WO2007123153A1 - Capsule for oral administration - Google Patents

Capsule for oral administration Download PDF

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Publication number
WO2007123153A1
WO2007123153A1 PCT/JP2007/058437 JP2007058437W WO2007123153A1 WO 2007123153 A1 WO2007123153 A1 WO 2007123153A1 JP 2007058437 W JP2007058437 W JP 2007058437W WO 2007123153 A1 WO2007123153 A1 WO 2007123153A1
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WO
WIPO (PCT)
Prior art keywords
capsule
parts
weight
gelatin
oral administration
Prior art date
Application number
PCT/JP2007/058437
Other languages
French (fr)
Japanese (ja)
Inventor
Ichiro Okamoto
Yuji Miyamoto
Hidekatsu Nishimura
Original Assignee
Ono Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ono Pharmaceutical Co., Ltd. filed Critical Ono Pharmaceutical Co., Ltd.
Publication of WO2007123153A1 publication Critical patent/WO2007123153A1/en

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Classifications

    • 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
    • A61K31/185—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
    • 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
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a capsule for oral administration containing a liquid drug, particularly (2R) -2-propyloctanoic acid.
  • Soft capsules using gelatin as a capsule base are dosage forms suitable for administering liquid active ingredients, and have been conventionally used in pharmaceutical preparations and health food preparations. After taking capsules, the capsule film quickly disintegrates in the gastrointestinal tract, and the contents are dispersed and dissolved more quickly than tablets. Therefore, capsule films are required to maintain stable disintegration during the storage period until the finished product is used. For the purpose of obtaining the same effectiveness regardless of which soft capsule is used at the time of use, for example, the capsule film has a uniform thickness and a uniform thickness so as not to show different disintegration properties between production lots. It is required to have a single composition.
  • Patent Document 1 a pentanoic acid derivative containing (2R) -2-propyloctanoic acid is used in oral forms such as tablets, pills, capsules, powders, and granules. It is described that it is administered as a solid composition for administration, and that the capsule includes a hard capsule and a soft capsule.
  • Patent Document 2 (2R) -2 propyloctanoic acid (lg) is encapsulated in a gelatin capsule to contain a capsule containing the active ingredient lOOmg.
  • 2R propyloctanoic acid
  • Patent Document 3 includes (2R) -2-propyloctanoic acid or a salt thereof, and includes proteins, polysaccharides, biodegradable brains. Sticks and hardened oils and fats Soft capsules having a capsule film with a moisture content of 4.0% to 10.0% are disclosed, comprising at least one selected capsule base and plasticizer.
  • Patent Document 1 European Patent No. 0632008
  • Patent Document 2 European Patent Publication No. 1174131
  • Patent Document 3 International Publication No. 2005Z120490 pamphlet
  • (2R) -2-propyloctanoic acid is a substance with strong irritation, so if it leaks soft capsule force in the oral cavity, it will have a very strong egg taste, burning sensation, etc.
  • soft capsules with bubbles in the capsule film have a lower strength than soft capsules without bubbles, so there is a high risk of leakage of (2R) —2-propyloctanoic acid during chewing It was a thing.
  • an object of the present invention is to solve the problem that air bubbles are mixed in the capsule film in the production process, and to have a capsule film having a uniform thickness and uniform composition, which is a pharmaceutical product for transportation and storage.
  • “crack” and “crack” do not occur, and even when chewing, (2R) -2-propyloctanoic acid does not leak easily and can exhibit a stable pharmacological effect.
  • (2R) -2-Propyloctanoic acid-containing soft capsules are provided There is to be.
  • the present inventors have added a nonionic surfactant, particularly polysorbate 80, to the raw material in the soft capsule manufacturing process, thereby providing a capsule film.
  • a nonionic surfactant particularly polysorbate 80
  • the present inventors have found that (2R) -2-propyloctanoic acid-containing soft capsules can be produced without mixing bubbles, and the present invention has been completed by conducting further detailed research based on this finding.
  • the present invention provides:
  • a composition containing a liquid drug and further containing a polyhydric alcohol, a sugar alcohol and Z or water is used as a content, and (B) a protein, a polyhydric alcohol, a nonionic interface. Containing an active agent and water, and further containing a phospholipid and Z or sugar alcohol, the composition as an outer membrane, and optionally (C) a protective membrane as the outermost membrane;
  • the capsule for oral administration has a configuration and does not contain bubbles having a major axis of 100 ⁇ m or more in the outer membrane;
  • the outer membrane contains (a) gelatin, (b) about 25 parts by weight to about 40 parts by weight of glycerin with respect to 100 parts by weight of gelatin, and (c) about 0.01 parts by weight with respect to 100 parts by weight of gelatin. Part to about 0.05 part by weight of polysorbate 80 and substantially free of sorbitol or substantially less than 20 parts by weight of sorbitol per 100 parts by weight of gelatin.
  • the capsule for oral administration according to the above [10] comprising a composition having a water content of about 5% to about 15% not contained in the composition;
  • composition for oral administration according to the above [9], wherein the composition is a bilayer soft capsule; [17] (A) a composition containing about lOOmg or about 300 mg of (2R) -2-propyloctanoic acid; (B) (a) gelatin, (b) about 30 parts by mass of glycerin with respect to 100 parts by mass of gelatin, and (c) about 0.025 parts by mass of polysorbate 80 with respect to 100 parts by mass of gelatin.
  • A a composition containing about lOOmg or about 300 mg of (2R) -2-propyloctanoic acid
  • B (a) gelatin, (b) about 30 parts by mass of glycerin with respect to 100 parts by mass of gelatin, and (c) about 0.025 parts by mass of polysorbate 80 with respect to 100 parts by mass of gelatin.
  • a two-layer soft capsule comprising a composition having a moisture content of about 5% to about 8% as an outer membrane, and further comprising (C) a protective membrane containing soybean lecithin in the outermost membrane; [18] (A) A composition containing about lOOmg or about 300 mg of (2R) -2-propyloctanoic acid is used as a content, and (B) (a) gelatin and (b) about 30 parts by mass with respect to 100 parts by mass of gelatin.
  • a double-layer membrane soft capsule comprising a composition having a moisture content of about 5% to about 12% containing 80 g as an outer membrane, and further comprising (C) a protective membrane comprising soybean lecithin in the outermost membrane; [19] The double-layer soft capsule according to [17] or [18], wherein the outer membrane does not contain bubbles having a major axis of 100 / zm or more;
  • An aqueous solution containing (a) gelatin, (b) about 30 parts by weight of glycerin with respect to 100 parts by weight of gelatin, and (c) about 0.025 parts by weight of polysorbate 80 with respect to 100 parts by weight of gelatin.
  • Form a sheet apply a medium chain fatty acid triglyceride solution of soybean lecithin on one side of the sheet to obtain a two-layer sheet, and cover the liquid material containing (2R) -2-propyloctanoic acid with the two-layer sheet.
  • the present invention relates to a method for producing a double-layer soft capsule characterized by subjecting the obtained live sphere to a drying step.
  • compositions containing (A) a liquid drug and may further contain a polyhydric alcohol, a sugar alcohol and Z or water, and (B) a protein, Contains alcohol, non-ionic surfactant and water, and further contains phospholipids and z or sugar alcohols.
  • the capsule for oral administration which has a structure and does not contain air bubbles (hereinafter sometimes abbreviated as the capsule of the present invention) has a structure and an outer membrane. minimum It is a capsule for oral administration that does not contain air bubbles, and has a content strength, a liquid drug, and optionally a polyvalent alcohol.
  • a composition that may contain alcohol, sugar alcohol and Z or water.
  • any capsule for oral administration satisfying the above-described configuration and composition can be used, and a soft capsule is particularly preferably used.
  • the capsule of the present invention is a capsule that does not contain bubbles in the outer membrane in order to have excellent effects as described later.
  • the outer membrane does not contain bubbles having a major axis of 100 m or more.
  • a bubble having a major axis of 100 ⁇ m or more means a bubble having a maximum inner diameter of 100 ⁇ m or more.
  • the presence or absence of bubbles can be confirmed visually or with a microscope.
  • the capsule of the present invention does not contain bubbles in the contents, outer membrane, or outermost membrane, or between the contents and the outer membrane, or between the outer membrane and the outermost membrane.
  • the liquid drug is, for example, a drug that is orally administered to a living body for the purpose of preventing or treating a disease and suppressing Z or symptom progression, and is appropriate.
  • Any fluid may be used as long as it has a good fluidity.
  • moderate fluidity means fluidity that can be press-fitted using, for example, a soft capsule filling machine, as will be described later.
  • the fluidity is preferably about 50,000 millipascal seconds (mPa's) or less in viscosity.
  • the liquid drug in the present invention may be not only a liquid but also a semi-solid exhibiting a gel-like form as long as it exhibits an appropriate fluidity as described above.
  • liquid drug in the present invention is not only a compound having an appropriate fluidity but also the following components which may be added to the content (for example, polyhydric alcohol, sugar alcohol, water, appropriate fats and oils, solvent)
  • a compound that can be a composition exhibiting an appropriate fluidity by appropriately combining additives, etc. is also included.
  • liquid drug in the present invention examples include (2R) -2-propyloctanoic acid, alphacalcidol, icosapentate ethyl, indomethacin farnesyl, gefarnate, saquinavir, cilostazol, sertin tin polen extract, Tretinoin (ATRA), tocopherol nicotinate, -fedipine, plastic
  • examples include drugs such as unothol, menatetrenone, ritonavir, oral pinabir'ritonavir, and epinastin hydrochloride, and active ingredients of various health foods that are administered in soft capsules.
  • (2R) -2-propyloctanoic acid is preferred as the liquid drug in the present invention.
  • (2R) -2-propyloctanoic acid has the formula (I)
  • (2R) 2 propyloctanoic acid is obtained by a method known per se, for example, European Patent 06.
  • the product of the reaction can be obtained by conventional purification means such as distillation under normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or force. It can be purified by means of ram chromatography or washing, recrystallization and the like. If desired, it may be subjected to a treatment such as freeze-drying.
  • the (2R) 2 propyloctanoic acid used in the present invention is not limited to a substantially pure and single substance, but includes impurities (for example, by-products derived from the production process, solvents, Raw materials, etc., or degradation products) may be contained as long as it is acceptable as an active pharmaceutical ingredient.
  • impurities for example, by-products derived from the production process, solvents, Raw materials, etc., or degradation products
  • (2R) The content of 2-propyloctanoic acid that is acceptable as an active pharmaceutical ingredient is, for example, about 20 ppm or less for heavy metals (eg, lead, bismuth, copper, cadmium, antimony, tin, mercury, etc.) It is preferable that the S-isomer, which is an optical isomer, is about 1.49% by weight or less, the residual solvents 2 propanol and heptane are about 5000 ppm or less in total, and the water content is about 0.2% by weight or less.
  • heavy metals eg, lead, bismuth, copper, cadmium, antimony, tin, mercury, etc.
  • the S-isomer which is an optical isomer
  • the residual solvents 2 propanol and heptane are about 5000 ppm or less in total
  • the water content is about 0.2% by weight or less.
  • (2R) -2-propyloctanoic acid used in the present invention in particular, (2R) -2-propyloctanoic acid having an optical purity exceeding about 99% ee, especially optical purity of about 99.3% ee
  • (2R) -2-propyloctanoic acid is preferred
  • the protein may be any protein as long as it can be used in a pharmaceutical composition for oral administration.
  • proteins that are generally used as a base for capsule films in the production of soft capsules such as gelatin, gelatin hydrolyzate, collagen, collagen hydrolyzate, and casein are preferably used.
  • gelatin is suitable as the protein in the present invention.
  • gelatin is generally called gelatin, however, alkali-treated gelatin, acid-treated gelatin, peptide gelatin, low-molecular gelatin, gelatin derivative, chemically modified gelatin, succinylated gelatin, etc. It may be.
  • its origin is, for example, gelatin derived from various animals such as mammals (eg, sushi, pigs, etc.), fish (eg, tilapia, Thailand, tuna, catfish, etc.), birds (eg, chicken, ostrich, etc.). Can be used without any particular limitation.
  • the polyhydric alcohol may be any polyhydric alcohol that can be used in a pharmaceutical composition for oral administration.
  • polyhydric alcohols that are generally used as plasticizers for capsule coatings in the production of soft force fillers such as glycerin, ethylene glycol, polyethylene glycol, propylene glycol, etc.
  • glycerin is preferred as the polyhydric alcohol in the present invention.
  • the glycerin may be any as long as it is generally called glycerin.
  • glycerin pharmacopoeia glycerin and concentrated glycerin are preferred.
  • concentrated glycerin is particularly preferred.
  • the nonionic surfactant may be any nonionic surfactant that can be used in a pharmaceutical composition for oral administration.
  • the Japanese Pharmacopoeia for example, the 14th revised Japanese Pharmacopoeia and the 15th revised Japanese Pharmacopoeia, etc.
  • the Pharmaceutical Additives Standard for example, the Pharmaceutical Additives Standard 2003
  • the Z or Food Additives Standard for example, nonionic surfactants described in the Food Additives Official Version 7
  • nonionic surfactants described in the Food Additives Official Version 7 can be preferably used.
  • cholesterol sucrose fatty acid ester, stearyl alcohol, polyoxyl 40 stearate, sorbitan sesquioleate, cetanol, cetomacrogol 1000, jetyl sebacate, sorbitan trioleate, polyoxyethylene octyl Phenol ether, polyoxyethylene hydrogenated castor oil 5, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, Polyoxyethylene hydrogenated castor oil 100, polyoxyethylene stearyl ether, polyoxyethylene sorbit beeswax, polyoxyethylene (20) polyoxypropylene (20) glyconore, polyoxyethylene (105) polio Cypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polysorbate 20, polysorbate 60, polysorbate 65
  • cholesterol for example, cholesterol, polyoxyl stearate 40, sorbitan sesquioleate, cetomacrogol 1000, jetyl sebacate, sorbitan trioleate, polyoxyethylene octyl ether, polyoxyethylene hydrogenated castor oil 5, polyoxy Ethylene hardened Castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 100, polyoxyethylene stearyl ether, polyoxyethylene Tylene sorbite beeswax, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene ( 160) Polyoxypropylene (30) Glycololole, Polysonolate 20, Polysonolebate 60, Polysonolebate 65, Polysorbate 80, Macrogol
  • polysorbate bets 80 are particularly preferred.
  • the phospholipid may be any phospholipid that can be used in a pharmaceutical composition for oral administration.
  • the Japanese Pharmacopoeia for example, the 14th revised Japanese Pharmacopoeia and the 15th revised Japanese Pharmacopoeia, etc.
  • the Pharmaceutical Additives Standard for example, the Pharmaceutical Additives Standard 2003
  • the Z or Food Additives Official for example, phospholipids described in the Food Additives 7th Edition
  • phospholipids described in the Food Additives 7th Edition can be preferably used.
  • soybean lecithin is particularly preferable.
  • the sugar alcohol can be used in a pharmaceutical composition for oral administration.
  • Any sugar alcohol may be used.
  • sugar alcohols generally used as plasticizers for capsule films in the production of soft capsules such as sorbitol, xylitol, and mannitol are preferably used.
  • sorbitol is suitable as the sugar alcohol in the present invention.
  • the water may be any water as long as it can be used in a pharmaceutical composition for oral administration.
  • normal water for example, tap water, well water, etc.
  • purified water for example, distilled water, ion exchange water, pure water, milliQ water, ultrapure water, etc.
  • sterilized purified water water for injection, etc.
  • purified water is particularly preferable.
  • the outermost membrane is a membrane that is optionally added to the configuration of the capsule of the present invention.
  • the outermost membrane is the outermost membrane. Shall be located.
  • the capsule of the present invention has "a protective film may be provided on the outermost film as desired", if the outermost film is not included in the configuration of the capsule of the present invention, the minimum The composition consists only of the contents and the outer membrane. However, even in this case, if necessary, another configuration (hereinafter sometimes referred to as an intermediate film) can be added between the contents and the outer film.
  • the minimum configuration is, for example, the contents, outer membrane, and outermost membrane as shown in FIG. However, even in this case, if necessary, another configuration (intermediate film) can be added between the contents and the outer membrane or between the outer membrane and the outermost membrane.
  • the capsule of the present invention when the capsule of the present invention includes the outermost membrane, there are at least two membranes of the outer membrane and the outermost membrane, and therefore the capsule of the present invention is a multilayer membrane (only the outer membrane and the outermost membrane). And / or capsules with a bilayer membrane).
  • a protective film is used as the outermost film.
  • protective film components include phospholipids, ethyl acrylate 'methyl methacrylate copolymer emulsion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, ethyl cellulose, and ethyl cellulose dispersion.
  • these components used as components of the protective film may be used as they are, or may be used after being dissolved in an appropriate solvent (for example, a medium-chain fatty acid triglyceride described later). Moreover, you may use combining arbitrary 2 or more types.
  • the film using these protective film components is, for example, the intermediate film described above between the contents and the outer film, or between the outer film and the outermost film. It can also be used as another configuration added as needed.
  • a protective film containing these components in the composition of the capsule of the present invention, it can occur in the capsule of the present invention having a structure having no protective film (the outer film is located on the outermost side).
  • Phenomena that are not desirable for pharmaceuticals can be prevented. Specifically, for example, (i) prevents the contents and Z or outer membrane from oxidizing (antioxidation), and (ii) prevents changes in the content and Z or outer membrane due to moisture (moisture prevention).
  • the protective film preferred in the present invention is a protective film containing phospholipid.
  • phospholipids include the phospholipids described above. Of these, soybean lecithin and its extract (for example, phosphatidylcholine) are particularly preferred, and soybean lecithin is particularly preferred.
  • a protective film containing phospholipids, particularly soybean lecithin is added to the capsule composition of the present invention, an effect of preventing adhesion can be obtained, and the capsules of the present invention adhere to each other or the capsule of the present invention. And the container thereof, or the capsule of the present invention and the machine used for manufacturing the same can be prevented. The presence or absence of adhesion can be determined by contacting capsules, capsules and containers, or capsules and machines.
  • Capsules of the present invention provided with a protective film containing phospholipids, especially soybean lecithin, during the manufacturing process, supply to the medical site, and during the storage period until they are taken, Even in this case (especially during the production process!), The above-mentioned adhesion preventing effect can be exhibited.
  • the outer membrane may contain "a protein, a polyhydric alcohol, a nonionic surfactant and water, and may further contain a phospholipid and Z or a sugar alcohol.”
  • a powerful composition consisting of, for example, fragrances (eg, pepper oil, cinnamon oil, strawberry and other fruit essences and flavors), preservatives (eg, paraffin) Ethyl hydroxybenzoate, propyl parahydroxybenzoate, etc.), pigments (eg yellow 4, yellow 5, red 3, blue 1, copper black fins, etc.), opaque glazes (eg titanium dioxide) , Bengala, iron sesquioxide, etc.), solubility regulator (eg cellulose acetate phthalate, alkali metal salt of hydroxypropylmethylcellulose, hydroxymethyl) Alkaline metal salt of roulose acetate succinate, alkali metal alginate, alkali metal polyacrylate, methylcellulose, carboxymethylcellulose, casein, collagen, agar powder
  • the content is composed of "a composition containing a liquid drug and further containing a polyhydric alcohol, a sugar alcohol and Z or water".
  • a composition containing a liquid drug and further containing a polyhydric alcohol, a sugar alcohol and Z or water in addition to these specified components, for example, appropriate oils and fats, solvents, additives and the like can be added to the powerful composition.
  • fats and oils include medium chain fatty acids [eg, vegetable oil (eg, soybean oil, cottonseed oil, safflower oil, corn oil, olive oil, coconut oil, perilla oil, sesame oil, etc.), fish oil (eg, cod liver oil, etc.) Etc.], medium-chain triglycerides (MCT) [for example, panacet (trade name, manufactured by Nippon Oil & Fats Co., Ltd.), ODO (trade name, manufactured by Nisshin Oil Co., Ltd.), etc.], and synthetic synthetic triglycerides [For example, triglycerides having a known composition such as 2-linoleoyl 1,3-dioctanol glycerol (8L8), 2-linoleoyl 1,3-dideanol glycerol (10L10), etc.] and the like.
  • MCT medium-chain triglycerides
  • MCT medium-chain triglycerides
  • panacet trade name, manufactured
  • These fats and oils may be used alone or in combination of two or more.
  • the solvent for example, the above medium chain fatty acid, the above medium chain fatty acid triglyceride and the like can be used, and water (for example, distilled water for injection, purified water, etc.) and the like can also be used. These solvents may be used alone or in combination of two or more.
  • the additive can be used without particular limitation as long as it is an additive generally used for oral preparations.
  • additives used in soft capsule formulation and oral solution are preferably used.
  • additives e.g., preservatives, preservative, surface active agents, solubilizing agents, emulsifiers, solvents, P H modifiers, buffering agents, suspension Suspending agents, thickeners, stabilizers, solubilizers, etc.
  • preservatives and preservatives for example, benzoic acid, sodium benzoate, sodium sorbate, parabens (e.g., ethyl oxybenzoate, ptyl parabenzoate, propyl noxybenzoate, etc.), etc. Can be used.
  • Surfactants, solubilizers, emulsifiers and solvents include, for example, hydroxypropyl methylcellulose (hypromellose), polybulurpyrrolidone, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol, Glycerin, ethanol, propylene glycol, water (for example, purified water, distilled water for injection, etc.) can be used.
  • the P H modifiers or buffering agents for example, an inorganic acid or an inorganic base (e.g., hydrochloric acid, sodium hydroxide, Mizusani ⁇ potassium, sodium hydrogen carbonate, etc.), organic acids (e.g., Kuen, malic , Tartaric acid, succinic acid and the like) or salts thereof.
  • the pH adjustment is generally used in the technical field of oral liquid preparations V, and should be performed according to a pH adjustment method or a similar method.
  • pH adjusters and buffering agents include weak acids [for example, phosphoric acid, carbonic acid, boric acid, sulfurous acid, organic sulfonic acid, organic carboxylic acids having 2 to 6 carbon atoms (for example, 1 to 3 valent carbon atoms having 2 to 6 carbon atoms)
  • Metal salts of organic carboxylic acids that is, aliphatic monocarboxylic acids, dicarboxylic acids or tricarboxylic acids having 2 to 6 carbon atoms, or other organic acids]
  • monovalent alkali metal salts for example, sodium Salts, potassium salts, lithium salts, rubidium salts, cesium salts, francium salts, etc.
  • metal hydroxides for example, monovalent alkali metal hydroxides (for example, sodium hydroxide, potassium hydroxide, water, etc.) Lithium oxide, rubidium hydroxide, cesium hydroxide, francium hydroxide Etc.) etc.
  • weak acids for example, phosphoric acid, carbonic
  • (2R) -2-propyloctanoic acid when used in combination, when (2R) -2-propyloctanoic acid is used as a liquid drug, (2R) -2-propyloctanoic acid having the properties of an oil can be made into an aqueous content.
  • the suspending agent or thickening agent for example, gum arabic, crystalline cellulose, bee gum, xanthan gum, gelatin, metrose and its edible salt, carmellose and its edible salt can be used.
  • the stabilizer for example, an edible salt of edetic acid, sodium chloride salt, an edible salt of pyrosulfite, or the like can be used.
  • solubilizer for example, cyclodextrin or arginine can be used.
  • additives are generally blended in proportions usually used for oral preparations.
  • additives such as those described in publicly known documents, for example, “Pharmaceutical Additives Encyclopedia” (edited by the Japan Pharmaceutical Additives Association) published in 2000, etc., can be used.
  • the above-mentioned additives that may be added to the contents and the outer film can be included.
  • a capsule containing a preferable example of each component described above is preferable, and a capsule containing a combination of the preferable examples of each component described above is more preferable.
  • “(A) (2R) -2-propyloctanoic acid and a composition that may further contain glycerin, sorbitol and Z or water is used as the content
  • C a protective membrane containing soy lecithin as the outermost membrane if desired.
  • a capsule for oral administration having a constitution is preferable.
  • the capsule is preferably a soft capsule as long as it is a capsule for oral administration satisfying these configurations and compositions. That is, it is preferable that the contents, outer film, and outermost film in the present invention correspond to the content liquid, the capsule film, and the coating layer of the soft capsule, respectively.
  • the content of each component is not particularly limited as long as it is an amount capable of forming a desired dosage form.
  • soft capsule of the present invention “( A) The composition contains (2R) -2-propyloctanoic acid and may further contain glycerin, sorbitol and Z or water, and (B) gelatin, glycerin, polysorbate 80 and water. And soy lecithin and / or sorbitol, the composition as an outer membrane, and optionally (C) a protective membrane containing soy lecithin in the outermost membrane.
  • composition of each component is exemplified by “a soft capsule for oral administration having a structure” (hereinafter, sometimes abbreviated as the soft capsule of the present invention containing (2R) -2-propyloctanoic acid). .
  • a soft capsule for oral administration having a structure hereinafter, sometimes abbreviated as the soft capsule of the present invention containing (2R) -2-propyloctanoic acid.
  • the content of gelatin in the composition forming the outer membrane is determined by applying it to the soft capsule manufacturing method described later, so long as it is an amount that can form an outer membrane sufficient to cover the contents. What is necessary is just to change suitably according to the quantity of the content, and the thickness of an outer membrane.
  • the gelatin content is about 50 mg to about 150 mg force per soft capsule, preferably about 60 mg.
  • To about 130 mg force S is more preferred, with about 80 mg to about 1 lOmg being particularly preferred.
  • about 92.3 mg of gelatin per soft capsule is preferred.
  • the gelatin content is preferably about 20 mg to about 90 mg per soft capsule.
  • 30 mg to about 80 mg force S is more preferred, and about 40 mg to about 70 mg force is particularly preferred.
  • about 50.Omg gelatin per soft capsule is preferred.
  • the capsule membrane thickness is about 0.05 mm to about 0.5 mm in abdominal thickness (more preferably about 0.1 mm to about 0.45 mm, particularly preferably about 0.14 mm to about 0.37 mm), with a first joint thickness of about 0.1 mm to about 0.55 mm (more preferably about In the range of 0.15 mm to about 0.5 mm, particularly preferably about 0.18 mm to about 0.42 mm, the second joint thickness is about 0.05 mm to about 0.5 mm (more preferably about 0.1 mm). To about 0.4 mm, particularly preferably about 0.14 mm to about 0.36 mm).
  • the size of the capsule differs depending on the type of capsule.
  • the major axis is within the range of 12.9 mm ⁇ 0.6 mm, and the minor axis Is preferably in the range of 7.8 mm ⁇ 0.3 mm.
  • the major axis is preferably in the range of 9.2 mm ⁇ 0.5 mm and the minor axis is preferably in the range of 5.8 mm ⁇ 0.2 mm.
  • No. 5 opal type is a suitable type for producing soft capsules containing only 300 mg of (2R) -2-propyloctanoic acid.
  • (2R) This type is suitable for producing soft capsules containing only 1 OO mg of 2-propyloctanoic acid.
  • the thickness of any one of the abdominal part, the first joint part, and the second joint part of the capsule film is more preferably adjusted so that all the thicknesses are within the above-mentioned range, and sorbitol in the outer membrane as described later.
  • the soft capsule of the present invention containing (2R) -2-propylotatanic acid was adjusted to about 150-euton (hereinafter abbreviated as N) by controlling the load of glycerin and glycerin to the preferred range.
  • the soft capsule of the present invention containing an acid can be imparted with the characteristic that “the contents do not easily leak during chewing”.
  • the crack load test can be performed by a known method. Specifically, for example, the sample can be measured by using a pressurizer capable of compressing the sample from above and below on two parallel surfaces, such as a Shimadzu small desktop tester (EZ Test-500N).
  • “abdomen”, “first joint”, and “second joint” used to indicate the thickness of the adventitia are terms commonly used by those skilled in the art, and “abdomen”
  • the first joint part is the part where the film sheet is first joined when the soft force capsule is molded.
  • Part means the part to which the film sheet is finally joined when the soft capsule is molded.
  • the film sheet means a sheet containing a capsule film component used in a soft capsule manufacturing method generally called a punching method such as a rotary die method.
  • the two coating sheets are molded with a die mold that matches the shape of the soft capsule, and the contents are filled, so that any shape, for example, an oval type, round (round) Soft capsules such as) type, suppository type, oblong type, tube type, etc. can be manufactured.
  • Abdomen, first joint, second The thicknesses of the two joints and each part of the capsule capsule film can be measured by a known method. For example, use a sharp knife such as a scissors knife to cut the center of the soft capsule and wash the contents (content liquid) with an organic solvent (for example, n-xane, ether, acetone, alternative chlorofluorocarbon).
  • an organic solvent for example, n-xane, ether, acetone, alternative chlorofluorocarbon.
  • the content of sorbitol in the composition forming the outer membrane is preferably about 20 parts by mass or less with respect to 100 parts by mass of gelatin, and is particularly preferably substantially free of sorbitol. .
  • the content of glycerin in the composition forming the outer membrane is preferably changed depending on whether or not the sorbitol is contained in the outer membrane. Specifically, when sorbitol is contained in the outer membrane, the content of glycerin is preferably about 20 parts by mass or less with respect to 100 parts by mass of gelatin. When the outer membrane is substantially free of sorbitol, the content of glycerin is preferably about 25 parts by weight to about 40 parts by weight with respect to 100 parts by weight of gelatin. On the other hand, it is preferably about 30 parts by mass.
  • the content of water in the composition forming the outer membrane can be indicated using an index of water content.
  • the water content can be measured by a known method. Specifically, the outer membrane is used as a sample (if the outermost membrane does not substantially contain water, the outer membrane and the outermost membrane can be combined into a sample), and its weight (weight before drying) And the weight after drying the sample at a high temperature (for example, 105 ° C) (weight after drying)
  • Moisture content (%) ⁇ (weight before drying-weight after drying) Z weight before drying ⁇ X I 0 0 can be calculated.
  • the content of water in the outer membrane is particularly preferably about 5% to about 9%, preferably about 5% to about 15%, more preferably about 5% to about 12%, in terms of water content. In particular, about 5% to about 8% is more preferable, and about 5.6% to about 7.3% is preferable.
  • the content of polysorbate 80 in the composition forming the outer membrane is 100 parts by mass of gelatin, The amount is preferably about 0.01 parts by weight to about 0.05 parts by weight, and particularly preferably about 0.025 parts by weight with respect to 100 parts by weight of gelatin.
  • the content of soybean lecithin in the composition forming the outer membrane is preferably substantially not contained or preferably not more than about 1 part by mass with respect to 100 parts by mass of gelatin. Especially preferred is /.
  • the content of (2R) -2-propyloctanoic acid in the composition constituting the content is about 30 mg to about
  • 600 mg strength S female about 50 mg to about 400 mg strength female, about lOO mg to about 300 mg strength S, especially about lOOmg or about 300 mg is particularly preferred.
  • the content of glycerin in the yarn constituting the content and the composition is substantially free or (2R)
  • It is preferably about 40 parts by mass or less with respect to 100 parts by mass of 2-propyloctanoic acid.
  • the content of sorbitol in the composition constituting the content is substantially free of (2
  • R) —2-Propyloctanoic acid is preferably about 20 parts by mass or less, particularly preferably substantially free from 100 parts by mass.
  • the content of water in the yarn and the composition constituting the content may be substantially not contained, or about 20 parts by mass or less with respect to 100 parts by mass of (2R) -2-powder pyroctanoic acid. Substantially virtually free! /, Especially preferred.
  • soft capsule of the present invention containing (2R) -2 propyloctanoic acid
  • preference is given to the examples of the above-mentioned components, and soft capsules containing by content are preferred.
  • preference is given to each of the above-mentioned components, and a combination of examples is preferred, and a soft capsule containing the content is preferred.
  • the outer membrane contains (a) gelatin, (b) about 25 parts by weight to about 40 parts by weight of glycerin and (c) 100 parts by weight of gelatin with respect to 100 parts by weight of gelatin. Containing about 0.01 parts by weight to about 0.05 parts by weight of polysorbate 80 and substantially free of sorbitol or about 20 parts by weight or less of sorbitol with respect to 100 parts by weight of gelatin, Preferably, the composition is substantially free of soy lecithin and has a water content of about 5% to about 15%.
  • sorbitol ie, (a) gelatin, (b) about 25 parts by weight to about 40 parts by weight of glycerin and 100 parts by weight of gelatin and ( c) about 0.1% to about 0.05 parts by weight of polysorbate 80 per 100 parts by weight of gelatin and substantially free of sorbitol and soy lecithin, with a water content of about 5% to about 15
  • gelatin ie, (a) gelatin, (b) about 30 parts by weight of glycerin with respect to 100 parts by weight of gelatin, and (c) about 0 with respect to 100 parts by weight of gelatin.
  • a composition comprising about 5% to about 8% water content containing 025 parts by weight of polysorbate 80 is preferred.
  • a composition comprising about 30 mg to about 600 mg of (2R) 2 propyl octanoic acid is preferred, preferably about 50 mg to about 400 mg of (2R) 2 -propyl octane.
  • About 100 mg to about 300 mg of (2R) a composition containing an acid-containing composition is more preferred.
  • Particularly preferred is a composition containing about 2 mg of propyloctanoic acid, or about 300 mg of (2R).
  • Particularly preferred is a composition comprising propyloctanoic acid.
  • the content containing only (2R) -2-propyloctanoic acid having these contents is particularly suitable.
  • the capsule of the present invention can be produced according to a known production method.
  • the soft capsule of the present invention is preferred.
  • the soft capsule of the present invention containing (2R) -2-propyloctanoic acid will be described, and the production method thereof will be specifically described.
  • a liquid drug other than (2R) -2-propyloctanoic acid it can be produced according to the following examples.
  • the soft capsule of the present invention containing (2R) -2 propyloctanoic acid can be produced according to a known method for producing soft capsules. Specifically, (1) “a composition containing (2R) -2-propyloctanoic acid, which may further contain a polyhydric alcohol, a sugar alcohol, and Z or water” as the contents; 2) “Contains a composition containing protein, polyhydric alcohol, nonionic surfactant and water, and further containing phospholipid and Z or sugar alcohol” as an outer membrane It can be produced by preparing a coating solution, subjecting it to a known capsule filling method such as a punching method (for example, a rotary die method), and drying the obtained capsule.
  • a known capsule filling method such as a punching method (for example, a rotary die method)
  • the outermost membrane When the outermost membrane is included in the composition of the soft capsule of the present invention containing (2R) -2-propyloctanoic acid, the outermost membrane may be applied separately after the outer membrane is applied, Outside in advance You may carry out by using the film
  • compositions containing 2 propyloctanoic acid and optionally further containing a polyhydric alcohol, a sugar alcohol, and Z or water are, as described above, a component having these specified components. It can be prepared using appropriate oils, additives, solvents and the like. As noted above, such compositions have moderate fluidity (e.g., fluidity that can be press-fitted using a soft capsule filling machine (e.g., fluidity with a viscosity of about 50,000 millipascal seconds (mPa's) or less)). Etc.) and the like, as well as liquids and semi-solids showing a gel-like form may be used. (2R) 2-Propyloctanoic acid is a single compound and is a liquid, so it is preferable to use the compound itself as a content (content liquid).
  • a composition containing "protein, polyhydric alcohol, nonionic surfactant and water, and further containing phospholipid and Z or sugar alcohol” as an outer membrane
  • the film solution of the above contains these components and can be formed into a thin film (the above-mentioned film sheet) in a molten state or a solution state, and further cooled and Z-dried after the film is formed. As long as it solidifies by this, it can be used without particular limitation.
  • a coating film solution can be prepared by mixing an appropriate amount of water (for example, purified water) with the above-described protein, polyhydric alcohol and nonionic surfactant.
  • a heating operation may be performed as desired.
  • the amount of water mixed here is larger than that corresponding to the moisture content of the outer membrane.
  • the outermost membrane when the outermost membrane is included in the configuration of the soft capsule of the present invention containing (2R) -2-propyloctanoic acid, the outermost membrane may be applied separately after the outer membrane is applied. Alternatively, it may be carried out by using a film sheet in which the outer film and the outermost film are previously formed into two layers.
  • the soft capsules before being subjected to the drying process hereinafter referred to as ⁇ soft capsules before being subjected to the drying process '' are distinguished from the soft capsules after being dried. It may be referred to as “live ball”.
  • coating By subjecting it to a method generally referred to as coating.
  • Coating is performed by placing a raw ball in a coating pan, sprinkling the coating liquid while rotating the pan, blowing air, and drying.
  • the coating liquid may contain the outermost film component or What is necessary is just to use what was melt
  • the outermost film is applied using a film sheet in which the outer film and the outermost film are two layers in advance
  • the outer surface after soft capsule molding prepare a sheet with the outer membrane component and the outermost membrane component in two layers in advance by applying the outermost membrane component or a solution of the outer membrane component dissolved in an appropriate solvent. By using it, a soft capsule live sphere can be obtained and further dried.
  • soy lecithin is used as a component of the outermost membrane, a method in which soy lecithin is dissolved in the medium-chain fatty acid triglyceride (MCT) or the like is preferably used on one side of the coating sheet.
  • MCT medium-chain fatty acid triglyceride
  • the soft capsule drying method may be any method that can be dried while maintaining the strong soft capsule shape! /, But uses a combination of tumbler drying and shelf drying. The method is preferably used. By performing these two drying steps, a uniform soft capsule having a stable shape can be produced.
  • the tumbler drying is performed at about 15 ° C to about 40 ° C, preferably about 20 ° C to about 35 ° C, particularly preferably about 23 ° C to about 30 ° C, for several hours to several days. Is carried out over a period of about 0.5 hours to about 1 day, more preferably about 1 hour to about 12 hours, particularly preferably about 1.5 hours to about 6 hours. Tumble drying is performed by rotating the tumbler containing the live sphere. If necessary, cloth, paper, sponge, etc. are placed in this tumbler together with the live sphere to reduce the amount of the outermost membrane component. It can also be adjusted to the desired amount.
  • Shelf drying is preferably from about 10 ° C to about 40 ° C, preferably from about 15 ° C to about 35 ° C, particularly preferably from about 20 ° C to about 30 ° C, for several hours to several days. Is performed for about 6 hours to about 4 days, more preferably for about 12 hours to about 3 days, particularly preferably for about 1 day to about 2 days.
  • the soft capsules are optionally wrapped as desired.
  • a package may be, for example, a hermetic package such as a non-unit package (for example, Balta package or bottle package) that is not individually packaged.
  • a medicine is sealed with a heat-adhesive film.
  • the heat seal includes PTP (Press Through Pack) packaging and SP (Strip Package) packaging.
  • PTP packaging materials include PCTFE (polychlorinated trifluoroethylene), PVC (polybulur chloride), PVDC (polyvinyl chloride) coated PVC (polyburized chloride), ⁇ (polypropylene), polypropylene multilayer, etc.
  • ⁇ Packaging is preferably used in combination with aluminum packaging.
  • the capsule of the present invention may be subjected to bag packaging or SP packaging, and then a certain amount thereof may be secondarily wrapped with polyethylene or aluminum foil (so-called pillow packaging).
  • a nonionic surfactant preferably polysorbate 80
  • the film solution can be defoamed.
  • defoaming has both the meanings of “suppressing foaming (generation of bubbles) of the film solution” and “extinguishing existing bubbles”. Therefore, it does not require time until the bubbles disappear, and the manufacturing time can be greatly reduced.
  • the soft capsule of the present invention containing (2R) 2-propyloctanoic acid produced in this way has no air bubbles mixed into the capsule membrane during the production process.
  • a (2R) -2-propyloctanoic acid-containing soft capsule with no capsule, uniform thickness, and uniform capsule film.
  • Such a soft capsule has a capsule film with a uniform thickness and a uniform composition, so that it can exhibit a stable pharmacological effect without unevenness when taken, and in the drug supply process such as transportation and storage, ⁇ crack '' and ⁇
  • the soft capsule of the present invention containing (2R) -2-propyloctanoic acid thus produced has excellent properties as a pharmaceutical product as described in International Publication No.
  • a well-known method can be used for the disintegration test method.
  • a method generally known as a capsule disintegration test method particularly a disintegration test method listed in each country's pharmacopoeia, especially Japan It is preferable to use the disintegration test method listed in the pharmacopoeia, particularly the disintegration test method listed in the 14th revised Japanese pharmacopoeia.
  • the soft capsule of the present invention containing (2R) -2-propyloctanoic acid prepared as described above has a disintegration test method of about 3 minutes to about 10 minutes, more preferably about 5 minutes to about 8 minutes, particularly preferably. Shows a disintegration time of about 5.7 minutes to about 6.3 minutes, so it can be “disintegrated easily in the stomach”.
  • the "fast dissolution" t ⁇ ⁇ characteristic can be confirmed by a dissolution test method.
  • a known method can be used.
  • a method generally known as a dissolution test method for internal solid preparations such as tablets and capsules especially a dissolution test method listed in the pharmacopoeia of each country, especially a dissolution test method listed in the Japanese pharmacopoeia, It is preferable to carry out in accordance with the dissolution test method listed in the Fourth Revised Japanese Pharmacopoeia.
  • the paddle method of the Japanese Pharmacopoeia Dissolution Test Method 2 is preferably performed.
  • Test solution 0. O5mol / L disodium monohydrogen phosphate ZO. 025mol / L citrate buffer (pH 8.0);
  • Liquid volume 900 mL
  • the soft capsules of the present invention containing (2R) -2-propyloctanoic acid produced as described above have a dissolution rate of about 60% or more (about 60%) 30 minutes after the start of the test by the dissolution test method. % To about 100%), preferably about 80% or more (about 80% to about 100%), more preferably about 90% or more (about 90% to about 100%). It can be said.
  • the dissolution rate refers to the amount of drug eluted in the test solution after an arbitrary period of time has elapsed since the start of the dissolution test, where the amount of drug in one capsule used in the dissolution test is 100. “Dissolution rate 30 minutes after the start of the test” refers to the dissolution rate after 30 minutes of dissolution test.
  • the amount of drug eluted can be determined by measuring the absorbance in the ultraviolet region. It can be determined by high-speed liquid chromatography.
  • the dissolution test can be performed at any time after the production of the soft capsule of the present invention containing (2R) 2-propyloctanoic acid.
  • the dissolution test is substantially immediately after production (for example, immediately after production to 10 days after production). Etc., preferably immediately after production to within 5 days after production, more preferably immediately after production to within 3 days, etc., particularly preferably immediately after production to within 24 hours.
  • the characteristic that “elution delay does not occur” is that the soft capsule of the present invention containing (2R) -2-propyloctanoic acid is stored for an arbitrary period, and then subjected to the dissolution test described above and compared with the initial value. This can be confirmed.
  • the initial value means a value obtained by subjecting the soft capsule to the dissolution test substantially immediately after production.
  • Storage conditions for confirming whether elution delay does not occur are not particularly limited. For example, it may be room temperature as is usually performed by those skilled in the art, and is generally referred to as a severe test. As such, high temperature and Z or high humidity conditions may be used. By using high temperature and Z or high humidity conditions, the result of long-term storage at room temperature can be obtained in a shorter period of time.
  • the degree of elution delay can be expressed using an index of change rate.
  • the rate of change (%) is the formula
  • Rate of change (%) ⁇ ( ⁇ -)) / A) X 1 0 0
  • A Initial value (dissolution rate); B: Calculated based on the dissolution rate after storage of any period.
  • the soft capsule of the present invention comprising (2R) -2-propyloctanoic acid prepared as described above has a temperature of about 25 ° C to about 30 ° C for about one and a half years (for example, about 16 (E.g., from about 17 months to about 19 months, etc., preferably from about 17 months to about 19 months) Even after storage, the dissolution rate does not change substantially compared to the initial value (dissolution rate), or the rate of change is within 20% Since it is preferably within 15%, more preferably within 10%, it can be said that “elution delay does not occur”.
  • (2R) 2-Propyloctanoic acid has very low toxicity and can be judged to be sufficiently safe for use as a medicine. For example, in a single intravenous dose using Inu, (2R) -2-propyloctanoic acid was found to be lOOmgZkg and no death occurred. Therefore The soft capsule of the present invention containing (2R) -2-propyloctanoic acid can be safely orally administered to a living body.
  • the soft capsule of the present invention containing (2R) 2-propyloctanoic acid contains (2R) -2-propyloctanoic acid as an effective component
  • mammals for example, human non-human animals
  • animals for example, monkeys, hidges, rabbits, horses, dogs, cats, rabbits, rats, mice, etc.
  • neurodegenerative diseases for example, neuropathies, diseases requiring nerve regeneration, eye diseases, sensory nerve diseases
  • (2R) -2-propyloctanoic acid can be applied, publicly known documents such as European Patent No.
  • the capsule of the present invention containing (2R) -2 propyloctanoic acid is orally administered to a living body for the above purpose.
  • prevention means prevention of the disease itself
  • treatment means guiding the disease state in the direction of healing
  • suppression of symptom progression is the disease state. It means to suppress the bad habit and keep it going.
  • the daily dosage of the capsule of the present invention comprising propyloctanoic acid varies depending on the degree of symptoms, age, sex, body weight, timing of administration, interval, etc. of the subject of administration, although not particularly limited, for example, when orally administered as a therapeutic agent for neurodegenerative diseases such as Parkinson's disease, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis.
  • As a daily dose soft capsules containing (2R) -2-propyloctanoic acid corresponding to about 50 mg to about 5000 mg, preferably about 10 mg to about 1200 mg are administered.
  • drugs used in combination include, for example, antiepileptic Drugs (for example, phenobarbital, mehobarbital, metalbital, primidone, phenytoin, ethotoin, trimethadione, ethosuximide, acetilphenetride, carbamazepine, acetazolamide, diazepam, sodium valproate), acetylcholine esterase inhibitor (For example, donevezil hydrochloride, TAK-147, rivastigmine, galantamine, etc.), neurotrophic factors (for example, ABS-205, etc.), aldose reductase inhibitors, antithrombotic drugs (for example, t-PA, heno Phosphorus, etc.), oral anticoagulants (for example, phafarin), synthetic antithrombin drugs (for example, gab
  • nicotine receptor modulator ⁇ -secretase inhibitor
  • 8 amyloid vaccine ⁇ -amyloid degrading enzyme
  • squalene synthase inhibitor therapeutic agent for abnormal behavior associated with progression of dementia, antihypertensive, diabetes treatment Drugs, antidepressants, anxiolytics, disease-modifying antirheumatic drugs, anti-site force-in drugs (for example, TNF inhibitors, MAP kinase inhibitors, etc.), parathyroid hormone (PTH), calcium receptor antagonists, etc. Is mentioned.
  • the above concomitant drugs are illustrative and are not limited thereto.
  • the administration method of these drugs used in combination is not particularly limited, and may be oral administration or parenteral administration. These drugs may be administered in combination of any two or more.
  • the drugs used in combination include not only those that have been found so far, but also those that will be found in the future based on the mechanism described above.
  • (2R) 2-propyloctanoic acid-containing capsules for oral administration useful for prevention and treatment of various diseases such as neurodegenerative diseases and suppression of Z or symptom progression can be provided.
  • the capsules for oral administration provided by the present invention particularly those having the structure of soft capsules, do not contain bubbles in the capsule film (outer film) because they do not enter the capsule film during the production process.
  • a (2R) -2-propyloctanoic acid-containing soft capsule with a capsule film of uniform thickness and uniform composition can be stably supplied to clinical sites without causing “cracking” or “cracking”.
  • the film solution can be defoamed during the preparation of the film solution during the manufacturing process. Can be significantly shortened.
  • the soft capsules obtained by the present invention are, as described in International Publication No. 2005Z120490 pamphlet, “the contents are not easily leaked during mastication”, “is easily disintegratable in the stomach” (2R) -2-propyloctanoic acid-containing soft capsules that maintain properties such as “fast dissolving” and “elution delays”, and the capsule film has a uniform thickness (uniform thickness, uniform A stable pharmacological effect with no unevenness when taken.
  • the soft capsules obtained according to the present invention can be attached to each other during the storage period from the production process to the medical site, and even during the storage period until they are taken, by providing an outermost film as desired. It is also possible to prevent the soft capsule and its container from adhering.
  • FIG. 1 is a view showing a cut surface of an example of a soft capsule of the present invention.
  • FIG. 2 is a photograph of the soft capsule of the present invention containing no bubbles.
  • FIG. 3 is a photograph of a soft capsule containing bubbles (the arrow indicates the position of the bubbles).
  • Gelatin (20 kg), concentrated glycerin (6 kg), and polysorbate 80 (5 g) were mixed at 70 ° C. in the presence of purified water (20 kg) to obtain a uniform solution.
  • This solution and (2R) -2 propyloctanoic acid (0.9 kg) were put into a soft capsule filling machine (rotary soft capsule molding machine H-1 type (forced mata)) to form a film sheet.
  • Soft capsule live spheres filled with propyloctanoic acid were obtained.
  • the obtained live spheres are subjected to tumbler drying (24 ° C, 3 hours), and after adjusting the amount of soy lecithin, they are further subjected to shelf drying (29 ° C, 27 hours) to make one capsule.
  • the moisture content of these soft capsules in the outer membrane was approximately 7.3%. Also, when visually confirmed, bubbles could not be observed.
  • Figure 2 below shows an example of a photograph (taken at 25x magnification).
  • Gelatin (15 kg), concentrated glycerin (4.5 kg), and polysorbate 80 (3.75 g) were mixed at 70 ° C. in the presence of purified water (15 kg) to obtain a uniform solution.
  • This solution and (2R) -2-propyloctanoic acid (1. Okg) were put into a soft capsule filling machine (rotary soft capsule molding machine H-1 type (forced mata)) to form a film sheet, Apply a separately prepared soy lecithin solution (0.1% soy lecithin / MCT solution) on one side and cover (2R) -2-propyloctanoic acid with a film sheet so that the coated surface is on the outside.
  • soft capsule live spheres filled with (2R) -2-propyloctanoic acid were obtained.
  • 2R -2-propyloctanoic acid
  • 1 capsule by subjecting the resulting live spheres to tumbler drying (22 ° C, 4 hours), adjusting the amount of soybean lecithin, and further subjecting to shelf drying (28.5 ° C, 26 hours)
  • Soft capsules containing lOOmg (2R) -2-propyloctanoic acid (Opal type (No. 2 Oval), major axis 9.2 mm ( ⁇ 0.5 mm), minor axis 5.8 mm ( ⁇ 0.2 mm), 3000 Capsenore) was obtained.
  • the water content of these soft capsules in the outer membrane was about 6.9%. Also confirmed visually However, the bubbles were unobservable.
  • the mixture was mixed at 70 ° C. in the presence of gelatin (52.7 kg), concentrated glycerin (15.8 kg), and purified water (49.5 kg). Next, polysorbate 80 (13.2 g) was added and mixed to obtain a uniform solution. This solution and (2R) -2-propyloctanoic acid (1.5 kg) are put into a soft capsule filling machine (rotary soft capsule molding machine (Kamata 10006)) to form a film sheet and separately prepared on one side.
  • a soft capsule filling machine rotary soft capsule molding machine (Kamata 10006)
  • Soy lecithin solution (1.0% Phosal 5 3 MCT (trade name: purchased from PHOSPHOLIPID) ZMCT diluted solution) is applied, and (2R) -2-propyl Soft capsule live spheres filled with (2R) -2-propyloctanoic acid were obtained by covering with octanoic acid.
  • the obtained live spheres are subjected to tumbler drying (room temperature, 30 minutes), and after adjusting the amount of soybean lecithin, they are further subjected to shelf drying (28 ° C, 40 hours), so that 300 mg ( 2R) -2 soft capsules containing propylooctanoic acid (Opal type (No. 5 Oval), major axis 11.9 mm, minor axis 8.2 mm, 3100 capsules) were obtained.
  • the water content in the outer membrane of these soft capsules was about 14%. Also, when visually confirmed, bubbles were not observable.
  • Gelatin (20 kg), concentrated glycerin (6 kg), and polysorbate 80 (5 g) were mixed at 70 ° C. in the presence of purified water (20 kg) to obtain a uniform solution.
  • This solution and (2R) -2 propyloctanoic acid (0.9 kg) were put into a soft capsule filling machine (rotary soft capsule molding machine H-1 type (forced mata)) to form a film sheet.
  • Soft capsule live spheres filled with propyloctanoic acid were obtained.
  • the obtained live spheres are subjected to tumbler drying (24 ° C, 3 hours), and after adjusting the amount of soy lecithin, they are further subjected to shelf drying (29 ° C, 27 hours) to make one capsule.
  • Soft capsules (Opal type (No. 5 Oval), major axis 12.8 mm, minor axis 7.7 mm, 1500 capsules) containing 300 mg of (2R) -2-propyloctanoic acid were obtained.
  • the moisture content in the outer membrane of these soft capsules is About 7.3%.
  • the bubbles were too strong to be observed.
  • Gelatin (15 kg), concentrated glycerin (4.5 kg), and polysorbate 80 (3.75 g) were mixed at 70 ° C. in the presence of purified water (15 kg) to obtain a uniform solution.
  • This solution and (2R) -2-propyloctanoic acid (1. Okg) were put into a soft capsule filling machine (rotary soft capsule molding machine H-1 type (forced mata)) to form a film sheet, Apply a separately prepared soy lecithin solution (0.1% soy lecithin / MCT solution) on one side and cover (2R) -2-propyloctanoic acid with a film sheet so that the coated surface is on the outside.
  • soft capsule live spheres filled with (2R) -2-propyloctanoic acid were obtained.
  • 1 capsule by subjecting the resulting live spheres to tumbler drying (22 ° C, 4 hours), adjusting the amount of soybean lecithin, and further subjecting to shelf drying (28.5 ° C, 26 hours)
  • soft capsules (Opal type (No. 2 Oval), major axis 9.4 mm, minor axis 5.8 mm, 3000 capsules) containing 10 mg of (2R) -2-propyloctanoic acid were obtained.
  • the water content in the outer membrane of these soft capsules was about 6.9%.
  • bubbles were not observed o
  • the present invention can be applied to pharmaceuticals as described below.
  • the (2R) -2-propyloctanoic acid-containing capsule for oral administration disclosed in the present invention contains (2R) -2-propyloctanoic acid as an active ingredient, (Eg, humans, non-human animals such as monkeys, hidges, rabbits, horses, dogs, cats, rabbits, rats, mice, etc.), for example, neurodegenerative diseases, neurological disorders, diseases that require nerve regeneration It can be used as a prophylaxis, treatment and Z or symptom progression inhibitor for eye diseases, sensory nerve diseases, motor nerve diseases, pain, functional brain diseases, etc., or as a nerve regeneration promoter or S 100 ⁇ increase inhibitor.
  • the capsule for oral administration containing (2R) 2 propyloctanoic acid disclosed in the present invention does not contain air bubbles in the capsule film in the production process.
  • the film (outer film) does not contain bubbles, and has a capsule film with a uniform thickness and uniform composition.
  • a stable supply to the clinical site as a soft capsule is possible.
  • the method disclosed in the present invention it takes a long time to remove bubbles in the conventional formulation, so that the manufacturing time can be greatly reduced.
  • the (2R) -2-propyloctanoic acid-containing capsules for oral administration disclosed in the present invention are “the contents do not easily leak during chewing”, “ Because it has properties such as “disintegrating easily in the stomach”, “fast dissolving”, “no dissolution delay”, and so on, even if it is accidentally chewed, it can cause edible taste, pain, and burning in the oral cavity. It can be taken safely without feeling sensation and can be absorbed quickly to obtain a certain pharmacological effect, so that the patient can take it with peace of mind.

Abstract

A capsule (in particular, a capsule having a constitution as a soft capsule) for oral administration which is a soft capsule containing (2R)-2-propyloctanoic acid, being free from the invasion of bubbles into a capsule coating (i.e., the outer coat) during the production process, having a capsule coating with an even thickness and a uniform composition, and showing a sufficiently high strength. Because of suffering from neither “cracking” nor “breakage” during distribution or storage, this soft capsule can be stably supplied into a clinical site. Upon mastication, moreover, it shows a stable efficacy while scarcely causing leakage of the contents therefrom, which ensures safe administration thereof.

Description

明 細 書  Specification
経口投与用カプセル  Capsule for oral administration
技術分野  Technical field
[0001] 本発明は、液状薬物、特に（2R)— 2—プロピルオクタン酸を含有してなる経口投 与用カプセルに関する。  The present invention relates to a capsule for oral administration containing a liquid drug, particularly (2R) -2-propyloctanoic acid.
背景技術  Background art
[0002] ゼラチンをカプセル基剤として用いたソフトカプセルは、液状の有効成分を投与す るのに適した剤形であり、従来より医薬製剤や健康食品製剤に多く用いられている。 ソフトカプセルは服用後、消化管内で速やかにカプセル皮膜が崩壊し、錠剤よりも速 やかな内容物の分散、溶解が行われるため、薬物の良好な吸収を期待できる剤形と されている。従って、カプセル皮膜には、完成した製品が使用されるまでの貯蔵期間 中、安定した崩壊性を維持し続けることが求められている。カロえてカプセル皮膜には 、使用時にどのソフトカプセルを服用したとしても等しい有効性が得られることを目的 として、例えば、製造ロット間で異なる崩壊性を示すことが無いように、均一な厚さ、均 一な組成を有することが求められている。  [0002] Soft capsules using gelatin as a capsule base are dosage forms suitable for administering liquid active ingredients, and have been conventionally used in pharmaceutical preparations and health food preparations. After taking capsules, the capsule film quickly disintegrates in the gastrointestinal tract, and the contents are dispersed and dissolved more quickly than tablets. Therefore, capsule films are required to maintain stable disintegration during the storage period until the finished product is used. For the purpose of obtaining the same effectiveness regardless of which soft capsule is used at the time of use, for example, the capsule film has a uniform thickness and a uniform thickness so as not to show different disintegration properties between production lots. It is required to have a single composition.
[0003] 一方、ァストロサイトの機能改善作用を有することから、脳機能改善剤として種々の 疾患に有効な（2R)— 2—プロピルオクタン酸については、種々の経口投与用医薬 組成物が知られており、特にカプセルに関しては、例えば以下の報告がある。  [0003] On the other hand, since (2R) -2-propyloctanoic acid is effective as a brain function improving agent for various diseases because it has an astrocyte function improving action, various pharmaceutical compositions for oral administration are known. In particular, for capsules, for example, there are the following reports.
[0004] 例えば、欧州特許第 0632008号明細書 (特許文献 1)には、（2R)— 2 プロピル オクタン酸を含むペンタン酸誘導体が、錠剤、丸剤、カプセル剤、散剤、顆粒剤等の 経口投与のための固体組成物として投与される旨、さらに該カプセル剤にはハード カプセル剤およびソフトカプセル剤が含まれる旨が記載されて ヽる。  [0004] For example, in European Patent No. 0632008 (Patent Document 1), a pentanoic acid derivative containing (2R) -2-propyloctanoic acid is used in oral forms such as tablets, pills, capsules, powders, and granules. It is described that it is administered as a solid composition for administration, and that the capsule includes a hard capsule and a soft capsule.
[0005] また、例えば、欧州特許公開第 1174131号明細書 (特許文献 2)には、（2R)—2 プロピルオクタン酸（lg)をゼラチンカプセルに封入することで、有効成分 lOOmg を含有するカプセル剤 10個を得たと ヽぅ製剤例が記載されて！ヽる。  [0005] Further, for example, in European Patent Publication No. 1174131 (Patent Document 2), (2R) -2 propyloctanoic acid (lg) is encapsulated in a gelatin capsule to contain a capsule containing the active ingredient lOOmg. When 10 drugs were obtained, a preparation example was written! Speak.
[0006] さらに、例えば、国際公開第 2005Z120490号パンフレット（特許文献 3)には、（2 R)—2—プロピルオクタン酸またはその塩を含有し、蛋白質、多糖類、生分解性ブラ スチックおよび硬化油脂力 選択される少なくとも一種のカプセル基剤および可塑剤 を含む、含水率が 4. 0%〜10. 0%のカプセル皮膜を有するソフトカプセル剤が開 示されている。 [0006] Further, for example, International Publication No. 2005Z120490 pamphlet (Patent Document 3) includes (2R) -2-propyloctanoic acid or a salt thereof, and includes proteins, polysaccharides, biodegradable brains. Sticks and hardened oils and fats Soft capsules having a capsule film with a moisture content of 4.0% to 10.0% are disclosed, comprising at least one selected capsule base and plasticizer.
[0007] 特許文献 1：欧州特許第 0632008号明細書 [0007] Patent Document 1: European Patent No. 0632008
特許文献 2 :欧州特許公開第 1174131号明細書  Patent Document 2: European Patent Publication No. 1174131
特許文献 3：国際公開第 2005Z120490号パンフレット  Patent Document 3: International Publication No. 2005Z120490 pamphlet
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0008] (2R) 2 プロピルオクタン酸を含有するソフトカプセル剤については、例えば、 前記特許文献 3のように、具体的な処方を記載した公知文献も存在する。しかしなが ら、かかる処方で（2R)—2—プロピルオクタン酸含有ソフトカプセルを製造した場合 、その製造工程においてしばしば後述の図 3に示すようにカプセル皮膜内に気泡が 混入し、一定の品質を有するものを得ることができな 、場合があると!/、う問題があった 。カプセル皮膜内に気泡が混入したソフトカプセルは、外見上カプセル皮膜の厚さは 均一であったとしても、その気泡が混入した部分の実質的な厚さは薄いため、強度面 で問題があり、また崩壊性にも影響を与える可能性があった。すなわちこのようなソフ トカプセルでは、輸送や保存等の医薬品供給過程において、「ヒビ」や「割れ」が発生 する危険性もあり、また、服用した際に有効性にムラが生じたりするおそれもある。加 えて、前記特許文献 3にも記載されているように、（2R)— 2 プロピルオクタン酸は 刺激性の強い物質であるため、 口腔内でソフトカプセル力 漏出すると極めて強いェ グ味ゃ灼熱感等を感じるが、カプセル皮膜内に気泡が混入したソフトカプセルは、気 泡が混入していないソフトカプセルに比べて強度が低いため、咀嚼時における（2R) —2—プロピルオクタン酸の漏出の危険性が高いものであった。  [0008] With regard to the soft capsule containing (2R) 2 propyloctanoic acid, for example, as in Patent Document 3, there is a known document describing a specific formulation. However, when (2R) -2-propyloctanoic acid-containing soft capsules are produced with such a formulation, bubbles are often mixed in the capsule film in the production process as shown in FIG. If you can't get what you have! Soft capsules with air bubbles mixed in the capsule film have a problem in strength, even though the capsule film thickness is uniform in appearance, the substantial thickness of the part where the air bubbles are mixed is thin. There was also the possibility of affecting disintegration. In other words, with such soft capsules, there is a risk of `` cracking '' and `` cracking '' in the pharmaceutical supply process such as transportation and storage, and there is also a risk that the effectiveness may be uneven when taken. is there. In addition, as described in Patent Document 3, (2R) -2-propyloctanoic acid is a substance with strong irritation, so if it leaks soft capsule force in the oral cavity, it will have a very strong egg taste, burning sensation, etc. However, soft capsules with bubbles in the capsule film have a lower strength than soft capsules without bubbles, so there is a high risk of leakage of (2R) —2-propyloctanoic acid during chewing It was a thing.
[0009] 従って、本発明の課題は、製造工程においてカプセル皮膜に気泡が混入するとい う問題を解決して、均一な厚さ、均一な組成のカプセル皮膜を有し、輸送や保存等 の医薬品供給過程においても「ヒビ」や「割れ」を発生することがなぐさらに咀嚼時に おいても（2R)—2—プロピルオクタン酸が容易に漏出することのない、安定した薬理 効果を示すことができる（2R)—2—プロピルオクタン酸含有ソフトカプセルを提供す ることにある。 Accordingly, an object of the present invention is to solve the problem that air bubbles are mixed in the capsule film in the production process, and to have a capsule film having a uniform thickness and uniform composition, which is a pharmaceutical product for transportation and storage. In the supply process, “crack” and “crack” do not occur, and even when chewing, (2R) -2-propyloctanoic acid does not leak easily and can exhibit a stable pharmacological effect. (2R) -2-Propyloctanoic acid-containing soft capsules are provided There is to be.
課題を解決するための手段  Means for solving the problem
[0010] 本発明者らは、上記の課題を解決するべく鋭意検討した結果、ソフトカプセルの製 造工程において、その原料に非イオン性界面活性剤、とりわけポリソルベート 80を加 えることで、カプセル皮膜に気泡を混入させることなく（2R)—2—プロピルオクタン酸 含有ソフトカプセルを製造することができることを見出し、この知見に基づいてさらに 詳細に研究を行うことにより本発明を完成した。  [0010] As a result of intensive studies to solve the above-mentioned problems, the present inventors have added a nonionic surfactant, particularly polysorbate 80, to the raw material in the soft capsule manufacturing process, thereby providing a capsule film. The present inventors have found that (2R) -2-propyloctanoic acid-containing soft capsules can be produced without mixing bubbles, and the present invention has been completed by conducting further detailed research based on this finding.
[0011] すなわち、本発明は、  [0011] That is, the present invention provides:
[1] (A)液状薬物を含有し、さらに多価アルコール、糖アルコールおよび Zまたは水 を含有していてもよい組成物を内容物とし、（B)蛋白質、多価アルコール、非イオン 性界面活性剤および水を含有し、さらにリン脂質および Zまたは糖アルコールを含 有して 、てもよ 、組成物を外膜として、所望によってさらに (C)保護膜を最外膜に有 して 、てもよ 、構成を有し、前記外膜中に長径 100 μ m以上の気泡を含まな 、経口 投与用カプセル；  [1] (A) A composition containing a liquid drug and further containing a polyhydric alcohol, a sugar alcohol and Z or water is used as a content, and (B) a protein, a polyhydric alcohol, a nonionic interface. Containing an active agent and water, and further containing a phospholipid and Z or sugar alcohol, the composition as an outer membrane, and optionally (C) a protective membrane as the outermost membrane; However, the capsule for oral administration has a configuration and does not contain bubbles having a major axis of 100 μm or more in the outer membrane;
[2]液状薬物が（2R)— 2—プロピルオクタン酸である前記 [1]記載の経口投与用力 プセル；  [2] The oral drug for oral administration according to the above [1], wherein the liquid drug is (2R) -2-propyloctanoic acid;
[3]蛋白質がゼラチンであり、多価アルコールがグリセリンである前記 [1]記載の経口 投与用カプセル；  [3] The capsule for oral administration according to the above [1], wherein the protein is gelatin and the polyhydric alcohol is glycerin;
[4]非イオン性界面活性剤がポリソルベート 80である前記 [ 1]記載の経口投与用力 プセル；  [4] The oral administration force Psel according to [1], wherein the nonionic surfactant is polysorbate 80;
[5]リン脂質が大豆レシチンである前記 [ 1]記載の経口投与用カプセル；  [5] The capsule for oral administration according to the above [1], wherein the phospholipid is soybean lecithin;
[6]糖アルコールがソルビトールである前記 [ 1]記載の経口投与用カプセル；  [6] The capsule for oral administration according to the above [1], wherein the sugar alcohol is sorbitol;
[7]保護膜がリン脂質を含有する前記 [1]記載の経口投与用カプセル；  [7] The capsule for oral administration according to the above [1], wherein the protective film contains a phospholipid;
[8]リン脂質が大豆レシチンである前記 [7]記載の経口投与用カプセル；  [8] The capsule for oral administration according to the above [7], wherein the phospholipid is soybean lecithin;
[9] (A) (2R)—2—プロピルオクタン酸を含有し、さらにグリセリン、ソルビトールおよ び Zまたは水を含有していてもよい組成物を内容物とし、（B)ゼラチン、グリセリン、 ポリソルベート 80および水を含有し、さらに大豆レシチンおよび/またはソルビトール を含有して ヽてもよ 、組成物を外膜として、所望によってさらに (C)大豆レシチンを含 有する保護膜を最外膜に有して!/ヽてもよ!ヽ構成を有する前記 [ 1 ]記載の経口投与用 カプセノレ； [9] A composition containing (A) (2R) -2-propyloctanoic acid and optionally further containing glycerin, sorbitol and Z or water, and (B) gelatin, glycerin, It may contain polysorbate 80 and water, and may further contain soy lecithin and / or sorbitol. Capsole for oral administration according to the above [1], having a protective film as an outermost film!
[10]ソフトカプセルである前記 [9]記載の経口投与用カプセル；  [10] The capsule for oral administration according to the above [9], which is a soft capsule;
[11]外膜が、（a)ゼラチン、（b)ゼラチン 100質量部に対して約 25質量部〜約 40質 量部のグリセリンおよび (c)ゼラチン 100質量部に対して約 0. 01質量部〜約 0. 05 質量部のポリソルベート 80を含有し、かつソルビトールを実質的に含まないか、また はゼラチン 100質量部に対して約 20質量部以下のソルビトールを含む、大豆レシチ ンを実質的に含まない含水率約 5%〜約 15%の組成物からなる前記 [10]記載の経 口投与用カプセル； [11] The outer membrane contains (a) gelatin, (b) about 25 parts by weight to about 40 parts by weight of glycerin with respect to 100 parts by weight of gelatin, and (c) about 0.01 parts by weight with respect to 100 parts by weight of gelatin. Part to about 0.05 part by weight of polysorbate 80 and substantially free of sorbitol or substantially less than 20 parts by weight of sorbitol per 100 parts by weight of gelatin. The capsule for oral administration according to the above [10], comprising a composition having a water content of about 5% to about 15% not contained in the composition;
[12]外膜が、実質的にソルビトールを含まない前記 [11]記載の経口投与用カプセ ル；  [12] The capsule for oral administration according to [11], wherein the outer membrane does not substantially contain sorbitol;
[13]外膜力 （a)ゼラチン、（b)ゼラチン 100質量部に対して約 30質量部のグリセリ ンおよび（c)ゼラチン 100質量部に対して約 0. 025質量部のポリソルベート 80を含 有する含水率約 5%〜約 8%の組成物力 なる前記 [12]記載の経口投与用カプセ ル；  [13] Outer membrane force (a) gelatin, (b) about 30 parts by mass of glycerin to 100 parts by mass of gelatin, and (c) about 0.025 parts by mass of polysorbate 80 to 100 parts by mass of gelatin The capsule for oral administration according to [12], wherein the composition has a water content of about 5% to about 8%;
[14]内容物力 約 50mg〜約 400mgの（2R)— 2—プロピルオクタン酸を含有する 組成物からなる前記 [9]記載の経口投与用カプセル；  [14] Capsule for oral administration according to the above [9], comprising a composition containing about 50 mg to about 400 mg of (2R) -2-propyloctanoic acid;
[15]内容物力 約 lOOmgまたは約 300mgの（2R)—2—プロピルオクタン酸を含有 する組成物力 なる前記 [14]記載の経口投与用カプセル；  [15] Capability of composition containing about 10 mg of content or about 300 mg of (2R) -2-propyloctanoic acid
[ 16]構成が二層膜ソフトカプセルである前記 [9]記載の経口投与用カプセル； [17] (A)約 lOOmgまたは約 300mgの（2R)—2—プロピルオクタン酸を含有する組 成物を内容物とし、 (B) (a)ゼラチン、（b)ゼラチン 100質量部に対して約 30質量部 のグリセリンおよび（c)ゼラチン 100質量部に対して約 0. 025質量部のポリソルベー ト 80を含有する含水率約 5%〜約 8%の組成物を外膜として、さらに（C)大豆レシチ ンを含有してなる保護膜を最外膜に有する構成を含む二層膜ソフトカプセル； [18] (A)約 lOOmgまたは約 300mgの（2R)—2—プロピルオクタン酸を含有する組 成物を内容物とし、 (B) (a)ゼラチン、（b)ゼラチン 100質量部に対して約 30質量部 のグリセリンおよび（c)ゼラチン 100質量部に対して約 0. 025質量部のポリソルベー ト 80を含有する含水率約 5%〜約 12%の組成物を外膜として、さらに（C)大豆レシ チンを含有してなる保護膜を最外膜に有する構成を含む二層膜ソフトカプセル； [19]外膜中に長径 100 /z m以上の気泡を含まない前記 [17]または [18]記載の二 層膜ソフトカプセル； [16] The capsule for oral administration according to the above [9], wherein the composition is a bilayer soft capsule; [17] (A) a composition containing about lOOmg or about 300 mg of (2R) -2-propyloctanoic acid; (B) (a) gelatin, (b) about 30 parts by mass of glycerin with respect to 100 parts by mass of gelatin, and (c) about 0.025 parts by mass of polysorbate 80 with respect to 100 parts by mass of gelatin. A two-layer soft capsule comprising a composition having a moisture content of about 5% to about 8% as an outer membrane, and further comprising (C) a protective membrane containing soybean lecithin in the outermost membrane; [18] (A) A composition containing about lOOmg or about 300 mg of (2R) -2-propyloctanoic acid is used as a content, and (B) (a) gelatin and (b) about 30 parts by mass with respect to 100 parts by mass of gelatin. Part of glycerin and (c) 100 parts by weight of gelatin about 0.025 parts by weight of polysorbate A double-layer membrane soft capsule comprising a composition having a moisture content of about 5% to about 12% containing 80 g as an outer membrane, and further comprising (C) a protective membrane comprising soybean lecithin in the outermost membrane; [19] The double-layer soft capsule according to [17] or [18], wherein the outer membrane does not contain bubbles having a major axis of 100 / zm or more;
[20]ゼラチンと、ゼラチン 100質量部に対して約 25質量部〜約 40質量部のグリセリ ンを含む水溶液に、ゼラチン 100質量部に対して約 0. 01質量部〜約 0. 05質量部 のポリソルベート 80を共存させることを特徴とする、該水溶液の消泡方法；  [20] In an aqueous solution containing gelatin and about 25 parts by weight to about 40 parts by weight of glycerin with respect to 100 parts by weight of gelatin, about 0.01 parts by weight to about 0.05 parts by weight with respect to 100 parts by weight of gelatin A method of defoaming the aqueous solution, characterized by coexisting Polysorbate 80 of
[21] (a)ゼラチン、（b)ゼラチン 100質量部に対して約 25質量部〜約 40質量部のグ リセリンおよび (c)ゼラチン 100質量部に対して約 0. 01質量部〜約 0. 05質量部の ポリソルベート 80を含有する水溶液力もシートを成形し、その外側片面に大豆レシチ ンの中鎖脂肪酸トリグリセリド溶液を塗布して二層シートを得、その二層シートで（2R) - 2-プロピルオクタン酸を含有する液状材料を覆 ヽ、得られた生球を乾燥工程に 付すことを特徴とする二層膜ソフトカプセルの製造方法。 [21] (a) gelatin, (b) about 25 parts by weight to about 40 parts by weight glycerin with respect to 100 parts by weight of gelatin, and (c) about 0.01 parts by weight to about 0 with respect to 100 parts by weight of gelatin. Aqueous solution containing 05 parts by mass of polysorbate 80 is also formed into a sheet, and a two-layer sheet is obtained by applying a medium chain fatty acid triglyceride solution of soybean lecithin to one side of the sheet. (2R)-2 -A method for producing a two-layer membrane soft capsule, comprising covering a liquid material containing propyloctanoic acid and subjecting the obtained raw spheres to a drying step.
[22]ゼラチンと、ゼラチン 100質量部に対して約 30質量部のグリセリンを含む水溶 液に、ゼラチン 100質量部に対して約 0. 025質量部のポリソルベート 80を共存させ る前記 [20]記載の消泡方法；および  [22] The above [20], wherein gelatin and an aqueous solution containing about 30 parts by mass of glycerol with respect to 100 parts by mass of gelatin coexist with about 0.025 parts by mass of polysorbate 80 with respect to 100 parts by mass of gelatin. Defoaming method of; and
[23] (a)ゼラチン、（b)ゼラチン 100質量部に対して約 30質量部のグリセリンおよび ( c)ゼラチン 100質量部に対して約 0. 025質量部のポリソルベート 80を含有する水溶 液力 シートを成形し、その外側片面に大豆レシチンの中鎖脂肪酸トリグリセリド溶液 を塗布して二層シートを得、その二層シートで（2R)—2—プロピルオクタン酸を含有 する液状材料を覆 ヽ、得られた生球を乾燥工程に付すことを特徴とする二層膜ソフト カプセルの製造方法等に関する。  [23] An aqueous solution containing (a) gelatin, (b) about 30 parts by weight of glycerin with respect to 100 parts by weight of gelatin, and (c) about 0.025 parts by weight of polysorbate 80 with respect to 100 parts by weight of gelatin. Form a sheet, apply a medium chain fatty acid triglyceride solution of soybean lecithin on one side of the sheet to obtain a two-layer sheet, and cover the liquid material containing (2R) -2-propyloctanoic acid with the two-layer sheet. The present invention relates to a method for producing a double-layer soft capsule characterized by subjecting the obtained live sphere to a drying step.
本発明で開示する、「 (A)液状薬物を含有し、さらに多価アルコール、糖アルコー ルおよび Zまたは水を含有していてもよい組成物を内容物とし、（B)蛋白質、多価ァ ルコール、非イオン性界面活性剤および水を含有し、さらにリン脂質および zまたは 糖アルコールを含有して 、てもよ 、組成物を外膜として、所望によってさらに (C)保 護膜を最外膜に有して 、てもよ 、構成を有する、気泡を含まな 、経口投与用カプセ ル」（以下、本発明のカプセルと略記する場合がある。）とは、内容物と外膜とで最小 の構成を成し、所望によって保護膜を最外膜に有して 、てもよ 、経口投与用のカブ セルであって、気泡を含まず、かつ内容物力 液状薬物と、所望によって多価アルコ ール、糖アルコールおよび Zまたは水を含有していてもよい組成物からなり、外膜がDisclosed in the present invention is a composition containing (A) a liquid drug and may further contain a polyhydric alcohol, a sugar alcohol and Z or water, and (B) a protein, Contains alcohol, non-ionic surfactant and water, and further contains phospholipids and z or sugar alcohols. “The capsule for oral administration which has a structure and does not contain air bubbles” (hereinafter sometimes abbreviated as the capsule of the present invention) has a structure and an outer membrane. minimum It is a capsule for oral administration that does not contain air bubbles, and has a content strength, a liquid drug, and optionally a polyvalent alcohol. A composition that may contain alcohol, sugar alcohol and Z or water.
、蛋白質、多価アルコール、非イオン性界面活性剤および水と、所望によってリン脂 質および Zまたは糖アルコールを含有して 、てもよ 、組成物力 なるものを意味する, Protein, polyhydric alcohol, nonionic surfactant and water, and optionally containing phospholipid and Z or sugar alcohol, but means a compositional force
。本発明のカプセルとしては、前記の構成ならびに組成を満たす経口投与用のカブ セルであればどのようなものであってもよぐ特にソフトカプセル剤が好適に用いられ る。 . As the capsule of the present invention, any capsule for oral administration satisfying the above-described configuration and composition can be used, and a soft capsule is particularly preferably used.
[0013] 本発明のカプセルは、後述するように優れた効果を具備するために、外膜中に気 泡を含まないカプセルである。好ましくは、外膜中に長径 100 m以上の気泡を含ま ない。ここで長径 100 μ m以上の気泡とは、気泡の内径の最大値が 100 μ m以上の ものをいう。気泡の有無は、目視、あるいは顕微鏡で観察することにより確認すること ができる。本発明のカプセルは、内容物、外膜、または最外膜中に、あるいは内容物 と外膜の間や外膜と最外膜の間に気泡を含まないことがさらに好ましい。  The capsule of the present invention is a capsule that does not contain bubbles in the outer membrane in order to have excellent effects as described later. Preferably, the outer membrane does not contain bubbles having a major axis of 100 m or more. Here, a bubble having a major axis of 100 μm or more means a bubble having a maximum inner diameter of 100 μm or more. The presence or absence of bubbles can be confirmed visually or with a microscope. More preferably, the capsule of the present invention does not contain bubbles in the contents, outer membrane, or outermost membrane, or between the contents and the outer membrane, or between the outer membrane and the outermost membrane.
[0014] 本発明にお 、て、液状薬物としては、例えば、疾病の予防、治療および Zまたは症 状進展抑制等の目的のために生体に経口的に投与される薬物であって、かつ適度 な流動性を有するものであればどのようなものであってもよい。ここで、適度な流動性 とは、後述するように、例えばソフトカプセル充填機を用いての圧入が可能な流動性 を意味する。具体的には、粘度で約 50000ミリパスカル秒 (mPa' s)以下の流動性で あることが好ましい。本発明における液状薬物は、上記のように適度な流動性を示す ものであれば、液体のみならず、ゲル状の態様を示す半固体であってもよい。また、 本発明における液状薬物には、化合物単体で適度な流動性を示すもののほか、内 容物に加えてもよい後述の成分 (例えば、多価アルコール、糖アルコール、水、適当 な油脂、溶媒、添加剤等)を適宜組み合わせることで、適度な流動性を示す組成物と なりうる化合物も含まれる。本発明における液状薬物としては、例えば、（2R)— 2— プロピルオクタン酸をはじめとして、アルファカルシドール、ィコサペント酸ェチル、ィ ンドメタシンフアルネシル、ゲファルナート、サキナビル、シロスタゾール、セル-チン ポーレンエキス、トレチノイン（ATRA)、ニコチン酸トコフエロール、 -フエジピン、プラ ウノトール、メナテトレノン、リトナビル、口ピナビル'リトナビル、塩酸ェピナスチン等の 薬物や、ソフトカプセルに充填して投与される種々の健康食品の有効成分等が挙げ られる。とりわけ、本発明における液状薬物としては、（2R)— 2—プロピルオクタン酸 が好適である。 In the present invention, the liquid drug is, for example, a drug that is orally administered to a living body for the purpose of preventing or treating a disease and suppressing Z or symptom progression, and is appropriate. Any fluid may be used as long as it has a good fluidity. Here, moderate fluidity means fluidity that can be press-fitted using, for example, a soft capsule filling machine, as will be described later. Specifically, the fluidity is preferably about 50,000 millipascal seconds (mPa's) or less in viscosity. The liquid drug in the present invention may be not only a liquid but also a semi-solid exhibiting a gel-like form as long as it exhibits an appropriate fluidity as described above. In addition, the liquid drug in the present invention is not only a compound having an appropriate fluidity but also the following components which may be added to the content (for example, polyhydric alcohol, sugar alcohol, water, appropriate fats and oils, solvent) In addition, a compound that can be a composition exhibiting an appropriate fluidity by appropriately combining additives, etc.) is also included. Examples of the liquid drug in the present invention include (2R) -2-propyloctanoic acid, alphacalcidol, icosapentate ethyl, indomethacin farnesyl, gefarnate, saquinavir, cilostazol, sertin tin polen extract, Tretinoin (ATRA), tocopherol nicotinate, -fedipine, plastic Examples include drugs such as unothol, menatetrenone, ritonavir, oral pinabir'ritonavir, and epinastin hydrochloride, and active ingredients of various health foods that are administered in soft capsules. In particular, (2R) -2-propyloctanoic acid is preferred as the liquid drug in the present invention.
[0015] 本発明において、（2R)— 2 プロピルオクタン酸は、式 (I)  In the present invention, (2R) -2-propyloctanoic acid has the formula (I)
[化 1]  [Chemical 1]
Figure imgf000008_0001
Figure imgf000008_0001
中  During
[化 2]  [Chemical 2]
は j8—配置であることを表す。 ]で示される化合物である。 Represents j8—configuration. It is a compound shown by this.
[0016] (2R) 2 プロピルオクタン酸は、それ自体公知の方法、例えば、欧州特許第 06  [0016] (2R) 2 propyloctanoic acid is obtained by a method known per se, for example, European Patent 06.
32008号明細書、国際公開第 99Z58513号パンフレット、国際公開第 00/4898 32008 specification, WO99Z58513 pamphlet, WO00 / 4898
2号パンフレット、特許第 3032447号明細書、特許第 3084345号明細書、国際公 開第 2003Z051852号パンフレツ卜、国際公開第 2003,097851号パンフレツ卜、 国際公開第 2004Z092113号パンフレツ卜、国際公開第 2004,110972号パンフ レット、国際公開第 2005Z105722号パンフレット等に記載された方法、これらに準 ずる方法、またはコンプリへンシヴ ·オーガニック ·トランスフォーメーションズ：ァ 'ガイ ド ·トウ■ _ ·ファンクショナル ·グループ ·プレパレーシヨンズ、セカンド ·エディション（リチ ヤードにラロック、ジョンワイリーアンドサンズ社， 1999) [Comprehensive Organic Tr ansformations： A Guide to Functional Group Preparations, 2na Edition、 Richard C. Larock, John Wiley & Sons Inc, 1999 )]に記載された方法等に従って、またはそれ らの方法を適宜組み合わせることにより製造することができる。反応の生成物は通常 の精製手段、例えば、常圧下または減圧下における蒸留、シリカゲルまたはケィ酸マ グネシゥムを用いた高速液体クロマトグラフィー、薄層クロマトグラフィー、あるいは力 ラムクロマトグラフィーまたは洗浄、再結晶等の方法により精製することができる。また 所望によって、凍結乾燥等の処理に付してもよい。 Pamphlet No. 2, Patent No. 3032447, Patent No. 3084345, International Publication No.2003Z051852 Pamphlet, International Publication No.2003,097851 Pamphlet, International Publication No.2004Z092113 Pamphlet, International Publication No. 2004, 110972 pamphlet, method described in the pamphlet of International Publication No. 2005Z105722, etc., or a method similar to these, or Comprehensive · Organic · Transformation: A Guide · Tow ■ _ · Functional · Group · Pre Parasites, Second Edition (Richard to Larock, John Wiley & Sons, 1999) [Comprehensive Organic Transforms: A Guide to Functional Group Preparations, 2na Edition, Richard C. Larock, John Wiley & Sons Inc, 1999)] In accordance with the method described in the above, or by appropriately combining these methods. Can. The product of the reaction can be obtained by conventional purification means such as distillation under normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or force. It can be purified by means of ram chromatography or washing, recrystallization and the like. If desired, it may be subjected to a treatment such as freeze-drying.
[0017] 本発明で用いられる (2R) 2 プロピルオクタン酸は、実質的に純粋で単一な物 質であるものに限定されず、不純物 (例えば、製造工程に由来する副生成物、溶媒、 原料等、または分解物等)を、医薬品原薬として許容される範囲であれば含有してい てもよい。 （2R)— 2—プロピルオクタン酸の、医薬品原薬として許容される不純物の 含有量は、例えば、重金属（例えば、鉛、ビスマス、銅、カドミウム、アンチモン、錫、 水銀等）は約 20ppm以下、光学異性体である S体は約 1. 49重量％以下、残留溶媒 である 2 プロパノールやヘプタンは合計約 5000ppm以下、水分は約 0. 2重量％ 以下であることが好ましい。本発明で用いられる（2R)—2—プロピルオクタン酸として は、特に、光学純度が約 99%e. e.を超える（2R)— 2 プロピルオクタン酸、とりわ け、光学純度が約 99. 3%e. e.以上の（2R)— 2 プロピルオクタン酸が好適である  [0017] The (2R) 2 propyloctanoic acid used in the present invention is not limited to a substantially pure and single substance, but includes impurities (for example, by-products derived from the production process, solvents, Raw materials, etc., or degradation products) may be contained as long as it is acceptable as an active pharmaceutical ingredient. (2R) —The content of 2-propyloctanoic acid that is acceptable as an active pharmaceutical ingredient is, for example, about 20 ppm or less for heavy metals (eg, lead, bismuth, copper, cadmium, antimony, tin, mercury, etc.) It is preferable that the S-isomer, which is an optical isomer, is about 1.49% by weight or less, the residual solvents 2 propanol and heptane are about 5000 ppm or less in total, and the water content is about 0.2% by weight or less. As (2R) -2-propyloctanoic acid used in the present invention, in particular, (2R) -2-propyloctanoic acid having an optical purity exceeding about 99% ee, especially optical purity of about 99.3% ee The above (2R) -2-propyloctanoic acid is preferred
[0018] 本発明において、蛋白質は、経口投与用の医薬組成物に用いることができる蛋白 質であればどのようなものであってもよい。例えば、ゼラチン、ゼラチン加水分解物、 コラーゲン、コラーゲン加水分解物、カゼイン等の一般的にソフトカプセル剤の製造 に際してカプセル皮膜の基剤として用いられる蛋白質が好ましく用いられる。特に、 本発明における蛋白質としては、ゼラチンが好適である。 In the present invention, the protein may be any protein as long as it can be used in a pharmaceutical composition for oral administration. For example, proteins that are generally used as a base for capsule films in the production of soft capsules such as gelatin, gelatin hydrolyzate, collagen, collagen hydrolyzate, and casein are preferably used. In particular, gelatin is suitable as the protein in the present invention.
[0019] 本発明において、ゼラチンは、一般的にゼラチンと称されるもののほ力 アルカリ処 理ゼラチン、酸処理ゼラチン、ぺプタイドゼラチン、低分子ゼラチン、ゼラチン誘導体 、化学修飾ゼラチン、コハク化ゼラチン等であってもよい。またその由来も、例えば、 哺乳類 (例えば、ゥシ、ブタ等）、魚類 (例えば、テラピア、タイ、マグロ、ナマズ等）、鳥 類 (例えば、ニヮトリ、ダチョウ等)等の各種動物に由来するゼラチンを特に限定する ことなく使用することがでさる。  [0019] In the present invention, gelatin is generally called gelatin, however, alkali-treated gelatin, acid-treated gelatin, peptide gelatin, low-molecular gelatin, gelatin derivative, chemically modified gelatin, succinylated gelatin, etc. It may be. In addition, its origin is, for example, gelatin derived from various animals such as mammals (eg, sushi, pigs, etc.), fish (eg, tilapia, Thailand, tuna, catfish, etc.), birds (eg, chicken, ostrich, etc.). Can be used without any particular limitation.
[0020] 本発明において、多価アルコールは、経口投与用の医薬組成物に用いることがで きる多価アルコールであればどのようなものであってもよい。例えば、グリセリン、ェチ レングリコール、ポリエチレングリコール、プロピレングリコール等の一般的にソフト力 プセル剤の製造に際してカプセル皮膜の可塑剤として用いられる多価アルコールが 好ましく用いられる。特に、本発明における多価アルコールとしては、グリセリンが好 適である。 [0020] In the present invention, the polyhydric alcohol may be any polyhydric alcohol that can be used in a pharmaceutical composition for oral administration. For example, polyhydric alcohols that are generally used as plasticizers for capsule coatings in the production of soft force fillers such as glycerin, ethylene glycol, polyethylene glycol, propylene glycol, etc. Preferably used. In particular, glycerin is preferred as the polyhydric alcohol in the present invention.
[0021] 本発明において、グリセリンは、一般的にグリセリンと称されるものであればどのよう なものであってもよい。例えば、局方グリセリンや濃グリセリン等が好ましぐ例えば、 濃グリセリン等が特に好まし 、。  In the present invention, the glycerin may be any as long as it is generally called glycerin. For example, pharmacopoeia glycerin and concentrated glycerin are preferred. For example, concentrated glycerin is particularly preferred.
[0022] 本発明において、非イオン性界面活性剤は、経口投与用の医薬組成物に用いるこ とができる非イオン性界面活性剤であればどのようなものであってもよい。例えば、 日 本薬局方 (例えば、第十四改正日本薬局方や第十五改正日本薬局方等)、医薬品 添加物規格 (例えば、医薬品添加物規格 2003)、および Zまたは食品添加物公定 書 (例えば、食品添加物公定書第七版)等に記載されて!、る非イオン性界面活性剤 を好ましく用いることができる。具体的には、例えば、コレステロール、ショ糖脂肪酸ェ ステル、ステアリルアルコール、ステアリン酸ポリオキシル 40、セスキォレイン酸ソルビ タン、セタノール、セトマクロゴール 1000、セバシン酸ジェチル、トリオレイン酸ソルビ タン、ポリオキシエチレンォクチルフエ-ルエーテル、ポリオキシエチレン硬化ヒマシ 油 5、ポリオキシエチレン硬化ヒマシ油 10、ポリオキシエチレン硬化ヒマシ油 20、ポリ ォキシエチレン硬化ヒマシ油 40、ポリオキシエチレン硬化ヒマシ油 50、ポリオキシェ チレン硬化ヒマシ油 60、ポリオキシエチレン硬化ヒマシ油 100、ポリオキシエチレンス テアリルエーテル、ポリオキシエチレンソルビットミツロウ、ポリオキシエチレン（20)ポ リオキシプロピレン（20)グリコーノレ、ポリオキシエチレン（105)ポリオキシプロピレン（ 5)グリコール、ポリオキシエチレン（120)ポリオキシプロピレン（40)グリコール、ポリオ キシエチレン（160)ポリオキシプロピレン（30)グリコール、ポリソルベート 20、ポリソ ルベート 60、ポリソルベート 65、ポリソルベート 80、マクロゴール 400、モノォレイン酸 ソルビタン、モノステアリン酸グリセリン、モノステアリン酸ソルビタン、モノラウリン酸ソ ルビタン、ラウリルジメチルアミンォキシド液、ラウリン酸ジエタノールアミド、ラウロマク 口ゴール、モノパルミチン酸ソルビタン等が挙げられる。これらのうち、例えば、コレス テロール、ステアリン酸ポリオキシル 40、セスキォレイン酸ソルビタン、セトマクロゴー ル 1000、セバシン酸ジェチル、トリオレイン酸ソルビタン、ポリオキシエチレンォクチ ルフエ-ルエーテル、ポリオキシエチレン硬化ヒマシ油 5、ポリオキシエチレン硬化ヒ マシ油 10、ポリオキシエチレン硬化ヒマシ油 20、ポリオキシエチレン硬化ヒマシ油 40 、ポリオキシエチレン硬化ヒマシ油 50、ポリオキシエチレン硬化ヒマシ油 60、ポリオキ シエチレン硬化ヒマシ油 100、ポリオキシエチレンステアリルエーテル、ポリオキシェ チレンソルビットミツロウ、ポリオキシエチレン（20)ポリオキシプロピレン（20)グリコー ル、ポリオキシエチレン（105)ポリオキシプロピレン（5)グリコール、ポリオキシェチレ ン（120)ポリオキシプロピレン（40)グリコール、ポリオキシエチレン（160)ポリオキシ プロピレン（30)グリコーノレ、ポリソノレべート 20、ポリソノレべート 60、ポリソノレべート 65、 ポリソルベート 80、マクロゴール 400、モノォレイン酸ソルビタン、モノステアリン酸ダリ セリン、モノステアリン酸ソルビタン、モノラウリン酸ソルビタン、ラウリルジメチルァミン ォキシド液、ラウリン酸ジエタノールアミド、ラウロマクロゴール、モノパルミチン酸ソル ビタン等が好ましぐ例えば、コレステロール、ステアリン酸ポリオキシル 40、セスキォ レイン酸ソルビタン、セトマクロゴール 1000、トリオレイン酸ソルビタン、ポリオキシェ チレン硬化ヒマシ油 60、ポリオキシエチレン（105)ポリオキシプロピレン（5)グリコー ル、ポリオキシエチレン（160)ポリオキシプロピレン（30)グリコール、ポリソルベート 2 0、ポリソノレべート 60、ポリソノレべート 80、マクロゴール 400、モノォレイン酸ソノレビタン 、モノステアリン酸グリセリン、モノステアリン酸ソルビタン、モノラウリン酸ソルビタン、ラ ゥロマクロゴール、モノパルミチン酸ソルビタン等がより好ましぐ例えば、ポリソルベー ト 80が特に好ましい。 [0022] In the present invention, the nonionic surfactant may be any nonionic surfactant that can be used in a pharmaceutical composition for oral administration. For example, the Japanese Pharmacopoeia (for example, the 14th revised Japanese Pharmacopoeia and the 15th revised Japanese Pharmacopoeia, etc.), the Pharmaceutical Additives Standard (for example, the Pharmaceutical Additives Standard 2003), and the Z or Food Additives Standard ( For example, nonionic surfactants described in the Food Additives Official Version 7) can be preferably used. Specifically, for example, cholesterol, sucrose fatty acid ester, stearyl alcohol, polyoxyl 40 stearate, sorbitan sesquioleate, cetanol, cetomacrogol 1000, jetyl sebacate, sorbitan trioleate, polyoxyethylene octyl Phenol ether, polyoxyethylene hydrogenated castor oil 5, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, Polyoxyethylene hydrogenated castor oil 100, polyoxyethylene stearyl ether, polyoxyethylene sorbit beeswax, polyoxyethylene (20) polyoxypropylene (20) glyconore, polyoxyethylene (105) polio Cypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polysorbate 20, polysorbate 60, polysorbate 65, polysorbate 80, macrogol 400 Sorbitan monooleate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, lauryldimethylamine oxide solution, lauric acid diethanolamide, lauromac mouthpiece, sorbitan monopalmitate and the like. Among these, for example, cholesterol, polyoxyl stearate 40, sorbitan sesquioleate, cetomacrogol 1000, jetyl sebacate, sorbitan trioleate, polyoxyethylene octyl ether, polyoxyethylene hydrogenated castor oil 5, polyoxy Ethylene hardened Castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 100, polyoxyethylene stearyl ether, polyoxyethylene Tylene sorbite beeswax, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene ( 160) Polyoxypropylene (30) Glycololole, Polysonolate 20, Polysonolebate 60, Polysonolebate 65, Polysorbate 80, Macrogol 400, Sorbitan monooleate, Darisyl monostearate, Solsol monostearate Tungsten, sorbitan monolaurate, lauryl dimethylamine oxide, diethanolamide laurate, lauromacrogol, sorbitan monopalmitate, etc. are preferred, for example, cholesterol, polyoxyl 40 stearate, sorbitan sesquioleate, cetomacrogol 1000 , Sorbitan trioleate, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polysorbate 20 and polysonoleate 60, Polysonoleate 80, Macrogol 400, Sonolebitan monooleate, Glycerol monostearate, Sorbitan monostearate, Sorbitan monolaurate, Lauromacrogol, Sorbi monopalmitate Emissions and the like are more preferred instrument for example, polysorbate bets 80 are particularly preferred.
[0023] 本発明において、リン脂質は、経口投与用の医薬組成物に用いることができるリン 脂質であればどのようなものであってもよい。例えば、 日本薬局方 (例えば、第十四 改正日本薬局方や第十五改正日本薬局方等)、医薬品添加物規格 (例えば、医薬 品添加物規格 2003)、および Zまたは食品添加物公定書 (例えば、食品添加物公 定書第七版)等に記載されているリン脂質を好ましく用いることができる。具体的には 、例えば、高度精製卵黄レシチン、精製卵黄レシチン、卵黄レシチン、精製大豆レシ チン、大豆レシチン、卵黄リン脂質、部分水素添加大豆リン脂質 (部分水添大豆リン 脂質)、水素添加大豆リン脂質 (水添大豆リン脂質)等を挙げることができる。なかでも 、大豆レシチンが特に好ましい。  [0023] In the present invention, the phospholipid may be any phospholipid that can be used in a pharmaceutical composition for oral administration. For example, the Japanese Pharmacopoeia (for example, the 14th revised Japanese Pharmacopoeia and the 15th revised Japanese Pharmacopoeia, etc.), the Pharmaceutical Additives Standard (for example, the Pharmaceutical Additives Standard 2003), and the Z or Food Additives Official ( For example, phospholipids described in the Food Additives 7th Edition) can be preferably used. Specifically, for example, highly purified egg yolk lecithin, purified egg yolk lecithin, egg yolk lecithin, purified soybean lecithin, soybean lecithin, egg yolk phospholipid, partially hydrogenated soybean phospholipid (partially hydrogenated soybean phospholipid), hydrogenated soybean phospholipid And lipid (hydrogenated soybean phospholipid). Of these, soybean lecithin is particularly preferable.
[0024] 本発明において、糖アルコールは、経口投与用の医薬組成物に用いることができ る糖アルコールであればどのようなものであってもよい。例えば、ソルビトール、キシリ トール、マン-トール等の一般的にソフトカプセル剤の製造に際してカプセル皮膜の 可塑剤として用いられる糖アルコールが好ましく用いられる。特に、本発明における 糖アルコールとしては、ソルビトールが好適である。 [0024] In the present invention, the sugar alcohol can be used in a pharmaceutical composition for oral administration. Any sugar alcohol may be used. For example, sugar alcohols generally used as plasticizers for capsule films in the production of soft capsules such as sorbitol, xylitol, and mannitol are preferably used. In particular, sorbitol is suitable as the sugar alcohol in the present invention.
[0025] 本発明において、水は、経口投与用の医薬組成物に用いることができる水であれ ばどのようなものであってもよい。例えば、常水（例えば、水道水、井水等）、精製水（ 例えば、蒸留水、イオン交換水、純水、 milliQ水、超純水等）、滅菌精製水、注射用 水等の医薬用水が好ましく用いられ、特に精製水が好適である。  [0025] In the present invention, the water may be any water as long as it can be used in a pharmaceutical composition for oral administration. For example, normal water (for example, tap water, well water, etc.), purified water (for example, distilled water, ion exchange water, pure water, milliQ water, ultrapure water, etc.), sterilized purified water, water for injection, etc. Are preferably used, and purified water is particularly preferable.
[0026] 本発明において、最外膜とは、所望によって本発明のカプセルの構成に加えられ る膜であり、最外膜を本発明のカプセルの構成として含む場合、最外膜は最も外側 に位置するものとする。  [0026] In the present invention, the outermost membrane is a membrane that is optionally added to the configuration of the capsule of the present invention. When the outermost membrane is included as the configuration of the capsule of the present invention, the outermost membrane is the outermost membrane. Shall be located.
[0027] 本発明のカプセルは、「所望によって保護膜を最外膜に有していてもよい」ものであ るため、本発明のカプセルの構成に最外膜を含まない場合は、その最小の構成は内 容物と外膜のみとなる。ただし、この場合においても必要に応じ、内容物と外膜の間 に別の構成（以下、中間膜ということがある。）を加えることができる。また、本発明の力 プセルの構成に最外膜を含む場合は、その最小の構成は、例えば、後記図 1に示す ように、内容物、外膜、および最外膜となる。ただし、この場合においても必要に応じ 、内容物と外膜の間に、あるいは外膜と最外膜の間に別の構成（中間膜)を加えるこ とができる。なお、本発明のカプセルの構成に最外膜を含む場合、外膜と最外膜の 少なくとも二つの膜が存在するため、本発明のカプセルは多層膜 (外膜と最外膜の みであれば二層膜)を有するカプセルと!/、うことができる。  [0027] Since the capsule of the present invention has "a protective film may be provided on the outermost film as desired", if the outermost film is not included in the configuration of the capsule of the present invention, the minimum The composition consists only of the contents and the outer membrane. However, even in this case, if necessary, another configuration (hereinafter sometimes referred to as an intermediate film) can be added between the contents and the outer film. When the outermost membrane is included in the configuration of the force capsule of the present invention, the minimum configuration is, for example, the contents, outer membrane, and outermost membrane as shown in FIG. However, even in this case, if necessary, another configuration (intermediate film) can be added between the contents and the outer membrane or between the outer membrane and the outermost membrane. Note that when the capsule of the present invention includes the outermost membrane, there are at least two membranes of the outer membrane and the outermost membrane, and therefore the capsule of the present invention is a multilayer membrane (only the outer membrane and the outermost membrane). And / or capsules with a bilayer membrane).
[0028] 本発明において、最外膜としては、保護膜が用いられる。保護膜の成分としては、 例えば、リン脂質や、アクリル酸ェチル 'メタアクリル酸メチルコポリマーエマルシヨン、 アミノアルキルメタアタリレートコポリマー E、アミノアルキルメタアタリレートコポリマー R S、ェチルセルロース、ェチルセルロース水分散液、カルボキシメチルェチルセル口 ース、タエン酸トリエチル、グリセリン脂肪酸エステル、トリァセチン、ヒドロキシプロピ ノレセノレロース、ヒドロキシプロピノレメチノレセノレロース、ヒドロキシプロピノレメチノレセノレ口 ースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、プロピレ ングリコール、ポリエチレングリコール、ポリビニルァセタールジェチルアミノアセテー ト、ポリビュルピロリドン、メタアクリル酸アクリル酸ェチルコポリマー、メタアクリル酸ェ チル 'メタアクリル酸塩化トリメチルアンモ-ゥムェチルコポリマー、メタアクリル酸コポ リマー L、メタアクリル酸コポリマー LD、メタアクリル酸ジメチルアミノエチル 'メタアタリ ル酸メチルコポリマー、メタアクリル酸メタアクリル酸メチルコポリマー、メチルセルロー ス、酸化チタン、酢酸フタル酸セルロース等が好ましく用いられる。保護膜の成分とし て用いられるこれらの成分は、そのまま用いてもよいし、適当な溶媒 (例えば、後記の 中鎖脂肪酸トリグリセリド等）に溶解して用いてもよい。また、任意の二種以上を組み 合わせて用いてもよい。なお、これら保護膜の成分を用いた膜は、最外膜である保護 膜以外にも、例えば、中間膜として前記した、内容物と外膜の間に、あるいは外膜と 最外膜の間に必要に応じて加えられる別の構成として用いることもできる。 In the present invention, a protective film is used as the outermost film. Examples of protective film components include phospholipids, ethyl acrylate 'methyl methacrylate copolymer emulsion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, ethyl cellulose, and ethyl cellulose dispersion. Solution, carboxymethylethyl cellulose, triethyl taenoate, glycerin fatty acid ester, triacetin, hydroxypropenoresenorelose, hydroxypropenoremethinoresenorelose, hydroxypropinoremethinoresenolate acetate acetate succinate, hydroxypropylmethylcellulose phthalate , Propire Glycol, polyethylene glycol, polyvinylacetal jetylaminoacetate, polybutylpyrrolidone, methacrylic acid ethyl acrylate copolymer, methacrylic acid acrylate trimethylammomethyl copolymer, methacrylic acid Polymer L, methacrylic acid copolymer LD, dimethylaminoethyl methacrylate'methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl cellulose, titanium oxide, and cellulose acetate phthalate are preferably used. These components used as components of the protective film may be used as they are, or may be used after being dissolved in an appropriate solvent (for example, a medium-chain fatty acid triglyceride described later). Moreover, you may use combining arbitrary 2 or more types. In addition to the protective film that is the outermost film, the film using these protective film components is, for example, the intermediate film described above between the contents and the outer film, or between the outer film and the outermost film. It can also be used as another configuration added as needed.
[0029] 本発明のカプセルの構成に、これらの成分を含む保護膜を含めることによって、保 護膜を有さない (外膜が最も外側に位置する)構成の本発明のカプセルに起こりうる、 医薬品にとって望ましくない現象を防ぐことができる。具体的には、例えば、（i)内容 物および Zまたは外膜の酸ィ匕を防いだり（酸化防止）、 (ii)内容物および Zまたは外 膜の水分による変化を防いだり (湿気防止）、 (iii)内容物および Zまたは外膜の光や 紫外線による変化を防いだり（光防止）、 (iv)内容物および Zまたは外膜の成分の移 動を防いだり、（V)本発明のカプセル同士の、または本発明のカプセルと容器の付着 を防いだり (付着防止）、あるいは、（vi)服用後の望ましくない崩壊'溶出を防いだり することができる。 [0029] By including a protective film containing these components in the composition of the capsule of the present invention, it can occur in the capsule of the present invention having a structure having no protective film (the outer film is located on the outermost side). Phenomena that are not desirable for pharmaceuticals can be prevented. Specifically, for example, (i) prevents the contents and Z or outer membrane from oxidizing (antioxidation), and (ii) prevents changes in the content and Z or outer membrane due to moisture (moisture prevention). (Iii) prevents the contents and Z or outer membrane from being changed by light or ultraviolet rays (light prevention), (iv) prevents the contents and Z or outer membrane components from moving, and (V) It is possible to prevent adhesion between capsules or between the capsule of the present invention and a container (anti-adhesion), or (vi) prevent undesirable disintegration and elution after taking.
[0030] 本発明にお ヽて好ま ヽ保護膜は、リン脂質を含有する保護膜である。ここでリン 脂質としては、例えば、前記のリン脂質等を挙げることができる。なかでも、特に大豆 レシチンやその抽出物（例えば、ホスファチジルコリン等）が好ましぐとりわけ大豆レ シチンが好ましい。リン脂質、特に大豆レシチンを含有する保護膜を本発明のカプセ ルの構成に加えることにより、特に付着防止の効果を得ることができ、本発明のカブ セル同士が付着したり、本発明のカプセルとその容器が付着したり、あるいは本発明 のカプセルとその製造に用いる機械が付着したりすることを防ぐことができる。付着の 有無は、カプセル同士、カプセルと容器、あるいはカプセルと機械を接触させることで 確認することができる。リン脂質、特に大豆レシチンを含有する保護膜を設けた本発 明のカプセルは、その製造過程から医療現場への供給過程、さらには服用されるま での保存期間中の 、ずれの期間にお ヽても（とりわけ、製造過程にお!、て)前記のよ うな付着防止効果を発揮することができる。 [0030] The protective film preferred in the present invention is a protective film containing phospholipid. Examples of phospholipids include the phospholipids described above. Of these, soybean lecithin and its extract (for example, phosphatidylcholine) are particularly preferred, and soybean lecithin is particularly preferred. By adding a protective film containing phospholipids, particularly soybean lecithin, to the capsule composition of the present invention, an effect of preventing adhesion can be obtained, and the capsules of the present invention adhere to each other or the capsule of the present invention. And the container thereof, or the capsule of the present invention and the machine used for manufacturing the same can be prevented. The presence or absence of adhesion can be determined by contacting capsules, capsules and containers, or capsules and machines. Can be confirmed. Capsules of the present invention provided with a protective film containing phospholipids, especially soybean lecithin, during the manufacturing process, supply to the medical site, and during the storage period until they are taken, Even in this case (especially during the production process!), The above-mentioned adhesion preventing effect can be exhibited.
[0031] 本発明のカプセルにおいては、内容物、外膜、最外膜のいずれの構成に関しても [0031] In the capsule of the present invention, the composition of the contents, the outer membrane, and the outermost membrane
、その他の添加物を加えることができる。 Other additives can be added.
[0032] 例えば、本発明において外膜は、「蛋白質、多価アルコール、非イオン性界面活性 剤および水を含有し、さらにリン脂質および Zまたは糖アルコールを含有して 、ても よい組成物」からなるものである力 力かる組成物にはこれらの明示した成分以外に も、例えば、香料 (例えば、ハツ力油、桂皮油、ストロベリーその他の果実エッセンスや フレーバー等）、防腐剤 (例えば、パラヒドロキシ安息香酸ェチル、パラヒドロキシ安息 香酸プロピル等）、色素（例えば、黄色 4号、黄色 5号、赤色 3号、青色 1号、銅クロ口 フィン等）、不透明ィ匕剤 (例えば、二酸化チタン、ベンガラ、三二酸化鉄等）、溶解度 調節剤（例えば、セルロースアセテートフタレート、ヒドロキシプロピルメチルセルロー スのアルカリ金属塩、ヒドロキシメチルセルロースアセテートサクシネートのアルカリ金 属塩、アルギン酸アルカリ塩、ポリアクリル酸アルカリ金属塩、メチルセルロース、カル ボキシメチルセルロース、カゼイン、コラーゲン、寒天末、ポリビュルアルコール、ぺク チン等)等をカ卩えることができる。 [0032] For example, in the present invention, the outer membrane may contain "a protein, a polyhydric alcohol, a nonionic surfactant and water, and may further contain a phospholipid and Z or a sugar alcohol." In addition to these specified ingredients, a powerful composition consisting of, for example, fragrances (eg, pepper oil, cinnamon oil, strawberry and other fruit essences and flavors), preservatives (eg, paraffin) Ethyl hydroxybenzoate, propyl parahydroxybenzoate, etc.), pigments (eg yellow 4, yellow 5, red 3, blue 1, copper black fins, etc.), opaque glazes (eg titanium dioxide) , Bengala, iron sesquioxide, etc.), solubility regulator (eg cellulose acetate phthalate, alkali metal salt of hydroxypropylmethylcellulose, hydroxymethyl) Alkaline metal salt of roulose acetate succinate, alkali metal alginate, alkali metal polyacrylate, methylcellulose, carboxymethylcellulose, casein, collagen, agar powder, polybulu alcohol, pectin, etc.) Can do.
[0033] また例えば、本発明において内容物は、「液状薬物を含有し、さらに多価アルコー ル、糖アルコールおよび Zまたは水を含有して 、てもよ 、組成物」からなるものである 力 力かる組成物にはこれらの明示した成分以外にも、例えば、適当な油脂、溶媒、 添加剤等を加えることができる。油脂としては、例えば、中鎖脂肪酸 [例えば、植物油 (例えば、大豆油、綿実油、サフラワー油、トウモロコシ油、ォリーブ油、ヤシ油、シソ 油、エゴマ油等）、魚油（例えば、タラ肝油等)等]、中鎖脂肪酸トリグリセリド (medium- chain triglycerides： MCT) [例えば、パナセート（商品名、日本油脂社製）、 ODO ( 商品名、 日清製油社製)等]、およびィ匕学合成トリグリセリド類 [例えば、 2—リノレオイ ルー 1, 3—ジォクタノィルグリセロール（8L8)、 2—リノレオイル一 1, 3—ジデカノィ ルグリセロール（10L10)等の既知組成トリグリセリドゃ構造脂質等]等が挙げられる。 これらの油脂は、それぞれ単独で、あるいは二種以上を組み合わせて用いてもよい。 溶媒としては、例えば、前記の中鎖脂肪酸や前記の中鎖脂肪酸トリグリセリド等を用 いることもできるし、水 (例えば、注射用蒸留水、精製水等)等を用いることもできる。こ れらの溶媒は、それぞれ単独で、あるいは二種以上を組み合わせて用いてもよい。 添加剤としては、一般的に経口投与製剤に用いられる添加剤であれば特に限定なく 用いることができる。特に経口投与用の医薬組成物、とりわけソフトカプセル製剤や 経口液剤に用いられる添加剤 (例えば、防腐剤、保存剤、界面活性剤、可溶化剤、 乳化剤、溶剤、 PH調節剤、緩衝剤、懸濁剤、粘稠剤、安定化剤、溶解補助剤等)等 が好ましく用いられる。これらの添加剤は、それぞれ単独で、あるいは二種以上を組 み合わせて用いてもよい。例えば、防腐剤や保存剤としては、例えば、安息香酸、安 息香酸ナトリウム、ソルビン酸ナトリウム、パラベン類 (例えば、パラォキシ安息香酸ェ チル、パラォキシ安息香酸プチル、ノ ォキシ安息香酸プロピル等)等を用いること ができる。界面活性剤や可溶化剤、あるいは乳化剤や溶剤としては、例えば、ヒドロ キシプロピルメチルセルロース（ヒプロメロース）、ポリビュルピロリドン、ショ糖脂肪酸 エステル、ポリオキシエチレン硬化ヒマシ油類、ポリソルベート 80、ポリエチレングリコ ール、グリセリン、エタノール、プロピレングリコール、水（例えば、精製水、注射用蒸 留水等)等を用いることができる。 PH調節剤や緩衝剤としては、例えば、無機酸また は無機塩基 (例えば、塩酸、水酸化ナトリウム、水酸ィ匕カリウム、炭酸水素ナトリウム等 )、あるいは有機酸 (例えば、クェン酸、リンゴ酸、酒石酸、コハク酸等)またはその塩 類等を用いることができる。 pHの調整は、一般に経口液剤の技術分野で汎用されて V、る pH調整方法またはこれに準ずる方法に従って行えばょ 、。 pH調節剤や緩衝剤 としては、弱酸 [例えば、リン酸、炭酸、ホウ酸、亜硫酸、有機スルホン酸、炭素数 2〜 6の有機カルボン酸（例えば、 1〜3価の炭素数 2〜6の有機カルボン酸、すなわち、 炭素数 2〜6の脂肪族モノカルボン酸、ジカルボン酸またはトリカルボン酸等）、また はその他の有機酸等]の金属塩 [例えば、一価のアルカリ金属塩 (例えば、ナトリウム 塩、カリウム塩、リチウム塩、ルビジウム塩、セシウム塩、フランシウム塩等)等]や金属 水酸化物 [例えば、一価のアルカリ金属水酸化物（例えば、水酸化ナトリウム、水酸ィ匕 カリウム、水酸化リチウム、水酸化ルビジウム、水酸化セシウム、水酸化フランシウム 等)等]等も用いることができる。これらを組み合わせて用いれば、液状薬物として（2 R)—2—プロピルオクタン酸を用いた際に、オイルの性状を有する（2R)—2—プロピ ルオクタン酸を水性の内容物とすることができる。懸濁剤や粘稠剤としては、例えば、 アラビアゴム、結晶セルロース、ビーガム、キサンタンガム、ゼラチン、メトロースおよび その可食性塩、カルメロースおよびその可食性塩等を用いることができる。安定化剤 としては、例えば、ェデト酸の可食性塩、塩ィ匕ナトリウム、ピロ亜硫酸の可食性塩等を 用いることができる。溶解補助剤としては、例えば、シクロデキストリンやアルギニン等 を用いることができる。これらの添加剤は、一般的に経口投与製剤に通常用いられる 割合で配合される。また、上記以外にも、公知の文献、例えば、薬事日報社 2000年 刊「医薬品添加物事典」（日本医薬品添加剤協会編集)等に記載されているような添 加剤を用いることもできる。 [0033] Further, for example, in the present invention, the content is composed of "a composition containing a liquid drug and further containing a polyhydric alcohol, a sugar alcohol and Z or water". In addition to these specified components, for example, appropriate oils and fats, solvents, additives and the like can be added to the powerful composition. Examples of fats and oils include medium chain fatty acids [eg, vegetable oil (eg, soybean oil, cottonseed oil, safflower oil, corn oil, olive oil, coconut oil, perilla oil, sesame oil, etc.), fish oil (eg, cod liver oil, etc.) Etc.], medium-chain triglycerides (MCT) [for example, panacet (trade name, manufactured by Nippon Oil & Fats Co., Ltd.), ODO (trade name, manufactured by Nisshin Oil Co., Ltd.), etc.], and synthetic synthetic triglycerides [For example, triglycerides having a known composition such as 2-linoleoyl 1,3-dioctanol glycerol (8L8), 2-linoleoyl 1,3-dideanol glycerol (10L10), etc.] and the like. These fats and oils may be used alone or in combination of two or more. As the solvent, for example, the above medium chain fatty acid, the above medium chain fatty acid triglyceride and the like can be used, and water (for example, distilled water for injection, purified water, etc.) and the like can also be used. These solvents may be used alone or in combination of two or more. The additive can be used without particular limitation as long as it is an additive generally used for oral preparations. In particular pharmaceutical compositions for oral administration, especially additives used in soft capsule formulation and oral solution (e.g., preservatives, preservative, surface active agents, solubilizing agents, emulsifiers, solvents, P H modifiers, buffering agents, suspension Suspending agents, thickeners, stabilizers, solubilizers, etc.) are preferably used. These additives may be used alone or in combination of two or more. For example, as preservatives and preservatives, for example, benzoic acid, sodium benzoate, sodium sorbate, parabens (e.g., ethyl oxybenzoate, ptyl parabenzoate, propyl noxybenzoate, etc.), etc. Can be used. Surfactants, solubilizers, emulsifiers and solvents include, for example, hydroxypropyl methylcellulose (hypromellose), polybulurpyrrolidone, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol, Glycerin, ethanol, propylene glycol, water (for example, purified water, distilled water for injection, etc.) can be used. The P H modifiers or buffering agents, for example, an inorganic acid or an inorganic base (e.g., hydrochloric acid, sodium hydroxide, Mizusani匕potassium, sodium hydrogen carbonate, etc.), organic acids (e.g., Kuen, malic , Tartaric acid, succinic acid and the like) or salts thereof. The pH adjustment is generally used in the technical field of oral liquid preparations V, and should be performed according to a pH adjustment method or a similar method. pH adjusters and buffering agents include weak acids [for example, phosphoric acid, carbonic acid, boric acid, sulfurous acid, organic sulfonic acid, organic carboxylic acids having 2 to 6 carbon atoms (for example, 1 to 3 valent carbon atoms having 2 to 6 carbon atoms) Metal salts of organic carboxylic acids, that is, aliphatic monocarboxylic acids, dicarboxylic acids or tricarboxylic acids having 2 to 6 carbon atoms, or other organic acids] [for example, monovalent alkali metal salts (for example, sodium Salts, potassium salts, lithium salts, rubidium salts, cesium salts, francium salts, etc.)] or metal hydroxides [for example, monovalent alkali metal hydroxides (for example, sodium hydroxide, potassium hydroxide, water, etc.) Lithium oxide, rubidium hydroxide, cesium hydroxide, francium hydroxide Etc.) etc.] can also be used. When these are used in combination, when (2R) -2-propyloctanoic acid is used as a liquid drug, (2R) -2-propyloctanoic acid having the properties of an oil can be made into an aqueous content. . As the suspending agent or thickening agent, for example, gum arabic, crystalline cellulose, bee gum, xanthan gum, gelatin, metrose and its edible salt, carmellose and its edible salt can be used. As the stabilizer, for example, an edible salt of edetic acid, sodium chloride salt, an edible salt of pyrosulfite, or the like can be used. As the solubilizer, for example, cyclodextrin or arginine can be used. These additives are generally blended in proportions usually used for oral preparations. In addition to the above, additives such as those described in publicly known documents, for example, “Pharmaceutical Additives Encyclopedia” (edited by the Japan Pharmaceutical Additives Association) published in 2000, etc., can be used.
[0034] さらにまた、本発明における最外膜には、前記した保護膜の成分の他、内容物や 外膜に加えてもよい前記の添加物等をカ卩えることもできる。  [0034] Furthermore, in the outermost film in the present invention, in addition to the above-described components of the protective film, the above-mentioned additives that may be added to the contents and the outer film can be included.
[0035] 本発明のカプセルにおいては、前記した各成分の好ましい例を含むカプセルが好 ましぐ前記した各成分の好ましい例の組み合わせを含むカプセルがより好ましい。と りわけ、「(A) (2R)—2—プロピルオクタン酸を含有し、さらにグリセリン、ソルビトール および Zまたは水を含有していてもよい組成物を内容物とし、（B)ゼラチン、グリセリ ン、ポリソルベート 80および水を含有し、さらに大豆レシチンおよび/またはソルビト ールを含有していてもよい組成物を外膜として、所望によってさらに (C)大豆レシチ ンを含有する保護膜を最外膜に有して 、てもよ 、構成を有する経口投与用カプセル 」が好適である。  [0035] In the capsule of the present invention, a capsule containing a preferable example of each component described above is preferable, and a capsule containing a combination of the preferable examples of each component described above is more preferable. In particular, “(A) (2R) -2-propyloctanoic acid and a composition that may further contain glycerin, sorbitol and Z or water is used as the content, and (B) gelatin, glycerin. , Polysorbate 80 and water, and a composition that may further contain soy lecithin and / or sorbitol as an outer membrane, and (C) a protective membrane containing soy lecithin as the outermost membrane if desired. However, a capsule for oral administration having a constitution ”is preferable.
[0036] 前記したように、かかるカプセルは、これらの構成ならびに組成を満たす経口投与 用のカプセルであればよぐ特にソフトカプセルであることが好ましい。すなわち、本 発明における内容物と外膜と最外膜が、それぞれソフトカプセルの内容液とカプセル 皮膜とコーティング層に相当するものが好ま 、。  [0036] As described above, the capsule is preferably a soft capsule as long as it is a capsule for oral administration satisfying these configurations and compositions. That is, it is preferable that the contents, outer film, and outermost film in the present invention correspond to the content liquid, the capsule film, and the coating layer of the soft capsule, respectively.
[0037] 本発明のカプセルにおいて、その各々の成分の含量は、所望の剤形を成型しうる 量であれば特に限定されない。以下、ソフトカプセルの構成を有する本発明のカプセ ル (以下、本発明のソフトカプセルと略記する場合がある。）の好ましい一例として「（ A) (2R)—2—プロピルオクタン酸を含有し、さらにグリセリン、ソルビトールおよび Z または水を含有していてもよい組成物を内容物とし、（B)ゼラチン、グリセリン、ポリソ ルベート 80および水を含有し、さらに大豆レシチンおよび/またはソルビトールを含 有して 、てもよ 、組成物を外膜として、所望によってさらに (C)大豆レシチンを含有 する保護膜を最外膜に有して 、てもよ 、構成を有する経口投与用ソフトカプセル」（ 以下、（2R)— 2—プロピルオクタン酸を含有する本発明のソフトカプセルと略記する 場合がある。）を挙げ、その各々の成分の含量を例示する。（2R)—2—プロピルオタ タン酸以外の液状薬物を用いる場合も、以下の例示に準じればよい。 [0037] In the capsule of the present invention, the content of each component is not particularly limited as long as it is an amount capable of forming a desired dosage form. Hereinafter, as a preferred example of the capsule of the present invention having a soft capsule structure (hereinafter sometimes abbreviated as “soft capsule of the present invention”), “( A) The composition contains (2R) -2-propyloctanoic acid and may further contain glycerin, sorbitol and Z or water, and (B) gelatin, glycerin, polysorbate 80 and water. And soy lecithin and / or sorbitol, the composition as an outer membrane, and optionally (C) a protective membrane containing soy lecithin in the outermost membrane. The composition of each component is exemplified by “a soft capsule for oral administration having a structure” (hereinafter, sometimes abbreviated as the soft capsule of the present invention containing (2R) -2-propyloctanoic acid). . When using a liquid drug other than (2R) -2-propylotatanic acid, the following examples may be used.
外膜を成す組成物中のゼラチンの含量は、後述するソフトカプセルの製造方法に 付すことで、内容物を覆うに充分な外膜を形成しうる量であればよぐ製造しようとす るソフトカプセルの内容物の量や外膜の厚さに応じて適宜変更すればよい。例えば、 1ソフトカプセルあたりに内容物として 300mgの（2R)— 2 プロピルオクタン酸のみ を含有するソフトカプセルを製造する場合、ゼラチンの含量は、 1ソフトカプセルあた り約 50mg〜約 150mg力 S好ましく、約 60mg〜約 130mg力 Sより好ましく、約 80mg〜 約 l lOmgが特に好ましい。とりわけ、 1ソフトカプセルあたり約 92. 3mgのゼラチンが 好適である。また、例えば、 1ソフトカプセルあたりに内容物として lOOmgの（2R) - 2 プロピルオクタン酸のみを含有するソフトカプセルを製造する場合、ゼラチンの含 量は、 1ソフトカプセルあたり約 20mg〜約 90mgが好ましぐ約 30mg〜約 80mg力 Sよ り好ましく、約 40mg〜約 70mg力特に好ましい。とりわけ、 1ソフトカプセルあたり約 5 0. Omgのゼラチンが好適である。外膜におけるゼラチンの含量をこれら好ましい範 囲に設定することにより、カプセル皮膜の厚さ (外膜の厚さ）を、腹部厚さで約 0. 05 mm〜約 0. 5mm (より好ましくは約 0. 1mm〜約 0. 45mm、特に好ましくは約 0. 14 mm〜約 0. 37mm)の範囲に、第一接合部厚さで約 0. 1mm〜約 0. 55mm (より好 ましくは約 0. 15mm〜約 0. 5mm、特に好ましくは約 0. 18mm〜約 0. 42mm)の 範囲に、第二接合部厚さで約 0. 05mm〜約 0. 5mm (より好ましくは約 0. lmm〜 約 0. 4mm、特に好ましくは約 0. 14mm〜約 0. 36mm)の範囲に調節することがで きる。なお、カプセルの大きさは、カプセルの型をどのような型にするかでも異なるが 、例えば、 No. 5オーパル型であれば、長径は 12. 9mm±0. 6mmの範囲内、短径 は 7. 8mm±0. 3mmの範囲内であることが好ましい。また、例えば、 No. 2オーバ ル型であれば、長径は 9. 2mm±0. 5mmの範囲内、短径は 5. 8mm±0. 2mmの 範囲内であることが好ましい。後述の実施例にも記載するように、 No. 5オーパル型 は（2R)— 2—プロピルオクタン酸のみを 300mg含有するソフトカプセルを製造する 際に好適な型であり、 No. 2オーパル型は、（2R)— 2—プロピルオクタン酸のみを 1 OOmg含有するソフトカプセルを製造する際に好適な型である。カプセル皮膜の腹部 、第一接合部、第二接合部の何れかの厚さを、より好ましくは全ての厚さを前記の範 囲内となるように調節し、さらに後述するように外膜におけるソルビトールとグリセリン の含量、ならびに含水率を好ましい範囲に調節することで、（2R)— 2—プロピルオタ タン酸を含有する本発明のソフトカプセルに、割れ荷重試験で約 150-ユートン (以 下、 Nと略記する。）以上（より好ましくは約 150N〜約 400N、特に好ましくは約 180 N〜約 350N、とりわけ好ましくは約 193N〜約 310N)の強度を付与することができ、 (2R)— 2—プロピルオクタン酸を含有する本発明のソフトカプセルに「咀嚼時に内容 物が容易に漏出することがない」という特性を付与することが可能である。なお、割れ 荷重試験は、公知の方法で行うことができる。具体的には、例えば、島津小型卓上試 験機（EZ Test— 500N)のような、サンプルを二枚の平行な面で上下から圧縮可能 な加圧機を用いて測定することができる。 The content of gelatin in the composition forming the outer membrane is determined by applying it to the soft capsule manufacturing method described later, so long as it is an amount that can form an outer membrane sufficient to cover the contents. What is necessary is just to change suitably according to the quantity of the content, and the thickness of an outer membrane. For example, when producing soft capsules containing only 300 mg of (2R) -2-propyloctanoic acid as the content per soft capsule, the gelatin content is about 50 mg to about 150 mg force per soft capsule, preferably about 60 mg. To about 130 mg force S is more preferred, with about 80 mg to about 1 lOmg being particularly preferred. In particular, about 92.3 mg of gelatin per soft capsule is preferred. For example, when producing soft capsules containing only lOOmg of (2R) -2-propyloctanoic acid as a content per soft capsule, the gelatin content is preferably about 20 mg to about 90 mg per soft capsule. 30 mg to about 80 mg force S is more preferred, and about 40 mg to about 70 mg force is particularly preferred. In particular, about 50.Omg gelatin per soft capsule is preferred. By setting the gelatin content in the outer membrane within these preferred ranges, the capsule membrane thickness (outer membrane thickness) is about 0.05 mm to about 0.5 mm in abdominal thickness (more preferably about 0.1 mm to about 0.45 mm, particularly preferably about 0.14 mm to about 0.37 mm), with a first joint thickness of about 0.1 mm to about 0.55 mm (more preferably about In the range of 0.15 mm to about 0.5 mm, particularly preferably about 0.18 mm to about 0.42 mm, the second joint thickness is about 0.05 mm to about 0.5 mm (more preferably about 0.1 mm). To about 0.4 mm, particularly preferably about 0.14 mm to about 0.36 mm). The size of the capsule differs depending on the type of capsule. For example, in the case of No. 5 opal type, the major axis is within the range of 12.9 mm ± 0.6 mm, and the minor axis Is preferably in the range of 7.8 mm ± 0.3 mm. For example, in the case of No. 2 oval type, the major axis is preferably in the range of 9.2 mm ± 0.5 mm and the minor axis is preferably in the range of 5.8 mm ± 0.2 mm. As described in the examples below, No. 5 opal type is a suitable type for producing soft capsules containing only 300 mg of (2R) -2-propyloctanoic acid. (2R) —This type is suitable for producing soft capsules containing only 1 OO mg of 2-propyloctanoic acid. The thickness of any one of the abdominal part, the first joint part, and the second joint part of the capsule film is more preferably adjusted so that all the thicknesses are within the above-mentioned range, and sorbitol in the outer membrane as described later. The soft capsule of the present invention containing (2R) -2-propylotatanic acid was adjusted to about 150-euton (hereinafter abbreviated as N) by controlling the load of glycerin and glycerin to the preferred range. Or more (more preferably from about 150 N to about 400 N, particularly preferably from about 180 N to about 350 N, particularly preferably from about 193 N to about 310 N), (2R) —2-propyloctane The soft capsule of the present invention containing an acid can be imparted with the characteristic that “the contents do not easily leak during chewing”. The crack load test can be performed by a known method. Specifically, for example, the sample can be measured by using a pressurizer capable of compressing the sample from above and below on two parallel surfaces, such as a Shimadzu small desktop tester (EZ Test-500N).
ここで、外膜の厚さを示すために用いた、「腹部」、「第一接合部」、および「第二接 合部」は、当業者によって通常用いられる用語であり、「腹部」は、ソフトカプセルを成 型する際に内容物充填によって皮膜が最も膨らむ部分を、「第一接合部」は、ソフト力 プセルを成型する際に最初に皮膜用シートが接合する部分を、「第二接合部」は、ソ フトカプセルを成型する際に最後に皮膜用シートが接合する部分を意味する。ここで 皮膜用シートとは、ロータリーダイ法等の一般的に打ち抜き法と称されるソフトカプセ ルの製造法において用いられる、カプセル皮膜の成分を含むシートを意味する。口 一タリーダイ法では、二枚の皮膜用シートをソフトカプセルの形状に合わせたダイ口 ールで成型しつつ内容物を充填することで、任意の形状、例えば、オーパル (oval) 型、ラウンド (round)型、サポジトリー（suppository)型、ォブロング（oblong)型、チ ユーブ (tube)型等のソフトカプセルを製造することができる。腹部、第一接合部、第 二接合部と 、つたカプセル皮膜の各部の厚さは、公知の手法で測定することができ る。例えば、ハサミゃナイフ等の鋭利な刃物を用いてソフトカプセル中央部を輪切り にし、内容物（内容液)を有機溶媒 (例えば、 n キサン、エーテル、アセトン、代替 フロン等)等を用いて洗浄した後、切断面を光学顕微鏡で観察しながらスケール等を 用いて測定することができる。前記したように、カプセル皮膜の腹部、第一接合部、第 二接合部の何れかの厚さを、より好ましくは全ての厚さを前記の範囲内にすることに よって、（2R)—2—プロピルオクタン酸を含有する本発明のソフトカプセルの強度を より向上させることができる。 Here, “abdomen”, “first joint”, and “second joint” used to indicate the thickness of the adventitia are terms commonly used by those skilled in the art, and “abdomen” When forming a soft capsule, the part where the film swells most by filling the contents is formed. The first joint part is the part where the film sheet is first joined when the soft force capsule is molded. “Part” means the part to which the film sheet is finally joined when the soft capsule is molded. Here, the film sheet means a sheet containing a capsule film component used in a soft capsule manufacturing method generally called a punching method such as a rotary die method. In the one-tally die method, the two coating sheets are molded with a die mold that matches the shape of the soft capsule, and the contents are filled, so that any shape, for example, an oval type, round (round) Soft capsules such as) type, suppository type, oblong type, tube type, etc. can be manufactured. Abdomen, first joint, second The thicknesses of the two joints and each part of the capsule capsule film can be measured by a known method. For example, use a sharp knife such as a scissors knife to cut the center of the soft capsule and wash the contents (content liquid) with an organic solvent (for example, n-xane, ether, acetone, alternative chlorofluorocarbon). It can be measured using a scale or the like while observing the cut surface with an optical microscope. As described above, by setting the thickness of any one of the abdominal part, the first joint part, and the second joint part of the capsule film, more preferably, all the thicknesses within the above range, (2R) -2 —The strength of the soft capsule of the present invention containing propyloctanoic acid can be further improved.
[0040] 外膜を成す組成物中のソルビトールの含量は、ゼラチン 100質量部に対して、約 2 0質量部以下であることが好ましぐ実質的にソルビトールを含まな 、ものが特に好ま しい。 [0040] The content of sorbitol in the composition forming the outer membrane is preferably about 20 parts by mass or less with respect to 100 parts by mass of gelatin, and is particularly preferably substantially free of sorbitol. .
[0041] 外膜を成す組成物中のグリセリンの含量は、前記ソルビトールを外膜に含むカゝ否か で変更することが好ましい。具体的には、外膜にソルビトールを含む場合、グリセリン の含有量は、ゼラチン 100質量部に対して、約 20質量部以下であることが好ましい。 外膜にソルビトールを実質的に含まない場合、グリセリンの含有量は、ゼラチン 100 質量部に対して、約 25質量部〜約 40質量部であることが好ましぐ特に、ゼラチン 1 00質量部に対して、約 30質量部であることが好ましい。  [0041] The content of glycerin in the composition forming the outer membrane is preferably changed depending on whether or not the sorbitol is contained in the outer membrane. Specifically, when sorbitol is contained in the outer membrane, the content of glycerin is preferably about 20 parts by mass or less with respect to 100 parts by mass of gelatin. When the outer membrane is substantially free of sorbitol, the content of glycerin is preferably about 25 parts by weight to about 40 parts by weight with respect to 100 parts by weight of gelatin. On the other hand, it is preferably about 30 parts by mass.
[0042] 外膜を成す組成物中の水の含量は、含水率という指標を用いて示すことができる。  [0042] The content of water in the composition forming the outer membrane can be indicated using an index of water content.
含水率は、公知の方法で測定することができる。具体的には、外膜をサンプルとして (最外膜が実質的に水を含まない場合は、外膜と最外膜を併せてサンプルとすること もできる。）、その重量 (乾燥前重量）と、そのサンプルを高温 (例えば、 105°C等)で 乾燥させた後の重量 (乾燥後重量)とを測定し、式  The water content can be measured by a known method. Specifically, the outer membrane is used as a sample (if the outermost membrane does not substantially contain water, the outer membrane and the outermost membrane can be combined into a sample), and its weight (weight before drying) And the weight after drying the sample at a high temperature (for example, 105 ° C) (weight after drying)
[数 1]  [Number 1]
含水率 （％) = { (乾燥前重量一乾燥後重量） Z乾燥前重量 } X I 0 0 によって算出することができる。外膜における水の含量は、含水率で、約 5%〜約 15 %が好ましぐ約 5%〜約 12%がより好ましぐ約 5%〜約 9%が特に好ましい。なか でも、約 5%〜約 8%がより好ましぐ特に、約 5. 6%〜約 7. 3%が好ましい。  Moisture content (%) = {(weight before drying-weight after drying) Z weight before drying} X I 0 0 can be calculated. The content of water in the outer membrane is particularly preferably about 5% to about 9%, preferably about 5% to about 15%, more preferably about 5% to about 12%, in terms of water content. In particular, about 5% to about 8% is more preferable, and about 5.6% to about 7.3% is preferable.
[0043] 外膜を成す組成物中のポリソルベート 80の含量は、ゼラチン 100質量部に対して、 約 0. 01質量部〜約 0. 05質量部であることが好ましぐ特に、ゼラチン 100質量部に 対して、約 0. 025質量部であることが好ましい。 [0043] The content of polysorbate 80 in the composition forming the outer membrane is 100 parts by mass of gelatin, The amount is preferably about 0.01 parts by weight to about 0.05 parts by weight, and particularly preferably about 0.025 parts by weight with respect to 100 parts by weight of gelatin.
[0044] 外膜を成す組成物中の大豆レシチンの含量は、実質的に含まないか、またはゼラ チン 100質量部に対して約 1質量部以下であることが好ましく、実質的に含まな!/、も のが特に好ましい。 [0044] The content of soybean lecithin in the composition forming the outer membrane is preferably substantially not contained or preferably not more than about 1 part by mass with respect to 100 parts by mass of gelatin. Especially preferred is /.
[0045] 内容物を成す組成物中の（2R)— 2 プロピルオクタン酸の含量は、約 30mg〜約 [0045] The content of (2R) -2-propyloctanoic acid in the composition constituting the content is about 30 mg to about
600mg力 S女子ましく、約 50mg〜約 400mg力 り女子ましく、約 lOOmg〜約 300mg力 S特 に好ましぐ約 lOOmgまたは約 300mgがとりわけ好ましい。 600 mg strength S female, about 50 mg to about 400 mg strength female, about lOO mg to about 300 mg strength S, especially about lOOmg or about 300 mg is particularly preferred.
[0046] 内容物を成す糸且成物中のグリセリンの含量は、実質的に含まないか、または（2R) [0046] The content of glycerin in the yarn constituting the content and the composition is substantially free or (2R)
2 プロピルオクタン酸 100質量部に対して約 40質量部以下であることが好ましく It is preferably about 40 parts by mass or less with respect to 100 parts by mass of 2-propyloctanoic acid.
、実質的に含まないものが特に好ましい。 Those which are substantially free of these are particularly preferred.
[0047] 内容物を成す組成物中のソルビトールの含量は、実質的に含まないか、または（2[0047] The content of sorbitol in the composition constituting the content is substantially free of (2
R)— 2—プロピルオクタン酸 100質量部に対して約 20質量部以下であることが好ま しぐ実質的に含まないものが特に好ましい。 R) —2-Propyloctanoic acid is preferably about 20 parts by mass or less, particularly preferably substantially free from 100 parts by mass.
[0048] 内容物を成す糸且成物中の水の含量は、実質的に含まないか、または（2R)— 2 プ 口ピルオクタン酸 100質量部に対して約 20質量部以下であることが好ましぐ実質的 に含まな!/、ものが特に好ま 、。 [0048] The content of water in the yarn and the composition constituting the content may be substantially not contained, or about 20 parts by mass or less with respect to 100 parts by mass of (2R) -2-powder pyroctanoic acid. Substantially virtually free! /, Especially preferred.
[0049] (2R)—2 プロピルオクタン酸を含有する本発明のソフトカプセルにおいては、前 記した各成分の好ま 、例を好ま 、含量で含むソフトカプセルが好ま 、。特に、 前記した各成分の好ま 、例の組み合わせを好ま 、含量で含むソフトカプセルが 好ましい。 [0049] In the soft capsule of the present invention containing (2R) -2 propyloctanoic acid, preference is given to the examples of the above-mentioned components, and soft capsules containing by content are preferred. In particular, preference is given to each of the above-mentioned components, and a combination of examples is preferred, and a soft capsule containing the content is preferred.
[0050] 具体的には、例えば、外膜が、（a)ゼラチン、（b)ゼラチン 100質量部に対して約 2 5質量部〜約 40質量部のグリセリンおよび (c)ゼラチン 100質量部に対して約 0. 01 質量部〜約 0. 05質量部のポリソルベート 80を含有し、かつソルビトールを実質的に 含まないか、またはゼラチン 100質量部に対して約 20質量部以下のソルビトールを 含む、大豆レシチンを実質的に含まない含水率約 5%〜約 15%の組成物力もなるも のが好ましい。なかでも、ソルビトールを実質的に含まないもの（すなわち、（a)ゼラチ ン、（b)ゼラチン 100質量部に対して約 25質量部〜約 40質量部のグリセリンおよび（ c)ゼラチン 100質量部に対して約 0. 01質量部〜約 0. 05質量部のポリソルベート 8 0を含有し、かつソルビトールおよび大豆レシチンを実質的に含まな 、含水率約 5% 〜約 15%の組成物力もなるもの）がより好ましぐ特に、（a)ゼラチン、（b)ゼラチン 10 0質量部に対して約 30質量部のグリセリンおよび (c)ゼラチン 100質量部に対して約 0. 025質量部のポリソルベート 80を含有する含水率約 5%〜約 8%の組成物からな るものが好適である。 [0050] Specifically, for example, the outer membrane contains (a) gelatin, (b) about 25 parts by weight to about 40 parts by weight of glycerin and (c) 100 parts by weight of gelatin with respect to 100 parts by weight of gelatin. Containing about 0.01 parts by weight to about 0.05 parts by weight of polysorbate 80 and substantially free of sorbitol or about 20 parts by weight or less of sorbitol with respect to 100 parts by weight of gelatin, Preferably, the composition is substantially free of soy lecithin and has a water content of about 5% to about 15%. Among them, those substantially free of sorbitol (ie, (a) gelatin, (b) about 25 parts by weight to about 40 parts by weight of glycerin and 100 parts by weight of gelatin and ( c) about 0.1% to about 0.05 parts by weight of polysorbate 80 per 100 parts by weight of gelatin and substantially free of sorbitol and soy lecithin, with a water content of about 5% to about 15 In particular, (a) gelatin, (b) about 30 parts by weight of glycerin with respect to 100 parts by weight of gelatin, and (c) about 0 with respect to 100 parts by weight of gelatin. A composition comprising about 5% to about 8% water content containing 025 parts by weight of polysorbate 80 is preferred.
[0051] また内容物に関していえば、例えば、約 30mg〜約 600mgの (2R) 2 プロピル オクタン酸を含有する組成物からなるものが好ましぐ約 50mg〜約 400mgの (2R) 2—プロピルオクタン酸を含有する組成物からなるものがより好ましぐ約 100mg〜 約 300mgの (2R)—2 プロピルオクタン酸を含有する組成物からなるものが特に好 ましぐ約 lOOmgまたは約 300mgの（2R)—2 プロピルオクタン酸を含有する組成 物からなるものがとりわけ好ましい。なかでも、内容物として、これらの含量の（2R)— 2—プロピルオクタン酸のみを含むものが特に好適である。  [0051] As regards the contents, for example, a composition comprising about 30 mg to about 600 mg of (2R) 2 propyl octanoic acid is preferred, preferably about 50 mg to about 400 mg of (2R) 2 -propyl octane. About 100 mg to about 300 mg of (2R) —a composition containing an acid-containing composition is more preferred. Particularly preferred is a composition containing about 2 mg of propyloctanoic acid, or about 300 mg of (2R). —2 Particularly preferred is a composition comprising propyloctanoic acid. Among them, the content containing only (2R) -2-propyloctanoic acid having these contents is particularly suitable.
[0052] 本発明のカプセルは、公知の製造方法に準じて製造することができる。以下、本発 明のソフトカプセルの好まし 、一例として（2R)— 2—プロピルオクタン酸を含有する 本発明のソフトカプセルを挙げ、その製造方法を具体的に説明する。勿論、（2R)— 2—プロピルオクタン酸以外の液状薬物を用いる場合も、以下の例示に準じて製造 することができる。  [0052] The capsule of the present invention can be produced according to a known production method. Hereinafter, the soft capsule of the present invention is preferred. As an example, the soft capsule of the present invention containing (2R) -2-propyloctanoic acid will be described, and the production method thereof will be specifically described. Of course, when a liquid drug other than (2R) -2-propyloctanoic acid is used, it can be produced according to the following examples.
[0053] (2R)—2 プロピルオクタン酸を含有する本発明のソフトカプセルは、公知のソフト カプセルの製造方法に準じて製造することができる。具体的には、（1)内容物として の「（2R)—2—プロピルオクタン酸を含有し、さらに多価アルコール、糖アルコール および Zまたは水を含有していてもよい組成物」と、 (2)「蛋白質、多価アルコール、 非イオン性界面活性剤および水を含有し、さらにリン脂質および Zまたは糖アルコー ルを含有して 、てもよ 、組成物」を外膜として付与するための皮膜用溶液とを用意し て、例えば、打ち抜き法 (例えば、ロータリーダイ法等)等の公知のカプセル充填法に 付し、さらに得られたカプセルを乾燥することによって製造することができる。なお、（ 2R)— 2—プロピルオクタン酸を含有する本発明のソフトカプセルの構成に最外膜を 含む場合、最外膜の付与は、外膜を付与した後に別途行ってもよいし、また、予め外 膜と最外膜が二層になった皮膜用シートを用いることにより行ってもよい。 [0053] The soft capsule of the present invention containing (2R) -2 propyloctanoic acid can be produced according to a known method for producing soft capsules. Specifically, (1) “a composition containing (2R) -2-propyloctanoic acid, which may further contain a polyhydric alcohol, a sugar alcohol, and Z or water” as the contents; 2) “Contains a composition containing protein, polyhydric alcohol, nonionic surfactant and water, and further containing phospholipid and Z or sugar alcohol” as an outer membrane It can be produced by preparing a coating solution, subjecting it to a known capsule filling method such as a punching method (for example, a rotary die method), and drying the obtained capsule. When the outermost membrane is included in the composition of the soft capsule of the present invention containing (2R) -2-propyloctanoic acid, the outermost membrane may be applied separately after the outer membrane is applied, Outside in advance You may carry out by using the film | membrane sheet | seat in which the film | membrane and the outermost film | membrane became two layers.
[0054] 「（2R)— 2 プロピルオクタン酸を含有し、さらに多価アルコール、糖アルコールお よび Zまたは水を含有していてもよい組成物」は、前記のように、これらの明示した成 分や、所望によって適当な油脂、添加剤、溶媒等を用いて調製することができる。前 記したように、かかる組成物は、適度な流動性 (例えば、ソフトカプセル充填機を用い ての圧入が可能な流動性 (例えば、粘度が約 50000ミリパスカル秒 (mPa' s)以下の 流動性等)等）を有するものであればよぐ液体は勿論のこと、ゲル状の態様を示す 半固体等であってもよい。 (2R) 2—プロピルオクタン酸は化合物単体で液体であ るため、それ自体を単独で内容物（内容液）として用いることが好ま 、。  [0054] "(2R) -2 A composition containing 2 propyloctanoic acid and optionally further containing a polyhydric alcohol, a sugar alcohol, and Z or water" is, as described above, a component having these specified components. It can be prepared using appropriate oils, additives, solvents and the like. As noted above, such compositions have moderate fluidity (e.g., fluidity that can be press-fitted using a soft capsule filling machine (e.g., fluidity with a viscosity of about 50,000 millipascal seconds (mPa's) or less)). Etc.) and the like, as well as liquids and semi-solids showing a gel-like form may be used. (2R) 2-Propyloctanoic acid is a single compound and is a liquid, so it is preferable to use the compound itself as a content (content liquid).
[0055] 「蛋白質、多価アルコール、非イオン性界面活性剤および水を含有し、さらにリン脂 質および Zまたは糖アルコールを含有して 、てもよ 、組成物」を外膜として付与する ための皮膜用溶液は、これらの成分を含有し、かつ溶融状態または溶液状態で薄い 皮膜 (前記の皮膜用シート）に形成することができ、さらに皮膜の形成後に冷却およ び Zまたは乾燥することによって固化するものであれば特に制限なく用いることがで きる。好ましくは、前記した蛋白質、多価アルコールおよび非イオン性界面活性剤に 、適当量の水 (例えば、精製水等)を混合することによってカゝかる皮膜用溶液を調製 することができる。皮膜用溶液の調製工程においては、所望によって、加熱操作を行 つてもよい。なお、以降の操作で乾燥を行うため、ここで混合する水の量は、前記の 外膜の含水率に相当するものよりも多 、ものが用いられる。  [0055] To provide a composition containing "protein, polyhydric alcohol, nonionic surfactant and water, and further containing phospholipid and Z or sugar alcohol" as an outer membrane The film solution of the above contains these components and can be formed into a thin film (the above-mentioned film sheet) in a molten state or a solution state, and further cooled and Z-dried after the film is formed. As long as it solidifies by this, it can be used without particular limitation. Preferably, a coating film solution can be prepared by mixing an appropriate amount of water (for example, purified water) with the above-described protein, polyhydric alcohol and nonionic surfactant. In the step of preparing the film solution, a heating operation may be performed as desired. In addition, since drying is performed in the subsequent operations, the amount of water mixed here is larger than that corresponding to the moisture content of the outer membrane.
[0056] 前記したように、（2R)— 2 プロピルオクタン酸を含有する本発明のソフトカプセル の構成に最外膜を含む場合、最外膜の付与は、外膜を付与した後に別途行ってもよ いし、また予め外膜と最外膜が二層になった皮膜用シートを用いることにより行っても よい。外膜を付与した後に別途最外膜を付与する場合は、乾燥工程に付す前のソフ トカプセル (以下、これら乾燥工程に付す前のソフトカプセルを、乾燥後のソフトカブ セルと区別するために「生球」と称することがある。）を一般的にコーティングと称され る方法に付すことによって行うことができる。コーティングは、コーティングパンに生球 を入れ、パンを回転させながらコーティング液をふりかけ送風し、乾燥させることによ つて行われる。コーティング液には、前記のように最外膜の成分か、あるいはそれを 適当な溶媒に溶解したものを用いればよいが、好ましくは、大豆レシチンを前記中鎖 脂肪酸トリグリセリド (MCT)等に溶解したものを用いればょ 、。 [0056] As described above, when the outermost membrane is included in the configuration of the soft capsule of the present invention containing (2R) -2-propyloctanoic acid, the outermost membrane may be applied separately after the outer membrane is applied. Alternatively, it may be carried out by using a film sheet in which the outer film and the outermost film are previously formed into two layers. When the outermost film is applied separately after the outer film is applied, the soft capsules before being subjected to the drying process (hereinafter referred to as `` soft capsules before being subjected to the drying process '' are distinguished from the soft capsules after being dried. It may be referred to as “live ball”.) By subjecting it to a method generally referred to as coating. Coating is performed by placing a raw ball in a coating pan, sprinkling the coating liquid while rotating the pan, blowing air, and drying. As described above, the coating liquid may contain the outermost film component or What is necessary is just to use what was melt | dissolved in the suitable solvent, However, Preferably, what melt | dissolved soybean lecithin in the said medium chain fatty acid triglyceride (MCT) etc. should be used.
[0057] 一方、予め外膜と最外膜が二層になった皮膜用シートを用いて最外膜を付与する 場合は、前記の皮膜用シートの片面 (ソフトカプセル成型後に外側となる面）に最外 膜の成分か、あるいはそれを適当な溶媒に溶解したものを塗布する等の手段を用い て、予め外膜成分と最外膜成分とが二層になったシートを調製し、それを用いること によりソフトカプセルの生球を得、さらに乾燥させることによって製造することができる 。最外膜の成分として大豆レシチンを用いる場合、皮膜用シートの片面に大豆レシチ ンを前記中鎖脂肪酸トリグリセリド (MCT)等に溶解したものを塗布する方法が好まし く用いられる。 [0057] On the other hand, in the case where the outermost film is applied using a film sheet in which the outer film and the outermost film are two layers in advance, on one side of the film sheet (the outer surface after soft capsule molding) Prepare a sheet with the outer membrane component and the outermost membrane component in two layers in advance by applying the outermost membrane component or a solution of the outer membrane component dissolved in an appropriate solvent. By using it, a soft capsule live sphere can be obtained and further dried. When soy lecithin is used as a component of the outermost membrane, a method in which soy lecithin is dissolved in the medium-chain fatty acid triglyceride (MCT) or the like is preferably used on one side of the coating sheet.
[0058] ソフトカプセルの乾燥方法は、力かるソフトカプセルの形状を維持したまま乾燥可能 なものであればどのような方法でもよ!/、が、タンブラ乾燥と棚乾燥の二工程を組み合 わせて用いる方法が好ましく用いられる。この二つの乾燥工程を行うことにより、形状 が安定した、均一なソフトカプセルを製造することができる。  [0058] The soft capsule drying method may be any method that can be dried while maintaining the strong soft capsule shape! /, But uses a combination of tumbler drying and shelf drying. The method is preferably used. By performing these two drying steps, a uniform soft capsule having a stable shape can be produced.
[0059] タンブラ乾燥は、約 15°C〜約 40°C、好ましくは約 20°C〜約 35°C、特に好ましくは 約 23°C〜約 30°Cで、数時間〜数日間、好ましくは約 0. 5時間〜約 1日、より好ましく は約 1時間〜約 12時間、特に好ましくは約 1. 5時間〜約 6時間かけて行われる。な お、タンブラ乾燥は生球を入れたタンブラを回転させながら行われる力 必要に応じ てこのタンブラに生球と一緒に布や紙、スポンジ等を入れておくことで最外膜の成分 量を所望の量に調節することもできる。  [0059] The tumbler drying is performed at about 15 ° C to about 40 ° C, preferably about 20 ° C to about 35 ° C, particularly preferably about 23 ° C to about 30 ° C, for several hours to several days. Is carried out over a period of about 0.5 hours to about 1 day, more preferably about 1 hour to about 12 hours, particularly preferably about 1.5 hours to about 6 hours. Tumble drying is performed by rotating the tumbler containing the live sphere. If necessary, cloth, paper, sponge, etc. are placed in this tumbler together with the live sphere to reduce the amount of the outermost membrane component. It can also be adjusted to the desired amount.
[0060] 棚乾燥は、約 10°C〜約 40°C、好ましくは約 15°C〜約 35°C、特に好ましくは約 20 °C〜約 30°Cで、数時間〜数日間、好ましくは約 6時間〜約 4日間、より好ましくは約 1 2時間〜約 3日間、特に好ましくは約 1日〜約 2日間かけて行われる。  [0060] Shelf drying is preferably from about 10 ° C to about 40 ° C, preferably from about 15 ° C to about 35 ° C, particularly preferably from about 20 ° C to about 30 ° C, for several hours to several days. Is performed for about 6 hours to about 4 days, more preferably for about 12 hours to about 3 days, particularly preferably for about 1 day to about 2 days.
[0061] 乾燥後、ソフトカプセルは、所望によって任意の包装が施される。かかる包装は、例 えば、個別に包装されていない非単位包装 (例えば、バルタ包装やボトル包装)等の ような気密包装であってもよいし、例えば、熱接着性フィルムで医薬品をシールする、 いわゆるヒートシールのような密封包装であってもよい。ヒートシールには、 PTP (Pre ss Through Pack)包装や SP (Strip Package)包装等が含まれる力 特に、 PT P包装が好ましい。 PTP包装の材質としては、 PCTFE (ポリクロ口トリフルォロェチレ ン）、 PVC (ポリビュルクロライド）、 PVDC (ポリビ-リデンク口ライド）コート PVC (ポリ ビュルクロライド）、 ρρ (ポリプロピレン）、ポリプロピレン系多層等が挙げられる。 ΡΤΡ 包装は、アルミ包装と併用することが好ましい。さらに本発明のカプセルは、 ΡΤΡ包 装や SP包装を施した後、その一定数量をポリエチレンやアルミ箔で二次包装 ( 、わ ゆるピロ一包装）してもよい。 [0061] After drying, the soft capsules are optionally wrapped as desired. Such a package may be, for example, a hermetic package such as a non-unit package (for example, Balta package or bottle package) that is not individually packaged. For example, a medicine is sealed with a heat-adhesive film. It may be sealed packaging such as so-called heat sealing. The heat seal includes PTP (Press Through Pack) packaging and SP (Strip Package) packaging. P packaging is preferred. PTP packaging materials include PCTFE (polychlorinated trifluoroethylene), PVC (polybulur chloride), PVDC (polyvinyl chloride) coated PVC (polyburized chloride), ρρ (polypropylene), polypropylene multilayer, etc. Is mentioned. ΡΤΡ Packaging is preferably used in combination with aluminum packaging. Furthermore, the capsule of the present invention may be subjected to bag packaging or SP packaging, and then a certain amount thereof may be secondarily wrapped with polyethylene or aluminum foil (so-called pillow packaging).
[0062] (2R) 2 プロピルオクタン酸を含有する本発明のソフトカプセルの製造にあたり 、皮膜用溶液の成分として、前記のように非イオン性界面活性剤 (好ましくはポリソル ペート 80)を共存させることで、該皮膜用溶液を消泡せしめることができる。ここで、「 消泡」とは、「皮膜用溶液の泡立ち（気泡の発生）を抑えること」ならびに「存在する気 泡を消すこと」という両方の意味を有する。従って、気泡が消えるまでの時間を必要と せず、製造時間の大幅な短縮が可能となる。このように製造された、 (2R) 2—プロ ピルオクタン酸を含有する本発明のソフトカプセルは、製造工程にお ヽてカプセル皮 膜に気泡が混入することがないので、カプセル皮膜 (外膜）に気泡を含まず、均一な 厚さ、均一な組成のカプセル皮膜を有する（2R)—2—プロピルオクタン酸含有ソフト カプセルとして臨床現場への安定供給が可能である。かかるソフトカプセルは、均一 な厚さ、均一な組成のカプセル皮膜を有するので、服用時にムラなく安定した薬理効 果を示すことができ、さらに、輸送や保存等の医薬品供給過程において「ヒビ」や「割 れ」が発生することもないし、例えば、高齢者等が誤って該ソフトカプセルを咀嚼した 際にも内容物である（2R)— 2—プロピルオクタン酸が容易に漏出することもない。加 えて、このように製造された、（2R)— 2—プロピルオクタン酸を含有する本発明のソフ トカプセルは、国際公開第 2005Z120490号パンフレットに記載されたような、医薬 品としての優れた特性を全て満たすものである。すなわち、前記のように「咀嚼時に 内容物が容易に漏出することがな 、」 、う特性を有するばかりか、「胃内易崩壊性 である」、「速溶性である」、「溶出遅延が起こらな ヽ」 t ヽぅ特性をも併せ持つ。  [0062] In the production of the soft capsule of the present invention containing (2R) 2-propyloctanoic acid, a nonionic surfactant (preferably polysorbate 80) is allowed to coexist as a component of the film solution as described above. The film solution can be defoamed. Here, “defoaming” has both the meanings of “suppressing foaming (generation of bubbles) of the film solution” and “extinguishing existing bubbles”. Therefore, it does not require time until the bubbles disappear, and the manufacturing time can be greatly reduced. The soft capsule of the present invention containing (2R) 2-propyloctanoic acid produced in this way has no air bubbles mixed into the capsule membrane during the production process. It can be stably supplied to clinical sites as a (2R) -2-propyloctanoic acid-containing soft capsule with no capsule, uniform thickness, and uniform capsule film. Such a soft capsule has a capsule film with a uniform thickness and a uniform composition, so that it can exhibit a stable pharmacological effect without unevenness when taken, and in the drug supply process such as transportation and storage, `` crack '' and `` For example, when the elderly or the like accidentally chews the soft capsule, the content (2R) -2-propyloctanoic acid does not easily leak. In addition, the soft capsule of the present invention containing (2R) -2-propyloctanoic acid thus produced has excellent properties as a pharmaceutical product as described in International Publication No. 2005Z120490 pamphlet. All of these are satisfied. That is, as described above, “the contents cannot be easily leaked out during mastication”, and not only have the characteristics of “easily disintegrating in the stomach”, “fast dissolving”, “elution delaying” It also has the characteristics of “not happening”.
[0063] ここで、 「胃内易崩壊性である」 t 、う特性は、崩壊試験法で確認することができる。  [0063] Here, the characteristics of "easily disintegrating in the stomach" can be confirmed by a disintegration test method.
崩壊試験法は、公知の方法を用いることができる。例えば、一般的にカプセルの崩 壊試験法として知られた方法、特に各国の薬局方収載の崩壊試験法、とりわけ日本 薬局方収載の崩壊試験法、なかでも第十四改正日本薬局方に収載の崩壊試験法 で行うことが好ましい。前記のように製造された（2R)—2—プロピルオクタン酸を含有 する本発明のソフトカプセルは、崩壊試験法で約 3分〜約 10分、より好ましくは約 5 分〜約 8分、特に好ましくは約 5. 7分〜約 6. 3分の崩壊時間を示すので、「胃内易 崩壊性である」 、うことができる。 A well-known method can be used for the disintegration test method. For example, a method generally known as a capsule disintegration test method, particularly a disintegration test method listed in each country's pharmacopoeia, especially Japan It is preferable to use the disintegration test method listed in the pharmacopoeia, particularly the disintegration test method listed in the 14th revised Japanese pharmacopoeia. The soft capsule of the present invention containing (2R) -2-propyloctanoic acid prepared as described above has a disintegration test method of about 3 minutes to about 10 minutes, more preferably about 5 minutes to about 8 minutes, particularly preferably. Shows a disintegration time of about 5.7 minutes to about 6.3 minutes, so it can be “disintegrated easily in the stomach”.
[0064] 「速溶性である」 t ヽぅ特性は、溶出試験法で確認することができる。溶出試験法は 、公知の方法を用いることができる。例えば、一般的に錠剤やカプセル剤等の内用 固形製剤の溶出試験法として知られた方法、特に各国の薬局方収載の溶出試験法 、とりわけ日本薬局方収載の溶出試験法、なかでも第十四改正日本薬局方に収載の 溶出試験法等に従って行うことが好ましい。具体的には、以下に記載のように日本薬 局方溶出試験第 2法のパドル法によって行うことが好ましい。 [0064] The "fast dissolution" t ヽ ぅ characteristic can be confirmed by a dissolution test method. As the dissolution test method, a known method can be used. For example, a method generally known as a dissolution test method for internal solid preparations such as tablets and capsules, especially a dissolution test method listed in the pharmacopoeia of each country, especially a dissolution test method listed in the Japanese pharmacopoeia, It is preferable to carry out in accordance with the dissolution test method listed in the Fourth Revised Japanese Pharmacopoeia. Specifically, as described below, the paddle method of the Japanese Pharmacopoeia Dissolution Test Method 2 is preferably performed.
[0065] mm  [0065] mm
<試験方法 >  <Test method>
第十四改正日本薬局方溶出試験法第 2法 (パドル法）；  14th revised Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method);
<試験条件 >  <Test conditions>
回 数： 50rpm〜75rpm；  Number of times: 50 rpm to 75 rpm;
試験液： 0. O5mol/L リン酸一水素ニナトリウム ZO. 025mol/L クェン酸緩衝 液 (pH 8. 0)；  Test solution: 0. O5mol / L disodium monohydrogen phosphate ZO. 025mol / L citrate buffer (pH 8.0);
液量： 900mL ;  Liquid volume: 900 mL;
温度： 37°C。  Temperature: 37 ° C.
[0066] 前記のように製造された（2R)— 2—プロピルオクタン酸を含有する本発明のソフト カプセルは、溶出試験法で、試験開始 30分後の溶出率が約 60%以上 (約 60%〜 約 100%)、好ましくは約 80%以上 (約 80%〜約 100%)、より好ましくは約 90%以 上 (約 90%〜約 100%)であるので、「速溶性である」ということができる。  [0066] The soft capsules of the present invention containing (2R) -2-propyloctanoic acid produced as described above have a dissolution rate of about 60% or more (about 60%) 30 minutes after the start of the test by the dissolution test method. % To about 100%), preferably about 80% or more (about 80% to about 100%), more preferably about 90% or more (about 90% to about 100%). It can be said.
[0067] なお、溶出率とは、溶出試験に用いる 1カプセル中の薬物の量を 100として、溶出 試験の試験開始から任意の時間経過後に試験液中に溶出した薬物の量をいう。「試 験開始 30分後の溶出率」とは、溶出試験を 30分間行った際の溶出率をいう。溶出し た薬物の量は、紫外部の吸光度を測定することにより求めることができ、例えば、高 速液体クロマトグラフィー法等によって求めることができる。溶出試験は、 (2R) 2— プロピルオクタン酸を含有する本発明のソフトカプセルの製造後いつ行っても力まわ ないが、例えば、実質的に製造直後の時点 (例えば、製造直後〜製造後 10日以内 等、好ましくは製造直後〜製造後 5日以内等、より好ましくは製造直後〜 3日以内等 、特に好ましくは、製造直後〜 24時間以内等）に測定することが好ましい。 [0067] The dissolution rate refers to the amount of drug eluted in the test solution after an arbitrary period of time has elapsed since the start of the dissolution test, where the amount of drug in one capsule used in the dissolution test is 100. “Dissolution rate 30 minutes after the start of the test” refers to the dissolution rate after 30 minutes of dissolution test. The amount of drug eluted can be determined by measuring the absorbance in the ultraviolet region. It can be determined by high-speed liquid chromatography. The dissolution test can be performed at any time after the production of the soft capsule of the present invention containing (2R) 2-propyloctanoic acid. For example, the dissolution test is substantially immediately after production (for example, immediately after production to 10 days after production). Etc., preferably immediately after production to within 5 days after production, more preferably immediately after production to within 3 days, etc., particularly preferably immediately after production to within 24 hours.
[0068] 「溶出遅延が起こらない」という特性は、（2R)— 2 プロピルオクタン酸を含有する 本発明のソフトカプセルを任意の期間保存した後に、前記の溶出試験に付し、初期 値と比較することで確認することができる。ここで初期値とは、実質的に製造直後の時 点で該ソフトカプセルを前記の溶出試験に付すことで得られる値を意味する。溶出遅 延が起こらないかどうかを確認するための保存の条件は特に限定されないが、例え ば、通常当業者によって行われるように室温であってもよいし、一般的に苛酷試験と 称されるように、高温および Zまたは高湿の条件であってもよい。高温および Zまた は高湿の条件にすることで、室温における長期間の保存の結果を、より短期間で得る ことができる。溶出遅延の程度は変化率という指標を用いて表すことができる。変化 率（％)は、式 [0068] The characteristic that “elution delay does not occur” is that the soft capsule of the present invention containing (2R) -2-propyloctanoic acid is stored for an arbitrary period, and then subjected to the dissolution test described above and compared with the initial value. This can be confirmed. Here, the initial value means a value obtained by subjecting the soft capsule to the dissolution test substantially immediately after production. Storage conditions for confirming whether elution delay does not occur are not particularly limited. For example, it may be room temperature as is usually performed by those skilled in the art, and is generally referred to as a severe test. As such, high temperature and Z or high humidity conditions may be used. By using high temperature and Z or high humidity conditions, the result of long-term storage at room temperature can be obtained in a shorter period of time. The degree of elution delay can be expressed using an index of change rate. The rate of change (%) is the formula
[数 2]  [Equation 2]
変化率 （％) = { ( Λ - Β ) /A ) X 1 0 0  Rate of change (%) = {(Λ-)) / A) X 1 0 0
A ：初期値 （溶出率） ； B ：任意の期問の保存後における溶出率 により算出することができる。  A: Initial value (dissolution rate); B: Calculated based on the dissolution rate after storage of any period.
[0069] 前記のように製造された（2R)— 2 プロピルオクタン酸を含有してなる本発明のソ フトカプセルは、約 25°C〜約 30°Cで約 1年半（例えば、約 16ヶ月〜約 20ヶ月間等、 好ましくは約 17ヶ月〜約 19ヶ月間等)保存した後でも、溶出率が初期値 (溶出率)と 比べて実質上変化しないか、または変化率が 20%以内、好ましくは 15%以内、より 好ましくは 10%以内であるので、「溶出遅延が起こらない」ということができる。  [0069] The soft capsule of the present invention comprising (2R) -2-propyloctanoic acid prepared as described above has a temperature of about 25 ° C to about 30 ° C for about one and a half years (for example, about 16 (E.g., from about 17 months to about 19 months, etc., preferably from about 17 months to about 19 months) Even after storage, the dissolution rate does not change substantially compared to the initial value (dissolution rate), or the rate of change is within 20% Since it is preferably within 15%, more preferably within 10%, it can be said that “elution delay does not occur”.
[0070] [毒性]  [0070] [Toxicity]
(2R) 2—プロピルオクタン酸の毒性は非常に低いものであり、医薬として使用す るために十分安全であると判断できる。例えば、ィヌを用いた単回静脈内投与では、 (2R)— 2—プロピルオクタン酸は、 lOOmgZkgで死亡例が見られなかった。従って 、 (2R)—2—プロピルオクタン酸を含有してなる本発明のソフトカプセルは、安全に、 生体に対して経口投与することが可能である。 (2R) 2-Propyloctanoic acid has very low toxicity and can be judged to be sufficiently safe for use as a medicine. For example, in a single intravenous dose using Inu, (2R) -2-propyloctanoic acid was found to be lOOmgZkg and no death occurred. Therefore The soft capsule of the present invention containing (2R) -2-propyloctanoic acid can be safely orally administered to a living body.
[0071] [医薬品への適用]  [0071] [Application to pharmaceutical products]
(2R) 2—プロピルオクタン酸を含有してなる本発明のソフトカプセルは、有効成 分として（2R)— 2—プロピルオクタン酸を含有していることから、哺乳動物（例えば、 ヒトゃ非ヒト動物（例えば、サル、ヒッジ、ゥシ、ゥマ、ィヌ、ネコ、ゥサギ、ラット、マウス 等)等）において、例えば、神経変性疾患、神経障害、神経再生を要する疾患、眼疾 患、感覚神経疾患、運動神経疾患、疼痛、機能性脳疾患等の予防、治療および Zま たは症状進展抑制剤として、あるいは神経再生促進剤や S 100 β増加抑制剤として 有用である。 （2R)— 2—プロピルオクタン酸を適用可能なこれらの疾患については、 公知の文献、例えば、欧州特許第 0632008号明細書、欧州特許公開第 1174131 号明細書、国際公開第 2005Ζ032535号パンフレット、国際公開第 2006/0982 92号パンフレツ卜、特開 2006— 290880号明細書、特開 2006— 290881号明細書 、国際公開第 2007Ζ000970号パンフレット、国際出願第 PCTZJP2007Z0545 12号パンフレット等に詳しく記載されている。  Since the soft capsule of the present invention containing (2R) 2-propyloctanoic acid contains (2R) -2-propyloctanoic acid as an effective component, mammals (for example, human non-human animals) (E.g., monkeys, hidges, rabbits, horses, dogs, cats, rabbits, rats, mice, etc.)), for example, neurodegenerative diseases, neuropathies, diseases requiring nerve regeneration, eye diseases, sensory nerve diseases It is useful as a prophylaxis, treatment and Z or symptom progression inhibitor for motor neuropathy, pain, functional brain disease, etc., or as a nerve regeneration promoter or S 100 β increase inhibitor. For these diseases to which (2R) -2-propyloctanoic acid can be applied, publicly known documents such as European Patent No. 0632008, European Patent Publication No. 1174131, International Publication No. 2005-032535, This is described in detail in Publication No. 2006/0982 92 Pamphlet, JP 2006-290880, JP 2006-290881, International Publication No. 2007-000970, International Application No. PCTZJP2007Z0545 12, etc.
[0072] (2R)— 2 プロピルオクタン酸を含有してなる本発明のカプセルは、前記の目的の ため、経口的に生体内に投与される。なお、本発明において、「予防」とは疾患の成 立そのものを予防することを意味し、「治療」とは病態を治癒の方向へ導くことを意味 し、「症状進展抑制」とは病態の悪ィ匕を抑制し進行をとどめることを意味する。  [0072] The capsule of the present invention containing (2R) -2 propyloctanoic acid is orally administered to a living body for the above purpose. In the present invention, “prevention” means prevention of the disease itself, “treatment” means guiding the disease state in the direction of healing, and “suppression of symptom progression” is the disease state. It means to suppress the bad habit and keep it going.
[0073] (2R)—2 プロピルオクタン酸を含有してなる本発明のカプセルの一日の投与量 は、症状の程度、投与対象の年齢、性別、体重、投与の時期、間隔等によって異なり 、特に限定されないが、例えば、パーキンソン病、パーキンソン症候群、アルッハイマ 一病、筋萎縮性側索硬化症、家族性筋萎縮性側索硬化症等の神経変性疾患の治 療剤として経口的に投与する場合、 1日用量として、約 50mg〜約 5000mg、好ましく は、約 lOOmg〜約 1200mg〖こ相当する（2R)—2—プロピルオクタン酸を含有するソ フトカプセルが投与される。  [0073] (2R) -2 The daily dosage of the capsule of the present invention comprising propyloctanoic acid varies depending on the degree of symptoms, age, sex, body weight, timing of administration, interval, etc. of the subject of administration, Although not particularly limited, for example, when orally administered as a therapeutic agent for neurodegenerative diseases such as Parkinson's disease, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, As a daily dose, soft capsules containing (2R) -2-propyloctanoic acid corresponding to about 50 mg to about 5000 mg, preferably about 10 mg to about 1200 mg are administered.
[0074] (2R) 2 プロピルオクタン酸を含有してなる本発明のカプセルを使用する際に は、他の薬剤を併用してもよい。併用される他の薬剤としては、例えば、抗てんかん 薬（例えば、フエノバルビタール、メホバルビタール、メタルビタール、プリミドン、フエ 二トイン、エトトイン、トリメタジオン、エトスクシミド、ァセチルフエネトライド、カルバマゼ ピン、ァセタゾラミド、ジァゼパム、バルプロ酸ナトリウム等）、アセチルコリンエステラー ゼ阻害薬 (例えば、塩酸ドネべジル、 TAK- 147,リバスチグミン、ガランタミン等）、 神経栄養因子 (例えば、 ABS— 205等)、アルドース還元酵素阻害薬、抗血栓薬 (例 えば、 t—PA、へノ リン等）、経口抗凝固薬 (例えば、ヮーフアリン等）、合成抗トロンビ ン薬 (例えば、メシル酸ガべキサート、メシル酸ナファモスタツト、アルガトロバン等）、 抗血小板薬 (例えば、アスピリン、ジピリダモール、塩酸チクロビジン、ベラプロストナト リウム、シロスタゾール、ォザダレルナトリウム等）、血栓溶解薬 (例えば、ゥロキナーゼ 、チソキナーゼ、アルテプラーゼ等）、ファクター Xa阻害薬、ファクター Vila阻害薬、 脳循環代謝改善薬 (例えば、イデべノン、ホバンテン酸カルシウム、塩酸アマンタジン 、塩酸メクロフエノキサート、メシル酸ジヒドロエルゴトキシン、塩酸ピリチォキシン、 γ —ァミノ酪酸、塩酸ビフエメラン、マレイン酸リスリド、塩酸インデロキサジン、 -セルゴ リン、プロペントフイリン等）、抗酸ィ匕薬 (例えば、エダラボン等）、グリセリン製剤 (例え ば、グリセオール等）、 セクレターゼ阻害薬 (例えば、 6—（4ービフエ-リル)メトキシ — 2— [2— (Ν, Ν—ジメチルァミノ）ェチル]テトラリン、 6— (4—ビフエ-リル)メトキシ - 2- (Ν, Ν ジメチルァミノ）メチルテトラリン、 6— (4—ビフエ-リル)メトキシ一 2— (Ν, Ν ジプロピルァミノ）メチルテトラリン、 2— (Ν, Ν ジメチルァミノ）メチル—6— (4，—メトキシビフエ-ル— 4—ィル)メトキシテトラリン、 6— (4—ビフエ-リル)メトキシ — 2— [2— (Ν, Ν—ジェチルァミノ）ェチル]テトラリン、 2— [2— (Ν, Ν ジメチルァ ミノ）ェチル ]—6— (4，—メチルビフエ-ルー 4—ィル)メトキシテトラリン、 2— [2— (Ν , Ν—ジメチルァミノ）ェチル ]ー6— (4'ーメトキシビフエ-ルー 4 ィル)メトキシテト ラリン、 6— (2，， 4，一ジメトキシビフエ-ル一 4—ィル)メトキシ一 2— [2— (Ν, Ν ジ メチルァミノ）ェチル]テトラリン、 6—[4ー（1, 3 ベンゾジォキソールー 5 ィル）フエ -ル]メトキシ— 2— [2— (Ν, Ν ジメチルァミノ）ェチル]テトラリン、 6— (3，， 4，—ジ メトキシビフエ-ルー 4—ィル)メトキシ— 2— [2— (Ν, Ν ジメチルァミノ）ェチル]テ トラリン、その光学活性体、その塩およびその水和物、 ΟΜ99— 2 (WO0lZ00663 )等）、 アミロイド蛋白凝集阻害作用薬 (例えば、 ΡΤΙ— 00703、 ALZHEMED (N C— 531)、 PPI— 368 (特表平 11— 514333)、 PPI— 558 (特表平 2001— 50085 2) , SKF- 74652 (Biochem. J. , 340 (1) , 283— 289, 1999)等）、月 g機會賦活 薬 (例えば、ァニラセタム、ニセルゴリン等）、ドーパミン受容体作動薬 (例えば、 L—ド ーノ 、ブロモクリプチン、パーゴライド、タリぺキソール、プラミぺキソール、カベルゴリ ン、ァマンタジン等）、モノアミン酸ィ匕酵素（MAO)阻害薬 (例えば、サフラジン、デブ レニル、セルジリン（セレギリン）、レマセミド（remacemide)、リルゾール（riluzole)等 )、抗コリン薬 (例えば、トリへキシフヱ-ジル、ビペリデン等）、 COMT阻害薬 (例えば 、ェンタカポン等)、筋萎縮性側索硬化症治療薬 (例えば、リルゾール等、神経栄養 因子等）、スタチン系高脂血症治療薬 (例えば、プラバスタチンナトリウム、アト口バス タチン、シンパスタチン、ロスノ スタチン等）、フイブラート系高脂血症治療薬 (例えば 、クロフイブラート等）、アポトーシス阻害薬（例えば、 CPI— 1189、 IDN— 6556、 CE P— 1347等）、神経分化'再生促進薬 (例えば、レテプリニム (Leteprinim)、キサリ プローデン (Xaliproden; SR— 57746— A)、 SB— 216763等）、非ステロイド性抗 炎症薬（例えば、メロキシカム、テノキシカム、インドメタシン、イブプロフェン、セレコキ シブ、口フエコキシブ、アスピリン、インドメタシン等）、ステロイド薬 (例えば、デキサメ サゾン、へキセストロール、酢酸コルチゾン等）、性ホルモンまたはその誘導体（例え ば、プロゲステロン、エストラジオール、安息香酸エストラジオール等）等が挙げられる[0074] When the capsule of the present invention containing (2R) 2-propyloctanoic acid is used, another drug may be used in combination. Other drugs used in combination include, for example, antiepileptic Drugs (for example, phenobarbital, mehobarbital, metalbital, primidone, phenytoin, ethotoin, trimethadione, ethosuximide, acetilphenetride, carbamazepine, acetazolamide, diazepam, sodium valproate), acetylcholine esterase inhibitor (For example, donevezil hydrochloride, TAK-147, rivastigmine, galantamine, etc.), neurotrophic factors (for example, ABS-205, etc.), aldose reductase inhibitors, antithrombotic drugs (for example, t-PA, heno Phosphorus, etc.), oral anticoagulants (for example, phafarin), synthetic antithrombin drugs (for example, gabexate mesilate, nafamostat mesilate, argatroban, etc.), antiplatelet drugs (for example, aspirin, dipyridamole, ticlovidin hydrochloride, Beraprostnatrium, cilostazo , Ozadarel sodium, etc.), thrombolytic agents (eg, urokinase, thisokinase, alteplase, etc.), factor Xa inhibitors, factor Vila inhibitors, cerebral circulation metabolism improvers (eg, idebenone, calcium hovantenate, hydrochloric acid) Amantadine, Meclofenoxate hydrochloride, Dihydroergotoxine mesylate, Pyrithioxine hydrochloride, γ —Aminobutyric acid, Bifumeran hydrochloride, Lisuride maleate, Indeloxazine hydrochloride, -Sergoline, Propentophylline, etc.), Anti-acid glaze ( For example, edaravone, etc.), glycerin preparations (eg, glyceol, etc.), secretase inhibitors (eg, 6- (4-biphenyl-methoxy) -2- [2— (Ν, Ν-dimethylamino) ethyl] tetralin, 6— (4-Bipheryl) methoxy-2- (Ν, Ν dimethylamino) methyltetralin 6- (4-biphenyl) methoxy-2- (Ν, Ν dipropylamino) methyltetralin, 2- (Ν, Ν dimethylamino) methyl-6- (4, -methoxybiphenyl-4-yl) methoxytetralin, 6— (4-Biphenyl) methoxy — 2— [2— (Ν, Ν-Jetylamino) ethyl] tetralin, 2- [2— (Ν, ジ メ チ ル dimethylamino) ethyl] —6— (4, Methylbiphe- 4- (yl) methoxytetralin, 2- [2— (Ν, Ν-dimethylamino) ethyl] -6- (4′-methoxybiphenyl- 4-yl) methoxytetralin, 6- (2,4,1 dimethoxybi 4- (yl) methoxy 2- (2)-(Ν, Ν-dimethylamino) ethyl] tetralin, 6- [4- (1,3 benzodioxol-5-yl) phenol] methoxy — 2— [2— (Ν, ジ メ チ ル dimethylamino) ethyl] tetralin, 6— (3, 4, 4-dimethoxybifu 4- (yl) methoxy-2- [2— (Ν, ジ メ チ ル dimethylamino) ethyl] tetralin, its optically active substance, its salt and its hydrate, ΟΜ99-2 (WO0lZ00663), etc.), amyloid protein Aggregation inhibitor (eg, ΡΤΙ—00703, ALZHEMED (N C- 531), PPI- 368 (special table Hei 11-514333), PPI- 558 (special table hei 2001- 50085 2), SKF-74652 (Biochem. J., 340 (1), 283- 289, 1999) , Etc.), month-activator (eg, aniracetam, nicergoline, etc.), dopamine receptor agonist (eg, L-dono, bromocriptine, pergolide, talipexol, pramipexole, cabergoline, amantadine, etc.), Monoamine oxyenzyme (MAO) inhibitors (eg, safradine, debrenyl, sergiline (selegiline), remacemide, riluzole, etc.), anticholinergic agents (eg, trihexifi-zil, biperiden, etc.) , COMT inhibitors (eg, entacapone, etc.), amyotrophic lateral sclerosis (eg, riluzole, etc.), statin hyperlipidemia (eg, pravastatin sodium, atto-mouth busta) Tin, sympastatin, rosnostatin, etc.), fibrate hyperlipidemia drugs (eg, clofibrate, etc.), apoptosis inhibitors (eg, CPI-1189, IDN-6556, CEP-1347, etc.), neuronal differentiation 'Regeneration promoters (eg, Leteprinim, Xali pro den; SR—57746—A), SB—216763, etc.), non-steroidal anti-inflammatory drugs (eg, meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxie) Shibu, oral fuecoxib, aspirin, indomethacin, etc.), steroid drugs (eg, dexamethasone, hexestrol, cortisone acetate, etc.), sex hormones or derivatives thereof (eg, progesterone, estradiol, estradiol benzoate, etc.)
。また、ニコチン受容体調節薬、 γセクレターゼ阻害作用薬、 |8アミロイドワクチン、 βアミロイド分解酵素、スクワレン合成酵素阻害薬、痴呆の進行に伴う異常行動ゃ徘 徊等の治療薬、降圧薬、糖尿病治療薬、抗うつ薬、抗不安薬、疾患修飾性抗リウマ チ薬、抗サイト力イン薬 (例えば、 TNF阻害薬、 MAPキナーゼ阻害薬等)、副甲状腺 ホルモン (PTH)、カルシウム受容体拮抗薬等が挙げられる。 . Also, nicotine receptor modulator, γ-secretase inhibitor, | 8 amyloid vaccine, β-amyloid degrading enzyme, squalene synthase inhibitor, therapeutic agent for abnormal behavior associated with progression of dementia, antihypertensive, diabetes treatment Drugs, antidepressants, anxiolytics, disease-modifying antirheumatic drugs, anti-site force-in drugs (for example, TNF inhibitors, MAP kinase inhibitors, etc.), parathyroid hormone (PTH), calcium receptor antagonists, etc. Is mentioned.
以上の併用薬剤は例示であって、これらに限定されるものではない。併用するこれ らの薬剤の投与方法は特に限定されず、経口投与であっても非経口投与であっても よい。また、これらの薬剤は、任意の 2種以上を組み合わせて投与してもよい。また、 併用する薬剤には、上記したメカニズムに基づいて、現在までに見出されているもの だけでなく今後見出されるものも含まれる。  The above concomitant drugs are illustrative and are not limited thereto. The administration method of these drugs used in combination is not particularly limited, and may be oral administration or parenteral administration. These drugs may be administered in combination of any two or more. In addition, the drugs used in combination include not only those that have been found so far, but also those that will be found in the future based on the mechanism described above.
発明の効果 [0076] 本発明によって、神経変性疾患等の種々の疾患の予防、治療および Zまたは症状 進展抑制に有用な、 (2R) 2—プロピルオクタン酸含有経口投与用カプセルを提供 することができる。本発明で提供される経口投与用カプセル、特にソフトカプセルの 構成を有するそれは、その製造工程にお ヽてカプセル皮膜に気泡が混入することが ないので、カプセル皮膜 (外膜）に気泡を含まず、均一な厚さ、均一な組成のカプセ ル皮膜を有する（2R)— 2—プロピルオクタン酸含有ソフトカプセルとして、「ヒビ」や「 割れ」を起こすことなく臨床現場への安定供給が可能である。カロえて、本発明で開示 する処方を用いれば、製造工程中、皮膜用溶液の調製時において、皮膜用溶液を 消泡せしめることができるので、気泡の除去に要する時間を必要とせず、製造時間の 大幅な短縮が可能である。さらに、本発明によって得られるソフトカプセルは、国際公 開第 2005Z120490号パンフレットに記載されているような、「咀嚼時に内容物が容 易に漏出することがない」、「胃内易崩壊性である」、「速溶性である」、「溶出遅延が 起こらな ヽ」等の特性を維持した（2R)— 2—プロピルオクタン酸含有ソフトカプセル であり、前記したカプセル皮膜の均一性 (均一な厚さ、均一な組成)と相俟って、服用 時にムラなく安定した薬理効果を示すことができる。加えて、本発明によって得られる ソフトカプセルは、所望によって最外膜を設けることにより、製造過程から医療現場へ の供給過程、さらには服用されるまでの保存期間中、ソフトカプセル同士が付着した り、あるいはソフトカプセルとその容器が付着したりすることをも防ぐことができる。 図面の簡単な説明 The invention's effect [0076] According to the present invention, (2R) 2-propyloctanoic acid-containing capsules for oral administration useful for prevention and treatment of various diseases such as neurodegenerative diseases and suppression of Z or symptom progression can be provided. The capsules for oral administration provided by the present invention, particularly those having the structure of soft capsules, do not contain bubbles in the capsule film (outer film) because they do not enter the capsule film during the production process. A (2R) -2-propyloctanoic acid-containing soft capsule with a capsule film of uniform thickness and uniform composition can be stably supplied to clinical sites without causing “cracking” or “cracking”. If the prescription disclosed in the present invention is used, the film solution can be defoamed during the preparation of the film solution during the manufacturing process. Can be significantly shortened. Furthermore, the soft capsules obtained by the present invention are, as described in International Publication No. 2005Z120490 pamphlet, “the contents are not easily leaked during mastication”, “is easily disintegratable in the stomach” (2R) -2-propyloctanoic acid-containing soft capsules that maintain properties such as “fast dissolving” and “elution delays”, and the capsule film has a uniform thickness (uniform thickness, uniform A stable pharmacological effect with no unevenness when taken. In addition, the soft capsules obtained according to the present invention can be attached to each other during the storage period from the production process to the medical site, and even during the storage period until they are taken, by providing an outermost film as desired. It is also possible to prevent the soft capsule and its container from adhering. Brief Description of Drawings
[0077] [図 1]本発明のソフトカプセルの一例の切断面を示す図である。 FIG. 1 is a view showing a cut surface of an example of a soft capsule of the present invention.
[図 2]気泡を含まない本発明のソフトカプセルの写真である。  FIG. 2 is a photograph of the soft capsule of the present invention containing no bubbles.
[図 3]気泡を含むソフトカプセルの写真である（矢印は気泡の位置を示す)。  FIG. 3 is a photograph of a soft capsule containing bubbles (the arrow indicates the position of the bubbles).
符号の説明  Explanation of symbols
[0078] 1 内容物 [0078] 1 Contents
2 外膜  2 Outer membrane
3 最外膜  3 outermost membrane
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0079] 以下、実施例によって本発明を詳述するが、本発明はこれらに限定されるものでは ない。 [0079] Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto. Absent.
[0080] 製剤例 1： (2R)— 2 プロピルオクタン酸（300mg)含有ソフトカプセルの製造  [0080] Formulation Example 1: (2R) — Production of Soft Capsules Containing 2 Propyloctanoic Acid (300 mg)
ゼラチン（20kg)、濃グリセリン (6kg)、およびポリソルベート 80 (5g)を、精製水（20 kg)の存在下、 70°Cで混和し、均一な溶液を得た。この溶液および（2R)—2 プロ ピルオクタン酸 (0. 9kg)を、ソフトカプセル充填機（ロータリー式軟カプセル成型機 H —1型 (力マタ)）に投入し、皮膜用シートを形成させるとともに、その片面に別途調製 した大豆レシチン溶液 (0. 1%大豆レシチン ZMCT溶液)を塗布して、塗布面が外 側になるように皮膜用シートで（2R)—2—プロピルオクタン酸を覆うことにより（2R) - 2 プロピルオクタン酸を充填したソフトカプセルの生球を得た。得られた生球をタン ブラ乾燥 (24°C、 3時間）に付し、大豆レシチンの量を調節した後でさらに棚乾燥 (29 。C、 27時間）に付すことにより、 1カプセル中に 300mgの（2R)— 2 プロピルォクタ ン酸を含有するソフトカプセル（オーパル型（No. 5 Oval)、長径 12. 9mm (±0. 6 mm)、短径 7. 8mm (±0. 3mm)、 1500カプセル）を得た。これらのソフトカプセル の外膜における含水率は、約 7. 3%であった。また、 目視で確認したところ、気泡は 観察できなかった。後述の図 2にその一例の写真 (倍率 25倍で撮影)を示す。  Gelatin (20 kg), concentrated glycerin (6 kg), and polysorbate 80 (5 g) were mixed at 70 ° C. in the presence of purified water (20 kg) to obtain a uniform solution. This solution and (2R) -2 propyloctanoic acid (0.9 kg) were put into a soft capsule filling machine (rotary soft capsule molding machine H-1 type (forced mata)) to form a film sheet. Apply a separately prepared soy lecithin solution (0.1% soy lecithin ZMCT solution) on one side, and cover (2R) -2-propyloctanoic acid with a film sheet so that the coated surface is on the outside ( 2R) -2 Soft capsule live spheres filled with propyloctanoic acid were obtained. The obtained live spheres are subjected to tumbler drying (24 ° C, 3 hours), and after adjusting the amount of soy lecithin, they are further subjected to shelf drying (29 ° C, 27 hours) to make one capsule. Soft capsules containing 300 mg (2R) -2-propyloctanoic acid (Opal type (No. 5 Oval), major axis 12.9 mm (± 0.6 mm), minor axis 7.8 mm (± 0.3 mm), 1500 capsules ) The moisture content of these soft capsules in the outer membrane was approximately 7.3%. Also, when visually confirmed, bubbles could not be observed. Figure 2 below shows an example of a photograph (taken at 25x magnification).
[0081] 製剤例 2 : (2R)—2 プロピルオクタン酸（lOOmg)含有ソフトカプセルの製造  [0081] Formulation Example 2: Production of soft capsules containing (2R) -2 propyloctanoic acid (lOOmg)
ゼラチン（15kg)、濃グリセリン (4. 5kg)、およびポリソルベート 80 (3. 75g)を、精 製水（15kg)の存在下、 70°Cで混和し、均一な溶液を得た。この溶液および（2R) - 2—プロピルオクタン酸（1. Okg)を、ソフトカプセル充填機（ロータリー式軟カプセル 成型機 H—1型 (力マタ)）に投入し、皮膜用シートを形成させるとともに、その片面に 別途調製した大豆レシチン溶液 (0. 1%大豆レシチン/ MCT溶液)を塗布して、塗 布面が外側になるように皮膜用シートで（2R)— 2—プロピルオクタン酸を覆うことによ り（2R)— 2—プロピルオクタン酸を充填したソフトカプセルの生球を得た。得られた 生球をタンブラ乾燥（22°C、 4時間）に付し、大豆レシチンの量を調節した後でさらに 棚乾燥（28. 5°C、 26時間）に付すことにより、 1カプセル中に lOOmgの（2R)— 2— プロピルオクタン酸を含有するソフトカプセル（オーパル型（No. 2 Oval)、長径 9. 2mm (±0. 5mm)、短径 5. 8mm (±0. 2mm)、 3000カプセノレ）を得た。これらの ソフトカプセルの外膜における含水率は、約 6. 9%であった。また、 目視で確認した ところ、気泡は観察できな力つた。 Gelatin (15 kg), concentrated glycerin (4.5 kg), and polysorbate 80 (3.75 g) were mixed at 70 ° C. in the presence of purified water (15 kg) to obtain a uniform solution. This solution and (2R) -2-propyloctanoic acid (1. Okg) were put into a soft capsule filling machine (rotary soft capsule molding machine H-1 type (forced mata)) to form a film sheet, Apply a separately prepared soy lecithin solution (0.1% soy lecithin / MCT solution) on one side and cover (2R) -2-propyloctanoic acid with a film sheet so that the coated surface is on the outside. As a result, soft capsule live spheres filled with (2R) -2-propyloctanoic acid were obtained. In 1 capsule by subjecting the resulting live spheres to tumbler drying (22 ° C, 4 hours), adjusting the amount of soybean lecithin, and further subjecting to shelf drying (28.5 ° C, 26 hours) Soft capsules containing lOOmg (2R) -2-propyloctanoic acid (Opal type (No. 2 Oval), major axis 9.2 mm (± 0.5 mm), minor axis 5.8 mm (± 0.2 mm), 3000 Capsenore) was obtained. The water content of these soft capsules in the outer membrane was about 6.9%. Also confirmed visually However, the bubbles were unobservable.
[0082] 製剤例 3： (2R)— 2 プロピルオクタン酸（300mg)含有ソフトカプセルの製造  [0082] Formulation Example 3: (2R) —Production of 2-propyloctanoic acid (300 mg) -containing soft capsule
ゼラチン（52. 7kg)、濃グリセリン（15. 8kg)、および精製水 (49. 5kg)の存在下、 70°Cで混和した。次にポリソルベート 80 (13. 2g)を加えて混和し、均一な溶液を得 た。この溶液および（2R)— 2 プロピルオクタン酸（1. 5kg)を、ソフトカプセル充填 機（ロータリー式軟カプセル成型機 (Kamata 10006) )に投入し、皮膜用シートを 形成させるとともに、その片面に別途調製した大豆レシチン溶液（1. 0% Phosal 5 3 MCT (商品名： PHOSPHOLIPID社より購入） ZMCT希釈溶液）を塗布して、 塗布面が外側になるように皮膜用シートで（2R)— 2—プロピルオクタン酸を覆うこと により（2R)— 2—プロピルオクタン酸を充填したソフトカプセルの生球を得た。得られ た生球をタンブラ乾燥 (室温、 30分）に付し、大豆レシチンの量を調節した後でさらに 棚乾燥（28°C、 40時間）に付すことにより、 1カプセル中に 300mgの（2R)—2 プロ ピルオクタン酸を含有するソフトカプセル（オーパル型（No. 5 Oval)、長径 11. 9m m、短径 8. 2mm, 3100カプセル）を得た。これらのソフトカプセルの外膜における 含水率は、約 14%であった。また、 目視で確認したところ、気泡は観察できなカゝつた  The mixture was mixed at 70 ° C. in the presence of gelatin (52.7 kg), concentrated glycerin (15.8 kg), and purified water (49.5 kg). Next, polysorbate 80 (13.2 g) was added and mixed to obtain a uniform solution. This solution and (2R) -2-propyloctanoic acid (1.5 kg) are put into a soft capsule filling machine (rotary soft capsule molding machine (Kamata 10006)) to form a film sheet and separately prepared on one side. Soy lecithin solution (1.0% Phosal 5 3 MCT (trade name: purchased from PHOSPHOLIPID) ZMCT diluted solution) is applied, and (2R) -2-propyl Soft capsule live spheres filled with (2R) -2-propyloctanoic acid were obtained by covering with octanoic acid. The obtained live spheres are subjected to tumbler drying (room temperature, 30 minutes), and after adjusting the amount of soybean lecithin, they are further subjected to shelf drying (28 ° C, 40 hours), so that 300 mg ( 2R) -2 soft capsules containing propylooctanoic acid (Opal type (No. 5 Oval), major axis 11.9 mm, minor axis 8.2 mm, 3100 capsules) were obtained. The water content in the outer membrane of these soft capsules was about 14%. Also, when visually confirmed, bubbles were not observable.
[0083] 製剤例 4： (2R)— 2 プロピルオクタン酸（300mg)含有ソフトカプセルの製造 [0083] Formulation Example 4: (2R) — Production of Soft Capsules Containing 2 Propyloctanoic Acid (300 mg)
ゼラチン（20kg)、濃グリセリン (6kg)、およびポリソルベート 80 (5g)を、精製水（20 kg)の存在下、 70°Cで混和し、均一な溶液を得た。この溶液および（2R)—2 プロ ピルオクタン酸 (0. 9kg)を、ソフトカプセル充填機（ロータリー式軟カプセル成型機 H —1型 (力マタ)）に投入し、皮膜用シートを形成させるとともに、その片面に別途調製 した大豆レシチン溶液 (0. 1%大豆レシチン ZMCT溶液)を塗布して、塗布面が外 側になるように皮膜用シートで（2R)—2—プロピルオクタン酸を覆うことにより（2R) - 2 プロピルオクタン酸を充填したソフトカプセルの生球を得た。得られた生球をタン ブラ乾燥 (24°C、 3時間）に付し、大豆レシチンの量を調節した後でさらに棚乾燥 (29 。C、 27時間）に付すことにより、 1カプセル中に 300mgの（2R)— 2 プロピルォクタ ン酸を含有するソフトカプセル（オーパル型（No. 5 Oval)、長径 12. 8mm、短径 7 . 7mm, 1500カプセル）を得た。これらのソフトカプセルの外膜における含水率は、 約 7. 3%であった。また、 目視で確認したところ、気泡は観察できな力つた。 Gelatin (20 kg), concentrated glycerin (6 kg), and polysorbate 80 (5 g) were mixed at 70 ° C. in the presence of purified water (20 kg) to obtain a uniform solution. This solution and (2R) -2 propyloctanoic acid (0.9 kg) were put into a soft capsule filling machine (rotary soft capsule molding machine H-1 type (forced mata)) to form a film sheet. Apply a separately prepared soy lecithin solution (0.1% soy lecithin ZMCT solution) on one side, and cover (2R) -2-propyloctanoic acid with a film sheet so that the coated surface is on the outside ( 2R) -2 Soft capsule live spheres filled with propyloctanoic acid were obtained. The obtained live spheres are subjected to tumbler drying (24 ° C, 3 hours), and after adjusting the amount of soy lecithin, they are further subjected to shelf drying (29 ° C, 27 hours) to make one capsule. Soft capsules (Opal type (No. 5 Oval), major axis 12.8 mm, minor axis 7.7 mm, 1500 capsules) containing 300 mg of (2R) -2-propyloctanoic acid were obtained. The moisture content in the outer membrane of these soft capsules is About 7.3%. In addition, when visually confirmed, the bubbles were too strong to be observed.
[0084] 製剤例 5： (2R)— 2 プロピルオクタン酸（lOOmg)含有ソフトカプセルの製造 [0084] Formulation Example 5: (2R) — Production of Soft Capsules Containing 2 Propyloctanoic Acid (lOOmg)
ゼラチン（15kg)、濃グリセリン (4. 5kg)、およびポリソルベート 80 (3. 75g)を、精 製水（15kg)の存在下、 70°Cで混和し、均一な溶液を得た。この溶液および（2R) - 2—プロピルオクタン酸（1. Okg)を、ソフトカプセル充填機（ロータリー式軟カプセル 成型機 H—1型 (力マタ)）に投入し、皮膜用シートを形成させるとともに、その片面に 別途調製した大豆レシチン溶液 (0. 1%大豆レシチン/ MCT溶液)を塗布して、塗 布面が外側になるように皮膜用シートで（2R)— 2—プロピルオクタン酸を覆うことによ り（2R)— 2—プロピルオクタン酸を充填したソフトカプセルの生球を得た。得られた 生球をタンブラ乾燥（22°C、 4時間）に付し、大豆レシチンの量を調節した後でさらに 棚乾燥（28. 5°C、 26時間）に付すことにより、 1カプセル中に lOOmgの（2R)— 2— プロピルオクタン酸を含有するソフトカプセル（オーパル型（No. 2 Oval)、長径 9. 4mm、短径 5. 8mm, 3000カプセル）を得た。これらのソフトカプセルの外膜におけ る含水率は、約 6. 9%であった。また、 目視で確認したところ、気泡は観察できなか つた o  Gelatin (15 kg), concentrated glycerin (4.5 kg), and polysorbate 80 (3.75 g) were mixed at 70 ° C. in the presence of purified water (15 kg) to obtain a uniform solution. This solution and (2R) -2-propyloctanoic acid (1. Okg) were put into a soft capsule filling machine (rotary soft capsule molding machine H-1 type (forced mata)) to form a film sheet, Apply a separately prepared soy lecithin solution (0.1% soy lecithin / MCT solution) on one side and cover (2R) -2-propyloctanoic acid with a film sheet so that the coated surface is on the outside. As a result, soft capsule live spheres filled with (2R) -2-propyloctanoic acid were obtained. In 1 capsule by subjecting the resulting live spheres to tumbler drying (22 ° C, 4 hours), adjusting the amount of soybean lecithin, and further subjecting to shelf drying (28.5 ° C, 26 hours) In addition, soft capsules (Opal type (No. 2 Oval), major axis 9.4 mm, minor axis 5.8 mm, 3000 capsules) containing 10 mg of (2R) -2-propyloctanoic acid were obtained. The water content in the outer membrane of these soft capsules was about 6.9%. In addition, when visually confirmed, bubbles were not observed o
産業上の利用可能性  Industrial applicability
[0085] 本発明は、以下に示すように医薬品への適用が可能である。  [0085] The present invention can be applied to pharmaceuticals as described below.
本発明で開示する、（2R)— 2—プロピルオクタン酸含有経口投与用カプセル、とり わけソフトカプセルの構成を有するそれは、（2R)— 2—プロピルオクタン酸を有効成 分として含有するので、哺乳動物（例えば、ヒト、非ヒト動物、例えば、サル、ヒッジ、ゥ シ、ゥマ、ィヌ、ネコ、ゥサギ、ラット、マウス等）に対し、例えば、神経変性疾患、神経 障害、神経再生を要する疾患、眼疾患、感覚神経疾患、運動神経疾患、疼痛、機能 性脳疾患等の予防、治療および Zまたは症状進展抑制剤として、あるいは神経再生 促進剤や S 100 β増加抑制剤として用いることができる。  The (2R) -2-propyloctanoic acid-containing capsule for oral administration disclosed in the present invention, particularly a soft capsule, contains (2R) -2-propyloctanoic acid as an active ingredient, (Eg, humans, non-human animals such as monkeys, hidges, rabbits, horses, dogs, cats, rabbits, rats, mice, etc.), for example, neurodegenerative diseases, neurological disorders, diseases that require nerve regeneration It can be used as a prophylaxis, treatment and Z or symptom progression inhibitor for eye diseases, sensory nerve diseases, motor nerve diseases, pain, functional brain diseases, etc., or as a nerve regeneration promoter or S 100 β increase inhibitor.
[0086] また、本発明で開示する、 (2R) 2 プロピルオクタン酸含有経口投与用カプセ ル、とりわけソフトカプセルの構成を有するそれは、その製造工程においてカプセル 皮膜に気泡が混入することがないので、カプセル皮膜 (外膜）に気泡を含まず、均一 な厚さ、均一な組成のカプセル皮膜を有する（2R)— 2—プロピルオクタン酸含有ソ フトカプセルとして臨床現場への安定供給が可能である。さらに本発明で開示する処 方を用いれば、従来の処方で気泡の除去に要して 、た時間が必要な 、ので製造時 間の大幅な短縮が可能となる。 [0086] Further, the capsule for oral administration containing (2R) 2 propyloctanoic acid disclosed in the present invention, in particular, having a soft capsule structure, does not contain air bubbles in the capsule film in the production process. The film (outer film) does not contain bubbles, and has a capsule film with a uniform thickness and uniform composition. A stable supply to the clinical site as a soft capsule is possible. Furthermore, if the method disclosed in the present invention is used, it takes a long time to remove bubbles in the conventional formulation, so that the manufacturing time can be greatly reduced.
加えて、本発明で開示する、（2R)— 2—プロピルオクタン酸含有経口投与用カプ セル、とりわけソフトカプセルの構成を有するそれは、「咀嚼時に内容物が容易に漏 出することがない」、「胃内易崩壊性である」、「速溶性である」、「溶出遅延が起こらな い」等の特性を有しているため、誤って咀嚼した際にも口腔内にエダ味や痛み、灼熱 感を感じることなく安全に服用することが可能で、かつ速やかに吸収されて一定の薬 理効果を得ることができるので、患者が安心して服用することができる。  In addition, the (2R) -2-propyloctanoic acid-containing capsules for oral administration disclosed in the present invention, particularly those having a soft capsule structure, are “the contents do not easily leak during chewing”, “ Because it has properties such as “disintegrating easily in the stomach”, “fast dissolving”, “no dissolution delay”, and so on, even if it is accidentally chewed, it can cause edible taste, pain, and burning in the oral cavity. It can be taken safely without feeling sensation and can be absorbed quickly to obtain a certain pharmacological effect, so that the patient can take it with peace of mind.

Claims

請求の範囲 The scope of the claims
[I] (A)液状薬物を含有し、さらに多価アルコール、糖アルコールおよび Zまたは水を 含有していてもよい組成物を内容物とし、（B)蛋白質、多価アルコール、非イオン性 界面活性剤および水を含有し、さらにリン脂質および Zまたは糖アルコールを含有し て!、てもよ 、組成物を外膜として、所望によってさらに (C)保護膜を最外膜に有して V、てもよ 、構成を有し、前記外膜中に長径 100 μ m以上の気泡を含まな 、経口投与 用カプセル  [I] (A) A composition containing a liquid drug, which may further contain a polyhydric alcohol, a sugar alcohol, and Z or water, and (B) a protein, a polyhydric alcohol, a nonionic interface Contains activator and water, plus phospholipids and Z or sugar alcohol !, but the composition as an outer membrane and optionally (C) a protective membrane on the outermost membrane V However, the capsule for oral administration has a structure and does not contain bubbles having a major axis of 100 μm or more in the outer membrane.
[2] 液状薬物が（2R)— 2—プロピルオクタン酸である請求の範囲 1記載の経口投与用 カプセノレ。  [2] The capsule for oral administration according to claim 1, wherein the liquid drug is (2R) -2-propyloctanoic acid.
[3] 蛋白質がゼラチンであり、多価アルコールがグリセリンである請求の範囲 1記載の経 口投与用カプセル。  [3] The capsule for oral administration according to claim 1, wherein the protein is gelatin and the polyhydric alcohol is glycerin.
[4] 非イオン性界面活性剤がポリソルベート 80である請求の範囲 1記載の経口投与用 カプセノレ。  [4] The capsule for oral administration according to claim 1, wherein the nonionic surfactant is polysorbate 80.
[5] リン脂質が大豆レシチンである請求の範囲 1記載の経口投与用カプセル。  [5] The capsule for oral administration according to claim 1, wherein the phospholipid is soybean lecithin.
[6] 糖アルコールがソルビトールである請求の範囲 1記載の経口投与用カプセル。 6. The capsule for oral administration according to claim 1, wherein the sugar alcohol is sorbitol.
[7] 保護膜がリン脂質を含有する請求の範囲 1記載の経口投与用カプセル。 [7] The capsule for oral administration according to claim 1, wherein the protective film contains a phospholipid.
[8] リン脂質が大豆レシチンである請求の範囲 7記載の経口投与用カプセル。 [8] The capsule for oral administration according to claim 7, wherein the phospholipid is soybean lecithin.
[9] (A) (2R)— 2—プロピルオクタン酸を含有し、さらにグリセリン、ソルビトールおよび[9] (A) (2R) —contains 2-propyloctanoic acid, and further contains glycerin, sorbitol and
Zまたは水を含有していてもよい組成物を内容物とし、（B)ゼラチン、グリセリン、ポリ ソルベート 80および水を含有し、さらに大豆レシチンおよび Zまたはソルビトールを 含有して!/、てもよ 、組成物を外膜として、所望によってさらに (C)大豆レシチンを含 有する保護膜を最外膜に有して 、てもよ 、構成を有する請求の範囲 1記載の経口投 与用カプセル。 A composition which may contain Z or water is contained, and (B) contains gelatin, glycerin, polysorbate 80 and water, and further contains soy lecithin and Z or sorbitol! / 2. The capsule for oral administration according to claim 1, wherein the composition is used as an outer membrane, and (C) a protective membrane containing soybean lecithin is further provided on the outermost membrane as desired.
[10] ソフトカプセルである請求の範囲 9記載の経口投与用カプセル。  [10] The capsule for oral administration according to claim 9, which is a soft capsule.
[II] 外膜が、（a)ゼラチン、（b)ゼラチン 100質量部に対して約 25質量部〜約 40質量 部のグリセリンおよび (c)ゼラチン 100質量部に対して約 0. 01質量部〜約 0. 05質 量部のポリソルベート 80を含有し、かつソルビトールを実質的に含まないか、または ゼラチン 100質量部に対して約 20質量部以下のソルビトールを含む、大豆レシチン を実質的に含まない含水率約 5%〜約 15%の組成物からなる請求の範囲 10記載の 経口投与用カプセル。 [II] The outer membrane is (a) gelatin, (b) about 25 parts by weight to about 40 parts by weight of glycerin with respect to 100 parts by weight of gelatin, and (c) about 0.01 parts by weight with respect to 100 parts by weight of gelatin. Soy lecithin containing about 0.5 parts by weight polysorbate 80 and substantially free of sorbitol or about 20 parts by weight or less of sorbitol per 100 parts by weight of gelatin 11. The capsule for oral administration according to claim 10, comprising a composition having a water content of substantially 5% to 15% substantially free of water.
[12] 外膜が、実質的にソルビトールを含まない請求の範囲 11記載の経口投与用カプセ ル。  [12] The capsule for oral administration according to claim 11, wherein the outer membrane does not substantially contain sorbitol.
[13] 外膜が、（a)ゼラチン、（b)ゼラチン 100質量部に対して約 30質量部のグリセリンお よび（c)ゼラチン 100質量部に対して約 0. 025質量部のポリソルベート 80を含有す る含水率約 5%〜約 8%の組成物力もなる請求の範囲 12記載の経口投与用カプセ ル。  [13] The outer membrane contains (a) gelatin, (b) about 30 parts by weight of glycerin with respect to 100 parts by weight of gelatin, and (c) about 0.025 parts by weight of polysorbate 80 with respect to 100 parts by weight of gelatin. 13. The capsule for oral administration according to claim 12, which also has a composition strength of about 5% to about 8% water content.
[14] 内容物が、約 50mg〜約 400mgの (2R) 2 プロピルオクタン酸を含有する組成 物からなる請求の範囲 9記載の経口投与用カプセル。  14. The capsule for oral administration according to claim 9, wherein the content comprises a composition containing about 50 mg to about 400 mg of (2R) 2 propyloctanoic acid.
[15] 内容物が、約 lOOmgまたは約 300mgの (2R) 2 プロピルオクタン酸を含有す る組成物力もなる請求の範囲 14記載の経口投与用カプセル。  [15] The capsule for oral administration according to claim 14, wherein the content also has a compositional strength containing about 10 mg or about 300 mg of (2R) 2 propyloctanoic acid.
[16] 二層膜ソフトカプセルである請求の範囲 9記載の経口投与用カプセル。  [16] The capsule for oral administration according to claim 9, which is a bilayer soft capsule.
[17] (A)約 lOOmgまたは約 300mgの（2R)—2 プロピルオクタン酸を含有する組成 物を内容物とし、 (B) (a)ゼラチン、（b)ゼラチン 100質量部に対して約 30質量部の グリセリンおよび（c)ゼラチン 100質量部に対して約 0. 025質量部のポリソルベート 8 0を含有する含水率約 5%〜約 8%の組成物を外膜として、さらに (C)大豆レシチン を含有してなる保護膜を最外膜に有する構成を含む二層膜ソフトカプセル。  [17] (A) A composition containing about lOOmg or about 300 mg of (2R) -2 propyloctanoic acid is used as a content, and (B) (a) gelatin, (b) about 30 parts per 100 parts by weight of gelatin. A composition having a water content of about 5% to about 8% containing about 0.025 parts by mass of polysorbate 80 per 100 parts by mass of glycerin and (c) gelatin as an outer membrane, and (C) soybean A two-layer soft capsule comprising a structure having a protective film containing lecithin as an outermost film.
[18] (A)約 lOOmgまたは約 300mgの（2R)— 2 プロピルオクタン酸を含有する組成 物を内容物とし、 (B) (a)ゼラチン、（b)ゼラチン 100質量部に対して約 30質量部の グリセリンおよび（c)ゼラチン 100質量部に対して約 0. 025質量部のポリソルベート 8 0を含有する含水率約 5%〜約 12%の組成物を外膜として、さらに (C)大豆レシチン を含有してなる保護膜を最外膜に有する構成を含む二層膜ソフトカプセル。  [18] (A) A composition containing about lOOmg or about 300mg of (2R) -2-propyloctanoic acid is used as a content, and (B) (a) gelatin, (b) about 30 parts per 100 parts by weight of gelatin. A composition having a water content of about 5% to about 12% containing about 0.025 parts by mass of polysorbate 80 per 100 parts by mass of glycerin and (c) gelatin as an outer membrane, and (C) soybean A two-layer soft capsule comprising a structure having a protective film containing lecithin as an outermost film.
[19] ゼラチンと、ゼラチン 100質量部に対して約 25質量部〜約 40質量部のグリセリンを 含む水溶液に、ゼラチン 100質量部に対して約 0. 01質量部〜約 0. 05質量部のポ リソルベート 80を共存させることを特徴とする、該水溶液の消泡方法。  [19] In an aqueous solution containing gelatin and about 25 parts by weight to about 40 parts by weight of glycerol with respect to 100 parts by weight of gelatin, about 0.01 parts by weight to about 0.05 parts by weight with respect to 100 parts by weight of gelatin A method for defoaming the aqueous solution, wherein polysorbate 80 coexists.
[20] (a)ゼラチン、（b)ゼラチン 100質量部に対して約 25質量部〜約 40質量部のグリセ リンおよび (c)ゼラチン 100質量部に対して約 0. 01質量部〜約 0. 05質量部のポリ ソルベート 80を含有する水溶液力もシートを成形し、その外側片面に大豆レシチン の中鎖脂肪酸トリグリセリド溶液を塗布して二層シートを得、その二層シートで（2R) - 2-プロピルオクタン酸を含有する液状材料を覆 ヽ、得られた生球を乾燥工程に 付すことを特徴とする二層膜ソフトカプセルの製造方法。 [20] (a) gelatin, (b) about 25 parts by weight to about 40 parts by weight of glycerin with respect to 100 parts by weight of gelatin, and (c) about 0.01 parts by weight to about 0 with respect to 100 parts by weight of gelatin. .05 parts by weight of poly Form a sheet with an aqueous solution containing sorbate 80, and apply a medium chain fatty acid triglyceride solution of soybean lecithin to the outer side of the sheet to obtain a two-layer sheet. The two-layer sheet contains (2R) -2-propyloctanoic acid. A method for producing a double-layer membrane soft capsule, comprising: covering a liquid material to be coated; and subjecting the obtained raw sphere to a drying step.
PCT/JP2007/058437 2006-04-19 2007-04-18 Capsule for oral administration WO2007123153A1 (en)

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Publication number Priority date Publication date Assignee Title
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JPH06502143A (en) * 1990-10-19 1994-03-10 プロヴァリス　ユーケー　リミテッド Two-phase release formulations for lipophilic drugs
JPH06502862A (en) * 1990-11-26 1994-03-31 ローン−プーラン・ロレ・ソシエテ・アノニム Spiramycin composition for oral administration and method for preparing the same
JPH10273436A (en) * 1997-03-31 1998-10-13 Tokai Capsule Kk Soft capsule for chewing
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JP2002087952A (en) * 2000-06-30 2002-03-27 Mcneil Ppc Inc Taste-intercepting pharmaceutical particle
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