TW200950819A - Film-coated preparation - Google Patents

Abstract

To obtain a calcium pantothenate-stabilized solid preparation which is little in the irregularity of the content of the calcium pantothenate in the preparation, and can be produced by a simple, and industrially, economically and environmentally advantageous production method. This film-coated preparation is characterized by applying a film layer containing pantothenic acid or its salt to a solid preparation containing a pharmaceutically effective ingredient except the pantothenic acid or its salt.

Description

200950819 IX. Description of the Invention: TECHNICAL FIELD The present invention relates to a solid preparation which is stably formulated with pantothenic acid or a salt thereof. More specifically, the present invention relates to a coated preparation which contains pantothenic acid or a salt thereof in a film layer to make it isothermally stable. [Prior Art] 'The Pantothenic Acid Group belongs to the vitamin B group' is a component of coenzyme A, an enzyme that undergoes acetylation, and is involved in the metabolism of sputum, lipids, and proteins. Moreover, calcium pantothenate has the effect of maintaining normal skin. Therefore, applying these effects, calcium pantothenate and other numerous active ingredients are formulated together with a multivitamin, as well as a nourishing agent, a sleep inhibitor, a vitamin I agent, a strong liver antidote, a female health care drug, a whole intestine/ Antidiarrheal drugs, gastrointestinal drugs, slowing drugs, allergic drugs, internal medicine for skin diseases, etc. However, when calcium pantothenate is a monomer, it is relatively stable. On the other hand, when it is mixed with other active ingredients such as ascorbic acid, thiamine or pyridoxine, it will become 〇4, and calcium pantothenate will be divided, and pantothenic acid will be distributed. Calcium also destabilizes ascorbic acid, thiamine or hydrazine, causing the active ingredients to also decompose. In particular, it has a characteristic that the tendency is remarkable when the calcium pantothenate and the ascorbic acid are blended together. Since the first sputum, various measures have been taken in solid preparations to stabilize calcium pantothenate. For example, there is a method of expecting that the content of the pantothenic dance will decrease over time to increase the amount of pantothenic acid added, and (4) the method of resolving the decomposed component, and by making a nucleated tablet or a laminated tablet, calcium pantothenate and Other methods of forming a knife are obtained by adding barium pantothenate to the sugar coating layer of the sugar-coated tablet 132033.doc 200950819 = (d) (d) method of stabilizing; separating the particles of the compounding component and reducing the contact of the components with each other 'delaying the decomposition of the component Method, etc. In addition, as a method of improving the method of the invention, the granulated product of calcium pantothenate and calcium lactate is stabilized (Patent Document D. As a result of improving the stability of the granulated product: The method also proposes a method for reducing the moisture in the preparation (Patent Document 2). Further, 'also tastes _ by the following method: after the tablet is coated with a water-soluble coating film, 'adding ubi-_ to the sugar-coated layer' The method of sugar-coated tablets (Patent ❹ ❹ Document 3), the method of It-type blending (4) (Patent Document * In the water system, the method of wet granulation together with the swelling agent (Patent Document 5), etc. In addition, there are problems in that the manufacturing steps are complicated, or the stability of the pantothenic acid is not sufficiently ensured. For example, if the granules which have stabilized the calcium pantothenate are separately produced in advance, the cost is increased due to an additional increase in the manufacturing steps. The main reason... Even if the moisture of the preparation is reduced, since calcium pantothenate itself is hygroscopic, stability cannot be guaranteed in some dosage forms or packaging forms. Another _ card product is used to make sugar coated tablets. Sugar coating step There is a disadvantage in that a polymer coating must be applied to a tablet in advance to impart water repellency and moisture resistance, and the step of forming a sugar coating layer takes a lot of time, so that not only the manufacturing cost is increased but also the load on the environment is caused. Also, the sugar-coated tablets have the following disadvantages: not only the tablets become larger and heavier, but also the quality deviation between the tablets is larger than that of the plain tablets (die) or the coated tablets. In the step, it is in a state of high temperature and high humidity, and therefore, it also affects the stability or appearance of other active components of pantothenic acid or coexistence due to poor moisture or temperature management in the manufacturing steps. A method which is capable of stabilizing calcium pantothenate by a method which is easy to use and which is also advantageous in the industrial production and economy, and is also advantageous in the aspect of the present invention. [Patent Document 1] Japanese Patent Laid-Open Publication No. Hei No. Hei. Japanese Laid-Open Patent Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. Document 5] Laid-Open Patent said present 2〇〇6 328〇〇1 Publication No. SUMMARY OF THE INVENTION

[Problem to be Solved by the Invention] An object of the present invention is to provide a solid preparation in which calcium pantothenate is stabilized, which has a small degree of unevenness in a preparation, and which can be utilized easily and industrially, economically, and environmentally. Method to manufacture. [Means for Solving the Problems] The inventors of the present invention have diligently studied to achieve the above object, and as a result, unexpectedly found that 'if the active ingredient other than pantothenic acid 35 is contained in the ID-form preparation, and the film layer coated with the (four) is blended Pan _, to ensure the stability of pan-acid mother. Further, it has been found that the deviation of the content of the preparation for the preparation is small, and thus the present invention has been completed. That is, the present invention provides a coated film of Helan, ... me. The coating preparation contains a pantothenic acid or a salt thereof on a solid agent containing a medicinal ingredient other than pantothenic acid or a salt thereof. The film layer is obtained. [Effects of the Invention] According to the present invention, a solid preparation which ensures the stability of pantothenic acid or a salt thereof can be obtained. In addition, the preparation of the present invention is manufactured by the method of being able to slap the shovel and squeezing the smears, so that the monthly b is easy to use and is advantageous in industrial production and mourning, 132033.doc 200950819, In addition, since the preparation can be miniaturized, the preparation is easy to swallow. 'Elderly and young children are also easy to take. Further, the present invention is widely applied to a multivitamin, a nourishing tonic, a sleepy inhibitor, a vitamin Β ̄, a strong liver. An antidote, a female health care medicine, a whole intestine/antidiarrheal medicine, a gastrointestinal drug, a laxative, an allergy, an internal medicine for dermatological administration, and the like, and a solid preparation in various therapeutic fields in which pantothenic acid or a salt thereof is formulated. The calcium pantothenate used in the present invention (chemical name: M〇n〇calcium bis[3_[(2R)-2,4-dihydroxy-3,3-dimethylbutanoylamino]propanoate]) is a molecular formula CuHwCaNsOw, molecular weight 476·53 The structural component of coenzyme A. Coenzyme A participates in acetylation in living organisms, and participates in the synthesis of substances necessary for various organisms such as steroids, fatty acids, and porphyrins, and participates in Since fat, protein, and carbohydrate are metabolized, calcium pantothenate is used together with various medicinal ingredients in medical pharmaceuticals, general pharmaceuticals, health foods, etc. 〇 as pantothenic acid or a salt thereof used in the present invention, In addition to the above-mentioned calcium pantothenate, a salt such as pantothenic acid or sodium pantothenate may be used. In the present invention, any of these may be used, and calcium pantothenate is preferably used. In the present invention, it is a substance other than pantothenic acid or a salt thereof. The medicinal ingredient is a component which, when used in combination with pantothenic acid or a salt thereof, has a function of decomposing pantothenic acid or a salt thereof and is detrimental to the stability of pantothenic acid or a salt thereof. Examples of such components include anti-defective acid and anti-acid. Bad jk sour mom, ascorbate sodium and other vitamins C. sulphate thiamine, thiamine hydrochloride, sulphate disulfide, dithio thiamine, thiamine sulfate, thiolamine hydrochloride, basal hydrochloride Otto broken sulphate 132033.doc 200950819 serotonamide, bis-isobutyl thiamine, bis-benzothiamine, phenylphosphine thiamine, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, pyridoxine hydrochloride Alcohol, pyridoxal phosphate, cyanocobalamin, salt Acidic hydroxylurmonium, hydroxycobaltium acetate, mecobalamin, nicotinic acid, nicotinamide, biotin, folic acid and other vitamins 8; autotrophic regulators such as acesulfame; thioramine, whey acid, etc. Vitamin-like effect substances; minerals such as calcium hydrogen phosphate and calcium lactate; acetic acid d_a_tocopherol ester, dl-a-tocopheryl acetate, succinic acid, tocopherol ester, succinic acid di_a sputum Such as vitamin E; ergo alcohol, bile alcohol and other vitamins D' L-cysteine, methionine, glycine, arginine and other amino acids; aminoethyl sulphate, Portuguese Sugar-inducing guanamine, glucuronolactone, glycyrrhizic acid, / ursodeoxycholic acid and other liver damage medications; Polygonum multiflorum extract, European hawthorn extract, Acanthopanax dry extract, Epimedium extract, Coix seed Extracts,. Natural medicinal extracts such as liver hydrolysate, bile extract powder, Bupleurum dry extract, Chuan No. dry extract, mountain red dry extract, and dried extract of eucalyptus. The "preparation of the present invention" is a coating preparation in which a pantoic acid or a salt-containing external component thereof is formulated in a solid preparation as described above, and pantothenic acid or a salt thereof is formulated in a film layer of the preparation of the package (IV). The dosage form 'rotary granules, fine granules, etc., particularly preferably tablets. X, can also make St:: acid or its salt coating agent for the tablets, granules, fine particles: coating, And filled in a hard capsule or a soft capsule to form a capsule. = The film layer of the invention of the invention has a high speed and does not reduce the absorption of the United States and has a decrease, and guarantees a strong sound as a film. From the point of view of the necessity of the adhesion rate of the second meaning / Ding Yi clothing not the film strength, it is better 132033.doc 200950819

EF, in addition to pantothenic acid or its salts, also contain water-soluble or gastric-soluble film substrates. Examples of such film base materials include, for example, methyl cellulose, hydroxypropyl cellulose hydroxypropyl fluorene cellulose, polyvinyl pyrrolidone, carboxyvinyl polymer, polyvinyl alcohol, and aminoalkyl methacrylate copolymer; E, polyvinyl acetal diethylamine acetate vinegar, etc., these may be used alone or in combination. The ratio of pantothenic acid or its salt to the film substrate in the β film layer depends on the type or dosage form of the film substrate used. However, in terms of mass ratio (calcium pantothenate: film substrate), the ratio of φ wei is preferably 1:99 to 95:5, particularly preferably 5:95 to 80:20, more preferably 10:90. ~70:30. In addition to the above-mentioned pantothenic acid or a salt thereof and a film substrate, it may be necessary to add, for example, a plasticizer, a coating agent, a dispersing agent, a coloring agent, an antifoaming agent, etc. to the film I, which is usually used in an envelope of an oral pharmaceutical product. Pharmaceutical supplements. Specific examples of the plasticizer include: Kadon 83, triethyl hexahydrate, glycerin, glycerin fatty acid ester, sesame oil, dimethyl polyoxyalkylene, a mixture of cerium oxide, D-sorbitol, Medium long chain triglyceride i, derived from maize * starch sugar alcohol liquid, triacetin, concentrated glycerol 'castor oil, diethyl phthalate, dibutyl phthalate, butyl Butyl phthalic acid butyl phthalate, polyoxyethylene (1 〇 5) polyoxypropylene (5) diol, propylene glycol, polysorbate 80, polyethylene glycol 4 〇〇, polyethylene glycol 6 〇〇, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, cottonseed oil, soybean oil mixture, glyceryl monostearate, etc., these may be used alone or in combination of two or more. In the case where a plasticizer is added to the film layer, the content of the plasticizer is preferably 40 mass. /. the following. 3 As a specific example of the coating agent, in addition to the above-mentioned film substrate, for example, it can be listed as 132033.doc 200950819: ethyl acrylate·methyl methacrylate copolymer dispersion, acetamidine glycerin fatty acid ester, mercapto amide Alkyl ester copolymer RS, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersion, octyl decyl triglyceride, Opadry AMB, Opadry OY-6950, Opadry OY-S-7135 〇padry oy-S-8471, Opadry OY-S-9607,

Opadry OY-S-22829 ' Opadry OY-S-22835 ' Opadry OY-S-

22961, eucalyptus oil, kaolin, cocoa butter, Prunella vulgaris, ricin wax, caramel, carnauba wax, carboxymethyl ethyl cellulose, sodium carboxymethyl starch, calcium carboxymethyl cellulose, carboxymethyl cellulose Sodium, hydrated cerium oxide, dry oxidized gelatin, dried milky white shellac, dry methacrylic acid copolymer, cold plum powder, fish scale foil, gold foil, silver foil, triethyl citrate, glycerin, glycerin fatty acid ester, Magnesium citrate, light anhydrous citric acid, hydroxypropyl cellulose containing light anhydrous citric acid, dilute liquid paraffin, cetyl wax, crystalline cellulose, hardened oil, synthetic Shishi acid, synthetic bismuth, high glucose water# , hard soil, broken (four) gelatin, wheat flour, wheat starch, rice powder, cellulose acetate, vinyl acetate resin, cellulose acetate phthalate, white beeswax, titanium oxide, magnesium oxide, dimethyl methacrylate Amino-based brewing, thioglycolic acid vinegar copolymer, dimercapto-polyoxymethane (internal administration), dimethyl (tetra) oxonium oxyhydroxide, sucrose mixture, calcined gypsum, sucrose fatty acid vinegar, agarwood, hydrogen peroxide (4) Glue, hydrogenated rosin glycerin, hard, hard Alcohol, stearic acid, stearic acid, calcium stearate, polyoxyl stearate 40, magnesium stearate, refined gelatin, fine gum, refined white sugar, zein, sesquiterpene isostearic acid Sorbitol, chlorinated alcohol, gypsum, gelatin, shellac, hawthorn guar xylitol fatty acid ester, D_sorbitol, D-sorbitol liquid, tricalcium phosphate Ί β stone, carbonic acid Calcium, carbonic acid 132033.doc 12 200950819 Magnesium, monosaccharide syrup, medium gold foil, precipitated calcium carbonate, low substituted hydroxypropyl cellulose, terpene resin, starch (soluble), corn syrup, corn oil, triacetin, calcium lactate , lactose, concentrated glycerin, white shellac, sugar, honey, stone

Wax, pearl powder, potato starch, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910. titanium oxide. polyethylene glycol 400 mixture, hydroxypropyl methyl cellulose phthalate, Piperonyl butoxide, castor oil, o-benzoic acid-ethylene, butyl phthalate, butyl butyl phthalate, glucose, fumaric acid, stearic acid Polyvinyl acetal diethylamine acetate. Hydroxypropyl fluorene cellulose 2910 mixture, polytriglucose, propylene glycol, bentonite, povidone, polyoxyethylene hardened castor oil 4 聚, polyoxyethylene hardened castor oil 60, Polyoxyethylene (105) polyoxypropylene (5) diol, polyoxyethylene (160) polyoxypropylene (30) diol, polysorbate 8 〇, polyethylene glycol 300, polyethylene glycol 400, poly Ethylene glycol 6 〇〇, polyethylene glycol 15 〇〇, polyethylene glycol 1540, polyethylene glycol 4 〇〇〇, polyethylene glycol 6 〇〇〇, polyethylene glycol 20000, polyethylene glycol 35000 , £>-mannose yeast, leeches, beeswax, myristyl alcohol, anhydrous citric acid hydrate, phthalic anhydride, anhydrous calcium hydrogen phosphate, methacrylic acid copolymerization L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium metasilicate aluminate, 2-methyl phthalocyanine methyl acrylate, methacrylic acid copolymer, lacquer wax, monostearic acid Aluminum, glyceryl monostearate, succinoic acid monolaurate, montan acid ester wax, medicinal carbon, polyglycerol, sulfuric acid dance, liquid stone butterfly, DL_malic acid, calcium orthophosphate, hydrogen phosphate Calcium, sodium hydrogen phosphate, either alone or in combination, from the viewpoint of adhesion effect, dihydrogen phosphate 4, rosin, etc. are preferable. Further, in these coating agents, it is resistant to the addition of talc. When the coating agent of 132033.doc -13 - 200950819 is added to the film layer, the content of the coating agent is preferably 4% by mass or less. Specific examples of the dispersing agent include methacrylic acid amine-based vinegar copolymer RS, Allah (four), gum arabic powder, oxalic acid propylene glycol vinegar, ethanol 'from acid, sodium carboxycellulose, agar powder, citric acid , sodium citrate, #油, glycerin fatty acid vinegar, magnesium citrate, light anhydrous citric acid, crystalline cellulose hardening / by, synthetic oxime acid, phosphoric acid test, safflower oil, hundred bee ❹ wax titanium oxide, Sodium sulfosuccinate, sucrose fatty acid ester, sodium hydroxide, stearic acid, stearic acid, refined oleic acid, refined soybean egg bowl, sesquistea sulphate, sorbitol Anhydride fatty acid ester, d_sorbitol, soybean oil, soybean imprinted phospholipid, low substituted hydroxypropyl cellulose, dextrin, corn starch, tragacanth powder, sorbitan trioleate, lactose, concentrated glycerin, Horse yam; house powder, ethyl cellulose, propyl fen powder, propylene glycol, propylene glycol fatty acid ester, bentonite, povidone, polyoxyethylene hardened lotus oil, polyoxyethylene hardened castor oil 40, polyoxyethylene Hardened castor oil 6〇, polyoxyethylene (1〇5) polyoxypropylene 5) diol, polyoxyethylene (160) polyoxypropylene (30) diol, polysorbate 2 oxime, polysorbate 6 〇, polysorbate 80 sodium silicate, polyethylene glycol 30 〇 , polyethylene glycol 4000, polyethylene glycol anhydrous sodium citrate, anhydrous sodium pyrophosphate, partial acid aluminate, sodium metaphosphate, lacquer wax, sorbitan monooleate, aluminum monostearate , singapore glycerin, sorbitol liver single-labeled acid ester, sorbitan monolaurate, sodium lauryl sulfate, polyglycerol, liquid paraffin, calcium hydrogen phosphate, etc., δ hai, etc. can be used alone Or use two or more kinds in combination. When the granules are added to the film layer, the content of the dispersant is preferably 25% by mass under 132033.doc •14-200950819. Specific examples of the coloring agent include catechin tannin powder, turmeric extract, yellow ferric oxide, Opaspray-Kl-24904, orange flavor, brown iron oxide, carbon black, caramel, magenta, and carotene solution. , β_carotene, licorice extract, gold foil, black iron oxide, light anhydrous citric acid, titanium oxide, ferric oxide, edible blue nickname, edible yellow No. 4, edible yellow No. 4 aluminum lake, edible Yellow No. 5, Edible Red No. 2, Edible Red No. 3, Q Edible Red No. 1 No. 2, sodium hydroxide, talc, copper chlorophyll sodium, chlorophyll copper, rye green leaf extract, d-borneol, myristate octyl Dodecyl ester, medicinal slave, riboflavin butyrate, riboflavin, green tea powder, riboflavin sodium phosphate, and rose spirit oil may be added alone or in combination of two or more. When the coloring agent is added to the film layer, the content of the coloring agent is preferably 3% by mass or less. Specific examples of the antifoaming agent include ethanol, glycerin fatty acid vinegar, dimethyl polyoxymethane (internal administration), dimethyl polyoxalate, dioxane mixed sputum, sucrose fatty acid ester, hydrazine. Resin emulsion, antimony defoamer, polyoxyl stearate S曰40, sorbitan fatty acid ester, sorbitan trioleate, poly. & sorbitol 80, these may be used alone or Mix two or more types. When the antifoaming agent is added to the film layer, the content of the antifoaming agent is preferably 10% by mass or less. The preparation of the present invention uses a coating liquid containing pantothenic acid or a salt thereof, a solid preparation containing a pharmacological component other than a pantothenic acid or a salt thereof, or the like; Made into a coating preparation. The method for producing a solid preparation is not particularly limited, and a medicinal ingredient other than pantoic acid or a salt thereof, 132033.doc e ❹ 200950819 is mixed with other medicinal ingredients which are optionally formulated, and a preparation additive is added as needed, and then used. It can be manufactured by the conventional method. These solid (four) agents are usually prepared by the usual method of formulation (Tsujin Kousuke Ueno Shou, "Pharmaceutical Development Basic Lecture XI Pharmaceutical Manufacturing Law (I), (below)", The Local Library, issued in 1971; Announced, "Preparation Engineering Handbook", The Local Library, issued in 1983; Nakai Yusuke, "The Latest Powder Material Design", Techn〇System, issued in 1988; Arakawa Text "Development of Pharmaceutical Products" "Unit operation and machinery of the preparation" "Guangchuan Bookstore, issued in 1989; Hiroshi Hiroshi, "Design and evaluation of oral preparations" - Pharmaceutical Times, issued in 1995; Hiroshi Hiroshi, "Design of oral preparations", Pharmaceutical Times, issued in 1995) to prepare P, for example, in the case of preparing tablets, granules, powders, etc., in the case of preparing granulated powders, the granulation method usually employed (using water or organic solvents) Spray granulation method of solution or dispersion, (4) granulation method, fluidized granulation method, rotary granulation method, rotary granulation method, etc. Wet granulation method using a granular binder Method, dry granulation method, etc.): made. The tablets can be prepared by mixing the original powder, the powder, the fine granules, and the granules as long as the preparation additives are subjected to compression molding. 'As a formulation additive used in the manufacture of a solid preparation, a pharmaceutically acceptable carrier can be cited, for example, an excipient, a binder, a disintegrant, a disintegration aid, a foaming agent, a moisture-proof agent, an interface; Agents, emulsifiers, antioxidants, fillers, preservatives, agents, sweeteners, flavoring agents, cooling agents, flavoring agents, perfumes, fragrances, colorants, and the like. Fang Xiang 132033.doc 200950819 As a specific example of the formulation additive, the previously known formulation additives which can be used in the solid preparation as described below can be used for the above purposes: lactose, white sugar, mannitol, xylitol, dextrin, Sorbitol, erythritol, reduced maltose mash, polytriglucose, povidone, cellulose, crystalline cellulose, low substituted hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose , polyethylene glycol, propylene glycol, polyoxyethylene polyoxypropylene diol, croscarmellose sodium, crospovidone, starch, pre-gelatinized starch, carboxymethylcellulose calcium, ethyl cellulose , carboxymethyl starch, fumaric acid, citric acid, stearic acid, magnesium stearate, calcium stearate, talc, light anhydrous citric acid, cerium oxide, talc, sucrose fatty acid ester, polyoxygen Ethylene (105) polyoxypropylene (5) diol, titanium oxide, sodium edetate, propyl gallate, calcium lactate, calcium carbonate, precipitated calcium carbonate, calcium citrate, calcium hydrogen phosphate, aluminum metasilicate Magnesium, gelatin, gum arabic, carnauba wax, white Wax, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylamine acetate, polyoxyethylene polyoxypropylene glycol, dimercapto polyoxyalkylene, glycerol phthalate, medium and long Chain triglyceride, amber gelatin, glycerin, hardened oil, caramel, sodium riboflavin phosphate, ferric oxide, red 102, yellow 5, and the like. There is no coating method for coating the above-mentioned solid preparation with a coating liquid to form a coating, such as '1 coating method, fluidized layer coating method, rotary coating method, dry coating method, or Such combinations of methods and the like. For example, a coating composition containing an acid or a salt thereof and, if necessary, a plasticizer, a coating agent, a dispersing agent, a coloring agent, an antifoaming agent, etc., is added to the film substrate, and dissolved and suspended in purified water. Or a lower alcohol such as ethanol or a mixed solution thereof, 132033.doc 200950819, to prepare a coating liquid, and to coat the preparation by a method conventionally used for the packaging. The coating liquid is preferably adjusted to have a solid content of usually 丨 咒 cursing mass%, particularly preferably adjusted to a solid fraction of 2 to 3 〇 mass%, more preferably adjusted to a solid fraction of 5 to 20% by mass. ❹

In the present invention, the thickness of the film layer formed on the solid preparation is different depending on the dosage form of the solid preparation or its mass, shape, and coating amount (the amount of pantothenic acid or a salt thereof), and it is not particularly specified. 〇〇1 pm~(9) μηι 'Specially good is (Μ _~2, _ μιη, better ι叫~说μπι. For example, if the tablet has a diameter of about 9 _, the quality is about 2 〇〇 Left and right, and the mass ratio of pantothenic acid to the film substrate in the coating layer is 1:1, when the amount of pantothenic acid is about 5 y for each tablet, the thickness is about 65 _, and when the amount of calcium pantothenate is For each tablet of 10 mg, the thickness is about 125 pm. For the preparation of the present invention, the surface layer or the undercoat layer may be formed on the upper side or the lower side of the film layer containing pantothenic acid or a salt thereof to form a two-layer film layer. Alternatively, a surface coating or a primer coating may be simultaneously applied to form a coating preparation having a three-layer film layer. For example, when the solid preparation contains a medicinal ingredient such as L-cysteine which gives off an unpleasant odor. Preferably, it is on the side or the lower side of the film layer containing pantothenic acid or a salt thereof, or on the upper and lower sides The coating is wrapped to cover the odor. In the envelope, a pharmaceutical additive for use in the coating of the above oral pharmaceutical product can be appropriately added, and in particular, from the viewpoint of the deodorizing effect, it is preferred to add Partial saponification of polyvinyl alcohol. From the viewpoint of reducing the effect of unpleasant odor, the degree of recombination of the partially saponified polyethylene glycol is preferably 7% to 7%, and particularly preferably 1% J32033. Doc •18· 200950819 mol%, and the average degree of polymerization is preferably 2〇〇~3,3〇〇, particularly preferably 300~1,500. Among them, the degree of saponification can be based on JIS K6726 (polyvinyl alcohol test) Further, the content of the polyvinyl alcohol in the envelope is preferably from 30 to 100% by mass, particularly preferably from 40%, from the viewpoints of the deodorizing effect, the strength of the bedding, and the ease of coating. 95% by mass. For the preparation of the present invention, the sugar coating may be further coated to form a sugar-coated tablet. If the sugar coating layer is coated on the upper side of the above-mentioned coating preparation, the content of calcium pantothenate between each tablet may also be formed. a sugar-coated tablet having a small deviation. The dosage of the preparation of the present invention is based on the suffering The body weight, age, sex, type of disease, and symptoms are appropriately selected. For example, in terms of calcium pantothenate, it is preferred to administer 〇mg to an adult a day. The coated preparation obtained in this manner is guaranteed to be pantothenic acid or Since the salt is stable, the content thereof is hardly decreased during the storage of the preparation. Moreover, since the preparation does not require a sugar coating step, the preparation can be miniaturized, and the preparation can be simplified and industrially, economically and environmentally. It is also advantageous to manufacture the method. Further, the difference in the content of each preparation is compared with the previous method in which calcium pantothenate is blended in the sugar coating layer to stabilize the calcium pantothenate. [Examples] The present invention will be specifically described by way of examples, but the present invention is not limited by the examples. Example 1: The manufacture of the coated sheet used 600 g of L-cysteine, 75 〇g of ascorbic acid, 1300 g of crystalline cellulose, partially pregelatinized starch 23 〇 、, hydroxypropyl cellulose LV, light no 132033. Doc •19- 200950819 15 g of hydroxamic acid, 5 g of magnesium stearate and 15 g of talc, using a conventional method to make the mass of each piece reach 200 mg, using a mortar rod of 8 mm ij in diameter to rotate The tablet press is used for tableting to obtain a die. Then, the tablet was placed in a coating pan, and sprayed with a coating solution of ethanol: purified water Si: containing 4% by mass of calcium pantothenate and 6 mass% of lanthanum propylcellulose. Coating until the mass increase of each tablet reaches 10 mg, obtaining a coating

The layer contained a coating of 4 mg of calcium pantothenate relative to each tablet, i.e., 21 mg. Comparative Example 1: Comparison of the manufacture of the coated sheets: 6 g of L-cysteine, 75 g of ascorbic acid, 6 g of calcium pantothenate, 1240 g of crystalline cellulose, 230 g of partially pregelatinized starch, hydroxypropyl fiber 75 g, light anhydrous citric acid 15 g, magnesium stearate 15 g and talc i5 g, using a conventional method, so that the mass of each piece reaches 2 〇〇 mg, using a diameter of 8 mmcj) The rods were compressed by a rotary tableting machine to obtain a die. Then, the tablet was placed in a coating pan and coated with a coating solution containing 5% by mass of hydroxypropylmethylcellulose in ethanol: purified water = 1:1 until the mass increase per tablet was reached. At 10 mg, a comparative capsule containing 4 mg of calcium pantothenate in each of the tablets, i.e., 21 mg, was obtained in the bare portion. Comparative Example 2: Comparison of the manufacture of sugar-coated tablets [Production of coated tablets] 600 g of L-cysteine, 75 g of ascorbic acid, 1300 g of crystalline cellulose, 23 g of partially pregelatinized starch, hydroxypropyl cellulose 75 Lu, light anhydrous arsenoic acid 15g, stearic acid 15g and talc 15g, by means of the common method to make the quality of each piece to a fine mg, using the diameter of 8 - research 132033.doc •20· 200950819 钵The rods were compressed by a rotary tableting machine to obtain a die. Then, the tablet was placed in a coating pan and spray coated with a coating liquid containing 5% by mass of hydroxypropyl hydrazine cellulose: purified water = 1:1 until the mass of each tablet was increased. The amount reached 10 mg. [Production of Sugar-coated Tablets] Next, 2.8% by mass of calcium pantothenate, 丄9 mass% of talc, 1.9 mass%/◦ of titanium oxide, 2.9% by mass of carbonated water, i% by mass of Ala 0 rubber powder, and the like are used. An aqueous solution of 5 8 % by mass of purified white sugar was coated with the underlying sugar coating until the mass increase of each tablet reached 1 〇 () mg. Thereafter, the sugar coating was applied using an aqueous solution containing 60% by mass of refined white sugar until the mass increase of the mother piece reached 5 〇 mg, and the sugar coating layer contained 4 mg of calcium pantothenate relative to 360 mg per piece. Sugar coated ingots. Test Example 1 [Stability (quantitative)] The coated tablets of Example 1 and Comparative Example and the sugar-coated tablets of Comparative Example 2 were placed in a glass bottle, and sealed at 40 ° C for 6 months, and used. HPLC method (High Perf0rmance Liquid Chr〇mat〇graphy, high performance liquid chromatography method), the total amount of calcium pantothenate in the preparation was determined for each of 20 tablets. The results are shown in Table 1. In the coated sheet of Example 1, the quantitative value of calcium pantothenate did not decrease with time, and the variation in the content of calcium pantothenate in each preparation was also very small. On the other hand, the quantitative value of calcium pantothenate in the coated tablets of Comparative Example 1 decreased over time. Further, in the sugar-coated tablet of Comparative Example 2, although the quantitative value of calcium pantothenate did not decrease with time, the deviation of the content of calcium pantothenate in the preparation was larger than that of the preparation of the present invention. I32033.doc 21 200950819 [Table i] Quantitative value (%) Initial period of storage period 40 °C 6 彳^^ Example 1 Average (n=20) 100.6 99.7~ Standard deviation 0.87 0.98^ Maximum 101.8 --~~—~ ~~— 101.2 Minimum 98.6 -----~~~ 97.3 Comparative Example 1 Average (n=20) 100.2 73,2 Standard deviation 0.58 A------ 1.44 Maximum 101.3 76.3 Minimum 99.3 70.3 Comparative Example 2 Average ( n=20) 100.3 99.8 Standard deviation 3.07 ------- 3.26 Maximum 105.6 104.3—~~~ Minimum 94.6 93.2 Example 2: Manufacturing of coated sheet L-halfamide 960 g, direct compression Ascorbic acid 1237.2 g, crystalline cellulose 754.8 g, low-substituted hydroxypropyl cellulose 2 〇〇 g, light anhydrous oxalic acid 16 g and magnesium stearate 32 g, by ordinary method, so that the quality of each piece reaches 200 The method of mg is performed by using a 8 mm (|) diameter mortar bar to perform tableting in a rotary tablet machine to obtain a die. Then, the tablet was placed in a coating pin and spray-coated with a coating solution containing 5% by mass of propylmethylcellulose-containing ethanol: purified water-1:1 until the mass of each tablet was increased. The amount reached 5 mg, and then, the use contained 6 mass. ; pantothenic acid, 4 mass 0 / 〇 hydroxypropyl hydrazine cellulose ethanol: purified water = 1:1 coating liquid for spray coating 'until the mass increase of each tablet reaches i 〇 mg, obtained Coating 132033.doc -22- 200950819 The layer contains a coating of 6 mg of calcium pantothenate relative to 215 mg per tablet. Example 3: The manufacture of the coated sheet used 4 g of L-cysteine, 250 g of ascorbic acid, 250 g of pyridoxine hydrochloride, 200 g of the final testin, 190 g of riboflavin, and citric acid. 50 g of thiamine, 0.5 g of biotin, 5 g of corn house powder, 424 5 g of crystalline cellulose, 200 g of hydroxypropyl cellulose, low-substituted propyl cellulose 丨丨〇g, magnesium stearate g and strontium The talc 10 g' is used to prepare a powder for tableting by a conventional method, and the obtained mixed powder is tableted by a rotary tableting machine with a mortar of 9 ηπηφ, so that the mass of each tablet reaches 210 mg, and a bare chip is obtained. . Then, the tablet was placed in a coating pan and spray coated with a coating liquid of purified water containing 20% by mass of Opadry AMB (premix of polyvinyl alcohol) until the mass per spindle was increased. The amount is up to 7 mg, and then spray coating is carried out using a coating solution containing 8% by mass of calcium pantothenate and 8% by mass of hydroxypropylmethylcellulose: purified water = hydrazine: hydrazine until each tablet When the mass increase amount reached 2 〇mg 〇, a coating sheet containing 1 〇 mg of calcium pantothenate in each of the tablets, i.e., 237 mg, was obtained. Test Example 2 [Stability (quantitative)] The coated sheets of Examples 2 and 3 were placed in a glass bottle, sealed and stored at 4 ° C for 6 months, and each piece was 2 pieces by HPLC. The formulation determines the quantitative value of calcium pantothenate in the formulation. The results are shown in Table 2. In the coated sheets of Examples 2 and 3, the content of 'pantothenic acid' did not decrease with time, and the deviation of the calcium pantothenate content of each preparation was also very small. 132033.doc -23- 200950819 [Table 2] Quantitative value storage period 6 θ average at 40 °C (n=20) 100.0 99.6 Example 2 Standard deviation 0.97 0.98 Maximum 101.8 101.9 Minimum? ί(η=20)~ ^ 98.2 97.5 100.3 99.8 Example 3 Standard deviation 0.69 0.72 Maximum—--- 102.4 101.2 Minimum 99.2 98.6 Example 4: Manufacture of the envelope

G uses 36 〇g of L-cysteine, ascorbic acid for direct compression, 283.1 g for cation cellulose, 75 g for low-substituted propylcellulose, 6 g of light anhydrous sulphuric acid, and magnesium sulphate i 2 g, by means of a conventional method, in such a manner that the mass of each piece reaches 200 mg, a small 8 mm (7) diameter mortar rod is used for tableting by a rotary tableting machine to obtain a bare piece. Then, the tablet was placed in a coating pan using 3:5% by mass of hydroxypropylmethylcellulose in ethanol: purified water-coating solution for spray coating until the mass increase of each tablet reached 5 ̄ Then, using a coating solution containing 3 mass% of pantothenic acid, 4.5 mass of hydroxypropylcellulose, purified water = 丨 包 包 =1 =1 =1 , , , , , , , , , , , , , , , , , , , , , , , , , , , , A coated sheet of 3 in the coating layer having a calcium pantothenate of 6 with respect to each sheet, that is, 22 Å was obtained. Example 5: Fabrication of a coated sheet 132033.doc • 24· 200950819 A bare chip was obtained in the same manner as in Example 4. Then, the tablet was placed in a coated steel containing 5 masses for use in a person. /. The coating liquid of hydroxypropyl fluorene cellulose, and deuterated water 1.1 was spray-coated until the mass of each sheet was 5 mg. Then, the content was 3 mass. /〇的泛酸#5,4 _ 5 质晋% $ $ 7 & Ethene without G-pyrrolidone oxime 30: Purified water = 1:1 sputum coating spray coating until the mass of each tablet increases The amount reaches ^ Ο

The coating layer of the coating layer containing 6 mg of calcium pantothenate relative to each tablet was obtained. Example 6: Fabrication of a coated sheet A die was obtained in the same manner as in Example 4. Then, the tablet was placed in a ready-to-wear steel, and spray coating was carried out using a coating liquid of purified water containing 2% by mass of yaw (a premix of polyethyl alcohol) until each _ The mass increase of the tablets reached 5 mg. Next, spray coating is carried out using a coating liquid containing 6% by mass of calcium pantothenate and 12% by mass of bloated (17 八 16 purified water until the mass increase per tablet reaches 18 mg, and then, Spray coating was carried out using a coating liquid containing purified water of 20% by mass of 2 〇 padry AMB until the mass increase per tablet reached 5 Å, and the coating layer was obtained to be 6 for each tablet, i.e., 228 mg. Test piece of mg of calcium pantothenate. Test Example 3 [Stability (quantitative)] The coated sheets of Examples 4 to 6 were placed in a glass bottle and sealed and stored at 4 °t for 6 months by HPLC. The quantitative value of calcium pantothenate in the preparation was determined. The results are not shown in Table 3. 132033.doc •25·200950819 The coated tablets of the examples have a small amount of decrease in calcium pantothenate content over time. [Table 3] Example 4 Example 5 Example 6 Initial conditions of storage conditions 6 months at 40 ° C, 6 months at 40 ° C, and 6 months at 40 ° C (%) 100.1 99.7 99.2 99.1 98.9 98.8

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Claims (1)

200950819 X. Patent Application Range 1. A packaging preparation containing a film containing pantothenic acid or a salt thereof in a solid preparation containing a pharmacological component other than pantothenic acid or a salt thereof. 2. The coated preparation of claim 1, wherein the mass ratio of pantothenic acid or a salt thereof to the film substrate in the film layer (pantothenic acid or a salt thereof: film substrate) is 1:99 to 95:5. 3. The coated preparation of claim 2, wherein the film substrate is a water-soluble and/or gastric-soluble film substrate. The coated preparation of claim 1, wherein the pantothenic acid or a salt thereof is calcium pantothenate. The envelope preparation according to any one of claims 1 to 4, wherein the film substrate is made of cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose or polyethylene. One or more selected from the group consisting of a bromohexanone, a carboxyvinyl polymer, a polyvinyl alcohol, an aminoalkyl methacrylate copolymer E, and a polyvinyl acetal diethylamine acetate. 132033.doc 200950819 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: © VIII. If there is a chemical formula in this case, please reveal the characteristics that can best show the invention. Chemical formula: (none) 132033.doc