WO2000071097A1 - Composition containing ascorbic acid salt - Google Patents

Composition containing ascorbic acid salt 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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WO
WIPO (PCT)
Prior art keywords
ascorbate
calcium
basic salt
granulated
composition
Prior art date
Application number
PCT/JP2000/003220
Other languages
French (fr)
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/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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.

Abstract

A composition comprising a granulated basic salt and an ascorbic acid salt. It is so stable as to be inhibited from suffering, e.g., coloration although containing the basic salt. It has excellent suitability for use as tablets (e.g., moldability, strength, and ability to disintegrate), and is reduced in tableting troubles (e.g., binding and capping). Since there is no need of separately forming a compact as the inner part and a coating layer therefor, such as a sugar coating, the production process can be simplified and the production time can be shortened. Further, an ingredient which has conventionally been incorporated into a coating layer such as a sugar coating can be incorporated into the composition while easily regulating its amount.

Description

明 細 書 ァスコルビン酸塩含有組成物 技術分野  Description Ascorbate-containing composition Technical field
本発明は、 ァスコルビン酸塩含有組成物に関し、 さらに詳細には （ 1 ) ァ スコルビン酸塩と顆粒化した塩基性塩を含有する組成物、 （2 ) ァスコルビ ン酸塩， 顆粒化した塩基性塩， 結合剤および崩壊剤を圧縮成形することを特 徴とするァスコルビン酸塩を含有する圧縮成形物の製造方法、 および （ 3 ) 顆粒化した塩基性塩を配合してなるァスコルビン酸塩を含有する組成物の 安定化方法に関する。 背景技術  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. Background art
総合ビタミン剤として、 各種ビタミン類の他に、 例えば鉄， 銅， カルシゥ ム， リ ン， カリウム， ョード， 亜鉛， マンガン， マグネシウム等のミネラル 成分を含有する製剤 〔例、 ミネラ （商品名， 武田薬品工業） 、 カルシックス (商品名， 大正製薬） 等〕 が知られている。  As a 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.
これらミネラル成分において、 例えばカルシウムは、 人間を含む哺乳動物 の骨や骨形成に不可欠な成分であるのみならず、 種々の生命現象を支える重 要な栄養素の 1つであることは今や広く知られている。 特に、 近年、 カルシ ゥムの摂取 ·吸収量が少ないことが骨粗鬆症の大きな原因となっていること、 さらにカルシウム不足は、 高血圧， 動脈硬化， 関節痛， 糖尿病， 免疫病， 肥 満等の疾患を招く原因となることが指摘されている。 また、 マグネシウムは 虚血性疾患や脳卒中等の循環器疾患の予防上必要不可欠なミネラルとして 認識され、 注目されている。 これらのミネラル成分は、 一般にその塩基性塩 として処方されることが多い。  Among these mineral components, 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. In particular, in recent years, 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.
従来、 ァスコルビン酸とミネラル成分との摂取を目的とした製剤として、 総合ビクミ ン錠においてミネラル成分としてのマグネシウム成分を糖衣層 に配合した総合ビタミン錠 （特開昭 6 2 - 2 2 8 0 2 2号公報） 、 ァスコル ビン酸カルシウム造粒物 （特開平 3— 4 7 1 2 1号公報） 、 非毒性カルシゥ ム塩にカルシウム易吸収性活性化剤としてのビタミン0 2あるいは D 3，ビタ ミ ン A , ビタミ ン C , ビタミ ン Eを配合する事を特徴とする易吸収活性化力 ルシゥム製剤 （特開平 5— 2 1 3 7 6 3号公報） 、 カルシウム換算量にして、 配合カルシウム総量の 8 %以上に相当するァスコルビン酸カルシウムを含 有することを特徴とするカルシウム製剤 （特開平 9一 1 5 7 1 7 4号公報） が報告されている。 Conventionally, as a preparation for ingestion of ascorbic acid and a mineral component, a general vitamin tablet in which a magnesium component as a mineral component was added to a sugar coating layer in a synthetic bicumin tablet (Japanese Patent Application Laid-Open No. 62-228802) No.), Askol Bottle calcium granules (JP 3 4 7 1 2 1 JP), vitamin 0 2 or D 3 as the calcium easily absorbable activator nontoxic Karushiu unsalted, Vita Mi emissions A, vitamin C , An easily absorbable activator characterized by the combination of vitamin E and a vitamin preparation (Japanese Patent Application Laid-Open (JP-A) No. 5-213637), equivalent to 8% or more of the total amount of calcium in terms of calcium A calcium preparation characterized by containing calcium ascorbate (JP-A-9-157171) has been reported.
しかし、 このうちァスコルビン酸塩が配合された組成物において、 上記ミ ネラル成分を塩基性塩として配合すると、 着色変化すること、 とりわけ水分 存在下あるいは高湿度条件 （湿度 7 5 %以上） において着色変化が顕著であ ることが判明した。 また、 ァスコルビン酸塩、 とりわけ、 ァスコルビン酸力 ルシゥムを配合した圧縮成形物は、 一般に、 錠剤特性（例、 成形性、 強度等） が劣り、 打錠障害 （例、 バインディング， キヤッビング等） を起こしやすい ことが知られている。  However, in the 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. In addition, 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.
本発明の第一の目的は、 塩基性塩と共に配合されていても着色変化等が抑 えられた安定なァスコルビン酸塩を含有する組成物を提供することである。 本願発明の第二の目的は、 優れた錠剤特性 （例、 成形性、 強度等） を有し、 打錠障害 （例、 バインディング， キヤッビング等） の少ないァスコルビン酸 塩を含有する組成物およびその製造方法を提供することである。 さらには塩 基性塩、 およびァスコルビン酸塩を共に含有する組成物の安定化方法を提供 することである。 発明の開示  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
本発明者らは、 塩基性塩と共に配合されていても、 着色変化等が抑えられ た安定で、 優れた錠剤特性を有し、 かつ打錠障害の少ないァスコルビン酸塩 を含有する組成物を検討した結果、 顆粒化した塩基性塩を配合することによ りァスコルビン酸塩を安定に維持することができること、 さらには結合剤お よび崩壊剤と共に圧縮成形することにより、 優れた錠剤特性を有し、 打錠障 害の少ないァスコルビン酸塩を含有する圧縮成形物を得ることができるこ とを見いだし、 さらに検討を加え、 本発明を完成した。 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.
すなわち、 本発明は、  That is, the present invention
( 1 ) ァスコルビン酸塩と顆粒化した塩基性塩を含有する組成物、  (1) a composition comprising ascorbate and a granulated basic salt,
(2) ァスコルビン酸塩と顆粒化した塩基性塩を含有する組成物が圧縮成形 物である前記 （ 1 ) 記載の組成物、  (2) The composition according to the above (1), wherein the composition containing ascorbate and the granulated basic salt is a compression-molded product.
(3)顆粒化した塩基性塩の平均粒子径が約 10乃至 1000 である前 記 （ 1 ) 記載の組成物、  (3) The composition according to the above (1), wherein the average particle size of the granulated basic salt is about 10 to 1000,
(4) ァスコルビン酸塩 100重量部に対して、 顆粒化した塩基性塩を約 1 0乃至 10000重量部配合してなる前記 （ 1 ) 記載の組成物、  (4) The composition according to the above (1), wherein the granulated basic salt is blended in an amount of about 10 to 10,000 parts by weight with respect to 100 parts by weight of ascorbate.
( 5) ァスコルビン酸塩がァスコルビン酸カルシウムである前記 （ 1 ) 記載 の組成物、  (5) The composition according to the above (1), wherein the ascorbate is calcium ascorbate,
( 6 ) ァスコルビン酸カルシウムが直打用ァスコルビン酸カルシウムである 前記 （ 5 ) 記載の組成物、  (6) The composition according to (5), wherein the calcium ascorbate is calcium ascorbate for direct hitting.
(7) 塩基性塩がカルシウム塩である前記 （ 1 ) 記載の組成物、  (7) The composition according to the above (1), wherein the basic salt is a calcium salt,
(8) さらに結合剤および崩壊剤を含有する前記 （ 1 ) 記載の組成物、 (8) The composition according to (1), further comprising a binder and a disintegrant.
(9) ァスコルビン酸塩、 顆粒化した塩基性塩、 結合剤および崩壊剤を圧縮 成形することを特徴とするァスコルビン酸塩を含有する圧縮成形物の製造 方法、 (9) A method for producing a compressed molded article containing ascorbate, which comprises compression-molding ascorbate, a granulated basic salt, a binder and a disintegrant,
( 10)顆粒化した塩基性塩を配合してなるァスコルビン酸塩を含有する組 成物の安定化方法、 および  (10) A method for stabilizing a composition containing ascorbate, which is obtained by mixing a granulated basic salt, and
( 1 1 ) ァスコルビン酸塩、 結合剤および崩壊剤を含有する圧縮成形物を製 造するための顆粒化した塩基性塩の使用  (11) Use of granulated basic salt for producing compression molded product containing ascorbate, binder and disintegrant
に関する。 発明を実施するための最良の形態 About. BEST MODE FOR CARRYING OUT THE INVENTION
本発明におけるァスコルビン酸塩とは、 ァスコルビン酸またはその誘導体 の塩を示す。 ァスコルビン酸の誘導体とはァスコルビン酸の配糖体 （例、 ァ スコルビン酸 2—ダルコシド等） ， ァスコルビン酸のエステル （例、 L—ァ スコルビン酸 2リン酸等） に代表されるァスコルビン酸のプロドラッグを含 む。 ァスコルビン酸のプロドラッグとは、 生体内における生理条件下で酵素 や胃酸等による反応によりァスコルビン酸に変換する化合物、 すなわち酵素 的に酸化， 還元， 加水分解等を起こしてァスコルビン酸に変化する化合物、 胃酸等により加水分解等を起こしてァスコルビン酸に変化する化合物をい う。 ァスコルビン酸またはその誘導体の塩としては、 アルカリ金属塩 （例、 ナト リ ウム塩， カリ ウム塩等） ， アルカリ土類金属塩 （例、 カルシウム塩， マグネシウム塩等） に代表されるァスコルビン酸の金属塩が挙げられる。 ミネラル成分の配合量を維持しつつ、 その供給源の 1つである塩基性塩の 配合量を減らす目的から、 ァスコルビン酸塩としては好ましくはァスコルビ ン酸の金属塩、 より好ましくはァスコルビン酸のアルカリ土類金属塩 （例、 カルシウム塩， マグネシウム塩等） 、 さらには好ましくは、 カルシウムのバ ィォアベイラビリティを改善する目的からァスコルビン酸カルシウムが挙 げられる。 ァスコルビン酸カルシウムとしては、 とりわけ、 特開平 3 — 4 7 1 2 1に記載されたァスコルビン酸カルシウム造粒物に代表される、 造粒物 1 0 gを 1 0 0 m lの水に溶解することにより得られる水溶液の p Hが 5 . 0乃至 7 . 0となる量の酒石酸， クェン酸等の有機固体酸 （好ましくは脂肪 族カルボン酸） を含有してなるァスコルビン酸カルシウム造粒物が好ましく、 該造粒物の平均粒子経が約 2 0 0乃至 4 0 0 ； u mである造粒物がより好ま しい。 さらに好ましくは、 直打用ァスコルビン酸カルシウムが好ましい。 直 打用ァスコルビン酸カルシウムとは、 直接打錠することができる組成物を意 味する。 好ましくは顆粒化されているものである。 例えば 「ァスコルビン酸 カルシウムを約 8 0乃至 9 9重量％、 結合剤 （例、 ヒドロキシプロピルメチ ルセルロース， ヒ ドロキシプロピルセルロース， メチルセルロース等） を約 0 . 5乃至 1 0重量％ぉよび、 酒石酸またはクェン酸等の固体有機酸 （好ま しくは脂肪族カルボン酸） を約 0 . 0 5乃至 1 5重量％から成る白色〜帯黄 白色の顆粒状または細粒状 （約 2 0 0乃至 4 0 0 u m ) の粉末」 、 具体的に は 「ァスコルビン酸カルシウムを約 9 0乃至 9 9重量％、 結合剤 （例、 ヒ ド ロキシプロピルメチルセルロース， ヒ ドロキシプロピルセルロース， メチル セルロース等） を約 2乃至 5重量％ぉよび、 酒石酸またはクェン酸等の固体 有機酸 （好ましくは脂肪族カルボン酸） を約 0 . 1乃至 5重量％から成る白 色〜帯黄白色の顆粒状または細粒状 （約 2 0 0乃至 4 0 0 ^ m) の粉末」 、 さらに具体的には 「ァスコルビン酸カルシウムを重量 9 7 %、 ヒドロキシフ。 口ピルメチルセルロース 2 . 9重量％ぉよび酒石酸 0 . 1重量％から成る白 色〜帯黄白色の細粒状 （約 2 5 0 m ) の粉末」 である。 このような直打用 ァスコルビン酸カルシウムは商業的に入手可能である。 また、 特開平 3— 4 7 1 2 1に準じて製造することも可能である。 このように、 ァスコルビン酸 カルシウムは顆粒化または細粒化したァスコルビン酸カルシウムをも包含 する。 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. to be converted to ascorbic acid, It refers to a compound that is converted to ascorbic acid by causing hydrolysis or the like by stomach acid. Examples of 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.), and more preferably, 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. More preferably, 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). ) 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. Thus, calcium ascorbate also includes granulated or finely divided calcium ascorbate.
以下に示すァスコルビン酸塩の量に関する記載においては、 実際のァスコ ルビン酸塩の量として規定する。 例えば、 直打用ァスコルビン酸を用いた時、 直打用ァスコルビン酸カルシウム全量ではなく、 その中に含まれるァスコル ビン酸カルシウムの量として規定する。  In the following description of the amount of ascorbate, it is specified as the actual amount of ascorbate. For example, when ascorbic acid for direct hit is used, it is defined as the amount of calcium ascorbate contained therein rather than the total amount of calcium ascorbate for direct hit.
本発明における塩基性塩とは、 ミネラル成分として配合されるものが多く、 該塩基性塩の 5重量％水溶液の p Hが約 8以上、 好ましくは p Hが約 8乃至 1 1を示す塩基性無機塩または塩基性有機塩 （例、 ダルコン酸カルシウム、 乳酸カルシウム、 クェン酸カルシウム等） である。 好ましくは塩基性無機塩、 より好ましくは塩基性アル力リ金属塩 （例、 塩基性ナトリゥム塩， 塩基性力 リウム塩等） または塩基性アルカリ土類金属塩 （例、 塩基性カルシウム塩， 塩基性マグネシウム塩等） に代表される塩基性無機金属塩 〔例、 炭酸カルシ ゥム （沈降炭酸カルシウムを含む） ， 酸化カルシウム， 水酸化カルシウム， 炭酸マグネシゥム、 酸化マグネシゥム， 水酸化マグネシゥム等〕 、 さらに好 ましくは塩基性アルカリ土類金属塩 （例、 塩基性カルシウム塩， 塩基性マグ ネシゥム塩等） 、 最も好ましくは塩基性カルシウム塩 〔例、 炭酸カルシウム (沈降炭酸カルシウムを含む） ， 酸化カルシウム， 水酸化カルシウム等〕 が 挙げられる。 このうち、 炭酸カルシウム （沈降炭酸カルシウムを含む） が好 ましい。  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.). Preferably 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.), most preferably basic calcium salts [eg, calcium carbonate (including precipitated calcium carbonate), calcium oxide, hydroxide Calcium, etc.]. Of these, calcium carbonate (including precipitated calcium carbonate) is preferred.
これらの塩基性塩は、 制酸剤ある t、は安定化剤等として配合されていても よい。 顆粒化した塩基性塩は、 薬理的に許容される賦形剤、 結合剤、 崩壊剤等を 含有することが多い。 例えば、 乳糖、 粉糖、 白糖、 D—マンニトール、 トウ モロコシデンプン （コンスターチ） 、 バレイショデンプン、 ヒドロキシプロ ピルスターチ、 無水ケィ酸、 リン酸水素カルシウム、 無水リン酸水素カルシ ゥム、 L-システィン等の賦形剤；メチルセルロース、 結晶セルロース [例、 アビセル K G 8 0 1 (商品名、 旭化成工業） 等] 、 ヒドロキシプロピルセル ロース、 ヒドロキシプロピルメチルセルロース （例えば、 ヒドロキシプロピ ルメチルセルロース 2 2 0 8、 ヒドロキシプロピルメチルセルロース 2 9 0 6、 ヒドロキシプロピルメチルセルロース 2 9 1 0等） 、 カルボキシメチル セルロース、 カルボキシメチルセルロースナトリウム、 ポリビニルアルコー ル、 ポリビニルピロリ ドン、 ゼラチン、 デキストリン、 デンプン、 アルファ 一化デンプン、 アラビアゴム末、 プルラン、 デンプン糊等、 好ましくは結晶 セルロース [例、 アビセル K G 8 0 1 (商品名、 旭化成工業） 等] 、 ヒドロ キシプロピルセルロース等の結合剤；カルボキシメチルセルロースカルシゥ ム [カルメロ一スカルシウム、 例えば、 E C G 5 0 5 (商品名、 五徳薬品） 等] 、 低置換度ヒドロキシプロピルセルロース [例、 LH- 11， LH-21 , LH- 31 , LH-22, LH-32, LH-20, LH-30, (商品名、 信越化学工業） 等] 、 クロスカル メロースナトリウム [例えば、 ァクジゾル（商品名、 旭化成工業)等]、 部分ァ ルファ一化デンプン、 カルボキシメチルスターチナトリウム、 低置換度カル ボキシメチルスターチナトリウム、 クロスポビドン等の崩壊剤等が挙げられ る。 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. 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. Excipients: 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, LH-31, LH-22, LH- 32, LH-20, LH-30, (trade name, Shin-Etsu Chemical Co., Ltd.), croscarmellose sodium [eg, axidisol (trade name, Asahi Kasei Kogyo), etc.], partially alpha starch, sodium carboxymethyl starch And disintegrating agents such as low-substituted sodium carboxymethyl starch and crospovidone.
塩基性塩の顆粒化の際、 少なく とも結合剤を用いることが好ましい。 これ ら賦形剤、 結合剤、 崩壊剤等は 2種以上組み合わせて用いることができる。 とりわけ、 結合剤として結晶セルロース [例、 アビセル K G 8 0 1 (商品名） 等] とヒドロキシプロピルセルロースとを組み合せて用いることが好ましい。 この時、結合剤中の結晶セルロースとヒドロキシプロピルセルロースの配合 比は、 ヒドロキシプロピルセルロース 1 0 0重量部当たり、 好ましくは結晶 セルロースを約 1乃至 1 0 0 0重量部、 より好ましくは約 1 0乃至 3 0 0重 量部である。 顆粒化した塩基性塩における結合剤の含有量は、 塩基性塩 1 0 0重量部に対して、 好ましくは約 1乃至 1 0 0 0重量部、 より好ましくは約 1乃至 1 0 0重量部である。 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. At this time, 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.
本発明組成物中の顆粒化した塩基性塩の配合量は配合すべきミネラル成 分とその量によって変化するが、 ァスコルビン酸塩 1 0 0重量部に対して、 例えば約 1 0乃至 1 0 0 0 0重量部、好ましくは約 5 0乃至 5 0 0 0重量部、 より好ましくは約 1 0 0乃至 1 0 0 0重量部である。  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.
顆粒化した塩基性塩の平均粒子径は、好ましくは約 1 0乃至 1 0 0 0 m、 より好ましくは約 1 0 0乃至 8 0 0 m、 さらに好ましくは約 2 0 0乃至 4 0 0 μ mである。  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 μm. It is.
本発明の組成物には、 以下に示す圧縮成形物 （例、 錠剤， カブレツ ト， チ ユアブル等） のみならず、 圧縮成形前の組成物、 および最終製剤としての組 成物 （例、 顆粒剤， カプセル剤等） をも含まれる。  The 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.).
例えば、 本発明の圧縮成形物は、 ァスコルビン酸塩と顆粒化した塩基性塩 を圧縮成形することにより得ることができる。 さらに結合剤および崩壊剤と 共に圧縮成形することが好ましい。 結合剤および崩壊剤として、 例えば上記 した顆粒化した塩基性塩に用いるものと同様のものが挙げられる。 圧縮成形 時に配合される結合剤としては、 好ましくは結晶セルロース [例、 アビセル K G 8 0 1 (商品名） 等] , ヒドロキシプロピルセルロース， ヒドロキシフ。 口ピルメチルセルロース （例えば、 ヒ ドロキシプロピルメチルセルロース 2 2 0 8、 ヒ ドロキシプロピルメチルセルロース 2 9 0 6、 ヒ ドロキシプロピ ルメチルセルロース 2 9 1 0等） 等、 より好ましくは結晶セルロース [例、 アビセル K G 8 0 1 (商品名） 等] 等が挙げられる。 圧縮成形時に用いられ る崩壊剤としては、 好ましくはカルボキシメチルセルロースカルシウム [力 ルメロースカルシウム、 例えば、 E C G 5 0 5 (商品名、 五徳薬品） 等] 、 低置換度ヒドロキシプロピルセルロース [例、 LH- 11 , LH-21 , LH-31 , LH-22, LH-32 , LH-20 , LH-30 , (商品名、 信越化学工業） 等] 、 クロスカルメロ一 スナト リ ウム [例えば、 ァクジゾル（商品名、 旭化成工業)等]等、 より好まし くは低置換度ヒドロキシプロピルセルロース等が挙げられる。  For example, 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. Examples of the binder and the disintegrant include those similar to those used for the above-mentioned granulated basic salt. As 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.), and more preferably 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.
圧縮成形時に配合される結合剤はァスコルビン酸塩 1 0 0重量部に対し て、 好ましくは約 1乃至 1000重量部、 より好ましくは約 1乃至 100重 量部である。 圧縮成形時に使用される崩壊剤はァスコルビン酸塩 100重量 部に対して、 好ましくは約 1乃至 1000重量部、 より好ましくは約 1乃至 100重量部である。 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.
圧縮成形時に配合される （ 1 ) ァスコルビン酸塩， （2) 顆粒化した塩基 性塩， （3) 結合剤， および （4) 崩壊剤の配合比 （重量） は、 例えば好ま しくは 100 ：約 10乃至 10000 ：約 1乃至 1000 ：約 1乃至 100 0、 好ましくは 100 ：約 50乃至 5000 ：約 1乃至 500 ：約 1乃至 5 00、 より好ましくは 100 ：約 100乃至 1000 ：約 1乃至 100 ：約 1乃至 100である。  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.
圧縮成形の際に、 所望により、 ァスコルビン酸塩以外のビタミ ン、 滑沢剤、 着香剤、 着色剤、 安定化剤、 吸着剤、 帯電防止剤、 矯味剤、 界面活性剤、 固 体有機酸等を加えてもよい。  During compression molding, if desired, vitamins other than ascorbate, lubricants, flavoring agents, coloring agents, stabilizers, adsorbents, antistatic agents, flavoring agents, surfactants, solid organic acids Etc. may be added.
ァスコルビン酸塩以外のビクミンとしては、 例えば、 ビタミン A、 ビクミ B、 ビタミン D、 ビタミン E、 ニコチン酸アミ ド等の水溶性および脂溶性 のビタミンを挙げられる。 具体的には、 例えばビクミン A、 ビクミン お よびその誘導体 （例、 プロスルチアミ ン， フルスルチアミ ン， ジセチアミ ン， ォク トチアミ ン， チアミ ンジスルフイ ド， シコチアミ ン， ビスイブチアミ ン， ビスベンチアミ ン， ベンフォチアミ ン等） 、 ビクミ ン B2、 ビクミ ン B6、 ビ クミ ン B丄 2 (例、 シァノコバラミ ン、 ヒドロキソコバラミ ン、 胙酸ヒドロキ ソコバラミ ン、 塩酸ヒ ドロキソコバラミ ン、 メコバラミ ン （メチルコバラミ ン） 、 補酵素型ビタミン B12等のコバラミン類縁化合物およびその塩等） 、 ニコチン酸ァミ ド、 パントテン酸またはその塩 （例、 パン 卜テン酸カルシゥ ム等） 、 葉酸、 ビォチン、 リポ酸、 イノシトール、 コ リ ン、 ビタミ ン D2、 ビタミ ン D 3、 ビタミ ン D4、 ビタミ ン D5、 ビクミ ン D 6、 ビタミ ン D 7、 ビ クミン E、 ビタミン 、 ビタミンし、 ビタミン P、 またはこれらの塩等が挙 げられる。 とりわけ、 塩基性塩としてカルシウム塩を選択した場合には、 力 ルシゥムの吸収性を向上させるため、 ビタミン D (特に好ましくはビタミン D3) を配合することが好ましい。 ビタミン D3は空気および光に不安定なた め、 ゼラチンビーズの如く保護されたビタミ ン D 3 〔例、 理研ビタミ ン社製 のゼラチンビーズ （理研ドライ D 3 - B5 (商品名） ） を使用することが、 とり わけ好ましい。 Examples of bicumin other than ascorbate include water-soluble and fat-soluble vitamins such as vitamin A, bicum B, vitamin D, vitamin E, and nicotinic acid amide. Specifically, for example, 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丄2 (eg, Shianokobarami down, hydroxocobalamin Mi emissions,胙酸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 pantothenate), folic acid, biotin, lipoic acid, inositol, colin, vitamin D 2, vitamin D 3, vitamin D 4, vitamin Down D 5, Bikumi emissions D 6, vitamin D 7, bi cumin E, vitamin, and vitamin, vitamin P, or the like salts thereof, can be mentioned up. In particular, when a calcium salt is selected as the basic salt, it is preferable to add vitamin D (particularly preferably vitamin D 3 ) in order to improve the absorption of potassium hydroxide. Vitamin D 3 is unstable to air and light Because, 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.
滑沢剤としては、 例えば、 ステアリ ン酸、 ステアリ ン酸マグネシウム、 ス テアリン酸カルシウム、 軽質無水ケィ酸、 タルク等が挙げられる。  Lubricants include, for example, stearate, magnesium stearate, calcium stearate, light silicic anhydride, talc and the like.
着香剤としては、 例えば、 各種フレーバー等が挙げられる。  Examples of the flavoring agent include various flavors.
着色剤としては、 例えば、 酸化鉄、 レーキ色素類、 タール色素、 カラメル、 ベンガラ等が挙げられる。  Examples of the coloring agent include iron oxide, lake pigments, tar pigments, caramel, red bengal and the like.
安定化剤としては、 例えば、 亜硫酸水素ナトリウム等が挙げられる 吸着剤としては、 例えば、 軽質無水ケィ酸、 ゲイ酸カルシウム 〔例、 フロ Examples of the stabilizer include sodium bisulfite and the like. Examples of the adsorbent include light caustic anhydride, calcium gayate [e.g.,
—ライ ト （商品名， エーザィ） 等が挙げられる。 — Lights (product name, Eisai), etc.
帯電防止剤としては、 例えば、 タルク、 軽質無水ゲイ酸等が挙げられる。 矯味剤としては、 例えば、 乳糖、 白糖、 ブドウ糖、 マンニトール等が挙げ られる。  Examples of the antistatic agent include talc and light gay anhydride. Examples of the flavoring agent include lactose, sucrose, glucose, mannitol and the like.
界面活性剤としては、 例えばアルキル硫酸ナト リ ウム等のァニオン系界面 活性剤；ポリォキシエチレンソルビタン脂肪酸エステル， ポリォキシェチレ ン脂肪酸エステル， ポリオキシエチレンヒマシ油誘導体， ポリプロピレンォ キサイ ドーポリエチレンォキサイ ドブロック共重合体 ί.プルロニック （商品 名） 等〕 等の非イオン系界面活性剤等が挙げられる。  Examples of the surfactant 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. Nonionic surfactants such as polymer {Pluronic (trade name) etc.].
固体有機酸としては一塩基性脂肪族カルボン酸 （例、 グリ コール酸） ， 二 塩基性脂肪族カルボン酸 （例、 酒石酸， フタール酸， マレイン酸， マロン酸， リ ンゴ酸， コハク酸） および三塩基性脂肪族カルボン酸 （例、 無水クェン酸， クェン酸） 等の脂肪族等の脂肪族カルボン酸、 またはエリソルビン酸および ァスコルビン酸等のエノール酸等が挙げられる。  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.
これらの添加物の配合量は各々適宜調節される。  The amount of each of these additives is appropriately adjusted.
ァスコルビン酸塩と顆粒化した塩基性塩を含有する本発明組成物は、 自体 公知の製剤学的手法の組み合わせにより製造することができる。 例えば、 本 発明の圧縮成形物は以下のようにして製造することができる。  The composition of the present invention containing ascorbate and a granulated basic salt can be produced by a combination of per se known pharmaceutical techniques. For example, the compression molded product of the present invention can be manufactured as follows.
( 1 ) 顆粒化した塩基性塩の製造 本願発明の顆粒化した塩基性塩は自体公知の方法、例えば圧密造粒機等の 乾式造粒機を利用した乾式造粒法、 あるいは転動造粒機， 撹拌造粒機， 流動 造粒機， 噴霧造粒機， 遠心転動造粒機， 転動流動造粒機， 押出し造粒機等の 湿式造粒機を利用した温式造粒法等により得ることができる。 湿式造粒法に 用いられる溶液としては、 例えば、 水， アルコール類（例、 メタノール， ェ タノ一ル， イソプロパノール等）， エステル類， ケトン類， エーテル類等の 有機溶媒またはその混合液が挙げられる。 好ましくは、 水， アルコール（さ らに好ましくはエタノール）あるいは水/アルコール（さらに好ましくはエタ ノール）混合液が用いられる。 (1) Production of granulated basic salt 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. 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. . Preferably, water, alcohol (more preferably, ethanol) or a mixed solution of water / alcohol (more preferably, ethanol) is used.
例えば、 流動層造粒機を使用する場合、 以下のように製造することができ る。 炭酸カルシウム、 炭酸マグネシウムおよび結晶セルロース 〔例、 セオラ ス K G 8 0 1 (商品名、 旭化成工業） 等〕 を流動層造粒機に入れ、 混合のの ち、 ヒ ドロキシブ口ピルメチルセルロース水溶液を噴霧して乾燥することに より顆粒原料を製造する。 該ヒドロキシプロピルセルロース水溶液の濃度は 好ましくは約 0 . 5乃至 2 0重量％、 より好ましくは約 1乃至 1 0重量％で ある。  For example, 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.
例えば、 攪拌造粒機を使用する場合、 以下のように製造することができる。 塩基性塩（例、炭酸カルシウム、炭酸マグネシウム等）、結晶セルロース〔例、 セォラス K G 8 0 1 (商品名、 旭化成工業） 等〕 およびヒドロキシプロピル セルロースをバーチカルグラ二ユレ一夕一 （パゥレック社製） に入れて混合 する。 得られた混合物に精製水を添加して造粒する。 得られた造粒物を真空 乾燥 （例えば、 4 0 °C , 1 6時間） することにより、 顆粒原料を製造する。 こうして製造された顆粒原料を所望により粉砕することにより、好ましく は平均粒子経約 1 0乃至 1 0 0 0 m、 より好ましくは平均粒子経約 1 0 0 乃至 8 0 0 m、 さらに好ましくは平均粒子経約 2 0 0乃至 4 0 0 mの顆 粒化した塩基性塩を得ることができる。  For example, 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. 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.
( 2 ) 圧縮形成物の製造  (2) Production of compacts
顆粒化した塩基性塩、 ァスコルビン酸塩 〔例、 ァスコルビン酸カルシウム 結晶、 直打用ァスコルビン酸カルシウム 〔(： ' CAL-97 (略称） 、 武田薬品ェ 業〕 等〕 ） 、 所望によりビタミン D 3ゼラチンビーズ 〔例、 ビタミン D 3 -B5 (商品名、 理研ビクミン） 〕 、 結合剤 〔例、 結晶セルロース 〔例、 セォラス K G 8 0 1 (商品名、 旭化成工業） 等〕 、 崩壊剤 〔例、 低置換度ヒド口キシ プロピルセルロース （例、 LH-11 (商品名、 信越化学工業） 等） および所望 により滑沢剤（例、ステアリン酸マグネシゥム等）等をタンブラ一混合機（昭 和化学機械製） 等で混合し、 打錠用顆粒を得る。 得られた打錠用顆粒を π— タリー打錠機 （菊水製作所製） 等で打錠することにより、 圧縮成形物 （例、 錠剤） を得ることができる。 圧縮成形時の打錠圧は、 好ましくは約 0 . 5乃 至 5 卜ン Zcm2、 より好ましくは約 1乃至 3 トン Zcm2である。 Granulated basic salt, ascorbate [eg, calcium ascorbate crystal, direct-use calcium ascorbate [(: 'CAL-97 (abbreviation), Takeda Pharmaceutical Co., Ltd.) Industry) etc.)), if desired, 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.) and, if desired, a lubricant (eg, magnesium stearate, etc.). Mix with a tumbler mixer (manufactured by Showa Kagaku Kikai) to obtain granules for tableting. By compressing the obtained granules for tableting with a π-tally tableting machine (manufactured by Kikusui Seisakusho) or the like, 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 .
所望により、 得られた圧縮成形物に被覆層 （糖衣層， フィルムコ一ティン グ層等） を形成させてもよい。 例えば、 糖衣機を使用して、 滅菌タルクおよ びアラビアゴム末等の散布剤を散布しながら、 酸化チタン、 滅菌タルク、 グ ラニユウ糖等を含有する練込液を注入し、 糖衣層を形成する。 その後、 さら に所望により着色、 さらにはカルナゥバロウ又は白ロウ等によりつや出しを 行う。  If desired, a coating layer (sugar coating layer, film coating layer, etc.) may be formed on the obtained compression molded product. For example, using a sugar-coating machine, 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.
また、 上記糖衣層の形成時に、 グラニユウ糖に代えてフィルムコ一ティン グ基剤を用いることによりフィルムコーティング層を形成することができ る。  In addition, when the sugar coating layer is formed, a film coating layer can be formed by using a film coating base instead of granulated sugar.
本発明組成物は哺乳動物、 とりわけヒトに安全に投与することができる。 その投与態様は経口投与が好ましい。その投与量はヒ卜成人（体重 5 0 k g ) 1日あたり、 ァスコルビン酸として約 5 0乃至 2 0 0 O m gであり、 1日あ たり約 1〜3回投与される。 また、 ミネラル成分としてカルシウムを配合す る際のカルシウムの投与量はヒト成人 （体重 5 O k ) 1日あたり、 約 3 0 0乃至 7 0 O m gが好ましい。 本発明はさらに以下の実施例、 参考例、 試験例で詳しく説明されるが、 こ れらは単なる例であって本発明を限定するものではない。  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. When calcium is added as a mineral component, the dosage of calcium is preferably about 300 to 70 Omg per day for a human adult (body weight 5 Ok). The present invention is further described in the following examples, reference examples and test examples, which are merely examples and do not limit the present invention.
実施例 1  Example 1
沈降炭酸カルシウム 2711.2g、 炭酸マグネシウム 240. Ogおよび結晶セル ロース 84.8gを流動層造粒機 （FD- 5S型、 バウレック社製） に入れ、 約 2分 間混合ののち、ヒドロキシプロピルセルロース 6重量 k溶液を 50gZ分の速 度で合計 2400g噴霧し、 乾燥して顆粒原料を製造した。 こうして得た顆粒原 料を粉砕 （スクリーン 1 .5mm ø、 パワーミル、 昭和化学機械製） することに より平均粒子経 3 2 0 の顆粒化した塩基性塩を得た。 得られた顆粒化し た塩基性塩、平均粒子経約 8 0 ;u mのァスコルビン酸カルシウム 1217.2g、 ビタミン D3ゼラチンビーズ 160.0g、 結晶セルロース 173.6g、 低置換度ヒド ロキシプロピルセルロース （LH-11 (商品名）信越化学工業社製） 160.4g、 ス テアリン酸マグネシウム 28.8gをクンブラー混合機 （TM- 15型、 昭和化学機 械製） で混合し、 打錠用組成物 （顆粒） を得た。 得られた打錠用組成物 （顆 粒） をロータリ一打錠機（コレク ト 12HUK、菊水製作所製） を用いて、 410mg/ 錠、 直径 9mm ø、 曲率半径 13匪、 回転数 30rpm、 打錠圧 2 トン/ cm2の条件で 打錠することにより錠剤を得た。 Precipitated calcium carbonate 2711.2 g, magnesium carbonate 240. Og and crystal cell 84.8 g of loin is placed in a fluidized bed granulator (FD-5S, manufactured by Baurek), mixed for about 2 minutes, and sprayed with a total of 2400 g of a hydroxypropylcellulose 6 wt. K solution at a speed of 50 gZ and dried. As a result, a granular raw material was produced. The granulated raw material thus obtained was pulverized (screen 1.5 mm, power mill, manufactured by Showa Chemical Machinery Co., Ltd.) to obtain a granulated basic salt having an average particle size of 320. 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). Using a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho), the obtained tableting composition (condyles) was 410 mg / tablet, diameter 9 mm ø, radius of curvature 13 bandits, rotation speed 30 rpm, and tableting. Tablets were obtained by tableting under a pressure of 2 ton / cm 2 .
6錠当たりの各成分の配合量を〔表 1〕に示す。 さらに、打錠用組成物（顆 粒）の流動性、圧縮成形性および錠剤の外観を錠剤の初期特性として〔表 2〕 にまとめた。  [Table 1] shows the amount of each component per 6 tablets. In addition, Table 2 summarizes the flowability, compression moldability, and tablet appearance of the tableting composition (condyles) as the initial properties of the tablet.
実施例 2  Example 2
ァスコルビン酸カルシウムに変えて、 平均粒子経 2 5 0 の直打用ァス コルビン酸カルシウム （C ' CAL-97 (略称）、 武田薬品工業） 1254.8gを使用す る以外は、 実施例 1と同様に製造し、 410mg/錠、 直径 9mm ø、 曲率半径 13龍 の錠剤を得た。  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 mmø, and a radius of curvature of 13 dragons.
6錠当たりの各成分の配合量を〔表 1〕に示す。 さらに、打錠用組成物（顆 粒）の流動性、圧縮成形性および錠剤の外観を錠剤の初期特性として〔表 2〕 にまとめた。  [Table 1] shows the amount of each component per 6 tablets. In addition, Table 2 summarizes the flowability, compression moldability, and tablet appearance of the tableting composition (condyles) as the initial properties of the tablet.
比較例  Comparative example
ァスコルビン酸カルシウム 1217.2g、 沈降炭酸カルシウム 2711 .2g、 炭酸 マグネシウム 240. Og および結晶セルロース 84.8g を流動層造粒機 （FD- 5S 型、 バウレック社製） に入れ、 約 2分間混合ののち、 ヒドロキシプロピルセ ルロースの 6%水溶液を 50gZ分の速度で 2400 · Ogを噴霧し乾燥して顆粒原料 を製造した。 こうして得た顆粒原料を粉碎 （スクリーン 1 .5mm ø、 パワーミ ル、 昭和化学機械製） することにより平均粒子経 3 5 0 mの顆粒化した塩 基性塩を得た。 得られた顆粒化した塩基性塩、 ビタミン D3ゼラチンビーズ'' 160. Og. 結晶セルロース （セォラス KG80 商品名）旭化成工業社製） 173.6g、 低置換度ヒドロキシプロピルセルロース （LH- 11 (商品名）信越化学工業社製） 160.4g、 ステアリン酸マグネシウム 28.8gを加え、 タンブラ一混合機 （TM- 15型、 昭和化学機械製） で混合し、 打錠用顆粒を得た。 得られた打錠用顆粒 を実施例 1と同じ条件で圧縮成形することにより、 410mg/錠、 直径 9mm ø、 曲率半径 13mmの錠剤を得た。 Put 1217.2 g of calcium ascorbate, 2711.2 g of precipitated calcium carbonate, 240. Og of magnesium carbonate and 84.8 g of crystalline cellulose in a fluid bed granulator (FD-5S, manufactured by Baurek), mix for about 2 minutes, and mix with hydroxy. A 6% aqueous solution of propylcellulose is sprayed with 2400 Was manufactured. The thus obtained granule raw material was ground (screen 1.5 mm ø, Powermill, manufactured by Showa Chemical Machinery Co., Ltd.) to obtain a base salt having an average particle diameter of 350 m which was granulated. The obtained granulated basic salt, vitamin D 3 gelatin beads '' 160. Og. 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 ø, and a radius of curvature of 13 mm.
6錠当たりの各成分の配合量を 〔表 1〕 に示す。 さらに、 打錠用顆粒の流 動性、 圧縮成形性および錠剤の外観を錠剤の初期特性として 〔表 2〕 にまと めた。 Table 1 shows the amounts of each component per 6 tablets. In addition, the fluidity, compression moldability and tablet appearance of the granules for tableting are summarized in Table 2 as the initial properties of the tablets.
Figure imgf000016_0001
Figure imgf000016_0001
〔表 2 〕  (Table 2)
錠剤の初期特性 Initial properties of tablets
実施例 1 実施例 2 比較例 打錠用顆粒の 良好 優れている 良好 流動性  Example 1 Example 2 Comparative Example Good for tableting granules Good Good Good flowability
圧縮成形性 良好 優れている 劣る 錠剤外観 白色 白色 黄褐色 試験例 1 Compression moldability Good Excellent Poor Tablet appearance White White Yellowish brown Test example 1
実施例 1、実施例 2および比較例で得た錠剤特性（厚み， 硬度， 崩壊時間） を測定した。 その結果を 〔表 3〕 に示す。  The properties (thickness, hardness, disintegration time) of the tablets obtained in Example 1, Example 2 and Comparative Example were measured. The results are shown in Table 3.
1 . 厚みの測定  1. Thickness measurement
実施例 1、 実施例 2および比較例で得た錠剤各 2 0錠の厚さをダイアルゲー ジ （ミツトヨ製） を用いて測定し、 その平均値を求めた。  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.
2 . 硬度の測定  2. Hardness measurement
実施例 1、 実施例 2および比較例で得た錠剤各 1 0錠の硬度を錠剤破壊強度 測定器 （富山産業株式会社製） を用いて測定し、 その平均値を求めた。  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.
3 . 崩壊時間の測定  3. Measurement of disintegration time
日本薬局方第十三改正版に定められた崩壊試験法 （ディスク無） に従い、 実 施例 1、 実施例 2および比較例で得た錠剤各 6錠の崩壊時間を測定し、 その 平均値を求めた。  According to the disintegration test method (without disc) specified in the thirteenth edition of the Japanese Pharmacopoeia, the disintegration time of each of the tablets obtained in Example 1, Example 2 and Comparative Example was measured, and the average value was calculated. I asked.
〔表 3〕  (Table 3)
錠剤特性  Tablet properties
Figure imgf000017_0001
試験例 2
Figure imgf000017_0001
Test example 2
安定性試験  Stability test
実施例 1、 実施例 2および比較例で得た錠剤各 2 4 0錠をポリ瓶 （ポリェチ レンキヤッブ付） で包装し、 温度 4 (TC， 湿度 7 5 %で 2ヶ月、 4ヶ月、 6 ヶ月保存した時の錠剤の外観変化を観察した。 結果を 〔表 4〕 に示す。 〔表 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)
安定性試験 （錠剤の外観変化）  Stability test (change in tablet appearance)
Figure imgf000018_0001
産業上の利用可能性
Figure imgf000018_0001
Industrial applicability
本発明のァスコルビン酸塩を含有する組成物は塩基性塩と共に配合され ていても着色変化等が抑えられ安定である。 本発明のァスコルビン酸塩を含 有する圧縮成形物は優れた錠剤特性 （例、 成形性、 強度、 崩壊性等） を有し、 打錠障害 （例、 バインディング， キヤッビング等） が少ない。 さらに、 圧縮 成形物内部とその糖衣層等の被覆層とに群分けする必要がないので、 製造ェ 程が簡略化できること， 製造時間が短縮できること， および従来糖衣層等の 被覆層に配合していた成分の配合量を容易に調整できることが挙げられる。 また、 ァスコルビン酸カルシウム， 炭酸カルシウムおよびビタミン D 3を 製剤中に配合することにより、 ミネラル成分としてのカルシウムを効率的に 摂取することが可能である。 さらに塩基性塩として炭酸マグネシウムを配合 することにより、 ミネラルとしてのマグネシウムも同時に摂取することが可 能である。 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.

Claims

請求の範囲 The scope of the claims
1 . ァスコルビン酸塩と顆粒化した塩基性塩を含有する組成物。 1. A composition comprising ascorbate and a granulated basic salt.
2 . ァスコルビン酸塩と顆粒化した塩基性塩を含有する組成物が圧縮成形物 である請求項 1記載の組成物。  2. The composition according to claim 1, wherein the composition containing ascorbate and the granulated basic salt is a compression molded product.
3 . 顆粒化した塩基性塩の平均粒子径が約 1 0乃至 1 0 0 0 である請求 項 1記載の組成物。  3. The composition according to claim 1, wherein the average particle size of the granulated basic salt is about 10 to 100.
4 . ァスコルビン酸塩 1 0 0重量部に対して、 顆粒化した塩基性塩を約 1 0 乃至 1 0 0 0 0重量部配合してなる請求項 1記載の組成物。  4. The composition according to claim 1, wherein the granulated basic salt is blended in an amount of about 10 to 1000 parts by weight with respect to 100 parts by weight of ascorbate.
5 . ァスコルビン酸塩がァスコルビン酸カルシウムである請求項 1記載の組 成物。 5. The composition of claim 1, wherein the ascorbate is calcium ascorbate.
6 . ァスコルビン酸カルシウムが直打用ァスコルビン酸カルシウムである請 求項 5記載の組成物。  6. The composition according to claim 5, wherein the calcium ascorbate is direct-acting calcium ascorbate.
7 . 塩基性塩がカルシウム塩である請求項 1記載の組成物。  7. The composition according to claim 1, wherein the basic salt is a calcium salt.
8 . さらに結合剤および崩壊剤を含有する請求項 1記載の組成物。  8. The composition according to claim 1, further comprising a binder and a disintegrant.
9 . ァスコルビン酸塩、 顆粒化した塩基性塩、 結合剤および崩壊剤を圧縮成 形することを特徴とするァスコルビン酸塩を含有する圧縮成形物の製造方 法。  9. A method for producing a compression-molded article containing ascorbate, which comprises compression-molding ascorbate, granulated basic salt, binder and disintegrant.
1 0 . 顆粒化した塩基性塩を配合してなるァスコルビン酸塩を含有する組成 物の安定化方法。  10. A method for stabilizing a composition containing ascorbate, comprising a granulated basic salt.
1 1 . ァスコルビン酸塩、 結合剤および崩壊剤を含有する圧縮成形物を製造 するための顆粒化した塩基性塩の使用。  1 1. Use of a granulated basic salt for producing a compression molded product containing ascorbate, a binder and a disintegrant.
PCT/JP2000/003220 1999-05-20 2000-05-19 Composition containing ascorbic acid salt WO2000071097A1 (en)

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