子油、胡桃油、しそ油、米油、パーム油、パーム核油、ぶどう油、パームオレイン、ヤシ油、綿実油、ヒマワリ油、コーン油、ごま油、オリーブ油、扁桃油、落花生油、椰子油、椿油が挙げられる。油性成分の含有量と成分（Ａ）～（Ｆ）の含有量の合計量に対する成分（Ａ）～（Ｆ）の量（成分（Ｄ）～（Ｆ）は任意）の合計量の割合は、通常３質量％以上、好ましくは４質量％以上である。上限は、通常９０質量％以下、好ましくは８０質量％以下である。 Examples of the oil component include fatty acid esters other than components (A) to (F), edible oils and fats, hydrocarbons, higher fatty acids, and higher alcohols, and edible oils and fats are preferred. For example, safflower oil, soybean oil, rapeseed oil, canola oil, flaxseed oil, coconut oil, walnut oil, perilla oil, rice oil, palm oil, palm kernel oil, grape oil, palm olein, coconut oil, cottonseed oil , Sunflower oil, corn oil, sesame oil, olive oil, tonsil oil, peanut oil, coconut oil and coconut oil. The ratio of the total amount of components (A) to (F) (components (D) to (F) is optional) to the total amount of oil component and components (A) to (F) 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.
　賦形剤としては、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、結晶セルロース、エチルセルロース、低置換度ヒドロキシプロピルセルロース等のセルロース及びその薬理学的に許容される誘導体；ポリビニルピロリドン、部分けん化ポリビニルアルコール等の合成高分子；ゼラチン、アラビアゴム末、プルラン、寒天、アルギン酸、アルギン酸ナトリウム、キタンサンガム等の多糖類；エタノール、グリセリン、イソブチルアルコール、イソプロピルアルコール、ブタノール、プロパノール、２－ペンタノール、２－メチルブタノール、３－メチル－２－ブタノール、３－メチル－２－ブテノール、１－ペンテン－３－オール等の低級アルコール類；水添ナタネ油アルコール、ラウリルアルコール、ステアリルアルコール、セチルアルコール、セトステアリルアルコール、ラノリンアルコール、オクチルドデカノール、その他の脂肪族高級アルコール等の高級アルコール類；トウモロコシデンプン、バレイショデンプン、α化デンプン、ヒドロキシプロピルスターチ等のスターチおよびその薬理学的に許容される誘導体；乳糖、果糖、ブドウ糖、白糖、トレハロース、パラチノース、マンニトール、ソルビトール、エリスリトール、キシリトール、還元パラチノース、粉末還元麦芽糖水飴、マルチトール等の糖類および糖アルコール類；軽質無水ケイ酸、微粒酸化ケイ素、微粒二酸化ケイ素、酸化チタン、水酸化アルミニウムゲル等の無機賦形剤が挙げられる。剤全量に対する賦形剤の含有量は、０．０１質量％以上が好ましい。上限は、７０質量％以下が好ましい。 Examples of the excipient include cellulose such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, crystalline cellulose, ethylcellulose, low-substituted hydroxypropylcellulose, and pharmacologically acceptable derivatives thereof; polyvinylpyrrolidone, partially saponified polyvinyl alcohol Synthetic polymers such as gelatin, gum arabic powder, pullulan, agar, alginic acid, sodium alginate, chitansan gum, etc .; ethanol, glycerin, isobutyl alcohol, isopropyl alcohol, butanol, propanol, 2-pentanol, 2-methylbutanol Lower alcohols such as 3-methyl-2-butanol, 3-methyl-2-butenol, 1-penten-3-ol; hydrogenated rapeseed oil alcohol, laur Higher alcohols such as alcohol, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, lanolin alcohol, octyldodecanol, and other aliphatic higher alcohols; starches such as corn starch, potato starch, pregelatinized starch, hydroxypropyl starch, and the like Pharmacologically acceptable derivatives: Lactose, fructose, glucose, sucrose, trehalose, palatinose, mannitol, sorbitol, erythritol, xylitol, reduced palatinose, powdered reduced maltose starch syrup, maltitol and sugar alcohols; Examples include inorganic excipients such as acid, fine silicon oxide, fine silicon dioxide, titanium oxide, and aluminum hydroxide 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.
　崩壊剤としては、例えば、クロスポビドン、カルメロースカルシウム、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、カルボキシメチルスターチナトリウム、ヒドロキシプロピルスターチ、部分α化デンプンが挙げられる。 Examples of the disintegrant include crospovidone, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, hydroxypropyl starch, and partially pregelatinized starch.
　結合剤としては、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、エチルセルロース、ポリビニルアルコール、ポリビニルピロリドン、ゼラチン、デキストリン、デンプン、α化デンプンが挙げられる。 Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, dextrin, starch, and pregelatinized starch.
　滑沢剤としては、例えば、ステアリン酸カルシウム、ステアリン酸マグネシウム、成分（Ｄ）及び成分（Ｅ）以外のショ糖脂肪酸エステル、軽質無水ケイ酸、フマル酸ステアリルナトリウム、ポリエチレングリコール、タルク、ステアリン酸が挙げられる。剤全量に対する滑沢剤の含有量は、０．０１質量％以上が好ましい。上限は、２５質量％以下が好ましい。 Examples of the lubricant include calcium stearate, magnesium stearate, sucrose fatty acid esters other than component (D) and component (E), light anhydrous silicic acid, sodium stearyl fumarate, polyethylene glycol, talc, and stearic acid. It is done. 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.
　着色剤としては、例えば、カラメル色素、ウコン色素、オレンジ色素、カカオ色素、トウガラシ色素、マリーゴールド色素、酸化鉄（ＩＩＩ）、二酸化チタン、ベニバナ色素、クチナシ色素、銅クロロフィル色素が挙げられる。 Examples of the colorant include caramel dye, turmeric dye, orange dye, cacao dye, red pepper dye, marigold dye, iron (III) oxide, titanium dioxide, safflower dye, gardenia dye, and copper chlorophyll dye.
　本発明の内服剤としては、例えば、経口投与（例えば、口腔内投与、舌下投与）の投与形態で用いられる剤が挙げられる。これらの中でも侵襲性の少ない投与形態が好ましく、経口投与（内服）がより好ましい。 Examples of the internal preparation of the present invention include agents used in oral administration forms (for example, oral administration, sublingual administration). Among these, a less invasive dosage form is preferable, and oral administration (internal use) is more preferable.
　経口投与剤（内服剤）又は経口投与用組成物（内服用組成物）の剤形としては、例えば、液状（液剤）、シロップ状（シロップ剤）、錠剤（錠剤、タブレット）、カプセル状（カプセル剤）、粉末状（顆粒、細粒）、ソフトカプセル状（ソフトカプセル剤）、固形状、半液体状、クリーム状、ペースト状が挙げられる。 Examples of the dosage form of the oral administration agent (internal use) or the composition for oral administration (composition for internal use) include, for example, liquid (solution), syrup (syrup), tablet (tablet, tablet), capsule (capsule) Agent), powder (granule, fine granule), soft capsule (soft capsule), solid, semi-liquid, cream, and paste.
　内服剤の投与対象は、ヒトを含む動物であればよく、通常はヒトであるが、ヒト以外の動物（例えば、マウス、ラット、ハムスター、イヌ、ネコ、ヒツジ、ヤギ、ウシ、ブタ、サルなどの哺乳類）であってもよい。 The administration target of the internal preparation may be an animal including a human, and is usually a human, but an animal other than a human (eg, mouse, rat, hamster, dog, cat, sheep, goat, cow, pig, monkey, etc. Mammals).
　本発明の内服剤は、食品組成物、医薬、医薬部外品として利用できる。食品組成物としては例えば、飲料（清涼飲料、炭酸飲料、栄養飲料、粉末飲料、果実飲料、乳飲料、ゼリー飲料など）、菓子類（クッキー、ケーキ、ガム、キャンディー、タブレット、グミ、饅頭、羊羹、プリン、ゼリー、アイスクリーム、シャーベットなど）、水産加工品（かまぼこ、ちくわ、はんぺんなど）、畜産加工品（ハンバーグ、ハム、ソーセージ、ウィンナー、チーズ、バター、ヨーグルト、生クリーム、チーズ、マーガリン、発酵乳など）、スープ（粉末状スープ、液状スープなど）、主食類（ご飯類、麺（乾麺、生麺）、パン、シリアルなど）、調味料（マヨネーズ、ショートニング、ドレッシング、ソース、たれ、しょうゆなど）が挙げられる。 The internal preparation of the present invention can be used as a food composition, medicine, or quasi drug. Examples of food compositions include beverages (soft drinks, carbonated drinks, nutritional drinks, powdered drinks, fruit drinks, milk drinks, jelly drinks, etc.), confectionery (cookies, cakes, gums, candies, tablets, gummies, buns, sheep candy) , Pudding, jelly, ice cream, sherbet, etc.), processed fishery products (kamaboko, chikuwa, hanpen, etc.), processed livestock products (hamburg, ham, sausage, winner, cheese, butter, yogurt, fresh cream, cheese, margarine, fermentation Milk, etc.), soup (powder soup, liquid soup, etc.), staple foods (rice, noodles (dried noodles, raw noodles), bread, cereals, etc.), seasonings (mayonnaise, shortening, dressing, sauce, sauce, soy sauce, etc.) ).
　本発明の内服剤の投与形態は通常は口腔内投与、舌下投与などの経口投与である。 The dosage form of the internal preparation of the present invention is usually oral administration such as buccal administration and sublingual administration.
　本発明の内服剤の剤形は、飲食品、医薬品及び医薬部外品のいずれとするかによって適宜決定することができ、特に限定されない。経口投与される際の剤形の例としては、液状（液剤）、シロップ状（シロップ剤）、錠剤、カプセル状（カプセル剤）、粉末状（顆粒状（顆粒剤）、細粒（散剤））、ソフトカプセル状（ソフトカプセル剤）、固形状（固形製剤）、半液体状、クリーム状、ペースト状が挙げられ、ソフトカプセル状（ソフトカプセル剤）が好ましい。 The dosage form of the internal preparation of the present invention can be determined as appropriate 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 are liquid (liquid), syrup (syrup), tablet, capsule (capsule), powder (granular (granule), fine (powder)) , Soft capsules (soft capsules), solids (solid preparations), semi-liquids, creams, and pastes, with soft capsules (soft capsules) being preferred.
　内服剤の製造方法は、特に限定されず、剤形及び用途に基づき常法に従えばよい。一例として、剤形がソフトカプセル剤である場合の製造方法を以下に示す。 The method for producing the internal preparation is not particularly limited, and may be followed according to a conventional method based on the dosage form and use. As an example, a production method when the dosage form is a soft capsule is shown below.
　まず、ソフトカプセル剤の内容物を調製する。成分（Ａ）及び成分（Ｃ）、必要に応じて添加される成分（Ｄ）～（Ｆ）、並びに油性成分等の任意成分を加温して混合した後、冷却する。加温は通常４０℃以上、好ましくは５０℃以上、より好ましくは５５℃以上で行う。上限は特にないが通常は１００℃以下、好ましくは９０℃以下、より好ましくは８０℃以下である。従って、加温は、通常４０～１００℃、好ましくは５０～９０℃、より好ましくは５５～８０℃で行う。混合は、均一になるように行うことが好ましく、必要に応じて撹拌する。冷却温度は、加温の温度にもよるが、通常は７０℃以下、好ましくは６０℃以下、より好ましくは４０℃以下である。下限は通常２０℃以上、好ましくは２２℃以上、より好ましくは２５℃以上である。従って、冷却温度は通常２０～７０℃、好ましくは２２～６０℃、より好ましくは２５～４０℃である。冷却後、成分（Ｂ）を加えて混合し（好ましくは均一になるように行う、必要に応じて撹拌する）、ソフトカプセル剤の内容物（以下、「内容液」とも記載する）を得る。混合（撹拌混合）は機械的に行うことが好ましい。装置としては特に限定はないが、例えば、ホモミキサー、高圧ホモジナイザー等の高速攪拌機、高圧粉砕機が挙げられる。 First, prepare the contents of the soft capsule. Components (A) and (C), components (D) to (F) added as necessary, and optional components such as oily components are heated and mixed, and then cooled. 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, more preferably 80 ° C. or lower. Therefore, the heating is usually performed at 40 to 100 ° C., preferably 50 to 90 ° C., more preferably 55 to 80 ° C. The mixing is preferably performed so as to be uniform, and stirred as necessary. The cooling temperature is usually 70 ° C. or lower, preferably 60 ° C. or lower, 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, more preferably 25 ° C. or higher. Therefore, the cooling temperature is usually 20 to 70 ° C., preferably 22 to 60 ° C., more preferably 25 to 40 ° C. After cooling, component (B) is added and mixed (preferably so as to be uniform, and stirred as necessary) to obtain the contents of the soft capsule (hereinafter also referred to as “content liquid”). Mixing (stir 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 pulverizer.
　次に、得られた内容液を皮膜基材で包含する。包含方法としては例えば、平板法、ロータリーダイ法が挙げられるが、後者を例に取り、メディシンタンク、ゼラチンメルティングタンクを備え、ダイロールをセット可能な充填機及びタンブラードライヤーを用いたと仮定して以下に説明する。 Next, the obtained content liquid is included in the coating substrate. Examples of the inclusion method include a flat plate method and a rotary die method. The latter is taken as an example, assuming that a medicine tank and a gelatin melting tank are provided, and a filling machine capable of setting a die roll and a tumbler dryer are used. Explained.
　得られた内容液を、メディシンタンクに入れ、充填機の所定の位置にセットする。メディシンタンクに入れる前に、必要に応じて内容液のエマルジョン化、サスペンジョン化等の前処理を行ってもよい。 ∙ Put the obtained content liquid in the medicine tank and set it in the specified position of the filling machine. Prior to putting in the medicine tank, pretreatment such as emulsification or suspension of the content liquid may be performed as necessary.
　ゼラチンメルティングタンクに、皮膜基材（例えば、ゼラチン、デンプン等の高分子）、必要に応じて可塑剤（例えば、グリセリン、ソルビトール等）及び精製水等を加え、加温溶解（例えば、約８０℃）後、脱泡操作を同タンクで行い、粘度を調整して皮膜原液とする。皮膜原液をフィルトレーションをしながら小分けタンク（通常、加温（５０～５５℃））に移しかえ、充填機の所定の位置にセットする。 To a gelatin melting tank, a film substrate (for example, a polymer such as gelatin or starch), a plasticizer (for example, glycerin, sorbitol, etc.), purified water, or the like is added as necessary, and heated to dissolve (for example, about 80 ° C), the defoaming operation is performed in the same tank, the viscosity is adjusted, and the film stock solution is obtained. Transfer the undiluted film solution to a small tank (usually warming (50 to 55 ° C)) while filtering, and set it at a predetermined position on the filling machine.
　調合された皮膜原液及び内容物を、充填機の所定の位置にセットし、所定のダイロールをセットした充填機でソフトカプセルを成型する。充填室の温度は、通常、２０～３０℃に調整する。充填室の相対湿度は通常、３０～５０％に維持する。成形直後のソフトカプセルを、充填機に連結されたタンブラードライヤーに送り込み、回転させながら室内条件と同様のクリーンエアーで、形の一時固定及び皮膜中の水分の一時乾燥を行う（通常、約１～４時間）。 ∙ Set the prepared film stock solution and contents at a predetermined position of the filling machine, and mold a soft capsule with a filling machine with a predetermined die roll 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%. The soft capsule immediately after molding 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).
　包含成形され、一時乾燥したソフトカプセルを、タンブラードライヤーに移して乾燥する。乾燥の際の温度は通常２０～３０℃であり、相対湿度３０～５０％である。乾燥時間は通常２４～４８時間である。乾燥は、例えば、充填時の含水率３０～４０％の場合には６～８％に低下するまで行う。 Included and temporarily dried soft capsules are transferred to a tumbler dryer and dried. The drying temperature is usually 20 to 30 ° C. and the relative humidity is 30 to 50%. The drying time is usually 24 to 48 hours. For example, when the water content at the time of filling is 30 to 40%, the drying is performed until the water content decreases to 6 to 8%.
　乾燥後のソフトカプセルは、必要に応じて、タンブラーで２分～１時間の磨きをかけてソフトカプセルを仕上げてもよい。 The dried soft capsules may be polished with a tumbler for 2 minutes to 1 hour, if necessary, to finish the soft capsules.
　本発明の内服剤は、健康食品、機能性食品、栄養補助食品（サプリメント）、特定保健用食品、医療用食品、病者用食品、乳児用食品、介護用食品、高齢者用食品等の食品、医薬品又は医薬部外品として利用することができる。 The oral preparations of the present invention are foods such as health foods, functional foods, dietary supplements (supplements), foods for specified health use, medical foods, foods for the sick, foods for infants, foods for nursing care, foods for the elderly, etc. It can be used as a medicine or quasi-drug.
実施例１～４６及び比較例１～３
　表１～７に記載の組成にて調製したソフトカプセル剤の内容物を以下の評価試験に供した。ソフトカプセル剤の調製は、常法に従って行った。すなわち、内容物としての各成分を混合した後、皮膜としての各成分をコーティングして、ソフトカプセル剤を得た。 Examples 1 to 46 and Comparative Examples 1 to 3
The contents of soft capsules prepared with the compositions described in Tables 1 to 7 were subjected to the following evaluation tests. The soft capsule was prepared according to a conventional method. That is, after mixing each component as the contents, each component as a film was coated to obtain a soft capsule.
＜内容液の分離＞
　各実施例及び比較例のソフトカプセルを５００ｍＬのガラスビンにそれぞれ入れ、室温に放置し、放置後の内容液の分離を目視で観察した。観察結果を以下の基準にて評価した。
　Ａ：２４時間後に内容液の分離なし
　Ｂ：１２時間後に内容液の分離なし
　Ｃ：１２時間後に内容液の分離あり
　Ｄ：６時間後に内容液の分離あり <Separation of liquid contents>
The soft capsules of each Example and Comparative Example were placed in a 500 mL glass bottle and left at room temperature, and the separation of the content liquid after being left was visually observed. The observation results were evaluated according to the following criteria.
A: No content liquid separation after 24 hours B: No content liquid separation after 12 hours C: Content liquid separation after 12 hours D: Content liquid separation after 6 hours
＜内容液の分散性＞
　第十六改正日本薬局方に収載された一般試験法の崩壊試験法に準拠し、各実施例及び比較例のソフトカプセル６粒を精製水中で崩壊させたときの分散性を、目視で観察した。目視観察の結果を以下の基準にて評価した。
　Ａ：油性成分の分離がなく、精製水への分散性が均一で良好
　Ｂ：油性成分の分離がわずかにあるが、精製水への分散性が均一で良好
　Ｃ：油性成分の分離がみられ、わずかに精製水へ分散する
　Ｄ：油性成分がほとんど分離し、精製水へ分散しない <Dispersibility of liquid contents>
In accordance with the disintegration test method of the general test method listed in the 16th revised Japanese Pharmacopoeia, the dispersibility when the 6 soft capsules of each Example and Comparative Example were disintegrated in purified water was visually observed. The results of visual observation were evaluated according to the following criteria.
A: No separation of oily component, dispersibility in purified water is uniform and good B: Separation of oily component is slight, but dispersibility in purified water is uniform and good C: Separation of oily component is observed Slightly disperse in purified water D: Oily component is almost separated and not dispersed in purified water
＜総合判断＞
　各実施例及び比較例のソフトカプセル内容液の分離の評価及び水への分散性の評価のうち一方がＢ以上かつもう一方がＣ以上であるか、又は両方ともＣ以上であること、中でも両方Ｂ以上であることにより、製剤として好適であると評価できる。 <Comprehensive judgment>
One of the evaluation of separation of the soft capsule content liquid and the evaluation of dispersibility in water in each of the examples and comparative examples is that one is B or more and the other is C or more, or both are C or more. It can be evaluated that it is suitable as a formulation by the above.
　評価試験の結果を、表１～７に示す。各実施例及び比較例で用いた成分に関する情報を、表８に示す。 The results of the evaluation test are shown in Tables 1-7. Table 8 shows information on the components used in each example and comparative example.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
　表１～７から以下のことが明らかである。比較例ではソフトカプセル内容液の分離の評価ができなかったか、又はＤの評価であったが、実施例では同評価及び水への分散性の評価のうち一方がＢ以上かつもう一方がＣ以上であるか、又は両方ともＣ以上であった。このことは、本発明の内服剤が油性成分の安定性と分散性を両立し得る内服剤であることを示している。 The following is clear from Tables 1-7. In the comparative example, the separation of the soft capsule content liquid could not be evaluated, or the evaluation was D. In the examples, one of the evaluation and the evaluation of the dispersibility in water was B or more and the other was C or more. Yes, or both were C or higher. This indicates that the internal preparation of the present invention is an internal preparation that can achieve both stability and dispersibility of the oil component.

Claims (10)

  1. 　成分（Ａ）：ｎ－３系脂肪酸、
    　成分（Ｂ）：結晶性油性成分、及び
    　成分（Ｃ）：ＨＬＢが５以下の、グリセリン脂肪酸エステル又はポリグリセリン脂肪酸エステル、を含む内服剤。     Component (A): n-3 fatty acid,
    Component (B): a crystalline oily component, and component (C): an internal preparation containing a glycerin fatty acid ester or polyglycerin fatty acid ester having an HLB of 5 or less.
  2. 　成分（Ｄ）：ＨＬＢが１０以上の親水性乳化剤をさらに含む、請求項１に記載の剤。 Component (D): The agent according to claim 1, further comprising a hydrophilic emulsifier having an HLB of 10 or more.
  3. 　成分（Ｅ）：ＨＬＢが５を超えて１０未満の乳化剤をさらに含む、請求項１又は２に記載の剤。 Component (E): The agent according to claim 1 or 2, further comprising an emulsifier having an HLB of more than 5 and less than 10.
  4. 　成分（Ｂ）が、ルテイン、カプサンチン、ゼアキサンチン、β-クリプトキサンチン、及びアスタキサンチンからなる群より選択される少なくとも１つを含む、請求項１～３のいずれか１項に記載の剤。 The agent according to any one of claims 1 to 3, wherein the component (B) comprises at least one selected from the group consisting of lutein, capsanthin, zeaxanthin, β-cryptoxanthin, and astaxanthin.
  5. 　成分（Ｂ）の含有量が、組成物全量に対し０．２質量％以上である、請求項１～４のいずれか１項に記載の剤。 The agent according to any one of claims 1 to 4, wherein the content of the component (B) is 0.2% by mass or more based on the total amount of the composition.
  6. 　成分（Ａ）の含有量が、組成物全量に対し６０質量％以下である、請求項１～５のいずれか１項に記載の剤。 The agent according to any one of claims 1 to 5, wherein the content of the component (A) is 60% by mass or less based on the total amount of the composition.
  7. 　成分（Ａ）がドコサヘキサエン酸である、請求項１～６のいずれか１項に記載の剤。 The agent according to any one of claims 1 to 6, wherein the component (A) is docosahexaenoic acid.
  8. 　ソフトカプセル剤である、請求項１～７のいずれか１項に記載の剤。 The agent according to any one of claims 1 to 7, which is a soft capsule.
  9. 　成分（Ａ）～（Ｃ）を含む内容物と、内容物を包含する皮膜とを有する、請求項８に記載の剤。 The agent according to claim 8, comprising a content containing components (A) to (C) and a film containing the content.
  10. 　成分（Ａ）：ｎ－３系脂肪酸、
    　成分（Ｂ）：結晶性油性成分、及び
    　成分（Ｃ）：ＨＬＢが５以下の、グリセリン脂肪酸エステル又はポリグリセリン脂肪酸エステル、を含む内容物を調製すること、並びに、内容物を皮膜基材で包含すること、を有する、ソフトカプセル剤の製造方法。     Component (A): n-3 fatty acid,
    Component (B): Crystalline oil component, and Component (C): Preparation of a content containing a glycerin fatty acid ester or polyglycerin fatty acid ester having an HLB of 5 or less, and the content is included in the coating substrate A method for producing a soft capsule.
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