JPH0672861A - Colored solid pharmaceutical preparation - Google Patents

Abstract

PURPOSE:To obtain the subject pharmaceutical preparation, excellent in safety and brightness and useful as a food, a medicine, etc., by coating and coloring a medicine such as a bare table with a coating layer comprising vitamin B12s. CONSTITUTION:The objective pharmaceutical preparation is obtained by coating and coloring a medicine such as a bare tablet with a coating layer comprising (B) preferably 0.001-20 pts.wt. vitamin B12s such as cyanocobalamin in (A) 100 pts.wt. coating agent containing granulated sugar or gelatin.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a colored solid preparation coated and colored with a coating layer containing vitamin B ₁₂ in the fields of foods, pharmaceuticals and the like.

[0002]

2. Description of the Related Art Conventionally, various products have been colored to distinguish them from other products or have a motivation for aesthetics through visual stimulation to enhance the willingness to purchase. For such coloring, various coloring agents such as tar dyes are used. One of them is known to use vitamin B ₁₂ in specific fields. Crystals of vitamin B ₁₂ have a dark red color, and the diluted solution thereof has a beautiful red color. There is a method (Japanese Patent Application Laid-Open No. 61-28365) in which a cyanocobalamin aqueous solution is used to color a fish paste or other proteinaceous food or its raw material in pink or pink. This method is a method in which an aqueous solution of cyanocobalamin is sprayed or kneaded into a proteinaceous food or its material, and vitamin B _{12 is} used as a coloring agent in a formulation completely different from the field, particularly in a solid formulation having a coating layer.
It does not give the idea of using the kind.

On the other hand, in the fields of pharmaceuticals and the like, the use of tar dyes is restricted due to safety problems,
White or vitamin B, for example, in Japanese Examined Patent Publication No. 61-3324
Yellowing due to ₂ has increased. There are also pink and yellow colorants that use ferric sesquioxide (such as red iron oxide), but the color tone is dark and the vividness is poor. As a result, the increase in similar color tones has caused problems such as deterioration of product image and fear of misuse due to difficulty in identifying products. In the field of preparations such as foods and pharmaceuticals, vitamin B ₁₂ may be added as one of the ingredients. In this case, the amount of vitamin B ₁₂ compounded is extremely small, and it cannot generally serve as a colorant. For example, according to the approval standard for the manufacture (import) of vitamin-based drug preparations (notice of the Director of the Pharmaceutical Affairs Bureau No. 92, Yakuhin No. 92, February 1, 1988), the daily dose or combination amount of cyanocobalamin and hydroxocobalamin is 1 to 1500 μg. In addition, for the purpose of homogenizing the content, vitamin B ₁₂ is used by diluting it with an inactive excipient (eg lactose, starches, etc.) (for example, to 1% adsorption powder). In many cases, coloring with the vitamin B ₁₂ itself is difficult in such usage. Therefore, it is not an example in which the vitamin B ₁₂ itself is blended as a coloring agent, especially as a coloring agent of a colored solid preparation coated and colored with a coating layer.

This is because, for example, vitamin B ₁₂ is unstable to light and heat [for example, C-12 of the 12th revised Japanese Pharmacopoeia manual (hereinafter sometimes referred to as "pharmacopeia")).
It is described on pages 99 to 1104 that "cyanocobalamin decomposes under strong light"], ascorbic acid, nicotinic acid amide, thiamine, talc which is generally used as a compounding ingredient of a solid preparation or contained in the ingredient. , Vitamin B ₁₂ becomes unstable due to the presence of metal ions
(Campbell. JA; J. Pharm. Sci .; 44, 2631
950), and that the stability of vitamin B ₁₂ is generally diminished when diluted, vitamin B ₁₂ should be used in solid preparations where quality changes are not desired.
_It is considered that the _12th class was considered to be unsuitable as a coloring agent. In order to prevent the decomposition of vitamin B ₁₂ compounds, for example, a method of improving stability and compoundability by dispersing in pregelatinized starch compounds (Japanese Patent Laid-Open No. 1-2033).
29) and methods of dispersing in a mixture of starch and dextrin (Japanese Patent Laid-Open No. 173823/1993). These methods are aimed at stabilizing vitamin B ₁₂ which is a small amount as a component of the preparation. , Vitamin B ₁₂
There is no suggestion to add the classes themselves to the solid dosage form as a colorant, especially a colored solid dosage form coated and colored with a coating layer. On the other hand, there is also a coloring method with vitamin B ₂ using a coating layer (Japanese Patent Publication No. Sho 61-3324), but since vitamin B ₂ and B ₁₂ have completely different properties such as stability, this coloring method is also a vitamin. It does not suggest that coloration with B ₁₂ compound.

[0005]

A stable colored solid preparation which does not have the drawbacks of conventional colored solid preparations such as safety and distinctiveness of products, particularly a colored solid preparation coated with a coating layer and colored. There is a need for the development of stable and safe formulations containing

[0006]

Means for Solving the Problems As a result of intensive studies on a colored solid preparation, the present inventors have surprisingly found that a solid preparation obtained by coating and coloring with a coating layer containing vitamin B ₁₂ has discoloration and content. It was found that there was no quality change such as deterioration and that it was stable and safe, and based on this, the present invention was completed. The present invention provides: (1) coated with a coating layer comprising a vitamin B ₁₂ compounds, colored colored solid preparation, (2) outside the coating layer containing a vitamin B ₁₂ such optically transparent inert layer is formed (1) Colored solid preparation of (1), (3) Vitamin B ₁₂
(1) A colored solid preparation according to (1) above, wherein a layer inactive against vitamin B ₁₂ is formed inside a coating layer containing a mixture, (4) a sugar-coated tablet, a capsule or a film coating preparation (1) (5) The colored solid preparation according to (1) above, wherein the vitamin B ₁₂ is cyanocobalamin, and (6) The above (1) above wherein the vitamin B ₁₂ is hydroxocobalamin acetate.
(7) The colored solid preparation of (1) which is a vitamin preparation, (8) The colored solid preparation of (1), wherein the coating layer containing vitamin B ₁₂ contains a saccharide, (9) Vitamin B ₁₂
(1) The colored solid preparation according to the above (1), wherein the coating layer containing a gelatin contains gelatin, and (10) the above (2) or (where the inert layer contains a granulated sugar, a cellulosic base, waxes, shellac or polyethylene glycol. 3) A colored solid preparation. (11) A method for producing a colored solid preparation, which comprises coating with a coating agent containing vitamin B ₁₂ and coloring.
(12) The colored solid preparation according to the above (11), wherein the content of vitamin B ₁₂ in the coating agent is 0.001 to 20 parts by weight relative to 100 parts by weight of the coating agent.

The color tone of the colored solid preparation of the present invention can be visually recognized as the color of the preparation (final product), and the kind and addition rate of vitamin B ₁₂ to be used and other additions may be added if desired. The colorants are mainly reddish, for example, pink, red, purple, etc., including all shades and similar colors, although they differ depending on the type and addition rate of the colorant. Vitamin B ₁₂ used in the present invention is vitamin B _12.
A compound having ₁₂ actions. For example, it is a compound containing a corrin ring having a tetrapyrrole skeleton in its chemical structural formula, that is, a corrinoid structure compound. In particular, a water-soluble compound composed of a choline ring containing a metal atom, a nucleotide part of the lower ligand, and an alkanocarane part is used. Preferably, cobalamin (a generic term for those having a vitamin B ₁₂ action) or the like, which contains cobalt metal at the center of the choline ring and forms a complex salt, is used. Specific examples of such vitamin B ₁₂ class,
For example, cyanocobalamin, hydroxocobalamin, Akokobaramin, nitrilase Toco rose Min, methylcobalamin, pseudoephedrine cyanocobalamin, Akuokobaramin, cobalamin, such as coenzyme B _12, pseudohalogen vitamin B _12, Factors A, vitamin B _12, such as factor III
Analogues or salts of vitamin B ₁₂ such as hydroxocobalamin acetate, hydroxocobalamin hydrochloride (eg,
One or a mixture of two or more selected from mineral acids such as hydrochloric acid and acetic acid, salts with organic acids and the like) is used. Further, cyanocobalamin and the like are most suitable for exhibiting a clear red color, and hydroxocobalamin acetate, hydroxocobalamin hydrochloride, hydroxocobalamin and the like are most suitable for dark red color. These vitamin B ₁₂ compounds can be produced by a known method or a method analogous thereto.

The colored solid preparation of the present invention is coated and colored with a coating layer containing vitamin B _{12 s} , and the coating and coloring with the coating layer can be performed using a coating agent containing vitamin B _{12 s.} it can. Vitamin B ₁₂ in such coatings
The compounding amount is usually 0.0 with respect to 100 parts by weight of the coating agent.
It is in the range of 01 to 20 parts by weight, preferably 0.01 to 5 parts by weight. If the amount is less than 0.001 part by weight, the coloring may be insufficient and fading may occur easily. On the other hand, if it exceeds 20 parts by weight, the color tone becomes dark and the manufacturing cost becomes high, and the value as a product becomes low. Coating agents containing vitamin B ₁₂ compounds may also contain additives for use in coatings in general than vitamin B ₁₂ compounds, their preparation as long object as it can be achieved in the present invention is not limited in any way, It can be produced in the same manner as a general coating agent (including capsules) except that it contains vitamin B ₁₂ . The coating agent containing vitamin B ₁₂ obtained according to a conventional method is used for producing the colored solid preparation of the present invention according to a known method for producing a coated preparation (eg, sugar-coated tablet, film coating preparation, capsule, etc.). Can be For example, as an additive which may be added in addition to vitamin B ₁₂ , for example, a sugar-based coating agent containing a sugar-based tablet, and most preferably a syrup containing sucrose, is used. Can be used to produce a film coating preparation, and a gelatin-based coating agent to produce a capsule or the like.
Furthermore, vitamin B ₁₂ is dissolved in water or an organic solvent containing water (for example, alcohols such as ethanol, ketones such as acetone) and added to the coated solid composition by spraying or dropping, Colored solid formulations can also be prepared. The mixing ratio of water and an organic solvent containing water can be appropriately changed depending on the amount of vitamin B ₁₂ used and the degree of dissolution, but the concentration of water is usually 1 to 99% by weight, preferably 5 to 95%. Contains by weight%. Furthermore, if desired, it is possible to add a liquid in which vitamin B ₁₂ is dispersed in an organic solvent not containing water, a vitamin B ₁₂ alone or a powder dispersed with another diluent (such as lactose) by spraying or spraying. Is. In this case, it is possible to manufacture a solid preparation which is not uniformly colored.

As a coating agent containing vitamin B ₁₂ for producing sugar-coated tablets, components of the sugar-coated layer as described in JP-A-1-197432 can be used in addition to vitamin B ₁₂ . Specific examples of such components include sucrose, talc, calcium hydrogen phosphate,
Precipitated calcium carbonate, calcium sulfate, kaolin, lactose, starch, crystalline cellulose, gum arabic powder, polyvinylpyrrolidone, pullulan, gelatin, hydroxypropyl cellulose (hereinafter sometimes referred to as HPC), hydroxypropylmethyl cellulose (hereinafter H
PMC) may be used. Further, the coloring agent, lubricant, concealing agent and the like described below are appropriately used for the coating agent,
It may be blended in an appropriate amount.

Examples of the coating agent containing vitamin B ₁₂ for producing a film coating preparation include, in addition to vitamin B ₁₂ types, for example, an aqueous film base described in JP-A-49-133515 and JP-A-2-174727. The enteric base described in 1 above, or a water-insoluble base and the like may be added. Specifically, for example, water-soluble cellulose such as hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose, a base only soluble in an acidic region such as polyvinyl acetal diethylaminoacetate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate. And enteric bases such as acrylic copolymers, water-insoluble bases such as ethyl cellulose, gelatin, shellac, sodium alginate and waxes, fatty acids (eg stearic acid or palmitic acid) and salts thereof (eg sodium). Or salt with potassium etc.), fatty alcohol (eg stearic alcohol or cetyl alcohol etc.), fatty acid glycerin ester and its hardened oil etc. Quality (e.g. hydrogenated cottonseed oil, hydrogenated castor oil or hydrogenated soybean oil, etc.) and, polyglycerol fatty acid esters (e.g. stearate penta (tetra) glyceride, mono stearate (tetra)
Glyceride, hexa (tetra) glyceride behenate, or the like) may be used in an appropriate amount to form a coating agent.

Vitamin B ₁₂ for producing capsules
The coating agents (capsules) containing the same are hard gelatin capsules described in the Pharmacopoeia (page D-175 to 176) in addition to vitamin B ₁₂ and British Pharmacopoeia (British Pharmacopeia).
poeia 1988 Volume, pages 622-624) Contains appropriate amounts of ingredients (eg, gelatin and the above film coating ingredients) used for producing soft capsules, enteric capsules, modified-release capsules, etc. listed. Good. These coating agents containing vitamin B ₁₂ may be used alone or in combination of two or more kinds, and may be coated and colored in a single layer or multiple layers to produce the colored solid preparation of the present invention. Furthermore, other components of the coating agent, such as coating aids (eg, polyethylene glycol, hydrogenated castor oil, etc.), extenders (eg, sugars such as lactose and granulated sugar, starches, etc.), colorants (eg, tar pigments) , Caramel, iron sesquioxide, titanium oxide, riboflavin, etc.), corrigents (eg, sweeteners, flavors, etc.) and the like may be appropriately added in appropriate amounts. The amount of the coating agent containing vitamin B ₁₂ used is 0.1 to 70 parts by weight, preferably 1 to 50 parts by weight, based on 100 parts by weight of the intended colored solid preparation. The coating agent containing these vitamin B ₁₂ compounds can be prepared by known coating means such as mixing, spraying, dropping,
Used according to filling, etc. For example, tablets, fine granules, granules, etc. coated with sugar coating or film are coated with a coating agent containing vitamin B _{12 in a} wet manner by a conventional method using a coating machine or the like for each solid intermediate product to be coated. It is obtained by doing. In addition, for capsule preparations, liquid intermediates such as liquids, powders, granules, tablets, etc. can be vitamin B using a capsule filling machine.
_The target preparation can also be obtained by filling a coating agent (capsule) containing ₁₂ kinds.

The solid preparation of the present invention is applicable to a wide range of drugs, quasi drugs, foods and the like. Examples of the drug include vitamin A main drug preparation, vitamin E main drug preparation, vitamin B ₁ main drug preparation, vitamin B ₆ main drug preparation, vitamin AD main drug preparation, and vitamin B ₁ , B ₆ , B ₁₂ main drug preparation, and further vitamin main drug preparations. Examples include vitamin-containing health drugs. For example, when it is applied to a vitamin main drug formulation described in the Pharmaceutical Manufacturing Guidelines (1991 edition, Pharmaceutical Industry Bulletin Company, pp. 579-596), etc., retinol acetate, retinol palmitate, vitamin A are the main components.
Oil, liver oil, strong liver oil, ergocalciferol, cholecalciferol, d-α-tocopherol succinate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, d-α-tocopherol acetate, dl-acetic acid α-tocopherol, d-α-tocopherol,
dl-α-tocopherol, thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine dicetyl sulfate ester salt, dicetiamine hydrochloride, fursultiamine hydrochloride, octothiamine, shicothiamine, bisbutyamine, bisbentiamine, fursultiamine,
Prosultiamine, benfotiamine, flavin adenine dinucleotide sodium, riboflavin, sodium riboflavin phosphate, riboflavin butyrate, pyridoxine hydrochloride, pyridoxal phosphate, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, cyanocobalamin,
Hydroxocobalamin, ascorbic acid, calcium ascorbate, sodium ascorbate, nicotinic acid, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, potassium magnesium aspartate equivalent mixture, inositol hexanicotinate, ursodes Oxycholic acid,
L-cysteine hydrochloride, L-cysteine, orotate, gamma-oryzanol, calcium glycerophosphate, calcium gluconate, precipitated calcium carbonate, calcium lactate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, glucuronolactone, glucuronic acid amide, chondroitin sulfate Sodium, processed garlic, carrot, yokuinin, etc. are used. Furthermore, vitamin-containing health drugs include, in addition to the above-mentioned main drugs, for example, caffeine, anhydrous caffeine, carnitine chloride, vitamins such as folic acid, and minerals,
Crude drugs and the like may be used as components. These components can be used in an appropriate mixing ratio as long as the purpose is achieved.

Further, other pharmaceutical ingredients which may be used in the colored solid preparation of the present invention are not particularly limited as long as the object of the present invention is achieved. Examples of the central nervous system drugs include diazepam, idebenone, Aspirin, ibuprofen, paracetamol, naproxen, piroxicam, diclofenac, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin, acetaminophen, etenzamid, ketoprofen, etc. , Triamterene, nifedipine, atenolol,
Spironolactone, metoprolol, pindolol, captopril, isosorbide nitrate, etc., as respiratory drugs, amlexanox, dextromethorphan, theophylline, pseudoephedrine, salbutamol,
Guaifenicin and the like, as digestive system drugs, benzimidazole drugs such as lansoprazole and omeprazole, cimetidine, ranitidine, pancreatin, bisacodyl, 5-aminosalicylic acid and the like, as antibiotics and chemotherapeutic agents, cephalexin, Cefacraw,
Cefradine, amoxicillin, bacampicillin, dicloxacillin, erythromycin, erythromycin stearate, lincomycin, doxycycline, trimethoprim / sulfamethoxazole, etc., and metabolic drugs such as serrapeptase, lysozyme chloride, adenosine triphosphate, glypenclamide, chloride Potassium or the like is used.

Further, the present invention can be applied to foods (eg chocolate, candy, gum, etc.) and quasi drugs (eg cosmetics). Further, when the solid preparation of the present invention is produced, the production method can be carried out according to a known general method as long as a solid preparation coated with a coating layer containing vitamin B ₁₂ and colored can be obtained. , in an amount that does not impair the coloring effect of vitamin B ₁₂ compounds, additives which are normally used, such as excipients (e.g.,
Lactose, starches, crystalline cellulose, talc, granulated sugar, porous substances, etc.), binders (eg pregelatinized starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan etc.), disintegrating agents [eg carboxymethylcellulose calcium , Croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose (hereinafter,
It may be described as L-HPC. ), Partially pregelatinized starch, etc.], lubricants (eg magnesium stearate, calcium stearate etc.), colorants (eg tar pigments, caramel, iron sesquioxide, titanium oxide, riboflavins etc.), flavoring agents (eg , Sweetener,
Fragrance, etc.) during the preparation (particularly the intermediate product to be coated),
You may mix | blend an appropriate amount.

The solid preparation of the present invention may be coated with a coating agent containing vitamin B ₁₂ and colored, and can be produced according to a method generally used for producing a colored solid preparation. For example, an intermediate powder, granules, pills, tablets, etc. are manufactured according to a conventional method by using pharmaceutical ingredients, foods or quasi-drugs and other ingredients and additives, and then a coating agent containing vitamin B ₁₂ Can be produced by coating, coloring, etc. In particular,
The pharmaceutical ingredients and other additives are mixed or kneaded with a solid carrier or solvent at -40 to 100 ° C (cooling or heating if necessary), and then the kneaded product is dried and conditioned as necessary. After granulating, powder, granules, granules, pills, tablets,
Alternatively, the present invention can be carried out by coating, coloring, etc. after molding into a capsule, and further coloring the empty capsule itself. Examples of the solid carrier to be used include, for example, the active ingredient, and optionally the above-mentioned additives (for example,
Lactose, crystalline cellulose, etc.) and, if desired, dry or wet granulated powders, granules, granules, pills, and tablets formed by compression in the usual manner, or empty capsules in the usual manner. Filled capsules are used,
As the solvent, for example, water, ethanol, acetone and a mixture thereof are used. Further, the above-mentioned components and additives may be added at an appropriate stage in the production process of the preparation of the present invention to the extent that the color tone is not impaired. For example, pharmaceutical ingredients and the like are mixed with granulated sugar and, if necessary, other ingredients or additives in a solution state and / or a suspension state, and the mixture is molded and then coated and colored. For example, coated powder, granules, pills, etc. It can be made into a colored solid preparation such as an agent, a tablet and a capsule. As a specific coating method, a method or the like generally used in the method for producing a coating agent as described in the Pharmacopoeia General Rules can be used, for example, a tumbling granulator, a stirring granulator, and a fluidizer. Granulator, centrifugal rolling granulator,
A coating composition containing vitamin B ₁₂ is added to the solid composition (intermediate product) to be coated, which is put in a general formulation manufacturing equipment such as a centrifugal tumbling fluidized granulator, a sugar coating machine, a film coating machine, and a capsule filling machine. The method of adding and coating is used. The coating agent may be added all at once or by a spray method. In addition, a coating agent containing the components of the solid composition to be coated in advance and vitamin B ₁₂ (with other components and additives if necessary) is put in a manufacturing apparatus, and a suitable liquid such as water or an organic solvent (eg alcohol) is added. , Acetone, etc.) and a mixture thereof to produce a solid component to be coated, so that the coating composition may be coated with the desired vitamin B ₁₂ -containing coating composition by the coating composition being wetted and dissolved. If the coating agent comprises a wax in addition the method, the coating agent is melted by applying heat, it is possible to cover with vitamin B ₁₂ compound. In addition, the inside and / or the outside of these colored coating layers may be coated with, for example, granulated sugar or a cellulosic base (for example, H
PC, HPMC, etc.), waxes (eg, carnauba wax, salamis wax, etc.), shellac (eg, "Pharmacopoeia")
The purified shellac described above, white shellac and the like), polyethylene glycol (for example, those having a polymerization degree of 200 to 20000) or a mixture thereof may be coated with an inert layer, and when coated on the outside, coloring This object is achieved if the light-transmissive inactive layer that allows the observed color to be observed is provided. Such an inactive layer can be formed, for example, by using a syrup solution in which granulated sugar is dissolved. At that time, the amount of the granulated sugar or the like used is 0.1 to 70 parts by weight, preferably 1 to 40 parts by weight with respect to 100 parts by weight of the coating agent containing vitamin B ₁₂ . The inert layer may be a single layer or multiple layers, usually one or two layers.

[0016]

The thus-obtained colored solid preparation coated with a coating agent containing vitamin B _{12 of the} present invention and colored is extremely stable against light, heat, humidity, etc., and its discoloration and content loss during storage are extremely small. The formulation of the present invention is extremely safe because it takes advantage of the color tone of vitamin B ₁₂ as a natural pigment. In addition, the colored solid preparation of the present invention, in particular, tablets and the like have the characteristic that not only color unevenness does not occur but also the beautiful color is maintained as it is. Furthermore, when the present tablet is, for example, a vitamin main preparation, vitamin B ₁₂ compounds can be added not only as a colorant but also as one of the main drug components.

Therefore, the colored preparation according to the present invention has excellent safety and aesthetic effect, which makes it easy to visually distinguish it from other products and avoid misuse.
Furthermore, a psychological effect can be expected. Additionally, or it can be easily changed the color tone by changing the type of the amount and vitamin B ₁₂ compound, depending on its amount, may be used as an active ingredient of vitamins. The solid preparation of the present invention can be used in the same manner as a known colored solid preparation containing the same active ingredient, and the vitamin preparation of the present invention is
It can be used in the same manner as a known vitamin preparation.

[0018]

EXAMPLES The present invention will be described in more detail with reference to Examples, Reference Examples and Experimental Examples, but the present invention is not limited thereto. In addition, the formula of the Hunter used to show the color change in the examples is as follows ("Weatherproof Light and Color", Saga Nagashi, Suga Test Instruments Publishing Co., Showa 52).
Year).

[Chemical 1] When the sample is illuminated with a xenon fade meter,
The amount of change from the initial is the color computer SM
-1 type (Suga Test Instruments Co., Ltd.) was used for measurement, and the color difference (ΔE) was calculated. If the value of the color difference is 3 or less, there is no change such as discoloration.

Example 1 1200 g of lactose, 500 g of corn starch, 50 g of HPC and 240 g of purified water were put into a high-speed stirring granulator (Vertical Granulator, FM-G25 manufactured by Paulec).
After kneading for 5 minutes, the kneaded material is dried at 40 ° C. in vacuum for 10 hours, taken out, and then crushed with a sizing machine (Showa Kagaku Kikai: Power Mill, P-3S, 1.5 mmφ punching screen). 1700 g of sized powder was obtained. Screened powder 1400g
To the above, 192 g of crystalline cellulose and 8 g of magnesium stearate were added, and mixed for 1 minute with a tumble type mixer (manufactured by Showa Kagaku Kikai: Tumble Mixer, TM-15).
The mixed powder is rotary tablet machine (Kikusui Seisakusho: Collect 1
9K, pestle; 8.0 mmφ) were pressed to obtain 9300 tablets, a lens type uncoated tablet having a weight of 160 mg, a thickness of 3.9 mm and a disintegration time of 1 minute or less. Take 9000 uncoated tablets and use the following sugar coating liquid 1 prepared in advance, and rotate the sugar coating drum at a rotation speed of about 40 using a sugar coating machine (Kikusui Seisakusho: NO-16-D).
A sugar-coated layer was formed at rpm and a blowing temperature of about 60 ° C. (sugar-coated tablet 1, weight: 320 mg). On the other hand, 4 kg of granulated sugar and 2 parts of water
A kg syrup was dissolved at a temperature of about 70 ° C. to prepare a white syrup solution (hereinafter referred to as “white syrup solution”). Further, 5 g of cyanocobalamin was dissolved in 743 g of this white syrup solution with stirring to prepare a red syrup solution (hereinafter referred to as "red syrup solution"). 2000 tablets of sugar-coated tablet 1 were coated with the red syrup solution under the above-mentioned sugar-coated conditions, and further polished with wax to give 345 mg of 1 tablet of red-coated tablet 1. <Sugar coating liquid 1> 8400 g of granulated sugar and 9 gum arabic
00 g and 4200 g of water were dissolved at a temperature of 70 ° C. 5800 g of talc was added to the liquid and dispersed by a stirrer to manufacture.

Example 2 4000 sugar-coated tablets 1 of Example 1 were taken, and 5 mg of each was coated with a white syrup solution under the same sugar-coating conditions as in Example 1. Further, the red syrup solution was used to coat each tablet to 350 mg. 2000 tablets of the coated tablet were taken and polished with wax to obtain a red sugar-coated tablet 2.

Example 3 The remaining 2000 tablets of the coated tablet of Example 2 were further coated with a white syrup solution at 10 mg per tablet, followed by polishing with wax to obtain a red sugar-coated tablet 3.

Example 4 2000 tablets of the sugar-coated tablet 1 of Example 1 were taken, 5 g of hydroxocobalamin acetate was dissolved in 743 g of white syrup with stirring, and a red-purple syrup solution was coated under the sugar-coating conditions of Example 1 and further coated with wax. Dashi stock, 1 tablet 345mg
To obtain a reddish purple sugar-coated tablet.

Example 5 545.8 g of fursultiamine hydrochloride and vitamin B ₆ 50
0 g, hydroxocobalamin acetate 7.8 g, crystalline cellulose 281.3 g, corn starch 120 g, HPC4
The sized powder was obtained in the same manner as in Example 1 using 5 g and 250 g of purified water. 300 g of this sized powder, acetic acid-dl-α-tocopherol gelatin beads (manufactured by Riken Vitamin: acetic acid-dl-α
-Containing 50% tocopherol) 200 g, gamma-oryzanol 10 g, crystalline cellulose 117 g, L-HP
57 g of C (HPC having a hydroxypropoxyl group content of 10.0 to 13.0% and an average particle size of 30 μm or less) and 4 g of magnesium stearate were mixed in the same manner as in Example 1 and then tableted (however, a punch Diameter is 9.0mmφ), 290
0 lens-shaped uncoated tablets were obtained. The uncoated tablets weighed 2
The amount was 40 mg, the thickness was 4.8 mm, and the disintegration time was 14 minutes.
2000 plain tablets were taken, and a sugar coating layer was formed in the same manner as in Example 1 using the following sugar coating solution 2 prepared in advance to prepare sugar coated tablets 2 (1 tablet; 370 mg). The obtained sugar-coated tablet 2 was put in a coating pan, and while stirring, 0.1 g of cyanocobalamin was dissolved in 910 g of sugar-coating solution 2 with stirring, and the solution was poured and evenly adhered to the surface of the tablet to coat 440 mg of pale tablet. I got a pink dragee. Furthermore, 0.3 g of cyanocobalamin is added to the white syrup solution 26
It was coated in the same manner with a pink syrup solution dissolved in 2 g with stirring (1 tablet; 475 mg), and then similarly coated with a white syrup solution to give a tablet weight of 480 mg. Then, it was polished with wax to obtain a pale pink sugar-coated tablet. <Kneading liquid 2> 2500 g of granulated sugar and gum arabic 2
70 g and 1200 g of water were dissolved at a temperature of 70 ° C. 90 g of titanium oxide, 670 g of precipitated calcium carbonate and 970 g of talc were added to the liquid, and the mixture was dispersed with a stirrer.

Example 6 Celsphere (spherical granulated product of crystalline cellulose, manufactured by Asahi Kasei:
200-300 μm) 750 g of fluidized granulation dryer (manufactured by Paulec: New Speed Dryer, FD-3S)
Then, a bulk liquid of the following composition prepared in advance was sprayed and coated by the bottom spray method while controlling the blowing temperature to about 65 ° C and the product temperature to about 40 ° C. When the bulk liquid of the total amount of the following formulation was sprayed, the spraying was stopped and the drying was performed for 3 minutes as it was, followed by sieving with a 32 mesh round sieve to obtain 870 g of a powder. <Bulk liquid> 1620 g of purified water, anhydrous caffeine 10
g, lactose 50 g, talc 40 g, L-HPC 40 g, H
40 g of PC was stirred to dissolve and disperse. 500 g of the obtained powder was put into the above fluidized granulation dryer, and the following film solution prepared in advance was sprayed and coated under the same conditions. After spraying the film solution of the total amount of the following formulation, stop spraying and continue drying for 1 minute.
Sieving with a round mesh sieve gave 515 g of a pink coated powder. <Film liquid> After 2.6 g of titanium oxide was dispersed in 370 g of purified water, 0.4 g of cyanocobalamin and 22.4 HPMC.
g, Macrogol 6000 4.6 g, and dissolve with a stirrer.

Example 7 100 g of gelatin and 0.01 g of cyanocobalamin were swollen in 50 g of purified water and then dissolved at about 45 ° C. The solution was centrifuged at 1000 rpm to remove bubbles contained therein, and then adjusted to have a water content of 35%. While keeping the preparation liquid at 40 ° C, stainless steel pins (diameter 5.8 mmφ and 5.6 mm) thinly coated with liquid paraffin.
φ) was dipped in the preparation liquid, slowly pulled up, and air-dried while inverting. After air drying, the diameter of 5.8mmφ is about 9c
Those having a diameter of 5.6 mm and a diameter of 5.6 mm were withdrawn from a stainless steel pin while cutting with a length of about 14 cm to obtain a pair of empty capsules colored pink. The empty capsule was stored in an environment of 25 ° C. and 50% until the water content became about 15%. The weight of the obtained pair of empty capsules was about 55 mg.

Experimental Example 1 The sugar-coated tablets of Example 1, Example 2 and Example 3 were placed in a glass bottle and stored in a tightly closed state at 50 ° C. and 40 ° C. for 4 weeks. The results of calculating the appearance change by visual observation and the color difference (ΔE) by the Hunter's formula after storage for 4 weeks in RH (RH: relative humidity) are shown in [Table 1] and [Table 2].

[Table 1]: Observation of appearance From the results of [Table 1], the red color immediately after production was maintained at 40 ° C., 50 ° C. and 40 ° C. 75% RH in all of Examples 1, 2 and 3 even after storage for 4 weeks. The coloration is found to be heat and humidity stable.

[Table 2]: Color difference (ΔE) In [Table 1], it was judged visually, but in [Table 2], the change in color tone was quantified. This numerical value shows the change (color difference) of the color after each storage with reference to the color immediately after the production, and if the color difference is 3 or less, there is no change such as discoloration. Therefore, the values in [Table 2] are 0.3 to 1.8.
It is clear that no discoloration occurs in the colored solid preparation of the present invention.

Experimental Example 2 With respect to the tablets of Example 3 whose appearance change was investigated in Experimental Example 1, the content of cyanocobalamin was quantified by high performance liquid chromatography. The residual rate with respect to the initials was calculated by the following formula and is shown in [Table 3]. Residual rate (%) = content after storage × 100 / content of initials

[Table 3]: Stability of content The results in Table 3 show that the coloration of the formulations according to the invention is stable to heat and humidity.

Experimental Example 3 The tablets of Example 3 were exposed to light (100,000 lux × 5, 10 hours) and scattered light (500 lux × 8 hours / day × 2, 4, 6 months) using a fade meter. A stability test was performed and the cyanocobalamin content was quantified by high performance liquid chromatography. The residual rate with respect to the initials was determined as follows and is shown in [Table 4]. Residual rate (%) = content after storage × 100 / content of initials

[Table 4] [Table 4] shows the quantification of the coloring components. Since the cyanocobalamin does not decompose even under strong light (short time) and scattered light (long time), and the content does not decrease, the preparation of the present invention is light. It turns out that it is stable.

Experimental Example 4 The formulations obtained in Example 2, Example 4, Example 5 and Example 6 were irradiated with a fade meter (100,000 lux × 5, 10 hours) and scattered light (500 lux × 8). The light stability test was carried out (hour / day × 2, 4, 6 months), and the results of visually observing the appearance are shown in [Table 5].

[Table 5]: Appearance observation From the results in Table 1, it is macroscopically proved that the colored preparation of the present invention is stable to light and hardly decomposes vitamin B _{12 s} .

Experimental Example 5 The sugar-coated tablet obtained in Example 5 was placed in a glass bottle and stored in a tightly closed state at 40 ° C. and 75% RH for 6 months. As a result, no change was observed by visual observation. Further, the results of calculating the color difference (ΔE) by the Hunter's formula are shown in Table 2.

[Table 6]: Color difference (ΔE) From the results in Table 2, it can be seen that the product of the present invention has no discoloration for 6 months under the conditions of 40 ° C. and 75% RH. This result is
Under normal commercial conditions, it is estimated that there is no change such as discoloration for at least 3 years.

[0031]

EFFECTS OF THE INVENTION It is possible to provide an extremely stable and highly safe colored solid preparation which is coated and colored with a coating layer containing vitamin B ₁₂ .

Claims (12)

[Claims] 1. A colored solid preparation coated and colored with a coating layer containing vitamin B ₁₂ . 2. The colored solid preparation according to claim 1, wherein a light-transmitting inert layer is formed on the outside of the coating layer containing vitamin B ₁₂ . 3. A colored solid preparation according to claim 1, wherein the inert layer is formed on the inside of the coating layer containing a vitamin B ₁₂ compounds against vitamin B ₁₂ compound. 4. The colored solid preparation according to claim 1, which is a sugar-coated tablet, a capsule or a film-coated preparation. 5. The colored solid preparation according to claim 1, wherein the vitamin B ₁₂ is cyanocobalamin. 6. The colored solid preparation according to claim 1, wherein the vitamin B ₁₂ is hydroxocobalamin acetate. 7. The colored solid preparation according to claim 1, which is a vitamin preparation. 8. The colored solid preparation according to claim 1, wherein the coating layer containing vitamin B ₁₂ contains a saccharide. 9. The colored solid preparation according to claim 1, wherein the coating layer containing vitamin B ₁₂ contains gelatin. 10. The colored solid preparation according to claim 2, wherein the inert layer contains granulated sugar, a cellulosic base, waxes, shellac or polyethylene glycol. 11. A method for producing a colored solid preparation, which comprises coating and coloring with a coating agent containing vitamin B ₁₂ . 12. The amount of vitamin B ₁₂ compounded in the coating agent is 0.001 to 20 relative to 100 parts by weight of the coating agent.
The method for producing a colored solid preparation according to claim 11, which is parts by weight.