WO2006106923A1 - Disintegrating tablet in oral cavity and process for producing the same - Google Patents

Abstract

It is intended to provide a disintegrating tablet in oral cavity which rapidly disintegrates in the oral cavity and has a hardness required for production, transportation or the like, and a technique for improving the productivity of the disintegrating tablet in oral cavity. The disintegrating tablet in oral cavity comprises mannitol and is characterized in that all or part of the mannitol is in the delta crystalline form. A process for producing the disintegrating tablet in oral cavity comprises the steps of preparing granulated matter using mannitol and a binder that dissolves or swells in water at normal temperature, and tableting this granulated matter, and is characterized in that all or part of the mannitol is in the delta crystalline form.

Description

 Specification

 Orally disintegrating tablet and method for producing the same

 Technical field

 [0001] The present invention relates to an orally disintegrating tablet, and more particularly, to an orally disintegrating tablet and a method for producing the orally disintegrating tablet capable of improving production efficiency without wear during production and transportation.

 Background art

 [0002] Currently, oral preparations such as tablets, capsules, condyles, and powders are most widely used as pharmaceutical dosage forms in terms of ease of use and ease of administration. However, many of these oral preparations have the problem that they are difficult to take for the elderly and children who have difficulty swallowing.

 [0003] For this reason, dry syrups and the like that can be suspended in water and made into syrup are also provided in order to facilitate administration, but in the case of powder or granular form. However, even if each dose is packaged, there is a risk that the contents may remain in the package, or a part of it may be spilled when opened, and there is a problem in taking the appropriate amount. The

[0004] Therefore, recently, for the purpose of solving the problem of ingestion, tablets or lozenges that can be taken without water and quickly disintegrate in the oral cavity, or when dissolved in water, are promptly used. Tablets or lozenges that are soluble in aqueous solvents are being developed.

[0005] For example, as a method for producing such a tablet! /, Troche, as described above, a method for producing an orally disintegrating tablet that compresses a mixture containing water at such a level that the particle surface wets (Patent Document 1). In addition, a method for producing an orally disintegrating tablet (Patent Documents 2 and 3) is known in which an amorphous saccharide is mainly used, compression molding is performed at a low pressure, and then the tablet is placed in a humidified state and moistened, and further dried. However, all of these technologies can produce a preparation that maintains the required speed and strength of disintegration in an aqueous solvent and the hardness required for portability, but the handling of moisture during the manufacturing process, It may cause problems in stability due to the relationship with the physiologically active ingredients used, such as requiring it to be left under high humidity, and is not always satisfactory from the point of manufacturing process management. . In addition, the preparation of the preparation according to the conventional technique has a problem that it is necessary to adjust the pressure at the time of compression molding to be constant, and the setting of manufacturing conditions becomes complicated. [0006] In contrast, the present inventors previously used granules coated with magnesium aluminate metasilicate on sugar, thereby handling moisture during the manufacturing process, leaving it under high humidity, The present inventors have found that an orally disintegrating tablet can be obtained by an ordinary production method without requiring a special production process, and filed a patent application (Patent Document 4).

 [0007] However, in producing an orally disintegrating tablet, further improvement in productivity has been demanded. In other words, as a general method for producing tablets, in order to simplify the process, the additives as raw materials are mixed and directly compressed (direct compression method), or the content of the physiologically active substance to be added In order to ensure uniformity, a method of once forming granules and tableting is used, but in the case of the direct compression method, it may be difficult to handle the raw material powder. In the case of the method of tableting after the formation, there is a drawback that the productivity is reduced due to powder scattering caused by the increase in the number of particles having a particle size of a certain value or less. Furthermore, when manufacturing an orally disintegrating tablet, it was necessary to spend more time on compression molding than usual in order to suppress tableting troubles such as fouling, caving, lamination, and die-friction.

. For this reason, there is a problem that productivity is insufficient because the number of tablets produced per unit time is smaller than that of normal tablets. In addition, if the tablet hardness is sufficiently controlled, there is a problem in that the yield is reduced due to breakage during production and transportation.

Patent Document 1: Japanese Patent Laid-Open No. 5-271054

 Patent Document 2: Japanese Patent Laid-Open No. 11-12162

 Patent Document 3: Japanese Patent Laid-Open No. 11-349475

 Patent Document 4: Japanese Patent Laid-Open No. 2002-308760

 Disclosure of the invention

 Problems to be solved by the invention

[0009] Therefore, in the production of orally disintegrating tablets, there is a need to provide a technique for improving productivity while simultaneously having rapid disintegration in the oral cavity and hardness necessary for production, transportation, etc. Providing such a technique is the subject of the present invention.

 Means for solving the problem

[0010] As a result of studying to solve the problems of the related art, the present inventors have reduced the compression molding time by using mannitol, which is entirely or partly a delta crystal as a carrier. Even if shortened, an orally disintegrating tablet with hardness that can withstand rapid oral disintegration, production, and transportation can be obtained, and powder scattering is suppressed by reducing the amount of fine powder during granulation. Furthermore, the present inventors have found that the damage of the preparation during production and transportation can be reduced by improving the compression moldability, thereby completing the present invention.

 [0011] That is, the present invention provides an orally disintegrating tablet containing mannitol, wherein all or part of the mannitol is a delta crystalline mannitol. .

 [0012] The present invention also relates to a method for producing an orally disintegrating tablet, comprising preparing a granulated product using mannitol and a binder that dissolves or swells in water at room temperature and compresses the granulated product. The present invention provides a method for producing an orally disintegrating tablet, characterized in that all or part of the mannitol is delta-type mannitol.

 The invention's effect

 [0013] According to the present invention, it is possible to stably tablet without causing tableting troubles such as wrinkle adhesion, cabbing, die friction and the like, and the oral cavity has quick disintegration even if the compression molding time is shortened. An internally disintegrating tablet can be obtained. In addition, powder scattering can be suppressed by reducing the fine powder during granulation. Furthermore, by improving the compression moldability, it is possible to reduce the breakage of the preparation during production and transportation.

 [0014] Thus, according to the present invention, in the production of an orally disintegrating tablet, a tablet having a rapid disintegration property and appropriate hardness is obtained, and the production time is shortened, the yield is improved, and the yield is improved. Can be improved.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0015] Mantle to be used in the present invention may be a force in which all mannitol is a delta type, a part of mannitol is a delta type, and other crystal forms may be used. Mantol is a type of white sugar alcohol. This product is sweet and can give a refreshing sensation in the oral cavity, and since it dissolves easily in water, it has been used in various preparations, especially intraoral quick-disintegrating tablets and troches. It is. Conventionally, however, mannitol has been considered to be susceptible to creaking between the mortars due to its poor bonding properties during compression molding. To improve this, a large amount of binder is required. However, when tableting property is increased, there is a problem that the expected disintegration property cannot be obtained. From these, it was said that some kind of technique was required for use.

 [0016] By the way, it was known that man-toll had alpha-, beta-, and delta-type polymorphs from the results of X-ray diffraction. For reducing squeaks, etc., it was completely unknown.

 [0017] In the present invention, a part or all of mannitol may be delta mannitol. In this case, the compression molding preparation disintegrates rapidly in the oral cavity. The amount may be such that the tableting trouble at the time of compression molding is eliminated. In this case, rapid disintegration in the oral cavity means that the disintegration time in the oral cavity is preferably within 3 minutes, more preferably within 1 minute, and more preferably within 30 seconds.

 [0018] Also, normally, when the powder to be tableted causes friction with the metal adhesion surface, the side surface of the tablet is scratched. If this phenomenon (difriction) continues for a long time, it will cause tableting troubles such as laminating. Although there are various evaluations of friction on the metal-attached surface, the simplest and possible method during production is to observe the side of the tablet and confirm that there are no scratches. This method is also used in the present invention. Adopted, it is possible to cut half of the amount to the extent that the above tableting obstacles are eliminated.

 [0019] The amount of delta mannitol that can be used in the present invention is not particularly limited as described above, but specifically, it is 3% by mass (hereinafter simply referred to as "%") of the entire man-tol. Or more, preferably 5% or more, more preferably 10% or more, and still more preferably 20% or more.

 [0020] On the other hand, the binder used in the present invention that dissolves or swells in water at room temperature (hereinafter sometimes simply referred to as "binder") is dissolved or swelled in water at room temperature. What is used as a binder is not particularly limited. In this case, the term “dissolving in water” specifically means that it dissolves at least 1 lg per liter of purified water at room temperature, and more preferably dissolves at least 10 g.

[0021] Preferred examples of the binder used in the present invention include polymer compounds. Examples of such a high molecular weight compound include hydrolyzed starches that are soluble in water by substituting a part of cellulose with a hydrophilic substituent, Examples thereof include a compound which has been made soluble in water by being unified, or a substance obtained by chemically changing cellulose, starch or the like by a microorganism. A compound obtained by synthesis is also effective for carrying out the present invention. Specific examples include hydroxypropylcellulose, hydroxychetinoresenorerose, hydroxypropinoremethinoresenellose, strength nomellose sodium, pregelatinized starch, dextrin, pullulan, polybulal alcohol, and soluble polybulur pyrrolidone. .

 [0022] Particularly preferable binders for exhibiting the effects of the present invention include starch-derived compounds (hereinafter referred to as "starches") that can be dissolved at room temperature or partially. Such compounds are those in which some or all of the starch, which is not normally dissolved in water, is in a state where all or part of the starch is dissolved, specifically starch alpha unification or hydrolyzate. Is mentioned.

 [0023] It should be noted that alpha unification refers to a state in which water enters a crystal structure by breaking a hydrogen bond for maintaining the crystal structure by heating starch that has penetrated water. Specifically, the starch can be alpha-ized by suspending it in water and heating the suspension. Alpha-ized starch also includes starch that is at least partially alpha-ized, i.e., substantially alpha-ized starch.

 [0024] Therefore, at present, alpha-ized starch is commercially available as an alpha-ized compound, and this can also be used. In addition, partially pregelatinized starch is commercially available as a substantially alpha-denatured starch, which may be used.

 [0025] Furthermore, 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. In addition, it is also available for pullulan, a natural polysaccharide with regular α-1,6-linked maltotriose obtained by culturing Aureoba sidium pullulans, a kind of black yeast. Fully demonstrate the effect of the patent.

 [0026] The ratio of mannitol and binder in the production of the orally disintegrating tablet of the present invention is not particularly limited, but preferably 0.05 to 20% of the binder with respect to mannitol, More preferably, it is 0.1-5%, More preferably, it is 0.5-3%.

[0027] These components can be mixed and granulated as they are. Better results are obtained. For this purpose, it is preferable to first dissolve or suspend the binder in a solvent such as purified water and granulate mannitol containing delta-type mannitol using this suspension.

 [0028] The granulating apparatus that can be used in this case is not particularly limited as long as it is a granulator capable of producing a granular material in the absence of fine powder. However, in consideration of productivity, etc., it is preferable that the fluidized bed granulator, the stirring granulator, the extrusion granulator, the rolling granulator, the Wurster granulator or a combination of these. The best granulator is a fluidized bed granulator.

 [0029] In order to further exhibit the effects of the present invention, an inorganic salt may be added. The inorganic salt that can be used in the present invention is not particularly limited, but it ensures compression moldability and further reduces friction with the metal adhesion surface during tableting such as die friction. Just do it.

 [0030] Examples of the inorganic salt satisfying such conditions include kai acids and calcium carbonate. Of these, carboxylic acids are preferred, and silicates are more preferred. Specific examples include magnesium silicate, calcium silicate, magnesium metasilicate, magnesium aluminum silicate, and light anhydrous carboxylic acid. Of these silicates, the more preferred silicate is magnesium aluminate metasilicate.

[0031] The addition amount of the inorganic salt is not intended to be otherwise limited, and preferably 0.5 relative mannitol 01-300 _^0/0, more preferably ί or 0.05 to 200 _^0/0, more preferably ί It is 0.1 to 100%.

 [0032] Further, the addition method of the inorganic salt is not particularly limited, for example, a method of adding together with mannitol at the time of granulation, a method of adding to the granulation liquid, a method of adding calories to the granulated granules, etc. There is. Alternatively, a method of coating an inorganic salt on a granulated product of mannitol and a binder that dissolves or swells in water at room temperature may be employed. Of these, the preferred method is the method of adding to the granulation liquid, the method of coating the granulated granule, the method of adding to the granulated granule, and the best method is mannitol and room temperature. This is a method of coating a granulated product of a binder that dissolves or swells in water, or a method of adding after granulation.

[0033] On the other hand, as the physiologically active ingredient that can be blended in the orally disintegrating tablet of the present invention, For example, sleep sedatives, anti-anxiety agents, antiepileptic agents, antipyretic analgesics, anti-parkinsonian agents, psychiatric agents, autonomic agents, antispasmodics, cardiotonic agents, arrhythmic agents, diuretics, Antihypertensive agent, vasoconstrictor, vasodilator, hyperlipidemia agent, antitussive agent, expectorant, bronchodilator, antidiarrheal agent, peptic ulcer agent, digestive stomach digester, antacid, laxative, hormone Bioactive ingredients that are active ingredients such as agents, vitamins, nourishing tonics, enzyme preparations, antidiabetic agents, antihistamines, allergic agents, antibiotic preparations, synthetic antibacterial agents, and anti-drunk agents can be used.

 Among these, as physiologically active ingredients of sleep sedatives and anxiolytics, for example, alprazolam, estazolam, quazepam, triazolam, brotizolam, amobarbital, tandospirone, etc., as physiologically active ingredients of antiepileptic agents, Phytoin, carbamazepine, clonazepam, phenytoin, etc. are examples of physiologically active ingredients of antipyretic analgesics such as acetaminophen, phenacetin, mefenam, aspirin, ethenzamide, isopropylantipyrine, sodium salicylate, indomethacin, diclofenac, Thiaramid, Actarit, Ampiroxicam, Ibuprofen, Etodolac, Ketoprofen, Zaltoprofen, Piroxicam, Planoprofen, Loxoprofen, etc. As a bioactive component of antiparkinsonian For example, amantadine, piperidene, selegiline, trihexifere-zil, strength belgorin, pergolide, etc., as the physiologically active ingredients of the neuropsychiatric agents, for example, chlorpromadine, perphenazine, triproperazine, imipramine, etizolam, olanzapine, Quazepam, sulpiride, haloperidol, risperidone, etc. are examples of physiologically active components of autonomic nerve agents, such as calpe mouth-um, distigmine, torazoline, etc., and physiologically active components of antiseptics are butyl bromide. Examples include scopolamine, papaverine, eperisone, tizazine and nocrophene.

[0035] In addition, examples of the cardiotonic agent include diquitoxin, digoxin, methyldigoxin, aminophylline, caffeine, ethylephrine, ubidecarenone, and the like, and examples of the arrhythmia agent include procainamide, atenolol, oxprenolol, carteolol, propranolol. Nord, nadolol, pindolol, bisoprolol, azimarin, pirucainide, propafenone, methiciletin, disopyramide, etc. As diuretics, for example, hydrothiazia thiazide, spirolalatone, acetazolamide, isosorbide, torasemide, furosemide, etc. For example, hydralazine, reserpine, alaspril, imidapril, quinapril, captopril, cilazapril, enalapril, lisinopril, methyldonocre, efodidipine, seripro oral, dicardipine, prazosin, betaxolol, manidipine, carvedilol, metoprolol, -Dipine, ferrodipine, doxazosin, etc., as vasoconstrictors, for example, middolin, dihydroergotamine, etc.As vasodilators, isosorbide mononitrate, etafenone, diltiazem, bedipine, dipyridamole, isosorbide nitrate, nicorandil, di Soldipine, nitroglycerin, difedipine, etc. are examples of antihyperlipidemic agents such as clofebrate, fenofibrate, bezafibrate, adolvastatin, elastane. , Nicomol, pravastatin, full pasta Chin, Purobukonore, simvastatin down, and the like, respectively.

 [0036] Further, as antitussives, for example, ephedrine, methylephedrine, noscalvin, benproperin and the like, such as carcistine, bromhexine, ambroxol, cherry bark, codin, dihydrocodine, tippe. Pidgin is a bronchodilator such as theophylline, fenoterol, salbutamol, clenbuterol, llulobuterol, trimethoquinol, pro-powered terol, formoterol, etc. Bacteria, lactamine, dimethicone, oral peramide, etc. include peptic ulcers such as glutamine, azulene, latidine, cimetidine, famotidine, -zatidine, oral xanthidine, aldioxa, pirenzepine, omebrazole, gefarnate, Sucralfate, sulpiride, sofalcone, teprenone, troxipide, isogladine, rabebrazole, lansoprazole, etc. As a healthy stomach antiseptic, for example, amylase, diastase, pancreatine, fumika tincture, carnitine, galactosidase, etc. For example, magnesium silicate, magnesium oxide, sodium hydrogen carbonate, magnesium carbonate, precipitated calcium carbonate and the like. As a laxative, for example, senna extract, sennoside, magnesium sulfate, picosulfate and the like can be mentioned.

[0037] Furthermore, as the hormonal agent, for example, levothyroxine, liothyronine, thiamazole, propylliouracil, cortisone, parameterzone, dexamethasone, betamethasone, prednisolone, testosterone, phosfestronole, estrionore, chronoremadinone, arrinole estre Nord, clomiphene, tanazol, tamsulosin, flavoxate, middolin, gal For example, vitamin A, calcitriol, thiamine, fursultiamine, riboflavin, pantethine, pantothenic acid, pyridoxine, folic acid, cobamide, mecobalamin, ascorbic acid, tocopherol, phenathadione, menatetrenone, piotin Examples of enzyme preparations include, for example, lysozyme, serrapeptase and the like, examples of antidiabetic agents include, for example, daliclazide, daribenclamide, glimepiride, tolptamide, metformin, carbolose, voglibose, etc. Examples of antihistamines include, for example, diphenhydramine, Promethazine, mequitazine, chlorpheniramine, clemastine, etc. are allergic agents such as ibudilast, azelastine, epinastine, cetirizine, sp Task door, Tiger - last, ketotifen, plan Norre cust, Bae Mirorasuto, mouth Ratajin and the like are each elevation up.

 [0038] Still further, antibiotics include clindamycin, lincomycin, noncomycin, force namicin, amoxicillin, ampicillin, cefaclonole, cephalexin, cefixime, cefpodoxime, cefdiel, cefteram, cefpodoxime, fosfomycin, faropenem, Examples include erythromycin, adisthromycin, clarithromycin, roxithromycin, kulam lamphenicol, tetracycline, minocycline, salazosulfaviridine, ciprofloxacin, gatifloxacin, norfloxacin, acyclovir, itraconazole, terbinafine, fluconazole, miconazole, etc. .

 [0039] The orally disintegrating tablet of the present invention includes, in addition to the above-mentioned components, any conventionally known optional components such as various lubricants, solubilizers, buffering agents as long as the effects of the present invention are not impaired. Adsorbent, Binder, Suspending agent, Antioxidant, Filler, PH adjuster, Excipient, Dispersant, Disintegrant, Disintegration aid, Dehumidifier, Preservative, Solvent, Solubilizer, Fluid An agent or the like can be used.

[0040] Among these, excipients include, for example, sugar alcohols such as lactose, refined sucrose, crystalline cellulose, corn starch, potato starch, mannitol, xylitol, sorbitol, erythritol, trehalose, inorganic salts, dextran, dextrin, glucose, Examples include powdered sugar. Examples of disintegrants include denpens such as corn starch and potato starch, partially alpha-monified starch, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl Examples include methylcellulose, crystalline cellulose, hydroxypropyl starch and the like. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxychetylcellulose, gum arabic, alpha-unified starch, sodium alginate, carboxyvinyl polymer, agar, honey and the like.

 [0041] Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, talc, and sucrose fatty acid ester. As coating agents, hydroxypropyl methylcellulose, ethyl acrylate 'methyl methacrylate copolymer, aminoacryl methacrylate copolymer E, aminoacryl methacrylate copolymer RS, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, And methacrylic acid copolymer S. Furthermore, examples of the taste masking component include citrate, tartaric acid, malic acid and the like. Examples of the foaming agent include sodium bicarbonate. Examples of artificial sweeteners include saccharin sodium, dipotassium glycyrrhizin, aspanolome, stevia and thaumatin. Examples of the masking agent include water-insoluble polymers such as ethyl cellulose and gastric polymers such as methyl methacrylate “butyl methacrylate” and “methylaminoethyl methacrylate” copolymer.

 [0042] The production of the orally disintegrating tablet of the present invention is not particularly limited as long as it is a general compression molding method. For example, a powder or a mixture of mannitol, which is delta-type crystalline man-tol, a binder and a physiologically active substance, and inorganic salts and other optional ingredients blended as necessary. An orally disintegrating tablet can be prepared by compression-molding the prepared granule with an ordinary tableting machine, such as a rotary tableting machine or a single tableting machine. In addition, the pressure at the time of compression molding is not particularly limited as long as the disintegration time in the mouth and the tissue are appropriate, and there are no cracks at the time of production and transportation. Is compression molded at 100 to 2000 kgf, more preferably 300 to 1500 kgf.

[0043] One of the effects of the present invention is that, during the production of an orally disintegrating agent, no fine powder of granulated material is generated and productivity is improved. There are various methods for this index, but if the proportion of powder finer than 20 OMesh (75 μm) is 20% or less, there is no problem. it can.

 [0044] In addition, the friability test can be used as one of the indicators for confirming the cracking and chipping during production and transportation of the orally disintegrating tablet of the present invention described above. This test is described in the 14th Amendment Japanese Pharmacopoeia. Normally, 100 tablets of compression-molded preparation were used, and the friability test was conducted for 4 minutes. It is said that there will be no cracks during production and transportation. Further, hardness can be used as another index. A very low hardness is very important as an indicator because it can lead to tablet breakage with a slight impact. The hardness of the orally disintegrating tablet of the present invention is preferably 5 kg because it can be produced and transported without breakage if it is 4 kg or more.

 Example

 [0045] Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

 [0046] Example 1

 A granulated liquid was prepared by dissolving 75 g of pregelatinized starch (Matsunoline CM: Matsutani Chemical Co., Ltd.) in 2500 g of purified water. Delta-type Mann-Tall (Partec Delta M: Merck / Delta-type Mann-Tall power 0%, the rest is Beta-type Mann-Tall) 1700g, Beta-type Mann-Tall (D-Manufacturer: Towa Kasei Co., Ltd.) ) 5160 g was charged into a fluidized bed granulator, and fluidized bed granulation (FLOWCOATER: manufactured by Freund Sangyo Co., Ltd.) was performed using the previously prepared granulation liquid. Using 5548g of this granulated product, crospopidone (Kollidon CL: BASF) 300g, magnesium metasilicate aluminate (Neusilin UFL2: manufactured by Fuji Chemical Industry Co., Ltd.) 60g, aspartame (PAL SWEET DIET: manufactured by Ajinomoto Co., Inc.) 60 g and 32 g of magnesium stearate (magnesium stearate: manufactured by Taihei Chemical Co., Ltd.) were added and mixed using a V-type mixer (V-type mixer: manufactured by Tsutsui Chemical Co., Ltd.) to obtain granules. The granules were tableted using a rotary tableting machine (VIRGO 0506SS2AY-000B00: Kikusui Seisakusho) so that each tablet was 150 mg to obtain an orally disintegrating tablet.

 [0047] Example 2

An orally disintegrating tablet was produced in the same manner as in Example 1, except that gelatinized corn starch (corn starch: manufactured by Nippon Shokuhin Kako Co., Ltd.) was used instead of a starch. [0048] Comparative Example 1

 An orally disintegrating tablet was produced in the same manner as in Example 1 except that Partek Delta M in Example 1 was changed to beta-type mantol.

[0049] Comparative Example 2

 An orally disintegrating tablet was produced in the same manner as in Example 1 except that the a-modified starch in Example 1 was changed to corn starch.

[0050] The formulations of Examples 1 and 2 and Comparative Examples 1 and 2 are summarized in Table 1 below.

 [table 1]

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Delta mannitol * 34 34 34 Solid mannitol 103.2 103.2 137.2 103.2 Gelatinized starch 1.5-1.5 Gelatinized corn starch-1.5

 Corn starch (not gelatinized) ― ― '·' ■ :: Crospopidone 7.5 7.5 ■ · '· 5 7.5 Magnesium aluminate metasilicate 1.5 1.5 1.5 1.5 Aspartame 1.5 1.5 1.5 1.5 Magnesium stearate 0.8 0.8 0.8 0.8

 Mouth t + 150 150 150 150

* Pacific Dolta M

[0051] Test Example 1

 The state of the fine powder of Example 2 and Comparative Examples 1 and 2 was confirmed. As a confirmation method, the proportion of particles of 20 OM (75 μm) or less was measured. The results are shown in Table 2.

[0052] [Table 2] Example 1 Example 2 Comparative Example 1 Comparative Example 2

Fine powder ratio of 200M or less (%) 1 3. 2 1 4. 2 2 2 2 6 2 0.2

[0053] As described above, the proportion of fine powder could be reduced by granulation using delta-type mannitol and alpha-ized starch. This can be expected to reduce the scattering of granulated materials and increase production efficiency.

[0054] Test example 2

 The granules obtained in Example 1 and Comparative Example 1 were tableted at a tableting pressure of 1000 kgf and a turntable speed of 20 rpm without using an external lubricant. Table 3 shows the physical properties at this time. The tests described in Table 3 were conducted as follows.

[0055] Hardness:

 It was measured using a hardness meter (tablet breaking strength measuring device: Toyama Sangyo).

 Abrasion test:

 Carried out in accordance with the 14th revised Japanese Pharmacopoeia. The friability tester (tablet friability tester: Minato Medical Co., Ltd.) was used for 4 minutes, and the number of tablets used in the test was 100 tablets.

 Disintegration time in the oral cavity:

 The tablet was put into the oral cavity, and the time until the tablet disappeared was measured.

 Whether tableting is impaired:

 Adherence of wrinkles, die friction, etc. were confirmed visually.

[0056] [Table 3] Example 1 Comparative Example 1

 Hardness (kgf) 6.8 5 5.4

 Abrasion test (%) 0.0 3 0. 1 6

 Disintegration time in the mouth (seconds) 1 F 1 8

 No tableting obstacles

 Occurrence

[0057] As shown in Table 3, it was shown that tableting failure occurred when delta-type mantol was not included. This result revealed that delta-type mantol is a very effective additive for stable production.

 [0058] Test Example 3

 The granules obtained in Example 1 and Comparative Example 1 were tableted using an external lubricant (external lubricant spray system: manufactured by Kikusui Seisakusho) at a tableting pressure of 1000 kgf and a turntable rotation speed of 50 rpm. Table 4 shows the physical properties in this case. The test method is the same as in Test Example 1.

 [0059] [Table 4]

[0060] As shown in Table 4, when tableting is performed using an external lubrication device when the number of rotations of the tableting machine is increased, delta mantles may be included, causing friction. found.

 [0061] Test Example 4

 The granules obtained in Example 1 and Comparative Example 2 were tableted using an external lubricant at a tableting pressure of 1000 kgf and a turntable speed of 50 rpm. Table 5 shows the physical properties of each case. The test method is the same as in Test Example 1.

[0062] [Table 5] Example 2 Comparative Example 2

 Hardness (kgf) 5.6 2 2.9

 Abrasion test (%) 0.1 9 2 0 8

 Disintegration time in the oral cavity (seconds) 2 8 5

 Absence of tableting failure None in particular None

[0063] As shown in Table 5, when the starch was not alpha-solidified, the friability was poor, and the tablets were concerned about tablet breakage during transportation. As a result, the use of alpha-ized starch was found to be important for the production of orally disintegrating tablets.

[0064] Example 3

 A granulated liquid was prepared by dissolving 75 g of a starch and 225 g of magnesium aluminate metasilicate in 2500 g of purified water. 1650 g of delta-type mantol (Partec Delta M) and 5060 g of beta-type mantol were charged into a fluidized bed granulator, and fluidized bed granulation was performed using the granulation liquid prepared earlier.

 [0065] Using 5608 g of this granulated product, 300 g of crospovidone, 60 g of aspartame and 32 g of magnesium stearate were added and mixed using a V-type mixer to obtain granules. The granules were tableted using a rotary tableting machine so that each tablet was 150 mg, to obtain an orally disintegrating tablet.

 [0066] Example 4

 A granulated liquid was prepared by dissolving 75 g of pregelatinized starch in 2500 g of purified water. Delta type mannitol (Partec Delta M) 1650 g and beta type mannitol 5060 g were charged into a fluidized bed granulator, and fluidized bed granulation was carried out using the previously prepared granulation liquid. Further, this granulated material was coated with a suspension obtained by suspending 225 g of magnesium aluminate metasilicate in purified water lOOOOg.

[0067] Using 5608 g of this granulated product, 300 g of crospovidone, 60 g of aspartame and 32 g of magnesium stearate were added and mixed using a V-type mixer to obtain granules. The granules were tableted using a rotary tableting machine so that each tablet was 150 mg, to obtain an orally disintegrating tablet. [0068] Test Example 5

 The granules of Examples 3 and 4 were tableted using an external lubricant at a tableting pressure of 1000 kgf and a turntable rotation speed of 50 rpm. The physical properties in this case are shown in Table 6. The test method is the same as in Test Example 1.

[0069] [Table 6]

産業上の利用可能性

Industrial applicability

 [0070] The orally disintegrating tablet of the present invention has both rapid disintegration properties in the oral cavity and hardness necessary for production, transportation, etc., and is advantageously used when orally administering various physiologically active substances. Is something that can be done.

 [0071] Further, according to the method for producing an orally disintegrating tablet of the present invention, tableting can be performed stably without causing tableting troubles such as wrinkle adhesion, cabbing, and die flicking, and the compression molding time can be shortened. An orally disintegrating tablet having rapid disintegration even when shrunk can be obtained. Also, powder scattering can be suppressed by reducing the fine powder during granulation. Furthermore, by improving the compression moldability, it is possible to reduce the breakage of the preparation during production and transportation.

 Therefore, the method of the present invention is extremely advantageous as a method for producing an orally disintegrating tablet.

Claims

The scope of the claims  [1] An orally disintegrating tablet containing mannitol, wherein all or part of the mannitol is delta-type mannitol.  [2] The orally disintegrating tablet according to claim 1, further comprising a binder that dissolves or swells in water at room temperature. [3] The orally disintegrating tablet according to claim 2, wherein the binder that dissolves or swells in water at room temperature is a polymer compound.  [4] The orally disintegrating tablet according to any one of claims 1 to 3, further comprising a physiologically active ingredient.  [5] A granulated product for a compression-molded preparation containing mannitol and a binder, wherein all or part of the mantle is delta-type mannitol. Grain.  6. The granulated product according to claim 5, wherein the binder is a binder that dissolves or swells in water at room temperature. 7. The granulated product according to claim 6, wherein the binder that dissolves or swells in water at room temperature is a polymer compound. 8. The granulated product according to claim 6 or 7, wherein the compression-molded preparation is an orally disintegrating tablet. [9] The granulated product according to any one of claims 5 to 8, which contains a physiologically active substance. [10] A method for producing an orally disintegrating tablet by preparing a granulated product using mantol and a binder that dissolves or swells in water at room temperature, and compresses the granulated product. A method for producing an orally disintegrating tablet, characterized in that all or a part thereof is delta-type crystalline mannitol.