KR20090103810A - Tablet - Google Patents

Abstract

PURPOSE: A tablet is provided to ensure degradability prevent attrition during coating. CONSTITUTION: A method for manufacturing a tablet with proper degradability and attrition resistance comprises a step of mixing a drug effective ingredient, carmellose or its salt, and composite containing silicon dioxide. The amount of carmellose or its salt is 1-20 mass%. The mass ratio of carmellose or its salt and silicon dioxide is 0.1-200.

Description

Tablets {TABLET}

The present invention relates to a tablet having both disintegratable and mechanical strength and a manufacturing method thereof.

Among oral dosage forms of pharmaceuticals, tablets are most widely used because they have advantages such as convenient preparation, accurate content of ingredients in the formulation, easy masking of bitter taste and the like, and mass production. On the other hand, since bioavailability tends to fluctuate depending on subtle differences in formulation technology, it is considered that tablets need to be carefully evaluated and quality controlled than other formulations.

In designing the formulation of tablets, in addition to requiring fluidity, binding, glidability, etc. of the raw powder, tablets after compression should have adequate mechanical strength and disintegration. In other words, when the mechanical strength is increased, the disintegration tends to be lowered, and when the disintegration is good, the mechanical strength tends to be lowered.

Carmellose or its salts and silicon dioxide are known as agent additives. Patent documents 1 to 10 are known as tablets in which these two kinds of additives are combined, but there is no description in these patent documents about how the mechanical strength of the tablet obtained when the two are combined is changed.

[Patent Document 1] Japanese Unexamined Patent Publication No. Hei 6-183964

[Patent Document 2] Japanese Unexamined Patent Publication No. 2003-119134

[Patent Document 3] Japanese Unexamined Patent Publication No. 2005-154281

[Patent Document 4] Japanese Unexamined Patent Publication No. 2007-332063

[Patent Document 5] Japanese Unexamined Patent Publication No. 2007-191419

[Patent Document 6] Japanese Patent Publication No. 2004/006945

[Patent Document 7] Japanese Unexamined Patent Publication No. 2005-194203

[Patent Document 8] Japanese Unexamined Patent Publication No. 2005-162619

[Patent Document 9] Japanese Patent Application Laid-Open No. 10-298061

[Patent Document 10] Japanese Unexamined Patent Publication No. 2007-169195

An object of the present invention is to provide a tablet having excellent disintegration property and excellent mechanical strength and a method for producing the same.

When the tablet is prepared, the inventors combine a carmelose or a salt thereof known as a formulation additive with silicon dioxide in combination to provide a disintegration property which shows good bioavailability, and at the same time, in mechanical strength, in particular during distribution and handling, Furthermore, it discovered that the tablet (predetermined) which hardly becomes a problem at the time of coating is obtained, and completed this invention.

That is, this invention provides the manufacturing method of the tablet with abrasion resistance characterized by containing (A) the manufacturing method of the tablet containing an active ingredient, (B) carmellose or its salt, and (C) silicon dioxide. It is.

Moreover, the tablet which has favorable disintegration characteristics which are characterized by containing (B) carmellose or its salt, and (C) silicon dioxide as a manufacturing method of the tablet containing (A) active ingredient, and the wear resistance. It is to provide a recipe.

The present invention also provides a tablet comprising (A) a peptic ulcer solvent, a gastric agent, a digestive agent, an antacid, a gastric mucosal restorative agent, and a medicinal agent selected from a gastric mucosa, (B) carmellose or a salt thereof, and (C) silicon dioxide. To provide.

Since the tablet obtained by the method of the present invention has good disintegration and hardly generates wear and tear, there is no wear and tear during the distribution step or handling, and furthermore, coating, and a good bioavailability is obtained. In particular, the tablet obtained by the method of the present invention is a method based on the instantaneous preparation of the 15th revised Japanese Pharmacy Room "Collapse Test Method", that is, a disintegration test apparatus under the following conditions (Test Solution: Water, Liquid Volume: 1000 ml, test temperature: 37 ± 2 ° C), the collapse time is less than 30 minutes, operating in accordance with the 15th revised Japanese Pharmacy Bureau commentary information `` tablet wear test method, i.e. It is particularly useful because the wear and tear of the sample is rotated 100 times and visually counted as the number of defects after the test is zero. According to the present invention, it is possible to easily manufacture tablets with improved wear and tear while maintaining disintegration showing good bioavailability.

The wear and tear resistance tablet of this invention is manufactured by containing (A) drug substance, (B) carmellose or its salt, and (C) silicon dioxide. More specifically, it manufactures by tableting the mixture or granulated material containing (A) active ingredient, (B) carmellose or its salt, and (C) silicon dioxide.

The tablet of this invention contains the (A) drug substance. The active ingredient may be a component that exhibits efficacy by oral administration, and is not particularly limited, but is not limited to herbal medicines, glucosamine hydrochloride, sodium chondroitin sulfate, simvastatin, povidone iodine, pimovendan, pantetin, cysteine, ascorbic acid, and hydrochloric acid. Pyridoxine, riboflavin, ibuprofen, dihydrocodein phosphate, dl-methyl-ephedrine hydrochloride, isopropide iodide, noscapine, chlorpheniramine maleic acid, thiamine nitrate, caffeine anhydride, chamomile, ubauci, naproxen, in the tablet of the present invention It is excluded from the medicinal ingredients contained (In addition, herbal medicine is Angelica peony extract, Kamisoyosan extract, Gyejibokyeonghwan extract, rhubarb persimmon chotang extract, Galguntang extract, Shiho-Gyeji-tang extract, Uiin-tang extract, Gyeji-gaeyoungbutang extract, Banggi Hwanggi-tang extract).

Examples of the medicinal ingredients include hypnotic / sedative drugs, antiepileptic drugs, antipyretic analgesic agents, excitatory and stimulant drugs, stimulants, mental neurological agents, skeletal muscle relaxants, autonomic neurologic agents, antispasmodic drugs, antiparkinsonants, antihistamines, antiallergic agents, Cardiovascular, arrhythmic, hypotensive, vasoconstrictor, vasodilator, peripheral vasodilator, hyperlipidemia, antitussive expectorant, peptic ulcer, psoriasis, digestive, antacid, suit, anti-diabetic, analgesic, economic gastric mucosa, antimicrobial, Hemostatic agents, vitamins, anticoagulants, liver disease agents, gout agents, enzyme preparations, diabetic agents, antimalignant tumor agents, anti-influenza virus agents, and the like.

More specifically, as a hypnotic and soothing agent, diazepam, estazolam, flulazepam, triazolam, nitrazepam, chlordiazepoxide, lorazepam, alprazolam, oxazolam, ethyllozephate, bromazepam And benzodiazepine-based drugs such as fludiazepam and topisopam, thienodiazepine-based drugs such as clothiazepam and ethizolam, and barbituric acid-based drugs such as phenobarbital. Examples of antiepileptic drugs include phenytoin, phenobarbital, primidone, sodium valproate, carbamazepine, ethosuccimid, clovazam, zonisamide, gabapentin, and topiramate. Antipyretic analgesic agents include acetaminophen, phenacetin, mefenamic acid, diclofenac, aspirin, ethenamide, salicylate, salicylic acid, flurubiprofen, ketoprofen, fenbufen, mepyrisol, indomethacin, roxofero And pens. Examples of the stimulant and stimulant include methanepetamine, glutamic acid and gamma aminobutyric acid. Examples of the scavenger include isoproterenol, diphenidol, and the like. Examples of the mental nerve agent include phenothiazine-based drugs such as chlorpromazine, butyrophenone-based drugs such as haloperidol, and tricyclic antidepressants. Examples of autonomic nerve agents include choline agonists such as acetylcholine, choline esterase inhibitors, and the like.

Antispasmodic drugs include choline blockers such as atropine and scopolamine. Antihistamines include ciproheptadine hydrochloride hydrate, diphenhydramine, clemastine fumarate, azelastine hydrochloride, oxatomide, methazine, epinastine hydrochloride, evastin, cetirizine hydrochloride, fexofenadine hydrochloride, olovatadine hydrochloride , Rotazine, and the like. Examples of the anti-allergic agent include sodium chromogric acid, tranilast, femirolast potassium, franlukast hydrate, montelukast, ramatrobane, spratastostylate, and the like.

Examples of cardiac agents include digoxin and digitoxin. Arrhythmia solvents such as procaineamide hydrochloride, disopyramid, cybenzorin succinate, pyrmenol hydrochloride, apridine hydrochloride, mexiretin hydrochloride, flecainide acetate, philcichinide hydrochloride, propaphenone hydrochloride and the like K channel blockers, such as a Na channel blocker, amiodarone hydrochloride, a sotarol hydrochloride, propranolol hydrochloride, a metoprolol tartarate, the beta blockers, such as atenolol and a carvedilol, etc. are mentioned. Diuretics such as trichlormethiazide, hydrochlorothiazide, tripamide, indamide, spironolactone, prosemid, prazosin hydrochloride, bunazosine hydrochloride, doxazosin mesylate, terrazosin hydrochloride hydrate , Α blockers such as urapidil, β-blockers such as propranolol hydrochloride, pindolol, cartolol hydrochloride, atenolol, metoprolol tartarate, bopindololmaronate, bisoprolol fumarate, cerifrolol hydrochloride, and tilysolol hydrochloride, Αβ blocking agents such as amosralol hydrochloride, carvedilol, and arotinol hydrochloride, nifedipine, nicardipine hydrochloride, diltiazem hydrochloride, nilvadipine, varinidi hydrochloride, nisoldipine, nirenedipine, amlodipine besylate, and mani Calcium antagonists such as dipine hydrochloride, benidipine hydrochloride, felodipine, eponidipine hydrochloride, azelnidipine, captopril, enalapril maleate, delapril hydrochloride, ACE inhibitors such as imidapril hydrochloride, quinapril hydrochloride, temocapryl hydrochloride, and ricinopril; and angiotensin II receptor antagonists such as candesaltan cilexetil, losaltan potassium, valsartan, olmesaltanmedoxomyl, and telmisartan. have. Hyperlipidemic drugs include: pravastatin sodium, atorvastatin calcium, pullastatin sodium, pitavastatin calcium, losvastatin calcium, ezetimibe, clofibrate, bezafibrate, fenofibrate, clinofibrate, tocopherolnicotinic acid ester, niceritrol , Nicomol, probucol, etc. are mentioned.

Antitussive expectorants include codeine phosphate, dextromethorphan hydrobromide, dimethorphan phosphate, tifepidinehibbenzate, methoxyphenamine hydrochloride, trimethoquinol hydrochloride, carbocysteine, acetylcysteine, ethylcysteine, brohexine Hydrochloride, cerapeptase, lysozyme chloride, ambroxol, theophyrin, aminopyrin and the like. Examples of peptic ulcer solvents include glutamine, gefarnate, setlaxate hydrochloride, cimetidine, ranitidine hydrochloride, pamotidine, roxatidine acetate ester hydrochloride, nizatidine, laputidine, omeprazole, lansoprazole, rabeprazole sodium, orno Prostill, enprosteel, microprostol, pyrenzepine hydrochloride, proglumid, etc. are mentioned.

As an example of the health agent, for example, anise fruit, aloe, fennel, turmeric, ointment, lotus leaf, potos, yellow wall, barberry, processed garlic, bonsul, kwak hyang, iris root, health, tanza , Cinnamon, Cinnamon, Gentian, Red ginseng, Pepper, Colostrum, Black pepper, Colombo, Condurango, Japanese pepper, Sanna, Jassori, Barn, Ginger, Small cow ), Cheongpi, Seok-geun-geun, Sentori-cho, Senburi, Creation (蒼朮), Jaso (,), Conventional incense (大 대 香), Rhubarb, Bamboo shoot ginseng, Clove Wood, dermis, red pepper, skin, animal wall (including ungdam), pine, nutmeg, ginseng, peppermint (including peppermint), essential, baekchul (白 朮), Hop, horse extract, watercolor leaf, bankshire, raw, gentian, yanggang, fennel oil, cinnamon oil, ginger oil, soybean oil, clove oil , Skin oil, peppermint oil, lemon oil, l-menthol, dl-men , There may be mentioned hydrochloric acid, betaine, glutamic acid hydrochloride, carnitine chloride, beta nekol chloride, dried yeast and so on.

Examples of the extinguishing agent include starch digestive enzyme, protein digestive enzyme, fat digestive enzyme, fibrin digestive enzyme, urodesoxycholine acid, oxycholate, cholic acid, bile acid, bile powder, bile extract (powder), dehydro Cholic acid, animal wall (including woongdam), and the like.

As a suit agent, for example, a suit probiotic component, Yeon-Duk-Tak, Sun Yat-Sen, five plums, a deficiency, and a dysentery are mentioned.

As an anticorrosive agent, for example, acrinoline, berberine chloride, guayacol, creosote, phenyl salicylate, guayacol, tannin berberine, bismuth bismuth tea, bismuth dibasic acid, bismuth bicarbonate, bismuth bisulfate, tannic acid, tannic acid Albumin, methylenethymtannin, kaolin, natural aluminum silicate, aluminum hydroxynaphthoacetic acid, pectin, medicinal charcoal, calcium lactate, sesame medicinal, plum, yellow wall, rhubarb, red ginseng, algae, zinnia, hawthorn, senburi , Sheep plum, etc. are mentioned.

As an analgesic antispasmodic agent, for example, oxyphencycline hydrochloride, dicyclomine hydrochloride, meticene hydrochloride, hydrobromic acid scopolamine, methyl bromide hydrobromide, methyl bromide bromide, methyl bromide bromide, methyl bromide- l-Hyostiamine, methyl bromide bromide, belladonna extract, diphenylpiperidinomethyldioxolane iodide, scofolia extract, scopolyazine total alkaloids citrate, papaverine hydrochloride, ethyl aminobenzoate, succinate Vi), zinnia, hinoki, peony, etc. are mentioned.

Examples of gastric mucosal restoratives include, for example, sodium azulensulfonic acid, aldioxa, glycylic acid and its salts and licorice extracts, L-glutamine, copper chloropyridine potassium, copper chloropyriline sodium, histidine hydrochloride, pork gastric pepsin digest, Gastric Acid Hydrolyzate, Methyl Methionine Sulfonium Chloride, Yeok Tree, Corydalis, Rhododendron, Sucralate, Levamifeed, Marzulene, Polar Presink, Sodium Alginate, Gefarnate, Tefrenone, Troxide, Benexate Hydrochloride Betadex, flaunotol, maleic acid isoglodine, sofalcone and the like.

As vitamins, for example, retinol acetate, retinol palmitate, vitamin A oil, liver oil, strong liver oil, ergocalciferol, cholecalciferol, succinic acid d-α-tocopherol, succinic acid dl-α- Tocopherol, succinic acid dl-α-tocopherol calcium acetate, d-α-tocopherol acetate, dl-α-tocopherol, d-α-tocopherol, dl-α-tocopherol, thiamine hydrochloride, bistiamine nitrate, thiamine disulfide, thiamine disetyl Sulfuric acid ester salt, dicetiamine hydrochloride, flusulthiamine hydrochloride, octothiamine hydrochloride, cicothiamine, bisibthiamine, bisbenthiamine, flusulthiamine, prosulthiamine, benfotiamine, riboflavin sodium phosphate, riboflavin phosphate, pyridoxal phosphate, hydride Roxocobalamin, Hydroxycobalamin Hydrochloride, Hydroxycobalamic Acetate, Cyanocobalamin, Calcium Ascorbate, Sodium Ascorbate, Nicotinic Acid, Nicotinateamide, Panthenol, Calcium Pantothenate, Sodium Pantothenate, Bio Tin, and the like.

As antacid, synthetic aluminum silicate, natural aluminum silicate, aluminum hydroxide, magnesium silicate aluminate, magnesium metasilicate aluminate, hydrotalcite, magnesium bismuth silicate, sodium bicarbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, precipitated carbonate Calcium, magnesium silicate, magnesium alumina hydroxide, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, amino acetic acid, dihydroxyaluminum amino acetate, glycine, squid bone, stone name, oyster shell, scofolia extract and the like.

Examples of the liver disease agent include ribavirin, lamivudine, entecavir hydrate, adefovir difficile, propagermanium, ursodeoxycholic acid, and the like. Antibacterial agents include various antibiotics, levofloxacin hydrate, opfloxacin, ciprofloxacin hydrochloride, tosufloxacin tosylate, norfloxacin, cytafloxacin hydrate, lomefloxacin hydrochloride, gatifloxacin, prurifloxacin, moxifloxacin hydrochloride And quinolone antibacterial agents such as enoxacin and sparfloxacin. Examples of diabetic agents include glybenclamide, glyclazide, glymepiride, nateglinide, mitiglinide calcium hydrate, metformin hydrochloride, buformin hydrochloride, pioglitazone hydrochloride, acarbose, boligibos, miglitol, and the like. . Anti-malignant tumor agents include fluorouracil, tegapur, doxyfluidine, capecitabine, pardrosol hydrochloride, anastrozole, exemestane, letrozole, cyclophosphamide, imatinib mesylate, and the like. Can be mentioned.

Examples of anti-influenza virus agents include oseltamiber phosphate and amantazin hydrochloride.

It is preferable to mix | blend a peptic ulcer solvent, a gastric agent, a digestive agent, an antacid, a gastric mucosal repair agent, a formal agent, vitamins, etc. among these active ingredients. In addition, in the case of a drug acting on the stomach such as an antacid, a dry stomach, a fire extinguishing agent, or a gastric mucosa repair agent, it is desired to have particularly good disintegration properties, and therefore, it is preferable to apply it to tablets containing these active ingredients. In particular, in the case of a tablet containing one or two or more selected from sodium hydrogen carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, calcium carbonate, precipitated calcium carbonate, magnesium silicate, calcium hydrogen phosphate and anhydrous calcium hydrogen phosphate, The effect of the present invention is remarkable. Especially, the tablet containing 2 or more types is more preferable.

Moreover, it is especially preferable to apply this invention to the tablet which mix | blended the antacid containing magnesium hydroxide, sodium hydrogencarbonate, and calcium carbonate. As for the compounding quantity of magnesium hydroxide, 0.01-20 weight% is preferable with respect to formulation whole quantity, 0.1-10 weight% is more preferable, 1-7 weight% is especially preferable. As for the compounding quantity of sodium hydrogencarbonate, 1-50 weight% is preferable with respect to tablet whole quantity, 5-40 weight% is more preferable, 10-30 weight% is especially preferable. As calcium carbonate, oyster shell, oyster shell powder, a grain of squid, squid bone, etc. which have calcium carbonate, precipitated calcium carbonate, or calcium carbonate as a main component are mentioned, for example. 10-80 weight% is preferable with respect to the tablet whole quantity, as for the compounding quantity of calcium carbonate, 15-70 weight% is more preferable, 20-60 weight% is especially preferable.

1: 0.1-15 are preferable, as for the mass ratio of magnesium hydroxide and sodium hydrogencarbonate, 1: 1-12 are more preferable, and 1: 3-9 are especially preferable. 1: 40-40 are preferable, as for the mass ratio of magnesium hydroxide and calcium carbonate, 1: 30-30 are more preferable, 1: 5-20 are especially preferable. As for mass ratio of sodium hydrogencarbonate and calcium carbonate, 0.1-15: 1-40 are preferable, 1-12: 3-30 are more preferable, 3-9: 5-20 are especially preferable.

As the antacid-containing tablets, drugs such as antacids, dry stomach agents, fire extinguishing agents, dressing agents, antimicrobial agents, analgesic analgesics, gastric mucosa restoratives, vitamins, and antifoam agents other than those described above can be used.

The drug substance containing these antacids is 1-90 mass% in the tablet of this invention, More preferably, it is 1.5-85 mass%, It is preferable to contain 2-80 mass% especially.

(B) As carmellose or its salt, carmellose, carmellose sodium, carmellose calcium, etc. are mentioned, Among these, carmellose calcium is especially preferable. By combining carmellose calcium with component (C), a particularly noticeable disintegration and improvement in mechanical strength are obtained. (B) Carmellose or its salt contains 1-20 mass%, further 1.5-18 mass%, especially 2-16 mass% in the refinement | purification of this invention, The point which obtains the favorable disintegration property and the improvement effect of mechanical strength is obtained. Preferred at

Examples of (C) silicon dioxide include hydrous silicon dioxide and hard silicic anhydride, and hydrous silicon dioxide is particularly preferable in view of the effect of improving disintegration and mechanical strength. The silicon dioxide (B) is preferably contained in the tablet of the present invention in an amount of 0.1 to 10% by mass, more preferably 0.2 to 9% by mass, in particular 0.3 to 8% by mass, in terms of achieving good disintegration and improvement in mechanical strength.

Moreover, in the refinement | purification of this invention, the content mass ratio ((B) / (C)) of (B) carmellose or its salt, and (C) silicon dioxide acquires favorable disintegration property and the improvement effect of mechanical strength. 0.1-200, Furthermore, 0.5-100, Especially 1-75 are preferable.

In the tablet of the present invention, additives such as excipients, disintegrating agents, binders, lubricants, glidants, colorants, and copulating agents may be further blended as necessary. Examples of excipients include lactose, starch, crystalline cellulose, sucrose, and mannitol. Examples of the binder include hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, alpha starch, polyvinylpyrrolidone, polyvinyl alcohol, pullulan and the like. Examples of disintegrating agents include crospovidone, corn starch, low-substituted hydroxypropyl cellulose, and the like. Examples of the lubricant include magnesium stearate, talc, hardened oil, and the like. As a coloring agent, a tar pigment, iron trioxide, etc. are mentioned. Mating agents include stevia, aspartame, fragrances and the like.

The tablets of the present invention have good disintegration and are excellent in mechanical strength, in particular in wear and tear resistance. More specifically, the method according to the instantaneous preparation of the 15th revised Japanese pharmacy room "Collapse test method", ie, a collapse test apparatus, was subjected to the following conditions (test liquid: water, liquid volume: 1000 ml, test temperature: 37 ± 2 ° C). The decay time for operation at is within 30 minutes. In addition, the method according to the 15th revised Japanese pharmacy room commentary reference information `` tablet hardness test method '', ie, the degree of wear caused by counting the number of defects with the naked eye after the test was put into the drum 100 rotation, and after the test 0. Thus, since the disintegration property is good and the wear and tear degree is low, the tablets are not scratched in the manufacturing step and the distribution step, and high bioavailability is obtained after taking.

Examples of the tablet of the present invention include uncoated tablet (predetermined tablet), multi-layered tablet, nucleated tablet, troche, intraoral disintegrating tablet, chewable tablet and the like.

In the tablet of the present invention, a film may be formed by a suitable means. As the tablet formed with a film, film-coated tablets and dragees may be mentioned. Since the tablet of this invention has very low abrasion, it hardly becomes a problem at the time of film formation, and it is easy to form the film suitable for a drug substance.

The manufacturing method of the tablet of this invention does not have to be specifically limited, (A) drug substance, (B) carmellose or its salt in a tablet (the tablet before film formation in the case of forming a film in a tablet), and (C) What is necessary is just the method manufactured so that silicon dioxide may contain. That is, the tablet of the present invention may be produced by direct powder compression, or may be manufactured by compression molding after granulation, such as dry granulation compression, semi-dry granulation compression, wet granulation compression, or the like. . The granulation method is not particularly limited, and extrusion granulation, fluidized bed granulation, stirring granulation, spray drying granulation, crushing granulation and the like may be employed. The method for producing a tablet of the present invention comprises tableting a mixture of (A) the active ingredient, (B) carmellose or its salt, and (C) silicon dioxide according to a conventional method, or (A) the active ingredient, ( A tablet can be prepared by preparing and tableting a granulated product containing B) carmellose or a salt thereof and (C) silicon dioxide. It is especially preferable to mix and assemble (A) an active ingredient and (B) carmellose or its salt, and to assemble by adding (C) silicon dioxide after that. What is necessary is just to tablet the obtained granulated material according to a conventional method, and to manufacture a tablet. Moreover, the obtained tablet can form a film according to a conventional method as desired, and can be made into a film-coated tablet or a dragee tablet.

EXAMPLE

Next, although an Example is given and this invention is demonstrated in detail, this invention is not limited to this.

1. Preparation of Tablets

Preparation

150 parts by mass of methyl methionine sulfonium chloride, 90 parts by mass of scofolia extract, 30 parts by mass of hop drying extract, 15 parts by mass of lipase AP, 24 parts by mass of biodiastatase (2000), 24 parts by mass of hydroxypropylcellulose, hardened oil 110 Mass part, 70 mass parts of carmellose calcium, 38 mass parts of corn starch, 10 mass parts of glycerol monostearate, 5 mass parts of polyoxyl stearate 40, and 25 mass parts of talc were granulated according to a conventional method. 591 mass parts of this granule and 9 mass parts of magnesium stearate were mixed, and it was set as the tableting granules. The tableting granules were compressed into tablets using a tableting machine equipped with a punch having a diameter of 7 mm to prepare 100 tablets of nuclear tablets.

Example 1

900 parts by mass of sodium hydrogen carbonate, 100 parts by mass of magnesium hydroxide, 1200 parts by mass of precipitated calcium carbonate, 120 parts by mass of polyvinyl alcohol, 150 parts by mass of carmellose calcium, 375 parts by mass of crystalline cellulose, 120 parts by mass of hardened oil, magnesium stearate 20 Mass parts were granulated according to a conventional method. 497.5 parts by mass of the granules and 2.5 parts by mass of hydrous silicon dioxide were mixed to obtain an outer layer granule. A tablet of 600 mg of one tablet was produced using a tableting machine equipped with a punch of φ11 mm from a tablet of 100 mg of one tablet prepared in the Production Example and 500 mg of the outer granules.

Example 2

900 parts by mass of sodium bicarbonate, 100 parts by mass of magnesium hydroxide, 1200 parts by mass of precipitated calcium carbonate, 120 parts by mass of polyvinyl alcohol, 150 parts by mass of carmellose calcium, 360 parts by mass of crystalline cellulose, 120 parts by mass of hardened oil, magnesium stearate 20 Mass parts were granulated according to a conventional method. 495 mass parts of this granules and 5 mass parts of hydrous silicon dioxide were mixed, and it was set as outer layer granules. A tablet of 600 mg of one tablet was produced using a tableting machine equipped with a punch of φ11 mm from a tablet of 100 mg of one tablet prepared in the Production Example and 500 mg of the outer granules.

Comparative Example 1

900 parts by mass of sodium bicarbonate, 100 parts by mass of magnesium hydroxide, 1200 parts by mass of precipitated calcium carbonate, 120 parts by mass of polyvinyl alcohol, 150 parts by mass of carmellose calcium, 390 parts by mass of crystalline cellulose, 120 parts by mass of hardened oil, magnesium stearate 20 Mass parts were granulated according to a conventional method to obtain outer layer granules. A tablet of 600 mg of one tablet was produced using a tableting machine equipped with a punch of φ11 mm from a tablet of 100 mg of one tablet prepared in the Production Example and 500 mg of the outer granules.

Comparative Example 2

900 parts by mass of sodium bicarbonate, 100 parts by mass of magnesium hydroxide, 1200 parts by mass of precipitated calcium carbonate, 120 parts by mass of polyvinyl alcohol, 150 parts by mass of low-substituted hydroxypropyl cellulose, 375 parts by mass of crystalline cellulose, 120 parts by mass of hardened oil, stear 20 parts by mass of magnesium acid was granulated according to a conventional method. 495 mass parts of this granules and 5 mass parts of hydrous silicon dioxide were mixed, and it was set as outer layer granules. A tablet of 600 mg of one tablet was produced using a tableting machine equipped with a punch of φ11 mm from a tablet of 100 mg of one tablet prepared in the Production Example and 500 mg of the outer granules.

Test Example 1

(Collapse test)

For each nucleated tablet obtained in Examples 1 and 2 and Comparative Examples 1 and 2, the disintegration time was measured using a disintegration test apparatus (NT-40H, manufactured by Toyama Industries, Ltd.). The test liquid was made into water (1000 ml, 37 degreeC), and 6 tablets were measured about each case, the average value was computed, and it was set as disintegration time (based on the 15th revised Japanese pharmacy room "collapse test method" immediate preparation).

(result)

In Examples 1 and 2 in which carmellose calcium and hydrous silicon dioxide were blended, the disintegration time was significantly shortened compared to Comparative Example 1 in which hydrous silicon dioxide was not blended or Comparative Example 2 in which carmellose calcium was not blended. The disintegration was good. Therefore, it was estimated that neutralization of gastric acid and the like are rapidly expressed, and the therapeutic effect is increased (Table 1).

Test Example 2

(Hardness)

For each nucleated tablet obtained in Examples 1 and 2 and Comparative Examples 1 and 2, tablet hardness was measured using a tablet hardness tester (PHARMA TEST PTB-311, manufactured by Japan Machinery). About 20 tablets were measured about each case, the average value was computed, and it was set as hardness.

(result)

About Examples 1 and 2 which mix | blended hydrous silicon dioxide, it turned out that hardness becomes high compared with the comparative example 1 which is not mix | blended. Therefore, it was inferred that it contributed very predominantly to the handling property at the time of manufacture and packaging, and the quality maintenance under circulation (Table 1).

Test Example 3

(Wearing test)

The wear-and-test test was done about each nucleated tablet obtained in Examples 1 and 2 and Comparative Examples 1 and 2. For each example, 15 tablets were set in a tablet abrasion tester (FRIABILATOR TFR-120, manufactured by Toyama Industries Co., Ltd.) for 100 revolutions (25 revolutions per 4 minutes), and the number of defects in the nucleated tablets after completion was visually confirmed. 15 revised Japanese pharmacy room commentary reference information "according to the friability test method of tablet").

(result)

About Examples 1 and 2 which mix | blended hydrous silicon dioxide, it turned out that abrasion resistance becomes high compared with the comparative example 1 which is not mix | blended. Moreover, the combination with carmellose calcium showed the favorable result. Therefore, it was inferred that it contributed very predominantly to the handling property at the time of manufacture and packaging, and the quality maintenance under circulation (Table 1).

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Nuclear 600 600 600 600 Sodium bicarbonate 900 900 900 900 Magnesium hydroxide 100 100 100 100 Precipitated calcium carbonate 1200 1200 1200 1200 Polyvinyl alcohol 120 120 120 120 Carmeloose Calcium 150 150 150 - Low Substitution Hydroxypropyl Cellulose - - - 150 Crystalline cellulose 375 360 390 375 Cured oil 120 120 120 120 Magnesium stearate 20 20 20 20 Function silicon dioxide 15 30 - 15 Total (mg / 6T) 3600 3600 3600 3600 Decay time (min) (n = 6) 20 16 42 47 Longitude (N) (n = 20) 10 12 7 8 Wear and tear test (defective) 0 0 5 3

From the results of Test Examples 1 to 3, it was found that the tablet containing the active ingredient, carmellose or its salt, and silicon dioxide had good disintegration properties and excellent mechanical strength.

Example 3

9.0 kg of sodium bicarbonate, 1.0 kg of magnesium hydroxide, 12.0 kg of precipitated calcium carbonate, 1.2 kg of polyvinyl alcohol, 1.5 kg of carmellose calcium, 3.5 kg of crystalline cellulose, 0.15 kg of cinnamon powder, 1.2 kg of hardened oil, 0.2 kg of magnesium stearate Granules were prepared by mixing, kneading using a mixer, then drying using a dryer, and sizing again using a sizing machine. 5.95 kg of granules and 0.05 kg of hydrous silicon dioxide were mixed to obtain 6.0 kg of outer layer granules.

12000 tablets of 1,600 mg of nucleated tablets were prepared using a nucleating tablet tableting machine equipped with a punch having a diameter of 11 mm for 12000 tablets of 1 tablet 100 mg and 6.0 kg of outer layer granules prepared in the production example. The obtained nucleated tablet had a collapse time of 17 minutes and a hardness of 11N.

Example 4

0.75 kg of methyl methionine sulfonium chloride, 0.45 kg of scofolia extract, 0.45 kg of dry extract, 0.25 kg of senburi powder, 0.15 kg of senburi powder, 0.075 kg of lipase AP, 0.12 kg of biodiastatase (2000), 0.12 kg of hydroxypropyl cellulose, 0.3 kg of hardened oil, 0.35 kg of carmellose calcium and 0.09 kg of corn starch were mixed and kneaded using a mixer, and then dried using a dryer, and then granulated using a sizing machine to prepare granules. 2.655 kg of granules and 0.045 kg of magnesium stearate were mixed into tablet granules, and tableted using a tableting machine equipped with a punch of φ 7 mm to prepare 30000 tablets of 90 mg of tablets. Into a tablet of 12000 tablets, 10 mg of 1 mg of dried oil was dissolved in anhydrous ethanol, 0.03 kg of hardened oil, 0.02 kg of monostearate, 0.08 kg of polyoxyl stearate, 0.008 kg of purified shellac, 0.008 kg of purified shellac, and 0.054 kg of talc. It applied as much as possible and it was set as the core tablet of 100 mg of 1 tablet.

9.0 kg of sodium bicarbonate, 1.0 kg of magnesium hydroxide, 12.0 kg of precipitated calcium carbonate, 1.2 kg of polyvinyl alcohol, 1.5 kg of carmellose calcium, 3.5 kg of crystalline cellulose, 0.15 kg of cinnamon powder, 1.2 kg of hardened oil, 0.2 kg of magnesium stearate Granules were prepared by mixing, kneading using a mixer, then drying using a dryer, and sizing again using a sizing machine. 5.95 kg of granules, 0.04 kg of hydrous silicon dioxide and 0.01 kg of l-menthol were mixed to obtain 6.0 kg of outer layer granules.

12000 tablets of 1 tablet of 100 mg mentioned above and 6.0 kg of outer-layer granules were compressed into tablets using the nucleus tableting machine provided with the punch of 11 mm, and 12000 tablets of 1,600 mg of nucleated tablets were produced.

Claims (20)

(A) The manufacturing method of the tablet containing an active ingredient, (B) Carmellose or its salt, and (C) Silicon dioxide manufacturing method of the tablet with wear resistance characterized by the above-mentioned. (A) A method for producing a tablet containing an active ingredient, comprising (B) carmellose or a salt thereof, and (C) silicon dioxide, wherein the tablet has a good disintegration property and has abrasion resistance. . The method according to claim 1 or 2, (B) The production method wherein carmellose or its salt is carmellose calcium. The method according to any one of claims 1 to 3, (C) The manufacturing method whose silicon dioxide is hydrous silicon dioxide. The method according to any one of claims 1 to 4, (B) The manufacturing method whose content of carmellose or its salt is 1-20 mass%. The method according to any one of claims 1 to 5, (C) The manufacturing method whose content of silicon dioxide is 0.1-10 mass%. The method according to any one of claims 1 to 6, (B) The manufacturing method whose content mass ratio ((B) / (C)) of carmellose or its salt and (C) silicon dioxide is 0.1-200. The method according to any one of claims 1 to 7, (A) A method in which a tablet containing an active ingredient is based on the 15th revised Japanese Pharmacy Disintegration Test "Disintegration Test Method" immediate release formulation (Test Solution: Water, Liquid Volume: 1000 ml, Test Temperature: 37 ± 2 ° C). ) Disintegration time by less than 30 minutes and method in conformity with Article 15 revised Japanese pharmacy room commentary reference information "tablet hardness test method of tablet" (put the tablet quantity of rule into drum 100 turns, and visually defect after test Manufacturing method in which the degree of wear and tear according to the method) is zero. The method according to any one of claims 1 to 8, (A) A manufacturing method in which the active ingredient is a drug acting on the stomach. The method according to any one of claims 1 to 9, (A) The manufacturing method in which the active ingredient is 1 type (s) or 2 or more types chosen from a peptic ulcer solvent, a gastric agent, a digestive agent, an antacid, a gastric mucosal restorative agent, and a formal agent. The method according to any one of claims 1 to 10, (A) The manufacturing method of which an active ingredient is chosen from sodium hydrogencarbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, calcium carbonate, precipitated calcium carbonate, magnesium silicate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate. (A) one or two or more active ingredients selected from a peptic ulcer solvent, a gastric agent, a digestive agent, an antacid, a gastric mucosal restorative agent and a formal agent, (B) carmellose or a salt thereof, and (C) silicon dioxide refine. The method of claim 12, (B) The tablet of carmellose or its salt is carmellose calcium. The method according to claim 12 or 13, (C) Purification wherein silicon dioxide is hydrous silicon dioxide. The method according to any one of claims 12 to 14, (B) Tablet which is content of 1-20 mass% of carmellose or its salt. The method according to any one of claims 12 to 15, (C) The tablet whose content of silicon dioxide is 0.1-10 mass%. The method according to any one of claims 12 to 16, (B) Carmelose or its salt, and (C) refinement | purification whose content mass ratio ((B) / (C)) of silicon dioxide is 0.1-200. The method according to any one of claims 12 to 17, The disintegration time by the method (test liquid: water, liquid amount: 1000 ml, test temperature: 37 ± 2 degreeC) based on the 15th revised Japanese pharmacy room "collapse test method" immediate release formulation is less than 30 minutes, and the 15th revised Japanese pharmacy room Commentary reference information Tablet which has the abrasion degree by the method based on "the friability test method of a tablet" (put a prescribed tablet quantity into a drum, rotate 100, and count the number of defects visually after a test). The method according to any one of claims 12 to 18, (A) Tablets whose active ingredient is 1 type (s) or 2 or more types chosen from sodium hydrogencarbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, calcium carbonate, precipitated calcium carbonate, magnesium silicate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate. The method according to any one of claims 12 to 18, (A) Tablets whose active ingredient is 2 or more types chosen from sodium hydrogencarbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, calcium carbonate, precipitated calcium carbonate, magnesium silicate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate.