JP2003313145A - Improved preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a solid preparation containing a lipophilic material having good fluidity and hardly causing oozing out. <P>SOLUTION: The solid preparation is obtained by forming an emulsion containing the lipophilic material, a water-soluble macromolecular compound and an adsorbent into powder by a spray-dry method. The solid preparation containing the lipophilic material is a stable preparation hardly causing oozing of the lipophilic material even after long-term preservation. The solid preparation has excellent fluidity to facilitate tableting or encapsulation. The cost required for cleaning is reduced because the attachment to a spray dryer is little. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an improved solid agent containing a fat-soluble substance. More specifically, it relates to a solid agent containing a fat-soluble substance produced by a spray drying method and a method for producing the same.

[0002]

2. Description of the Related Art In general, it is often difficult to solidify a fat-soluble substance that is liquid at room temperature, and there are few reports on a technique for solidifying a fat-soluble substance having a low viscosity.
Japanese Patent Application Laid-Open No. 6-81725 discloses a solidifying agent in which an oily substance to which a stabilizer is added is adsorbed and supported on a porous carrier. Further, Japanese Patent Laid-Open No. 4-275216 discloses a solid composition characterized by adding a hardness enhancer to an emulsion containing a fat-soluble drug and freeze-drying the emulsion. JP 11-246
Japanese Patent No. 548 discloses a method for producing a solid agent comprising oily vitamin E and betaine. However, even when these techniques are used, the problem that the oily substance oozes out on the surface and the preparation is adsorbed on the packaging material when stored for a long time has not been solved.

Further, JP-A-9-169639 describes a method for producing a solid preparation in which teprenone, which is an oily drug, is adsorbed on silicon dioxide powder. Although this method is simple, it has the drawback that the bulk density of the granules is low and the fluidity is poor.

JP-A-2000-86506 discloses that after lactose, mannitol, silicon dioxide and a water-soluble binder are dissolved in water,
A technique for adsorbing teprenone to the granules obtained by spray drying is disclosed. This method is not suitable for mass production because it is produced by a discontinuous process of producing granules to be seeds and adsorbing teprenone to the granules. Further, there is a drawback that the uniformity of the main drug is deteriorated.

Japanese Patent Laid-Open No. 2000-247869 discloses that gelatin and hydrous gelatin are used as an oily substance and after emulsification in water,
Oily substance-containing powders produced by spray drying are described. Further, in JP-A-2000-44462, a fat-soluble drug,
A free-flowing powder containing gelatin or casein and an adsorbent is described. However, gelatin solidifies when the temperature of the emulsion drops, and thus a device for maintaining the temperature at a constant level is required.

Further, JP-A-48-67418 and JP-A-53-9
In 9317, as a method of solidifying a non-aqueous liquid, a method of mixing and heating with calcium lactate hydrate is described, but when using teprenone as a main drug, the main drug at the time of compression molding is described. The bleeding cannot be suppressed.

[0007]

[Patent Document 1] JP-A-6-181725

[Patent Document 2] Japanese Patent Laid-Open No. 4-275216

[Patent Document 3] Japanese Patent Laid-Open No. 11-246548

[Patent Document 4] Japanese Unexamined Patent Publication No. 9-169639

[Patent Document 5] Japanese Patent Laid-Open No. 2000-86506

[Patent Document 6] Japanese Patent Laid-Open No. 2000-247869

[Patent Document 7] Japanese Patent Laid-Open No. 2000-44462

[Patent Document 8] Japanese Patent Application Laid-Open No. 48-67418

[Patent Document 9] JP-A-53-99317

[0008]

Therefore, the present invention does not require special manufacturing equipment and can be mass-produced in only one step, and has no exudation of a fat-soluble component and is excellent in fluidity. It is an object to provide a solid agent containing a fat-soluble substance having excellent content uniformity.

[0009]

[Means for Solving the Problems] In view of the above situation,
As a result of earnest research, the present inventors have found that the above problems can be solved by applying the spray drying method, and completed the present invention.

That is, according to the present invention, (1) a solid agent containing a fat-soluble substance, a water-soluble polymer substance and an adsorbent; The solid agent powdered by the method, (3) the fat-soluble substance is vitamin A, vitamin D, vitamin E,
Vitamin Ks, coenzyme Qs, the above solid agents that are terpenes, (4) the above solid agents that the fat-soluble substance is tocopherols, ubidecarenone or teprenone, and (5) the polymer substance is polyvinyl alcohol, pullulan or Arabic. The solid agent which is a rubber, (6) adsorbent is silica dioxide, hydrous silicon dioxide, light anhydrous silicic acid, calcium silicate, magnesium silicate, aluminum silicate, magnesium aluminate silicate, magnesium aluminometasilicate, The above-mentioned solid agent which is magnesium aluminum silicate or light aluminum oxide, (7) the viscosity of the emulsion containing the fat-soluble substance, the water-soluble polymer substance and the adsorbent is 50 to 5000.
cps / 1000rpm above solid agent, (8) bulk density 0.2 ~ 0.5g /
The above solid agents in ml and a method for producing these solid agents.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The solid agent according to the present invention can be used as a food, a feed, a drug, a quasi drug, or an additive thereof.

In the present invention, the solid agent means powder, fine particles,
It means granules, microcapsules and the like. A tablet, a film-coated tablet, a chewable agent, a caplet, or a capsule may be filled with the above solid agent as a raw material before use.

The fat-soluble substance in the present invention means, for example, the following components. Vitamin A's such as retinol, retinoic acid, retinoid, carotene, vitamin D's such as cholecalciferol, ergocalciferol, tocopherol, tocopheryl acetate, tocopherol succinate, vitamin E's such as tocopherol nicotinate, tocotrienol, phytonadione, menatetrenone Such as vitamin Ks, coenzyme Q6, coenzyme Qs such as coenzyme Q10, squalene, geranyl farnesyl pyrophosphate, terpenes such as teprenone, flurbiprofen axetil, clofibrate, gefarnate, plautonol, indomethacin farnesyl, etc. Can be mentioned.

In the solid agent according to the present invention, the content of the fat-soluble substance is not particularly limited, but it is usually 90% or less, preferably 80% or less. However, even if it is contained at a high concentration of 50% or more, it does not adversely affect the properties such as fluidity, bulk density, and exudation.

In the present invention, the water-soluble polymer substance means a water-soluble substance which maintains a stable emulsified state with the fat-soluble substance, and the fat-soluble substance is in a colloidal state even if the emulsion is dried by some method. Those having the ability to maintain are preferred. Specifically, polyvinyl alcohol (degree of polymerization: 700
˜4500, average molecular weight: 30,000 to 200,000), pullulan, gum arabic and the like. The content of the water-soluble polymer substance in the solid agent of the present invention is usually 1 to 50%, preferably 5 to 20%.

In the present invention, the adsorbent means a powdery porous inorganic substance such as silicon dioxide (hydrous silicon dioxide, light anhydrous silicic acid), calcium silicate, magnesium silicate, aluminum silicate, silicic acid. Magnesium aluminate, magnesium aluminometasilicate, magnesium aluminum silicate, light aluminum oxide, preferably silicon dioxide, calcium silicate,
It is magnesium aluminometasilicate. Further, these adsorbents may be further mixed with a component having an oil absorbing ability such as dextrin and calcium hydrogen phosphate. The content of the adsorbent is usually 1 to 50%, preferably 5 to 25%.

The solid agent of the present invention may contain other medicinal components as long as there is no pharmacological problem. Drugs that can be combined include, for example, hypnotic sedatives, anxiolytics, cardiotonics, antipyretic analgesics and antiphlogistics, antispasmodics, antitussives, expectorants, antihistamines, antiasthmatics, antihypertensives, analgesics, antiarrhythmics, hyperlipidemia Examples include symptomatic agents, central nervous system stimulants, antibiotics, gastrointestinal agents, hormone agents, crude drugs, vitamin agents and the like.

As a hypnotic sedative, amobarbital,
Examples include estazolam, flunitrazepam, nitrazepam, phenobarbital, bromvalerylurea, triclofos sodium, flurazepam hydrochloride, midazolam, lormetazepam, nimetazepam and the like.

Examples of anti-anxiety agents include diazepam, oxazolam, mexazolam, tandospirone, etizolam, chlorazepate dipotassium, bromazepam and the like.

Examples of the cardiotonic agent include amrinone, olprinone hydrochloride, colforsin daropate hydrochloride, dobutamine hydrochloride, digitoxin, digoxin, denopamine, docarpamine, bucladesine sodium, vesnarinone, milrinone, lanatoside C and the like.

Examples of the antipyretic analgesic and anti-inflammatory agent include aspirin, acetaminophen, ampiroxicam, ibuprofen, indomethacin, aminopyrine, etodolac, etenzamid, ketoprofen, salidone, diclofenac, fenoprofen calcium, lopenzarit disodium and the like.

Examples of the antispasmodic include eperisone hydrochloride, scopolamine hydrobromide, butylscopolamine bromide, papaverine hydrochloride, isoxpurine hydrochloride, etomidrine, methyloctatatropin bromide and the like.

As the antitussive expectorant, dextromethorphan hydrobromide, cloperastine hydrochloride, ephedrine hydrochloride, dihydrocodeine phosphate, benproperine phosphate,
Examples thereof include dimemorphan phosphate.

As the antihistamine, diphenhydramine hydrochloride, chlorpheniramine maleate, azelastine hydrochloride, dimenhydrinate, clemastine fumarate,
Examples include alimemazine tartrate and the like.

As an asthma drug, isoprenaline hydrochloride,
Mabuterol hydrochloride, diprophylline, ipratropium bromide, formoterol fumarate, salbutamol sulfate and the like can be mentioned.

As antihypertensive agents, amosulalol hydrochloride, imidapril hydrochloride, efonidipine hydrochloride, quinapril hydrochloride,
Guanfacine hydrochloride, clonidine hydrochloride, temocapril hydrochloride, delapril hydrochloride, varnidipine hydrochloride, betaxolol hydrochloride, benazepril hydrochloride, manidipine hydrochloride, carvedilol, candesartan cilexetil, guanabenz acetate, cilazapril, trandopril, nilvadipine, budralalin, loranapril, enalapril, enalapril. Can be mentioned.

Examples of the antispasmodic agents include diphenidol hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, promethazine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, scopolamine hydrobromide, butylscopolamine, oxyphencycline hydrochloride, methixene hydrochloride, papaverine hydrochloride, diprophylline. , Dimenhydrinate, meclizine hydrochloride, betahistine mesylate, promethazine methylene disalicylate, and the like.

As antiarrhythmic agents, amiodarone hydrochloride,
Examples thereof include indenolol hydrochloride, bumolol hydrochloride, bepridil hydrochloride, timolol maleate, cibenzoline succinate, sotalol hydrochloride, pilsicainide hydrochloride, pirmenol hydrochloride and flecainide.

High-lipid plasma therapeutic agents include clofibrate aluminum, colestimide, simvastatin, fenofibrate, fluvastatin sodium, cerivastatin, niceritrol, pravastatin sodium,
Examples thereof include melinamide.

Examples of the central nervous system stimulant include caffeine, anhydrous caffeine and the like.

Examples of the antibiotics include vancomycin, tobramycin, cefthromine sodium, imipenem, cefmenoxime, flomoxel sodium, erythromycin, aztreonam and the like.

Examples of the gastrointestinal drug include cetraxate hydrochloride, copper chlorophyllin metal salt, cimetidine, famotidine, ranitidine, omeprazole, rabeprazole, lansoprazole, rebamipide, sucralfate and the like.

Examples of hormone agents include nandrolone, prednisolone, estradiol, glucagon, insulin and the like.

Examples of the herbal medicines are red scallions, Acacia catechu, Amacha, fennel, turmeric, turmeric, pearl millet, sardines, sardines, spruce, sardines, sardines,
Rhinoceros, cuckoo, licorice, pheasant, swordfish, cinnamon sardine, ginger ginger, red ginger, red pearl, pomegranate,
Hawthorn, hawthorn, dio, sikon, peony,
Ginger, senna, senburi, soup, soybean, clove, chimp, spruce, tragacanth, peppermint oil, sandalnut, maho, menthol, ryukotsu,
Ryukyo, forsythia, wakka cutlet and the like can be mentioned. These may be added as an extract,
Moreover, you may add as an extract and a powder.

Examples of the vitamin agent include vitamin B group such as thiamine, riboflavin and biotin, vitamin C group such as ascorbic acid, nicotinic acid, pantothenic acid, folic acid and the like, and derivatives or salts thereof.

The solid agent according to the present invention may contain various commonly used additives. Examples of additives include stabilizers, surfactants, solubilizers, buffers, sweeteners, corrigents, suspending agents, antioxidants, cooling agents, flavoring agents / fragrances, emulsifiers, pH adjusters. Examples thereof include agents, dispersants, preservatives and preservatives.

Examples of the stabilizer include adipic acid, ascorbic acid, aspartic acid, sodium sulfite, sodium benzoate, sodium edetate, erythorbic acid, sodium ersorbate, sodium citrate,
Glycine, glycerin, glycerin fatty acid ester, polyoxyethylene polyoxypropylene glycol, anhydrous sodium citrate, glyceryl monostearate,
Examples thereof include sodium hydrogen phosphate.

As the surfactant, sucrose fatty acid ester, stearyl alcohol, sorbitan sesquioleate, cetanol, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polysorbate, macrogol, monoolein. Examples thereof include sorbitan acid, glyceryl monostearate, sorbitan monolaurate, sodium lauryl sulfate, and lauromacrogol.

As the solubilizer, aspartic acid, arginine, sodium benzoate, ethanol, sodium sorbitan chloride fatty acid ester, sodium hydrogen carbonate,
Examples thereof include polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polysorbate, mannitol, and anhydrous ethanol.

As the buffering agent, ascorbic acid, magnesium L-aspartate, aminoethyl sulfonic acid,
L-arginine, benzoic acid, sodium benzoate, citric acid, calcium citrate, sodium citrate, disodium citrate, glycine, sodium hydrogen carbonate, lactic acid, glucose, anhydrous citric acid, anhydrous sodium citrate, anhydrous phosphoric acid Sodium hydrogen, sodium metaphosphate, sodium hydrogenphosphate, dipotassium phosphate, potassium dihydrogenphosphate, sodium dihydrogenphosphate and the like can be used.

Examples of the sweetener include aspartame, armature, licorice, fructose, fructose glucose solution, glucose fructose syrup, reduced maltose syrup, dipotassium glycyrrhizinate,
Monoammonium glycyrrhizinate, potassium acesulfame, high fructose syrup, glucose, starch syrup, lactose, sucrose,
Examples thereof include purified sucrose, honey, saccharin, sodium saccharin, stevia, sucralose, erythritol, xylitol, sorbitol, maltitol, maltose, mannitol and simple syrup.

As the corrigent, ascorbic acid, L-aspartic acid, DL-alanine, disodium 5'-inosinate, fennel, sodium chloride, orange oil,
Cocoa powder, camphor, glycine, glycerin, L-glutamic acid, saffron, tartaric acid, ginger, D-sorbitol, peppermint, adipic acid, fumaric acid, peppermint, borneol, menthol, rheumatoid, green tea powder,
Apple juice, cider vinegar, lemon oil, rose oil, royal jelly and the like can be used.

As the suspending agent, for example, carrageenan,
Carboxyvinyl polymer, agar, xanthan gum, glycerin fatty acid ester, titanium oxide, sucrose fatty acid ester, stearyl alcohol, aluminum stearate, cetanol, sorbitan fatty acid ester,
Soy lecithin, propylene glycol fatty acid ester,
Pectin, propylene glycol, polyoxyethylene hydrogenated castor oil, polyethylene glycol, methyl cellulose, glyceryl monostearate, liquid paraffin and the like can be mentioned.

As antioxidants, ascorbic acid, L-
Ascorbic acid stearic acid ester, sodium bisulfite, sodium sulfite, erythorbic acid, cysteine hydrochloride, soybean lecithin, butylhydroxyanisole,
Examples include propyl gallate and the like.

Examples of the cooling agent include geraniol, peppermint water, peppermint oil, borneol, menthol and mint.

As the flavor and fragrance, fennel, ethyl vanillin, ethyl maltol, orange, camphor,
Keihi, sugar flavor, cinnamaldehyde, cherry flavor, peppermint, vanilla flavor, vanillin, bitter essence, fruit flavor, flavor GI, vermouth flavor, borneol, maltol, mix flavor, mint flavor, menthol, eucalyptus, roux, lemon powder, lemon Examples thereof include oil, rosin and rose oil.

As the emulsifier, carrageenan, carboxyvinyl polymer, carmellose sodium, guar gum, glycerin fatty acid ester, polyethylene glycol distearate, sucrose fatty acid ester, stearyl alcohol, stearic acid, cetanol, sorbitan fatty acid ester, soybean lecithin, hydroxypropyl Examples thereof include cellulose, propylene glycol, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, polysorbate, myristyl alcohol, glyceryl monostearate, sorbitan monolaurate, and sodium lauryl sulfate.

Examples of the pH adjusting agent include dilute hydrochloric acid, sodium citrate, glycine, succinic acid, acetic acid, tartaric acid, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, monosodium fumarate, phosphoric acid, trisodium phosphate and phosphoric acid. Examples thereof include sodium hydrogen, dipotassium phosphate, sodium dihydrogen phosphate and the like.

As the dispersant, aminoalkyl methacrylate polymer RS, oleic acid, carboxyvinyl polymer, carmellose sodium, glycerin, crystalline cellulose, choline phosphate, soybean lecithin, sorbitan sesquioleate, dextrin, corn starch, trioleic acid. Sorbitan, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, glyceryl monostearate, sodium lauryl sulfate, liquid paraffin and the like can be used.

Preservatives include aminoethyl sulfonic acid, benzoic acid, sodium benzoate, ethanol, sodium edetate, agar, sodium citrate, sodium salicylate, sorbic acid, isopropyl paraoxybenzoate, ethyl paraoxybenzoate and the like. be able to.

Preservatives include sodium benzoate, sodium edetate, glycerin, salicylic acid, sodium salicylate, D-sorbitol, sorbic acid, isobutyl paraoxybenzoate, ethyl paraoxybenzoate,
Examples thereof include butyl paraoxybenzoate, methyl paraoxybenzoate, propylene glycol and the like.

[0052]

PRODUCTION EXAMPLE A method for producing a solid agent containing a fat-soluble substance according to the present invention may be a commonly used method and is not particularly limited. As an example thereof, a manufacturing method by a spray dry method will be shown below. For example, a water-soluble polymer such as polyvinyl alcohol is dissolved in purified water heated to 80 to 90 ° C., and after cooling, a fat-soluble substance such as tocopherol, ubiquinone, and teprenone is added, using a high-speed stirrer, etc.
Emulsify for about 5 to 20 minutes at about 10,000 rpm. Add silicic acids (calcium silicate, magnesium silicate, light anhydrous silicic acid, etc.) and excipients (mannitol, crystalline cellulose, etc.) as adsorbents to the emulsion, perform uniform dispersion operation with a high-speed stirrer, and emulsify and suspend. Get the liquid. Suspension viscosity is 50
It is preferably about 10000 cps / 3000 rpm, and more preferably about 50 to 5000 cps / 1000 rpm. The obtained suspension is dried with a spray dryer,
Highly flowable powders or granules containing fat-soluble substances can be obtained. The spray dryer can be used in any type such as a disk type and a nozzle type, and the spray drying conditions are usually used conditions, for example, an inlet temperature of 160 to 220 ° C and an outlet temperature of 75 to 120 ° C. . It is also possible to use an air scraper to increase the recovery of powder or granules.

The solid agent thus produced has an average particle diameter of 20 to 200 μm, an angle of repose of 30 to 50 °, and a bulk density of 0.2 to 0.5 g /
ml.

[0054]

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

Example 1 300 g of polyvinyl alcohol (Gosenol EG05, Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved in 2700 g of purified water at 80 ° C. to prepare teprenone.
1250 g was added, and the mixture was stirred at 8000 rpm for 15 minutes using a high speed stirrer (Homomixer, manufactured by Tokushu Kika Kogyo Co., Ltd.). 250g of calcium silicate (Fluorite RE, Eisai) and light anhydrous silicic acid (Brand name: AEROSIL, Nippon Aerosil) 125
g, mannitol (Towa Kasei) 250 g, crystalline cellulose
250 g (Avicel 301, Asahi Kasei) was added. Further purified water 250
0 g was added and stirred for 15 minutes to obtain a uniform emulsion suspension. The apparent viscosity of this suspension was 3000 mPa · S. This suspension was spray-dried using a spray dryer (OD22M, manufactured by Okawara Kakoki Co., Ltd.) under the conditions of an inlet temperature of 140 ° C, an outlet temperature of 93 ° C, a disk rotation speed of 6000 rpm, and a spraying speed of 18.7 kg / h. , About 3 kg of free-flowing powder was obtained. The resulting granules have good fluidity, an average particle size of 152 μm, a bulk density of 0.39 g / ml, and an angle of repose.
It was 44.33 ° and the teprenone content in 1 g was 515 mg.

Formulation Example 1 To 97.1 g of the free-flowing powder obtained in Example 1, 0.9 g of magnesium stearate (NOF Corporation), 20 g of hydroxypropyl cellulose (L-HPC LH21, Nippon Soda), crystalline cellulose (Avicel 102) , Asahi Kasei) 34 g and calcium silicate (Florite RE, Eisai) 8 g were added, and compression molding was performed with a diameter of 7.5 mm and a punching pressure of 650 kg. The obtained tablet physical properties are good and the hardness is
33KN, disintegration time was about 500 seconds.

Example 2 300 g of polyvinyl alcohol (Gosenol EG05, Nippon Synthetic Chemical Industry) was dissolved in 2700 g of purified water at 80 ° C. to prepare teprenone.
1250 g was added, and the mixture was stirred at 8000 rpm for 15 minutes using a high speed stirrer (Homomixer, manufactured by Tokushu Kika Kogyo Co., Ltd.). 250g of calcium silicate (Fluorite RE, Eisai), 125g of light anhydrous silicic acid (AEROSIL, Nippon Aerosil), 250g of mannitol (Towa Kasei), crystalline cellulose (Avicel 3)
01, Asahi Kasei) 250g was added. Add 5000g of purified water
After stirring for 15 minutes, a uniform emulsion suspension was obtained. The apparent viscosity of this suspension was 1000 mPa · S. Using a spray dryer (OD22M, manufactured by Okawara Kakoki Co., Ltd.), this suspension is
Inlet temperature 140 ℃, outlet temperature 98 ℃, disk rotation speed 6000r
Spray drying was carried out under the conditions of pm and spray rate of 12.9 kg / h to obtain about 3.3 kg of free-flowing powder. The fluidity of the obtained granules is good,
The average particle size was 109 μm, the bulk density was 0.39 g / ml, the angle of repose was 38.33 °, and the content of teprenone in 1 g was 490 mg.

Formulation Example 2 To 97.1 g of the free-flowing powder obtained in Example 2, 0.9 g of magnesium stearate (NOF Corporation), 27 g of crospovidone (Crospovidone XL, ISPE Japan), calcium silicate (flow) Light RE, Eisai) 10g added, diameter
It was compression-molded with 7.5 mm and a punching pressure of 430 kg. The obtained tablets had good physical properties, a hardness of 31 KN and a disintegration time of about 442 seconds.

Example 3 300 g of polyvinyl alcohol (Gosenol EG05, Nippon Synthetic Chemical Industry) was dissolved in 2700 g of purified water at 80 ° C. to prepare teprenone.
1250 g was added, and the mixture was stirred at 8000 rpm for 15 minutes using a high speed stirrer (Homomixer, manufactured by Tokushu Kika Kogyo Co., Ltd.). To this was added 375 g of calcium silicate (Fluorite RE, Eisai), 62.5 g of light anhydrous silicic acid (AEROSIL, Nippon Aerosil), and 125 g of mannitol (Towa Kasei Kogyo). Further purified water 4000
g was added and stirred for 15 minutes to obtain a uniform emulsion suspension. The apparent viscosity of this suspension was 800 mPa · S. This suspension was spray-dried using a spray dryer (OD22M, manufactured by Okawara Kakohki Co., Ltd.) under the conditions of an inlet temperature of 140 ° C, an outlet temperature of 75 ° C, a disk rotation speed of 6000 rpm, and a spraying speed of 17.1 kg / h. ,
About 3.3 kg of free-flowing powder was obtained. The fluidity of the obtained granules is good, the average particle size is 96 μm, the bulk density is 0.32 g / ml, and the angle of repose is 38.
The teprenone content in 1 g was 578 mg.

Formulation Example 3 To 84.6 g of the fluid powder obtained in Example 3, 0.4 g of magnesium stearate (NOF Corporation), 10 g of crospovidone (Crospovidone XL, ISPE Japan), anhydrous calcium hydrogen phosphate (Anhydrous calcium phosphate GS, Kyowa Chemical Industry) 50g, calcium silicate (Fluorite RE,
15 g of Eisai) was added, and compression molding was performed with a diameter of 7.5 mm and a pressing pressure of 600 kg. The obtained tablets had good physical properties, a hardness of 41 KN and a disintegration time of about 700 seconds.

Example 4 300 g of polyvinyl alcohol (Gosenol EG05, Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved in 2700 g of purified water at 80 ° C. to prepare teprenone.
1250 g was added, and the mixture was stirred at 8000 rpm for 15 minutes using a high speed stirrer (Homomixer, manufactured by Tokushu Kika Kogyo Co., Ltd.). To this was added 375 g of calcium silicate (Fluorite RE, Eisai), 62.5 g of light anhydrous silicic acid (AEROSIL, Nippon Aerosil), and 125 g of crystalline cellulose (Avicel 301, Asahi Kasei). Further, 4000 g of purified water was added and stirred for 15 minutes to obtain a uniform emulsified suspension. The apparent viscosity of this suspension was 700 mPa · S. Using a spray dryer (OD22M, manufactured by Okawara Kakoki Co., Ltd.), this suspension was heated at an inlet temperature of 140 ° C. and an outlet temperature of 78.
Spray drying was carried out under the conditions of ℃, disk rotation speed 6000 rpm, and spraying speed 16.8 kg / h to obtain about 3.6 kg of fluid powder. The resulting granules have good fluidity, an average particle size of 106 μm and a bulk density of 0.29.
g / ml, repose angle 38 °, teprenone content in 1g is 578m
It was g.

Formulation Example 4 To 84.6 g of the fluid powder obtained in Example 4, 0.4 g of magnesium stearate (NOF Corporation), 10 g of crospovidone (Crospovidone XL, ISPE Japan), anhydrous calcium hydrogen phosphate (Fujicalin, Fuji Chemical Industry) 35 g and calcium silicate (Fluorite RE, Eisai) 10 g were added, and compression molding was performed with a diameter of 7.5 mm and a pressing pressure of 400 kg. The obtained tablets had good physical properties, a hardness of 3 KN and a disintegration time of about 280 seconds.

Test Example 1 Measurement of content by particle size The solid preparation produced by the method of Example 1 was used for 30 <, 60, 83,
Sieving with 100, 140, 200, 200> Mesh, and the content of teprenone was measured according to a conventional method. as a result,
The solid agent according to the present invention had a uniform teprenone content regardless of the particle size (Table 1).

Table 1 Content by particle size ―――――――――――――――― 30 Mesh <99.5% 60 Mesh 97.3% 83 Mesh 96.3% 100 Mesh 95.6% 140 Mesh 98.7% 200 Mesh 102.1% 200 Mesh> 104.0% ――――――――――――――――

[0065]

Industrial Applicability According to the present invention, a solid agent containing a high concentration of a fat-soluble substance and excellent in uniformity can be obtained. The solid agent is substantially spherical in shape, has excellent fluidity, and has a high bulk density. Further, by mixing the solid agent according to the present invention with an inorganic excipient such as saccharides, celluloses, silicic acids, and calcium phosphate, the compression moldability is good,
Moreover, it is possible to manufacture a tablet in which the fat-soluble substance does not exude or stick to the tableting machine.

Further, conventionally, when a spray dryer was used for producing solid agents such as powders and granules of a fat-soluble substance, the drug adhered to the spray dryer, which required extremely labor for cleaning. Although the solid agent according to the present invention contains a fat-soluble substance in a high concentration, it hardly adheres to a spray dryer and can be easily cleaned.

   ─────────────────────────────────────────────────── ─── Continued front page    F-term (reference) 4C076 AA29 AA31 AA32 AA36 BB01                       CC22 DD21 DD27 DD29 EE06                       FF01 FF04 FF07 GG02 GG11                       GG14

Claims (12)

[Claims] 1. A solid agent containing a fat-soluble substance, a water-soluble polymer substance and an adsorbent. 2. The solid agent according to claim 1, wherein an emulsion containing a fat-soluble substance, a water-soluble polymer substance and an adsorbent is powdered by a spray drying method. 3. The fat-soluble substances are vitamins A and vitamin D.
The solid preparation according to claim 1 or 2, which is a compound, a vitamin E, a vitamin K, a coenzyme Q, or a terpene. 4. The solid preparation according to claim 1, wherein the fat-soluble substance is tocopherols, ubidecarenone or teprenone. 5. The solid agent according to claim 1, wherein the water-soluble polymer substance is polyvinyl alcohol, pullulan or gum arabic. 6. The adsorbent is silicic acid dioxide, hydrous silicon dioxide, light anhydrous silicic acid, calcium silicate, magnesium silicate, aluminum silicate, magnesium aluminate silicate, magnesium aluminometasilicate, magnesium aluminum silicate or The solid agent according to any one of claims 1 to 5, which is light aluminum oxide. 7. The solid agent according to claim 1, wherein the emulsion containing the fat-soluble substance, the water-soluble polymer substance and the adsorbent has a viscosity of 50 to 5000 cps / 1000 rpm. 8. A bulk density of 0.2 to 0.5 g / ml.
The solid agent according to any one of 1. 9. A fat-soluble substance is emulsified with a water-soluble polymer substance,
A method for producing a solid agent, which comprises adding an adsorbent, emulsifying and suspending, and pulverizing by spray drying. 10. The fat-soluble drug is vitamin A or vitamin D.
The method for producing a solid agent according to claim 9, wherein the solid agent is vitamins, vitamins E, vitamins K, coenzymes Q, and terpenes. 11. The method for producing a solid agent according to claim 9, wherein the water-soluble polymer substance is polyvinyl alcohol, pullulan or gum arabic. 12. The adsorbent is silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid, calcium silicate, magnesium silicate, aluminum silicate, magnesium aluminate silicate, magnesium aluminometasilicate, magnesium aluminum silicate or light adsorbent. It is aluminum oxide, The manufacturing method of the solid agent in any one of Claims 9-11.