WO2010038695A1

WO2010038695A1 - Compression-molded preparation and method for producing the same

Info

Publication number: WO2010038695A1
Application number: PCT/JP2009/066753
Authority: WO
Inventors: 裕里子小野; 陽彦洞口; 信夫山田
Original assignee: 大洋薬品工業株式会社
Priority date: 2008-09-30
Filing date: 2009-09-28
Publication date: 2010-04-08
Also published as: JP5694773B2; JPWO2010038695A1; TW201023850A; CN102170912A

Abstract

Provided are a compression-molded preparation such as an oral disintegrating preparation which has a property of rapidly disintegrating in the oral cavity and also has a hardness required for production, transportation, or the like and simultaneously does not cause a problem even if the preparation is produced with high productivity; and a method for producing the same. The compression-molded preparation contains a sugar alcohol, starch or a starch-derived compound and a polymeric binder selected from the group consisting of a polyvinyl alcohol-based polymer and copolyvidone. The method for producing the compression-molded preparation comprises a step of granulating a sugar alcohol with an aqueous solution obtained by dissolving starch or a starch-derived compound and a polymeric binder selected from the group consisting of a polyvinyl alcohol-based polymer and copolyvidone to form granules, and then a step of compression–molding the resulting granules.

Description

COMPRESSION MOLDED PREPARATION AND METHOD FOR PRODUCING THE SAME

The present invention relates to a compression-molded preparation such as an orally disintegrating tablet and a method for producing the same. More specifically, the present invention has excellent disintegrability in the oral cavity while having hardness that does not cause wear during production and transportation. Furthermore, the present invention relates to a compression-molded preparation with improved manufacturability in existing facilities and a method for producing the same.

Currently, oral preparations such as tablets, capsules, granules, and powders are most widely used as pharmaceutical dosage forms from the viewpoint of simplicity and ease of administration. However, many of such oral preparations have a problem that it is difficult to take for elderly people, children and patients who have difficulty swallowing.

For this reason, dry syrups and the like that can be suspended in water and made into syrups are also provided for ease of taking, but when this preparation is in the form of powder or granules, Even if each dose is packaged, the contents may remain in the package, or a part of the package may be spilled when opened, and there is a problem in taking an appropriate amount.

Therefore, in recent years, tablets or lozenges that can be taken without water and quickly disintegrate in the oral cavity, or tablets that dissolve quickly in an aqueous solvent when taken in water for the purpose of solving the problem of dosing. The development of lozenges is ongoing.

For example, as a method for producing a tablet or a troche as described above, a method for producing an orally disintegrating tablet (Table 1) that compresses a mixture containing water at a level where the particle surface is moistened, or an amorphous saccharide is mainly used. In addition, a method for producing an orally disintegrating tablet (Patent Documents 2 and 3) is known in which a tablet is compression-molded at a low pressure, moistened and moistened, and further dried. However, all of these technologies are capable of rapid disintegration in aqueous solvents and preparations that retain the hardness required for portability, but they can handle moisture during the manufacturing process and under high humidity. In view of the relationship with the physiologically active ingredient to be used, there is a possibility that it may cause a problem in stability, and it is not always satisfactory from the viewpoint of manufacturing process management. In addition, in preparation preparations according to the prior art, it is necessary to adjust the pressure at the time of compression molding to be constant, and there is a problem that the setting of manufacturing conditions becomes complicated.

On the other hand, the present inventors have previously used granules in which sugar is coated with magnesium aluminate metasilicate, thereby handling moisture during the manufacturing process, leaving it under high humidity, special manufacturing processes, etc. Was found that an orally disintegrating tablet can be obtained by an ordinary production method (Patent Document 4).

However, in the production of compression-molded preparations such as orally disintegrating tablets, further improvement in productivity has been demanded. That is, as a general manufacturing method of tablets, in order to simplify the process, additives that are raw materials are mixed and directly compressed (direct compression method), and the content of the physiologically active substance to be added is uniform. In order to ensure the above, a method of once forming granules and tableting is used. However, in the case of the direct compression method, it may be difficult to handle the powder as the raw material, and in the case of the method of tableting after forming the granule, the number of particles having a certain particle size or less increases. In particular, there is a drawback that the productivity is reduced due to powder scattering and the like. Furthermore, in the case of producing a compression molding preparation, it has been necessary to spend more time for compression molding than usual in order to suppress tableting troubles such as wrinkle adhesion, capping, lamination, and die friction. For this reason, there is a problem that productivity is inferior because the number of tablets produced per unit time is smaller than that of normal tablets. Further, when the hardness of the tablet cannot be sufficiently controlled, there is a problem that the yield is lowered due to damage during production and transportation.

As a technique for solving the above-described manufacturing problems, the present inventor uses mannitol, which is entirely or partially delta-type crystals, as a carrier component, so that even if the compression molding time is shortened, An orally disintegrating tablet that is a compression-molded preparation having a hardness that can withstand rapid disintegration, production, and transportation can be obtained, and powder scattering can be suppressed by reducing the amount of fine powder during granulation, The inventors found that damage to the preparation during production and transportation can be reduced by improving the compression moldability, and filed a patent application (Patent Document 5). However, even if this invention is used, the production quantity per hour of the compression molding machine is reduced as compared with normal tableting, or a special machine such as an external lubrication device that is not used in normal compression molding is not used. And compression molding was not possible. Therefore, there is still room for improvement as a method for producing a compression-molded preparation with high economic efficiency.

Japanese Patent Laid-Open No. 5-271054 Japanese Patent Laid-Open No. 11-12162 Japanese Patent Laid-Open No. 11-349475 JP 2002-308760 A WO 2006/106923

Therefore, in the production of compression-molded preparations, it has the necessary hardness for production, transportation, etc. while having rapid disintegration properties in the oral cavity, and at the same time, high productivity can be secured without using special equipment. The provision of such a technique is demanded, and it is an object of the present invention to provide such a technique.

The inventors of the present invention have been diligently researching on a compression molding preparation, and granulating sugar alcohol such as mannitol using a solution containing starch or a starch-derived processed product and a specific polymer binder such as polyvinyl alcohol. As a result, it was found that a compression-molded preparation having excellent disintegration properties and sufficient hardness as an orally disintegrating tablet can be obtained even under extremely high-speed tableting conditions, and the present invention has been completed.

That is, the present invention is a compression-molded preparation containing a sugar-based alcohol, starch or a starch-derived compound, and a polymer-based binder selected from the group consisting of a polyvinyl alcohol-based polymer and copolyvidone.

In the present invention, the sugar alcohol is granulated with an aqueous solution in which starch or a starch-derived compound and a polymer binder selected from the group consisting of a polyvinyl alcohol polymer and copolyvidone are dissolved to form granules, and then compressed. A method for producing a compression-molded preparation characterized by molding.

According to the present invention, even if tableting is performed at a speed exceeding 50,000 tablets / hour using a high-speed tableting machine, no special device is required, and tableting troubles such as sticking, capping, and die friction are prevented. A compression-molded preparation having both disintegration and hardness can be obtained without causing it. Even for high-speed tableting, the hardness of the preparation or the disintegration time in the oral cavity can be adjusted by appropriately adjusting the tableting pressure.

As described above, according to the present invention, since it is possible to prepare a compression-molded preparation such as an orally disintegrating tablet having appropriate disintegration property and appropriate hardness in the oral cavity at high speed, production time is shortened, yield is improved, and yield is increased. Improvements can be made, and productivity can be greatly improved.

Examples of the sugar alcohol used in the compression-molded preparation of the present invention include mannitol, xylitol, sorbitol, erythritol, etc. Among them, mannitol is preferable. Further, when mannitol is used as the sugar alcohol, it is preferable that all mannitol is delta type, or a part of mannitol is delta type, and other crystal forms are other than that.

In other words, it is known that mannitol has alpha, beta, and delta crystal polymorphs that are identified from the results of X-ray diffraction. It is desirable that at least a part of delta mannitol is contained in order to have an action such as reduction.

When mannitol is used as the sugar alcohol, the amount of delta-type mannitol is not particularly limited, but is 3% by mass (hereinafter simply referred to as “%”) or more, preferably 5% or more of the whole mannitol. Yes, more preferably 10% or more, still more preferably 20% or more.

The starch or starch-derived compound (hereinafter referred to as “starch”) used in the present invention is used as a binder that dissolves or swells in water at room temperature (hereinafter sometimes simply referred to as “binder”). Is.

Among these starches, starch-derived compounds are those in which starch, which is not normally dissolved in water, is dissolved in whole or in part by some method. Specifically, starch starch is pregelatinized or hydrolyzed. Things.

It should be noted that pregelatinization refers to a state in which water enters the crystal structure by breaking the hydrogen bond for maintaining the crystal structure by heating the starch soaked in water. Specifically, starch can be suspended in water and the suspension can be heated to alpha. Pregelatinized starch also includes starch that is at least partially pregelatinized, that is, substantially pregelatinized starch.

Also, since pregelatinized starch is commercially available as a pregelatinized compound, it can be used. Further, since partially pregelatinized starch is commercially available as substantially pregelatinized starch, it may be used.

Further, additives obtained by hydrolyzing starch are also “starches” and can be sufficiently used in the present invention. A specific example of such a starch hydrolyzate is dextrin. Furthermore, this patent also relates to pullulan, which is a natural polysaccharide in which maltotriose is regularly α-1,6-linked, obtained by culturing Aureobasidium pullulans , a kind of black yeast. Fully demonstrate the effect.

Furthermore, polyvinyl alcohol polymers and copolyvidone used in the present invention also act as binders (hereinafter, these may be collectively referred to as “polymer binders”).

Of these, the polyvinyl alcohol-based polymer is polyvinyl alcohol or a copolymer of vinyl alcohol and other monomers described later. Among them, as a copolymer of polyvinyl alcohol, a copolymer in which another polymer branches from a part of the main chain such as a graft copolymer, a copolymer in which polymer structural units are randomly arranged, such as a random copolymer, or Examples thereof include block copolymers. Specific examples of the graft copolymer include polyvinyl alcohol-polyethylene glycol graft copolymer, and specific examples of the random copolymer include polyvinyl alcohol-acrylic copolymer.

Among the above polymer-based binders, polyvinyl alcohol having a molecular weight of about 10,000 to 300,000, particularly about 30,000 to 200,000 is preferable. This polyvinyl alcohol can be produced or obtained by polymerizing vinyl acetate and saponifying it. The saponification type is classified into a complete saponification type and a partial saponification type, but the present invention sufficiently exhibits the effect of the present invention regardless of which polyvinyl alcohol is used.

Among the polymer-based binders, the polyvinyl alcohol-polyethylene glycol graft copolymer has a main chain of polyethylene glycol (PEG) portion and a side chain of polyvinyl alcohol (PVA) portion as represented by the following formula (I): It is a graft copolymer of PEG and PVA composed of

The polyvinyl alcohol-polyethylene glycol graft copolymer preferably has a molecular weight of about 10,000 to 100,000, particularly about 30,000 to 70,000. The polyvinyl alcohol-polyethylene glycol graft copolymer preferably has a weight ratio of PEG part to PVA part of 1: 0.1 to 10. As this polyvinyl alcohol-polyethylene glycol graft copolymer, Kollicoat IR (trade name) manufactured by BASF is commercially available, and can be used, but other products may also be used.

Further, among the polymer binders, the polyvinyl alcohol-acrylic copolymer is a copolymer containing PVA, acrylic acid and methyl (meth) acrylate as represented by the following formula (II).

The polyvinyl alcohol-acrylic copolymer preferably has a molecular weight of about 10,000 to 200,000, particularly about 30,000 to 100,000. The polyvinyl alcohol copolymer preferably has a weight ratio of PVA to acrylic acid and methyl methacrylate of 1: 0.01 to 0.1: 0.1 to 0.5. As this polyvinyl alcohol-acrylic copolymer, POVACOAT (trade name) manufactured by Nisshin Kasei Co., Ltd. is commercially available. This can be used, but other products may also be used.

Furthermore, among the polymer binders, copolyvidone is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate, as represented by the following formula (III).

The copolyvidone preferably has a molecular weight of about 10,000 to 100,000, particularly about 45,000 to 70,000. The weight ratio of 1-vinyl-2-pyrrolidone and vinyl acetate in this copolyvidone is not particularly limited, but is preferably 1: 5 to 0.1, more preferably 1: 1 to 0.5. As this copolyvidone, Kollidon VA64 (trade name) is commercially available from BASF, and can be used, but other products may also be used.

In the compression-molded preparation of the present invention, the amount of sugar alcohol is about 30 to 98%, preferably 50 to 95% in the preparation. Further, the compounding amount of starches is about 0.01 to 10% in the preparation, preferably about 0.05 to 5%, and the amount of the polymer binder is about 0.01 to 10% in the preparation, preferably Is about 0.05 to 2%. In addition, the blending ratio of starch to sugar alcohol is preferably 0.1 to 5 with respect to sugar alcohol 100, and the blending ratio of polymer binder to sugar alcohol 100 is 0.5 to sugar alcohol 100. Or 10 is preferred.

As an example of a preferable method for preparing the compression-molded preparation of the present invention using each of the above-mentioned components, first, starches and a polymer binder are dissolved or suspended in a solvent such as purified water, and this dissolution or suspension is performed. The method of granulating sugar alcohols, such as a mannitol, using a liquid is mentioned.

The granulator used in this case is not particularly limited as long as it is a granulator capable of forming a granular material with almost no fine powder like ordinary tableting granules. However, in consideration of productivity, etc., preferably a fluidized bed granulator, a stirring granulator, an extrusion granulator, a rolling granulator, a Wurster granulator, or a granulator that combines these is best. Examples of such granulators include fluidized bed granulators.

The granulated product thus granulated is then compression molded and formulated. This compression molding can be used without particular limitation as long as it is a general compression molding method. For example, a granule prepared from a powder prepared by mixing mannitol as a sugar alcohol, starches, a polymer-based binder, and a physiologically active substance, and inorganic salts and other optional components blended as necessary. It is possible to prepare a compression-molded preparation by compression molding using a tableting machine such as a rotary tableting machine or a single-shot tableting machine.

In consideration of actual production, a preferred compression molding machine is a rotary tableting machine. In this case, as long as actual production is involved, the productivity per hour of compression molding is not particularly limited, but is preferably 50,000 tablets or more per hour, more preferably 100,000 tablets. That's it. The rotary tableting machine greatly affects the tableting characteristics because the compression molding time varies depending on the number of rotations of the turntable. It is also known that the size of the turntable as well as the rotation speed of the turntable affects the tableting characteristics.

Therefore, by adjusting these factors, there will be a difference in production capacity. Usually, the lower the rotation speed of the turntable or the shorter the radius, there is no occurrence of tableting trouble and stable production can be achieved. On the other hand, if the rotational speed is low and / or the radius of the turntable is short, the productivity per hour falls, so it is not suitable for actual production. Therefore, when expressed by the product of the square of the number of revolutions per hour (rpm) of the turntable and the radius of the turntable (in this case, the radius is the distance (m) from the center to the center of the die), preferably 50 or more, preferably It is suitable for actual production when tableting is performed under conditions of 80 or more, more preferably 150 or more.

Further, the pressure at the time of compression molding is not particularly limited as long as the disintegration time and texture in the oral cavity are appropriate, and there are no cracks at the time of production and transportation, preferably 100 to 2000 kgf, More preferably, compression molding is performed at 300 to 1500 kgf.

Furthermore, the compression-molded preparation of the present invention can be made into an orally disintegrating tablet. The orally disintegrating tablet of the present invention may be rapidly disintegrated when a compression-molded preparation is included in the oral cavity, and the specific disintegration time is preferably within 3 minutes after being included in the oral cavity. Is within 1 minute, more preferably within 30 seconds. And the orally disintegrating tablet which reached this invention is improved more than before with respect to the cracks, chipping, etc. of transportation etc., and has provided the durability similar to a normal compression molding formulation. As an index for verifying these, evaluation is carried out using the tablet friability test method described in the 15th revised Japanese Pharmacopoeia.

Specifically, 100 tablets compressed into a friability tester described in the 15th revision Japanese Pharmacopoeia are put in, and the apparatus is operated for 30 minutes. Next, the tablet weight before and after the test is measured, and the reduction rate of the tablet weight is determined by the following equation. As a result, a tablet weight reduction rate of 5.0% or less is a preferred compression molding preparation of the present invention, and a compression molding preparation of 2.0% or less, particularly 1.0% or less is preferred.

Reduction rate (%) = (weight before test-weight after test) / weight before test x 100

In the production of the compression-molded preparation of the present invention, other known binders can be used in addition to the aforementioned starches and polymer binders. Preferred examples of such a binder include a compound that can dissolve in water by substituting a part of cellulose with a hydrophilic substituent, and can be dissolved in water by hydrolyzing and pregelatinizing starches. Examples include compounds obtained by chemically changing cellulose, starch, and the like as described above with microorganisms. Specific examples include hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carmellose sodium, dextrin, pullulan, and soluble polyvinylpyrrolidone.

Furthermore, the addition method of the inorganic compound is not particularly limited. For example, together with sugar alcohol such as mannitol, a method of adding during granulation, a method of adding to a binder liquid (granulation liquid), a granule after granulation There is a method of adding to. Moreover, you may employ | adopt the method of coating an inorganic compound on the granulated material of sugar alcohol, starches, and a polymer type binder. Among these, the preferred method is the method of adding to the binder solution, the method of coating the granules after granulation, the method of adding to the granules after granulation, and the best method is dissolving in mannitol and water at room temperature. Alternatively, it is a method of coating on a granulated product of a swelling binder or a method of adding after granulation.

The compression-molded preparation of the present invention basically contains a physiologically active substance as an active ingredient. The compounding of the physiologically active substance into the compression molding preparation may be carried out at any stage of the production of the compression molding preparation. For example, a method of blending a physiologically active ingredient together with sugar alcohol at the time of granulation, or adding to a binder solution And a method of blending with granulated granules.

Furthermore, the physiologically active ingredient that can be blended as an active ingredient is not particularly limited. Agent, autonomic nerve agent, antispasmodic agent, cardiotonic agent, arrhythmic agent, diuretic agent, antihypertensive agent, vasoconstrictor, vasodilator, hyperlipidemia agent, antitussive agent, expectorant, bronchodilator, antipruritic agent Peptic ulcer agent, healthy stomach digestive agent, antacid, laxative, hormone agent, vitamin agent, nourishing tonic, enzyme preparation, diabetic agent, antihistamine, allergic agent, antibiotic preparation, synthetic antibacterial agent, sickness prevention A physiologically active ingredient which is an active ingredient such as an agent can be used.

Among these, as physiologically active components of sleep sedatives and anxiolytic agents, for example, alprazolam, estazolam, quazepam, triazolam, brotizolam, amobarbital, tandospirone, etc., as physiologically active components of antiepileptic agents, for example, phenytoin, Carbamazepine, clonazepam, phenytoin, etc., as the physiologically active components of antipyretic analgesics, for example, acetaminophen, phenacetin, mefenamic acid, aspirin, ethenamide, isopropylantipyrine, sodium salicylate, indomethacin, diclofenac, tiaramid, actarit, ampiroxicam, Ibuprofen, etodolac, ketoprofen, zaltoprofen, piroxicam, pranoprofen, loxoprofen, etc. are the bioactive ingredients of anti-parkinsonian drugs For example, amantadine, biperidene, selegiline, trihexyphenidyl, cabergoline, pergolide, and the like as the physiologically active ingredients of the neuropsychiatric agent, for example, chlorpromazine, perphenazine, triproperazine, imipramine, etizolam, olanzapine, Quazepam, sulpiride, haloperidol, risperidone, etc. are examples of physiologically active components of autonomic nerve agents, such as carpronium, distigmine, tolazoline, etc., and physiologically active components of antispasmodics are butylscopolamine bromide, papaverine, eperisone, tizanidine , Baclofen and the like.

Examples of the cardiotonic agent include dichitoxin, digoxin, methyldigoxin, aminophylline, caffeine, ethylephrine, ubidecalenone, and examples of the arrhythmia agent include procainamide, atenolol, oxprenolol, carteolol, propranolol, and nadolol. , Pindolol, bisoprolol, ajmarin, pirucainide, propaphenone, methiciletin, disopyramide, etc., as diuretics, for example, hydrochlorothiazide, spironolactone, acetazolamide, isosorbide, torasemide, furosemide, etc. , Alasepril, imidapril, quinapril, captopril, cilazapril, enalapril, lisinopril, methyldova, efonidipine Seriprolol, nicardipine, prazosin, betaxolol, manidipine, carvedilol, metoprolol, cilnidipine, felodipine, doxazosin, etc., as vasoconstrictors, for example, midodrine, dihydroergotamine, etc., as vasodilators, for example, isosorbide mononitrate, Etaphenone, diltiazem, benidipine, dipyridamole, isosorbide nitrate, nicorandil, nisoldipine, nitroglycerin, nifedipine and the like as the hyperlipidemic agent, for example, clofebrate, fenofibrate, bezafibrate, adolvastatin, elastase, nicomol, pravastatin , Fluvastatin, probucol, simvastatin and the like.

Furthermore, as antitussives, for example, ephedrine, methylephedrine, noscapine, benproperin and the like, and as an expectorant, for example, carbocysteine, bromhexine, ambroxol, cherry bark, codeine, dihydrocodeine, tipepidine and the like are bronchodilators. As, for example, theophylline, fenoterol, salbutamol, clenbuterol, tulobuterol, trimethoquinol, procaterol, formoterol, etc., as antidiarrheal agent / intestinal, for example, berberine, albumin, bifidobacteria, lactamine, dimethicone, loperamide, etc. Examples of ulcers include glutamine, azulene, ranitidine, cimetidine, famotidine, nizatidine, loxatidine, aldioxa, pirenzepine, omeprazole, gefa Nart, sucralfate, sulpiride, cefircon, teprenone, troxipide, irsogladine, rabeprazole, lansoprazole and the like as gastric digestive agents, for example, amylase, diastase, pancreatin, fomikatinki, carnitine, galactosidase, etc. Examples include magnesium silicate, magnesium oxide, sodium hydrogen carbonate, magnesium carbonate, precipitated calcium carbonate, and examples of laxatives include senna extract, sennoside, magnesium sulfate, and picosulfate.

Furthermore, as hormonal agents, for example, levothyroxine, liothyronine, thiamazole, propylliouracil, cortisone, parameterzone, dexamethasone, betamethasone, prednisolone, testosterone, phosfestol, estriol, chlormadinone, allylestrenol, clomiphene, tanazole, Tamsulosin, flavoxate, midodrine, gamma oryzanol, etc., as vitamin agents, for example, vitamin A, calcitriol, thiamine, fursultiamine, riboflavin, panthetin, pantothenic acid, pyridoxine, folic acid, cobamide, mecobalamin, ascorbic acid, tocopherol Phytonadione, menatetrenone, biotin, etc. are examples of enzyme preparations such as lysozyme, serrapeptase, etc. Examples of antidiabetic agents include gliclazide, glibenclamide, glimepiride, tolbutamide, metformin, acarbose, voglibose, etc., and antihistamines include, for example, diphenhydramine, promethazine, mequitazine, chlorpheniramine, clemastine, etc. Examples include ibudilast, azelastine, epinastine, cetirizine, suplatast, tranilast, ketotifen, pranlukast, pemirolast, loratadine and the like.

Still further, antibiotics include, for example, clindamycin, lincomycin, vancomycin, kanamycin, amoxicillin, ampicillin, cefaclor, cephalexin, cefixime, cefpodoxime, cefdinir, cefteram, cefpodoxime, fosfomycin, faropenem, erythromycin, azithromycin, clarithromycin , Roxithromycin, chloramphenicol, tetracycline, minocycline, salazosulfapyridine, ciprofloxacin, gatifloxacin, norfloxacin, acyclovir, itraconazole, terbinafine, fluconazole, miconazole and the like.

In the orally disintegrating tablet of the present invention, conventionally known optional components such as various lubricants, solubilizers, buffers, adsorbents, etc., as long as the effects of the present invention other than the above components are not impaired. , Suspending agents, antioxidants, fillers, pH adjusting agents, excipients, dispersants, disintegrating agents, disintegrating aids, moisture-proofing agents, preservatives, solvents, solubilizing agents, fluidizing agents, etc. be able to.

Among these, examples of excipients include lactose, purified white sugar, crystalline cellulose, dextran, dextrin, glucose, and powdered sugar. Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl methylcellulose, crystalline cellulose, and hydroxypropyl starch.

Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, talc, and sucrose fatty acid ester. Examples of the coating agent include hydroxypropyl methylcellulose, ethyl acrylate / methyl methacrylate copolymer, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid Acid copolymer S etc. are mentioned. Furthermore, examples of the taste masking component include citric acid, tartaric acid, malic acid and the like. Examples of the foaming agent include sodium bicarbonate. Examples of the artificial sweetener include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia, thaumatin and the like. Examples of the masking agent include water-insoluble polymers such as ethyl cellulose and gastric polymers such as methyl methacrylate / butyl methacrylate / diethylaminoethyl methacrylate copolymer.

The compression-molded preparation of the present invention described above has both sufficient hardness during production and transportation and rapid disintegration in the oral cavity. In addition, for example, even in high-speed tableting of 50,000 to 200,000 tablets per hour, since there is no tableting trouble and the friability is low, high productivity can be expected.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

Example 1
Orally disintegrating tablets:
Orally disintegrating tablets were produced according to the formulation and production method shown in Table 1 below.

<Production method>
Polyvinyl alcohol and pregelatinized starch were dissolved in water to prepare an aqueous solution. Using this aqueous solution, a mixture of D-mannitol and delta mannitol was granulated in a fluidized bed. Crospovidone, aspartame, and magnesium stearate were added to this granulated product and compression molded to obtain 180 mg orally disintegrating tablets per tablet. For compression molding, Hata Seisakusho's HT-X45MS-UW medium size tablet press (turntable radius: 23 cm, number of punches: 45), tableting pressure of 800 kgf, turntable rotation speed Was changed from 20 times to 60 times / min to produce an orally disintegrating tablet (referred to as “Tablet 1”). Tablets 2 to 4 are the same as in the above production method except that polyvinyl alcohol-polyethylene glycol graft copolymer (tablet 2), copolyvidone (tablet 3), and polyvinyl alcohol-acrylic copolymer (tablet 4) are used instead of polyvinyl alcohol. It was prepared as follows.

Example 2
Evaluation of orally disintegrating tablets (1):
For the orally disintegrating tablets prepared in Example 1, the tablets 1 to 4 obtained were evaluated for hardness, friability, disintegration time in the oral cavity, and tableting failure. The results are shown in Table 2.

<Evaluation method>
Evaluation of each item was performed as follows.
Hardness: The hardness of the tablet was measured using a hardness meter (tablet breaking strength measuring instrument TH-303MP: Toyama Sangyo Co., Ltd.).
Abrasion degree: A friability tester (tablet friability tester: Minato Medical Co., Ltd.) was used to check the state of tablet abrasion (test time 30 minutes, tablet quantity 100 tablets).
Oral disintegration time: An adult male was used as a panel, the manufactured tablet was included in the mouth, and the time until the tablet disintegrated was measured.
Presence / absence of tableting failure: The presence or absence of tableting failure such as capping, lamination, sticking, die friction and wrinkle adhesion during tableting was evaluated.

As a result, an orally disintegrating tablet with excellent hardness and friability and no tableting trouble was obtained at a rotational speed of 20 to 60 times / minute. According to the formulation of the present invention, 50,000 tablets or more per hour were obtained. It became clear that high-speed tableting is possible.

Example 3
Evaluation of orally disintegrating tablets (2):
In tablet 1 of Example 1, an orally disintegrating tablet was prepared in the same manner except that the turntable rotation speed was 40 times / minute and the tableting pressure was changed. The hardness, friability, The disintegration time and the presence or absence of tableting failure were evaluated in the same manner as in Example 2. The results are shown in Table 3.

From this result, it is clear that even in the case of high speed rotation of 40 rotations / minute, it is possible to obtain an intraoral rapidly disintegrating tablet having excellent hardness and friability and no tableting trouble. It was revealed that orally disintegrating tablets with different hardness and disintegrating time in the oral cavity can be obtained by changing the tablet pressure.

The compression-molded preparation of the present invention combines the rapid disintegration property in the oral cavity with the hardness necessary for production, transportation, etc., and can be advantageously used when orally administering various physiologically active substances. It is.

Further, according to the method for producing a compression-molded preparation of the present invention, it is possible to stably perform tableting without causing tableting troubles such as wrinkle adhesion, capping and die friction without using an external sliding device. Even if the time is shortened, a compression-molded preparation having rapid disintegration can be obtained. Further, since the compression molding can be performed at a high speed, the productivity is dramatically improved.

Therefore, the method of the present invention is extremely advantageous as a method for producing a compression-molded preparation.

Claims

A compression-molded preparation containing sugar alcohol, starch or a starch-derived compound, and a polymer binder selected from the group consisting of polyvinyl alcohol polymers and copolyvidone.
2. The compression molded preparation according to claim 1, wherein the sugar alcohol is mannitol.
3. The compression-molded preparation according to claim 1 or 2, wherein all or part of mannitol is a delta type.
The compression-molded preparation according to any one of claims 1 to 3, wherein the sugar alcohol content is 30 to 98 mass% with respect to the total composition of the preparation.
5. The compression-molded preparation according to any one of claims 1 to 4, wherein the starch or the starch-derived compound is soluble in water or hot water.
6. The compression-molded preparation according to any one of claims 1 to 5, wherein the starch or starch-derived compound is all or part of starch that is pregelatinized.
The compression-molded preparation according to any one of claims 1 to 6, wherein the content of starch or starch-derived compound is 0.01 to 10% by mass relative to the total composition of the preparation.
The compression-molded preparation according to any one of claims 1 to 7, wherein the polyvinyl alcohol-based polymer is polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, or polyvinyl alcohol-acrylic copolymer.
The compression-molded preparation according to any one of claims 1 to 8, wherein the content of the polymer binder is 0.01 to 10% by mass with respect to the total composition of the preparation.
The compression-molded preparation according to any one of claims 1 to 9, further comprising a physiologically active ingredient.
The compression-molded preparation according to any one of claims 1 to 9, which is an orally disintegrating tablet.
The sugar alcohol is granulated with an aqueous solution in which starch or a starch-derived compound and a polymer-based binder selected from the group consisting of a polyvinyl alcohol-based polymer and copolyvidone are dissolved to form granules, which are then compression-molded. A method for producing a compression-molded preparation.
The method for producing a compression-molded preparation according to claim 12, wherein the polyvinyl alcohol-based polymer is polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer or polyvinyl alcohol-acrylic copolymer.
Furthermore, the manufacturing method of the compression molding formulation of Claim 12 or 13 which mix | blends a bioactive component in any process of a compression molding formulation.
The method for producing a compression-molded preparation according to any one of claims 12 to 14, wherein the number of tableting per hour is 50,000 tablets or more.