JP7036856B2 - Orally disintegrating tablet - Google Patents

Description

The present invention relates to an orally disintegrating tablet having both high tablet hardness and high disintegration property. The present invention also relates to a method for producing the orally disintegrating tablet and drug-free granules used in the orally disintegrating tablet.

In recent years, there has been an increasing need for dosage forms that can be taken with a small amount of water or without water, especially in the field of elderly people and children.
Orally disintegrating tablets are developed as a dosage form that is easy to take for elderly people and patients who have difficulty swallowing because they disintegrate in the oral cavity and are easier to take than ordinary tablets. However, since orally disintegrating tablets have the property of being easily disintegrated even by mechanical stimuli, there are problems such as being more fragile than ordinary tablets during transportation, storage, or handling in dispensing. be. Therefore, it is not suitable for one-pack preparation, which is often performed in clinical practice, in which the medicines taken by the patient at one time are put together in one package. Therefore, an orally disintegrating tablet having high disintegration while maintaining a high hardness that can withstand transportation, storage, or handling in preparation is desired.

Patent Document 1 describes an orally rapidly disintegrating tablet containing D-mannitol having an average particle diameter of 31 μm to 80 μm, an active ingredient, a disintegrant, and 0.01% by mass to 0.5% by mass of stearic acid or a metal stearic acid salt. It has been disclosed. However, in order to manufacture the orally rapidly disintegrating lock described in Patent Document 1, a special facility called an external gliding spray device is indispensable.

Patent Document 2 describes a fast-disintegrating solid preparation containing an active ingredient, D-mannitol having an average particle size of 30 μm to 300 μm, a disintegrant, and celluloses. According to the report, it is possible to obtain an orally disintegrating tablet which has a hardness that does not cause a problem in practical use even with a low dry compression pressure and has no problem in rapid disintegration and manufacturability. However, the fast-disintegrating solid preparation described in Patent Document 2 tends to have a lower hardness than ordinary tablets.

International Publication No. 2003/103713 Japanese Unexamined Patent Publication No. 2001-58944

As a mechanism for disintegrating the tablet, it is conceivable that the water permeates into the inside of the tablet, so that the binding force of each component contained in the tablet is reduced and the tablet disintegrates. Since tablets are also required to have hardness that can withstand transportation, storage, or handling in preparation, the drug contained in the tablets or additives such as binders for achieving high hardness permeate the water. May inhibit and delay tablet disintegration. This tendency is particularly strong in tablets containing a poorly soluble drug or additive in water, or a binder or the like whose viscosity increases when water is contained and which inhibits the permeability of water.
In order to enhance the permeability of water in tablets, it is conceivable to contain an additive for ensuring the permeability of water in addition to the drug granulated together with the drug or the additive. However, if an additive for ensuring the permeability of the water is added as the bulk powder, the handleability of the additive may be poor and the tableting property may be poor in the tablet manufacturing process.

As a result of diligent studies, the present inventor added granules composed of a specific additive (hereinafter referred to as drug-free granules) in addition to the drug granulated together with the drug or the additive to form a tablet. The present invention has been completed by finding that it is possible to solve the above-mentioned problems and to provide an orally disintegrating tablet having both high tablet hardness and high disintegration property.

That is, the present invention includes the following inventions.
(1) An orally disintegrating tablet consisting of a drug, drug-free granules, and optionally a pharmaceutically acceptable additive, wherein the drug-free granules contain crystalline cellulose, mannitol, and low-substituted hydroxypropyl cellulose. Orally disintegrating tablets, including;
(2) The content of crystalline cellulose is 5 to 50% by mass, the content of mannitol is 20 to 90% by mass, and the degree of substitution of hydroxypropyl cellulose is low with respect to the total mass of the drug-free granules. The orally disintegrating tablet according to (1), wherein the content is 3 to 50% by mass (however, the total content of crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose does not exceed 100% by mass).
(3) The orally disintegrating tablet according to (1) or (2), wherein the average particle size of mannitol contained in the drug-free granules is 15 to 160 μm;
(4) The orally disintegrating tablet according to any one of (1) to (3), wherein the crystalline cellulose contained in the drug-free granules has a bulk density of 0.11 to 0.43 g / cm ³ .
(5) The oral disintegration according to any one of (1) to (4), wherein the degree of substitution of the hydroxypropoxy group of the low degree of substitution hydroxypropyl cellulose contained in the drug-free granules is 8 to 14%. Tablets;
(6) Addition of one or more selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, stearyl sodium fumarate, sucrose fatty acid ester, hydrogenated oil, glycerin, glycerin fatty acid ester, carnauba wax and talc. The orally disintegrating tablet according to any one of (1) to (5), which comprises an agent;
(7) Further containing one or more additives selected from the group consisting of carmellose calcium, carmellose, croscarmellose sodium, crospovidone, corn starch and sodium starch glycolate, (1) to (6). Orally disintegrating tablet according to any one of the above;
(8) Any of (1) to (7) further containing one or more additives selected from the group consisting of light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate and fumed silica. Orally disintegrating tablet according to item 1;
(9) The orally disintegrating tablet according to any one of (1) to (8), wherein the drug-free granules have an average particle size of 50 to 200 μm;
(10) The orally disintegrating tablet according to any one of (1) to (9), wherein the drug is bulk powder or is granulated with a pharmaceutically acceptable additive;
(11) The orally disintegrating tablet according to any one of (1) to (10), wherein the drug is a poorly soluble drug or a pharmaceutically acceptable salt thereof;
(12) The orally disintegrating tablet according to any one of (1) to (10), wherein the drug is an easily soluble drug or a pharmaceutically acceptable salt thereof;
(13) The orally disintegrating tablet according to any one of (1) to (12), wherein the drug-free granules do not contain pregelatinized starch;
(14) The orally disintegrating tablet according to any one of (1) to (13), wherein the drug-free granules do not contain crospovidone;
(15) After producing drug-free granules containing crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose, the drug-free granules, the drug and optionally a pharmaceutically acceptable additive are mixed and compressed. The method for producing an orally disintegrating tablet according to any one of (1) to (14), which comprises the above;
(16) The content of crystalline cellulose is 5 to 50% by mass with respect to the total mass of drug-free granules containing crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose, and the content of mannitol is 20 to 90. It is by mass% and the content of low-substituted hydroxypropyl cellulose is 3 to 50% by mass (however, the total content of crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose does not exceed 100% by mass). ) And drug-free granules with an average particle size of 50-200 μm;
(17) The drug-free granules according to (16), which does not contain crospovidone; and (18) the drug-free granules according to (16) or (17), which do not contain pregelatinized starch.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide an orally disintegrating tablet having both high tablet hardness and high disintegration without requiring special techniques, equipment and work. Further, according to the present invention, it is possible to provide a method for producing the orally disintegrating tablet and drug-free granules used for the orally disintegrating tablet.

One embodiment of the invention is an orally disintegrating tablet comprising a drug, drug-free granules, and optionally pharmaceutically acceptable additives, wherein the drug-free granules are crystalline cellulose, mannitol and low substitution. It is an orally disintegrating tablet containing hydroxypropyl cellulose.

<Drug-free granules>
As used herein, the term "drug-free granules" is a granular component added as a component other than a drug granulated with a drug or an additive, and is a drug granulated with the drug or the additive. By being tableted together with, it constitutes an orally disintegrating tablet.
By containing the drug-free granules, the orally disintegrating tablet of the present invention can have a high hardness that can withstand transportation, storage, or handling in preparation, and can ensure the permeability of water. Therefore, it can have high disintegration property.

The drug-free granules contain at least crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose, and may further contain pharmaceutically acceptable additives other than crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose. It does not contain a drug, that is, an active ingredient or an active ingredient for realizing the efficacy / effect of the orally disintegrating tablet.
In one embodiment of the drug-free granules, the total content of crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose is 30 to 100% by mass, more preferably 50, based on the total mass of the drug-free granules. It is -100% by mass, more preferably 70 to 100% by mass, and even more preferably 80 to 100% by mass.
In one embodiment of the drug-free granule, the drug-free granule may be a granule composed substantially only of crystalline cellulose, mannitol and low-degree-of-substitution hydroxypropyl cellulose. Here, "substantially composed of crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose" means that crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose are used with respect to the total mass of the drug-free granules. It means that the total content is 95-100% by mass, more preferably 98-100% by mass, still more preferably 99-100% by mass.

In the present specification, the average particle size of mannitol contained in the drug-free granules is preferably 15 to 160 μm, more preferably 20 to 160 μm, still more preferably 20 to 50 μm.
The mannitol in the present specification is preferably D-mannitol, and examples thereof include α-type, β-type, and δ-type, but from the viewpoint of availability or manufacturing cost, α-type is used. β-type or a mixture thereof is preferable.
In the present specification, the "average particle size" is represented by a volume-equivalent particle size, and can be measured by a powder particle size measuring method using a laser diffraction method. More specifically, it can be measured using a powder particle size measuring device (Microtrac MT3000II type manufactured by Microtrac Bell).

In the present specification, the content of mannitol with respect to the total mass of the drug-free granules is 20 to 90% by mass, preferably 45 to 90% by mass, and more preferably 60 to 80% by mass. If it is 20% by mass or more, a good mouth feeling and a feeling of coldness can be given in the oral cavity. Further, if it is within 90% by mass, the permeability of water becomes good and the desired disintegration property can be exhibited.

In the present specification, the bulk density of the crystalline cellulose contained in the drug-free granules is preferably 0.11 to 0.43 g / cm ³ , and more preferably 0.11 to 0.29 g / cm ³ .
In the present specification, the bulk density of crystalline cellulose can be measured according to the measuring method described in the section of crystalline cellulose of the 17th revised Japanese Pharmacopoeia.
In the present specification, the content of crystalline cellulose with respect to the total mass of the drug-free granules is preferably 5 to 50% by mass, more preferably 5 to 30% by mass, still more preferably 10 to 20% by mass. If it is 5% by mass or more, the orally disintegrating tablet can be given the desired moldability. Further, if it is within 50% by mass, the tactile sensation in the oral cavity is excellent and the desired disintegration property can be exhibited.

As used herein, low-degree-of-substitution hydroxypropyl cellulose means cellulose into which a small amount of hydroxypropoxy groups have been introduced. The degree of hydroxypropoxy group substitution is 8 to 14% by mass, more preferably 8 to 11% by mass. When the degree of substitution of the hydroxypropoxy group is 8% by mass or more, the swelling property after water absorption is high and the desired disintegration property can be exhibited. If it is within 14% by mass, it has appropriate swelling property and hydrophilicity, and can exhibit the desired disintegration property.
In the present specification, the degree of substitution of the hydroxypropoxy group can be measured according to the measuring method described in the section of low degree of substitution hydroxypropyl cellulose of the 17th revised Japanese Pharmacopoeia.

In the present specification, the content of hydroxypropyl cellulose having a low degree of substitution with respect to the total mass of the drug-free granules is preferably 3 to 50% by mass, more preferably 5 to 30% by mass, still more preferably 10 to 20% by mass. If it is 3% by mass or more, the desired disintegration property can be obtained, and if it is 50% by mass or less, the tactile sensation in the oral cavity is excellent and the desired formability can be exhibited.

As used herein, the drug-free granules may contain pharmaceutically acceptable additives other than crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose, such which include excipients, disintegration. Examples thereof include agents, binders, lubricants, fluidizers, sweeteners, fragrances, stabilizers, plasticizers, colorants, and flavoring agents. These additives may be added alone or in combination of two or more in an appropriate amount.

In the present specification, the excipients that may be contained in the drug-free granules include, for example, erythritol, sorbitol, xylitol, martitol, lactate (including anhydrous lactate), sucrose (including purified sucrose), and trehalose water. Japanese products, powdered reduced malt sugar water candy, dextrin, corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, sodium hydrogen carbonate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium tertiary phosphate, Calcium carbonate, precipitated calcium carbonate, calcium silicate, calcium lactate and the like can be exemplified, and one or a mixture of two or more of these may be used.

In the present specification, examples of the disintegrant that may be contained in the drug-free granules include crospovidone, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, and carboxymethyl cellulose sodium and starch. Examples thereof include sodium glycolate and hydroxypropyl starch, and one or a mixture of two or more of these may be used.

In the present specification, examples of the binder that may be contained in the drug-free granules include purulan, pectin, sodium alginate, gum arabic, guar gum, canten, water candy, hydroxypropyl cellulose, pregelatinized starch, and polyvinyl. Pyrrolidone, carboxyvinyl polymer, polyvinyl alcohol, ammonium alkyl methacrylate copolymer, ethyl cellulose, carboxyvinyl polymer, carboxymethyl ethyl cellulose, hypromellose, purulan, polyvinyl alcohol / polyethylene glycol / graft copolymer, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer , Methyl cellulose, Mitsurou, Macrogol, methacrylic acid copolymer and the like can be exemplified, and one or a mixture of two or more of these may be used.

In the present specification, examples of the lubricant that may be contained in the drug-free granules include stearic acid, stearyl sodium fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, hydrogenated oil, and glycerin. Examples thereof include glycerin fatty acid ester, carnauba wax, and talc, and one or a mixture of two or more of these may be used.

In the present specification, examples of the fluidizing agent that may be contained in the drug-free granules include light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate, stearic acid, and talc. One or a mixture of two or more of these may be used.

In the present specification, the sweeteners that may be contained in the drug-free granules include, for example, aspartame, saccharin, stevia, amacha powder, sucralose, acesulfame potassium, sucrose, sorbitol, reduced maltose water candy, saccharin, and saccharin. , And taumatin and the like can be exemplified, and one or a mixture of two or more of these may be used.

In the present specification, the fragrances that may be contained in the drug-free granules include, for example, orange, vanilla, strawberry, yogurt, menthol, fennel oil, keihi oil, peppermint oil, peppermint oil, green tea powder and the like. It can be exemplified, and one or a mixture of two or more of these may be used.

In the present specification, examples of the colorant that may be contained in the drug-free granules include iron sesquioxide, yellow iron sesquioxide, iron black oxide, titanium oxide, tartrazine, edible yellow No. 4, and edible yellow 4. No. aluminum lake, edible yellow No. 5, edible red No. 2, edible red No. 3, edible red No. 102, edible blue No. 1, methylene blue, carmine, riboflavin, etc. can be exemplified, and one or more of these can be exemplified. It may be mixed and used.

In the present specification, examples of the flavoring agent that may be contained in the drug-free granules include glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, and sodium chloride. And menthol and the like can be exemplified, and one or a mixture of two or more of these may be used.

In the present specification, examples of the plasticizer that may be contained in the drug-free granules include triethyl citrate, glycerin, triacetin, castor oil, macrogol, propylene glycol, and glycerin monostearate. , One or a mixture of two or more of these may be used.

In the present specification, as the stabilizer that may be contained in the drug-free granules, a stabilizer that is known per se in the pharmaceutical pharmaceutical field can be used.

One aspect of the present invention is an orally disintegrating tablet containing drug-free granules having an average particle size of 50-200 μm.

Another aspect of the present invention is that the content of crystalline cellulose is 5 to 50% by mass, the content of mannitol is 20 to 90% by mass, and the degree of substitution is low with respect to the total mass of the drug-free granules. Intraoral contains drug-free granules with a hydroxypropyl cellulose content of 3-50% by weight (however, the total content of crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose does not exceed 100% by weight). It is a disintegrating tablet.

Another aspect of the present invention is that the content of crystalline cellulose is 5 to 50% by mass, the content of mannitol is 20 to 90% by mass, and the degree of substitution is low with respect to the total mass of the drug-free granules. The content of hydroxypropyl cellulose is 3 to 50% by mass (however, the total content of crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose is 28 to 100% by mass, more preferably 70 to 100% by mass. ), An orally disintegrating tablet containing drug-free granules.

Another aspect of the present invention is that the content of crystalline cellulose is 5 to 50% by mass, the content of mannitol is 20 to 90% by mass, and the degree of substitution is low with respect to the total mass of the drug-free granules. The content of hydroxypropyl cellulose is 3 to 50% by mass (however, the total content of crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose is 95 to 100% by mass, more preferably 98 to 100% by mass, and further. It is an orally disintegrating tablet containing drug-free granules (preferably 99 to 100% by mass).

Another aspect of the present invention comprises crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose, the content of crystalline cellulose being 5-50% by mass with respect to the total mass of drug-free granules, and the inclusion of mannitol. The ratio is 20 to 90% by mass, and the content of low-substituted hydroxypropyl cellulose is 3 to 50% by mass (however, the total content of crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose is 100). Drug-free granules (not exceeding% by mass) and having an average particle size of 50 to 200 μm.

Yet another aspect of the present invention is that the content of crystalline cellulose is 5-50% by mass with respect to the total mass of drug-free granules, including crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose. The content is 20 to 90% by mass, and the content of low-substituted hydroxypropyl cellulose is 3 to 50% by mass (however, the total content of crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose is 28 to 100% by mass, more preferably 70 to 100% by mass), and the average particle size is 50 to 200 μm, which is a drug-free granule.

Yet another aspect of the present invention is that the content of crystalline cellulose is 5 to 50% by mass with respect to the total mass of drug-free granules, including crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose. The content is 20 to 90% by mass, and the content of low-substituted hydroxypropyl cellulose is 3 to 50% by mass (however, the total content of crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose is 95 to 100% by mass, more preferably 98 to 100% by mass, still more preferably 99 to 100% by mass), and the average particle size is 50 to 200 μm.

One aspect of the invention is the drug-free granules that do not contain either or both of crospovidone and pregelatinized starch, and another aspect is either or both of crospovidone and pregelatinized starch. It is an orally disintegrating tablet containing the drug-free granules that do not contain.
From the viewpoint of oral disintegration, it is preferable that crospovidone is not contained in the drug-free granules.
From the viewpoint of orally disintegrating property, it is preferable that the pregelatinized starch is not contained in the drug-free granules.

<Drug>
As used herein, the term "drug" means an active ingredient or an active ingredient for realizing the efficacy and effect of the orally disintegrating tablet of the present invention, and is not limited as long as it is an ingredient that can be orally administered. However, for example, antipyretic, analgesic and anti-inflammatory drugs, psychiatric drugs, antidepressants, antidepressants, sleep sedatives, antispasmodics, central nervous system drugs, brain metabolism improving drugs, cerebral circulation improving drugs, antiepileptic drugs, sympathetic nerve excitement. Drugs, gastrointestinal drugs, antioxidants, anti-ulcers, antitussives and sputum, antiemetics, respiratory promoters, bronchial dilators, allergic drugs, dental and oral medicines, antihistamines, cardiotonics, arrhythmia drugs, diuretics, blood pressure lowering Drugs, vasoconstrictors, coronary vasodilators, peripheral vasodilators, hyperlipidemia agents, biliary agents, antibiotics, chemotherapeutic agents, diabetic agents, osteoporosis agents, anti-rheumatic agents, hormone agents, One or more components selected from alkaloid drugs, sulfa agents, gout remedies, blood coagulation inhibitors, antineoplastic agents, nourishing tonic health agents and the like can be exemplified.

The drug in the present specification may be either a poorly soluble drug or a poorly soluble drug. The poorly soluble drug in the present specification is a drug that is poorly soluble in water, that is, "almost insoluble in water", "extremely insoluble in water", "difficult to dissolve in water" and "insoluble in water" according to the Japanese Pharmacopoeia. It means a drug that is said to be "slightly difficult to dissolve", and specifically, it means a drug that requires 30 mL or more of water at room temperature when it is vigorously shaken every 5 minutes for 30 seconds when 1 g of the drug is dissolved. For example, prazosin hydrochloride, carvegilol, pindrol, fexophenazine hydrochloride, mesalazine, nicardipine hydrochloride, nifedipine, digitoxin, bromhexine hydrochloride, carbocysteine, verapamil hydrochloride, phenytoin, indomethacin, flurubiprofen, amlogipin besilate. , Methyldopa hydrate, olmesartane medoxomil, candesartan cilexetil, thermisartan, balsartan, simethidine, phenytoin, omeprazole, sulfirido, metoclopramide, dipyridamole, sirostazole, fluconazole, clotrimazole, ofhroxacin, tosylate tosylin , Chloramphenyl, riphanpicin, enoxacin hydrate, naridix acid, phenobarbital, diazepam, phenytoin, diphenhydramine, clemastine fumarate, losbustatin calcium, nitrazepam, acetaminophen, diclofenac, aspirin, ketoprofen, mosupride citrate hydrate , Paloxetine Hydrochloride Hydrate, Salpogrelate Hydrochloride, Donperidone, Corhitin, Alloprinol, Phenytoin, Acethexamide, Epalestat, Glybenclamid, Torbutamide, Pioglidazone Hydrochloride, Diflucortron valerate, Fluorometron, Betamethasone, Disopyramide , Acetazolamide, spironolactone, ibprofen, mephenamic acid, phenytoin, azimarin, isosorbide nitrate, noscapin, epinephrine, prednisolone, prostaglandins E1 and E2, and the like, but are not limited thereto.

The easily soluble drug in the present specification is a drug that is easily soluble in water, that is, is defined as "extremely soluble in water", "easily soluble in water", and "slightly soluble in water" according to the regulations of the Japanese Pharmacopoeia. It means a drug, specifically, a drug in which the amount of water required at room temperature is less than 30 mL when vigorously shaken every 5 minutes for 30 seconds when dissolving 1 g of the drug. For example, propranolol hydrochloride, zyrthiazem hydrochloride, captopril, hydralazine hydrochloride, rosartan potassium, montelcasto sodium, lanitidin hydrochloride, clopidogrel sulfate, chlorpheniramine maleate, ethyrefrin hydrochloride, butylscopolamine bromide, sodium hydrogencarbonate, donepezil. , Memantin hydrochloride, aminophyllin hydrate, codeine phosphate hydrate, atropin sulfate hydrate, ascorbic acid, arginine hydrochloride and the like, and are not limited thereto.

In the present specification, the amount of the drug contained in the orally disintegrating tablet is 0.1 to 70% by mass, preferably 0.1 to 50% by mass, more preferably, with respect to the total mass of the orally disintegrating tablet. It is 0.1 to 30% by mass, more preferably 0.1 to 10% by mass, and particularly preferably 0.1 to 5% by mass.
In the present specification, the drug may be in the form of bulk powder, or may be granulated with a pharmaceutically acceptable additive to form drug-containing granules. Examples of the additives that can be contained in the drug-containing granules include excipients, disintegrants, binders, lubricants, fluidizers, sweeteners, fragrances, and stabilizers exemplified in the item of drug-free granules. , Plasticizers, colorants, and additives of the same type as flavoring agents, and specific examples thereof can also be exemplified by specific examples of the same type. Further, as the additive that can be contained in the drug-containing granules, crystalline cellulose, mannitol or low-degree-of-substitution hydroxypropyl cellulose contained in the drug-free granules can be exemplified. These additives may be added alone or in combination of two or more in an appropriate amount. Further, since the pharmaceutically acceptable additive contained in the drug-containing granules and the pharmaceutically acceptable additive contained in the drug-free granules can be used independently, they can be used independently. They may be the same kind of additives or different kinds of additives.
In the present specification, the content of the drug with respect to the total mass of the drug-containing granules is preferably 0.1 to 90% by mass, more preferably 0.1 to 70% by mass, still more preferably 1 to 50% by mass.
In the present specification, the average particle size of the drug-containing granules is preferably 50 to 200 μm, more preferably 50 to 150 μm.
In the present specification, as a method for granulating drug-containing granules, for example, it is known in the pharmaceutical pharmaceutical formulation field such as a stirring granulation method, an extrusion granulation method, a fluidized bed granulation method, and a dry granulation method. Granulation method can be mentioned.
The drug-containing granules may be coated.

<Pharmally acceptable additives>
As used herein, the orally disintegrating tablet may contain a drug and drug-free granules, as well as optionally pharmaceutically acceptable additives. Here, "desirably" is determined by the configuration necessary for solving the problem of the present invention.
If desired, the "pharmaceutically acceptable additive" contained in the orally disintegrating tablet is the powder of the drug or the outside of the drug-containing granules in which the drug is granulated together with the pharmaceutically acceptable additive. And means a pharmaceutically acceptable additive that may be present outside the drug-free granules. That is, if desired, the "pharmaceutically acceptable additive" contained in the orally disintegrating tablet, the "pharmaceutically acceptable additive" contained in the drug-containing granules, and the "pharmacy" contained in the drug-free granules. Although "acceptable additives" are independent and separate concepts, they may be the same kind of additives or different kinds of additives.

If desired, the "pharmaceutically acceptable additive" contained in the orally disintegrating tablet includes an excipient, a disintegrant, a binder, a lubricant, and a fluidizing agent exemplified in the above-mentioned item of drug-free granules. , Additives of the same type as sweeteners, flavors, stabilizers, plasticizers, colorants, flavoring agents and the like can be mentioned, and specific examples thereof can also exemplify specific examples of the same type. Further, as the additive that can be contained in the drug-containing granules, crystalline cellulose, mannitol or low-degree-of-substitution hydroxypropyl cellulose contained in the drug-free granules can be exemplified. These additives may be added alone or in combination of two or more in an appropriate amount.
There is a pharmaceutically acceptable additive outside the drug-containing granules in which the raw powder of the drug or the additive for which the drug is pharmaceutically acceptable is granulated, and outside the drug-free granules. When the externally present pharmaceutically acceptable additive contains crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose at the same time, the externally present pharmaceutically acceptable additive is not granulated and therefore the external. The pharmaceutically acceptable additives present in the drug-free granules can be distinguished from the drug-free granules.

As one aspect, the "pharmaceutically acceptable additive" optionally contained in the orally disintegrating tablet is magnesium stearate, or crospovidone.

In the present specification, the content of the "pharmaceutically acceptable additive" contained in the orally disintegrating tablet as desired is preferably 0 to 60% by mass, preferably 0.5 to 60% by mass, based on the total mass of the orally disintegrating tablet. 50% by mass is more preferable, and 1 to 30% by mass is further preferable.

As one embodiment of the present invention, the orally disintegrating tablet or drug-free granule of the present invention further comprises stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, sucrose fatty acid ester, cured oil, glycerin, glycerin fatty acid. It may contain one or more additives selected from the group consisting of esters, carnauba wax and talc.

In another embodiment of the invention, the orally disintegrating tablets or drug-free granules of the invention are further selected from the group consisting of carmellose calcium, carmellose, croscarmellose sodium, crospovidone, corn starch and sodium starch glycolate. It may contain one or more additives.

As yet another embodiment of the present invention, the orally disintegrating tablet or drug-free granule of the present invention is further selected from the group consisting of light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate and fumed silica1. It may contain seeds or two or more additives.

When the additive is contained in the orally disintegrating tablet of the present invention, the additive may be independently contained in the drug-free granules, may be contained in the drug-containing granules, or may be contained in the drug-containing granules. , The drug may be contained as an additive contained outside the drug-free granules and outside the drug or the drug-containing granules, if desired.

In the present specification, examples of the content of the drug-free granules with respect to the total mass of the orally disintegrating tablet include, for example, 30 to 98% by mass, 30 to 70% by mass, or 40 to 95% by mass.

In the present specification, when a drug is granulated together with a pharmaceutically acceptable additive and contained in an orally disintegrating tablet as a drug-containing granule, the content of the drug-containing granule with respect to the total mass of the orally disintegrating tablet Examples include, for example, 10 to 60% by mass, 20 to 60% by mass, or 20 to 50% by mass.

In the present specification, when the drug is contained in the orally disintegrating tablet as it is, the content of the drug with respect to the total mass of the orally disintegrating tablet is preferably 1 to 40% by mass, more preferably 5 to 20% by mass. preferable.

In the present specification, the content of drug-containing granules in which the bulk powder of the drug or the drug is granulated with a pharmaceutically acceptable additive, the content of the drug-free granules, and optionally an orally disintegrating tablet. The total content with the content of the "pharmaceutically acceptable additive" contained in the above is 100% by mass with respect to the total mass of the orally disintegrating tablet.

In the present specification, the orally disintegrating lock may be formed into, for example, a round shape, an elliptical shape, a spherical shape, a polygonal plate shape, a rod shape, a donut shape, a laminated lock, a nucleated lock, or the like. It can also be coated with a coating agent if necessary. It is also possible to print marks, characters, etc. for improving the distinctiveness, and a dividing line for division may be attached.

<Manufacturing of orally disintegrating tablets>
In the present specification, the orally disintegrating tablet is prepared by producing drug-free granules containing crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose, and then the drug-free granules, the drug and optionally a pharmaceutically acceptable addition. It can be produced by mixing and compressing the agent.
As a method for producing the drug-free granules, for example, a granulation method known per se in the pharmaceutical formulation field such as a stirring granulation method, an extrusion granulation method, a fluidized bed granulation method, and a dry granulation method. Can be mentioned. Crystalline cellulose, mannitol and low-degree-of-substitution hydroxypropyl cellulose can be granulated by any of the above-mentioned granulation methods.
The drug may be used as the bulk powder or as drug-containing granules which have been granulated with a pharmaceutically acceptable additive. As a method for granulating the drug-containing granules, for example, a granulation method known per se in the pharmaceutical formulation field such as a stirring granulation method, an extrusion granulation method, a fluidized bed granulation method, and a dry granulation method. Can be mentioned.
The pharmaceutically acceptable additive to be mixed as desired may be the bulk powder, or the pharmaceutically acceptable additive itself may be granulated. Examples of the granulation method of the pharmaceutically acceptable additive itself include a stirring granulation method, an extrusion granulation method, a fluidized bed granulation method, and a dry granulation method in the pharmaceutical pharmaceutical formulation field. Examples thereof include granulation methods known per se.
The drug-free granules, the drug or the drug-containing granules in which the drug is granulated together with the pharmaceutically acceptable additive and, if desired, the pharmaceutically acceptable additive are mixed and then compressed in the next step. Attached to the process. In the present specification, the compression step may be referred to as a locking step.
In the mixing step, after the drug-free granules and the drug-containing granules in which the drug or the drug is pharmaceutically acceptable are mixed and the drug-containing granules are granulated or the like, further pharmaceutically acceptable addition is desired. The agents may be mixed.
In the present specification, the tableting step can be carried out by using, for example, a single-shot tableting machine, a rotary type tableting machine, or the like. The pressure at the time of tableting is usually 4 to 20 kN, more preferably 5 to 13 kN.
The hardness of the tablet is not particularly limited, but a certain degree of hardness is required to prevent damage due to transportation of the tablet, packaging, and the like. In the present invention, 50 N or more is preferable.

The disintegration property of the tablet can be evaluated as the disintegration time in the oral cavity, and the disintegration time in the oral cavity is not particularly limited, but is preferably within 30 seconds in the oral cavity when taken without water, for example.

<Use of orally disintegrating lock>
In the orally disintegrating tablet of the present invention, the dose of the orally disintegrating tablet is appropriately determined according to the active ingredient contained and the content thereof, the age, body weight, sex, symptom, sensitivity to the drug, etc. of the administration target. Will be done. Since the orally disintegrating tablet of the present invention is rapidly disintegrated by saliva when contained in the mouth, it can be taken without water.

The present invention will be described in more detail below with reference to Test Examples and Examples, but the present invention is not limited thereto.

<Ingredients of drug-free granules and characteristics of orally disintegrating tablets>
In Test Examples 1 to 14, the relationship between the components of the drug-free granules, the hardness (N) of the tablets produced from the drug-free granules, and the oral disintegration time (seconds) was examined.

Test Example 1
400 g of D-mannitol (manufactured by Mitsubishi Life Science Co., Ltd., average particle diameter of about 20 μm) is put into a fluidized bed granulator (manufactured by Paulek Co., MP-01 type), and 350 g of purified water is sprayed and then dried to contain no drug. Granules were obtained. To 99 parts by mass of the obtained drug-free granules, 1 part by mass of magnesium stearate is added and mixed, and then tableted with a rotary tableting machine (VELA-5 type manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 8 kN. To produce a tablet having a tablet mass of 160 mg and a tablet diameter of 8 mm.

Test Example 2
280 g of D-mannitol (manufactured by Mitsubishi Life Science Co., Ltd., average particle diameter of about 20 μm) and 120 g of crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.11 g / cm ³ ) are fluidized bed granulators (manufactured by Paulec, MP-01 type). ), 350 g of purified water was sprayed and then dried to obtain drug-free granules. To 99 parts by mass of the obtained drug-free granules, 1 part by mass of magnesium stearate was added and mixed, and then tableting was performed with a rotary tableting machine (VELA-5 type manufactured by Kikusui Seisakusho Co., Ltd.). It was not possible to lock due to poor filling.

Test Example 3
280 g of D-mannitol (manufactured by Mitsubishi Life Science Co., Ltd., average particle diameter of about 20 μm) and 120 g of low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropoxy group substitution degree 8%) are fluidized bed granulators (manufactured by Paulec). , MP-01 type), sprayed with 350 g of purified water, and dried to obtain drug-free granules. To 99 parts by mass of the obtained drug-free granules, 1 part by mass of magnesium stearate is added and mixed, and then tableted with a rotary tableting machine (VELA-5 type manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 8 kN. To produce a tablet having a tablet mass of 160 mg and a tablet diameter of 8 mm.

Test Example 4
Erisritol (manufactured by Bussan Food Science Co., Ltd.) 253.8 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.11 g / cm ³ ) 84.8 g, low substitution degree hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropoxy group substitution degree) 84.8 g (8%) was put into a fluidized bed granulator (MP-01 type manufactured by Paulec Co., Ltd.), and 350 g of purified water was sprayed and dried to obtain drug-free granules. To 99 parts by mass of the obtained drug-free granules, 1 part by mass of magnesium stearate is added and mixed, and then tableted with a rotary tableting machine (VELA-5 type manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 8 kN. To produce a tablet having a tablet mass of 160 mg and a tablet diameter of 8 mm.

Test Example 5
Erythritol was replaced with xylitol (manufactured by Mitsubishi Life Science Co., Ltd.), and tablets having a tablet mass of 160 mg and a tablet diameter of 8 mm were produced in the same manner as in Test Example 4 except for the above.

Test Example 6
240 g of D-mannitol (manufactured by Mitsubishi Life Science Co., Ltd., average particle diameter of about 20 μm), 40 g of crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.11 g / cm ³ ), low substitution degree hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd., hydroxy) 120 g of propoxy group substitution degree (8%) was put into a fluidized bed granulator (MP-01 type manufactured by Paulec Co., Ltd.), and 350 g of purified water was sprayed and dried to obtain drug-free granules. To 99 parts by mass of the obtained drug-free granules, 1 part by mass of magnesium stearate is added and mixed, and then tableted with a rotary tableting machine (VELA-5 type manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 8 kN. To produce a tablet having a tablet mass of 160 mg and a tablet diameter of 8 mm.

Test Example 7
The blending amounts of crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.11 g / cm ³ ) and low degree of substitution hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd., degree of substitution of hydroxypropoxy group 8%) are adjusted to 80 g and 80 g, respectively. A tablet having a tablet mass of 160 mg and a tablet diameter of 8 mm was produced in the same manner as in Test Example 6 except for the replacement.

Test Example 8
The blending amounts of crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.11 g / cm ³ ) and low degree of substitution hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd., degree of substitution of hydroxypropoxy group 8%) are adjusted to 120 g and 40 g, respectively. A tablet having a tablet mass of 130 mg and a tablet diameter of 8 mm was produced in the same manner as in Test Example 6 except for the replacement.

Test Example 9
D-mannitol (manufactured by Mitsubishi Life Science Co., Ltd., average particle size approx. 20 μm), crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.11 g / cm ³ ), and low-substituted hydroxypropyl cellulose (manufactured by Shinetsu Chemical Industry Co., Ltd., hydroxypropoxy). The compounding amount of (base substitution degree 8%) was changed to 380.8 g, 21.3 g and 21.3 g, respectively, and the same as in Test Example 6 were produced to produce tablets having a tablet mass of 160 mg and a tablet diameter of 8 mm.

Test Example 10
D-mannitol (manufactured by Mitsubishi Life Science Co., Ltd., average particle size approx. 20 μm), crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.29 g / cm ³ ), and low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Industry Co., Ltd., hydroxypropoxy). The blending amounts of (base substitution degree 8%) were changed to 190.3 g, 211.8 g and 21.3 g, respectively, and the same as in Test Example 6 were used to produce tablets having a tablet mass of 160 mg and a tablet diameter of 8 mm.

Test Example 11
D-mannitol (manufactured by Mitsubishi Life Science Co., Ltd., average particle size approx. 20 μm), crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.11 g / cm ³ ), and low-substituted hydroxypropyl cellulose (manufactured by Shinetsu Chemical Industry Co., Ltd., hydroxypropoxy). The compounding amount of (base substitution degree 8%) was changed to 190.3 g, 21.3 g and 211.8 g, respectively, and the other tablets were produced in the same manner as in Test Example 6 with a tablet mass of 130 mg and a tablet diameter of 8 mm.

Test Example 12
D-mannitol (manufactured by Mitsubishi Life Science Co., Ltd., average particle size approx. 20 μm), crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.11 g / cm ³ ), and low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Industry Co., Ltd., hydroxypropoxy). The base substitution degree (8%) and the amount of light anhydrous silicic acid (manufactured by Freund Sangyo Co., Ltd.) were changed to 251.8 g, 84.8 g, 84.8 g and 2 g, respectively, and the other parts were the same as in Test Example 6. , A tablet having a tablet mass of 160 mg and a tablet diameter of 8 mm was produced.

Test Example 13
D-mannitol (manufactured by Mitsubishi Life Science Co., Ltd., average particle size approx. 20 μm), crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.11 g / cm ³ ), and low degree of substitution hydroxypropyl cellulose (manufactured by Shinetsu Chemical Industry Co., Ltd., hydroxypropoxy) The base substitution degree (8%) and anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry Co., Ltd.) were changed to 203.0 g, 67.8 g, 67.8 g and 84.8 g, respectively, and the others were Test Example 6 In the same manner as above, a tablet having a tablet mass of 160 mg and a tablet diameter of 8 mm was produced.

Test Example 14
D-mannitol (manufactured by Mitsubishi Life Science Co., Ltd., average particle size approx. 20 μm), crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.11 g / cm ³ ), and low-substituted hydroxypropyl cellulose (manufactured by Shinetsu Chemical Industry Co., Ltd., hydroxypropoxy). The mixing amounts of base substitution degree 8%) and precipitated calcium carbonate (manufactured by Shiraishi Calcium Co., Ltd.) were changed to 203.0 g, 67.8 g, 67.8 g and 84.8 g, respectively, and the others were the same as in Test Example 6. A tablet having a tablet mass of 160 mg and a tablet diameter of 8 mm was produced.

<Measurement of tablet hardness>
In the present specification, the hardness of the tablet was measured using a load cell type tablet hardness meter (manufactured by Okada Seiko Co., Ltd., PC-30 type).
<Measurement of oral disintegration time of tablets>
In the present specification, the orally disintegrating time of the tablet is measured by including the orally disintegrating tablet in the oral cavity of a healthy adult male and the time until the orally disintegrating tablet completely disintegrates.
For the tablets obtained in Test Examples 1 to 14, the content, hardness and oral disintegration time of the components of each tablet are shown in Table 1-1 and Table 1-2. In Table 1-1 and Table 1-2, "%" represents the content ratio of each component with respect to the total mass of the drug-free granules in the tablet in mass%.

In Test Examples 1 to 3, drug-free granules were produced without adding any of D-mannitol, crystalline cellulose, or low-degree-of-substitution hydroxypropyl cellulose, and the orally disintegrating tablets were produced by tableting. As a result, none of the tablets became an orally disintegrating tablet having a high hardness of 50 N or more and a high disintegration time of 30 seconds or less.

In Test Examples 4 and 5, drug-free granules containing erythritol and xylitol instead of D-mannitol without adding D-mannitol were produced, and orally disintegrating tablets were produced by tableting. As a result, none of the tablets became an orally disintegrating tablet having a high hardness of 50 N or more and a high disintegration time of 30 seconds or less.

On the other hand, in the tablets obtained by tableting the drug-free granules of Test Examples 6 to 14 containing D-mannitol, crystalline cellulose, and low-degree-of-substitution hydroxypropyl cellulose, the oral cavity has both desired hardness and disintegration property. An internally disintegrating tablet could be obtained.

<Characteristics of ingredients of drug-free granules and characteristics of orally disintegrating tablets>
D-mannitol, crystalline cellulose, and low-degree-of-substitution hydroxypropyl cellulose having various properties were blended according to Test Example 6 to produce drug-free granules. 1 part by mass of magnesium stearate was added to 99 parts by mass of the drug-free granules, and the hardness and oral disintegration time of the tablets obtained by tableting were measured. Details of each test example are shown below, and the results are shown in Table 2. In Table 2, "%" represents the content ratio of each component with respect to the total mass of the drug-free granules in the tablet in mass%.

Test Example 15
D-mannitol (manufactured by Mitsubishi Life Science Co., Ltd., average particle size approx. 20 μm) 240 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.11 g / cm ³ ) 80 g, low substitution hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd., hydroxy) 80 g of propoxy group substitution degree (8%) was put into a fluidized bed granulator (MP-01 type manufactured by Paulec Co., Ltd.), and 350 g of purified water was sprayed and dried to obtain drug-free granules. To 99 parts by mass of the obtained drug-free granules, 1 part by mass of magnesium stearate is added and mixed, and then tableted with a rotary tableting machine (VELA-5 type manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 10 kN. To produce a tablet having a tablet mass of 160 mg and a tablet diameter of 8 mm.

Test Example 16
D-mannitol (manufactured by Mitsubishi Life Science Co., Ltd., average particle size approx. 50 μm) 253.8 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.11 g / cm ³ ) 84.8 g, low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.) 84.8 g of hydroxypropoxy group substitution degree (8%) manufactured by the company was put into a fluidized bed granulator (MP-01 type manufactured by Paulec), and 350 g of purified water was sprayed and dried to obtain drug-free particles. rice field. To 99 parts by mass of the obtained drug-free granules, 1 part by mass of magnesium stearate is added and mixed, and then tableted with a rotary tableting machine (VELA-5 type manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 10 kN. To produce a tablet having a tablet mass of 160 mg and a tablet diameter of 8 mm.

Test Example 17
D-mannitol (manufactured by Rocket Japan, average particle size approx. 160 μm) 253.8 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.11 g / cm ³ ) 84.8 g, low substitution hydroxypropyl cellulose (Shinetsu Chemical Industry Co., Ltd.) 84.8 g of hydroxypropoxy group substitution degree (8%) was put into a fluidized bed granulator (MP-01 type manufactured by Paulec), and 350 g of purified water was sprayed and dried to obtain drug-free granules. .. To 99 parts by mass of the obtained drug-free granules, 1 part by mass of magnesium stearate is added and mixed, and then tableted with a rotary tableting machine (VELA-5 type manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 11 kN. To produce a tablet having a tablet mass of 160 mg and a tablet diameter of 8 mm.

Test Example 18
D-mannitol (manufactured by Mitsubishi Life Science Co., Ltd., average particle size approx. 20 μm) 253.8 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.29 g / cm ³ ) 84.8 g, low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.) 84.8 g of hydroxypropoxy group substitution degree (8%) manufactured by the company was put into a fluidized bed granulator (MP-01 type manufactured by Paulec), and 350 g of purified water was sprayed and dried to obtain drug-free particles. rice field. To 99 parts by mass of the obtained drug-free granules, 1 part by mass of magnesium stearate is added and mixed, and then tableted with a rotary tableting machine (VELA-5 type manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 10 kN. To produce a tablet having a tablet mass of 160 mg and a tablet diameter of 8 mm.

Test Example 19
D-mannitol (manufactured by Mitsubishi Life Science Co., Ltd., average particle size approx. 20 μm) 253.8 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.43 g / cm ³ ) 84.8 g, low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.) 84.8 g of hydroxypropoxy group substitution degree (8%) manufactured by the company was put into a fluidized bed granulator (MP-01 type manufactured by Paulec), and 350 g of purified water was sprayed and dried to obtain drug-free particles. rice field. To 99 parts by mass of the obtained drug-free granules, 1 part by mass of magnesium stearate is added and mixed, and then tableted with a rotary tableting machine (VELA-5 type manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 10 kN. To produce a tablet having a tablet mass of 160 mg and a tablet diameter of 8 mm.

Test Example 20
D-mannitol (manufactured by Mitsubishi Life Science Co., Ltd., average particle size approx. 20 μm) 253.8 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.11 g / cm ³ ) 84.8 g, low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.) 84.8 g of hydroxypropoxy group substitution degree (11%) manufactured by the company was put into a fluidized bed granulator (MP-01 type manufactured by Paulec), and 350 g of purified water was sprayed and then dried to obtain drug-free particles. rice field. To 99 parts by mass of the obtained drug-free granules, 1 part by mass of magnesium stearate is added and mixed, and then tableted with a rotary tableting machine (VELA-5 type manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 10 kN. To produce a tablet having a tablet mass of 160 mg and a tablet diameter of 8 mm.

Test Example 21
D-mannitol (manufactured by Mitsubishi Life Science Co., Ltd., average particle size approx. 20 μm) 253.8 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., bulk density 0.11 g / cm ³ ) 84.8 g, low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.) 84.8 g of hydroxypropoxy group substitution degree (14%) manufactured by the company was put into a fluidized bed granulator (MP-01 type manufactured by Paulec), and 350 g of purified water was sprayed and then dried to obtain drug-free particles. rice field. To 99 parts by mass of the obtained drug-free granules, 1 part by mass of magnesium stearate is added and mixed, and then tableted with a rotary tableting machine (VELA-5 type manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 8 kN. To produce a tablet having a tablet mass of 160 mg and a tablet diameter of 8 mm.

In Test Examples 15 to 21, drug-free granules were prepared using D-mannitol having a different average particle size, crystalline cellulose having a different bulk density, or hydroxypropyl cellulose having a low degree of substitution and having a different degree of hydroxypropoxy group substitution. Manufactured. From these drug-free granules, an orally disintegrating tablet having both desired hardness and disintegration property could be obtained.
When the average particle size of D-mannitol was small, the hardness of the tablets tended to be high, and when the bulk density of the crystalline cellulose was small, the hardness of the tablets tended to be high. In addition, when the degree of hydroxypropoxy group substitution of low degree of substitution hydroxypropyl cellulose was large, the oral disintegration time tended to be long.

<Orally disintegrating lock and its characteristics>
The drug-free granules produced in Test Example 7 were mixed with the bulk powder of the drug, the drug-containing granules or the drug-containing coated granules, and the tablets were beaten to obtain an orally disintegrating tablet. The hardness and oral disintegration time of the tablets obtained by tableting were measured. Details of each test example are shown below, and the results are shown in Table 3. In Table 3, "%" represents the content of each component with respect to the total mass of the tablet in mass%.

Example 1
94 parts by mass of drug-free granules of Test Example 7 and 5 parts by mass of memantin hydrochloride (bulk powder) are mixed, 1 part by mass of magnesium stearate is added to the mixture, and after mixing, a rotary tableting machine (Kikusui Seisakusho) Tableting was performed with a tableting pressure of 6 kN using VELA-5 type manufactured by the same company to produce tablets having a tablet mass of 190 mg and a tablet diameter of 8 mm.

Example 2
94 parts by mass of drug-free granules of Test Example 7 and 5 parts by mass of ascorbic acid (bulk powder) are mixed, 1 part by mass of magnesium stearate is added to the mixture, and after mixing, a rotary tableting machine (Kikusui Seisakusho Co., Ltd.) VELA-5 type) was used for tableting at a tableting pressure of 6 kN to produce tablets having a tablet mass of 190 mg and a tablet diameter of 8 mm.

Example 3
94 parts by mass of drug-free granules of Test Example 7 and 5 parts by mass of sodium hydrogen carbonate (bulk powder) are mixed, 1 part by mass of magnesium stearate is added to the mixture, and after mixing, a rotary tableting machine (Kikusui Seisakusho) Tableting was performed with a tableting pressure of 6 kN using VELA-5 type manufactured by the same company to produce tablets having a tablet mass of 190 mg and a tablet diameter of 8 mm.

Example 4
94 parts by mass of drug-free granules of Test Example 7 and 5 parts by mass of acetaminophen (bulk powder) are mixed, 1 part by mass of magnesium stearate is added to the mixture, and after mixing, a rotary tableting machine (Kikusui Seisakusho) Tableting was performed with a tableting pressure of 6 kN using VELA-5 type manufactured by the same company to produce tablets having a tablet mass of 190 mg and a tablet diameter of 8 mm.

Example 5
94 parts by mass of drug-free granules of Test Example 7 and 5 parts by mass of thermisartan (bulk powder) are mixed, 1 part by mass of magnesium stearate is added to the mixture, and after mixing, a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) , VELA-5 type) was tableted at a tableting pressure of 6 kN to produce tablets having a tablet mass of 190 mg and a tablet diameter of 8 mm.

Example 6
94 parts by mass of drug-free granules of Test Example 7 and 5 parts by mass of amlogipin besilate (bulk powder) are mixed, 1 part by mass of magnesium stearate is added to the mixture, and after mixing, a rotary tableting machine (Kikusui) is used. Tableting was performed with a tableting pressure of 6 kN using VELA-5 type manufactured by Mfg. Co., Ltd. to produce tablets having a tablet mass of 190 mg and a tablet diameter of 8 mm.

Example 7
94 parts by mass of drug-free granules of Test Example 7 and 5 parts by mass of candesartane cilexetil (bulk powder) are mixed, 1 part by mass of magnesium stearate is added to the mixture, and after mixing, a rotary tableting machine (Kikusui) is used. Tableting was performed with a tableting pressure of 6 kN using VELA-5 type manufactured by Mfg. Co., Ltd. to produce tablets having a tablet mass of 190 mg and a tablet diameter of 8 mm.

Example 8
94 parts by mass of drug-free granules of Test Example 7 and 5 parts by mass of febuxostat (bulk powder) are mixed, 1 part by mass of magnesium stearate is added to the mixture, and after mixing, a rotary tableting machine (Kikusui Seisakusho) Tableting was performed with a tableting pressure of 6 kN using VELA-5 type manufactured by the same company to produce tablets having a tablet mass of 190 mg and a tablet diameter of 8 mm.

Example 9
Mix 80 g of febuxostat, 392 g of D-mannitol (manufactured by Kao), and 120 g of crystalline cellulose (manufactured by Asahi Kasei), and put the mixture into a rolling fluidized bed granulator (manufactured by Freund Sangyo, SFC-MINI type). Then, 160 g of purified water in which 8 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) was dissolved was sprayed and then dried to obtain drug-containing granules. 37.5 parts by mass of the obtained drug-containing granules and 61.5 parts by mass of the drug-free granules of Test Example 7 are mixed, 1 part by mass of magnesium stearate is added and mixed, and then a rotary tableting machine (Kikusui) is used. Tableting was performed at VELA-5) of Mfg. Co., Ltd. at a tableting pressure of 6 kN to produce tablets having a tablet mass of 190 mg and a tablet diameter of 8 mm.

Example 10
300 g of the drug-containing granules obtained in Example 9 was put into a rolling fluidized bed granulator (SFC-MINI type manufactured by Freund Sangyo Co., Ltd.), and 877.3 g of a coating liquid (composition: methacrylic acid copolymer LD (manufactured by Ebonic)) was charged. ) 38.0%, triethyl citrate (manufactured by Morimura Brothers) 1.4%, talc (manufactured by Matsumura Sangyo Co., Ltd.) 3.6%, purified water 57%) and dried to coat drug-containing granules. Granules were produced. 55.5 parts by mass of the obtained coated granules and 43.5 parts by mass of the drug-free granules of Test Example 7 are mixed, 1 part by mass of magnesium stearate is added and mixed, and then a rotary tableting machine (Kikusui Seisakusho, Ltd., Tableting was performed with VELA-5) at a tableting pressure of 6 kN to produce tablets having a tablet mass of 190 mg and a tablet diameter of 8 mm.

As a result of the above, by using the drug-free granules of the present invention, an orally disintegrating tablet having both high hardness and disintegration property could be obtained regardless of the characteristics of the drug (poor solubility, easy solubility, etc.). In addition, similar results could be obtained regardless of whether the drug was in the form of bulk powder, drug-containing granules, or coated granules.

<Presence / absence of crospovidone and characteristics of orally disintegrating tablets>
Test Examples 22 and 23
Test Examples 22 and 23 were carried out to examine the effect of the presence or absence of crospovidone on the drug-free granules.
According to the method described in Example 9 or Test Example 6, drug-containing granules and drug-free granules having a blending ratio of each component shown in Table 4 were produced. The obtained drug-containing granules and drug-free granules were mixed so as to have the blending ratios shown in Table 4, and magnesium stearate was used in Test Example 22 and magnesium stearate and crospovidone (BASF Japan, Inc.) were used in Test Example 23. (Manufactured by) is added so as to have the blending ratio shown in Table 4, and after mixing, tableting is performed with a rotary tableting machine (Kikusui Seisakusho, VELA-5) at a tableting pressure of 10 kN, and each tablet has a tablet mass of 130 mg and a tablet. A tablet having a diameter of 8 mm was produced.
For each tablet, hardness and oral disintegration time were measured. In Table 4, "%" represents the content of each component with respect to the total mass of the tablet in mass%.

As a result of the above, the tablet of Test Example 22 containing crospovidone in drug-free granules had a high hardness of 50 N or more, but was an orally disintegrating tablet having a high disintegration time of 30 seconds or less. did not become. On the other hand, it was shown that the tablet of Test Example 23 containing no crospovidone in the drug-free granules has both high hardness and disintegration property.

<Presence / absence of crospovidone and humidification stability of orally disintegrating tablets>
Test Examples 24-26
Test Examples 24 to 26 were carried out in order to investigate the effect of the presence or absence of crospovidone on the tablet on the humidification stability of the tablet.
(1) Production of Drug-Containing Granules According to the method described in Example 9, febuxostat, D-mannitol, crystalline cellulose and hydroxypropyl cellulose are each in a mass ratio of 6: 30: 4: 0.4. The mixture is weighed so that it becomes The drug-containing granules were obtained by spraying purified water in which the substance was dissolved and then drying.
(2) Production of Drug-Free Granules of Formulation 1 According to the method described in Test Example 6, D-mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, and crospovidone are each in a mass ratio of 54: Granules were granulated so as to be 20:20: 6, and drug-free granules of Formulation 1 were prepared.
(3) Production of Orally Disintegrating Tablets The drug-containing granules obtained in (1) above, the drug-free granules obtained in Test Example 7, the drug-free granules of Formulation 1 obtained in (2) above, and cloth. Using povidone and magnesium stearate, tablets were produced at a tableting pressure of 11 kN so as to have the compounding ratio shown in Table 5 according to the methods described in Test Examples 22 and 23. In Table 5, "%" represents the content of each component with respect to the total mass of the tablet in mass%.
That is, the tablet of Test Example 24 does not contain crospovidone, the tablet of Test Example 25 contains crospovidone in the drug-free granules, and the tablet of Test Example 26 contains crospovidone in the drug-containing granules. And is contained outside the drug-free granules.
(4) Humidification Stability Test Each tablet was evaluated by measuring the hardness immediately after tableting and the hardness of the tablet at 40 ° C., 75% RH, under opening and after storage for 7 days.

As a result of the above, in the tablets of Test Examples 25 and 26 containing crospovidone in the tablets, the hardness was low after storage at 40 ° C., 75% RH, under opening for 7 days, and the crospovidone was not contained in the tablets. Compared with the tablet of Example 24, the humidification stability tended to be relatively poor. In addition, the tablet of Test Example 26 containing crospovidone in the drug-free granules had a higher hardness under humidification than the tablet of Test Example 25 containing crospovidone in the drug-free granules.

<Presence / absence of pregelatinized starch and characteristics of orally disintegrating tablets>
Test Examples 27 and 28
Test Examples 27 and 28 were carried out to examine the effect of the presence or absence of pregelatinized starch on the drug-free granules.
According to the method described in Test Example 6, drug-free granules having a blending ratio of each component shown in Table 6 were produced. Magnesium stearate was added to the obtained drug-free granules in Test Example 27, and magnesium stearate and pregelatinized starch were added in Test Example 28 so as to have the blending ratios shown in Table 6 to obtain a rotary tableting machine (rotary tableting machine). Kikusui Seisakusho, VELA-5) performed tableting with a tableting pressure of 8 kN in Test Example 27 and a tableting pressure of 10 kN in Test Example 28, respectively, to produce tablets having a tablet mass of 130 mg and a tablet diameter of 8 mm, respectively. In Table 6, "%" represents the content of each component with respect to the total mass of the tablet in mass%.
For each tablet, hardness and oral disintegration time were measured.

As a result of the above, the tablet of Test Example 27 containing pregelatinized starch in the drug-free granules had a high hardness of 50 N or more, but was an orally disintegrating tablet having a high disintegration time of 30 seconds or less. It didn't happen. On the other hand, it was shown that the tablet of Test Example 28 containing no pregelatinized starch in the drug-free granules has both high hardness and disintegration property.

The present invention can provide an orally disintegrating tablet having both high tablet hardness and high disintegration without requiring special techniques, equipment and work.

Claims (17)

Orally disintegrating tablets consisting of drugs, drug-free granules, and optionally pharmaceutically acceptable additives, said drug-free granules are crystalline cellulose, mannitol having an average particle size of 15-160 μm and low. Degree of Substitution An orally disintegrating tablet containing hydroxypropyl cellulose and free of crospovidone and cornitol . The content of crystalline cellulose is 5 to 50% by mass, the content of mannitol is 20 to 90% by mass, and the content of low-substituted hydroxypropyl cellulose is based on the total mass of the drug-free granules. The orally disintegrating tablet according to claim 1, wherein the content is 3 to 50% by mass (however, the total content of crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose does not exceed 100% by mass). The orally disintegrating tablet according to claim 1 or 2, wherein the average particle size of mannitol contained in the drug-free granules is 15 to 80 μm. The orally disintegrating tablet according to any one of claims 1 to 3, wherein the crystalline cellulose contained in the drug-free granules has a bulk density of 0.11 to 0.43 g / cm ³ . The orally disintegrating tablet according to any one of claims 1 to 4, wherein the hydroxypropoxy group of the low-substitution hydroxypropyl cellulose contained in the drug-free granule has a substitution degree of 8 to 14%. Further, it contains one or more additives selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, sucrose fatty acid ester, hydrogenated oil, glycerin, glycerin fatty acid ester, carnauba wax and talc. , The orally disintegrating tablet according to any one of claims 1 to 5. One of claims 1 to 6, further comprising one or more additives selected from the group consisting of carmellose calcium, carmellose, croscarmellose sodium, crospovidone, corn starch and sodium starch glycolate. Orally disintegrating tablets as described in. The one according to any one of claims 1 to 7, further comprising one or more additives selected from the group consisting of light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate and fumed silica. Orally disintegrating tablet. The orally disintegrating tablet according to any one of claims 1 to 8, wherein the drug-free granules have an average particle size of 50 to 200 μm. The orally disintegrating tablet according to any one of claims 1 to 9, wherein the drug is bulk powder or is granulated with a pharmaceutically acceptable additive. The orally disintegrating tablet according to any one of claims 1 to 10, wherein the drug is a poorly soluble drug or a pharmaceutically acceptable salt thereof. The orally disintegrating tablet according to any one of claims 1 to 10, wherein the drug is an easily soluble drug or a pharmaceutically acceptable salt thereof. The orally disintegrating tablet according to any one of claims 1 to 12, wherein the drug-free granules do not contain pregelatinized starch. After producing drug-free granules containing crystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose, the drug-free granules, the drug and optionally a pharmaceutically acceptable additive are mixed and compressed. The method for producing an orally disintegrating tablet according to any one of claims 1 to 13. Drug-free granules containing crystalline cellulose, mannitol having an average particle size of 15 to 160 μm and low-substituted hydroxypropyl cellulose, and free of crospovidone and corn starch, with respect to the total mass of the drug-free granules. The content of crystalline cellulose is 5 to 50% by mass, the content of mannitol is 20 to 90% by mass, and the content of low-substituted hydroxypropyl cellulose is 3 to 50% by mass (however, crystalline). Drug-free granules having a total content of cellulose, mannitol and low-substituted hydroxypropyl cellulose not exceeding 100% by mass) and an average particle size of 50-200 μm. The drug-free granule according to claim 15, wherein the average particle size of mannitol contained in the drug-free granule is 15 to 80 μm . The drug-free granule according to claim 15 or 16, which does not contain alferated starch.