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WO2000071097A1 - Composition contenant du sel d'acide ascorbique - Google Patents

Composition contenant du sel d'acide ascorbique Download PDF

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Publication number
WO2000071097A1
WO2000071097A1 PCT/JP2000/003220 JP0003220W WO0071097A1 WO 2000071097 A1 WO2000071097 A1 WO 2000071097A1 JP 0003220 W JP0003220 W JP 0003220W WO 0071097 A1 WO0071097 A1 WO 0071097A1
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WIPO (PCT)
Prior art keywords
ascorbate
calcium
basic salt
granulated
composition
Prior art date
Application number
PCT/JP2000/003220
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English (en)
Japanese (ja)
Inventor
Hiroshi Matoba
Atsuko Hayano
Tadashi Makino
Original Assignee
Takeda Chemical Industries, 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 Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to AU47785/00A priority Critical patent/AU4778500A/en
Publication of WO2000071097A1 publication Critical patent/WO2000071097A1/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals

Definitions

  • the present invention relates to an ascorbate-containing composition, and more particularly, to (1) a composition containing ascorbate and granulated basic salt, (2) ascorbate, granulated basic salt , A method for producing a compression-molded article containing ascorbate characterized by compression-molding a binder and a disintegrant, and (3) containing ascorbate obtained by blending a granulated basic salt
  • the present invention relates to a method for stabilizing a composition.
  • multivitamin preparation in addition to various vitamins, preparations containing mineral components such as iron, copper, calcium, phosphorus, potassium, eodo, zinc, manganese, and magnesium [eg, Minera (trade name, Takeda Pharmaceutical Co., Ltd.) Industrial), Calsix (trade name, Taisho Pharmaceutical), etc.] are known.
  • calcium for example, is now widely known to be not only an indispensable component of bone and bone formation in mammals including humans, but also one of the important nutrients supporting various life phenomena. ing.
  • low intake and absorption of calcium has been a major cause of osteoporosis, and calcium deficiency has been linked to diseases such as hypertension, arteriosclerosis, arthralgia, diabetes, immune disease, and obesity. It has been pointed out that this may cause inconvenience.
  • Magnesium is also recognized as a mineral that is indispensable for the prevention of cardiovascular diseases such as ischemic disease and stroke, and has attracted attention.
  • These mineral components are generally often formulated as their basic salts.
  • composition containing ascorbate when the above mineral component is blended as a basic salt, the color changes, especially in the presence of moisture or high humidity conditions (75% or more humidity). Was found to be significant.
  • compression molded products containing ascorbate, especially ascorbic acid generally have poor tablet properties (eg, moldability, strength, etc.) and are susceptible to tableting failures (eg, binding, cabbing, etc.). It is known.
  • a first object of the present invention is to provide a composition containing a stable ascorbate salt, which suppresses a change in coloring and the like even when blended with a basic salt.
  • a second object of the present invention is to provide a composition containing ascorbic acid salt having excellent tablet properties (eg, moldability, strength, etc.) and little tableting trouble (eg, binding, cabbing, etc.) and its production. Is to provide a way. It is still another object of the present invention to provide a method for stabilizing a composition containing both a basic salt and ascorbate. Disclosure of the invention
  • the present inventors have studied a composition containing ascorbate, which is stable, has excellent tablet characteristics, and has little tableting trouble, even when formulated together with a basic salt, with suppressed color change and the like. As a result, it is possible to maintain stable ascorbate by blending the granulated basic salt, and to have excellent tablet properties by compression molding with binder and disintegrant. It is possible to obtain a compression-molded product containing ascorbate having less tableting trouble. After further investigation, the present invention was completed.
  • composition comprising ascorbate and a granulated basic salt
  • composition according to the above (1), wherein the composition containing ascorbate and the granulated basic salt is a compression-molded product.
  • composition according to (5), wherein the calcium ascorbate is calcium ascorbate for direct hitting.
  • composition according to (1) further comprising a binder and a disintegrant.
  • a method for producing a compressed molded article containing ascorbate which comprises compression-molding ascorbate, a granulated basic salt, a binder and a disintegrant,
  • Ascorbate in the present invention refers to a salt of ascorbic acid or a derivative thereof.
  • Derivatives of ascorbic acid are prodrugs of ascorbic acid represented by glycosides of ascorbic acid (eg, ascorbic acid 2-darcoside, etc.) and esters of ascorbic acid (eg, L-ascorbic acid diphosphate, etc.) Including No.
  • a prodrug of ascorbic acid is a compound that is converted to ascorbic acid by a reaction with an enzyme or stomach acid under physiological conditions in a living body, that is, a compound that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • Ascorbic acid refers to a compound that is converted to ascorbic acid by causing hydrolysis or the like by stomach acid.
  • the salts of ascorbic acid or its derivatives include alkali metal salts (eg, sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.). Salts.
  • Ascorbate is preferably a metal salt of ascorbic acid, more preferably an alkali of ascorbic acid, for the purpose of reducing the amount of the basic salt, which is one of the sources, while maintaining the amount of the mineral component.
  • Earth metal salts eg, calcium salts, magnesium salts, etc.
  • calcium ascorbate for the purpose of improving the bioavailability of calcium.
  • As calcium ascorbate in particular, by dissolving 10 g of granulated material represented by calcium ascorbate granules described in JP-A-3-471121, in 100 ml of water Calcium ascorbate granules containing an organic solid acid (preferably aliphatic carboxylic acid) such as tartaric acid and citric acid in an amount such that the pH of the resulting aqueous solution is 5.0 to 7.0 are preferable.
  • Granules having an average particle size of about 200 to 400; um are more preferred.
  • calcium ascorbate for direct hitting is preferable.
  • Direct compression calcium ascorbate means a composition that can be directly compressed. It is preferably granulated. For example, "about 80 to 99% by weight of calcium ascorbate, about 0.5 to 10% by weight of a binder (eg, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, etc.), tartaric acid or White to yellowish white granules or fine granules (about 200 to 400 um) comprising about 0.05 to 15% by weight of a solid organic acid such as citric acid (preferably an aliphatic carboxylic acid).
  • a binder eg, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, etc.
  • tartaric acid eg, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, etc.
  • White to yellowish white granules or fine granules about 200 to 400 um
  • a solid organic acid such as citric
  • Powder specifically, about 90 to 99% by weight of calcium ascorbate, and about 2 to 5% by weight of a binder (eg, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, etc.).
  • % And solids such as tartaric acid or citric acid
  • a white to yellowish white granular or fine (about 200 to 400 ⁇ m) powder comprising about 0.1 to 5% by weight of an organic acid (preferably aliphatic carboxylic acid); Specifically, the white to yellowish white fine granules consisting of 9.7% by weight of calcium ascorbate, 2.9% by weight of hydroxymethyl cellulose and 0.1% by weight of tartaric acid (about 250 m ) Powder ”.
  • Such direct-acting calcium ascorbate is commercially available. It is also possible to produce according to Japanese Patent Application Laid-Open No. 3-47112.
  • calcium ascorbate also includes granulated or finely divided calcium ascorbate.
  • the amount of ascorbate it is specified as the actual amount of ascorbate.
  • amount of calcium ascorbate contained therein rather than the total amount of calcium ascorbate for direct hit.
  • the basic salt in the present invention is often formulated as a mineral component.
  • a 5% by weight aqueous solution of the basic salt has a pH of about 8 or more, preferably a pH of about 8 to 11 Inorganic salts or basic organic salts (eg, calcium dalconate, calcium lactate, calcium citrate, etc.).
  • a basic inorganic salt more preferably a basic alkali metal salt (eg, a basic sodium salt, a basic lithium salt, etc.) or a basic alkaline earth metal salt (eg, a basic calcium salt, a basic Basic inorganic metal salts represented by magnesium salts (eg, calcium carbonate (including precipitated calcium carbonate), calcium oxide, calcium hydroxide, magnesium carbonate, magnesium oxide, magnesium hydroxide, etc.), and more preferred.
  • Basic alkaline earth metal salts eg, basic calcium salts, basic magnesium salts, etc.
  • These basic salts may be compounded as an antacid, such as a stabilizer.
  • Granulated basic salts often contain pharmacologically acceptable excipients, binders, disintegrants and the like.
  • pharmacologically acceptable excipients for example, lactose, powdered sugar, sucrose, D-mannitol, corn starch (constarch), potato starch, hydroxypropyl starch, calcium anhydride, calcium hydrogen phosphate, calcium hydrogen phosphate calcium, L-cysteine, etc.
  • methylcellulose methylcellulose, crystalline cellulose [eg, Avicel KG801 (trade name, Asahi Kasei Kogyo) etc.], hydroxypropylcellulose, hydroxypropylmethylcellulose (eg, hydroxypropylmethylcellulose 228, hydroxypropylmethylcellulose 299) 06, hydroxypropylmethylcellulose 2910), carboxymethylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, dextrin, starch, alcohol Binders such as starch starch, gum arabic powder, pullulan, starch paste, preferably crystalline cellulose [eg, Avicel KG801 (trade name, Asahi Kasei Kogyo) etc.], hydroxypropyl cellulose, etc .; carboxymethylcellulose calcium [Carmellose calcium, for example, ECG505 (trade name, Gotoku Yakuhin) etc.], low-substituted hydroxypropylcellulose [eg, LH-11, LH-21,
  • the basic salt When granulating the basic salt, it is preferable to use at least a binder. These excipients, binders, disintegrants and the like can be used in combination of two or more. In particular, it is preferable to use a combination of crystalline cellulose [eg, Avicel KG801 (trade name) or the like] and hydroxypropyl cellulose as a binder.
  • the mixing ratio of crystalline cellulose and hydroxypropyl cellulose in the binder is preferably about 1 to 100 parts by weight, more preferably about 10 to 100 parts by weight of hydroxypropyl cellulose per 100 parts by weight. It is a 300 weight part.
  • the content of the binder in the granulated basic salt is as follows. It is preferably about 1 to 100 parts by weight, more preferably about 1 to 100 parts by weight, based on 0 parts by weight.
  • the amount of the basic salt granulated in the composition of the present invention varies depending on the mineral component to be blended and the amount thereof. For example, about 10 to 100 parts by weight of ascorbate is used. 100 parts by weight, preferably about 500 to 500 parts by weight, more preferably about 100 to 100 parts by weight.
  • the average particle size of the granulated basic salt is preferably about 100 to 100 m, more preferably about 100 to 800 m, and still more preferably about 200 to 400 ⁇ m. It is.
  • composition of the present invention includes not only the following compression-molded products (eg, tablets, carburets, and chewables), but also compositions before compression-molding, and compositions as final preparations (eg, granules) , Capsules, etc.).
  • the compression-molded product of the present invention can be obtained by compression-molding ascorbate and a granulated basic salt. Further, it is preferable to perform compression molding together with a binder and a disintegrant.
  • the binder and the disintegrant include those similar to those used for the above-mentioned granulated basic salt.
  • the binder to be mixed at the time of the compression molding preferably, crystalline cellulose [eg, Avicel KG801 (trade name) or the like], hydroxypropylcellulose, or hydroxyph.
  • Oral propyl methylcellulose for example, hydroxypropylmethylcellulose 228, hydroxypropylmethylcellulose 290, hydroxypropylmethylcellulose 290, etc.
  • crystalline cellulose eg, Avicel KG800] 1 (product name) etc.
  • Disintegrants used in compression molding are preferably carboxymethylcellulose calcium [potassium lumellose calcium, for example, ECG505 (trade name, Gotoku Yakuhin), etc.], low-substituted hydroxypropylcellulose [eg, LH-11 , LH-21, LH-31, LH-22, LH-32, LH-20, LH-30, (trade name, Shin-Etsu Chemical Co., Ltd.), etc., croscarmellodium sodium [for example, axidol (trade name, Asahi Kasei Kogyo) and the like, and more preferably low-substituted hydroxypropylcellulose.
  • ECG505 trade name, Gotoku Yakuhin
  • croscarmellodium sodium for example, axidol (trade name, Asahi Kasei Kogyo) and the like, and more preferably low-substituted hydroxypropylcellulose.
  • the binder incorporated during compression molding is 100 parts by weight of ascorbate. And preferably about 1 to 1000 parts by weight, more preferably about 1 to 100 parts by weight.
  • the disintegrant used in the compression molding is preferably about 1 to 1000 parts by weight, more preferably about 1 to 100 parts by weight, based on 100 parts by weight of ascorbate.
  • the compounding ratio (weight) of (1) ascorbate, (2) granulated basic salt, (3) binder, and (4) disintegrant, which is blended during compression molding is, for example, preferably 100: about 10 to 10000: about 1 to 1000: about 1 to 1000, preferably 100: about 50 to 5000: about 1 to 500: about 1 to 500, more preferably 100: about 100 to 1000: about 1 to 100: It is about 1 to 100.
  • vitamins other than ascorbate lubricants, flavoring agents, coloring agents, stabilizers, adsorbents, antistatic agents, flavoring agents, surfactants, solid organic acids Etc. may be added.
  • bicumin other than ascorbate examples include water-soluble and fat-soluble vitamins such as vitamin A, bicum B, vitamin D, vitamin E, and nicotinic acid amide.
  • bicumin A, bicumin and its derivatives eg, prosultiamin, fursultiamin, dicetiamine, octothiamin, thiamine disulfide, sicothiamine, bisivbutiamin, bisbenthamine, benfothiamin, etc.
  • emissions B 2 Bikumi emissions B 6
  • bi Kumi emissions B ⁇ 2 eg, Shianokobarami down, hydroxocobalamin Mi emissions, ⁇ hydroxy Sokobarami down, hydrochloric human Dorokisokobarami down, Mekobarami emissions (Mechirukobarami down), coenzyme vitamin B 12 And related salts of cobalamin, etc.
  • nicotinic acid amide, pantothenic acid or a salt thereof eg, calcium pantoth
  • vitamin D particularly preferably vitamin D 3
  • Vitamin D 3 is unstable to air and light
  • vitamin D 3 EXAMPLE protected as gelatin beads, Riken Vitamin Co. gelatin beads - be used (RIKEN dry D 3 B5 (trade name)), avian not preferred.
  • Lubricants include, for example, stearate, magnesium stearate, calcium stearate, light silicic anhydride, talc and the like.
  • flavoring agent examples include various flavors.
  • coloring agent examples include iron oxide, lake pigments, tar pigments, caramel, red bengal and the like.
  • Examples of the stabilizer include sodium bisulfite and the like.
  • Examples of the adsorbent include light caustic anhydride, calcium gayate [e.g.,
  • antistatic agent examples include talc and light gay anhydride.
  • flavoring agent examples include lactose, sucrose, glucose, mannitol and the like.
  • surfactant examples include anionic surfactants such as sodium alkylsulfate; polyoxyethylene sorbitan fatty acid esters, polyoxetylene fatty acid esters, polyoxyethylene castor oil derivatives, and polypropylene oxide dope polyethylene oxide block.
  • anionic surfactants such as sodium alkylsulfate; polyoxyethylene sorbitan fatty acid esters, polyoxetylene fatty acid esters, polyoxyethylene castor oil derivatives, and polypropylene oxide dope polyethylene oxide block.
  • Nonionic surfactants such as polymer ⁇ Pluronic (trade name) etc.].
  • Solid organic acids include monobasic aliphatic carboxylic acids (eg, glycolic acid), dibasic aliphatic carboxylic acids (eg, tartaric acid, phthalic acid, maleic acid, malonic acid, lingoic acid, succinic acid) and tribasic acids.
  • Aliphatic carboxylic acids such as basic aliphatic carboxylic acids (eg, citric anhydride, citric acid); and enolic acids such as erythorbic acid and ascorbic acid.
  • composition of the present invention containing ascorbate and a granulated basic salt can be produced by a combination of per se known pharmaceutical techniques.
  • the compression molded product of the present invention can be manufactured as follows.
  • the granulated basic salt of the present invention can be obtained by a method known per se, for example, a dry granulation method using a dry granulator such as a compaction granulator, or a tumbling granulator, a stirring granulator, a fluidized granulator. It can be obtained by a warm granulation method using a wet granulator such as a spray granulator, a centrifugal tumbling granulator, a tumbling fluidized granulator, and an extrusion granulator.
  • a dry granulation method such as a compaction granulator, or a tumbling granulator, a stirring granulator, a fluidized granulator. It can be obtained by a warm granulation method using a wet granulator such as a spray granulator, a centrifugal tumbling granulator, a tumbling fluidized granulator, and an ex
  • Examples of the solution used in the wet granulation method include organic solvents such as water, alcohols (eg, methanol, ethanol, isopropanol, etc.), esters, ketones, ethers and the like or a mixture thereof. .
  • organic solvents such as water, alcohols (eg, methanol, ethanol, isopropanol, etc.), esters, ketones, ethers and the like or a mixture thereof.
  • water, alcohol (more preferably, ethanol) or a mixed solution of water / alcohol (more preferably, ethanol) is used.
  • a fluidized bed granulator when using a fluidized bed granulator, it can be manufactured as follows. Calcium carbonate, magnesium carbonate, and crystalline cellulose (eg, Seolas KG801 (trade name, Asahi Kasei Kogyo), etc.) are placed in a fluidized bed granulator, mixed, and sprayed with an aqueous solution of hydroxymethyl propyl methylcellulose. Drying produces a granular material.
  • the concentration of the aqueous hydroxypropylcellulose solution is preferably about 0.5 to 20% by weight, more preferably about 1 to 10% by weight.
  • a stirring granulator when using a stirring granulator, it can be manufactured as follows. Basic salts (eg, calcium carbonate, magnesium carbonate, etc.), crystalline cellulose [eg, CEOLUS KG801 (trade name, Asahi Kasei Kogyo), etc.] and hydroxypropyl cellulose can be converted to vertical granules (Parek Co., Ltd.). And mix. Purified water is added to the obtained mixture and granulated. The obtained granules are dried in a vacuum (for example, at 40 ° C. for 16 hours) to produce a raw material for granules.
  • Basic salts eg, calcium carbonate, magnesium carbonate, etc.
  • crystalline cellulose eg, CEOLUS KG801 (trade name, Asahi Kasei Kogyo), etc.
  • hydroxypropyl cellulose can be converted to vertical granules (Parek Co., Ltd.). And mix. Purified water is added to
  • the granulated raw material thus produced is optionally pulverized to preferably have an average particle diameter of about 100 to 100 m, more preferably an average particle diameter of about 100 to 800 m, and still more preferably an average particle diameter of about 100 to 800 m.
  • Granulated basic salts of about 200 to 400 m in diameter can be obtained.
  • Granulated basic salt ascorbate [eg, calcium ascorbate crystal, direct-use calcium ascorbate [(: 'CAL-97 (abbreviation), Takeda Pharmaceutical Co., Ltd.) Industry) etc.)
  • vitamin D 3 gelatin beads eg, vitamin D 3 -B5 (trade name, RIKEN Vicmin)
  • binders eg, crystalline cellulose [eg, Theoras KG801 (trade name, Asahi Kasei) Industrial) etc.
  • disintegrant eg, low-substituted hydroxypropyl propylcellulose (eg, LH-11 (trade name, Shin-Etsu Chemical Co., Ltd.), etc.
  • a lubricant eg, magnesium stearate, etc.
  • a compression molded product (eg, tablet) can be obtained.
  • the compression pressure during compression molding is preferably about 0.5 to 5 ton Zcm 2 , more preferably about 1 to 3 ton Zcm 2 .
  • a coating layer (sugar coating layer, film coating layer, etc.) may be formed on the obtained compression molded product.
  • a kneading solution containing titanium oxide, sterile talc, granu sugar, etc. is injected while spraying a spraying agent such as sterilized talc and gum arabic powder to form a sugar-coated layer. I do. Thereafter, if necessary, coloring is performed, and further polishing is performed with carnauba wax or white wax.
  • a film coating layer can be formed by using a film coating base instead of granulated sugar.
  • the composition of the present invention can be safely administered to mammals, especially humans.
  • the mode of administration is preferably oral administration.
  • the dose is about 50 to 200 mg as ascorbic acid per day for a human adult (body weight 50 kg), and is administered about 1 to 3 times a day.
  • the dosage of calcium is preferably about 300 to 70 Omg per day for a human adult (body weight 5 Ok).
  • the resulting granulated basic salt, average particle through about 8 0; um of Asukorubin calcium 1217.2G, vitamin D 3 gelatin beads 160.0 g, crystalline cellulose 173.6G, low-substituted hydroxyaldehyde cellulose (LH-11 ( 160.4 g of the product (manufactured by Shin-Etsu Chemical Co., Ltd.) and 28.8 g of magnesium stearate were mixed with a Kumbler mixer (TM-15, manufactured by Showa Chemical Machinery Co., Ltd.) to obtain a tableting composition (granules).
  • the obtained tableting composition (condyles) was 410 mg / tablet, diameter 9 mm ⁇ , radius of curvature 13 bandits, rotation speed 30 rpm, and tableting. Tablets were obtained by tableting under a pressure of 2 ton / cm 2 .
  • Table 1 shows the amount of each component per 6 tablets.
  • Table 2 summarizes the flowability, compression moldability, and tablet appearance of the tableting composition (condyles) as the initial properties of the tablet.
  • Example 2 Same as in Example 1 except that calcium ascorbate was directly used and 1254.8 g of calcium ascorbate (C'CAL-97 (abbreviation), Takeda Pharmaceutical Co., Ltd.) having an average particle diameter of 250 was used instead of calcium ascorbate To obtain a tablet with a dose of 410 mg / tablet, a diameter of 9 mm ⁇ , and a radius of curvature of 13 dragons.
  • C'CAL-97 abbreviation
  • Table 1 shows the amount of each component per 6 tablets.
  • Table 2 summarizes the flowability, compression moldability, and tablet appearance of the tableting composition (condyles) as the initial properties of the tablet.
  • Crystalline cellulose (Seolas KG80 trade name, manufactured by Asahi Kasei Corporation) 173.6 g, low-substituted hydroxypropylcellulose (LH-11 (trade name) ) 160.4 g of Shin-Etsu Chemical Co., Ltd.) and 28.8 g of magnesium stearate were added and mixed with a tumbler mixer (TM-15, manufactured by Showa Chemical Machinery Co., Ltd.) to obtain granules for tableting.
  • the obtained granules for tableting were subjected to compression molding under the same conditions as in Example 1 to obtain tablets having a dose of 410 mg / tablet, a diameter of 9 mm ⁇ , and a radius of curvature of 13 mm.
  • Table 1 shows the amounts of each component per 6 tablets.
  • Table 2 shows the initial properties of the tablets.
  • Example 1 Example 2 Comparative Example Good for tableting granules Good Good Good flowability
  • Example 1 The thickness of each of the 20 tablets obtained in Example 1, Example 2, and Comparative Example was measured using a dial gauge (manufactured by Mitutoyo), and the average value was determined.
  • Example 1 The hardness of each of the 10 tablets obtained in Example 1, Example 2 and Comparative Example was measured using a tablet breaking strength measuring device (manufactured by Toyama Sangyo Co., Ltd.), and the average value was determined.
  • Example 4 Each 240 tablets obtained in Example 1, Example 2 and Comparative Example were packed in a plastic bottle (with polyethylene cap) and stored at temperature 4 (TC, 75% humidity for 2 months, 4 months, 6 months) The changes in the appearance of the tablets were observed when the test was performed, and the results are shown in [Table 4]. (Table 4)
  • the composition containing ascorbate of the present invention is stable even when blended with a basic salt, because it suppresses color change and the like.
  • the compression-molded article containing ascorbate of the present invention has excellent tablet properties (eg, moldability, strength, disintegration, etc.) and has few tableting troubles (eg, binding, cabbing, etc.). Furthermore, since it is not necessary to divide the inside of the compression molded product and its coating layer such as a sugar coating layer, the production process can be simplified, the manufacturing time can be shortened, and it is blended into the coating layer such as the conventional sugar coating layer. Can be easily adjusted. Further, by blending calcium Asukorubin acid, calcium carbonate and vitamin D 3 in the formulation, it is possible to ingest calcium as mineral components efficiently. Furthermore, by adding magnesium carbonate as a basic salt, it is possible to ingest magnesium as a mineral at the same time.

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Abstract

L'invention concerne une composition comprenant un sel de base granulé et un sel d'acide ascorbique. Bien que contenant un sel basique, ladite composition ne subit pas d'altération, par exemple de coloration, du fait de sa stabilité élevée. Elle peut parfaitement être utilisée sous forme de comprimés (ex. du fait de son aptitude au moulage, de sa résistance et de sa capacité de désintégration), et pose peu de problèmes pour la fabrication de comprimés (ex. liaison et décalottage). Etant donné qu'il n'est pas nécessaire de former séparément une structure compacte pour la partie intérieure et une couche d'enrobage pour celle-ci, telle qu'une couche de sucre, le processus de production peut être simplifié et le temps de production écourté. Par ailleurs, un ingrédient incorporé habituellement à la couche d'enrobage, tel qu'une couche de sucre, peut être incorporé à la composition en dose facile à moduler.
PCT/JP2000/003220 1999-05-20 2000-05-19 Composition contenant du sel d'acide ascorbique WO2000071097A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU47785/00A AU4778500A (en) 1999-05-20 2000-05-19 Composition containing ascorbic acid salt

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/139842 1999-05-20
JP13984299 1999-05-20

Publications (1)

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WO2000071097A1 true WO2000071097A1 (fr) 2000-11-30

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Cited By (22)

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JP2006008667A (ja) * 2004-05-26 2006-01-12 Takeda Chem Ind Ltd ビタミンｃ類を含む安定化された固形製剤
WO2006030826A1 (fr) * 2004-09-17 2006-03-23 Eisai R & D Management Co., Ltd. Composition medicamenteuse
US7973160B2 (en) 2000-10-20 2011-07-05 Eisai R&D Management Co., Ltd. Nitrogen-containing aromatic derivatives
US8058474B2 (en) 2003-11-11 2011-11-15 Eisai R&D Management Co., Ltd. Urea derivative and process for preparing the same
WO2012091040A1 (fr) * 2010-12-27 2012-07-05 富田製薬株式会社 Particule nucléaire de type à désagrégation pour formulation pharmaceutique
US8865737B2 (en) 2006-08-28 2014-10-21 Eisai R&D Management Co., Ltd. Antitumor agent for undifferentiated gastric cancer
US8952035B2 (en) 2007-11-09 2015-02-10 Eisai R&D Management Co., Ltd. Combination of anti-angiogenic substance and anti-tumor platinum complex
US8962655B2 (en) 2007-01-29 2015-02-24 Eisai R&D Management Co., Ltd. Composition for treatment of undifferentiated gastric cancer
US8962650B2 (en) 2011-04-18 2015-02-24 Eisai R&D Management Co., Ltd. Therapeutic agent for tumor
US8969344B2 (en) 2005-08-02 2015-03-03 Eisai R&D Management Co., Ltd. Method for assay on the effect of vascularization inhibitor
US9006256B2 (en) 2006-05-18 2015-04-14 Eisai R&D Management Co., Ltd. Antitumor agent for thyroid cancer
US9012458B2 (en) 2010-06-25 2015-04-21 Eisai R&D Management Co., Ltd. Antitumor agent using compounds having kinase inhibitory effect in combination
US9334239B2 (en) 2012-12-21 2016-05-10 Eisai R&D Management Co., Ltd. Amorphous form of quinoline derivative, and method for producing same
US9945862B2 (en) 2011-06-03 2018-04-17 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
US10259791B2 (en) 2014-08-28 2019-04-16 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US10517861B2 (en) 2013-05-14 2019-12-31 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of endometrial cancer subjects to lenvatinib compounds
US11090386B2 (en) 2015-02-25 2021-08-17 Eisai R&D Management Co., Ltd. Method for suppressing bitterness of quinoline derivative
US11369623B2 (en) 2015-06-16 2022-06-28 Prism Pharma Co., Ltd. Anticancer combination of a CBP/catenin inhibitor and an immune checkpoint inhibitor
US11547705B2 (en) 2015-03-04 2023-01-10 Merck Sharp & Dohme Llc Combination of a PD-1 antagonist and a VEGF-R/FGFR/RET tyrosine kinase inhibitor for treating cancer
US12220398B2 (en) 2015-08-20 2025-02-11 Eisai R&D Management Co., Ltd. Tumor therapeutic agent
US12226409B2 (en) 2017-05-16 2025-02-18 Eisai R&D Management Co., Ltd. Treatment of hepatocellular carcinoma
US12303505B2 (en) 2017-02-08 2025-05-20 Eisai R&D Management Co., Ltd. Tumor-treating pharmaceutical composition

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JPS62228022A (ja) * 1985-12-13 1987-10-06 Takeda Chem Ind Ltd 綜合ビタミン糖衣錠
JPH05306229A (ja) * 1992-03-03 1993-11-19 Lederle Japan Ltd カルシウム含有チユアブル錠

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JPS62228022A (ja) * 1985-12-13 1987-10-06 Takeda Chem Ind Ltd 綜合ビタミン糖衣錠
JPH05306229A (ja) * 1992-03-03 1993-11-19 Lederle Japan Ltd カルシウム含有チユアブル錠

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US7973160B2 (en) 2000-10-20 2011-07-05 Eisai R&D Management Co., Ltd. Nitrogen-containing aromatic derivatives
US8372981B2 (en) 2000-10-20 2013-02-12 Eisai R&D Management Co., Ltd. Nitrogen-containing aromatic derivatives
US8058474B2 (en) 2003-11-11 2011-11-15 Eisai R&D Management Co., Ltd. Urea derivative and process for preparing the same
JP2006008667A (ja) * 2004-05-26 2006-01-12 Takeda Chem Ind Ltd ビタミンｃ類を含む安定化された固形製剤
US9504746B2 (en) 2004-09-17 2016-11-29 Eisai R&D Management Co., Ltd. Pharmaceutical compositions of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
WO2006030826A1 (fr) * 2004-09-17 2006-03-23 Eisai R & D Management Co., Ltd. Composition medicamenteuse
AU2005283422B2 (en) * 2004-09-17 2010-05-13 Eisai R & D Management Co., Ltd. Medicinal composition
JP4834553B2 (ja) * 2004-09-17 2011-12-14 エーザイ・アール・アンド・ディー・マネジメント株式会社 医薬組成物
AU2005283422C1 (en) * 2004-09-17 2017-02-02 Eisai R & D Management Co., Ltd. Medicinal composition
US8969379B2 (en) 2004-09-17 2015-03-03 Eisai R&D Management Co., Ltd. Pharmaceutical compositions of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7=methoxy-6-quinolinecarboxide
US8969344B2 (en) 2005-08-02 2015-03-03 Eisai R&D Management Co., Ltd. Method for assay on the effect of vascularization inhibitor
US9006240B2 (en) 2005-08-02 2015-04-14 Eisai R&D Management Co., Ltd. Method for assay on the effect of vascularization inhibitor
US9006256B2 (en) 2006-05-18 2015-04-14 Eisai R&D Management Co., Ltd. Antitumor agent for thyroid cancer
US8865737B2 (en) 2006-08-28 2014-10-21 Eisai R&D Management Co., Ltd. Antitumor agent for undifferentiated gastric cancer
US8962655B2 (en) 2007-01-29 2015-02-24 Eisai R&D Management Co., Ltd. Composition for treatment of undifferentiated gastric cancer
US8952035B2 (en) 2007-11-09 2015-02-10 Eisai R&D Management Co., Ltd. Combination of anti-angiogenic substance and anti-tumor platinum complex
US9012458B2 (en) 2010-06-25 2015-04-21 Eisai R&D Management Co., Ltd. Antitumor agent using compounds having kinase inhibitory effect in combination
WO2012091040A1 (fr) * 2010-12-27 2012-07-05 富田製薬株式会社 Particule nucléaire de type à désagrégation pour formulation pharmaceutique
US8962650B2 (en) 2011-04-18 2015-02-24 Eisai R&D Management Co., Ltd. Therapeutic agent for tumor
US9945862B2 (en) 2011-06-03 2018-04-17 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
US11598776B2 (en) 2011-06-03 2023-03-07 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
US9334239B2 (en) 2012-12-21 2016-05-10 Eisai R&D Management Co., Ltd. Amorphous form of quinoline derivative, and method for producing same
US10517861B2 (en) 2013-05-14 2019-12-31 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of endometrial cancer subjects to lenvatinib compounds
US10259791B2 (en) 2014-08-28 2019-04-16 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US10822307B2 (en) 2014-08-28 2020-11-03 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US11186547B2 (en) 2014-08-28 2021-11-30 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US10407393B2 (en) 2014-08-28 2019-09-10 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US11090386B2 (en) 2015-02-25 2021-08-17 Eisai R&D Management Co., Ltd. Method for suppressing bitterness of quinoline derivative
US11547705B2 (en) 2015-03-04 2023-01-10 Merck Sharp & Dohme Llc Combination of a PD-1 antagonist and a VEGF-R/FGFR/RET tyrosine kinase inhibitor for treating cancer
US12083112B2 (en) 2015-03-04 2024-09-10 Eisai R&D Management Co., Ltd. Combination of a PD-1 antagonist and a VEGFR/FGFR/RET tyrosine kinase inhibitor for treating cancer
US11369623B2 (en) 2015-06-16 2022-06-28 Prism Pharma Co., Ltd. Anticancer combination of a CBP/catenin inhibitor and an immune checkpoint inhibitor
US12220398B2 (en) 2015-08-20 2025-02-11 Eisai R&D Management Co., Ltd. Tumor therapeutic agent
US12303505B2 (en) 2017-02-08 2025-05-20 Eisai R&D Management Co., Ltd. Tumor-treating pharmaceutical composition
US12226409B2 (en) 2017-05-16 2025-02-18 Eisai R&D Management Co., Ltd. Treatment of hepatocellular carcinoma

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