WO2007123153A1 - Capsule pour administration orale - Google Patents

Capsule pour administration orale 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
English (en)
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/fr

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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.

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  • Neurosurgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une capsule (en particulier, une capsule constituée comme une capsule molle) pour administration orale qui est une capsule molle contenant de l'acide (2R)-2-propyloctanoïque, exempte d'invasion de bulles dans un enrobage de capsule (c'est-à-dire, l'enrobage externe) pendant le procédé de fabrication, dont l'enrobage de capsule est d'épaisseur et de composition uniforme et dont la résistance est suffisamment élevée. En raison du fait qu'elle ne souffre ni de « craquelure » ni de « rupture » pendant la distribution ou le stockage, cette capsule molle peut être disponible de façon stable dans un site clinique. De plus, lors de la mastication, elle montre une efficacité stable tout en ne provoquant guère de fuite du contenu à partir de celle-ci, ce qui assure une administration sans danger.
PCT/JP2007/058437 2006-04-19 2007-04-18 Capsule pour administration orale WO2007123153A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006115116 2006-04-19
JP2006-115116 2006-04-19

Publications (1)

Publication Number Publication Date
WO2007123153A1 true WO2007123153A1 (fr) 2007-11-01

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PCT/JP2007/058437 WO2007123153A1 (fr) 2006-04-19 2007-04-18 Capsule pour administration orale

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WO (1) WO2007123153A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114632068A (zh) * 2020-12-16 2022-06-17 李振全 咀嚼式胶囊的组成物

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JPH06502143A (ja) * 1990-10-19 1994-03-10 プロヴァリス　ユーケー　リミテッド 親油性薬剤用の２相放出配合物
JPH06502862A (ja) * 1990-11-26 1994-03-31 ローン−プーラン・ロレ・ソシエテ・アノニム 経口投与用スピラマイシン組成物及びその調製法
JPH10273436A (ja) * 1997-03-31 1998-10-13 Tokai Capsule Kk 咀嚼用ソフトカプセル剤
JP2000309525A (ja) * 1999-02-26 2000-11-07 Shionogi & Co Ltd 服用性を改良した咀嚼型ソフトカプセル剤およびその製法
JP2001039863A (ja) * 1999-07-27 2001-02-13 Fuji Oil Co Ltd 軟カプセルの製造法並びに被覆剤又は滑沢剤
JP2002087952A (ja) * 2000-06-30 2002-03-27 Mcneil Ppc Inc 味遮蔽製薬粒子
JP2003521551A (ja) * 1997-12-26 2003-07-15 ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー ゼラチン組成物
JP2004175746A (ja) * 2002-11-28 2004-06-24 Okuno Chem Ind Co Ltd ソフトカプセルおよびその製造方法
WO2005120490A1 (fr) * 2004-06-11 2005-12-22 Ono Pharmaceutical Co., Ltd. Gélule stable vis-à-vis de la mastication
JP2006008654A (ja) * 2003-11-21 2006-01-12 Wakunaga Pharmaceut Co Ltd カプセル剤、カプセル剤の製造方法およびカプセル皮膜

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06502143A (ja) * 1990-10-19 1994-03-10 プロヴァリス　ユーケー　リミテッド 親油性薬剤用の２相放出配合物
JPH06502862A (ja) * 1990-11-26 1994-03-31 ローン−プーラン・ロレ・ソシエテ・アノニム 経口投与用スピラマイシン組成物及びその調製法
JPH10273436A (ja) * 1997-03-31 1998-10-13 Tokai Capsule Kk 咀嚼用ソフトカプセル剤
JP2003521551A (ja) * 1997-12-26 2003-07-15 ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー ゼラチン組成物
JP2000309525A (ja) * 1999-02-26 2000-11-07 Shionogi & Co Ltd 服用性を改良した咀嚼型ソフトカプセル剤およびその製法
JP2001039863A (ja) * 1999-07-27 2001-02-13 Fuji Oil Co Ltd 軟カプセルの製造法並びに被覆剤又は滑沢剤
JP2002087952A (ja) * 2000-06-30 2002-03-27 Mcneil Ppc Inc 味遮蔽製薬粒子
JP2004175746A (ja) * 2002-11-28 2004-06-24 Okuno Chem Ind Co Ltd ソフトカプセルおよびその製造方法
JP2006008654A (ja) * 2003-11-21 2006-01-12 Wakunaga Pharmaceut Co Ltd カプセル剤、カプセル剤の製造方法およびカプセル皮膜
WO2005120490A1 (fr) * 2004-06-11 2005-12-22 Ono Pharmaceutical Co., Ltd. Gélule stable vis-à-vis de la mastication

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114632068A (zh) * 2020-12-16 2022-06-17 李振全 咀嚼式胶囊的组成物

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