JP2006045134A - Manufacturing method for compression-molded preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for manufacturing a compression-molded preparation with controlled elution of a medicine. <P>SOLUTION: A mixture, which comprises a medicine-containing fine particle coated with a coating agent soluble in an alcohol solvent but insoluble in water and a shaping agent insoluble in the alcohol solvent, is compression-molded and the thus-obtained compression-molded product is treated with the alcohol solvent. Thus, elution-controlling functions of the coated medicine-containing fine particle, which are lost by compression molding, are regenerated inside the compression-molded product to give the compression-molded preparation with controlled elution of medicines. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for producing a compression-molded preparation, more specifically, a mixture containing drug-containing fine particles coated with a water-insoluble coating agent soluble in an alcohol solvent and an excipient insoluble in an alcohol solvent. And it is related with the manufacturing method of the compression molding formulation which processes the obtained compression molding thing with an alcohol solvent.

In addition, the present invention includes an intraoral rapidly disintegrating tablet, more specifically, the following components, the hardness (measured in the diameter direction of the tablet, the same applies hereinafter) having a hardness of 20 N or more and a porosity of 20 to 50%. It relates to fast disintegrating tablets.
(1) Drug-containing fine particles coated with a water-insoluble coating agent that is soluble in an alcohol solvent
(2) A mixture containing a water-soluble binder soluble in an alcohol solvent and a water-soluble saccharide

  Regarding compression-molded preparations containing drug-containing fine particles with controlled drug elution, Patent Document 1 discloses particles obtained by spraying a suspension containing a bitter-tasting drug and the like and a preparation carrier onto a rotating disk spray dryer. Describes a method for producing an intraorally rapidly disintegrating tablet that is compressed after mixing with a saccharide. Patent Document 2 discloses an average particle diameter of 5 to 400 μm comprising active ingredient particles coated with a sustained release polymer composition. Describes a method of manufacturing tablets that compress microcapsules.

  Patent Document 3 describes a tablet production method in which sustained-release particles having an average particle diameter of 300 μm or less, in which a drug-containing core substance is coated with a hydrophobic organic compound-water-insoluble polymer mixed film, are compression-molded. .

  However, these patent documents do not describe post-processing to a compression-molded preparation.

  Recently, a preparation that can be easily taken by infants, elderly people, and severely ill patients with weak swallowing power, and rapidly disintegrating tablets in the oral cavity have been used with the expectation of quick action. Is a method in which a drug formulation component consisting of a drug and a drug additive is molded at a low density and then wetted with alcohol to remove the alcohol. Patent Document 5 discloses a method for tableting a mixture containing a drug, sugar and water. Patent Document 6 discloses a method of tableting a mixture of a drug, a water-soluble binder, and a water-soluble excipient, and then humidifying and drying with water vapor. Patent Document 7 discloses a method including a water-soluble additive, a drug, and water. A method in which a compound is compression-molded and glazed after drying is described. Patent Document 8 describes a method in which a drug and a saccharide having low moldability are granulated with a saccharide having high moldability and then the granulated product is compression-molded. .

  Furthermore, as a method not performing compression molding, it has been proposed to produce an orally rapidly disintegrating tablet by freeze-drying. For example, Patent Document 9 contains a dispersant, a water-soluble saccharide, and functional particles. It is described that a functional fine particle-containing intraorally rapidly disintegrating tablet is produced by filling an aqueous dispersion into a mold and removing water.

WO02 / 002083 brochure

Japanese Patent No. 2601660 WO00 / 24423 brochure Japanese Patent Laid-Open No. 10-298061 Japanese Patent Laid-Open No. 5-271054 JP-A-8-291051 WO93 / 15724 brochure WO95 / 20380 brochure WO02 / 100381 brochure

The method for producing a compression-molded preparation of the present invention regenerates the elution control function of the coated drug-containing fine particles lost by the compression molding inside the compression-molded product. Sex tablets have a short disintegration time and well-controlled drug dissolution.

  The present invention compression-molds a mixture containing drug-containing fine particles coated with a water-insoluble coating agent that is soluble in an alcohol solvent and an excipient insoluble in an alcohol solvent, and the resulting compression-molded product is alcohol-based. Providing a method for producing a compression-molded preparation with controlled drug elution by regenerating the elution control function of coated drug-containing fine particles lost by compression molding within the compression-molded product by treating with a solvent. To do.

The present invention also provides an intraoral rapidly disintegrating tablet containing the following components, having a hardness of 20 N or more and a porosity of 20 to 50%.
(1) Drug-containing fine particles coated with a water-insoluble coating agent that is soluble in an alcohol solvent
(2) A mixture containing a water-soluble binder soluble in an alcohol solvent and a water-soluble saccharide In addition, the method for producing a compression-molded preparation of the present invention contains drug-containing fine particles and an excipient insoluble in the alcohol solvent. Further, a binder and a lubricant soluble in an alcohol solvent may be added to the mixture to be compression molded.

  The compounding ratio of each component in the production method of the present invention can be expressed by the content of each component per the total amount of the compression molding preparation [component weight (g) / compression molding weight (g) × 100]. ~ 70 w / w%, preferably 0.02 to 10 w / w% of a water-insoluble coating agent soluble in an alcoholic solvent, 1 to 98 w / w% of an excipient insoluble in an alcoholic solvent, When a soluble binder and lubricant are contained in the system solvent, it is preferably 0.1 to 30 w / w% and 0.01 to 10 w / w%, respectively.

  The drug is 0.5 to 20 w / w%, the alcohol-based solvent-soluble and water-insoluble coating agent is 0.5 to 5 w / w%, and the alcohol-based solvent-insoluble excipient is 10 to 95 w / w%. More preferably, in the case where a soluble binder and lubricant are contained in the alcohol solvent, 0.5 to 5 w / w% and 0.03 to 3 w / w%, respectively. More preferred.

  As a coating agent that is soluble and insoluble in an alcohol solvent, a coating agent that dissolves 20 mg or more in 1 ml of an alcohol solvent (25 ° C.) and dissolves only 1 mg or less in 1 ml of water (25 ° C.). Only one type may be used, or two or more types may be mixed and used.

  Specific examples of the water-insoluble coating agent that is soluble in an alcohol solvent include a cellulose coating agent (for example, ethyl cellulose), an acrylic acid coating agent [for example, a methacrylic acid / methyl methacrylate copolymer (for example, Laem Eudragit L, S), methacrylic acid / ethyl acrylate copolymer (for example, Eudragit L30D-55, L100-55 by Laem), methyl methacrylate / ethyl acrylate copolymer (for example, Eudragit NE30D manufactured by Reem Co., Ltd., methyl methacrylate / ethyl acrylate / (β-methacryloyloxyethyl) trimethylammonium chloride copolymer (for example, Eudragit RL, RS manufactured by Laem Co.) and methyl methacrylate / methacrylic acid 1 or 2 or more selected from the group consisting of butyl / methacrylic acid dimethylaminoethyl copolymer (for example, Eudragit E100 manufactured by Rohm Co., Ltd.) and the like. Ethyl cellulose, methyl methacrylate / ethyl acrylate copolymer It is preferable to use 1 or 2 or more selected from the group consisting of methyl methacrylate, ethyl acrylate, (β-methacryloyloxyethyl) trimethylammonium chloride copolymer.

  Examples of excipients that are insoluble in alcoholic solvents include excipients that dissolve only 1 mg or less per 1 ml of alcohol (25 ° C). Even if only one type is used, two or more types are mixed. May be used.

  Specific examples of excipients that are insoluble in alcoholic solvents include inorganic excipients (eg, calcium citrate, calcium phosphate, calcium hydrogen phosphate, magnesium aluminate metasilicate), water-soluble sugars (eg, mannitol, xylitol, Erythritol, maltitol, sorbitol, lactose, sucrose, maltose, trehalose), preferably a water-soluble saccharide, and one or more selected from the group consisting of mannitol, erythritol, xylitol, lactose More preferably it is used.

  Examples of binders that are soluble in alcohol solvents include those that dissolve 20 mg or more with respect to 1 ml of alcohol solvent (25 ° C.). Even if only one type is used, two or more types are used. May be used in combination.

  Specific examples of the binder soluble in the alcohol solvent include one or more selected from the group consisting of a cellulose binder (for example, hydroxypropylcellulose) and a polyvinyl binder (for example, polyvinylpyrrolidone). It is preferable to use one or more selected from the group consisting of hydroxypropylcellulose and polyvinylpyrrolidone.

  As the lubricant, general-purpose ones can be used as appropriate. For example, talc, light anhydrous silicic acid, hydrous silicon dioxide, alkaline earth metal stearate (for example, magnesium stearate, calcium stearate), high sucrose One or more selected from the group consisting of fatty acid esters (for example, sucrose stearic acid ester and sucrose behenic acid ester) and glycerin higher fatty acid esters (for example, glycerin behenic acid ester) can be used.

  In addition, compression molding formulations may contain disintegrants (eg, corn starch, potato starch, sodium carboxymethyl starch, partially pregelatinized starch, carboxymethylcellulose calcium, carboxymethylcellulose, low substituted hydroxypropylcellulose, crosslinked carboxy Sodium methylcellulose, crosslinked polyvinylpyrrolidone, crystalline cellulose), sweeteners [for example, saccharin, aspartame (1-methyl N-L-α-aspartyl-L-phenylalanine, manufactured by Ajinomoto Co., Inc.), stevia, acesulfame potassium], flavor (for example, l-menthol, orange oil, fennel oil, cinnamon oil, clove oil, turpentine oil, mint oil, eucalyptus oil), colorant (for example, edible red No. 2, No. 3, edible yellow No. 4, No. 5) Edible green No. 3, edible blue No. 1, No. 2, these aluminum lakes, iron sesquioxide, yellow sesquioxide), flavoring agents (eg sodium chloride), solubilizers (eg cyclodextrin, arginine, Lysine, trisaminomethane) and the like may be added.

As the drug, any drug that can be administered orally can be contained, and the kind thereof is not particularly limited. Examples of drugs that can be contained are given below.
(1) Antipyretic analgesic / anti-inflammatory agent (for example, indomethacin, acetylsalicylic acid, diclofenac sodium, ketoprofen, ibuprofen, mefenamic acid, azulene, phenacetin, isopropylantipyrine, acetaminophenone, phenylbutazone, flufenamic acid, sodium salicylate, salicylamide, etodolac , Celecoxib, valdecoxib, etc.);
(2) steroidal anti-inflammatory agents (for example, dexamethasone, hydrocortisone, prednisolone, triamcinolone, etc.);
(3) Anti-ulcer agents (for example, ecabet sodium, emprostil, sulpiride, cetraxate hydrochloride, gefarnate, irsogladine maleate, cimetidine, ranitidine hydrochloride, famotidine, nizatidine, loxatidine acetate hydrochloride, omeprazole, lansoprazole, etc.);
(4) Coronary vasodilators (nifedipine, isosorbide nitrate, diltiazem hydrochloride, trapidil, dipyridamole, dilazep hydrochloride, nicardipine hydrochloride, verapamil hydrochloride, etc.);
(5) Peripheral vasodilators (eg, ifenprodil tartrate, pentoxifylline, etc.);
(6) Antibiotics (for example, ampicillin, bacampicillin hydrochloride, aspoxicillin, amoxiline, cephalexin, ceftazidime, cefuroxime sodium, minocycline hydrochloride, chloramphenicol, tetracycline, erythromycin, etc.);
(7) Synthetic antibacterial agents (for example, nalidixic acid, pyrometic acid, pipemidic acid trihydrate, enoxacin, sinoxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, sulfamethoxazole / trimethoprim, etc.);
(8) antiviral agents (eg, acyclovir, ganciclovir, valganciclovir, etc.);
(9) Antiseptics (for example, propantheline bromide, atropine sulfate, oxapium bromide, timepidium bromide, butyl scopolamine bromide, trospium chloride, butropium bromide, N-methyl scopolamine methyl sulfate, methyl octatropine bromide, etc. );
(10) Antitussives (eg, tipepidine hibenzate, ephedrine, codeine phosphate, dextromethorphan hydrobromide, dimemorphan phosphate, fominoben hydrochloride, benproperin phosphate, eprazinone hydrochloride, clofedanol hydrochloride, noscapine, pentoxy citrate Syberin etc.);
(11) An expectorant (for example, bromhexine hydrochloride, carbocysteine, ethylcysteine hydrochloride, methylcysteine hydrochloride, etc.);
(12) Bronchodilators (for example, theophylline, aminophylline, cromoglycate sodium, procaterol hydrochloride, trimethoquinol hydrochloride, diprofilin, salbutamol sulfate, formoterol fumarate, orciprenaline sulfate, clenbuterol hydrochloride, terbutaline sulfate, mabuterol hydrochloride, hydrobromic acid Fenoterol, methoxyphenamine hydrochloride, etc.);
(13) cardiotonic agents (for example, dopamine hydrochloride, dobutamine hydrochloride, docarpamine, denopamine, caffeine, digoxin, ubidecarenone, etc.);
(14) Diuretics (for example, furosemide, acetazolamide, trichloromethiazide, hydrochlorothiazide, triamterene, piretanide, mefluside, azosemide, etc.);
(15) Muscle relaxants (for example, tolperisone hydrochloride, eperisone hydrochloride, tizanidine hydrochloride, mephenesin, chlorzoxazone, metcarbamol, pridinol mesylate, afroqualone, baclofen, dantrolene sodium, etc.);
(16) Brain metabolism improving agent (for example, nicergoline, meclofenoxate hydrochloride, tartilelin etc.);
(17) Minor tranquilizers (eg, oxazolam, diazepam, clothiazepam, medazepam, fludiazepam, nitrazepam, chlordiazepoxide, etc.);
(18) Major tranquilizers (for example, sulpiride, clocapramine hydrochloride, zotepine, chlorpromazine, haloperidol, etc.);
(19) β-blockers (for example, bisoprolol fumarate, pindolol, propranolol hydrochloride, carteolol hydrochloride, metoprolol tartrate, acebutol hydrochloride, bubutolol hydrochloride, alprenolol hydrochloride, arotinolol hydrochloride, oxprenolol hydrochloride, nadolol hydrochloride, indenolol hydrochloride) , Timolol maleate, befnolol hydrochloride, bupranolol hydrochloride, etc.);
(20) Antiarrhythmic agents (for example, procainamide hydrochloride, disopyramide, azimarin, quinidine sulfate, aprindine hydrochloride, propaphenone hydrochloride, mexiletine hydrochloride, azimiride hydrochloride, etc.);
(21) Gout therapeutic agent (for example, allopurinol, probenecid, colchicine, benzbromarone, bucolome, etc.);
(22) Blood coagulation inhibitor (for example, ticlopidine hydrochloride, warfarin potassium, (2R, 3R) -3-acetoxy-5- [2- (dimethylamino) ethyl] -2,3-dihydro-8-methyl-2- (4-methylphenyl) -1,5-benzothiazepine-4 (5H) -one maleate, etc.);
(23) Migraine agents (eg, Rizatriptan benzoate);
(24) antiepileptic agents (eg, phenytoin, sodium valproate, carbamazepine, etc.);
(25) antiallergic agents (for example, chlorpheniramine maleate, clemastine fumarate, mequitazine, alimemazine tartrate, ebastine, epinastine hydrochloride, loratadine, amlexanox, tranilast, bepotastine besylate);
(26) Antiemetics (for example, diphenidol hydrochloride, metoclopramide, domperidone, betahistine mesylate, trimebbutine maleate, ondansetron, ramosetron hydrochloride);
(27) Antihypertensive agents (for example, resinamine, methyldopa, prarozocine hydrochloride, bunazosin hydrochloride, clonidine hydrochloride, budralazine, urapidil, etc.);
(28) Hyperlipidemia agent (for example, pravastatin sodium, fluvastatin sodium, etc.);
(29) Sympathomimetic agents (eg, dihydroergotamine mesylate, isoproterenol hydrochloride, ethylephrine hydrochloride, etc.);
(30) Alzheimer's dementia therapeutic agent (for example, donepezil hydrochloride, etc.);
(31) Oral anticancer agents (for example, marimastat etc.);
(32) Alkaloid narcotics (for example, morphine, codeine, cocaine, etc.);
(33) vitamin preparations (eg, vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, vitamin E, folic acid, etc.);
(34) Frequent urine treatment (for example, flavoxate hydrochloride, oxybutynin hydrochloride, etc.);
(35) Angiotensin converting enzyme inhibitor (for example, imidapril hydrochloride, enalapril maleate, alaspril, delapril hydrochloride, etc.);
(36) A therapeutic agent for erectile dysfunction (for example, sildenafil citrate, vardenafil hydrochloride, avanafil).

  Preparation of a mixture containing drug-containing fine particles and an insoluble excipient in an alcoholic solvent can be performed by a conventional mixing method in the pharmaceutical field. For example, a double cone mixer (for example, double cone made by Hachishu Kakoki) Mixer), fluidized bed granulator (for example, multiplex manufactured by POWREC, Spiraflow manufactured by Freund Corporation), high-speed agitation granulator (for example, high-speed mixer manufactured by Fukae Powtech, vertical granulator manufactured by POWREC), or vibration It can be performed using a sieve (for example, a vibrating sieve manufactured by Dalton).

  In addition, when a binder that is soluble in an alcohol solvent is used, an excipient that is insoluble in the alcohol solvent may be granulated in advance with a binder that is soluble in the alcohol solvent. It can be produced by adding an aqueous solution or aqueous suspension of a binder soluble in an alcoholic solvent to an excipient insoluble in the alcoholic solvent, mixing, granulating and drying.

The compression molding can be performed using a normal tableting machine such as a rotary three-layer tableting machine RT-3L-14 manufactured by Kikusui Seisakusho, a double tablet press collect D65RC manufactured by Kikusui Seisakusho, or a clean press collect 18HUK manufactured by Kikusui Seisakusho. For example, it can be implemented by the following method.
(1) The compression molding of a mixture containing a lubricant and a fluidizing agent and the compression molding of a mixture containing a drug-containing fine particle and an alcohol-insoluble excipient are alternately performed (Japanese Patent Application Laid-Open No. 10-298061). )
(2) Compression molding while spraying lubricant powder (Japanese Patent Publication Nos. 41-1273 and 48-20103)
(3) Chamfering through an anti-stick film (Japanese Patent Laid-Open No. 8-19589) or
(4) A small amount of lubricant that does not affect the disintegration / dissolvability of the compression-molded preparation is added to a mixture containing drug-containing fine particles and an excipient that is insoluble in an alcohol solvent. Even if the elution control function is lost due to breakage of the coating of the drug-containing fine particles at the compression molding stage, the elution control function can be achieved by treatment with an alcohol solvent after the compression molding. Can be played.

  The drug-containing fine particles coated with an alcohol-based solvent-soluble and water-insoluble coating agent preferably have an average particle size of 350 μm or less and an average particle size of 300 μm or less so that deformation due to compression molding does not increase. Is more preferable.

  As the alcohol solvent used for the treatment of the compression molded product, methanol, ethanol, n-propanol, i-propanol, n-butanol, 2-methoxyethanol (methyl cellosolve manufactured by Katayama Chemical Co., Ltd.) and the like can be used. It is preferable to use those having a boiling point of 85 ° C. or less at normal pressure, such as methanol, ethanol, i-propanol, etc., and particularly ethanol is preferably used.

  The treatment of the compression molded product with the alcohol solvent is performed by (a) adding the alcohol solvent in a liquid state to the compression molded product, (b) spraying the alcohol solvent on the compression molded product, or (c) the compression molded product. Can be carried out by evaporating the alcoholic solvent from the compression-molded product by a conventional method such as heating, decompression or ventilation.

  When infiltrating with an alcohol solvent vapor, the vapor temperature is preferably 60 ° C. or lower, more preferably 40 ° C. or lower in consideration of the stability of the drug. By treatment with alcohol solvent, the soluble and water-insoluble coating agent dissolves in the alcohol solvent that covers the drug-containing fine particles contained in the compression molded product, and solidifies when the alcohol solvent is distilled off. By doing so, the elution control function lost by compression molding is reproduced.

  In addition, when compression molding is performed by containing a soluble binder in an alcohol solvent, the alcohol soluble binder is dissolved and solidified by treatment with an alcohol solvent performed after compression molding. For this reason, the hardness of the compression-molded preparation can be improved at the same time by the treatment with the alcohol solvent, and a molded preparation having a high hardness can be obtained even when molding while suppressing the pressure at the time of compression molding relatively low. For example, even if the hardness before the treatment with the alcohol solvent is 2 to 15 N, the hardness can be increased to 20 to 80 N by the treatment with the alcohol solvent.

  Since the binder contained in the compression-molded preparation is dissolved by the treatment with the alcohol solvent, if the treatment time is increased to a certain limit, the amount of the binder dissolved increases, and the increase in hardness becomes large in the next drying step. If the required hardness cannot be obtained or the disintegration time becomes long, the required hardness can be selected by appropriately selecting the amount of binder in the compression molded product, the processing time, the amount of alcohol solvent to be applied, etc. Can achieve the decay time.

In order to regenerate the elution control function of drug-containing fine particles to the inside of the compression molded product by the treatment with the alcohol solvent performed after the compression molding, it is necessary that the alcohol solvent penetrates into the compression molded product. The porosity calculated by the following formula is preferably 20 to 50%, more preferably 25 to 40%.
Porosity (%) = (V × ρ−M) ÷ (V × ρ) × 100
[Wherein V represents the volume (ml) of the compression-molded preparation, ρ represents the density (g / ml) of the portion other than the voids of the compression-molded preparation, and M represents the weight (g) of the compression-molded preparation. ]
The shape of the compression-molded preparation obtained by the method for producing a compression-molded preparation of the present invention includes tablet type, elliptical sphere, sphere, and square shape, and the volume of the compression-molded preparation from the viewpoint of ease of taking. Is in the range of 0.02 to 1 ml / tablet, preferably 0.05 to 0.5 ml / tablet.

  The drug-containing fine particles coated with the alcohol-based solvent-soluble and water-insoluble coating agent used in the method for producing the compression-molded preparation of the present invention can be produced by the following drug-containing core particle production process and coating process. .

(Drug-containing core particle manufacturing process)
The drug-containing core particles are prepared using known drugs such as wet granulation, dry granulation, layering granulation, heating granulation, impregnation granulation, spray drying granulation, etc., using the above drugs and various additives as required. It can be prepared by the grain method.

In order to prepare the drug-containing core particles by the wet granulation method, for example, the following method can be used.
(1) A binder solution is added to a mixture of drug and various preparation additives (hereinafter referred to as drug mixture), and the mixture is stirred and granulated using a high-speed rolling granulator or the like (WO00 / 24379).
(2) The binder solution is added to the drug mixture and kneaded, and then granulated and sized using an extrusion granulator.
(3) The drug mixture is granulated by spraying the binder solution under flow using a fluidized bed granulator, a tumbling stirred fluidized bed granulator, or the like (WO94 / 8709).

  Formulation additives used for the production of drug-containing core particles include excipients (eg, celluloses such as crystalline cellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium; corn starch, potato starch, partial alpha Modified starch, starches such as sodium carboxymethyl starch) and the like, and these are used as powders. When the granulation of (1) is performed, it is preferable to use an excipient having a property of retaining a solvent as an excipient.

  As the binder, hydroxypropylcellulose, polyvinylpyrrolidone and the like can be used, and as the solvent, water and aqueous alcohol such as aqueous ethanol can be used.

  To prepare by the dry granulation method, the drug mixture is granulated using a roller compactor and a roll granulator.

  To prepare by the layering granulation method, add the drug mixture while spraying the binder solution onto the rolled inert carrier using a centrifugal fluid granulator, etc., and attach the drug mixture on the carrier Let Examples of inert carriers include crystalline lactose, crystalline cellulose, crystals of saccharides such as crystalline sodium chloride, or inorganic salt crystals, spherical granules (for example, spherical granules of crystalline cellulose (for example, Asahi Kasei Selfia CP-203), Spherical granule of crystalline cellulose and lactose (eg, Freund Sangyo Non-Parel-105), refined white sugar spheroids (eg, Freund Sangyo Non-Parel-103), refined sucrose and corn starch spheroids (eg, , Freund Sangyo Non-Parallel-101)] and the like can be used.

In order to prepare by the heating granulation method, it can be prepared by the following method.
(A) Using a stirring granulator, a high-speed stirring granulator, etc., at a temperature at which the heated molten material melts a drug mixture containing a substance (heated molten substance) that melts upon heating, such as polyethylene glycol, fats and oils, and wax. Stir and granulate.
(B) Using a centrifugal fluid granulator or the like, add the drug mixture containing the heated molten substance to an inert carrier that has been rolled at a temperature at which the heated molten substance melts, and place the drug mixture on the carrier. Adhere.

  To prepare by the impregnation granulation method, a solution containing a drug at an appropriate concentration and a porous carrier are mixed, the drug solution is sufficiently retained in the pores of the carrier, and then dried to remove the solvent. As the porous carrier, magnesium aluminate metasilicate (Neusilin manufactured by Fuji Chemical Industry), calcium silicate (Elite fluorite) and the like can be used.

  To prepare by the spray drying granulation method, a solution or suspension of the drug is sprayed in a hot air stream using a spray dryer such as a spray dryer and dried.

  In order to prepare a drug-containing core particle having a particle size of about 45 to 195 μm, wet granulation using a high-speed rolling granulator (for example, a binder solution in an excipient having a property of retaining a drug and a solvent) And high-speed rolling granulation), wet granulation using a fluidized bed granulator (for example, fluidizing drugs and excipients, spraying a binder solution to granulate), impregnation Granules and spray-dried granulation are preferred.

(Coating process)
The coating of the drug-containing core particles is performed by providing a coating layer of a coating agent that is soluble in an alcohol solvent and water-insoluble on the surface of the drug-containing core particles prepared as described above. In order to provide the coating layer on the drug-containing core particles, any coating method usually used in the field of pharmaceutical technology can be used. For example, a coating agent that is soluble in an alcohol-based solvent and water-insoluble, and if necessary, a plasticizer (for example, triethyl citrate, triacetin) and the lubricant are dissolved or dispersed in a solvent to form a coating solution, which is usually used The drug-containing fine particles can be obtained by spraying and drying the drug-containing core particles using a coating apparatus.

  Examples of the solvent for the coating solution include alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methoxyethanol (methyl cellosolve manufactured by Katayama Chemical Industry), water, a mixture of water and alcohol solvents, and the like. Can be used. As the coating apparatus, a fluidized bed coating apparatus, a centrifugal fluidized bed coating apparatus, a pan coating apparatus, or the like can be used.

  The intraoral rapidly disintegrating tablet of the present invention can be efficiently produced by the method for producing a compression-molded preparation of the present invention.

  As the drug-containing fine particles coated with a coating agent that is soluble and water-insoluble in an alcohol-based solvent used in an intraoral rapidly disintegrating tablet, those used in the method for producing a compression-molded preparation of the present invention can be used as they are. In order to suppress the rough feeling after disintegration in the oral cavity, the average particle size is preferably 350 μm or less, and more preferably 300 μm or less.

  Specific examples of the water-insoluble coating agent that is soluble in an alcohol solvent include a cellulose coating agent, an acrylic acid coating agent, and the like. Ethyl cellulose, a methacrylic acid / methyl methacrylate copolymer (for example, Eudragit L, S), methacrylic acid / ethyl acrylate copolymer (for example, Eudragit L30D-55, L100-55, manufactured by Laem), methyl methacrylate / ethyl acrylate copolymer (for example, , Eudragit NE30D manufactured by Laem Co., Ltd., methyl methacrylate / ethyl acrylate / (β-methacryloyloxyethyl) trimethylammonium chloride copolymer (e.g. Eudragit RL, RS manufactured by Laem Co.) and methyl methacrylate / metaact Le butyl methacrylate-dimethylaminoethyl methacrylate copolymer (for example, Rohm Co. Eudragit E100) are preferably used one or more selected from the group consisting of the like.

  As the water-soluble saccharide used in the intraoral quick disintegrating tablet, the water-soluble saccharide listed as one of the excipients insoluble in the alcohol solvent used in the method for producing the compression-molded preparation of the present invention is used. One or two or more selected from the group consisting of mannitol, erythritol, xylitol, and lactose can be used.

  As a water-soluble binder soluble in an alcohol solvent used for an orally rapidly disintegrating tablet, 20 mg or more of a bond that dissolves in 1 ml of an alcohol solvent (25 ° C.) and 1 ml of water (25 ° C.) An agent can be mention | raise | lifted and only 1 type may be used or 2 or more types may be mixed and used.

  Specific examples of water-soluble binders that are soluble in alcohol solvents include one or more selected from the group consisting of cellulose binders (for example, hydroxypropylcellulose) and polyvinyl binders (for example, polyvinylpyrrolidone). It is preferable to use one or more selected from the group consisting of hydroxypropylcellulose and polyvinylpyrrolidone.

  Further, in the intraoral quick disintegrating tablet of the present invention, if necessary, a lubricant, a disintegrating agent, a sweetening agent, a flavoring agent, a coloring agent, a flavoring agent, a dissolution aid, which are used in the method for producing a compression-molded preparation. An agent or the like may be added.

  The mixture containing a water-soluble binder soluble in an alcohol solvent and a water-soluble saccharide may be a mixture of these components or the like, or a granulation of these components. A granulated product containing a water-soluble saccharide granulated using a water-soluble binding agent can be produced in the same manner as the granulated product in the drug-containing fine particle production process. In addition, an aqueous solution or aqueous suspension of a water-soluble binder that is soluble in an alcohol solvent can be added, mixed, granulated, and dried.

  The compounding ratio of each component in the intraoral rapidly disintegrating tablet of the present invention can be expressed as the content of each component per total amount of the tablet [component weight (g) / tablet weight (g) × 100]. ~ 70 w / w%, 0.02 to 10 w / w% soluble and water-insoluble coating agent in alcoholic solvent, 1 to 98 w / w% water-soluble saccharide, water-soluble binder soluble in alcoholic solvent It is preferable to set it as 0.1-30 w / w%, and when it contains a lubricant, it is preferable to set it as 0.01-10 w / w%.

  In addition, 0.5 to 20 w / w% of drug, 0.5 to 5 w / w% of water-insoluble coating agent soluble in alcoholic solvent, 10 to 95 w / w% of water-soluble saccharide, dissolved in alcoholic solvent The water-soluble water-soluble binder is more preferably 0.5 to 5 w / w%, and when a lubricant is contained, it is more preferably 0.03 to 3 w / w%.

  Examples of the orally rapidly disintegrating tablet of the present invention include tablets, ellipsoids, spheres, and squares, and the volume of the orally rapidly disintegrating tablet is preferably 0.02 to 1 ml / tablet. Is preferably in the range of 0.05 to 0.5 ml / tablet.

  The intraoral rapidly disintegrating tablet of the present invention has a hardness of 20 N or more, preferably 30 N or more, and the aforementioned porosity is 20 to 50%, preferably 25 to 40%. The disintegration time of the orally rapidly disintegrating tablet is within 60 seconds, preferably within 45 seconds, more preferably within 30 seconds in the oral cavity, and the disintegration test method defined in the Japanese Pharmacopoeia (14th revision). (Up and down movement: 29 to 32 reciprocations / minute; 37 ° C .; water) is within 200 seconds, preferably within 150 seconds, and more preferably within 100 seconds.

  In the intraoral rapidly disintegrating tablet of the present invention, the elution of the drug is sufficiently controlled by the coating with the alcohol-based solvent-soluble and water-insoluble coating agent. Therefore, it is prescribed in the Japanese Pharmacopoeia (14th revision). The drug dissolution rate (the amount of drug dissolved in water ÷ the total amount of drug in the intraoral rapidly disintegrating tablet × 100) by the second dissolution test (paddle rotation speed: 50 rpm; 37 ° C .; water) is 20 in 1 minute after the start of dissolution. Even if the drug is a drug that produces an unpleasant taste in the oral cavity, the taste of the drug can be sufficiently masked. In addition, if it is 75% or more 30 minutes after the start of elution in the same elution test method, it is possible to obtain a rapid drug effect while masking the taste of the drug.

  In addition, if a drug with finer dissolution control function is applied to the drug-containing microparticles as a coating with an alcohol-based solvent-soluble and water-insoluble coating agent, the drug dissolution rate in the dissolution test method can be increased without increasing the disintegration time. Can be reduced to 60% or less in 60 minutes after the start of elution, and a sustained-release intraoral quick disintegrating tablet can be obtained.

  The intraorally rapidly disintegrating tablet of the present invention can be produced according to the method for producing a compression-molded preparation of the present patent application, and contains drug-containing fine particles coated with a soluble and water-insoluble coating agent in an alcohol solvent and an alcohol solvent. A mixture containing a soluble water-soluble binder and a water-soluble saccharide is mixed, compression molded, and then treated with an alcohol solvent.

  The mixing of the drug-containing fine particles and the granulated product can be performed in the same manner as in the case of the mixture containing the drug-containing fine particles and an excipient insoluble in the alcohol solvent.

  For compression molding, the molding method in the production method of the compression molding preparation of the present invention can be applied as it is, but since the hardness can be improved by subsequent treatment with an alcohol-based solvent, at the stage of compression molding The hardness may be about 5 to 10 N, and compression molding may be performed with a molding pressure of 5 to 30 MPa.

The treatment with an alcohol solvent can be applied as it is in the method for producing a compression-molded preparation of the present invention, and the elution control function is lost due to damage to the coating of the drug-containing fine particles at the stage of compression molding. In addition, the elution control function can be regenerated by treatment with an alcohol solvent.

Example 1
(1) Preparation of core particles High-speed rolling of 83 parts by weight of bepotastine besylate, 15 parts by weight of crystalline cellulose (Avicel PH-301 manufactured by Asahi Kasei Corporation) and 2 parts by weight of hydroxypropyl cellulose (HPC-SL manufactured by Nippon Soda Co., Ltd.) It was charged in a granulator (Newgra Machine NC-200 manufactured by Seishin Enterprise Co., Ltd.) and premixed for 1 minute. Purified water was added at a rate of 9 g / min while stirring at 25 ° C. and 600 rpm, and granulated for about 30 minutes. After granulation, it was dried at 45 ° C. for 3 hours with a box dryer to obtain bepotastine besylate-containing core particles having an average particle size of 117 μm.
(2) Coated ethylcellulose aqueous dispersion (FMC, Aquacoat; solid content 30 w / w% content) 164.0 g, ethyl acrylate / methyl methacrylate copolymer aqueous emulsion (Laid Eudragit) NE30D (containing 30% w / w solid content) 16.4 g, 9.8 g of triethyl citrate and 54.1 g of calcium stearate were dissolved or dispersed in 1255.7 g of purified water to prepare a coating solution. Using a Wurster fluidized bed coating apparatus (SPC 0.5 / 1, manufactured by Paulek), the coating ratio (ratio of the coating layer to the core particles) of the coating solution is 120 g of the bepotastine besylate-containing core particles in a fluid state. Spraying to 60 w / w% gave about 180 g of coated particles with an average particle size of 130 μm.
(3) Preparation of externally added part granules Using a tumbling fluidized bed granulator (MP-01 / 03 manufactured by POWREC), 5 w with respect to 98 parts by weight of D-mannitol (manufactured by Nikken Kasei) in a fluidized state. A granule was sprayed with 40 parts by weight of an aqueous solution of / w% polyvinylpyrrolidone (Collidon K30 manufactured by BASF), and dried to prepare externally added granules.
(4) Preparation of intraoral rapidly disintegrating tablet 7.7 parts by weight of the coated particles of (2) above and 92.3 parts by weight of externally added part granules of (3) above were mixed to obtain a drug formulation component. Further, 1 part by weight of magnesium stearate as a lubricant and 19 parts by weight of crystalline cellulose (Avicel PH-102 manufactured by Asahi Kasei Co., Ltd.) as a fluidizing agent were mixed to obtain a mixture of the lubricant and the fluidizing agent.
A mixture of a lubricant and a fluidizing agent is supplied to the first pre-compression site of a three-layer tableting machine (manufactured by Kikusui Seisakusho, cocoon size: 10 mm in diameter). Without supplying anything, the drug formulation component was supplied to the main compression site, the mixture of lubricant and fluidizing agent was tableted, discharged from the tablet press, and then the drug formulation component was tableted with the same punch.
The drug formulation component was 300 mg per tablet, and the tableting pressure was adjusted so that the hardness of the tablets to be produced was about 6N. The tablet of the drug formulation component obtained by tableting is left in a desiccator filled with ethanol vapor for 16 hours at 25 ° C. and then left in a box-type dryer for 3 hours to give ethanol. Distilled off to produce an orally rapidly disintegrating tablet. When the hardness in the diameter direction was measured with a Schleuniger tablet hardness tester, the hardness of the intraorally rapidly disintegrating tablet was 45N. In addition, the time (disintegration time) required for dissolving one tablet (in the mouth) and dissolving spontaneously (without chewing or moving the tongue violently) was 13 seconds.
(5) Dissolution test Before the tableting, the 14th revised Japanese Pharmacopoeia for three types of preparations: tablets of drug prescriptions obtained by tableting, tablets of drug prescription obtained by tableting, and intraoral quick disintegrating tablets According to the second dissolution test method (paddle rotation speed: 50 rpm; 37 ° C), a dissolution test was performed with 900 mL of purified water, and the concentration of bepotastine besylate in the eluate was calculated by measuring the absorbance at 260 nm. The elution rate was calculated from the concentration and the amount of eluate. The results are shown in FIG.
Due to the influence of tableting, the dissolution rate of bepotastine besylate was high immediately after the start of the dissolution test in the tablet of the drug formulation component obtained by tableting, but in the oral rapidly disintegrating tablet treated with ethanol, Similar to the drug formulation components before the tablets, it showed slow dissolution.
From these facts, it is considered that the coating of the coated particles contained in the drug prescription ingredients before tableting was damaged by tableting, but was repaired by ethanol treatment.

Example 2
(1) Preparation of core particles 83 parts by weight of bepotastine besylate and 15 parts by weight of crystalline cellulose (Avicel PH-301 manufactured by Asahi Kasei Co., Ltd.) were charged into a tumbling fluidized bed granulator (MP-01 / 03 manufactured by POWREC). The product temperature was preheated to 45 ° C at 300 rpm for 31 ° C. While continuing stirring at the same rotational speed, 28.6 parts by weight of an aqueous solution of 7% hydroxypropylcellulose (HPC-SL manufactured by Nippon Soda Co., Ltd.) was sprayed on the mixture for about 26 minutes for granulation. After granulation, the air supply temperature in the fluidized bed granulator was set to 70 ° C. and dried until the exhaust temperature reached 45 ° C. to obtain bepotastine besylate-containing core particles having an average particle size of 126 μm.
(2) Coated ethylcellulose aqueous dispersion (FMC Aquacoat; solid content 30 w / w%) 181.0 g, triethyl citrate 11.5 g and calcium stearate 54.3 g were dissolved or dispersed in purified water 1253.2 g. A coating solution was prepared. Using a Wurster fluidized bed coating apparatus (SPC 0.5 / 1, manufactured by Paulek), the coating ratio (ratio of the coating layer to the core particles) of the coating solution is 120 g of the bepotastine besylate-containing core particles in a fluid state. It sprayed until it became 60 w / w%, and 177 g of coated particles with an average particle diameter of 134 μm were obtained.
(3) Preparation of intraoral rapidly disintegrating tablet 7.7 parts by weight of the coated particles of (2) above and 92.3 parts by weight of the externally added part granules of Example 1- (3) were mixed to obtain a drug formulation component. .
An intraoral quick disintegrating tablet was prepared by treating the mixture of the above drug formulation components and the lubricant and fluidizing agent of Example 1- (4) in the same manner as in Example 1- (4).
When measured in the same manner as in Example 1- (4), the hardness and disintegration time of this intraorally rapidly disintegrating tablet were 50 N and 15 seconds. Moreover, the disintegration time by the disintegration test method (vertical movement: 29-32 reciprocations / min; 37 ° C; water) specified in the Japanese Pharmacopoeia (14th revision) was 12 seconds.
(4) Dissolution test Example 1- (5) for three types of preparations: a drug formulation component before tableting, a tablet of the drug formulation component obtained by tableting, and an intraoral rapidly disintegrating tablet subjected to ethanol treatment. ) And the dissolution test was performed. The results are shown in FIG.
Due to the effect of tableting, the dissolution rate of bepotastine besylate was high immediately after the start of the dissolution test in the tablet of the drug prescription component obtained by tableting. Immediately after the start of the test, the dissolution rate was lower than that of the drug formulation components before tableting.
For these reasons, the coating of the coated particles contained in the drug prescription ingredients before tableting is damaged by tableting, but it is repaired by ethanol treatment, and it is more excellent in suppressing bitterness in the oral cavity than before tableting. It is thought that it became.

Example 3
(1) Preparation of core particles 68 parts by weight of diltiazem hydrochloride, 30 parts by weight of crystalline cellulose (Avicel PH-301 manufactured by Asahi Kasei Co., Ltd.) and 2 parts by weight of hydroxypropyl cellulose (HPC-SL manufactured by Nippon Soda Co., Ltd.) are rolled at high speed. The mixture was charged in a granulating apparatus (Newgra Machine NC-200 manufactured by Seishin Enterprise Co., Ltd.) and premixed at 25 ° C. and 600 rpm for 1 minute. Purified water was added at a rate of 9 g / min while stirring at the same rotational speed, and granulated for about 30 minutes. After granulation, it was dried at 45 ° C. for 3 hours on a drying shelf to obtain diltiazem hydrochloride-containing core particles having an average particle size of 176 μm.
(2) 60 g of coating ethyl cellulose (EC # 10 manufactured by Dow Chemical Company) and 60 g of talc (P3 manufactured by Nippon Talc Co.) were dissolved or dispersed in 1380 g of a mixed solution of 70% ethanol-30% water to prepare a coating solution. Using a Wurster fluidized bed coating apparatus (SPC 0.5 / 1 manufactured by Paulek), the coating ratio of the coating liquid (ratio of the coating layer to the core particles) is 60 w with respect to 150 g of dilutiazem hydrochloride-containing core particles in a fluid state. It sprayed until it became / w%, and 223g of covering particles with an average particle diameter of 200 micrometers were obtained.
(3) Preparation of intraoral rapidly disintegrating tablet 10.6 parts by weight of the coated particles of (2) above and 89.4 parts by weight of the externally added part granules of Example 1- (3) were mixed to obtain a drug formulation component. .
An intraoral quick disintegrating tablet was prepared by treating the mixture of the above drug formulation components and the lubricant and fluidizing agent of Example 1- (4) in the same manner as in Example 1- (4).
When measured in the same manner as in Example 1- (4), the hardness and disintegration time of this intraorally rapidly disintegrating tablet were 54 N and 15 seconds.
(4) Dissolution test Before the tableting, the 14th revised Japanese Pharmacopoeia for three types of preparations: tablets of drug prescriptions obtained by tableting, tablets of the drug prescription obtained by tableting, and intraoral quick disintegrating tablets According to the second dissolution test method (paddle rotation speed: 50 rpm; 37 ° C.), a dissolution test is performed with 900 mL of purified water, and the concentration of diltiazem hydrochloride in the eluate is calculated by measuring the absorbance at 260 nm. The elution rate was calculated from the amount of the eluate. The results are shown in FIG.
In the tablet of the drug formulation component obtained by tableting, the dissolution control ability is weakened due to the effect of tableting, and the dissolution rate of diltiazem hydrochloride 60 minutes after the start of dissolution is increased to about 160% of the drug formulation component before tableting. However, in the intraoral rapidly disintegrating tablet that has been treated with ethanol, the dissolution rate of diltiazem hydrochloride is low to 70% or less of the drug formulation component before tableting.
From these facts, the coating of the coated particles contained in the drug prescription ingredients before tableting was damaged by tableting, but it was repaired by ethanol treatment, resulting in a film with better sustained release than before tableting. Conceivable.

Example 4
(1) Coating powder mixture consisting of 90 parts by weight of coating ethyl acrylate / methyl methacrylate / (β-methacryloyloxyethyl) trimethylammonium chloride copolymer (Eudragit RLPO manufactured by Laem Co.) and 10 parts by weight of sodium carboxymethylcellulose (Rame 75 g Eudragit RD 100), 15 g nonionic surfactant (polysorbate 80 manufactured by Nikko Chemicals) and 15 g calcium stearate were dissolved or dispersed in 895 g water to prepare a coating solution. The coating liquid was applied to 150 g of dilutiazem hydrochloride-containing core particles of Example 3- (1) fluidized using a Wurster fluidized bed coating apparatus (SPC 0.5 / l manufactured by Paulek). The mixture was sprayed until the ratio of the core particles to 40% was obtained to obtain 190 g of coated particles having an average particle diameter of 150 μm.
(2) Preparation of intraoral rapidly disintegrating tablet 9.3 parts by weight of the coated particles of (1) above and 90.7 parts by weight of the externally added part granules of Example 1- (3) were mixed to obtain a drug formulation component. .
An intraoral quick disintegrating tablet was prepared by treating the mixture of the above drug formulation components and the lubricant and fluidizing agent of Example 1- (4) in the same manner as in Example 1- (4).
When measured in the same manner as in Example 1- (4), the hardness and disintegration time of this intraorally rapidly disintegrating tablet were 44 N and 12 seconds.
(3) Dissolution test The dissolution test was carried out in the same manner as in Example 3- (4) for the intraoral rapidly disintegrating tablet of (2) above. The results are shown in FIG.

Example 5
(1) Preparation of core particles 82 parts by weight of bepotastine besylate and 14 parts by weight of crystalline cellulose (Avicel PH-301 manufactured by Asahi Kasei Co., Ltd.) were charged into a rolling fluidized bed granulator (MP-01 / 03 manufactured by Paulec) Preheating was performed at 45 ° C. and 300 rpm until the product temperature reached 31 ° C. While stirring at the same rotational speed, 57.1 parts by weight of an aqueous solution of 7% hydroxypropylcellulose (HPC-SL manufactured by Nippon Soda Co., Ltd.) was sprayed for about 26 minutes and granulated. After granulation, the air supply temperature in the fluidized bed granulator was set to 70 ° C. and dried until the exhaust temperature reached 45 ° C. to obtain bepotastine besylate-containing core particles.
(2) Example 2- (2) with respect to 150 g of bepotastine besylate-containing core particles of the above (1) fluidized by using a coating Wurster fluidized bed coating apparatus (SPC 0.5 / 1 manufactured by POWREC). ) Was sprayed until the coating rate (ratio of the coating layer to the core particles) reached 70 w / w% to obtain 220 g of coated particles having an average particle size of 204 μm.
(3) Preparation of intraoral rapidly disintegrating tablet After heating and melting 20 parts by weight of 1-menthol, it is adsorbed to 80 parts by weight of crystalline cellulose (Avicel PH-301 manufactured by Asahi Kasei Co., Ltd.) to prepare menthol / Avicel trituration. did.
1.3 parts by weight of this menthol / Avicel trituration, 6.9 parts by weight of the coated particles of the above (2), 91.3 parts by weight of externally added part granules of Example 1- (3), and 0 part of Aspartame manufactured by Ajinomoto Co., Inc. 5 parts by weight were mixed to obtain a drug formulation component.
An intraoral quick disintegrating tablet was prepared by treating the mixture of the above drug formulation components and the lubricant and fluidizing agent of Example 1- (4) in the same manner as in Example 1- (4).
When measured in the same manner as in Example 1- (4), the hardness and disintegration time of this intraorally rapidly disintegrating tablet were 79 N and 15 seconds. Moreover, the disintegration time by the disintegration test method (vertical movement: 29-32 reciprocations / min; 37 ° C; water) prescribed in the Japanese Pharmacopoeia (14th revision) was 30 seconds.
(4) Dissolution test The dissolution test was carried out in the same manner as in Example 1- (5) for the intraoral rapidly disintegrating tablet of (3) above. The results are shown in FIG.

Example 6
(1) Preparation of externally added part granules Using a tumbling fluidized bed granulator (MP-01 / 03, manufactured by Paulek), 98 parts by weight of D-mannitol was fluidized and 5 w / w% hydroxypropylcellulose (Nihon Soda) An external additive granule was prepared by spraying 40 parts by weight of an HPC-SL) aqueous solution and granulating it, followed by drying.
(2) Preparation of intraoral rapidly disintegrating tablet 6.9 parts by weight of coated particles of Example 5- (2), 1.3 parts by weight of menthol / avicel trituration of Example 5- (3), (1) 91.3 parts by weight of the externally added part granule and 0.5 part by weight of aspartame manufactured by Ajinomoto Co., Inc. were mixed to obtain a drug formulation component.

An intraoral quick disintegrating tablet was prepared by treating the mixture of the above drug formulation components and the lubricant and fluidizing agent of Example 1- (4) in the same manner as in Example 1- (4).
When measured in the same manner as in Example 1- (4), the hardness and disintegration time of this intraorally rapidly disintegrating tablet were 58 N and 23 seconds. Moreover, the disintegration time by the disintegration test method (vertical movement: 29-32 reciprocations / min; 37 ° C; water) prescribed in the Japanese Pharmacopoeia (14th revision) was 48 seconds.
(3) Dissolution test The dissolution test was carried out in the same manner as in Example 1- (5) for the intraorally rapidly disintegrating tablet of (2) above. The results are shown in FIG.

Example 7
(1) Preparation of externally added part granules Using a tumbling fluidized bed granulator (MP-01 / 03 manufactured by Paulek), 98 parts by weight of α-lactose monohydrate (DMV lactose 200M) was fluidized. Then, 40 parts by weight of a 5 w / w% hydroxypropylcellulose (Nippon Soda Co., Ltd. HPC-SL) aqueous solution was sprayed and granulated, and then dried to prepare externally added granules.
(2) Preparation of intraoral rapidly disintegrating tablet 6.9 parts by weight of coated particles of Example 5- (2), 1.3 parts by weight of menthol / avicel trituration of Example 5- (3), (1) 91.3 parts by weight of the externally added part granule and 0.5 part by weight of aspartame manufactured by Ajinomoto Co., Inc. were mixed to obtain a drug formulation component.

An intraoral quick disintegrating tablet was prepared by treating the mixture of the above drug formulation components and the lubricant and fluidizing agent of Example 1- (4) in the same manner as in Example 1- (4).
When measured in the same manner as in Example 1- (4), the hardness and disintegration time of this intraorally rapidly disintegrating tablet were 36 N and 35 seconds. Moreover, the disintegration time by the disintegration test method (vertical movement: 29-32 reciprocations / min; 37 ° C; water) prescribed in the Japanese Pharmacopoeia (14th revision) was 54 seconds.
(3) Dissolution test The dissolution test was carried out in the same manner as in Example 1- (5) for the intraorally rapidly disintegrating tablet of (2) above. The results are shown in FIG.

Example 8
(1) Preparation of externally added part granules Using a tumbling fluidized bed granulator (MP-01 / 03 manufactured by Paulek), 98 parts by weight of α-lactose monohydrate (DMV lactose 200M) was fluidized. Then, 40 parts by weight of a 5 w / w% hydroxypropylcellulose (Nippon Soda Co., Ltd. HPC-SL) aqueous solution was sprayed and granulated, and then dried to prepare externally added granules.
(2) Preparation of intraoral rapidly disintegrating tablet 6.9 parts by weight of coated particles of Example 5- (2), 1.3 parts by weight of menthol / avicel trituration of Example 5- (3), (1) 91.3 parts by weight of the externally added part granule and 0.5 part by weight of aspartame manufactured by Ajinomoto Co., Inc. were mixed to obtain a drug formulation component.
An intraoral quick disintegrating tablet was prepared by treating the mixture of the above drug formulation components and the lubricant and fluidizing agent of Example 1- (4) in the same manner as in Example 1- (4).
When measured in the same manner as in Example 1- (4), the hardness and disintegration time of this intraorally rapidly disintegrating tablet were 45 N and 12 seconds. Moreover, the disintegration time by the disintegration test method (vertical movement: 29-32 reciprocations / min; 37 ° C; water) prescribed in the Japanese Pharmacopoeia (14th revision) was 54 seconds.
(3) Dissolution test The dissolution test was carried out in the same manner as in Example 1- (5) for the intraorally rapidly disintegrating tablet of (2) above. The results are shown in FIG.

Example 9
(1) Preparation of intraoral rapidly disintegrating tablet 7.2 parts by weight of coated particles of Example 5- (2), 1.3 parts by weight of menthol / Avicel trituration of Example 5- (3), manufactured by Ajinomoto Co., Inc. 0.5 parts by weight of aspartame, 89.1 parts by weight of lactose for direct hitting (Pharmacose DCL14 manufactured by DMV) and 1.9 parts by weight of polyvinylpyrrolidone (Collidon K30 manufactured by BASF) were mixed with did.
An intraoral quick disintegrating tablet was prepared by treating the mixture of the above drug formulation components and the lubricant and fluidizing agent of Example 1- (4) in the same manner as in Example 1- (4).
When measured in the same manner as in Example 1- (4), the hardness and disintegration time of this intraorally rapidly disintegrating tablet were 57 N and 27 seconds.
(2) Dissolution test The dissolution test was carried out in the same manner as in Example 1- (5) for the intraoral rapidly disintegrating tablet of (1) above. The results are shown in FIG.

Example 10
(1) Preparation of core particles 82 parts by weight of bepotastine besylate and 14 parts by weight of crystalline cellulose (Avicel PH-301 manufactured by Asahi Kasei Co., Ltd.) were charged into a rolling fluidized bed granulator (MP-01 / 03 manufactured by Paulec) Preheating was performed at 45 ° C. and 300 rpm until the product temperature reached 31 ° C. While stirring at the same rotational speed, 57.1 parts by weight of an aqueous solution of 7% hydroxypropylcellulose (HPC-SL manufactured by Nippon Soda Co., Ltd.) was sprayed for about 26 minutes and granulated. After granulation, the air supply temperature in the fluidized bed granulator was set to 70 ° C. and dried until the exhaust temperature reached 45 ° C. to obtain bepotastine besylate-containing core particles.
(2) Example 2- (2) with respect to 120 g of bepotastine besylate-containing core particles of the above (1), which was fluidized using a coating Wurster fluidized bed coating apparatus (SPC 0.5 / 1 manufactured by POWREC). The coating solution was sprayed until the coverage ratio (ratio of the coating layer to the core particles) reached 70 w / w% to obtain 184 g of coated particles having an average particle diameter of 163 μm.
(3) Preparation of intraoral rapidly disintegrating tablet 7.2 parts by weight of the coated particles of (2) above, 1.3 parts by weight of menthol / Avicel trituration of Example 5- (3), 0 part of Aspartame manufactured by Ajinomoto Co., Inc. 5 parts by weight, 89.1 parts by weight of lactose for direct hitting (Rockit Pearlitol 100SD) and 1.9 parts by weight of polyvinylpyrrolidone (BASF Kollidon K30) were mixed to obtain a drug formulation component.
An intraoral quick disintegrating tablet was prepared by treating the mixture of the above drug formulation components and the lubricant and fluidizing agent of Example 1- (4) in the same manner as in Example 1- (4).
When measured in the same manner as in Example 1- (4), the hardness and disintegration time of this intraorally rapidly disintegrating tablet were 58 N and 28 seconds.
(4) Dissolution test The dissolution test was carried out in the same manner as in Example 1- (5) for the intraoral rapidly disintegrating tablet of (3) above. The results are shown in FIG.

Example 11
(1) Preparation of intraorally rapidly disintegrating tablet 7.2 parts by weight of coated particles of Example 10- (2), 1.3 parts by weight of menthol / Avicel trituration of Example 5- (3), manufactured by Ajinomoto Co., Inc. 0.5 parts by weight of aspartame, 89.1 parts by weight of lactose for direct hitting (Pharmacose DCL14 manufactured by DMV) and 1.9 parts by weight of polyvinylpyrrolidone (Collidon K30 manufactured by BASF) were mixed to obtain a drug formulation component.
An intraoral quick disintegrating tablet was prepared by treating the mixture of the above drug formulation components and the lubricant and fluidizing agent of Example 1- (4) in the same manner as in Example 1- (4).
When measured in the same manner as in Example 1- (4), the hardness and disintegration time of this intraorally rapidly disintegrating tablet were 57 N and 20 seconds.
(2) Dissolution test The dissolution test was carried out in the same manner as in Example 1- (5) for the intraoral rapidly disintegrating tablet of (1) above. The results are shown in FIG.

Example 12
(1) Preparation of core particles 85 parts by weight of bepotastine besylate and 15 parts by weight of crystalline cellulose (Asahi Kasei Co., Ltd., Avicel PH-102) were charged into a high-speed agitation granulator (ultra-compact high-speed mixer manufactured by Fukae Pautech). Premixed for 1 minute. While stirring this at 50 ° C. and 850 rpm, 30 g of purified water was added and granulated for about 10 minutes. After granulation, it was dried at 45 ° C. for 3 hours with a box dryer to obtain bepotastine besylate-containing core particles having an average particle size of 237 μm.
(2) Example 2- (2) with respect to 150 g of bepotastine besylate-containing core particles of the above (1) fluidized by using a coating Wurster fluidized bed coating apparatus (SPC 0.5 / 1 manufactured by POWREC). The coating solution was sprayed until the coverage (ratio of the coating layer to the core particles) was 40 w / w%, to obtain 185 g of coated particles having an average particle diameter of 275 μm.
(3) Preparation of externally added part granules Using a fluidized bed granulator (MP-10 manufactured by Paulek), 38.5 parts by weight of D-mannitol (manufactured by Nikken Kasei Co., Ltd.) in a fluidized state By spraying 30 parts by weight of a mixed aqueous solution of 3 w / w% polyvinylpyrrolidone (Collidon K30 manufactured by BASF) and 1.7 w / w% hydroxypropylcellulose (HPC-SL manufactured by Nippon Soda Co., Ltd.), and then drying. External granules were prepared.
(4) Preparation of intraorally rapidly disintegrating tablet 5.5 parts by weight of the coated particles of (2) above, 1.3 parts by weight of menthol avicel trituration of Example 5- (3), external parts of (3) above 92.2 parts by weight of granules, 0.5 parts by weight of aspartame manufactured by Ajinomoto Co., Inc., and 0.5 parts by weight of magnesium stearate (manufactured by Tyco Healthcare) were mixed to obtain a drug formulation component.
The above drug prescription ingredients are tableted with a rotary tableting machine using a tablet of 300 mg, diameter 10 mm, 13 mmR with a tableting pressure of 100 kg / kg, and treated with ethanol as in Example 1- (4). Thus, an intraoral rapidly disintegrating tablet was produced.
When measured in the same manner as in Example 1- (4), the hardness and disintegration time of this intraorally rapidly disintegrating tablet were 50 N and 15 seconds. Moreover, the disintegration time by the disintegration test method (vertical motion: 29-32 reciprocations / min; 37 ° C; water) prescribed in the Japanese Pharmacopoeia (14th revision) was 78 seconds.
(5) Dissolution test The dissolution test was carried out in the same manner as in Example 1- (5) for the intraorally rapidly disintegrating tablet of (4) above. The results are shown in FIG.

Regarding the prescription drug prescription component in Example 1, the tablet of the prescription drug component obtained by tableting, and the intraorally rapidly disintegrating tablet treated with ethanol, the 14th revised Japanese Pharmacopoeia dissolution test method 2 (solvent: The graph which shows the elution test result of bepotastine besylate in water). For the drug prescription component before tableting in Example 2, the tablet of the drug prescription component obtained by tableting and the intraoral rapidly disintegrating tablet treated with ethanol, the 14th revised Japanese Pharmacopoeia dissolution test method 2 (solvent: The graph which shows the elution test result of bepotastine besylate in water). For the drug prescription components before tableting in Example 3, the tablets of the drug prescription components obtained by tableting and the intraorally rapidly disintegrating tablets treated with ethanol, the 14th revised Japanese Pharmacopoeia dissolution test method 2 (solvent: The graph which shows the elution test result of diltiazem hydrochloride in water. The graph which shows the dissolution test result of the diltiazem hydrochloride in the 14th revision Japanese Pharmacopoeia dissolution test 2nd method (solvent: water) about the intraoral quick disintegrating tablet in Example 4. FIG. The graph which shows the dissolution test result of the bepotastine besylate in the 14th revision Japanese Pharmacopoeia dissolution test 2nd method (solvent: water) about the intraoral quick disintegrating tablet in Example 5. FIG. The graph which shows the dissolution test result of bepotastine besylate in the 14th revision Japanese Pharmacopoeia dissolution test 2nd method (solvent: water) about the intraoral quick disintegrating tablet in Example 6. FIG. The graph which shows the dissolution test result of the bepotastine besylate in the 14th revision Japanese Pharmacopoeia dissolution test 2nd method (solvent: water) about the intraoral quick disintegrating tablet in Example 7. FIG. The graph which shows the dissolution test result of the bepotastine besylate in the 14th revision Japanese Pharmacopoeia dissolution test 2nd method (solvent: water) about the intraoral quick disintegrating tablet in Example 8. FIG. The graph which shows the dissolution test result of the bepotastine besylate in the 14th revision Japanese Pharmacopoeia dissolution test 2nd method (solvent: water) about the intraoral quick disintegrating tablet in Example 9. FIG. The graph which shows the dissolution test result of the bepotastine besylate in the 14th revision Japanese Pharmacopoeia dissolution test 2nd method (solvent: water) about the intraoral quick disintegrating tablet in Example 10. FIG. The graph which shows the dissolution test result of the bepotastine besylate in the 14th revision Japanese Pharmacopoeia dissolution test 2nd method (solvent: water) about the intraoral quick disintegrating tablet in Example 11. FIG. The graph which shows the dissolution test result of the bepotastine besylate in the 14th revision Japanese Pharmacopoeia dissolution test 2nd method (solvent: water) about the intraoral quick disintegrating tablet in Example 12. FIG.

Claims (20)

A mixture containing drug-containing fine particles coated with a water-insoluble coating agent soluble in an alcohol solvent and an excipient insoluble in an alcohol solvent is compression molded, and the resulting compression molded product is treated with the alcohol solvent. Thus, a method for producing a compression-molded preparation in which drug elution is controlled by regenerating the elution control function of the coated drug-containing fine particles lost by the compression molding inside the compression-molded product. The method according to claim 1, wherein the compression-molded preparation further contains a binder and a lubricant soluble in an alcohol solvent. The drug content in the compression-molded preparation is 0.1 to 70 w / w%, the content of the coating agent that is soluble in the alcohol solvent and water-insoluble is 0.02 to 10 w / w%, and is insoluble in the alcohol solvent. The content of the agent is 1 to 98 w / w%, the content of the binder soluble in the alcohol solvent is 0.1 to 30 w / w%, and the content of the lubricant is 0.01 to 10 w / w%. The method according to claim 2. An alcohol-based solvent-soluble and water-insoluble coating agent dissolves 20 mg or more in 1 ml of alcohol solvent (25 ° C.) and dissolves only 1 mg or less in 1 ml of water (25 ° C.). The solvent-insoluble excipient dissolves only 1 mg or less in 1 ml of alcohol solvent (25 ° C), and the binder soluble in alcohol solvent is 20 mg in 1 ml of alcohol solvent (25 ° C). The method according to claim 3, which dissolves as described above. The alcohol-based solvent-soluble and water-insoluble coating agent is one or more selected from the group consisting of a cellulose-based coating agent and an acrylic acid-based coating agent, and the alcohol-insoluble solvent-insoluble excipient is a water-soluble saccharide. The method according to claim 4, wherein the binder soluble in the alcohol solvent is one or more selected from the group consisting of cellulose-based and polyvinyl-based binders. Soluble and water-insoluble coating agent in alcohol solvent is ethyl cellulose, methacrylic acid / methyl methacrylate copolymer, methacrylic acid / ethyl acrylate copolymer, methyl methacrylate / ethyl acrylate copolymer, methacrylic 1 or 2 selected from the group consisting of methyl methacrylate / ethyl acrylate / (β-methacryloyloxyethyl) trimethylammonium chloride copolymer and methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer And the one or more selected from the group consisting of mannitol, xylitol, erythritol, maltitol, sorbitol, lactose, sucrose, maltose and trehalose is an alcohol-soluble solvent. The method of claim 5, wherein the solubility of the binder is one or more selected from the group consisting of polyvinyl pyrrolidone and hydroxypropyl cellulose. The method according to claim 6, wherein the alcohol solvent is ethanol. The method according to claim 2, wherein the compression-molded preparation has a porosity of 20 to 50% and the drug-containing fine particles have an average particle size of 350 µm or less. The method according to claim 8, wherein the compression molding is performed at 5 to 30 MPa, the hardness before treatment with an alcohol solvent is 2 to 15 N, and the hardness after treatment with an alcohol solvent is 20 to 80 N. The method according to claim 9, wherein the compression molding is performed by any of the following methods.
(1) The compression molding of the mixture containing the lubricant and the fluidizing agent and the compression molding of the mixture containing the drug-containing fine particles and the excipient insoluble in the alcohol solvent are alternately performed.
(2) Compression molding while spraying lubricant powder
(3) Chamfering through an anti-stick film or
(4) A small amount of lubricant that does not affect the disintegration / dissolvability of the compression-molded preparation is added to the mixture containing the drug-containing fine particles and the excipient insoluble in the alcohol solvent, and then molded. An intraoral quick disintegrating tablet containing the following components, having a hardness of 20 N or more and a porosity of 20 to 50%.
(1) Drug-containing fine particles coated with a water-insoluble coating agent that is soluble in an alcohol solvent
(2) A mixture containing a water-soluble binder soluble in an alcohol solvent and a water-soluble saccharide The mixture containing a water-soluble binder soluble in an alcohol solvent and a water-soluble saccharide is a granulated product containing a water-soluble saccharide granulated using a water-soluble binder soluble in an alcohol solvent. 11. Orally rapidly disintegrating tablet according to 11. The content of the drug in the intraoral quick disintegrating tablet is 0.1 to 70 w / w%, the content of the water-insoluble coating agent soluble in the alcohol solvent is 0.02 to 10 w / w%, the content of the water-soluble saccharide The intraorally rapidly disintegrating tablet according to claim 11 or 12, wherein the amount is 1 to 98 w / w%, and the content of a water-soluble binder soluble in an alcohol solvent is 0.1 to 30 w / w%. A water-insoluble coating agent that is soluble in an alcohol solvent dissolves 20 mg or more in 1 ml of an alcohol solvent (25 ° C.) and dissolves only 1 mg or less in 1 ml of water (25 ° C.). A saccharide dissolves only 1 mg or less in 1 ml of an alcoholic solvent (25 ° C.) and dissolves 20 mg or more in 1 ml of water (25 ° C.), and is soluble in an alcoholic solvent. The orally rapidly disintegrating tablet according to claim 13, wherein 20 mg or more is dissolved in 1 ml of an alcohol solvent (25 ° C) and 1 ml of water (25 ° C). The alcohol-based solvent-soluble and water-insoluble coating agent is one or more selected from the group consisting of a cellulose-based coating agent and an acrylic acid-based coating agent, and the water-soluble binder soluble in the alcohol-based solvent is a cellulose-based and The intraoral quick disintegrating tablet according to claim 14, wherein the tablet is one or more selected from the group consisting of polyvinyl binders. Soluble and water-insoluble coating agent in alcohol solvent is ethyl cellulose, methacrylic acid / methyl methacrylate copolymer, methacrylic acid / ethyl acrylate copolymer, methyl methacrylate / ethyl acrylate copolymer, methacrylic 1 or 2 selected from the group consisting of methyl methacrylate / ethyl acrylate / (β-methacryloyloxyethyl) trimethylammonium chloride copolymer and methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer The water-soluble saccharide is one or more selected from the group consisting of mannitol, xylitol, erythritol, maltitol, sorbitol, lactose, sucrose, maltose and trehalose, and is soluble in an alcohol solvent. There polyvinylpyrrolidone and 1 or larger than 2, claim 15 intraorally rapidly disintegrating tablet according selected from the group consisting of hydroxypropyl cellulose. The intraoral rapidly disintegrating tablet according to claim 11 or 12, wherein the drug-containing fine particles have an average particle size of 350 µm or less. The drug produces an unpleasant taste, and is based on the dissolution test method method 2 (paddle rotation speed: 50 rpm; 37 ° C .; water) defined in the Japanese Pharmacopoeia (14th revision). 18. The intraoral rapidly disintegrating tablet according to claim 17, wherein the drug dissolution rate is 30% or less in 1 minute after the start of dissolution and the disintegration time in the oral cavity is within 60 seconds. The intraoral rapidly disintegrating tablet according to claim 18, wherein the drug is an antiallergic agent. The intraorally rapidly disintegrating tablet according to claim 19, wherein the drug is bepotastine besylate.

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