JP2003055197A - Functional particle-containing intraoral disintegrative preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a functional particle-containing intraoral disintegrative preparation, by which the preparation having a good oral touch, hardly permitting the proliferation of saprophytes and capable of being easily dried is obtained without damaging the functional particles in a compression process and without causing a difference in the contents of the functional particles between the preparations. SOLUTION: The method for producing the functional particle-containing intraoral disintegrative preparation is characterized by filling a mold with an aqueous dispersion containing (a) a dispersing agent having a dispersion- maintaining factor of >=75% and a viscosity of <=100 mPa.s, when homogeneously added to water in a concentration of 1 wt.%, (b) a water-soluble saccharide, and (c) the functional particles, and then removing water.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an orally rapidly disintegrating preparation containing functional particles and a method for producing the same.

[0002]

2. Description of the Related Art Solid preparations for oral administration have hitherto been
Formulations such as fine granules, granules, tablets and capsules are used. However, these dosage forms have problems that they are too small and difficult to handle for infants, the elderly, and critically ill patients, and that swallowing is difficult. Various sex preparations are being developed.

On the other hand, for the purpose of improving the therapeutic effect and improving patient compliance, preparations having various functions such as controlling the release rate of the drug from the preparation and masking the taste of the drug contained in the preparation have been studied. It is also used in clinical settings.

Therefore, in addition to having such a function,
Compared with conventional preparations for oral administration, for the development of a preparation with improved ingestability, which has a suitable size for infants, the elderly, and critically ill patients, is easy to handle, and is easy to swallow. It has been proposed to develop a formulation in which particles having the above-mentioned functions (functional particles) are incorporated into an orally rapidly disintegrating formulation.

Regarding the method for producing a rapidly disintegrating preparation in the oral cavity, the method for producing such a preparation is described in, for example, Japanese Patent Publication No. 7-503.
No. 237, JP-A-5-271054, and JP-A-8-29.
No. 1051 and the like.

Japanese Patent Publication No. 7-503237 includes a drug which is difficult to compress by compression-molding a drug together with a fusible binder and melting and solidifying the binder in the obtained tablets. , Soft, chewable and rapidly disintegrating porous tablets are described.

[0007] JP-A-5-271054 discloses that a mixture of a drug, a saccharide, and a water content such that the particle surface of the saccharide is moistened is tableted to give an appropriate strength and fast dissolution and disintegration in the oral cavity. It is described that an orally soluble tablet having properties is obtained.

[0008] JP-A-8-291051 discloses a tableting step in which a tablet material in a dry state containing a drug, a water-soluble binder and a water-soluble excipient is pressure-molded under a low pressure; There is described a method for producing a fast-dissolving tablet, which comprises a moistening step for absorbing moisture and a drying step for drying the moistened tablet.

However, since all of these methods include a step of compression molding, if an attempt is made to produce an orally rapidly disintegrating preparation containing the functional particles by using these methods, the functional particles are damaged by the compression. Therefore, it is impossible to obtain a preparation that maintains the function of the functional particles.

On the other hand, a method for producing a preparation that rapidly disintegrates in the oral cavity without the above-mentioned compression molding step is as follows:
For example, JP-A-53-44619 and WO93 / 1276.
9, JP-A-9-502622, JP-A-11-1164
No. 66 etc., in these methods, a drug, a water-soluble natural polymer substance (gelatin, agar, xanthan gum, guar gum, dextrin, etc.), a solution or dispersion liquid containing a saccharide, etc. is filled in a template, It produces a formulation that is dried and rapidly disintegrates in the oral cavity.

However, since the preparations obtained by these methods use natural polymer substances, various bacteria are easily proliferated, and when the polymer substances are dissolved in water, the viscosity is high and the towing in the oral cavity is difficult. Because of its threadiness, it feels bad to take.

[0012] Furthermore, if an attempt is made to produce a preparation containing functional particles by these methods, the functional particles will settle or float in the dispersion liquid during the production process. There is also a problem that the amount varies, and even in the same preparation, a nonuniform preparation having a biased distribution of functional particles can be obtained.

Further, in Japanese Patent Laid-Open No. 11-116464,
Ventilation at room temperature from a cream composition which is an aqueous suspension obtained by mixing a drug, a saccharide having a water solubility of 30 g / 100 g or less, and a saccharide having a water solubility of 30 g / 100 g or more with water. It is described that moisture is removed by drying or the like to obtain a rapidly soluble solid preparation. In this method, neither compression molding nor natural polymer is used, but since it takes a long time to dry and the suspension becomes a creamy composition with high stirring resistance, a formulation containing functional particles by this method is used. However, it is difficult to uniformly disperse the functional particles.

[0014]

Therefore, these problems have been solved, the functional particles are not damaged by compression molding, the content of the functional particles does not vary between the preparations, and the feeling of ingestion is good. , As a result of intensive research to develop an orally rapidly disintegrating preparation containing functional particles, in which various bacteria do not easily propagate and the drying process is easy, a high dispersion is maintained when it is evenly contained in water. When a functional particle-containing rapidly disintegrating preparation containing an aqueous dispersion containing a dispersant, a water-soluble saccharide, and functional particles, which produces a high rate and low viscosity, is dissolved, the above-mentioned problems are solved. Was discovered, and the present invention has been completed.

[0015]

The present invention comprises (a) 1% by weight.
When it is uniformly contained in water at 25 ° C., it contains a dispersant having a dispersion maintenance rate at 25 ° C. of about 75% or more and a viscosity of about 100 mPa · s or less, (b) a water-soluble saccharide, and (c) functional particles. The present invention relates to a method for producing an orally rapidly disintegrating preparation containing functional particles, which comprises filling a mold with an aqueous dispersion; and removing water.

The orally rapidly disintegrating preparation containing functional particles obtained by this method has the following characteristics. 1. Since compression molding is not included in the manufacturing process,
The function of the functional particles contained is maintained without being impaired. Since a dispersant having a high dispersion maintenance rate of about 75% or more at 25 ° C. is used when it is uniformly contained in water at 2.1% by weight, only a small amount of the dispersant is used. Thus, regardless of the specific gravity of the functional particles, water repellency, etc., the dispersion state of the functional particles in the aqueous dispersion is maintained in good condition even when filling the mold or removing the water after filling. There is no variation in the content of functional particles between
A formulation in which the functional particles are evenly distributed is obtained even in the formulation. Further, since the dispersant having a high dispersion maintenance rate is used, the amount of the dispersant used can be small. When uniformly dispersed in water at 3.1% by weight, a dispersant having a low viscosity of about 100 mPa · s or less at 25 ° C. is used, so that the stirring resistance of the aqueous dispersion is low and the dispersion is uniform. It is easy to be formed and has no spinnability even after disintegration in the oral cavity, and the manufactured preparation has a good feeling of ingestion. 4. Since it does not contain a large amount of natural polymer substances, it is difficult for bacteria to propagate.

The functional particles to be contained in the rapidly disintegrating buccal preparation containing the functional particles produced by the method of the present invention are not limited to simply containing the drug but controlling the release of the contained drug. Desired drug that has been subjected to treatments such as coating, microsphere formation and matrix formation for the purpose of (sustained release, gastric solubility, enteric coating, colon targeting, etc.), taste masking of the drug itself, shading, moisturizing, etc. It means any particles that contain, and is not particularly limited as long as it does not dissolve in the aqueous dispersion during production.

The particle size of such functional particles is not particularly limited, but the average particle size is about 45 to 250 μm from the viewpoint that there is no rough feeling even after disintegration in the oral cavity during administration.
Are preferred. Particularly, the average particle size is 50 to 200 μm,
The ratio of the functional particles having a particle diameter of 250 μm or more to 10% or less of the total amount of the functional particles can be preferably used.

Specific examples of the functional particles include coated particles in which a coating layer is provided around the drug-containing core particles for the above-mentioned purpose, microspheres or matrix in which the drug is encapsulated in a water-insoluble substance. Examples thereof include particles. The functional particles to be contained in the rapidly disintegrating oral cavity preparation containing the functional particles by the method of the present invention and the method for producing the same will be described in detail later.

The dispersant which can be used in the method of the present invention has a dispersion retention rate at 25 ° C. of not less than about 75% and a viscosity of not more than about 100 mPa · s when uniformly contained in water at 1% by weight. It is an agent.

The dispersion maintenance rate in the method of the present invention is 1
When nifedipine particles (average particle size 50 to 100 μm, solubility in water at 25 ° C. of 1 mg / ml or less) are uniformly dispersed in a liquid containing a weight% dispersant, and allowed to stand for 5 hours, It is a value indicating how much the dispersed state can be maintained as compared with the case where the dispersed state is completely maintained. Specifically, 1 part by weight of nifedipine particles are uniformly dispersed in 99 parts by weight of a liquid containing 1% by weight of a dispersant, and 50 ml of the resulting dispersion is added to a Nessler tube (inner diameter:
22 mm) and let stand for 5 hours (25 ° C). After standing still,
1 ml of the dispersion is sampled from the upper and lower central portions of the solution, and the concentration of nifedipine particles is measured. Theoretical particle concentration of the dispersion (ie
When the ratio (particle amount / dispersion amount) is 100, the ratio (%) of the particle concentration in the central portion of the dispersion after standing is defined as the dispersion maintenance rate.

When 1% by weight of the dispersant which can be used in the method of the present invention is uniformly contained in water, the dispersion maintenance ratio is about 75% or more, preferably about 90% or more under the above measurement conditions.

Further, one dispersant which can be used in the method of the present invention is
The viscosity (25 ° C.) measured by a B-type viscometer when it is uniformly contained in water by weight% is about 100 mPa · s or less, preferably about 50 mPa · s or less.

In the method of the present invention, any dispersant can be used as long as it has the above dispersion maintenance ratio and viscosity.

Examples of such a dispersant include a complex composed of fine particles of a water-insoluble substance and a water-soluble substance. In particular, a water dispersion containing fine particles of a water-insoluble substance and a water-soluble substance is dried. The complex obtained by

As the water-insoluble substance, a water-insoluble fibrous substance can be mentioned, and in particular, microcrystalline cellulose can be mentioned. The fine particles of the water-insoluble substance preferably have an average particle diameter of 30 μm or less,
It is particularly preferably 15 μm or less, most preferably 10 μm or less.

Examples of the water-soluble substance include locust bean gum, guar gum, tamarind gum, quince seed gum, karaya gum, gum arabic, tragacanth gum, ghatti gum, arabinogalactan, agar, carrageenan, alginic acid and its salts, furceleran, pectin. , Quince, xanthan gum, curdlan, pullulan, dextran, gellan gum, gelatin, cellulose derivatives such as sodium carboxymethyl cellulose, sodium polyacrylate, water-soluble starch derivatives such as sodium chondroitin sulfate, sodium starch glycolate, starch hydrolyzate, dextrin , Glucose, fructose, xylose, sorbose, sucrose, lactose, maltose, isomerized sugar, coupling sugar, palatinose, neo Yuga, reduced starch saccharification candy, lactulose, polydextrose, fructooligosaccharides,
Examples include galactooligosaccharides, xylitol, mannitol, maltitol and sorbitol. Of these, sodium carboxymethyl cellulose, karaya gum, xanthan gum, and dextrin are preferable.

Specific examples of the dispersant include microcrystalline cellulose coated with sodium carboxymethylcellulose (for example, Avicel RC591NF and Avicel CL611, both manufactured by Asahi Kasei), microcrystalline cellulose coated with karaya gum and dextrin (for example, Avicel). RC-N81, manufactured by Asahi Kasei), microcrystalline cellulose coated with xanthan gum and dextrin (Avicel RC-N30, manufactured by Asahi Kasei), JP-A-7-
70365, JP-A-7-102113, JP-A-7-17
3332, JP-A-7-268129, JP-A-8-151
481, the composition comprising microcrystalline cellulose and a water-soluble substance described in JP-A-9-3243, and the like. Among them, microcrystalline cellulose coated with sodium carboxymethyl cellulose is most preferable.

In the method of the present invention, a water-soluble saccharide is contained in the aqueous dispersion in addition to the above-described dispersant and functional particles. In addition to having such properties, it is possible to rapidly disintegrate in the oral cavity, and further, it is possible to obtain effects such as no spinnability after disintegration in the oral cavity.

As the water-soluble saccharide in the method of the present invention, a saccharide having a solubility in water of 5% or more at 25 ° C. can be used, and such water-soluble saccharides can be used alone or in combination. Specifically, glucose, fructose, saccharose, lactose, maltose, mannitol,
One or more selected from xylitol, sorbitol, trehalose and erythritol can be used, and among them, lactose, maltose, mannitol,
One or more selected from erythritol can be preferably used. When two or more kinds of sugars are used in combination, preferred combinations are a combination of lactose and mannitol, a combination of mannitol and erythritol, a combination of lactose and erythritol, and a combination of mannitol and maltose.

In the method of the present invention, if desired, additives may be used in addition to the above-mentioned functional particles, dispersant, and water-soluble saccharide. Such additives are not particularly limited as long as they do not adversely affect the ingestibility, hardness and disintegration time of the manufactured preparation, and any additive can be used. Specifically, sweeteners such as aspartame, saccharin sodium, saccharin, stevia, glycyrrhizin, and acesulfame potassium; citric acid,
Acidulants such as tartaric acid and malic acid; menthol, peppermint oil, peppermint, orange, lemon lime, lemon,
Fragrances such as strawberries; caramel, Anato extract pigment, β-
Colorants such as carotene and beet red can be mentioned.

In order to produce an orally rapidly disintegrating preparation containing functional particles by the method of the present invention, first, the functional particles, the water-soluble saccharide and the dispersant are added to water to prepare an aqueous dispersion. The blending ratio and blending amount of the functional particles, water-soluble saccharides, and dispersant to be blended are appropriately determined according to the type of drug contained in the functional particles, the intended use of the functional particle-containing rapidly disintegrating buccal preparation, etc. to be produced. It can be, but with respect to the total weight of the aqueous dispersion,
The content of the dispersant in the aqueous dispersion is preferably 0.05 to
It is 2.0% by weight, more preferably 0.1 to 0.8% by weight. The content of the water-soluble saccharide is 30 to 1000 parts by weight, preferably 30 to 500 parts by weight, more preferably about 50 to 400 parts by weight, and the content of the functional particles is 1 part by weight of the dispersant. 1 to 500 parts by weight of the dispersant
Parts by weight, preferably about 10 to 200 parts by weight. The order of addition is not particularly limited as long as a uniform aqueous dispersion is finally obtained. Preferably, after dispersing the dispersant in water, the functional particles and the water-soluble saccharide are added. The addition to water is preferably performed with stirring. As a stirring method, a magnetic stirrer, propeller stirring, homomixer, homogenizer or the like can be used. It is preferable that the water-soluble saccharide is not completely dissolved in the aqueous dispersion, but it may be completely dissolved.

Next, the prepared aqueous dispersion is filled in a mold.
As the mold that can be used, any one can be used as long as it has a function as a mold, for example, made of metal,
A resin film or the like can be used. Preferably, a resin film sheet having multiple depressions for storing tablets, such as used in PTP packaging, can be used. PTP as above as template
When using a resin film sheet having a large number of dents for storing tablets for packaging, after filling the water dispersion liquid, water is removed by drying or the like, and then a cover sheet for PTP packaging is attached, The product form can be used as it is. As the resin film sheet, a sheet of polypropylene, polyvinyl chloride, polyvinylidene chloride or the like can be used. The shape of the mold is not particularly limited, and examples thereof include those having a desired size, for example, those having a cylindrical recess having a diameter of 5 to 20 mm and a height of 2 to 10 mm. Such a mold is filled with the aqueous dispersion prepared above and then water is removed from the aqueous dispersion. As a method for removing water, any method can be used as long as it does not affect each component contained in the aqueous dispersion, but for example, drying such as natural drying, ventilation drying, reduced pressure drying, and freeze drying. A method can be mentioned, and freeze-drying is preferable. The freeze-drying may be carried out by freezing the aqueous dispersion filled in the mold and placing it under reduced pressure to sublimate the water according to a conventional method, and it can be easily carried out using a known freeze-drying machine.

The orally rapidly disintegrating preparation containing functional particles of the present invention prepared by the above method has a dispersion retention rate at 25 ° C. when (a) 1 wt% is uniformly contained in water. It contains a dispersant having a viscosity of about 75% or more and a viscosity of about 100 mPa · s or less, (b) a water-soluble saccharide, and (c) the functional particles. In the present formulation, the content of the dispersant is about 0.07 to 4% by weight, preferably about 0.07 to 2.8% by weight, more preferably about 0.14 to 1.12% by weight. The amount of water-soluble saccharides to be added is 3 with respect to 1 part by weight of the dispersant.
0 to 1000 parts by weight, preferably 30 to 500 parts by weight,
It is more preferably about 50 to 400 parts by weight, and the amount of the functional particles to be blended is 1 to 500 parts by weight, preferably about 10 to 200 parts by weight, relative to 1 part by weight of the dispersant. The hardness of this preparation is 10 N or higher, preferably about 19.6 N or higher, more preferably about 29.4 N or higher (when measuring hardness with a tablet tester (Model 6D, manufactured by Freund Industries)). In addition, the disintegration time of the 13th revised Japanese Pharmacopoeia disintegration test (test solution: water) of this preparation is preferably about 60 seconds or less, more preferably about 30 seconds or less,
The oral disintegration time is preferably about 60 seconds or less, more preferably about 30 seconds or less, and most preferably about 20 seconds or less.

The functional particles contained in the rapidly disintegrating buccal preparation containing the functional particles in the method of the present invention are as defined above, but will be described in detail below. The functional particles can contain any drug as long as it is a drug that can be orally administered, and the type thereof is not particularly limited. The following are examples of drugs that can be contained.

(1) Antipyretic analgesic and anti-inflammatory agent (for example, indomethacin, acetylsalicylic acid, diclofenac sodium, ketoprofen, ibuprofen, mefenamic acid, azulene, phenacetin, isopropylantipyrine, acetaminophenone, benzadac, phenylbutazone, flufenamic acid, sodium salicylate) , Salicylamide, sazapyrine, etodolac, etc.); (2) Steroid anti-inflammatory agents (eg, dexamethasone, hydrocortisone, prednisolone, triamcinolone, etc.); (3) Anti-ulcer agents (eg, ecabet sodium, enprostil, sulpiride, hydrochloric acid) Cetraxate, gefarnate, irsogladine maleate, cimetidine, ranitidine hydrochloride, famotidine, nizatidine, roxatidine acetate hydrochloride Omeprazole, etc. lansoprazole); (4) coronary vasodilators (nifedipine, isosorbide dinitrate, diltiazem hydrochloride, trapidil, dipyridamole,
Dilazep hydrochloride, verapamil, nicardipine, nicardipine hydrochloride, verapamil hydrochloride, etc.); (5) peripheral vasodilators (eg, ifenprodil tartrate, cinepazide maleate, cyclandrate, cinnarizine, pentoxifylline);

(6) Antibiotics (eg ampicillin,
Amoxicillin, cephalexin, erythromycin ethylsuccinate, bacampicillin hydrochloride, minocycline hydrochloride, chloralphenicol, tetracycline, erythromycin, ceftazidime, cefuroxime sodium,
(7) Synthetic antibacterial agents (for example, nalidixic acid, pyromidic acid, pipemidic acid trihydrate, enoxacin, sinoxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, sulfa). (8) Antiviral agents (eg, acyclovir, ganciclovir, etc.); (9) Antispasmodic agents (eg, propantheline bromide, atropine sulfate, oxapium bromide, timepidium bromide, bromide). Butylscopolamine, trospium chloride, butropium bromide, N-methylscopolamine methylsulfate, methyloctatropine bromide, etc .; (10) Antitussives (eg, tipepidine hibenzate, methylephedrine hydrochloride, codeine phosphate, tranilast,
Dextromethorphan hydrobromide, Dimemorphan phosphate, Clobutinol hydrochloride, Hominoben hydrochloride, Benproperin phosphate, Epradinone hydrochloride, Clofedanol hydrochloride, Ephedrine hydrochloride, Noscapine, Pentoxiverine citrate, Oxelazine citrate, Isoaminyl citrate, etc. );

(11) Solvent release agent (eg, bromhexine hydrochloride, carbocysteine, ethylcysteine, methylcysteine hydrochloride, etc.); (12) Bronchodilator (eg, theophylline, aminophylline, sodium cromoglycate, procaterol hydrochloride, trihydrochloride). Methoquinol, Diprophylline, Salbutamol Sulfate, Chlorprenaline Hydrochloride, Formoterol Fumarate, Orciprenaline Sulfate, Pirbuterol Hydrochloride, Hesoprenaline Sulfate, Vitorterol Mesylate,
Clenbuterol hydrochloride, terbutaline sulfate, mabuterol hydrochloride, fenoterol hydrobromide, methoxyphenamine hydrochloride, etc.); (13) Cardiotonic agents (for example, dopamine hydrochloride, dobutamine hydrochloride, docarpamine, denopamine, caffeine, digoxin, digitoxin, ubidecalenone, etc.); (14) Diuretics (eg, furosemide, acetazolamide, trichlormethiazide, meticlotiazide, hydrochlorothiazide, hydroflumethiazide, ethiazide,
Cyclopenthiazide, spironolactone, triamterene, fluorothiazide, pyrethanide, mefurside, ethacrynic acid, azosemide, clofenamide, etc .; (15) Muscle relaxants (eg, chlorphenesin carbamic acid, tolperisone hydrochloride, eperisone hydrochloride, tizanidine hydrochloride, mephenesin, Chlorzoxazone, fenprobamate, methocarbamol, chlormezanone, pridinol mesylate, afloqualone, baclofen, dantrolene sodium etc.);

(16) Cerebral metabolism improving agents (for example, nicergoline, meclofenoxate hydrochloride, tartileline, etc.); (17) Minor tranquilizers (for example, oxazolam, diazepam, clothiazepam, medazepam, temazepam, fludiazepam, meprobamate, nitrazepam, (18) Major tranquilizers (eg, sulpiride, clocapramine hydrochloride, zotepine, chlorpromazine, haloperidol, etc.); (19) β-blockers (eg, bisoprolol fumarate, pindolol hydrochloride, probranolol hydrochloride, carteolol hydrochloride, tartaric acid) Metoprolol, labetanol hydrochloride, acebutolol hydrochloride, bufetrol hydrochloride, alprenolol hydrochloride, arotinolol hydrochloride, oxprenolol hydrochloride Nadolol, hydrochloric bucumolol, hydrochloric indenolol, timolol maleate, hydrochloride befunolol,
(20) antiarrhythmic agents (eg, procainamide hydrochloride,
Disopyramide, ajmaline, quinidine sulfate, aplindine hydrochloride, propaphenone hydrochloride, mexiletine hydrochloride, azimilide hydrochloride, etc.);

(21) A therapeutic agent for gout (for example, allopurinol, probenecid, colchicine, sulfinpyrazone, benzbromarone, bucolome, etc.); (22) Anticoagulant (for example, ticlopidine hydrochloride,
Dicoumarol, Warfarin potassium, (2R, 3R)
-3-acetoxy-5- [2- (dimethylamino) ethyl] -2,3-dihydro-8-methyl-2- (4-methylphenyl) -1,5-benzothiazepine-4 (5H)
-On-maleate, etc.); (23) Thrombolytic agent (eg, methyl (2E, 3Z)-
3-benzylidene-4- (3,5-dimethoxy-α-methylbenzylidene) -N- (4-methylpiperazine-1)
-Yl) succinamate / hydrochloride, etc.); (24) Agent for liver diseases (for example, (±) r-5-hydroxymethyl-t-7- (3,4-dimethoxyphenyl))
-4-oxo-4,5,6,7-tetrahydrobenzo [b] furan-c-6-carboxylic acid lactone and the like); (25) Antiepileptic agent (eg, phenytoin, sodium valproate, metalpital, carbamazepine, etc.) ;

(26) Antihistamines (for example, chlorpheniramine maleate, clemastine fumarate, mequitazine, alimemazine tartrate, cyclohebutazine hydrochloride, bepotastine besylate, etc.); (27) Antiemetics (eg diphenidol hydrochloride, metoclopramide, domperi) Don, betahistine mesylate, trimebutine maleate, etc.); (28) antihypertensive agents (eg, dimethylaminoethyl reserpine hydrochloride hydrochloride, resinamine, methyldopa, pralazosin hydrochloride, bunazosin hydrochloride, clonidine hydrochloride, budralazine,
Urapidil, N- [6- [2-[(5-bromo-2-pyrimidinyl) oxy] ethoxy] -5- (4-methylphenyl) -4-pyrimidinyl] -4- (2-hydroxy-1,1- Dimethylethyl) benzenesulfonamide
(29) Hyperlipidemia agents (eg pravastatin sodium, fluvastatin sodium etc.); (30) Sympathomimetics (eg dihydroergotamine mesylate, isoproterenol hydrochloride, etilefrine hydrochloride etc.);

(31) Oral antidiabetic agents (eg, glibengramid, tolbutamide, glymidine sodium, etc.); (32) Oral anticancer agents (eg, marimasat etc.); (33) Alkaloid narcotics (eg, morphine, codeine, cocaine). Etc.); (34) Vitamin preparations (for example, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, folic acid, etc.); (35) Treatments for frequent urination (for example, flavoxate hydrochloride, oxybutynin hydrochloride, terroridine hydrochloride, etc.) (36) Angiotensin converting enzyme inhibitor (for example, imidapril hydrochloride, enalapril maleate, alacepril, delapril hydrochloride, etc.).

As described above, as a specific example of the functional particles, for the purpose of controlling the release of the contained drug, masking the taste of the drug, shading, moisturizing, etc., around the core particle containing the drug. Examples thereof include coated particles provided with a coating layer and microspheres or matrix particles in which a drug is encapsulated in a water-insoluble substance. When the coated particles are used as the functional particles, the component contained in the coating layer may be any as long as it controls the release of the drug contained in the coated particles, masks the taste, shields light, retains moisture, etc. Although those can be used, specifically, coating agents such as water-soluble polymers, water-insoluble polymers, enteric polymers, gastric soluble polymers, and hydrophobic organic compounds can be used.

Examples of the water-soluble polymer include (1) water-soluble cellulose ethers such as methyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose; (2) water-soluble polyvinyl derivatives such as polyvinylpyrrolidone and polyvinyl alcohol; and (3). Examples thereof include alkylene oxide polymers such as polyethylene glycol and polypropylene glycol.

Examples of the water-insoluble polymer include (1) water-insoluble cellulose ether such as ethyl cellulose; and (2) ethyl acrylate / methyl methacrylate / trimethylammonium ethyl methacrylate chloride copolymer (for example, trade name: Examples thereof include water-insoluble acrylic acid-based copolymers such as Eudragit RS, manufactured by Laem Pharma, and methyl methacrylate / ethyl acrylate copolymer (for example, trade name: Eudragit NE30D, manufactured by Laem Pharma).

Examples of enteric polymers include (1) hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate,
Enteric cellulose derivatives such as hydroxymethylethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethyl ethyl cellulose, ethyl hydroxyethyl cellulose phthalate); (2) Styrene / acrylic acid copolymer, methyl acrylate / acrylic acid copolymer, methyl acrylate / methacrylic acid copolymer, butyl acrylate / styrene / acrylic acid copolymer, methacrylic acid / methyl methacrylate copolymer Polymer (for example, trade name: Eudragit L100, Eudragit S, all manufactured by Reem Pharma), methacrylic acid acryl Ethyl copolymer (e.g., trade name: Eudragit L100-55, manufactured frame Pharma AG), enteric acrylic acid-based copolymers such as methyl acrylate-methacrylic acid-octyl acrylate copolymer;
(3) Vinyl acetate / maleic anhydride copolymer, styrene / maleic anhydride copolymer, styrene / maleic acid monoester copolymer, vinyl methyl ether / maleic anhydride copolymer, ethylene / maleic acid Enteric maleic acid such as anhydride copolymer, vinyl butyl ether / maleic anhydride copolymer, acrylonitrile / methyl acrylate / maleic anhydride copolymer, butyl acrylate / styrene / maleic anhydride copolymer Copolymers; (4) Polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate, polyvinyl acetoacetal phthalate, and other enteric polyvinyl derivatives can be mentioned.

Examples of the gastric-soluble polymer are (1) a gastric-soluble polyvinyl derivative such as polyvinyl acetal diethylaminoacetate; and (2) methyl methacrylate.
Examples thereof include gastric-soluble acrylic acid-based copolymers such as butyl methacrylate / dimethylaminoethyl methacrylate copolymer (for example, trade name: Eudragit E, manufactured by Rohm Pharma).

Examples of hydrophobic organic compounds include (1) higher fatty acids such as stearic acid, lauric acid, myristic acid, palmitic acid and behenic acid; (2) lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol. Higher alcohols such as; (3) higher fatty acid triglycerides such as stearic acid triglyceride, myristic acid triglyceride, palmitic acid triglyceride, lauric acid triglyceride; and (4) hydrogenated castor oil, hardened coconut oil, beef tallow, etc. Mention may be made of good natural fats and oils.

In addition to the above coating agent components, the coating layer may further contain various additives such as a colorant, a masking agent, a plasticizer, and a lubricant, if necessary. Examples of such a coloring agent include food coloring, lake coloring, caramel, carotene, anat, cochineal, ferric sesquioxide, and opaque coloring agent OPALUX mainly composed of lake coloring and syrup. it can. Specifically, food red No. 2 and 3,
Edible aluminum lakes such as Yellow No. 4, No. 5, Green No. 3, Blue No. 1, No. 2, Purple No. 1, Anat (a natural pigment derived from Beninoki), carmine (aluminum carminate), pearl essence (mainly guanine) And the like) can be used. As the masking agent, titanium dioxide, precipitated calcium carbonate, calcium hydrogen phosphate, calcium sulfate, etc. can be used. As the plasticizer, in addition to phthalic acid derivatives such as diethyl phthalate, dibutyl phthalate and butyl phthalyl butyl glycolate, silicone oil, triethyl citrate, triethyl acetyl citrate, triacetin, propylene glycol, polyethylene glycol, etc. may be used. it can. As a lubricant, magnesium stearate,
Talc, synthetic magnesium silicate, particulate silicon oxide, etc. can be used.

Specific examples of the coating layer that the coated particles can have include a mixed film of an enteric polymer and a hydrophobic organic compound (JP 2000-103732), a mixture of a water-insoluble polymer and a hydrophobic organic compound. Film (Japanese Patent Laid-Open No. 2000-19
8747) and the like.

The above-mentioned coating layer is not limited to one layer, but 2
It may be composed of more than one layer. For example, a multilayer coating layer in which all adjacent layers contain different hydrophobic organic compound-water-soluble polymer mixtures (Japanese Patent Application No. 2001-2001).
018807) and the like.

The drug-containing core particles coated in the coated particles are particles containing a drug desired to be blended alone or in combination with various pharmaceutical additives commonly used in this field, and having an average particle diameter of About 40-245 μm, especially about 45
Particles of ˜195 μm can be preferably used.

The drug-containing core particles include, in addition to drugs, formulation additives that can be used in formulations for oral administration, such as excipients, disintegrants, binders, lubricants, surfactants, fragrances, coloring agents, A sweetening agent, a solubilizing agent, etc. can be contained. Excipients include lactose, sucrose, mannitol, xylitol,
Erythritol, sorbitol, maltitol, calcium citrate, calcium phosphate, crystalline cellulose, magnesium aluminometasilicate and the like can be used. As the disintegrant, corn starch, potato starch, sodium carboxymethyl starch, partially pregelatinized starch, carboxymethyl cellulose calcium, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, crosslinked carboxymethylcellulose sodium, crosslinked polyvinylpyrrolidone, etc. can be used. . As the binder, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol,
Dextrin, pregelatinized starch and the like can be used. As the lubricant, magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, hydrous silicon dioxide and the like can be used.

As the surfactant, phospholipid, glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, sucrose fatty acid ester, etc. Can be used. As a fragrance,
Orange oil, fennel oil, cinnamon oil, clove oil, turpentine oil, peppermint oil, eucalyptus oil can be used. As coloring agents, food red No. 2, food No. 3, food yellow 4
No. 5, No. 5, food green No. 3, food blue No. 1, No. 2, aluminum lakes thereof, iron sesquioxide, yellow sesquioxide, etc. can be used. As the sweetener, saccharin, aspartame and the like can be used. Then, as the solubilizing agent, cyclodextrin, arginine, lysine, trisaminomethane or the like can be used.

The drug-containing core particles are prepared by wet granulation, dry granulation, layering granulation, heat granulation, impregnation granulation, spray drying granulation using the above-mentioned drugs and various additives as required. It can be prepared by a known granulation method such as granulation.

In order to prepare the drug-containing core particles by the wet granulation method, the following method can be used. (1) A binder solution is added to a mixture of a drug and various formulation additives (hereinafter referred to as a drug mixture), and the mixture is stirred and granulated.
Stir and granulate using a high-speed stirring granulator or the like. (2) A binder solution is added to the drug mixture and kneaded, and then granulated and sized using an extrusion granulator. (3) Using a fluidized bed granulator, a tumbling stirred fluidized bed granulator, etc., the binder mixture is sprayed under fluidization to granulate the drug mixture.

For preparation by the dry granulation method, the drug mixture is granulated by using a roller compactor, a roll granulator and the like.

For the preparation by the layering granulation method, a centrifugal fluidized granulator or the like is used, and the drug mixture is added while spraying the binder solution onto the tumbled inert carrier, and the drug is added onto the carrier. Apply the mixture. Examples of the inert carrier include crystalline lactose, crystalline cellulose, crystals of saccharides such as crystalline sodium chloride or inorganic salts, spherical granules [for example, spherical granules of crystalline cellulose (trade name: Avicel SP, manufactured by Asahi Kasei),
Spherical granules of crystalline cellulose and lactose (trade name: Nonparel NP-5, NP-7, manufactured by Freund Sangyo), spherical granules of purified white sugar (trade name: Nonparel-103, manufactured by Freund Sangyo), lactose and Spherical granulated product of pregelatinized starch, etc.)
Etc. can be used.

The heat granulation method can be prepared by the following method. (1) Using a stirring granulator, a high-speed stirring granulator, or the like, at a temperature at which a molten substance melts a drug mixture containing a substance that melts by heating (heated molten substance), such as polyethylene glycol, fats and oils, and wax. Stir and granulate. (2) Using a centrifugal fluidized granulator or the like, the drug mixture containing the heat-melting substance is added to an inert carrier that has been rolled at a temperature at which the heat-melting substance melts, and the drug mixture is added onto the carrier. Attach it.

To prepare by the impregnation granulation method, a solution containing a drug at an appropriate concentration is mixed with a porous carrier, the drug solution is sufficiently retained in the pores of the carrier, and then dried to remove the solvent. To remove. As the porous carrier, magnesium aluminometasilicate (trade name: Neusilin, manufactured by Fuji Chemical Industry Co., Ltd.), calcium silicate (trade name: Fluorite, manufactured by Eisai) and the like can be used.

To prepare by the spray drying granulation method, a spray dryer such as a spray dryer is used to spray a solution or suspension of the drug in a hot air stream to dry it.

Further, for example, in order to prepare fine particles having a particle size of about 45 to 195 μm, wet granulation using a high-speed rolling granulator (for example, an excipient having a property of retaining a drug or a solvent is used as a binder. High-speed rolling granulation by adding a solution
-128774 method), impregnation granulation, and spray drying granulation are preferable.

In order to prepare coated particles as an example of functional particles, the drug-containing core particles prepared as described above are provided with the above-mentioned coating layer. For providing the coating layer on the drug-containing core particles, any coating method commonly used in the field of formulation technology can be used. For example, coating agents such as water-soluble polymers, water-insoluble polymers, enteric-coated polymers, gastric-soluble polymers, hydrophobic organic compounds, and if necessary, colorants, masking agents, plasticizers, lubricants dissolved in solvents Alternatively, it is dispersed into a coating liquid, which is sprayed onto the drug-containing core substance using a commonly used coating device,
The coated particles can be obtained by drying.

Solvents for the coating solution include methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methoxyethanol (trade name: methyl cellosolve, manufactured by Katayama Chemical Industry), 2-ethoxyethanol (trade name: cellosolve). , Katayama Chemical Industry)
Hydrocarbons such as hexane, cyclohexane, petroleum ether, petroleum benzine, ligroin, benzene, toluene, xylene; ketones such as acetone and methyl ethyl ketone; dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride, trichloroethylene, 1 , Halogenated hydrocarbons such as 1,1-trichloroethane; esters such as acetic acid methyl ester, acetic acid ethyl ester and acetic acid butyl ester; ethers such as isopropyl ether and dioxane; water and the like. As a coating device,
A fluidized bed coating device, a centrifugal fluidized bed coating device, a pan coating device and the like can be used.

When microspheres / matrix particles are used as the functional particles, they can be easily prepared by a known microsphere forming or matrix forming method. There is a method like. (1) A method in which a powder of a drug and a water-insoluble substance is attached to the periphery of an inert core particle while being sprayed with an aqueous binder solution by centrifugal fluidization granulation, and dried at high temperature. (2) A method in which a drug and a water-insoluble substance are heated to a temperature equal to or higher than the melting point of the water-insoluble substance to melt and then spray-cooled. (3) Method in which a drug and a water-insoluble substance are heated to a temperature above the melting point of the water-insoluble substance and melted, and then dropped on a high-speed rotating disk at a constant speed (spray chilling) As the water-insoluble substance, for example, a carbon number of 14 to 22 is used. Saturated fatty acids (eg myristic acid, stearic acid, palmitic acid, behenic acid), higher alcohols having 16 to 22 carbon atoms (eg cetyl alcohol, stearyl alcohol), higher alkane mixtures (paraffin), fatty acids and water-insoluble higher 1 Examples thereof include esters (waxes) with dihydric alcohols / dihydric alcohols. As the wax, any of vegetable waxes (for example, hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated castor oil, carnauba wax) and animal waxes (beeswax, spermaceti, wool wax) can be used. As the inert core particles in (1), the same inert carriers as used in the layering granulation can be used, and as the binder, hydroxypropyl cellulose, polyethylene glycol, hydroxypropyl methyl cellulose, Conventional water soluble binders such as polyvinylpyrrolidone can be used. Drying at high temperature heats the water-insoluble substance near the melting point to melt the water-insoluble substance and form a matrix. In this method, the particle size of the microspheres / matrix particles produced can be adjusted by adjusting the particle size of the inert core particles and the amount of the drug and the water-insoluble substance attached. In (2), by adjusting the spray nozzle,
In (3), by adjusting the rotation speed of the high-speed rotating disk and the dropping speed, the generated microspheres /
The particle size of the matrix particles can be adjusted. In addition, in any of the methods (1) to (3), by adding a water-soluble low-molecular substance, a surfactant, a disintegrant, etc. at the time of production, the drug dissolution rate from the generated microspheres / matrix particles It can be accelerated, and conversely, by adding a hydrophobic substance, a water-swellable substance, and a substance that gels with water at the time of production, it is possible to slow the drug elution rate from the microsphere / matrix particles produced.

[0066]

EXAMPLES The orally rapidly disintegrating preparation containing functional particles of the present invention and the method for producing the same will be described in detail below with reference to Examples.

Example 1 (1) Hammer mill (egg sample mill KII GWH
1, 66 parts by weight of ascorbic acid pulverized by Fuji Paudal, microcrystalline cellulose (Avicel PH-M2)
5, Asahi Kasei) 33 parts by weight was stirred (700 rpm) using a high-speed stirring granulator (Newgra Machine NG-200, manufactured by Seishin Enterprise Co., Ltd.), and a hydroxypropyl cellulose solution (ethanol 59.4 parts by weight) was stirred. And water 39.6
Hydroxypropyl cellulose (HPC
-SL, manufactured by Nippon Soda) 1 part by weight dissolved) 400
ml was added and granulated for 25 minutes. The obtained granulated product is 45
After drying at ℃ for 3 hours, it is sieved and the particle size is 75 to 15
A 0 μm fraction was obtained as ascorbic acid-containing core particles.
Wurster type fluidized bed coating device (GPCG-1,
80 g of ascorbic acid-containing core particles
20 g of a coating solution (ethyl cellulose (Ethocel # 10, manufactured by Dow Chemical Co.)), and a methacrylic acid / methyl methacrylate copolymer (Eudragit L1)
00, manufactured by Laem Pharma) 20 g, stearic acid 4
(0 g dissolved in 920 g of ethanol) was sprayed to give a coating rate (ratio of the coating layer to the core particles) of 30% by weight to obtain coated fine particles. (2) 55 g of water containing 0.5% by weight of Avicel RC-591NF (microcrystalline cellulose coated with sodium carboxymethyl cellulose, manufactured by Asahi Kasei)
In addition, 0.16 g of aspartame, 40 g of ascorbic acid-containing coated fine particles of the above (1), and 33.9 mannitol.
g and erythritol 70.9 g were added to obtain a coated fine particle dispersion. 500 mg of this coated fine particle dispersion is
After filling the 0 mm concave hole, it was freeze-dried (condition: pre-cooling;
-40 ° C., 3 hours, drying; −20 ° C., 0.1 torr, 2 hours and 20 ° C., 0.1 torr, 16 hours) to give an orally rapidly disintegrating tablet of the present invention. The obtained oral rapidly disintegrating tablet was administered to three healthy male adults, and the oral disintegration time was measured. The average oral disintegration time was 21 seconds, and the oral rapidly disintegrating property was excellent.

Example 2 930 mg of the coated fine particle dispersion liquid obtained in Example 1 (2)
Was filled in a concave hole with a diameter of 15 mm and then freeze-dried (conditions:
The same procedure as in Example 1 (2) was carried out to obtain an orally rapidly disintegrating tablet of the present invention. The hardness of the obtained orally rapidly disintegrating tablets was measured using a tablet tester (Model 6D, manufactured by Freund Corporation) (6 tablets), and the average was 38.2N. In addition, a disintegration test was conducted according to the 13th Revised Japanese Pharmacopoeia Disintegration Test Method (test solution: water), and the disintegration time was measured (3
Number), and the average was 24.3 seconds. From the above, it can be seen that the preparation obtained by the method of the present invention has high hardness even though the disintegration time is very short.

Example 3 53.4 g of water containing 0.5% by weight of Avicel RC-591NF, 0.16 g of aspartame, 1.6 g of lemon flavor, coated fine particles containing ascorbic acid prepared in Example 1 (1) 40 g, 33.9 g of mannitol and 70.9 g of erythritol were added to obtain a coated fine particle dispersion. This coated fine particle dispersion liquid (500 mg) was filled in a concave hole having a diameter of 10 mm and then freeze-dried (condition: the same as in Example 1 (2)) to obtain an orally rapidly disintegrating tablet of the present invention.

Example 4 (1) 10 parts by weight of diltiazem hydrochloride pulverized with a sample mill (manufactured by Fuji Paudal), 69 parts by weight of mannitol, microcrystalline cellulose (Avicel PH-M25, manufactured by Asahi Kasei) 2
0 parts by weight of high-speed agitation granulator (Newgra Machine NG
-200, manufactured by Seishin Enterprise Co., Ltd. (700 rp)
m), under stirring, 400 ml of hydroxypropyl cellulose solution (one part by weight of hydroxypropyl cellulose (HPC-SL, Nippon Soda) dissolved in a mixed solution of 59.4 parts by weight of ethanol and 39.6 parts by weight of water) was added. And then 25
Granulated for minutes. The obtained granulated product was dried at 45 ° C. for 3 hours and then sieved to obtain a fraction having a particle size of 75 to 150 μm as drug-containing core particles. Using a Wurster type fluidized bed coating device (GPCG-1, manufactured by Glatt), while flowing into 80 g of diltiazem hydrochloride-containing core particles, 40 g of coating solution (ethyl cellulose (Etocel # 10, manufactured by Dow Chemical Co.) and 40 g of stearic acid were added to ethanol. 92
(Dissolved in 0 g) was sprayed so that the coverage (ratio of the coating layer to the core particles) was 25% by weight to obtain coated fine particles. (2) To 27.5 g of water containing 0.5% by weight of Avicel RC-591NF, 0.08 g of aspartame, 20 g of coated fine particles containing diltiazem hydrochloride of the above (1), 17 g of mannitol and 35.4 g of erythritol were added,
A coated fine particle dispersion was obtained. This coated fine particle dispersion 500
mg was filled in a concave hole having a diameter of 10 mm and then freeze-dried (condition: the same as in Example 1 (2)) to obtain an orally rapidly disintegrating tablet of the present invention.

Example 5 Water 2 containing 1 wt% Avicel RC-591NF
To 7.5 g, aspartame 0.08 g, Example 4
Coated fine particles 20 containing diltiazem hydrochloride prepared in (1)
g, mannitol 17 g, and erythritol 35.4 g were added to obtain a coated fine particle dispersion. This coated fine particle dispersion liquid (500 mg) was filled in a concave hole having a diameter of 10 mm and then freeze-dried (condition: the same as in Example 1 (2)) to obtain an orally rapidly disintegrating tablet of the present invention.

Example 6 (1) 53.2 parts by weight of diltiazem hydrochloride crushed with a sample mill (manufactured by Fuji Paudal), 26.6 parts by weight of mannitol, microcrystalline cellulose (Avicel PH-M25, manufactured by Asahi Kasei) 19.9 Parts by weight are stirred (450 rpm) using a high-speed agitation granulator (Neugra Machine NG-350, manufactured by Seishin Enterprise Co., Ltd.), and a mixture of hydroxypropyl cellulose solution (68 parts by weight ethanol and 30 parts by weight water is stirred). 450 ml of 2 parts by weight of hydroxypropyl cellulose (HPC-SL, manufactured by Nippon Soda Co., Ltd.) was added,
Granulated for 30 minutes. The obtained granulated product was dried at 45 ° C. for 16 hours and then sieved to obtain a fraction having a particle size of 75 to 150 μm as drug-containing core particles. Using a Wurster type fluidized bed coating device (GPCG-1, manufactured by Glatt), while flowing into 80 g of diltiazem hydrochloride-containing core particles, 40 g of coating solution (ethyl cellulose (Etocel # 10, manufactured by Dow Chemical Co.), stearic acid (Kao Corporation) Made) 1
0 g of ethanol dissolved in 950 g) was sprayed so that the coverage (ratio of the coating layer to the core particles) was 50% by weight to obtain coated fine particles. The obtained coated particles were sieved to obtain a fraction having a particle size of 75 to 250 μm as diltiazem hydrochloride-containing coated particles. (2) To 40.8 g of water containing 1% by weight of Avicel RC-591NF, 1.2 g of aspartame, the above (1)
23.4 g of the coated fine particles containing diltiazem hydrochloride and 54.6 g of lactose (450 Mesh product, DMV) were added,
A coated fine particle dispersion was obtained. This coated fine particle dispersion 500
mg was filled in a concave hole having a diameter of 12 mm and then freeze-dried (condition: the same as in Example 1- (2)) to obtain an orally rapidly disintegrating tablet of the present invention.

Example 7 (1) Worcester type fluidized bed coating apparatus (GPCG)
No. 1, manufactured by Glatt) was applied to 80 g of diltiazem hydrochloride-containing core particles obtained in Example 6- (1) under a flow of 40 g of a coating solution (ethyl cellulose (Ethocel # 10, manufactured by Dow Chemical Co.), stearic acid ( Kao) 40g
Was dissolved in 920 g of ethanol) to spray a coating ratio (ratio of the coating layer to the core particles) of 50% by weight to obtain coated fine particles. The obtained coated particles were sieved to obtain a fraction having a particle size of 75 to 250 μm as diltiazem hydrochloride-containing coated particles. (2) To 8.5 g of water containing 1% by weight of Avicel RC-591NF, 0.13 g of aspartame, 0.13 g of lemon flavor (manufactured by Ogawa Fragrance Co., Ltd.), and 4.88 g of coated fine particles containing diltiazem hydrochloride of (1) above. , Lactose (200 Mes
11.38 g of h product, DMV) was added to obtain a coated fine particle dispersion. 500 mg of this coated fine particle dispersion is
After filling a 2 mm concave hole, freeze-drying (conditions: Example 1-
(Same as (2)) to obtain an orally rapidly disintegrating tablet of the present invention. The hardness of the obtained orally rapidly disintegrating tablets was measured with a tablet tester (Model 6D, manufactured by Freund Sangyo Co., Ltd.) (6 tablets), and the average was 10.0 N. Moreover, when the obtained rapidly disintegrating buccal tablets were administered to three healthy adult males and the disintegrating time in the buccal cavity was measured, it was 17 seconds on average, and the oral rapidly disintegrating properties were excellent.

Example 8 Water containing 1 wt% Avicel RC-591NF 8.
To 5 g, aspartame 0.13 g, lemon flavor (manufactured by Ogawa Fragrance Co., Ltd.) 0.13 g, diltiazem hydrochloride-containing coated fine particles 4.88 g obtained in Example 7- (1), mannitol 3.79 g, and erythritol 7.58 g were added. Then, a coated fine particle dispersion was obtained. 500 mg of this coated fine particle dispersion
Filled in a concave hole with a diameter of 12 mm, and then freeze-dried (conditions:
The same as in Example 1- (2)) to obtain an orally rapidly disintegrating tablet of the present invention. The hardness of the obtained orally rapidly disintegrating tablets was measured with a tablet tester (Model 6D, manufactured by Freund Sangyo Co., Ltd.) (6 tablets), and the average was 26.5N.

Example 9 (1) 175.7 g of acetaminophen and 70.3 g of hydroxypropyl cellulose were dissolved in 1054 g of ethanol, and this solution and magnesium aluminometasilicate (Neucillin NS2N, manufactured by Fuji Chemical Industry Co., Ltd.) 200
g was mixed and stirred using a Shinagawa mixer, and impregnated and granulated. The obtained granulated product was dried at 45 ° C. for 16 hours and then sieved to obtain a fraction having a particle size of 75 to 150 μm as drug-containing core particles. Wurster type fluidized bed coating equipment (G
PCG-1, manufactured by Glatt), using acetaminophen-containing core particles in a flow rate of 80 g under an ethyl cellulose solution (Ethocel # 10 (manufactured by Dow Chemical Co.): 3 parts by weight,
Ethanol: 63.05 parts by weight, water: 33.95 parts by weight) were sprayed so that the coverage (ratio of the coating layer to the core particles) was 25% by weight to obtain coated fine particles. The obtained coated particles were sieved to obtain a fraction having a particle diameter of 75 to 250 μm as acetaminophen-containing coated particles. (2) To 8.5 g of water containing 1% by weight of Avicel RC-591NF, 0.13 g of aspartame, 0.13 g of lemon flavor (manufactured by Ogawa Fragrance Co., Ltd.), and acetaminophen-containing coated fine particles of the above (1) 4. 88 g, lactose (200 Me
sh product, DMV) 11.38 g was added to obtain a coated fine particle dispersion. 500 mg of this coated fine particle dispersion was filled in a concave hole having a diameter of 12 mm, and then freeze-dried (condition: Example 1
-(Same as (2)) to obtain an orally rapidly disintegrating tablet of the present invention.
The hardness of the obtained orally rapidly disintegrating tablets was measured using a tablet tester (Model 6D, manufactured by Freund Sangyo Co., Ltd.) (6 tablets), and the average was 15.8 N. In addition, when the obtained rapidly disintegrating buccal tablets were administered to 3 healthy adult males and the disintegrating time in the oral cavity was measured, it was 16 seconds on average,
It had an excellent oral rapid disintegration property.

Example 10 Water containing 1% by weight Avicel RC-591NF 8.
To 5 g, aspartame 0.13 g, lemon flavor (manufactured by Ogawa Fragrance Co., Ltd.) 0.13 g, acetaminophen-containing coated fine particles 4.88 g obtained in Example 9- (1), mannitol 3.79 g, and erythritol 7.58 g were added. Added to obtain a coated fine particle dispersion. 500 mg of this coated fine particle dispersion
Filled in a concave hole with a diameter of 12 mm, and then freeze-dried (conditions:
The same as in Example 1- (2)) to obtain an orally rapidly disintegrating tablet of the present invention. The hardness of the obtained orally rapidly disintegrating tablets was measured using a tablet tester (Model 6D, manufactured by Freund Sangyo Co., Ltd.) (6 tablets), and the average was 16.7 N.

Example 11 Water containing 1% by weight of Avicel RC-591NF 8.
5 g, aspartame 0.13 g, lemon flavor (manufactured by Ogawa Fragrance Co., Ltd.) 0.13 g, acetaminophen-containing coated fine particles 3.25 g obtained in Example 9- (1), lactose (200
(Mesh, DMV) 13 g was added to obtain a coated fine particle dispersion. This coated fine particle dispersion liquid (500 mg) has a diameter of 12
After filling in the concave hole of mm, freeze-drying (condition: Example 1-
(Same as (2)) to obtain an orally rapidly disintegrating tablet of the present invention. The hardness of the obtained orally rapidly disintegrating tablets was measured using a tablet tester (Model 6D, manufactured by Freund Sangyo Co., Ltd.) (6 tablets), and the average was 15.8 N. Moreover, when the obtained rapidly disintegrating buccal tablets were administered to 3 healthy adult males and the disintegrating time in the buccal cavity was measured, it was 11 seconds on average, and it had excellent rapid disintegrating buccal properties.

Example 12 Water containing 1% by weight of Avicel RC-591NF 9.
To 75 g, aspartame 0.13 g, lemon flavor (manufactured by Ogawa Fragrance Co., Ltd.) 0.13 g, acetaminophen-containing coated fine particles 3.75 g obtained in Example 9- (1), and lactose (20
0Mesh, DMV) 11.25 g was added to obtain a coated fine particle dispersion. 500 mg of this coated fine particle dispersion,
After filling in a concave hole having a diameter of 12 mm, it was freeze-dried (condition: the same as in Example 1- (2)) to obtain an orally rapidly disintegrating tablet of the present invention. The hardness of the obtained orally rapidly disintegrating tablets was measured using a tablet tester (Model 6D, manufactured by Freund Sangyo Co., Ltd.) (6 tablets), and the average was 12.0 N. Moreover, when the obtained rapidly disintegrating buccal cavity was administered to three healthy adult males and the disintegrating time in the buccal cavity was measured, it was 10 seconds on average, and the oral cavity rapidly disintegrating property was excellent.

Example 13 Water containing 1% by weight of Avicel RC-591NF 9.
To 75 g, aspartame 0.13 g, lemon flavor (manufactured by Ogawa Fragrance Co., Ltd.) 0.13 g, acetaminophen-containing coated fine particles 4.5 g obtained in Example 9- (1), lactose (200
(Mesh, DMV) 10.5 g was added to obtain a coated fine particle dispersion. 500 mg of this coated fine particle dispersion was filled in a concave hole having a diameter of 12 mm, and then freeze-dried (condition: Example 1
-(Same as (2)) to obtain an orally rapidly disintegrating tablet of the present invention.
The hardness of the obtained orally rapidly disintegrating tablets was measured using a tablet tester (Model 6D, manufactured by Freund Sangyo Co., Ltd.) (6 tablets), and the average was 12.0 N. Moreover, when the obtained rapidly disintegrating buccal tablets were administered to three healthy adult males, and the disintegrating time in the oral cavity was measured, it was 12 seconds on average,
It had an excellent oral rapid disintegration property.

Example 14 Water containing 1 wt% Avicel RC-591NF 9.
In 75 g, aspartame 0.13 g, lemon flavor (manufactured by Ogawa Fragrance Co., Ltd.) 0.13 g, acetaminophen-containing coated fine particles obtained in Example 9- (1) 5.25 g, and lactose (20
(0Mesh, DMV) 9.75 g was added to obtain a coated fine particle dispersion. This coated fine particle dispersion liquid (500 mg) was filled in a concave hole having a diameter of 12 mm and then freeze-dried (condition: the same as in Example 1- (2)) to obtain an orally rapidly disintegrating tablet of the present invention. The hardness of the obtained orally rapidly disintegrating tablets was measured using a tablet tester (Model 6D, manufactured by Freund Sangyo) (6 tablets), and the average was 13.8 N.

Example 15 Water containing 1% by weight of Avicel RC-591NF 9.
To 75 g, aspartame 0.13 g, lemon flavor (manufactured by Ogawa Fragrance Co., Ltd.) 0.13 g, acetaminophen-containing coated fine particles 6 g obtained in Example 9- (1), lactose (200 Me)
sh, DMV) 9 g was added to obtain a coated fine particle dispersion. This coated fine particle dispersion liquid (500 mg) was filled in a concave hole having a diameter of 12 mm and then freeze-dried (condition: the same as in Example 1- (2)) to obtain an orally rapidly disintegrating tablet of the present invention. The hardness of the obtained orally rapidly disintegrating tablet was measured by a tablet tester (model 6).
D (manufactured by Freund Sangyo) was measured (6
Number), and the average was 12.8N.

Example 16 Water containing 1% by weight of Avicel RC-591NF 9.
In 75 g, aspartame 0.13 g, lemon flavor (manufactured by Ogawa Fragrance Co., Ltd.) 0.13 g, acetaminophen-containing coated fine particles 6.75 g obtained in Example 9- (1), lactose (20
0Mesh, DMV) 8.25 g was added to obtain a coated fine particle dispersion. This coated fine particle dispersion liquid (500 mg) was filled in a concave hole having a diameter of 12 mm and then freeze-dried (condition: the same as in Example 1- (2)) to obtain an orally rapidly disintegrating tablet of the present invention. The hardness of the obtained orally rapidly disintegrating tablets was measured with a tablet tester (Model 6D, manufactured by Freund Sangyo Co., Ltd.) (6 tablets), and the average was 12.7 N.

Example 17 (1) 69.3 parts by weight of ecabet sodium pulverized with a sample mill (manufactured by Fuji Paudal), partially pregelatinized starch (P
29.7 parts by weight of CS-PC10 (manufactured by Asahi Kasei) were stirred (600 rpm) using a high-speed stirring type granulator (Newgra Machine NG-200, manufactured by Seishin Enterprise Co., Ltd.), and a hydroxypropylcellulose solution (ethanol 49 was stirred). 250 ml of hydroxypropyl cellulose (HPC-SL, manufactured by Nippon Soda Co., Ltd.) was added to a mixed solution of 49 parts by weight of water and 250 parts of water, and the mixture was granulated for 24 minutes. The obtained granulated product was dried at 45 ° C. for 16 hours and then sieved to obtain a fraction having a particle size of 75 to 150 μm as drug-containing core particles. Wurster type fluidized bed coating equipment (GPCG-
1. Using Glatt), while flowing into 80 g of ecabet sodium-containing core particles, 40 g of a coating solution (ethyl cellulose (Etocel # 10, manufactured by Dow Chemical Co.) and 10 g of stearic acid (manufactured by Kao) are dissolved in 950 g of ethanol. The coated particles were sprayed so that the coverage (ratio of the coating layer to the core particles) was 30% by weight to obtain coated fine particles. The obtained coated particles are sieved to obtain a particle size of 75-25.
The 0 μm fraction was obtained as coated particles containing sodium echabet. (2) In 8.5 g of water containing 1% by weight of Avicel RC-591NF, 0.13 g of aspartame, 0.13 g of lemon flavor (manufactured by Ogawa Fragrance Co., Ltd.), and coated particles containing sodium ecabet of the above (1). 88 g, lactose (450 Me
sh product, DMV) 11.38 g was added to obtain a coated fine particle dispersion. 500 mg of this coated fine particle dispersion was filled in a concave hole having a diameter of 12 mm, and then freeze-dried (condition: Example 1
-(Same as (2)) to obtain an orally rapidly disintegrating tablet of the present invention.
The hardness of the obtained orally rapidly disintegrating tablets was measured with a tablet tester (Model 6D, manufactured by Freund Sangyo Co., Ltd.) (6 tablets), and the average was 17.0 N.

Example 18 (1) Diltiazem hydrochloride 40.0 parts by weight crushed with a sample mill (manufactured by Fuji Paudal), mannitol 40.0 parts by weight, microcrystalline cellulose (Avicel PH-M25, Asahi Kasei) 20.0 Parts by weight are stirred (450 rpm) using a high-speed agitation granulator (Neugra Machine NG-350, manufactured by Seishin Enterprise Co., Ltd.) to form a hydroxypropylcellulose solution (a mixture of 68 parts by weight of ethanol and 30 parts by weight of water) under agitation. Add 435 ml of hydroxypropyl cellulose (HPC-SL, manufactured by Nippon Soda Co., Ltd., 2 parts by weight),
Granulated for 30 minutes. The obtained granulated product was dried at 45 ° C. for 16 hours and then sieved to obtain a fraction having a particle size of 75 to 150 μm as drug-containing core particles. Using a Wurster type fluidized bed coating device (GPCG-1, manufactured by Glatt), while flowing into 80 g of diltiazem hydrochloride-containing core particles, 40 g of coating solution (ethyl cellulose (Etocel # 10, manufactured by Dow Chemical Co.)), stearic acid (Kao Corporation) Made) 4
0 g of ethanol dissolved in 920 g of ethanol was sprayed so that the coating ratio (the ratio of the coating layer to the core particles was 60% by weight) to obtain coated microparticles. A fraction of 75 to 250 μm was obtained as coated particles containing diltiazem hydrochloride (2) Water containing 2% by weight of Avicel RC-N81 5
1.0 g, aspartame 0.8 g, strawberry flavor (manufactured by Ogawa Fragrance Co., Ltd.) 0.8 g, diltiazem hydrochloride-containing coated fine particles 29.3 g in the above (1), lactose (450 Mes
h product, DMV) 68.3 g was added to obtain a coated fine particle dispersion. This coated fine particle dispersion liquid (470 mg) was treated with a diameter of 12
After filling in the concave hole of mm, freeze-drying (condition: Example 1-
(Same as (2)) to obtain an orally rapidly disintegrating tablet of the present invention.

Example 19 Water containing 1% by weight of Avicel RC-N30 51.0
In g, 0.8 g of aspartame, 0.8 g of strawberry flavor (manufactured by Ogawa Fragrance Co., Ltd.), 29.3 g of coated fine particles containing diltiazem hydrochloride obtained in Example 18- (1), and lactose (450
(Mesh product, DMV) 68.3 g was added to obtain a coated fine particle dispersion. 470 mg of this coated fine particle dispersion was filled in a concave hole having a diameter of 12 mm, and then freeze-dried (condition: the same as in Example 1- (2)) to obtain an orally rapidly disintegrating tablet of the present invention.

Example 20 (1) Worcester type fluidized bed coating apparatus (GPCG)
No. 1, manufactured by Glatt) was applied to 80 g of diltiazem hydrochloride-containing core particles obtained in Example 6- (1) under a flow of 40 g of a coating solution (ethyl cellulose (Ethocel # 10, manufactured by Dow Chemical Co.), stearic acid ( Kao) 40g
Was dissolved in 920 g of ethanol) to spray a coating rate (ratio of the coating layer to the core particles) of 40% by weight to obtain coated fine particles. The obtained coated particles were sieved to obtain a fraction having a particle size of 75 to 250 μm as diltiazem hydrochloride-containing coated particles. (2) In 102.0 g of water containing 1% by weight of Avicel RC-591NF, 3.0 g of aspartame, 3.0 g of strawberry flavor (manufactured by Ogawa Fragrance Co., Ltd.), and 58.5 g of coated fine particles containing diltiazem hydrochloride according to (1) above. , Lactose (450
136.5 g of the product (Mesh product, DMV) was added to obtain a coated fine particle dispersion. 500 mg of this coated fine particle dispersion,
After filling the concave hole with a diameter of 12 mm with a filling device (mono dispenser, model 4NDPLO4G15, manufactured by Hyōjin Equipment Co., Ltd.), freeze-drying (condition: same as Example 1- (2)).
Then, an orally rapidly disintegrating tablet of the present invention was obtained.

Experimental Example 1 99 parts by weight of water was added to 1 part by weight of Avicel RC-591NF, and the mixture was stirred with a magnetic stirrer for 1 hour.
By allowing it to stand for 6 hours, 1% by weight of Avicel RC-
An aqueous dispersion containing 591NF was prepared, and the viscosity at 25 ° C. was measured using a B-type viscometer to find that it was 17 mPa · s. Then, 99 parts by weight of the liquid, 1 part by weight of nifedipine particles (manufactured by Wako Pure Chemical Industries, Lot No. KCR6473, average particle size: 72 μm, particles having a particle size of 36 μm or less and particles having a particle size of 147 μm or more, 10% each) Was added, and the mixture was stirred for 2 minutes to disperse the mixture, and then 50 ml was poured into a Nessler tube (inner diameter 22 mm) and allowed to stand. 0 and 5 hours after the start of standing, 1 ml of the dispersion was accurately sampled from the upper and lower central portions, and the concentration of nifedipine particles was measured. Regarding the concentration of nifedipine particles in the sample, (a) acetone was added to the sample to dissolve nifedipine, (b) Avicel RC-591NF was removed by filtration, and (c) the filtrate was dissolved in the Japanese Pharmacopoeia 13th Edition. Dilute with the second liquid, (d)
The nifedipine concentration of the diluted sample was measured and calculated by absorbance measurement (measurement wavelength: 350 nm). The theoretical nifedipine particle concentration (nifedipine particle amount / dispersion liquid amount) is 10
Table 1 shows the ratio (%) of the nifedipine particle concentration in the upper and lower central portions of the dispersion after each standing time when 0 was set.
When nifedipine particles were added to water and dispersed in the same manner as above, water and nifedipine particles were completely separated within 5 hours.

[0088]

[Table 1]

As is clear from Table 1, the value after standing for 5 hours, that is, the dispersion retention rate was 94.7%, and Avicel RC-591NF (microcrystalline cellulose coated with carboxymethyl cellulose) was used as a dispersant. It was found that when the nifedipine particles were used to disperse in water, a good dispersion state was maintained for a long time. This indicates that microcrystalline cellulose coated with sodium carboxymethyl cellulose (Avicel RC-591NF) can be preferably used as a dispersant in the method of the present invention.

Experimental Example 2 Coated fine particles obtained in Example 4 (1), Example 4 (2)
The rapidly disintegrating tablets in the oral cavity obtained in (4) was subjected to a dissolution test (test solution: second disintegration test solution) according to the Japanese Pharmacopoeia 13th Edition to examine the dissolution characteristics of diltiazem hydrochloride. The results are shown in Fig. 1. As is clear from FIG. 1, the dissolution characteristics of the coated fine particles and the rapidly disintegrating tablet in the oral cavity are almost the same as the dissolution characteristics of diltiazem hydrochloride. From this, it was found that the production method of the present invention can provide a rapidly disintegrating preparation in the oral cavity without impairing the function of the functional particles such as coated particles.

Experimental Example 3 Coated fine particles obtained in Example 6 (1), Example 6 (2)
The rapidly disintegrating tablets in buccal cavity obtained in (1) was subjected to a dissolution test (test liquid: first disintegration test liquid) according to the Japanese Pharmacopoeia Thirteenth Edition to examine the dissolution properties of diltiazem hydrochloride. The result is shown in Figure 2.
Shown in. As is clear from FIG. 2, the dissolution characteristics of the coated fine particles and the rapidly disintegrating tablet in the oral cavity are substantially the same as the dissolution characteristics of diltiazem hydrochloride. From this, it was found that the production method of the present invention can provide a rapidly disintegrating preparation in the oral cavity without impairing the function of the functional particles such as coated particles.

Experimental Example 4 The storage stability of the orally rapidly disintegrating tablet obtained in Example 6 (2) was evaluated. The results are shown in Fig. 3. (Dissolution test method: same as in Experimental Example 3) As is clear from Fig. 3, it was found that a rapidly disintegrating preparation in the oral cavity with high storage stability can be obtained by the manufacturing method of the present invention.

Experimental Example 5 Coated fine particles obtained in Example 7 (1), Example 7 (2)
Then, the rapidly disintegrating buccal tablets obtained in Example 8 were subjected to a dissolution test (test solution: second disintegration test solution) according to the Japanese Pharmacopoeia 13th Edition to examine the dissolution characteristics of diltiazem hydrochloride. The results are shown in Fig. 4. As is clear from FIG. 4, the dissolution characteristics of the coated fine particles and the rapidly disintegrating tablet in the oral cavity are substantially the same as the dissolution characteristics of diltiazem hydrochloride. From this, it was found that the production method of the present invention can provide a rapidly disintegrating preparation in the oral cavity without impairing the function of the functional particles such as coated particles.

Experimental Example 6 Coated fine particles obtained in Example 9 (1), Example 9 (2)
Further, the rapidly disintegrating buccal tablets obtained in Example 10 were subjected to a dissolution test (test liquid: disintegration test second liquid) according to the 13th revised Japanese Pharmacopoeia to examine the dissolution properties of acetaminophen. Results are shown in FIG. As is clear from FIG. 5, the acetaminophen elution characteristics of the coated microparticles and the orally rapidly disintegrating tablet are almost the same. From this, it was found that the production method of the present invention can provide a rapidly disintegrating preparation in the oral cavity without impairing the function of the functional particles such as coated particles.

Experimental Example 7 Coated fine particles obtained in Example 17 (1), Example 17
The rapidly disintegrating tablets in buccal cavity obtained in (2) was subjected to a dissolution test (test liquid: disintegration test second liquid) according to the 13th revised Japanese Pharmacopoeia to examine the dissolution characteristics of ecabet sodium.
Results are shown in FIG. As is clear from FIG. 6, the ecabet sodium dissolution characteristics of the coated microparticles and the orally rapidly disintegrating tablet are almost the same. From this, it was found that the production method of the present invention can provide a rapidly disintegrating preparation in the oral cavity without impairing the function of the functional particles such as coated particles.

Experimental Example 8 Coated fine particles obtained in Example 18 (1), Example 18
With respect to the rapidly disintegrating buccal tablets obtained in (2), a dissolution test (test liquid: second disintegration test liquid) was conducted according to the Japanese Pharmacopoeia Thirteenth Edition to examine the dissolution characteristics of diltiazem hydrochloride. The results are shown in Fig. 7. As is clear from FIG. 7, the dissolution characteristics of diltiazem hydrochloride of the coated fine particles and the orally rapidly disintegrating tablet are almost the same. From this, it was found that the production method of the present invention can provide a rapidly disintegrating preparation in the oral cavity without impairing the function of the functional particles such as coated particles.

Experimental Example 9 Coated fine particles obtained in Example 18 (1), Example 19
With respect to the rapidly disintegrating buccal tablets obtained in (2), a dissolution test (test liquid: second disintegration test liquid) was conducted according to the Japanese Pharmacopoeia Thirteenth Edition to examine the dissolution characteristics of diltiazem hydrochloride. The results are shown in Fig. 8. As is clear from FIG. 8, the dissolution characteristics of the coated fine particles and the rapidly disintegrating buccal tablets of diltiazem hydrochloride are almost the same. From this, it was found that the production method of the present invention can provide a rapidly disintegrating preparation in the oral cavity without impairing the function of the functional particles such as coated particles.

Experimental Example 10 Regarding the orally rapidly disintegrating tablet obtained in Example 20 (2),
Initial filling (up to 100 tablets at the beginning of filling), middle filling (200 to 400 tablets after starting filling), late filling (3 hours in filling machine)
A sample was obtained by filling it after leaving for a while). Tablet weight uniformity (n = 20) and content uniformity (n = 10) were examined for each sample. The results are shown in Table 2.

[0099]

[Table 2]

As is clear from Table 2, segregation of weight and content due to phase separation is not observed at any filling time. From this, if the manufacturing method of the present invention,
It was found that the filling liquid has excellent dispersibility, and functional particles such as coated particles can be uniformly dispersed in the filling liquid, and uniform filling is possible.

Reference Example 1 Water containing 0.5% by weight of Avicel RC-591NF 33.
0.2 parts by weight of aspartame, 33.4 parts by weight of mannitol and 33 parts by weight of erythritol were added to 4 parts by weight to obtain a suspension. 500 mg of this suspension is 10 mm in diameter
After filling in the concave hole of No. 1 and freeze-dried, an orally rapidly disintegrating tablet was obtained.

Reference Example 2 Water containing 0.5% by weight of Avicel RC-591NF 33.
0.2 parts by weight of aspartame, 33.4 parts by weight of mannitol and 33 parts by weight of lactose were added to 4 parts by weight to obtain a suspension. This suspension (500 mg) was filled in a concave hole having a diameter of 10 mm and freeze-dried to obtain an orally rapidly disintegrating tablet.

Reference Example 3 Water containing 0.5% by weight of Avicel RC-591NF 33.
4 parts by weight, 0.2 parts by weight of aspartame, 33.
4 parts by weight and 33 parts by weight of erythritol were added to obtain a suspension. This suspension (500 mg) was filled in a concave hole having a diameter of 10 mm and freeze-dried to obtain an orally rapidly disintegrating tablet.

Reference Example 4 Water containing 0.5% by weight of Avicel RC-591NF 33.
4 parts by weight, 0.2 parts by weight of aspartame, 66.
4 parts by weight was added to obtain a suspension. 500 mg of this suspension
Was filled in a concave hole having a diameter of 10 mm and then freeze-dried to obtain an orally rapidly disintegrating tablet.

Reference Example 5 Water containing 0.5% by weight of Avicel RC-591NF 33.
0.2 parts by weight of aspartame, 33.4 parts by weight of mannitol and 33 parts by weight of maltose were added to 4 parts by weight to obtain a suspension. This suspension (500 mg) was filled in a concave hole having a diameter of 10 mm and freeze-dried to obtain an orally rapidly disintegrating tablet.

[Brief description of drawings]

FIG. 1 shows the dissolution characteristics of diltiazem hydrochloride from the coated fine particles obtained in Example 4 (1) and the orally rapidly disintegrating tablet of the present invention obtained in Example 4 (2).

FIG. 2 shows the dissolution characteristics of diltiazem hydrochloride from the coated fine particles obtained in Example 6 (1) and the orally rapidly disintegrating tablet of the present invention obtained in Example 6 (2).

FIG. 3 shows the storage stability of the orally rapidly disintegrating tablet of the present invention obtained in Example 6 (2).

FIG. 4 shows the dissolution characteristics of diltiazem hydrochloride from the coated fine particles obtained in Example 7 (1) and the orally rapidly disintegrating tablets of the present invention obtained in Example 7 (2) and Example 8. .

FIG. 5 shows the dissolution characteristics of acetaminophen from the coated fine particles obtained in Example 9 (1) and the orally rapidly disintegrating tablets of the present invention obtained in Example 9 (2) and Example 10. Show.

FIG. 6 shows dissolution characteristics of ecabet sodium from the coated fine particles obtained in Example 17 (1) and the orally rapidly disintegrating tablet of the present invention obtained in Example 17 (2).

FIG. 7 shows the dissolution characteristics of diltiazem hydrochloride from the coated fine particles obtained in Example 18 (1) and the orally rapidly disintegrating tablet of the present invention obtained in Example 18 (2).

FIG. 8 shows the dissolution characteristics of diltiazem hydrochloride from the coated fine particles obtained in Example 18 (1) and the orally rapidly disintegrating tablet of the present invention obtained in Example 19 (2).

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/38 A61K 47/38 (72) Inventor Takashi Ishibashi 545 Nagasonemachi, Sakai City, Osaka Prefecture 12-Shimonoike Housing 103 F term (reference) 4C076 AA39 BB01 DD38 DD59 EE09 EE10 EE30 EE31 EE32 EE36 EE38 EE41 EE48 FF06 GG06

Claims (22)

[Claims] 1. A dispersant having a dispersion maintenance ratio at 25 ° C. of 75% or more and a viscosity of 100 mPa · s or less when (a) is uniformly contained in water at 1% by weight, (b) a water-soluble saccharide, and (C) A method for producing an orally rapidly disintegrating preparation containing functional particles, which comprises filling a mold with an aqueous dispersion containing functional particles and removing water. 2. The method according to claim 1, wherein the dispersant is a composite of fine particles of a water-insoluble substance and a water-soluble substance. 3. The method according to claim 2, wherein the dispersant is a complex obtained by drying treatment of an aqueous dispersion containing fine particles of a water-insoluble substance and a water-soluble substance. 4. The method according to claim 2, wherein the water-insoluble substance is a fibrous substance. 5. The method according to claim 4, wherein the fine particles of the water-insoluble substance are microcrystalline cellulose. 6. The average particle size of the fine particles of the water-insoluble substance is
The manufacturing method according to any one of claims 2 to 5, which has a thickness of 30 µm or less. 7. The water-soluble substance is locust bean gum,
Guar gum, tamarind gum, quince seed gum, karaya gum, gum arabic, tragacanth gum, ghatti gum, arabinogalactan, agar, carrageenan, alginic acid and its salts, farcelane, pectin, quince, xanthan gum, curdlan, pullulan, dextran, gellan gum, gelatin , Sodium carboxymethyl cellulose, sodium polyacrylate, sodium chondroitin sulfate, sodium starch glycolate, starch hydrolyzate, dextrins, glucose, fructose, xylose, sorbose, sucrose, lactose, maltose, isomerized sugar, coupling sugar, palatinose , Neo sugar, reduced starch saccharified candy, lactulose,
The method according to any one of claims 2 to 6, which is one or more selected from polydextrose, fructooligosaccharide, galactooligosaccharide, xylitol, mannitol, maltitol and sorbitol. 8. The method according to claim 1, wherein the dispersant is microcrystalline cellulose coated with one or more selected from sodium carboxymethyl cellulose, karaya gum-dextrin mixture and xanthan gum-dextrin mixture. 9. The method according to claim 8, wherein the dispersant is microcrystalline cellulose coated with sodium carboxymethyl cellulose. 10. The water-soluble saccharide is one or more selected from glucose, fructose, sucrose, lactose, maltose, mannitol, xylitol, sorbitol, trehalose and erythritol.
10. The manufacturing method according to any one of 9 to 10. 11. The method according to claim 10, wherein the water-soluble saccharide is one or more selected from lactose, maltose, mannitol, and erythritol. 12. The average particle diameter of the functional particles is 50 to 2
The production method according to any one of claims 1 to 11, wherein the proportion of the functional particles having a particle size of 00 µm and a particle diameter of 250 µm or more is 10% or less of the total amount of the functional particles. 13. The production method according to claim 1, wherein the functional particles are coated particles. 14. The content of the dispersant in the aqueous dispersion is
The manufacturing method according to claim 1, which is 0.05 to 2.0% by weight. 15. The amount of the water-soluble saccharide in the aqueous dispersion is 30 to 1000 parts by weight per 1 part by weight of the dispersant, and the amount of the functional particles is 1 per part by weight of the dispersant.
15. The method according to claim 14, which is about 500 parts by weight. 16. The method according to claim 14, wherein the water-soluble saccharide is not completely dissolved in water in the aqueous dispersion. 17. The method according to claim 1, wherein water is removed from the aqueous dispersion containing the functional particles by freeze-drying. 18. (a) A dispersant having a dispersion maintenance ratio at 25 ° C. of 75% or more and a viscosity of 100 mPa · s or less when uniformly contained in water at 1% by weight, (b) a water-soluble saccharide, and (C) Functional particle intraoral rapidly disintegrating preparation containing functional particles. 19. (a) A dispersant having a dispersion maintenance rate at 25 ° C. of 75% or more and a viscosity of 100 mPa · s or less when uniformly contained in water at 1% by weight, (b) a water-soluble saccharide, and (C) An orally rapidly disintegrating preparation containing functional particles, which is obtained by filling a mold with an aqueous dispersion containing functional particles and removing water. 20. The content of the dispersant in the preparation is 0.
The orally rapidly disintegrating preparation containing functional particles according to claim 18 or 19, which is 07 to 4% by weight. 21. The amount of the water-soluble saccharide in the preparation is 30 to 1,000 parts by weight per 1 part by weight of the dispersant, and the amount of the functional particles is 1 per part by weight of the dispersant.
1 to 500 parts by weight, any one of claims 18 to 20.
An orally rapidly disintegrating preparation containing the functional particle as described in the item. 22. The orally rapidly disintegrating preparation containing a functional particle according to any one of claims 18 to 21, which has a hardness of 10 N or more and an orally disintegrating time of 60 seconds or less.