HK1139048A - Film coating preparation - Google Patents

Description

Film-coated preparation

Technical Field

The present invention relates to solid formulations stably incorporating pantothenic acid or salts thereof. More particularly, it relates to a film-coated preparation containing pantothenic acid or a salt thereof stably in a film coat.

Background

Calcium pantothenate belongs to vitamin B group, is a component of coenzyme a (coenzyme a) of acetylase, and is involved in metabolism of sugar, fat, protein, and the like. Moreover, it also has the function of keeping the skin function normal. Therefore, by utilizing these effects, calcium pantothenate is incorporated together with other active ingredients into a tonic agent represented by a multivitamin agent, a refreshing agent, and vitamin B₁The preparation can be made into preparations such as liver-strengthening antidote, female health-care medicine, intestine-regulating and antidiarrheal medicine, gastrointestinal medicine, constipation medicine, allergy medicine, and oral medicine for dermatosis.

However, calcium pantothenate is stable when it is a monomer, but becomes unstable when it is blended with other active ingredients such as ascorbic acid, thiamine, and pyridoxine, and not only calcium pantothenate is decomposed, but calcium pantothenate also causes the active ingredients such as ascorbic acid, thiamine, and pyridoxine to become unstable, and these active ingredients are also decomposed. This tendency is particularly evident when calcium pantothenate is admixed with ascorbic acid.

Conventionally, various studies have been made on solid preparations for stabilizing calcium pantothenate. For example, a method of increasing the amount of the material to supplement the decomposed component in anticipation of a decrease in the content with time; a method for separating calcium pantothenate from other components by forming a core sheet or a laminate sheet; a method for stabilizing a sugar-coated tablet by adding calcium pantothenate to the sugar-coated tablet; a method of granulating the blended components separately to reduce the contact of the components with each other and retard the decomposition of the components, and the like. As a method for improving the above method, a stable granulated product of calcium pantothenate or calcium lactate has been proposed (patent document 1). As a method for increasing the stability of the granulated product, a method for reducing the water content in the preparation has also been proposed (patent document 2). Further, the following methods have been attempted: a method in which a tablet is coated with a water-soluble film and then calcium pantothenate is added to a sugar-coated tablet to prepare a sugar-coated tablet (patent document 3); a method of blending calcium pantothenate by a dry method (patent document 4); and a method of wet granulation in an aqueous system together with a swelling agent (patent document 5).

However, the production processes of the above methods are complicated, and there is a problem that the stability of calcium pantothenate cannot be sufficiently ensured. For example, when a stable granulated product of calcium pantothenate is separately produced in advance, a separate production process is required, which leads to an increase in cost. Further, even when the preparation is subjected to low water differentiation, calcium pantothenate itself has hygroscopicity, and therefore, depending on the dosage form and packaging form, stability may not be ensured. On the other hand, in the sugar coating step for producing sugar-coated tablets, it is necessary to coat the tablets with a polymer film in advance to impart water resistance and moisture resistance, and the time required for the step of coating the sugar coating layer is long, so that not only the production cost is increased, but also the environmental load is large. In addition, there is a disadvantage in that the tablet weight of the sugar-coated tablet is greatly increased and the quality deviation of each tablet is larger than that of a plain tablet (bare tablet) or a film-coated tablet. Further, since the sugar coating step is in a high-temperature and high-humidity state, the stability, appearance, and the like of calcium pantothenate and other active ingredients coexisting therein are also affected by moisture, poor temperature control, and the like in the production step.

Therefore, it is desired to find a method for stabilizing calcium pantothenate by a simple method which is advantageous in terms of industrial, cost, and environmental aspects.

Patent document 1: japanese patent laid-open No. Hei 3-123729

Patent document 2: japanese patent laid-open No. 2003-128543

Patent document 3: japanese patent laid-open No. 2004-107273

Patent document 4: japanese patent laid-open No. 2006-111535

Patent document 5: japanese patent laid-open No. 2006-328001

Disclosure of Invention

The purpose of the present invention is to provide a stable solid preparation of calcium pantothenate which has a small variation in the content of the preparation and can be produced by a simple method which is industrially advantageous, cost-effective, and environmentally friendly.

The present inventors have conducted intensive studies to achieve the above object, and as a result, have unexpectedly found that: the stability of calcium pantothenate can be ensured by incorporating an active ingredient other than calcium pantothenate into a solid preparation and incorporating calcium pantothenate into a film coating for coating the preparation. Further, it was found that the content of the preparation has a small variation, and the present invention was completed.

That is, the present invention provides a film-coated preparation which is obtained by coating a solid preparation containing a medicinal component other than pantothenic acid or a salt thereof with a film containing pantothenic acid or a salt thereof.

According to the present invention, a solid preparation in which the stability of pantothenic acid or a salt thereof is ensured can be obtained. In addition, the present inventionThe clear preparation can be produced by a simple method which is industrially advantageous, cost-effective and environmentally friendly since it does not require a sugar coating step, and can be easily swallowed because it can be miniaturized, and can be conveniently taken by the elderly and children. In addition, the invention can be widely applied to nourishing and strengthening agents represented by compound vitamin agents, sobering agents and vitamin B₁In solid preparations in various therapeutic fields containing pantothenic acid or its salt, such as agent, liver-strengthening antidote, health-care medicine for female, intestine-regulating and antidiarrheal medicine, gastrointestinal medicine, constipation medicine, allergy medicine, and oral medicine for dermatosis.

Detailed Description

The calcium pantothenate (chemical name: calcium bis [ 3- [ (2R) -2, 4-dihydroxy-3, 3-dimethylbutyrylamino ] propionate) used in the present invention is represented by the formula: c₁₈H₃₂CaN₂O₁₀Molecular weight: 476.53, and coenzyme A. Coenzyme a is typically acetylated in the living body, and is involved not only in the synthesis of various substances essential to the living body, such as steroids, fatty acids, and porphyrins, but also in the metabolism of fats, proteins, and carbohydrates, and therefore calcium pantothenate is used together with various pharmaceutically effective components in medical drugs, general drugs, health foods, and the like.

As the pantothenic acid or a salt thereof to be used in the present invention, there may be mentioned, in addition to the above-mentioned calcium pantothenate, salts such as pantothenic acid and sodium pantothenate. Any of them can be used in the present invention, but calcium pantothenate is preferably used.

The active ingredient other than pantothenic acid or a salt thereof in the present invention means an ingredient having an action of decomposing pantothenic acid or a salt thereof and impairing the stability thereof when used in combination with pantothenic acid or a salt thereof. Examples of such components include vitamin C compounds such as ascorbic acid, calcium ascorbate, and sodium ascorbate; thiamine nitrate, thiamine hydrochloride, thiamine disulfide nitrate (Japanese original: nitric acid ビスチアミン), thiamine disulfide, thiamine dicetyl sulfate, furethine hydrochloride, hydrochloric acid-based thiamine (Japanese original: hydrochloric acid ジセチアミン), octothiamine, secortiamine, sulbuthiamine, bisbenzoylthiamine, benfotiamine, riboflavin butyrate, riboflavin sodium phosphate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamine, hydroxocobalamine hydrochloride, hydroxocobalamine acetate, mecobalamine, nicotinic acid, nicotinamide, biotin, folic acid, and other vitamin B groups; autonomic nerve regulators such as γ -oryzanol; vitamin-like substances such as lipoamide and orotic acid; calcium hydrogen phosphate, calcium lactate, etc.; vitamin E such as d-alpha-tocopheryl acetate, dl-alpha-tocopheryl acetate, d-alpha-tocopheryl succinate, and dl-alpha-tocopheryl calcium succinate; vitamin D such as calciferol, cholecalciferol, etc.; amino acids such as L-cysteine, methionine, glycine, arginine hydrochloride, etc.; drugs for liver disorders such as taurine, glucuronamide, glucuronolactone, glycyrrhizic acid, and ursodeoxycholic acid; polygoni Multiflori radix extract, fructus crataegi Pinnatifidae extract, radix Acanthopanacis Senticosi dry extract, herba Epimedii extract, Coicis semen extract, liver hydrolysate, bile extract powder, bupleuri radix dry extract, rhizoma Ligustici Chuanxiong dry extract, fructus crataegi (Japanese original text: クラテグス) dry extract, Poria dry extract, etc.

The preparation of the present invention is a film-coated preparation prepared by incorporating a medicinal ingredient other than the above-mentioned pantothenic acid or a salt thereof into a solid preparation and incorporating pantothenic acid or a salt thereof into a film-coating for coating the preparation. The dosage form of the solid preparation includes tablets, granules, fine granules and the like, and particularly, tablets are preferable. Further, the tablet, granule or fine granule may be coated with a coating agent containing pantothenic acid or a salt thereof, and then filled into a hard capsule or a soft capsule to prepare a capsule.

From the viewpoint of ensuring the strength as a film without lowering the adhesion rate at the time of coating with a base material having instant solubility and no lowering of absorbability while maintaining stability, a film base material having water solubility or gastric solubility is preferably contained in the film coating of the preparation of the present invention in addition to pantothenic acid or a salt thereof. Examples of the film base include methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, carbopol, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, and the like, and these may be used alone or in a mixture of 2 or more.

The ratio of pantothenic acid or a salt thereof to the film base in the film coat varies depending on the type and the form of the film base to be used, and is preferably 1: 99 to 95: 5, particularly preferably 5: 95 to 80: 20, and more preferably 10: 90 to 70: 30 in terms of the mass ratio (calcium pantothenate: film base).

In the film coating, in addition to the pantothenic acid or a salt thereof and the film base, a pharmaceutical additive commonly used in a coating film of an oral pharmaceutical, such as a plasticizer, a coating agent, a dispersant, a colorant, and an antifoaming agent, may be added as necessary.

Specific examples of the plasticizer include カリオン 83, triethyl citrate, glycerin fatty acid ester, sesame oil, a mixture of dimethylpolysiloxane and silica, D-sorbitol, medium-chain triglyceride, corn starch alcohol solution, triacetin, condensed glycerin, castor oil, diethyl phthalate, dibutyl phthalate, butyl phthalyl butyl glycolate, polyoxyethylene (105) polyoxypropylene (5) glycol, propylene glycol, polysorbate 80, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, a mixture of cottonseed oil and soybean oil, and glycerin monostearate, and these may be used alone or in combination of 2 or more. When a plasticizer is added to the film coat, the content thereof is preferably 40% by mass or less.

Specific examples of the coating agent include, in addition to the film base, a dispersion of an ethyl acrylate-methyl methacrylate copolymer, an acetyl glycerin fatty acid ester, an aminoalkyl methacrylate copolymer RS, gum arabic powder, ethylcellulose, an aqueous dispersion of ethylcellulose, octyldecyl triglyceride, Opadry AMB, Opadry OY-6950, Opadry OY-S-7135, Opadry OY-S-8471, Opadry OY-S-9607, Opadry OY-S-22829, Opadry OY-S-22835, Opadry OY-S-22961, olive oil, kaolin, cacao butter, prunella vulgaris, castor wax, caramel, carnauba wax, carboxymethyl ethyl cellulose, sodium carboxymethyl starch, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydrated silicon dioxide, sodium carboxymethyl cellulose, sodium, Dried aluminum hydroxide gel, dried milky white shellac, dried methacrylic acid copolymer LD, wintersweet powder, fish scale foil, gold foil, silver foil, triethyl citrate, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, hydroxypropyl cellulose containing light anhydrous silicic acid, light liquid paraffin, spermaceti, microcrystalline fiber, solidified oil, synthetic aluminum silicate, synthetic wax, high dextrose syrup, hard wax, succinylated gelatin, wheat flour, wheat starch, rice starch, cellulose acetate, vinyl acetate resin, cellulose acetate phthalate, white wax, titanium oxide, magnesium oxide, dimethylaminoethyl methacrylate/methyl methacrylate copolymer, dimethylpolysiloxane (for internal use), dimethylpolysiloxane/silica mixture, plaster of paris, sucrose fatty acid ester, powdered cinnamon, aluminum hydroxide gel, hydrogenated rosin glycerin ester, Stearyl alcohol, stearic acid, aluminum stearate, calcium stearate, polyoxyl stearate 40, magnesium stearate, refined gelatin, refined shellac, refined white sugar, zein, sorbitan sesquioleate, cetyl alcohol, gypsum, gelatin, shellac, sorbitan fatty acid ester, D-sorbitol solution, tricalcium phosphate, talc, calcium carbonate, magnesium carbonate, simple syrup, gold silver foil (Japanese original: Chinese gold foil), precipitated calcium carbonate, low-substitution hydroxypropylcellulose, terpene resin, starch (soluble), corn syrup, corn oil, triacetin, calcium lactate, lactose, concentrated glycerin, white shellac, white sugar, honey, paraffin, pearl powder, potato starch, hypromellose acetate succinate, hydroxypropylmethylcellulose 2910. titanium oxide. polyethylene glycol 400 mixture, Hydroxypropyl methylcellulose phthalate, piperonyl butoxide, castor oil, diethyl phthalate, dibutyl phthalate, butyl phthalyl butyl glycolate, glucose, fumaric acid stearic acid polyvinylacetal diethylaminoacetate hydroxypropylmethyl cellulose 2910 mixture, pullulan, propylene glycol, bentonite, povidone, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polysorbate 80, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 20000, polyethylene glycol 35000, D-mannitol, syrup, beeswax, myristyl alcohol, anhydrous silicic acid hydrate, sodium hydrogen carbonate, Phthalic anhydride, anhydrous calcium hydrogen phosphate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium metasilicate aluminate, 2-methyl-5-vinylpyridine methacrylate/methacrylic acid copolymer, wood wax, aluminum monostearate, glyceryl monostearate, sorbitan monolaurate, montanate wax, medicinal charcoal, lauroyl alcohol, calcium sulfate, liquid paraffin, DL-malic acid, calcium monohydrogen phosphate, calcium hydrogenphosphate, sodium hydrogenphosphate, calcium dihydrogenphosphate, rosin and the like, and these may be used alone or in combination of 2 or more. In view of the adhesion preventing effect, talc is preferably added to these coating agents. When a coating agent is added to the film coating, the content thereof is preferably 40% by mass or less.

Specific examples of the dispersant include aminoalkyl methacrylate copolymer RS, gum arabic, acacia powder, propylene glycol alginate, ethanol, oleic acid, sodium carboxymethylcellulose, agar powder, citric acid, sodium citrate, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, microcrystalline fiber, solidified oil, synthetic aluminum silicate, choline phosphate, safflower oil, white wax, titanium oxide, dioctyl sodium sulfosuccinate, sucrose fatty acid ester, sodium hydroxide, stearic acid, magnesium stearate, refined oleic acid, refined soybean lecithin, sorbitan sesquioleate, sorbitan fatty acid ester, D-sorbitol, soybean oil, soybean lecithin, low-substituted hydroxypropylcellulose, dextrin, corn starch, tragacanth powder, sorbitan trioleate, lactose, condensed glycerin, potato starch, sucrose, Hydroxyethyl cellulose, hydroxypropyl starch, propylene glycol fatty acid ester, bentonite, povidone, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (105) polyoxypropylene (5) diol, polyoxyethylene (160) polyoxypropylene (30) diol, polysorbate 20, polysorbate 60, polysorbate 80, sodium polyphosphate, polyethylene glycol 300, polyethylene glycol 4000, polyethylene glycol 6000, anhydrous sodium citrate, anhydrous sodium pyrophosphate, magnesium metasilicate aluminate, sodium metaphosphate, wood wax, sorbitan monooleate, aluminum monostearate, glyceryl monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, lauroyl alcohol, liquid paraffin, calcium hydrogen phosphate, and the like, they may be used alone or in combination of 2 or more. When a dispersant is added to the film coat, the content thereof is preferably 25% by mass or less.

Specific examples of the coloring agent include Axiandaning (Japanese original: アセンヤクタンニン) powder, turmeric extract, yellow ferric oxide, オパスプレ -K-1-24904, orange essence, brown iron oxide, carbon black, caramel, carmine, carotene solution, beta-carotene, licorice extract, gold foil, black iron oxide, light anhydrous silicic acid, titanium oxide, ferric oxide, edible blue No. 1, edible yellow No. 4 aluminum lake, edible yellow No. 5, edible red No. 2, edible red No. 3, edible red No. 102, sodium hydroxide, talc, copper sodium chlorophyll, copper chlorophyll, extract of rye green leaf, d-borneol, myristyl dodecate, medicinal charcoal, riboflavin butyrate, riboflavin, green tea powder, riboflavin sodium phosphate, rose oil, etc., these may be added alone or in combination of 2 or more. When a colorant is added to the film coat, the content thereof is preferably 35% by mass or less.

Specific examples of the defoaming agent include ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for internal use), dimethylpolysiloxane-silica mixture, sucrose fatty acid ester, silicone resin emulsion, silicone defoaming agent, polyoxyl stearate 40, sorbitan fatty acid ester, sorbitan trioleate, and polysorbate 80, and these can be used alone or in a mixture of 2 or more. When a defoaming agent is added to the film coat, the content thereof is preferably 10% by mass or less.

The formulation of the invention is manufactured by the following method: coating solid preparation or its crystal containing medicinal components except pantothenic acid or its salt with coating solution containing pantothenic acid or its salt to obtain film coated preparation.

The method for producing a solid preparation is not particularly limited, and a preparation can be produced by incorporating an active ingredient other than pantothenic acid or a salt thereof and another active ingredient added as needed, and adding a preparation additive as needed, by a conventional method. The solid preparation is prepared by a common preparation method (published in 1971 in "XI manufacturing method for drugs" (upper and lower) in basic lecture of drug development ", prefecture library, Zhongjing was published in 1983 in the book of pharmaceutical engineering," Zhongjing was published in 1989 in テクノシステム in 1988 in the material design of latest powder ", published in 1988 in the book of Japan, unit operations and machines for drug development 11 in the text of Kagaku (Kagaku), Guanchuan bookshop in 1989 in the book of Japan, Qiaogtian in the design and evaluation of oral preparations, published in 1995 in the press of pharmacy, Qiaogtian in the book of Japan, designed in the prescription of oral preparations, published in 1995 in the press of pharmacy, and published in 1995 in the press of pharmacy). For example, when it is necessary to produce a granulated powder in the production of tablets, granules, powders, and the like, it is possible to produce the powder by a common granulation method (a wet granulation method such as a spray granulation method using a solution or a dispersion containing water or an organic solvent, a stirring granulation method, a fluidized granulation method, a rolling granulation method, or a rolling fluidized granulation method, a dry granulation method such as a compacting granulation method using a powder-granular binder, and the like). The tablet can also be prepared by mixing the raw material, powder, fine granule, or granule with the preparation additives, and compression molding.

Examples of the formulation additives used for formulating solid preparations include pharmaceutically acceptable carriers such as excipients, binders, disintegrants, disintegration aids, lubricants, glidants, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, emulsifiers, antioxidants, fillers, preservatives, sweeteners, taste-improving agents, cooling agents, flavoring agents, fragrances, colorants, and the like.

As specific examples of the additives for the preparation, lactose, white sugar, mannitol, xylitol, dextrin, sorbitol, erythritol, reduced maltose syrup, pullulan, povidone, cellulose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, propylene glycol, polyoxyethylene polyoxypropylene glycol, croscarmellose sodium, crospovidone, starch, gelatinized starch, carboxymethylcellulose calcium, ethyl cellulose, carboxymethyl starch, fumaric acid, citric acid, stearic acid, magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, silicon dioxide, talc, sucrose fatty acid ester, polyoxyethylene (105) polyoxypropylene (5) glycol, titanium oxide, sodium edetate, propyl gallate, calcium lactate, and the like can be used to achieve the above-mentioned object, Conventionally known additives for solid preparations such as calcium carbonate, precipitated calcium carbonate, calcium silicate, calcium hydrogen phosphate, magnesium aluminate metasilicate, gelatin, gum arabic, carnauba wax, white wax, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, polyoxyethylene polyoxypropylene glycol, dimethylpolysiloxane, glycerin fatty acid ester, medium-chain fatty acid triglyceride, succinylated gelatin, glycerin, solidified oil, caramel, riboflavin sodium phosphate, ferric oxide, red No. 102, yellow No. 5, and the like.

The coating method of film-coating the above solid preparation with a coating solution is not particularly limited, and examples thereof include pan coating, fluidized bed coating, roll coating, dry coating, and a combination thereof. For example, if necessary, a plasticizer, a coating agent, a dispersant, a colorant, an antifoaming agent, and the like are added to pantothenic acid or a salt thereof and a film base, the obtained composition for film coating is dissolved and suspended in purified water, a lower alcohol such as ethanol, or a mixture thereof to prepare a coating solution, and the preparation is coated by a method generally used for film coating. The solid content of the coating liquid is preferably adjusted to 1 to 50% by mass, particularly preferably adjusted to 2 to 30% by mass, and more preferably adjusted to 5 to 20% by mass.

In the present invention, the thickness of the film coat formed in the solid preparation varies depending on the dosage form, the quality, the shape and the coating amount (the blending amount of pantothenic acid or a salt thereof) of the solid preparation, and is not particularly limited, but is preferably 0.01 to 5000. mu.m, particularly preferably 0.1 to 2000. mu.m, and more preferably 1 to 500. mu.m. For example, in the case of a tablet having a diameter of about 9mm and a mass of about 200mg, when the mass ratio of calcium pantothenate in the coating layer to the film base material is 1: 1, the film coating thickness is about 65 μm at 5mg of calcium pantothenate blended in each tablet, and about 125 μm at 10 mg.

The preparation of the present invention may be a film-coated preparation in which a double-layer film coating is formed by applying an outer coating or a lower coating to the upper or lower side of a film coating containing pantothenic acid or a salt thereof, or a film-coated preparation in which a three-layer film coating is formed by applying both an outer coating and a lower coating.

For example, when a pharmaceutical ingredient exhibiting an unpleasant odor such as L-cysteine is contained in the solid preparation, it is preferable to coat a film coat containing pantothenic acid or a salt thereof on or under or on both sides of the film coat to mask the unpleasant odor. The coating film may be appropriately added with the above-mentioned pharmaceutical additives used in the coating film of the oral pharmaceutical, and particularly, from the viewpoint of the deodorizing effect, a partially saponified product of polyvinyl alcohol is preferably added.

From the viewpoint of the effect of reducing the unpleasant odor, the saponification degree of the partially saponified polyvinyl alcohol is preferably 70 to 97 mol%, particularly preferably 78 to 96 mol%, and the average polymerization degree is preferably 200 to 3300, particularly preferably 300 to 1500. Here, the saponification degree can be measured according to JIS K6726 (polyvinyl alcohol test method). The content of polyvinyl alcohol in the coating film is preferably 30 to 100% by mass, and particularly preferably 40 to 95% by mass, from the viewpoints of the deodorizing effect, the film strength, and the ease of coating.

The preparation of the present invention may be further coated with sugar coating to prepare sugar-coated tablets. When a sugar-coated layer is applied to the film-coated preparation, a sugar-coated tablet having a small variation in calcium pantothenate content among tablets can also be obtained.

The dosage of the preparation of the present invention can be suitably selected depending on the body weight, age, sex, kind of disease and symptoms of a patient, and for example, calcium pantothenate is preferably administered in an amount of 0.1 to 200mg per day to an adult.

The film-coated preparation obtained by the above-mentioned method is hardly found to decrease in the content thereof during the storage of the preparation because the stability of pantothenic acid or a salt thereof is ensured. Further, since the preparation does not require a sugar coating step, the preparation can be miniaturized and can be produced by a simple method which is advantageous in terms of industrial, cost, and environment. In addition, the content variation in each preparation is small as compared with the conventional method in which calcium pantothenate is incorporated into a sugar-coated layer and stabilized.

The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto.

Example 1: manufacture of film-coated tablets

The tablets were compressed in a rotary tablet press using 600g of L-cysteine, 750g of ascorbic acid, 1300g of microcrystalline cellulose, 230g of partially gelatinized starch, 75g of hydroxypropylcellulose, 15g of light anhydrous silicic acid, 15g of magnesium stearate and 15g of talc by a conventional method using a punch (Japanese original text: pestle) having a diameter of 8mm phi to give a tablet having a mass of 200mg per tablet. Then, the tablets were put into a coating pan, and spray-coated with a coating solution containing 4 mass% of calcium pantothenate, 6 mass% of hydroxypropylmethylcellulose, ethanol and purified water at a ratio of 1: 1 until the mass of each tablet increased by 10mg, to obtain film-coated tablets each containing 4mg of calcium pantothenate and having a tablet weight of 210mg in the coating layer.

Comparative example 1: manufacture of comparative film-coated tablets

The tablets were compressed in a rotary tablet press using 600g of L-cysteine, 750g of ascorbic acid, 60g of calcium pantothenate, 1240g of microcrystalline fiber, 230g of partially gelatinized starch, 75g of hydroxypropylcellulose, 15g of light anhydrous silicic acid, 15g of magnesium stearate and 15g of talc by a conventional method using a punch having a diameter of 8mm phi to obtain a tablet having a mass of 200mg per tablet. Then, the tablets were put into a coating pan and coated with a coating solution containing 5 mass% of hydroxypropylmethylcellulose, ethanol and purified water at a ratio of 1: 1 until the mass of each tablet increased by 10mg, to obtain comparative film-coated tablets in which the tablet portions contained 4mg of calcium pantothenate weighed 210 mg.

Comparative example 2: production of comparative sugar-coated tablets

[ production of film-coated tablets ]

The tablets were compressed in a rotary tablet press using 600g of L-cysteine, 750g of ascorbic acid, 1300g of microcrystalline cellulose, 230g of partially gelatinized starch, 75g of hydroxypropyl cellulose, 15g of light anhydrous silicic acid, 15g of magnesium stearate and 15g of talc by a conventional method using a punch having a diameter of 8mm phi to obtain plain tablets having a mass of 200mg per tablet. Then, the tablets were put into a coating pan and spray-coated with a coating solution of 1: 1 ethanol containing 5 mass% of hydroxypropylmethylcellulose and purified water until the mass of each tablet increased by 10 mg.

[ production of sugar-coated tablets ]

Then, an aqueous solution containing 2.8 mass% of calcium pantothenate, 1.9 mass% of talc, 1.9 mass% of titanium oxide, 2.9 mass% of calcium carbonate, 1 mass% of gum arabic, and 58.3 mass% of refined white sugar was used for under-sugar coating until the mass of each tablet increased by 100 mg. Then, sugar-coated tablets were obtained by sugar-coating with an aqueous solution containing 60 mass% of refined white sugar until the mass of each tablet increased by 50mg, to obtain sugar-coated tablets containing 4mg of calcium pantothenate in a tablet weight of 360mg in the sugar-coated layer.

Test example 1

[ stability (quantitation) ]

The film-coated tablets of example 1 and comparative example 1 and the sugar-coated tablets of comparative example 2 were filled in a glass bottle, and stored at 40 ℃ for 6 months with a cap closed, and the quantitative value of calcium pantothenate in each preparation was measured by HPLC method to give 20 tablets in total. The results are shown in Table 1.

In the film-coated tablet of example 1, the quantitative value of calcium pantothenate did not decrease with time, and the content variation of each formulation was very small. In response to this, the quantitative value of calcium pantothenate in the film-coated tablet of comparative example 1 decreased with the passage of time. In addition, although the quantitative value of calcium pantothenate in the sugar-coated tablet of comparative example 2 did not decrease with time, the variation in the calcium pantothenate content of each formulation was larger than that of the present formulation.

[ Table 1 ] quantitative value (%)

Example 2: manufacture of film-coated tablets

960g of L-cysteine, 1237.2g of ascorbic acid for direct compression, 754.8g of microcrystalline fiber, 200g of low-substituted hydroxypropyl cellulose, 16g of light anhydrous silicic acid and 32g of magnesium stearate are used for direct compression, and compression is carried out in a rotary compression machine by a conventional method by using a punch with the diameter of 8mm phi, so as to obtain a plain tablet with the mass of 200mg per tablet. Then, the tablets were put into a coating pan, and spray-coated with a coating solution containing 5 mass% of hydroxypropylmethylcellulose in ethanol and purified water in a ratio of 1: 1 until the mass of each tablet increased by 5mg, and then spray-coated with a coating solution containing 6 mass% of calcium pantothenate and 4 mass% of hydroxypropylmethylcellulose in ethanol and purified water in a ratio of 1: 1 until the mass of each tablet increased by 10mg, to obtain film-coated tablets containing 6mg of calcium pantothenate in the coating layer and weighing 215 mg.

Example 3: manufacture of film-coated tablets

Powder for tabletting was prepared by a conventional method using 400g of L-cysteine, 250g of ascorbic acid, 250g of pyridoxine hydrochloride, 200g of nicotinamide, 190g of riboflavin sodium phosphate, 50g of thiamine nitrate, 0.5g of biotin, 5g of corn starch, 424.5g of microcrystalline fiber, 200g of hydroxypropyl cellulose, 110g of low-substitution hydroxypropyl cellulose, 10g of magnesium stearate, and 10g of talc, and the obtained mixed powder was tableted with a punch pin having a diameter of 9mm phi in a rotary tablet press to obtain a plain tablet having a mass of 210mg per tablet. Then, the tablets were put into a coating pan, and spray-coated with a coating solution containing 20 mass% of opadry AMB (a premix of polyvinyl alcohol) in purified water until the mass of each tablet increased by 7mg, and then spray-coated with a coating solution containing 8 mass% of calcium pantothenate, 8 mass% of hydroxypropyl methylcellulose, ethanol, and purified water in a ratio of 1: 1 until the mass of each tablet increased by 20mg, to obtain film-coated tablets containing 10mg of calcium pantothenate and having a tablet weight of 237 mg.

Test example 2

[ stability (quantitation) ]

The film-coated tablets of examples 2 and 3 were filled in a glass bottle, stored at 40 ℃ with a cap closed for 6 months, and the quantitative value of calcium pantothenate in each preparation was measured by HPLC method and was counted into 20 tablets. The results are shown in Table 2.

The calcium pantothenate content of the film-coated tablets of examples 2 and 3 did not decrease with time, and the deviation of the calcium pantothenate content of each formulation was extremely small.

[ Table 2 ] quantitative value (%)

Example 4: manufacture of film-coated tablets

360g of L-cysteine, 464g of ascorbic acid for direct compression, 283.1g of microcrystalline cellulose, 75g of low-substitution hydroxypropyl cellulose, 6g of light anhydrous silicic acid and 12g of magnesium stearate are used for direct compression in a rotary tablet press by a conventional method by using a punch with the diameter of 8mm phi to obtain a tablet with the mass of 200 mg. Then, the tablets were put into a coating pan, spray-coated with a coating solution containing 5 mass% of hydroxypropylmethylcellulose in ethanol and purified water in a ratio of 1: 1 until the mass of each tablet increased by 5mg, and then spray-coated with a coating solution containing 3 mass% of calcium pantothenate, 4.5 mass% of hydroxypropylcellulose in ethanol and purified water in a ratio of 1: 1 until the mass of each tablet increased by 15mg, to obtain film-coated tablets containing 6mg of calcium pantothenate in the coating layer and weighing 220 mg.

Example 5: manufacture of film-coated tablets

A base tablet was obtained in the same manner as in example 4. Then, the tablets were put into a coating pan, and spray-coated with a coating solution containing 5 mass% of hydroxypropylmethylcellulose, ethanol and purified water in a ratio of 1: 1 until the mass of each tablet increased by 5mg, and then spray-coated with a coating solution containing 3 mass% of calcium pantothenate, 4.5 mass% of polyvinylpyrrolidone K30, ethanol and purified water in a ratio of 1: 1 until the mass of each tablet increased by 15mg, to obtain film-coated tablets each weighing 220mg containing 6mg of calcium pantothenate in the coating layer.

Example 6: manufacture of film-coated tablets

A base tablet was obtained in the same manner as in example 4. Then, the tablets were put into a coating pan and spray-coated with a coating solution containing 20 mass% opadry AMB (a premix of polyvinyl alcohol) in purified water until the mass of each tablet was increased by 5 mg. Then, spray-coating was performed with a coating solution containing refined water containing 6 mass% of calcium pantothenate and 12 mass% of Opadry AMB until the mass of each tablet increased by 18mg, and then spray-coating was performed with a coating solution containing refined water containing 20 mass% of Opadry AMB until the mass of each tablet increased by 5mg, to obtain a film-coated tablet containing 6mg of calcium pantothenate in the coating layer and having a tablet weight of 228 mg.

Test example 3

[ stability (quantitation) ]

The film-coated tablets of examples 4 to 6 were put into a glass bottle, and the glass bottle was sealed at 40 ℃ for 6 months, and then the quantitative value of calcium pantothenate in the preparation was measured by HPLC. The results are shown in Table 3.

The film-coated tablets of the examples showed less decrease in calcium pantothenate content with time.

[ Table 3 ]

Claims (5)

1. A film-coated preparation which is characterized in that a solid preparation containing a medicinal component other than pantothenic acid or a salt thereof is coated with a film-coating containing pantothenic acid or a salt thereof.

2. The film-coated preparation according to claim 1, wherein the mass ratio of pantothenic acid or a salt thereof to the film base (pantothenic acid or a salt thereof: film base) in the film coating is 1: 99 to 95: 5.

3. The film-coated formulation according to claim 2, wherein the film substrate is a water-soluble and/or stomach-soluble film substrate.

4. The film-coated formulation of claim 1, wherein the pantothenic acid or salt thereof is calcium pantothenate.

5. The film-coating formulation according to any one of claims 1 to 4, wherein the film base material is 1 or 2 or more selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, carbopol, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, and polyvinylacetal diethylaminoacetate.