JP2003081814A - Method for producing tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing tablets containing coated granules, wherein it can be prevented that the coating films of the coated granules are partially broken. SOLUTION: This method for producing the tablets is characterized by tableting aqueous enteric polymer coated granules containing a physiologically active substance unstable to an acid at a temperature exceeding room temperature.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing tablets.

[0002]

[Prior Art] With the aging of the population and changes in the living environment,
There is a demand for the development of an orally disintegrating solid preparation that can be taken easily while maintaining the convenience of handling that is characteristic of tablets, and that can be taken easily anytime, anywhere without water. There is. On the other hand, when the physiologically active substance is a substance exhibiting bitterness, it is preferable to mask the bitterness by covering the physiologically active substance from the viewpoint of drug compliance. Also,
When the physiologically active substance is a substance that is easily decomposed by an acid, it is necessary to coat the physiologically active substance so as to prevent the decomposition by the gastric acid and sufficiently reach the intestine. Coated tablets, capsules and the like are usually used for such problems. Although the two have contradictory properties, tablets containing coated fine granules have been conventionally developed to satisfy these requirements at the same time. For example, Japanese Patent Publication No. 6-502194 (USP 5,464,63)
2) discloses a rapidly disintegrating multiparticulate tablet characterized in that the active substance is present in the form of fine particles coated with the active substance. Further, Japanese Patent Application Laid-Open No. 2000-281564 discloses an orally disintegrating tablet containing coated fine particles in the tablet. However, in the production of tablets containing coated granules, a part of the coating film of granules may be destroyed during tableting, which reduces the effect of masking the bitterness, There is a problem that the acid resistance decreases.

[0003]

Therefore, the present invention aims to prevent a part of the coating film of the granules from being destroyed during tableting in the production of tablets containing the coated granules. To aim.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have found that by compressing coated granules at a temperature above room temperature, it is possible to reduce the breakage of the coating film of the granules during compression. Has been completed.

That is, the present invention provides (1) a method for producing a tablet, which comprises tableting a coated granule containing a physiologically active substance at a temperature exceeding room temperature, and (2) the physiologically active substance is
The method according to (1) above, which is an acid-labile physiologically active substance, and (3) the above-mentioned method (2), wherein the acid-labile physiologically active substance is a proton pump inhibitor (PPI). ) The production method according to the above (1), wherein the PPI is a benzimidazole compound or a salt thereof, (5) The production method according to the above (3), wherein the benzimidazole compound is lansoprazole or an optically active substance thereof, (6) coating The production method according to (1) above, wherein the granules are enterically coated granules, (7) the production method according to (5) above, wherein the enteric coating layer contains an aqueous enteric polymer base, ) The production method according to the above (6), wherein the water-based enteric polymer base is a methacrylic acid copolymer, (9) the temperature above room temperature is about 2
The manufacturing method according to (1) above, which is 5 ° C. or higher, (10) the manufacturing method according to (1) above, wherein the temperature above room temperature is from about 25 ° C. to about 50 ° C., and (11) the temperature above room temperature. The production method according to (1) above, which is at a temperature of about 25 ° C to about 40 ° C, (12) the production method according to (1) above, wherein the tablet is an orally disintegrating tablet, and (13) acid-labile physiological activity. A method for producing an orally disintegrating tablet, which comprises compressing enteric coated granules containing a substance and heated to about 25 ° C to about 50 ° C, (1
4) The production method according to the above (13), wherein the tableting machine is heated.
(15) The tableting machine is a rotary tableting machine, and the rotary turntable is heated and then tableted (14)
(16) A method for reducing the destruction of the coating film of the coated granules, which comprises heating the coated granules containing a physiologically active substance to a temperature above room temperature to tablet the mixture,
(17) A method for lowering the acid resistance of a tablet containing a coated granule, comprising heating the coated granule containing a physiologically active substance to a temperature higher than room temperature for tableting, (1)
8) A method for improving the hardness of a tablet, which comprises heating a coated granule containing a physiologically active substance to a temperature higher than room temperature to form a tablet, and (19) a composition containing a physiologically active substance. (20) A tablet obtained by coating with a coating layer, adding an additive to the obtained coated granule, heating the mixture of the coated granule and the additive to a temperature above room temperature, and compressing the mixture, (20) The tablet according to (19) above, wherein the physiologically active substance is an acid-labile physiologically active substance, and (21) the above-mentioned (20), wherein the acid-labile physiologically active substance is a benzimidazole compound or a salt thereof. The tablet described in (22), the tablet described in (21) above, wherein the benzimidazole compound is lansoprazole or an optically active substance thereof, (23) a tablet obtained by the method described in (1) above, (24) a hot-pressed tablet Tablets with improved acid resistance due to (2 ) Warming tablet tablet hardness was enhanced by, (26) tablets fracture is reduced in the coating film of the coated granules containing by heating tablet, (27) acid ratio of about 10%
A tablet containing coated granules, the hardness of which is increased and the breaking of the coating film of the coated granules is reduced, (28)
Enteric coated granules containing lansoprazole or an optically active substance thereof, heated to a temperature above room temperature,
(29) The granule according to (28) above, wherein the enteric coating layer contains an aqueous enteric polymer base, and (30) the above (28) wherein the aqueous enteric polymer base is a methacrylic acid copolymer. (31) The granules according to (28) above, wherein the temperature above room temperature is about 25 ° C. or higher, and (32) above (28) above about 28 ° C. to about 50 ° C. (33) The temperature above room temperature is about 25 ° C to about 40 ° C.
(30) The granules according to the above (30) having a temperature of (30), (34) the acid resistance of the enteric-coated granules containing an acid-labile physiologically active substance and heated to a temperature above room temperature are improved. And use for manufacturing tablets.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION "Coated granules" used in the present invention means granules to be coated with a coating agent. Here, the term “coating” includes not only the case where the object (particles) to be covered is completely covered but also the case where a part of the object is exposed. The “physiologically active substance” contained in the “granule” is not particularly limited as long as it is preferably coated for the purpose of masking taste and odor, enteric coating or sustained release. Preferable examples of the coating include physiologically active substances exhibiting a bitter taste and acid-labile physiologically active substances.

The "physiologically active substance" may be any of solid, powdery, crystalline, oily and solution forms, for example, a nutritional tonic health drug, antipyretic analgesic / antiinflammatory drug, psychotropic drug, anxiolytic drug. , Antidepressant, hypnotic sedative, antispasmodic, central nervous system agonist, cerebral metabolism improver, cerebral circulation improver, antiepileptic drug, sympathomimetic, gastrointestinal drug, antacid, antiulcer drug, antitussive expectorant ,
Antiemetics, respiratory stimulants, bronchodilators, antiallergic agents,
Dental oral medicine, antihistamine, cardiotonic agent, arrhythmia agent,
Diuretics, antihypertensives, vasoconstrictors, coronary vasodilators, peripheral vasodilators, hyperlipidemic agents, choleretic agents, antibiotics, chemotherapeutic agents, diabetes agents, osteoporosis agents, anti Rheumatic drugs,
1 selected from skeletal muscle relaxants, anticonvulsants, hormones, alkaloid narcotics, sulfa drugs, gout remedies, anticoagulants, antineoplastic agents, Alzheimer's disease remedies, etc.
One kind or two or more kinds of pharmaceutical ingredients are used. Each of these physiologically active substances may be a free form or a salt. Further, it may be a racemate or an optically active substance. Alternatively, it may be a prodrug. Examples of the nutritional tonic medicine include vitamin A, vitamin D, vitamin E (d-α-tocopherol acetate, etc.), vitamin B ₁ (dibenzoylthiamine, fursultiamine hydrochloride, etc.), vitamin B ₂ (riboflavin butyrate, etc.). , Vitamin B ₆ (pyridoxine hydrochloride, etc.), vitamin C (ascorbic acid, sodium L-ascorbate, etc.), vitamin B ₁₂ (hydroxocobalamin acetate, cyanocobalamin, etc.) vitamins, minerals such as calcium, magnesium, iron, proteins, amino acids , Oligosaccharides, crude drugs and the like. Examples of the antipyretic analgesic and anti-inflammatory drug include aspirin, acetaminophen, etenzamid, ibuprofen, diphenhydramine hydrochloride, dl-chlorpheniramine maleate, dihydrocodeine phosphate, noscapine, methylephedrine hydrochloride, phenylpropanolamine hydrochloride, caffeine, and anhydrous caffeine. , Serrapeptase, lysozyme chloride, tolfenamic acid, mefenamic acid,
Diclofenac sodium, flufenamic acid, salicylamide, aminopyrine, ketoprofen, indomethacin, bucolome, pentazocine and the like can be mentioned. Examples of the psychotropic drug include chlorpromazine, reserpine and the like. Examples of the anxiolytic drug include alprazolam, chlordiazepoxide, diazepam and the like. Examples of the antidepressant include imipramine, maprotiline hydrochloride, amphetamine and the like. Hypnotic sedatives include, for example, estazolam, nitrazepam, diazepam, perrapine, phenobarbital sodium and the like. Antispasmodics include, for example, scopolamine hydrobromide, diphenhydramine hydrochloride, papaverine hydrochloride and the like.

Examples of the central nervous system acting drugs include citicoline. Examples of the cerebral metabolism improving agent include meclofenixate hydrochloride and the like. Examples of the cerebral circulation improving agent include vinpocetine and the like. Examples of the antiepileptic agent include phenytoin and carbamazepine. Examples of the sympathomimetic agent include isoproterenol hydrochloride and the like. Examples of the gastrointestinal drug include digestive digestive agents such as diastase, sugar-containing pepsin, funnel extract, cellulase AP3, lipase AP and cinnamon oil, berberine chloride, resistant lactic acid bacteria, and intestinal regulating agents such as bifidobacteria. Examples of the antacid include magnesium carbonate, sodium hydrogen carbonate, magnesium aluminometasilicate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium oxide and the like. Examples of the antiulcer agent include PPIs such as benzimidazole compounds such as lansoprazole, omeprazole, rabeprazole, and pantoprazole or salts thereof (including each optically active substance), histamine H ₂ receptors such as famotidine, cimetidine, and ranitidine hydrochloride. Examples include antagonists. Examples of the antitussive and expectorant include cloperastine hydrochloride, dextromethorphan hydrobromide, theophylline, potassium guaiacolsulfonate, guaifenesin, codeine phosphate and the like. Examples of the antiemetic agent include diphenidol hydrochloride and metoclopramide. Examples of the respiratory stimulant include levallorphan tartrate and the like. Examples of the bronchodilator include theophylline, salbutamol sulfate and the like. Examples of antiallergic agents include amlexanox and seratrodast. Examples of the oral medicine include oxytetracycline, triamcinolone acetonide, chlorhexidine hydrochloride, lidocaine and the like. Examples of the antihistamine include diphenhydramine hydrochloride, promethazine, isothipendyl hydrochloride, dl-chlorpheniramine maleate and the like. Examples of the cardiotonic agent include caffeine and digoxin. Examples of the antiarrhythmic agent include procainamide hydrochloride, propranolol hydrochloride, pindolol and the like. Examples of diuretics include thiaside agents such as isosorbide, furosemide and HCTZ.

Examples of the antihypertensive agent include delapril hydrochloride, captopril, hexamethonium bromide, hydralazine hydrochloride, labetalol hydrochloride, manidipine hydrochloride, candesartan cilexetil, methyldopa, losartan, valsartan, eposartan, irbesartan, tasosartan, telmisartan, etc. . Examples of the vasoconstrictor include phenylephrine hydrochloride and the like. Examples of the coronary vasodilator include carbochromene hydrochloride, molsidomine, perapamil hydrochloride and the like. Examples of the peripheral vasodilator include cinnarizine and the like. Examples of the hyperlipidemic agent include cerivastatin sodium, simvastatin, pravastatin sodium and the like. Examples of the choleretic agent include dehydrocholic acid, trepipton and the like. Antibiotics include
For example, cephalexin, cefaclor, amoxicillin, pibmecillinum hydrochloride, cefotiam hexetyl hydrochloride, cefadroxil, cefixime, cefditoren pivoxil, cefteram pivoxil, cefpodoxymiproxetil, cefotiam hydrochloride, cefazoplan hydrochloride, cefmenoxim hydrochloride, etc. Synthetic antibacterial agents such as cephem, ampicillin, cyclacillin, sulbenicillin sodium, nalidixic acid and enoxacin, monobactams such as carmonam sodium, penems and carbapenems are listed. Examples of chemotherapeutic agents include sulfamethizole,
Examples thereof include sulfamethizole hydrochloride and thiazosulfone. Examples of the antidiabetic agent include tolbutamide, voglibose, pioglitazone hydrochloride, glibenclamide, troglidazone, rosiglitazone maleate, acarbose, miglitol, emiglitate and the like.
Examples of the osteoporosis agent include ipriflavone. Examples of the skeletal muscle relaxant include methocarbamol. Examples of the antispasmodic include meclizine hydrochloride, dimenhydrinate and the like. Antirheumatic drugs include methotrexate, bucillamine, and the like. Examples of the hormonal agents include liothyronine sodium, dexamethasone sodium phosphate, prednisolone, oxendron, leuprorelin acetate and the like. Examples of the alkaloid narcotics include opium, morphine hydrochloride, tocon, oxycodone hydrochloride, opium alkaloid hydrochloride, cocaine hydrochloride and the like. Examples of the sulfa drug include sufamine, sulfisomidine, sulfamethizole and the like. As a gout remedy,
Examples include allopurinol and colchicine.
Examples of the blood coagulation inhibitor include dicoumarol. Examples of the anti-neoplastic agents include 5-fluorouracil, uracil, mitomycin and the like. Examples of the therapeutic agent for Alzheimer's disease include idebenone and vinpocetine.

Among the above-mentioned medicinal ingredients, nutritional tonic health medicine, antipyretic analgesic and anti-inflammatory drug, hypnotic sedative, central nervous system acting drug, gastrointestinal drug, antiulcer drug, antitussive expectorant drug, antiallergic drug, antiarrhythmic drug, diuretic drug. A blood pressure-lowering agent, a vasoconstrictor, a coronary vasodilator, an antihyperlipidemic agent, a diabetes agent, an osteoporosis agent, a skeletal muscle relaxant, and an antidepressant are preferably used. In the present invention, pharmaceutical ingredients particularly preferably used are antiulcer agents such as lansoprazole; antidiabetic agents such as voglibose and pioglitazone hydrochloride; antihypertensive agents such as manidipine hydrochloride and candesartan cilexetil. Further, two or more kinds of these pharmaceutical ingredients may be blended in the rapidly disintegrating solid preparation of the present invention. The pharmaceutical component may be diluted with a diluent or the like generally used in the fields of medicine and food. Moreover, you may use what was processed for the purpose of masking the bitterness of a pharmaceutical ingredient. The above-mentioned pharmaceutical components are used in an amount of 0.01 to 90 parts by weight, preferably 0.02 to 50 parts by weight, and more preferably 0.05 to 30 parts by weight, based on 100 parts by weight of the solid preparation.

Examples of the "acid-labile physiologically active substance" include compounds (particularly pharmaceutical ingredients) that are unstable in the acidic region and / or are inactive by the acid, and specific examples thereof include PPI. To be Examples of PPI include benzimidazole compounds having antiulcer action or salts thereof (including racemic compound and optically active substance) (eg, lansoprazole, omeprazole, rabeprazole, pantoprazole, perprazole, reminoprazole,
TU-199 etc.) and the like. Among them, lansoprazole, omeprazole, rabeprazole, pantoprazole and the like are preferable, and lansoprazole and its optically active substance are particularly preferable. As the optically active form of lamprazole, the R form is particularly preferable. Other PPIs include tenatoprazole.

The above-mentioned "granule" may contain, in addition to the physiologically active substance, a binder, a lubricant, an excipient and the like used in the production of the following general preparations. The added amount is the amount used for the production of general preparations. When the physiologically active substance is an “acid-labile physiologically active substance”, it is preferable to incorporate a basic inorganic salt into the granules in order to stabilize the physiologically active substance in the preparation. Examples of the "basic inorganic salt" include:
Basic inorganic salts of sodium, potassium, magnesium and / or calcium (eg, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, etc.) can be mentioned. .

The above-mentioned "granular body" is not particularly limited as long as it is in a granular form, and may be one having no nucleus or one having a nucleus. When the granule has a nucleus, the nucleus may or may not contain a physiologically active substance. The particle size of the granules may be determined according to the desired particle size of the coated granules. Particle size The particles may be produced by a method known per se or a method similar thereto depending on the form. When the granules have no nucleus, they can be produced by a granulation method known per se. Examples of "granulation method" include tumbling granulation method (eg, centrifugal tumbling granulation method), fluidized granulation method (eg, tumbling fluidized bed granulation, fluidized granulation, etc.), and stirring granulation method. Can be mentioned. Of these, the fluidized granulation method is preferable. The rolling fluidized bed granulation method is particularly preferable. Specific examples of the tumbling granulation method include, for example, "CF device" manufactured by Freund.
And the like. Specific examples of the tumbling fluidized bed granulation method include a method using "Spiraflow", "Multiplex" manufactured by Paulec, "New Malmo" manufactured by Fuji Paudal. The spraying method of the mixed solution can be appropriately selected according to the type of the granulating device, for example, a top play method, a bottom spray method,
Any of a tangential spray method and the like may be used. Of these, the tangential spray method is preferable.

On the other hand, the granule having a core can be produced by coating the core with a physiologically active substance by a method known per se. For example, according to the production method (coating method) described in JP-A-5-092918, a nucleus containing crystalline cellulose and lactose, an acid-labile physiologically active substance, and if necessary, a basic inorganic salt and a binder are used. , A lubricant, an excipient, a water-soluble polymer and the like (hereinafter sometimes abbreviated as a coating layer).

The average particle size of the "nucleus" is about 40 to 350.
μm, preferably about 50-250 μm, more preferably about 100-250 μm, particularly preferably about 100-20.
It is 0 μm. As a core having such an average particle diameter, a No. 50 (300 μm) sieve is passed through, and a No. 60 (250 μm)
The particles remaining on the (.mu.m) sieve are about 5 w / w% or less and the particles passing through the No. 282 (53 .mu.m) screen are about 10 w / w% or less on the whole. Specific volume of "nucleus" is 5 ml / g or less, preferably 4 ml
/ G, more preferably 3 ml / g or less. The "nuclear"
For example, (1) spherical granules of crystalline cellulose and lactose, (2) 150 to 250 μ of crystalline cellulose
m spherical granulation product (Asahi Kasei Co., Ltd., Avicel SP),
(3) Lactose (9 parts) and alpha starch (1 part) 50-
250 μm agitated granulated product, (4) JP-A-61-2132
No. 01 gazette, fine particles of 250 μm or less obtained by classifying the microcrystalline cellulose spherical granules, (5) processed products such as waxes formed into a spherical shape by spray chilling or melt granulation, (6) gelatin beads of oil component Processed products such as (7) calcium silicate, (8) starch, (9)
Porous particles such as chitin, cellulose and chitosan,
(10) Bulk products such as granulated sugar, crystalline lactose, crystalline cellulose or sodium chloride, and processed products thereof can be mentioned. Further, these cores may be produced by a pulverization method or a granulation method known per se and sieved to prepare particles having a desired particle size.

Examples of the "spherical granulated product of crystalline cellulose and lactose" include (i) crystalline cellulose (3 parts)
Spherical granulated product of 100 to 200 μm (eg, Nonpareil 105 (70-140) (particle size 1
100-200 μm), manufactured by Freund), (ii) 150-25 with crystalline cellulose (3 parts) and lactose (7 parts)
0 μm spherical granulated product (eg, Nonpareil NP-7: 3, manufactured by Freund), (iii) crystalline cellulose (4.5 parts)
And lactose (5.5 parts) with a spherical granulation product of 100 to 200 μm (eg, Nonpareil 105T (70-140) (particle size 100 to 200 μm, manufactured by Freund), etc.),
(Iv) Spherical granulated product of 150 to 250 μm with crystalline cellulose (5 parts) and lactose (5 parts) [eg, nonpareil NP
-5: 5, manufactured by Freund) and the like. In order to produce a preparation excellent in solubility while maintaining appropriate strength, the "core" is preferably a spherical granulated product of crystalline cellulose and lactose, more preferably a spherical granulated product of crystalline cellulose and lactose. And those containing about 50% by weight or more of lactose. About 20-50 crystalline cellulose
Preference is given to those containing about 40% to about 50% by weight and lactose about 50 to 80% by weight, preferably about 50 to 60% by weight. As the nucleus used in the present invention,
A spherical granulated product of crystalline cellulose and lactose is preferable, and a spherical granulated product of 100 to 200 μm formed of crystalline cellulose (4.5 parts) and lactose (5.5 parts) is more preferable. The “nucleus” may contain a physiologically active substance such as the above-mentioned medicinal components. However, since the release layer of the physiologically active substance can be controlled by the coating layer containing the physiologically active substance, the nucleus is a physiologically active substance. Need not be included. The "nucleus" may be in the form of fine particles, and preferably has a spherical shape as uniform as possible in order to reduce variations in coating.

By coating the thus obtained granules with a coating agent by a method known per se, "coated granules" can be obtained. Examples of the coating agent include enteric polymer (eg, cellulose acetate phthalate, cellulose acetate phthalate, methacrylic acid (hereinafter referred to as methacrylic acid) copolymer L, and methacrylic acid copolymer LD.
(Eudragit L30D-55 (trade name: manufactured by Rehm Co.), methacrylic acid copolymer S, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, Kollicoat MAE30DP
(Trade name; manufactured by BASF Co., Ltd.), Polykid PA30 (trade name: manufactured by Sanyo Kasei Co., Ltd.), carboxymethylethyl cellulose, shellac, methacrylic acid copolymer [for example, Eudragit NE30D (trade name), Eudragit RL30D (trade name) ), Eudragit RS30D
(Trade name), etc.], triethyl citrate, polyethylene glycol, acetylated monoglyceride, triacetin, castor oil, etc.), gastric soluble polymer (eg, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, etc.), water-soluble polymer (eg,
Hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc., sparingly soluble polymer (eg, ethyl cellulose, aminoalkyl methacrylate copolymer R)
S, ethyl acrylate / methyl methacrylate copolymer, etc.), wax and the like. You may use these individually or in mixture of 2 or more types. As a coating agent for enteric coating, cellulose acetate phthalate (CAP),
Hydroxypropylmethylcellulose phthalate (hereinafter referred to as HP-55), hydroxymethylcellulose acetate succinate, methacrylic acid copolymer [for example, Eudragit L30D-55, Kollicoat MAE30DP, Polykid PA30, etc.], carboxymethylethylcellulose, shellac, etc. Those containing an aqueous enteric polymer base are preferred. The water-based enteric polymer base is preferably a methacrylic acid copolymer.

The coating layer may be formed of a plurality of layers. For example, granules, methacrylic acid copolymer, coated with an enteric coating layer containing polyethylene glycol, methacrylic acid copolymer, coated with an enteric coating layer containing triethyl citrate, further, Examples thereof include a method of coating an enteric coating layer containing an acrylic acid copolymer and polyethylene glycol. Further, for example, the enteric coating layer may be overcoated with a water-soluble sugar alcohol such as mannitol for the purpose of improving the strength of the tablet.

The enteric coating layer is preferably a layer covering the entire surface of the composition containing the physiologically active substance with a thickness of 10 to 100 μm, preferably 20 to 70 μm, and more preferably 30 to 50 μm. Therefore, the smaller the particle size of the coated granules, the greater the weight percentage of the enteric coating layer in the entire coated granules. Usually, the enteric coating layer is 20 to 90% by weight, preferably 30 to 90% by weight of the whole coated granule.
70% by weight, more preferably 50 to 70% by weight.

The particle size of the coated granules is not particularly limited, but fine granules or granules are preferable, and in the case of an orally rapidly disintegrating tablet, the average particle size thereof is about 10 in order to prevent the feeling of roughness and discomfort in the mouth. It is 400 μm or less. The average particle size is preferably 200 to 400 μm, more preferably 300 to 40.
It is 0 μm.

The "coated granules" are described in JP-A 2000-
281564 and JP 2000-103731.
The fine granules described in the publication are particularly preferred.

In the method for producing tablets of the present invention, the coated granules may be tableted alone, but preferably the coated granules and additives are mixed and tableted. At this time, the additives may be granulated in advance and mixed. The additive may be any additive as long as it is used in the production of general preparations, and the amount of addition is the amount used in the preparation of general preparations. As the "additive", for example, water-soluble sugar alcohol, crystalline cellulose, low-substituted hydroxypropyl cellulose, etc. are used, and further, a binder, an acidulant, a foaming agent, an artificial sweetener, a flavor, a lubricant, a colorant. , Stabilizers, excipients, disintegrants, etc. are also used. The “water-soluble sugar alcohol” is obtained by adding 1 g of sugar alcohol to water and shaking the mixture vigorously for 5 seconds at 20 ° C. for 30 seconds to dissolve the water within about 30 minutes.
It means a sugar alcohol that is less than ml. Examples of the "water-soluble sugar alcohol" include sorbitol, mannitol, maltitol, reduced starch saccharified product, xylitol,
Examples thereof include reduced palatinose and erythritol. These may be used as a mixture of two or more kinds thereof at an appropriate ratio. The "water-soluble sugar alcohol" is preferably mannitol, xylitol or erythritol, more preferably mannitol or erythritol, particularly preferably mannitol. As erythritol, those having a particle size of 50 mesh or less are used, which are usually produced by fermentation of yeast with glucose as a raw material. The erythritol can be obtained as a commercial product [Nikken Chemical Co., Ltd.]. In the case of an orally disintegrating agent, the "water-soluble sugar alcohol" is usually about 5 to 97 parts by weight with respect to 100 parts by weight of the total amount of additives in order to obtain sufficient formulation strength and sufficient orally disintegrating property. Preferably about 10 to 90 parts by weight, more preferably about 20 to 80 parts by weight.
In the case of mannitol or erythritol, it is usually about 5 to 90 parts by weight, preferably about 10 to 80 parts by weight, more preferably about 20 to about 100 parts by weight of the additive.
80 parts by weight, most preferably about 50 to 80 parts by weight.

The "crystalline cellulose" may be one obtained by partially depolymerizing α-cellulose and purifying it. Moreover, what is called microcrystalline cellulose is also included. Specific examples of the crystalline cellulose include CEOLUS KG 801, Avicel PH 101, and Avicel PH.
102, Avicel PH 301, Avicel PH 30
2, Avicel RC-591 (crystalline cellulose / carmellose sodium) and the like. Preferable one is Ceorus KG 801 which is called highly molded Avicel. These crystalline celluloses may be used alone,
Two or more kinds can be used in combination. These crystalline celluloses can be obtained as commercial products [Asahi Kasei Co., Ltd.]. The crystalline cellulose may be added in an amount of about 3 to 50 parts by weight, preferably about 5 to 40 parts by weight, and most preferably about 5 to 20 parts by weight, based on 100 parts by weight of the additive.

The "low-substituted hydroxypropyl cellulose" has a hydroxypropoxyl group content (hereinafter sometimes abbreviated as HPC group content) in hydroxypropyl cellulose of about 5.0 to 9.9% by weight. Low-substituted hydroxypropyl cellulose, especially about 5.0
A low-substituted hydroxypropyl cellulose having a content of about 7.0 wt% and a low-substituted hydroxypropyl cellulose having a content of about 7.0-9.9 wt% are used. Examples of the low-substituted hydroxypropyl cellulose having an HPC group content of about 7.0 to 9.9% include LH-22 and LH-32.
And mixtures thereof, and these are available as commercial products [Shin-Etsu Chemical Co., Ltd.]. It can also be produced by a method known per se, for example, the method described in JP-B-57-53100 described below or a method analogous thereto. Examples of the low-substituted hydroxypropylcellulose having an HPC group content of about 5.0 to 7.0% include LH-23 and LH-3 described in Reference Examples below.
3 and mixtures thereof, and these can be produced by a method known per se, for example, the method described in JP-B-57-53100 or a method analogous thereto. The "hydroxypropoxyl group content is 5.0
The particle size of "about 7.0% by weight of low-substituted hydroxypropylcellulose" is, for example, about 5 to 60 as an average particle size.
μm, preferably about 7-50 μm, more preferably about 1
It is 0 to 40 μm. Within such a range, L-HPC having a relatively large particle size (for example, an average particle size of about 26-
By using 40 μm L-HPC), a preparation having excellent disintegration can be produced. On the other hand, by using L-HPC having a relatively small particle size (for example, L-HPC having an average particle size of about 10 to 25 μm), a drug product having excellent drug product strength can be produced. Therefore, the particle size of L-HPC can be appropriately selected according to the characteristics of the intended preparation. Low-substituted hydroxypropyl cellulose having an HPC group content of 5.0 to 7.0% by weight, and HPC group content of 7.0 to 9.
In the case of an orally disintegrating tablet, 9% of the low-substituted hydroxypropyl cellulose is usually about 3 to 100 parts by weight of the total amount of the additives in order to obtain sufficient orally disintegrating property and sufficient formulation strength. 50 parts by weight, preferably about 5 to 40 parts by weight, more preferably 5 to 20 parts by weight are used.

Examples of the "binder" include hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, α-starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan and low-substituted hydroxypropylcellulose. When crystalline cellulose is used as the binder, a solid preparation having a higher preparation strength can be obtained while maintaining excellent oral disintegration. Examples of the "acidulant" include citric acid (citric acid anhydride), tartaric acid, malic acid and the like. Examples of the "foaming agent" include sodium bicarbonate and the like. Examples of the “artificial sweetener” include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia, thaumatin and the like. The "fragrance" may be either synthetic or natural, and examples thereof include lemon, lime, orange, menthol and strawberry. As the "lubricant",
Examples thereof include magnesium stearate, sucrose fatty acid ester, polyethylene glycol, talc and stearic acid. Examples of the "colorant" include food dyes such as food yellow No. 5, food red No. 2, food blue No. 2, and the like;
Examples include edible lake pigments, red iron oxide, and the like. Examples of the “stabilizer” include the above-mentioned basic inorganic salts and the like. Examples of the “excipient” include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, titanium oxide and the like.

As the "disintegrant", a disintegrant commonly used in the field of formulation can be used. For example, (1) crospovidone, (2) croscarmellose sodium (FM).
C-Asahi Kasei), carmellose calcium (Gutoku Yakuhin) and other disintegrants called super disintegrants, (3) carboxymethyl starch sodium (eg, Matsutani Chemical Co., Ltd.),
(4) Low-substituted hydroxypropyl cellulose (eg, manufactured by Shin-Etsu Chemical Co., Ltd.), (5) Corn starch and the like. A particularly preferred disintegrant is, for example, crospovidone. The "crospovidone" is cross-linked with a chemical name of 1-ethenyl-2-pyrrolidinone homopolymer, including those called polyvinylpolypyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinone homopolymer. The polymer may be any of the above polymers, and specific examples include Kollidon CL (manufactured by BASF), Polyplasdone XL (manufactured by ISP), and Polyplasdone XL-1.
0 (manufactured by ISP), Polyplasdon INF-10 (IS
P company). Usually the molecular weight is 1,000,000
Is over. These disintegrants may be used alone or in combination of two or more. For example, crospovidone alone or a combination of crospovidone and another disintegrant can be mentioned. Such a disintegrant is usually about 1 to 15 parts by weight, based on 100 parts by weight of the total amount of the additive for the orally disintegrating tablet.
The content is preferably about 1 to 10 parts by weight, more preferably about 3 to 7 parts by weight.

The method for producing tablets of the present invention is characterized in that the coated granules at a temperature above room temperature are compressed. In the present specification, tableting the raw material powder or granules heated to a temperature higher than room temperature in this way may be simply referred to as "heated tableting". In the present specification, "room temperature" refers to the temperature in the room where tableting is performed in the production of ordinary tablets, and the temperature is usually about 20 ° C to about 23 ° C. That is, the “temperature above room temperature” means a temperature above this temperature, and preferably the lower limit is about 25 ° C. The temperature varies depending on the coating agent used, raw material powder, granules, etc., but is usually preferably about 25 ° C. to about 50 ° C., more preferably about 25 ° C.
It is about 40 ° C. The temperature can be varied depending on the desired tablet quality. For example, when the acid resistance of the tablets obtained by the production method of the present invention exceeds the target value, the temperature of the coated granules may be increased.

The method for raising the temperature of the coated granules to above room temperature is not particularly limited. For example, with a non-contact type infrared heater or warm air, or a contact type resistance heater,
The coated granules may be heated directly, or the entire tableting machine or the part of the tableting machine with which the coated granules come into contact (eg, the rotary table turntable). The coated granules are indirectly heated by, for example, heating the tableting machine in a small chamber to heat the small chamber, or heating the small chamber partially covering the tableting die and the granule supply unit. You may warm it. The heating of the small chamber can be performed, for example, by blowing warm air. Further, both the coated granules and the tableting machine or a part thereof, or both the coated granules and the small chamber in which they are installed may be heated.
When heating the coated granules for tableting or a part or the whole of the tableting machine, the portion where the coated granules are in direct contact (for example,
It is generally preferable to heat the rotating disk and the punch in a non-contact manner, but it is also effective to heat the portion not in direct contact with a contact type resistance heater. The portion that does not directly contact means the back surface of the rotary disk, the upper punch holder, the lower punch holder, or the like. Alternatively, the tableting machine may be warmed by running the tableting machine idly in advance. Further, if the temperature of the tablet machine rises and is affected by the external temperature by continuously operating the tablet machine, an appropriate sensor is provided in the tablet machine or a small room in which they are installed, and the temperature is adjusted to the above temperature. It is preferable. As such a tablet manufacturing apparatus, any tablet manufacturing apparatus equipped with a temperature control unit for maintaining the temperature of the coated granules at a predetermined temperature during tableting can be used. It is suitable. Preferred embodiments of the present invention will be described with reference to the accompanying drawings. FIG. 1 shows a schematic configuration of a rotary tableting machine 1 which is an embodiment of a tablet tableting device according to the present invention. However, the tablet compression device of the present invention is not limited to this rotary type compression machine. The tableting machine 1 has a tableting chamber (housing) 2 configured by combining transparent plate materials. A vertical rotation shaft 4 drivingly connected to a motor 3 is arranged in the tableting chamber 2. The rotary shaft 4 supports a turntable 5, and the rotary shaft 4 and the turntable 5 are rotated in a predetermined direction at a constant speed based on the drive of the motor 3.

The turntable 5 has a plurality of tableting cells penetrating the turntable 5 and extending in parallel with the rotary shaft 4 at regular intervals on a circle having a predetermined radius around the rotary shaft 4 ( Mortar) 6 is formed. Below each tableting cell 6, a lower tableting rod (pestle) 7 having an upper end portion having an outer diameter substantially the same as the inner diameter of the tableting cell 6 is arranged.
Each lower tableting rod 7 is supported by an elevating mechanism (not shown) that rotates with the rotation of the rotating shaft 4, and while the turntable 5 makes one rotation, the lower tabletting rod 7 is driven by the motor 3 in accordance with the rotational position. The most lowered position (the position where the upper end of the rod is most lowered in the tablet cell) and the most raised position (the position where the upper end of the rod protrudes above the tablet cell).
It is designed to move between and.

An upper tableting rod (punch) 8 is arranged above each tableting cell 6. Each upper tableting rod 8 is supported by an elevating mechanism (not shown) that rotates with the rotation of the rotating shaft 4, and while the turntable 5 makes one rotation, it drives the motor 3 depending on the rotational position. On the basis of this, it moves between the most lowered position (the lower end of the rod is the most lowered position in the tableting cell) and the most raised position (the lower end of the rod is retracted above the tableting cell). Is done. Further, the lower end portion of each upper tableting rod 8 has an outer diameter substantially the same as the inner diameter of the tableting cell 6, and the tableting cell 6 cooperates with the upper end portion of the lower tableting rod 7 for tableting. The tableting powder is pressed from above and below so that tablets can be molded.

The tableting machine 1 is further provided with a powder supply device 9 for supplying and filling the tableting powder to each tableting cell 6. The powder supply device 9 guides, for example, a powder supply hopper 10 for dropping the powder onto the turntable 5 and the tableting powder supplied from the hopper 10 to the turntable 5 to each tableting cell 6. It is equipped with a feeder 11.

According to the tableting machine 1 having the above construction, the tableting powder is dropped and supplied from the hopper 11 onto the turntable 5. The powder on the turntable 5 is guided to each tableting cell 6 by the feeder 11 based on the rotation of the turntable 5. While the tableting cells 6 are being filled with powder, the lower tableting rod 7 is at the most lowered position, whereby a predetermined amount of powder is filled in each tableting cell 6. Next, the lower end portion of the upper tableting rod 8 is inserted into the tableting cell 6 filled with a predetermined amount of powder from above. At the same time, the lower tableting rod 7 rises. As a result, the powder in the tableting cell 6 becomes lower in the tableting rod 7 and the upper tableting rod 8.
It is compressed between and to form tablets. After tableting, the upper tableting rod 8 is retracted from the tableting cell 6 above it.
Then, the formed tablet is pushed out of the tableting cell 6 by the ascent of the lower tableting rod 7 and collected in a tray (not shown) provided on the outer periphery of the turntable 5.

Next, the heating device of the tableting machine 1 will be described. The warming device 12 keeps the powder for tableting (mixed powder of the main drug fine particles and the excipient powder) at a predetermined temperature or a predetermined temperature range before or during the production of tablets by the tableting machine 1.
Therefore, in the present embodiment, the heating device 12 is
A warm air heater 13 and a radiant heater (contact type and non-contact type heater) 14 are provided. The warm air heater 13 includes a warm air generating source 15, an adiabatic air supply duct 16 for guiding the warm air generated by the warm air generating source 15 to the tableting chamber 2, and the tableting chamber 2.
An exhaust duct 17 is provided for guiding the air of the above. On the other hand, the radiant heater 14 includes one or a plurality of non-contact type heaters (for example, an infrared heater 18a) arranged in the tableting chamber 2 in the vicinity of the turntable 5 in a non-contact manner with the turntable 5, in particular. It has a contact heater (for example, a resistance heater 18b) provided in contact with the lower surface or the outer peripheral surface of the turntable 5. It is preferable that the non-contact type heater 18a and the contact type heater 18b are detachable so that they can be taken out from the tableting chamber 2 when they are not needed.

In order to control the heating device 12, the tableting chamber 2
A plurality of temperature detectors 19 (19a to 19e) are arranged in the. The temperature detector 19 may be arranged at, for example, the turntable 5, the hopper 10, the air supply duct 16,
The surface of the exhaust duct 17 or one or more locations in the vicinity thereof is preferable. However, the location of the temperature detector is not limited to a specific location as long as the temperature of the tableting powder or the temperature of the turntable 5 can be detected directly or indirectly.

As shown in FIG. 2, the heating control unit 20 for controlling the heating device 12 includes a heating device 12 such as the hot air source 15, the non-contact infrared heater 18a or the contact resistance heater 18b. , A plurality of temperature detectors 19, a tabletting machine drive motor controller 21, and a power switch 22 are electrically connected.

The heating controller 20 having the above structure
It operates based on the program shown in FIG. It should be noted that this program is a subroutine of the main program that manages the entire tablet machine 1, and is repeatedly executed at regular intervals set by the timer of the main program. Specifically, the heating controller 20 first determines whether or not the power switch 22 is turned on (ST1). Power switch 2
If 2 is off, the program waits. When the power switch 22 is turned on, it is determined whether or not the temperature t detected by the temperature detector 19 exceeds a predetermined reference temperature α (ST2).

The reference temperature α differs depending on the detection part (target) of the temperature detector 19, and can be set according to each sensor. For example, when the temperature detector 19 detects the ambient temperature (room temperature) of the tableting chamber 2, the reference temperature α is, for example, 2
Set to 5 ° C. However, the reference temperature is not limited to that value, and can be set to an appropriate value in the range of, for example, about 25 ° C to about 50 ° C. On the other hand, the temperature detector 19
Detects the surface temperature of the turntable 5 or the temperature of the portion where the tableting powder comes into contact, the reference temperature is about 30 ° C to
Set to an arbitrary value of about 40 ° C.

When the detected temperature t is equal to or lower than the reference temperature, the heating device 12 is turned on (ST3), and the tablet machine drive motor control unit 2 is operated.
The drive of the motor 3 is prohibited via 1 (ST4). As a result, the tableting device waits until the temperature of the tableting powder before tableting reaches or exceeds the reference temperature. On the other hand, when the tableting powder is sufficiently heated by the heating device 12 and the detected temperature t exceeds the reference temperature, the heating device 12 is turned off (ST.
5) The driving of the motor 3 is permitted via the tablet machine driving motor control unit 21 (ST6). Although the temperature may be controlled based on the output of the sensor during tableting, if the temperature of the tableting powder can be maintained at a predetermined reference temperature or higher by the heat generated in the device during tableting, It is not necessary to control the lower limit temperature after starting the lock.

The tablet of the present invention is manufactured by a method conventionally used in the field of pharmaceutical preparation, except that coated granules having a temperature above room temperature are compressed. For example, there may be mentioned a method of mixing with coated granules, optionally with additives and water, tableting, and optionally drying. The “mixing” is performed by a generally used mixing method, for example, mixing, kneading, granulation and the like. The "mixing" means, for example, a vertical granulator VG10 (manufactured by Paulec), a universal kneader (manufactured by Hata Tekko Co., Ltd.), a fluidized bed granulator LAB-1, FD-3S (manufactured by Paulec), a V-type mixer. , A tumbler mixer or the like.

"Tabletting" is performed by using a single tableting machine (Kikusui Seisakusho), a rotary type tableting machine (Kikusui Seisakusho) or the like, and 1 to 80 kN / cm ² , 5 to 50 kN / cm ² , preferably 15 to. It is carried out by tableting at a pressure of 40 kN / cm ² . In the case of a rotary tableting machine, a normal rotation speed, for example, 3 to 120 min ^-1 , preferably 3 to 80 min ^-1 , more preferably 5 to 60 min.
^The tablet may be tableted with ^-1 . "Drying" means, for example, vacuum drying,
Any method used for drying general preparations such as fluidized bed drying may be used.

The tablets of the invention thus obtained have a reduced destruction of the coating film of the coated granules. For example, in the case of a tablet containing an acid-labile physiologically active substance in a coated granule, even if the tablet is produced using a rotary tableting machine under normal pressure and rotation speed, dissolution in an acidic solution The rate, ie the acid resistance, is reduced. Depending on the coating agent used, it can usually be reduced to about 10% or less, and further to about 7% or less. Depending on the components used, a more preferable acid resistance is about 5% or less,
It is more preferably about 3% or less. Most preferably, it can be about 1% or less. Here, the acid resistance is defined as 0.1N HCl 50 according to the Japanese Pharmacopoeia Second Method.
Elution test was performed at 0 mL (75 rpm) for 1 hour, the eluate was collected, filtered through a 0.45 μm membrane filter, the absorbance was measured, and the dissolution rate of the drug into 0.1N HCl was calculated to obtain the value. To be In addition, the warm-pressed tablet of the present invention has improved hardness as compared with a tablet obtained by tableting powder or granules at room temperature. As such a tablet, not only when using coated granules as a raw material, but also when using ordinary powder or granules, tablets with improved hardness can be obtained. Here, the hardness of the tablet is a degree indicating the hardness of the tablet, and usually refers to the compressive force when the tablet is compressed and broken in the diameter direction. The hardness depends on the size of the tablet and the tableting pressure, but according to the present invention, the hardness is about 1 even at the normal tableting pressure.
A hardness of 0 to 300 N can be achieved. When the above-mentioned coated granules are subjected to hot-pressing, a tablet having both improved acid resistance and hardness can be obtained. For example, a hardness of usually about 10 to 200 N, preferably about 15 to 80 N can be achieved. For example, in the case of an orally disintegrating tablet containing an enteric coated granule having a diameter of 9 mm, which belongs to the lowest hardness tablet, according to the present invention, a usual tableting pressure is about 10 to 50 N, preferably about 15 to 40 N. ,
More preferably, a hardness of 20 to 35 N is obtained. Therefore, in order to maintain the desired acid resistance, strength and hardness of the coating film, it is not necessary to increase the pressure or reduce the rotation speed, and it is possible to produce tablets with desired characteristics without reducing the production efficiency. it can.

The tablets obtained by the production method of the present invention can be taken in the same manner as ordinary tablets. For example, in the case of an orally disintegrating tablet, it may be taken by chewing without water and swallowing. Further, the dose of the tablet varies depending on the pharmaceutical ingredient, the subject to be administered, the type of disease and the like, but may be selected from the range in which the dose as the pharmaceutical ingredient is an effective amount. For example, when the pharmaceutical ingredient is lansoprazole, the rapidly disintegrating solid preparation of the present invention has a peptic ulcer (eg, gastric ulcer,
Duodenal ulcer, anastomotic ulcer, Zollinger-Ellison syndrome, etc.), gastritis, reflux esophagitis, gastroesophageal reflux disease without esophagitis (symptomatic Gast)
roesophageal Reflux Disease (symptomatic GERD)) and the like; Helicobacter pylori eradication; suppression of upper gastrointestinal bleeding due to peptic ulcer, acute stress ulcer and hemorrhagic gastritis; invasive stress (major vascular surgery requiring intensive management after surgery or cerebrovascular accident requiring intensive care, head trauma) , Prevention of upper gastrointestinal bleeding due to multiple organ failure, stress resulting from extensive burns; treatment and prevention of ulcers caused by non-steroidal anti-inflammatory drugs; treatment and prevention of hyperacidity and ulcers due to postoperative stress; preanesthetic administration , Etc., and the dosage is 1 adult (60 kg body weight),
0.5-1500 mg / day, preferably 5-500 mg / day, more preferably 5-150 mg of lansoprazole
/ Day. Lansoprazole may be used in combination with other drugs (antitumor agent, antibacterial agent, etc.). In particular, the combination of erythromycin antibiotics (eg, clarithromycin, etc.) and penicillin antibiotics (eg, amoxicillin, etc.) can be used in combination with H. An excellent effect for eradication of Helicobacter pylori can be achieved.

When the pharmaceutical ingredient is voglibose, the tablet of the present invention is useful for the treatment and prevention of obesity, hyperlipidemia, hyperlipidemia, diabetes, etc., and the dosage is 1 adult (60 kg Per body weight) as voglibose.
01-30 mg / day, preferably 0.01-10 mg / day
The day, more preferably 0.1 to 3 mg / day. The tablet may be administered once a day or in 2 to 3 divided doses.

[0044]

The present invention will be described in more detail below with reference to examples and reference examples, but these do not limit the present invention. The physical properties of the tablets obtained in the examples were measured by the following test methods. [Hardness test] The hardness was measured using a tablet hardness meter (manufactured by Toyama Sangyo Co., Ltd.). The test is performed 10 times and the average value is shown. [Acid resistance rate: Elution rate with 0.1N HCl] 500 mL (75 rp) of 0.1N HCl according to Japanese Pharmacopoeia Second Method
m), 1 hour dissolution test, collecting eluate, 0.45
After filtering with a μm membrane filter, the absorbance was measured and the dissolution rate of the drug in 0.1N HCl was calculated.

Example 1 (1) Manufacture of dry powder A nonpareil 105 (trade name) (particle size 100 to 200 μm)
m) 41.58 kg was put in a tumbling flow type coating granulator [MP-400 manufactured by Paulec Co., Ltd.], and the blast temperature was controlled so that the exhaust temperature in the steady state was about 31 ° C, and the tangential spray method was used. , Feeding rate 1.
The bulk liquid having the following composition prepared in advance was spray-coated at a rate of 4 kg / min. When the specified amount of the bulk liquid of 257.6 kg was sprayed, the production of the undercoat film-nucleated powder of (2) was continued. [Bulk liquid] Lansoprazole 39.6 kg Magnesium carbonate 13.2 kg Low-substituted hydroxypropyl cellulose LH-32 6.6 kg (Hydroxypropoxyl group content: 8.8% by weight) Hydroxypropyl cellulose (Type SL) 13.2 kg Purified water 185 L

(2) Manufacture of undercoated film dry-coated powder Following the preparation of dry-coated powder of (1) above, the blowing temperature was controlled so that the exhaust temperature in the steady state was about 41 ° C., and the following composition was prepared in advance. The undercoat film liquid was sprayed by a tangential spray system at a supply rate of 1.2 kg / min. When the prescribed amount of 132.0 kg of film liquid was sprayed, the spraying was stopped, and after drying for about 11 minutes, it was passed through a No. 42 round sieve (350 μm) and a No. 100 round sieve (150 μm), Hanging film nucleated powder 1
32 kg was obtained. [Undercoat film liquid] Hydroxypropyl methylcellulose 9.24 kg (Type 2910, viscosity 3 centistokes) Titanium oxide (TiO ₂ ) 3.96 kg Sterilized talc [Matsumura Sangyo Co., Ltd.] 3.96 kg Low-substituted hydroxypropyl cellulose LH -32 6.6 kg (Hydroxypropoxyl group content: 8.8% by weight) Mannitol 9.24 kg Purified water 99.0 L

(3) Manufacture of enteric-coated nucleated powder 44.0 kg of the undercoat film nucleated powder described in (2) above was added to a rolling fluid type coating granulator [MP-4 manufactured by Paulec Co., Ltd.].
00 type], the air temperature is controlled so that the exhaust temperature in a steady state is about 42 ° C., and the enteric film solution (A) having the following composition prepared in advance is supplied by a tangential spray method at a supply rate of 1.05 kg / A prescribed amount of 54.6 kg of enteric film solution was sprayed so that the amount became minutes. [Enteric film solution (A)] Eudragit L30D-55 32.05 kg Eudragit NE30D 3.570 kg Polyethylene glycol 6000 1.071 kg Glycerin monostearate 0.629 kg Polysorbate 80 0.189 kg Iron trioxide 0.006 kg Yellow iron trioxide 0 0.006 kg anhydrous citric acid 0.013 kg purified water 44.3 L Subsequently, the blown air temperature was controlled so that the exhaust temperature in the steady state was about 42 ° C, and the enteric film solution (B) of the following composition prepared in advance was tangential sprayed. The specified amount is 2 so that the supply rate is 1.00 kg / min.
01.6 kg of enteric film solution was sprayed. [Enteric film solution (B)] Eudragit L30D-55 117.6 kg Eudragit NE30D 13.06 kg Triethyl citrate 7.854 kg Glycerin monostearate 2.521 kg Polysorbate 80 0.756 kg Iron sesquioxide 0.025 kg Yellow ferric sesquioxide 0 0.025 kg anhydrous citric acid 0.021 kg purified water 59.7 L Subsequently, the blast temperature was controlled so that the exhaust temperature in the steady state was about 42 ° C, and the enteric film solution (A) having the above-mentioned composition was tangentially sprayed. The specified amount is 2 so that the supply rate is 1.05 kg / min.
7.3 kg of enteric film solution was sprayed.

(4) Manufacture of overcoated mannitol enteric coated dry powder After the above (3), the exhaust temperature in the steady state was about 42 ° C.
The blast temperature was controlled so that the temperature of the film was controlled so that a film solution having the following composition prepared in advance was sprayed by a tangential spray method at a supply rate of 0.64 kg / min.
When the prescribed amount of 29.4 kg was sprayed, the spraying was stopped, the drying was continued as it was, and the exhaust temperature reached 65 ° C., followed by cooling. This was sieved using No. 35 round sieve (420 μm) and No. 60 round sieve (250 μm) to obtain 106 kg of overcoat enteric coated dry powder. The average particle size of the obtained overcoat enteric coated dry powder was 340 μm. [Film liquid] Mannitol 4.2kg Purified water 25.2L

(5) Preparation of additive granulated powder Fluidized bed granulation dryer [FD-WSG-1 manufactured by Paulec Co., Ltd.]
Type 5] crushed mannitol 9.45 kg, low-substituted hydroxypropyl cellulose (LH-33) 1.5 kg,
Crystalline cellulose 1.5kg, crospovidone 0.75k
g, aspartame 0.45kg, supply air temperature 67
Mannitol 0.7 at ℃, flow at 4m ³ / min of air supply
5 kg, anhydrous citric acid 0.15 kg, purified water 5.1 kg
The entire amount of the solution dissolved in was sprayed at a supply rate of 87 g / min, and after the spraying was completed, the product was dried until the exhaust temperature reached 45 ° C. to obtain a dry powder. Screen size of the obtained dried powder is 1.5m
The powder was sized with an mφ power mill (manufactured by Showa Kagaku Kikai Kosakusho) to obtain an additive granulated powder.

(6) Preparation of mixed powder 5.294 Overcoat enteric coated dry powder of the above (4)
Into a tumbler mixer (Showa Kagaku Kikai Kosakusho, TM-60S type), add 5 kg and 5.926 kg of the additive granulated powder of (5) and 0.06 kg of flavor (STRAWBERRY DURAROME, Nippon Firmenig Co., Ltd.), Rotation speed 20m
In- ¹ was mixed for 5 minutes, 0.12 kg of magnesium stearate was added, and further mixed for 1 minute at a rotational speed of 20 min- ¹ to obtain a mixed powder.

(7) Production of orally disintegrating tablets 1 kg of the above mixed powder was used with a rotary tableting machine [Kikusui Seisakusho, Correct 19K type] to make 1 tablet 285 mg, 9 m long.
Tableting was performed with a punch having a flat surface of mφ corner so that the tableting pressure was about 19 kN / punch. At this time, as the mixed powder, two levels were used: a mixed powder at room temperature (21 ° C) and a mixed powder heated to 50 ° C with a thermostat,
The tableting machine is at room temperature (21 ° C.) (normal case), and the space surrounded by the safety cover in which the powder supply part and the die and punch are installed (referred to as tableting chamber in the following examples) is heated to 40 ° C. by hot air. From 2 to 50 when heated to 50 ° C. Tableting was performed quickly so that the temperature of the heated mixed powder did not drop, and the tableting chamber was kept warm by hot air during tableting. In the following examples, when the mixed powder at room temperature was tableted with a tableting machine at room temperature, the conventional condition was used, and the method of tableting by heating both the mixed powder and / or the tableting machine was hot pressing. It is called a lock.

(8) Effect of hot-pressing The hardness of tablets obtained and the dissolution rate in acidic solution (referred to as acid resistance rate in the following examples. The lower the acid resistance rate, the better the acid resistance). The results are shown in Table 1.

[0053]

[Table 1]

As shown in Table 1, by heating both the powder mixture and the tableting machine, the acid resistance was 0.8%, that is, about 1/10 of the acid resistance of 9.2% under the conventional conditions. Was improved,
When the heated mixed powder was cooled again to room temperature and tableted under the conventional conditions, the acid resistance was 5.8%. In other words, the acid resistance could be improved from 9.2% to 5.8% by heating the mixed powder as a pretreatment and then tableting under the conventional conditions, but the heated state was maintained during tableting. By doing so, the acid resistance was further improved and the acid resistance was 0.8%. Further, even with the same tableting pressure, the hardness was increased by heating the tableting machine.

Example 2 The following (1) to (5) are the same as in Example 1. (1) Manufacture of nucleated powder (2) Manufacture of undercoat film nucleated powder (3) Manufacture of enteric-coated nucleated powder (4) Mannitol overcoat Manufacture of enteric-coated nucleated powder (5) Additive granulation Manufacture of powder (6) Manufacture of mixed powder (7) Manufacture of orally disintegrating tablet Using a rotary tableting machine (Kikusui Seisakusho, Correct 19K type), weigh 1 kg of the mixed powder of (6) above. Tablets of two different types (hereinafter abbreviated as tablet A and tablet B) were tabletted. Tablet A is 285 mg and is tableted with a 9 mmφ corner plane punch to have a hardness of around 25 N. Tablet B is 570 mg and is 12 mmφ with a square plane punch having a hardness of 36.
Tableted so as to be near N. At this time, the mixed powder is warmed by a thermostatic machine to quickly press the mixed powder so that the temperature of the mixed powder does not decrease, and the tableting machine heats the tableting chamber with warm air before and during tableting. The average temperature of the mixed powder and the tableting machine was set to a heating level of room temperature to 40 ° C.

(8) Effect of warming and tableting Table 2 shows the hardness and acid resistance of the tablets obtained from tablet A. In addition, the * mark in Table 2 shows the conventional conditions shown in Example 1 and the conditions in which both the mixed powder and the tableting machine were heated.

[0057]

[Table 2] As shown in Table 2, the higher the heating level of the powder mixture and the tableting machine, the lower the acid resistance. Further, even with the same hardness, the tableting pressure could be lowered as the heating level was higher, that is, the hardness could be increased with the same tableting pressure. The hardness and acid resistance of the tablets obtained for tablet B are shown in Table 3. The mark * in Table 3 is the case where the mixed powder at room temperature was tabletted with a tableting machine at room temperature.

[0058]

[Table 3] As shown in Table 3, the higher the heating level of the powder mixture and the tableting machine, the lower the acid resistance. Further, even with the same hardness, the tableting pressure could be lowered as the heating level was higher, that is, the hardness could be increased with the same tableting pressure. Further, if the heating levels of the tablets A and B were about the same, the acid resistance was about the same.

Example 3 (1) Manufacture of Nucleated Powder Powder Nonpareil 105 (trade name) (particle size 100 to 200 μm)
m) 41.58 kg was put in a tumbling flow type coating granulator [MP-400 manufactured by Paulec Co., Ltd.], and the blast temperature was controlled so that the exhaust temperature in the steady state was about 31 ° C, and the tangential spray method was used. , Feeding rate 1.
The bulk liquid having the following composition prepared in advance was spray-coated at a rate of 4 kg / min. When the specified amount of the bulk liquid of 257.6 kg was sprayed, the production of the undercoat film-nucleated powder of (2) was continued. [Bulk liquid] Lansoprazole 39.6 kg Magnesium carbonate 13.2 kg Low-substituted hydroxypropyl cellulose LH-32 6.6 kg (Hydroxypropoxyl group content: 8.8% by weight) Hydroxypropyl cellulose (Type SL) 13.2 kg Purified water 185 L

(2) Manufacture of Nucleated Powder with Undercoat Film Subsequent to the manufacture of the nucleated powder with the above (1), the blast temperature was controlled so that the exhaust temperature in a steady state was about 41 ° C. The undercoat film liquid was sprayed by a tangential spray system at a supply rate of 1.2 kg / min. When the prescribed amount of 132.0 kg of film solution was sprayed, the spraying was stopped, and after being dried for about 10 minutes, it was passed through a No. 42 round sieve (350 μm) and a No. 100 round sieve (150 μm), Hanging film nucleated powder 1
32 kg was obtained. [Undercoat film liquid] Hydroxypropyl methylcellulose 9.24 kg (Type 2910, viscosity 3 centistokes) Titanium oxide (TiO ₂ ) 3.96 kg Sterilized talc [Matsumura Sangyo Co., Ltd.] 3.96 kg Low-substituted hydroxypropyl cellulose LH -32 6.6 kg (Hydroxypropoxyl group content: 8.8% by weight) Mannitol 9.24 kg Purified water 99.0 L

(3) Manufacture of enteric-coated nucleated powder 44.0 kg of the undercoat film nucleated powder of the above (2) was added to a rolling fluid type coating granulator [MP-4 manufactured by Paulec Co., Ltd.].
00 type], the air temperature is controlled so that the exhaust temperature in a steady state is about 42 ° C., and the enteric film solution (A) having the following composition prepared in advance is supplied by a tangential spray method at a supply rate of 1.05 kg / A prescribed amount of 54.6 kg of enteric film solution was sprayed so that the amount became minutes. [Enteric film solution (A)] Eudragit L30D-55 32.05 kg Eudragit NE30D 3.570 kg Polyethylene glycol 6000 1.071 kg Glycerin monostearate 0.629 kg Polysorbate 80 0.189 kg Iron trioxide 0.006 kg Yellow iron trioxide 0 0.006 kg anhydrous citric acid 0.013 kg purified water 44.3 L Subsequently, the blown air temperature was controlled so that the exhaust temperature in the steady state was about 42 ° C, and the enteric film solution (B) of the following composition prepared in advance was tangential sprayed. The specified amount is 2 so that the supply rate is 1.00 kg / min.
01.6 kg of enteric film solution was sprayed. [Enteric film solution (B)] Eudragit L30D-55 117.6 kg Eudragit NE30D 13.06 kg Triethyl citrate 7.854 kg Glycerin monostearate 2.521 kg Polysorbate 80 0.756 kg Iron sesquioxide 0.025 kg Yellow ferric sesquioxide 0 0.025 kg anhydrous citric acid 0.021 kg purified water 59.7 L Subsequently, the blast temperature was controlled so that the exhaust temperature in the steady state was about 42 ° C, and the enteric film solution (A) having the above-mentioned composition was tangentially sprayed. The specified amount is 2 so that the supply rate is 1.05 kg / min.
7.3 kg of enteric film solution was sprayed.

(4) Manufacture of mannitol overcoat enteric coated dry powder Following the above (3), the exhaust temperature in the steady state was about 42 ° C.
The temperature of the blown air was controlled so that a film liquid of the following composition prepared in advance was sprayed by a tangential spray system at a supply rate of 0.90 kg / min.
When the prescribed amount of 29.4 kg was sprayed, the spraying was stopped, the drying was continued as it was, and the exhaust temperature reached 65 ° C., followed by cooling. This was sieved using No. 35 round sieve (420 μm) and No. 60 round sieve (250 μm) to obtain 106 kg of overcoat enteric coated dry powder. The average particle size of the obtained overcoated enteric coated dry powder was 357 μm. [Film liquid] Mannitol 4.2kg Purified water 25.2L

(5) Production of additive granulated powder In a fluidized bed granulation dryer [Glatt, WSG120], 75.6 kg of pulverized mannitol, 12 kg of low-substituted hydroxypropyl cellulose (LH-33), 12 kg of crystalline cellulose, Crospovidone 6kg, aspartame 3.
Add 6 kg, supply temperature 90 ℃, supply amount 1700 m ³ /
It was made to flow for hr, and a solution prepared by dissolving 7.38 kg of mannitol and 1.476 kg of anhydrous citric acid in 50.2 L of purified water was sprayed. The liquid supply rate was started from 1200 g / min and was adjusted from 750 g / min to 650 g / min on the way, and spraying was stopped when the prescribed amount of 48 kg of liquid was sprayed. After spraying, supply air from 1700m ³ / hr to 160
It was adjusted to 0 m ³ / hr and dried until the exhaust temperature reached 58 ° C. to obtain a dried powder. The obtained dry powder was sized with a Comil [Quadro Co.] having a screen size of 1.5 mmφ to obtain an additive-granulated powder.

(6) Preparation of mixed powder Overcoat enteric coated dry powder 108.8 of the above (4)
8 kg, 115.55 kg of the above-mentioned (5) additive granulated powder and 1.2 kg of flavor (STRAWBERRY DURAROME, Nippon Firmenig Co., Ltd.) were put into a V-type mixer [Pharmatech, 800 L], and the rotation speed was 10 min ^−1. Was mixed for 10 minutes, 2.4 kg of magnesium stearate was added, and further mixed for 1 minute at a rotation speed of 5 min ⁻¹ to obtain a mixed powder.

(7) Preparation of orally disintegrating tablet Using the rotary tableting machine [Fette Co., Model 2090], 1 tablet of 285 mg, 9 mg of the mixed powder of the above (6) was mixed.
Tableting was carried out with a punch having a flat surface with a corner of mmφ so that the tableting pressure was about 17 kN / punch. Tablet machine rotation speed was 2 levels of ^39min -1 (10 million in tablets / hr) and ^50min -1 (12.9 million in tablets / hr). At this time, the mixed powder is heated by a thermostatic machine, and the tableting machine heats the tableting chamber mainly with a rotary turntable with warm air before tableting, so that the average temperature of the mixed powder and the tableting machine is increased. Was set to a heating level of room temperature (20 ° C) to 40 ° C.

(8) Effect of Warming Tableting The acid resistance of the tablets obtained at the respective numbers of rotations of the tableting machine is shown in Tables 4 and 5.

[0067]

[Table 4]

[0068]

[Table 5]

As shown in Tables 4 and 5, the higher the heating level of the powder mixture and the tableting machine, the lower the acid resistance. In addition, it has been found that under the conventional conditions (both of the mixed powder and the temperature of the tablet machine are room temperature), acid resistance can be improved by slowing the compression speed of the tablet machine by slowing down the rotation speed of the tablet machine. The number of rotations of the tabletting machine is 1 to improve 3 to 5%.
It was necessary to slow it down to about 0 min ^-1 . The heated tableting was able to improve the acid resistance without slowing down the rotation speed of the tableting machine.

Tables 6 and 7 show the hardness of the tablets obtained at the respective numbers of revolutions of the tabletting machine.

[0071]

[Table 6]

[0072]

[Table 7]

As shown in Tables 6 and 7, the tablet hardness was higher than that of the conventional condition by the hot-pressing.

Example 4 Rotary tableting machine for industrial production (Kikusui company, 45 punches)
The turntable (diameter: 520 mmφ) was heated by a contact resistance heater attached to the turntable, and it was confirmed that the turntable temperature rose to the target temperature. A sheet-shaped silicon rubber heater (262.5 W / 450 cm ² ) is used for the contact resistance heater,
The heater temperature can be adjusted to 45, 50, 5 by adjusting the voltage.
The examination was conducted at 5 and 60 ° C. The results are shown in Table 8.
It was confirmed that the rotary tabletting machine turntable was heated to the target temperature (30-40 ° C) by the contact resistance heater.

[Table 8]

Example 5 (1) Preheating of tablet press Rotary tablet press for industrial production (Fette, 209)
The 0-type turntable (diameter 535 mmφ), the upper punch folder and the lower punch folder were heated by a contact resistance heater to raise the turntable temperature to 45 ° C. A sheet-shaped silicon rubber heater (total: 975 W) was used as the contact-type resistance heater. (2) Production of orally disintegrating tablet Mixed powder 5 prepared by the same production method as in item (6) of Example 3
Using 5 kg (room temperature), a rotary tableting machine (Fette, model 2090) preheated in (1), 1
Tablet 570mg, 12mmφ corner flat punch with hardness of 37N
Tableted so that it would be in the vicinity. Tablet machine rotation speed is 39 min
^-1 (100,000 tablets / hr) and 50 mm-1 (125,000 tablets / hr), and sampling was performed at a turntable temperature of 28 to 36 ° C. As a control, a turntable having a room temperature (room temperature even after mixing) was prepared and the acid resistance was compared with that of a preheated turntable. (3) Effect of warming tableting Table 9 shows the acid resistance of tablets obtained at each number of rotations of the tableting machine.
Summarized in. As a result, when a rotary tableting machine for industrial production is tableted by heating with a contact resistance heater, the acid resistance is lower than that when tableting at room temperature, and the acid resistance may be further improved. Was shown.

[Table 9]

[0076]

As is apparent from the above, the tablets obtained by the production method of the present invention have reduced destruction of the coating film of the coated granules. Therefore, in a tablet containing enteric coated granules containing an acid-labile physiologically active substance, dissolution in the presence of acid as in the stomach is improved. Further, the hardness of the tablet can be improved.

[Brief description of drawings]

FIG. 1 is a diagram showing a schematic configuration of a rotary tableting machine which is an embodiment of a tablet tableting device according to the present invention.

FIG. 2 is a diagram showing a schematic configuration of a heating device control of the device of FIG.

FIG. 3 is a diagram showing a program for operating the heating device of FIG.

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Claims (34)

[Claims] 1. A method for producing a tablet, which comprises compressing coated granules containing a physiologically active substance at a temperature exceeding room temperature. 2. The method according to claim 1, wherein the physiologically active substance is an acid-labile physiologically active substance. 3. The method according to claim 2, wherein the acid-labile physiologically active substance is a proton pump inhibitor (PPI). 4. The method according to claim 1, wherein the PPI is a benzimidazole compound or a salt thereof. 5. The method according to claim 3, wherein the benzimidazole compound is lansoprazole or an optically active substance thereof. 6. The method according to claim 1, wherein the coated granules are enteric coated granules. 7. The method according to claim 5, wherein the enteric coating layer contains an aqueous enteric polymer base. 8. The method according to claim 6, wherein the water-based enteric polymer base is a methacrylic acid copolymer. 9. The method according to claim 1, wherein the temperature above room temperature is about 25 ° C. or higher. 10. The temperature above room temperature is from about 25 ° C. to about 50.
The method according to claim 1, wherein the temperature is ° C. 11. The temperature above room temperature is about 25 ° C. to about 40.
The method according to claim 1, wherein the temperature is ° C. 12. The method according to claim 1, wherein the tablet is an orally disintegrating tablet. 13. An acid-labile physiologically active substance is contained,
A method for producing an orally disintegrating tablet, which comprises compressing enteric coated granules heated to about 25 ° C to about 50 ° C. 14. The manufacturing method according to claim 13, wherein the tableting machine is heated. 15. The tablet press is a rotary tablet press,
15. The manufacturing method according to claim 14, wherein the rotary turntable is tableted after being heated. 16. A coated granule containing a physiologically active substance,
A method for reducing the destruction of the coating film of the coated granules, which comprises heating to a temperature above room temperature and tableting. 17. A coated granule containing a physiologically active substance,
A method for lowering the acid resistance of a tablet containing the coated granules, which comprises heating to a temperature above room temperature and tableting. 18. A coated granule containing a physiologically active substance,
A method for improving the hardness of a tablet, which comprises heating to a temperature above room temperature and tableting. 19. A composition containing a physiologically active substance is coated with a coating layer, an additive is added to the obtained coated granules, and the mixture of the coated granules and the additive is heated to a temperature above room temperature. Tablets obtained by warming and tableting. 20. The tablet according to claim 19, wherein the physiologically active substance is an acid-labile physiologically active substance. 21. The tablet according to claim 20, wherein the acid-labile physiologically active substance is PPI of a benzimidazole compound or a salt thereof. 22. The tablet according to claim 21, wherein the benzimidazole compound is lansoprazole or an optically active substance thereof. 23. A tablet obtained by the method according to claim 1. 24. A tablet having an acid resistance improved by hot-pressing. 25. A tablet whose hardness is increased by hot-pressing. 26. A tablet in which the breaking of the coating film of the coated granules contained therein is reduced by hot-pressing. 27. The acid resistance is about 10% or less, hardness is increased, and breakage of the coating film of the coated granules is reduced.
A tablet containing coated granules. 28. An enteric coated granule containing lansoprazole or an optically active substance thereof, which is heated to a temperature higher than room temperature. 29. The granule according to claim 28, wherein the enteric coating layer contains an aqueous enteric polymer base. 30. The granule according to claim 28, wherein the water-based enteric polymer base is a methacrylic acid copolymer. 31. The granules of claim 28, wherein the temperature above room temperature is about 25 ° C. or higher. 32. The temperature above room temperature is from about 25 ° C. to about 50.
29. The granule according to claim 28, which has a temperature of ° C. 33. The temperature above room temperature is from about 25 ° C. to about 40.
The granule according to claim 30, which has a temperature of ° C. 34. Use for the manufacture of tablets with improved acid resistance of enteric coated granules containing acid labile bioactive substances and heated above room temperature.