Patent Description:
As a final form of a solid pharmaceutical, there is known a tablet.

Among tablets, an orally disintegrating tablet (OD tablet) is a dosage form that easily disintegrates and is easy to take. The OD tablet generally has low tablet hardness, and hence there is a demand for prevention of cracking of the OD tablet in handling of the tablet at a production site and later in a medical setting (Non Patent Literature <NUM>). PL1 is dedicated to the preparation of granulated composite particles, comprising a sugar/sugar alcohol (mannitol,xylitol), a disintegrant (crospovidone), a swelling binder (microcrystalline cellulose) and a highly absorbent excipient (magnesium aluminometasilicate) by a spray dried granulation process. The granulated particles are used to prepare OD tablets by compression.

NPL2, PL2 and PL3 disclose the preparation of OD tablets.

A primary object of the present invention is to provide a composite granulated product that is optimal for allowing a tablet, preferably an orally disintegrating tablet (OD tablet) to be excellent in disintegrability and show proper hardness.

The inventors of the present invention have made extensive investigations in view of the problem of the related art described above.

Then, the inventors of the present invention have found that, when an OD tablet is produced using a composite granulated product including a sugar or a sugar alcohol, a swelling binder, a disintegrating agent, and a highly absorbent excipient, the OD tablet has high hardness and is also excellent in disintegrability.

The inventors of the present invention have also found that, particularly when an OD tablet is produced using a composite granulated product obtained by performing wet granulation in a binding solution using a sugar or a sugar alcohol, a swelling binder, a disintegrating agent, and an excipient, then adding layering granulation with a highly absorbent excipient, and further performing layering granulation (surface-modifying granulation) with a disintegrating agent, the OD tablet has high hardness and is also excellent in disintegrability.

The present invention is directed to the following composite granulated product and manufacturing method therefor as defined in the appended claims.

A manufacturing method for a composite granulated product including a sugar or a sugar alcohol, a swelling binder, a disintegrating agent, and a highly absorbent excipient,.

The manufacturing method for a composite granulated product according to the item <NUM>, in which the sugar or the sugar alcohol is at least one kind of component selected from the group consisting of D-mannitol, trehalose, xylitol, erythritol, lactose, and sucrose.

The manufacturing method for a composite granulated product according to the item <NUM> or <NUM>, in which the swelling binder is at least one kind of component selected from the group consisting of a polyvinyl alcohol-based polymer, partially pregelatinized starch, hydroxypropyl cellulose, and crystalline cellulose.

The manufacturing method for a composite granulated product according to any one of the items <NUM> to <NUM>, in which the swelling binder has an average particle diameter of from <NUM> to <NUM>.

The manufacturing method for a composite granulated product according to any one of the items <NUM> to <NUM>, in which the highly absorbent excipient is at least one kind of component selected from the group consisting of light anhydrous silicic acid, hydrated silicon dioxide, calcium silicate, magnesium aluminometasilicate, starch, calcium carbonate, kaolin, silicic acid, potassium hydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, dipotassium phosphate, disodium phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, calcium lactate, magnesium aluminosilicate, calcium silicate, and magnesium silicate.

The manufacturing method for a composite granulated product according to any one of the items <NUM> to <NUM>, in which the first disintegrating agent is hydroxypropyl cellulose, and the second disintegrating agent is at least one kind of component selected from the group consisting of starch, crospovidone, and croscarmellose sodium.

The manufacturing method for a composite granulated product according to any one of the items <NUM> to <NUM>, in which the composite granulated product is a composite granulated product for an orally disintegrating tablet.

A manufacturing method for a granule for tableting, including (<NUM>) a step of adding and mixing at least one kind of hardness modifier selected from the group consisting of crystalline cellulose, a D-mannitol granulated product, and isomalt into a composite granulated product obtained by the manufacturing method for a composite granulated product of any one of the items <NUM> to <NUM>.

The manufacturing method for a granule for tableting according to the item <NUM>, in which the granule for tableting is a granule for tableting for an orally disintegrating tablet.

A manufacturing method for a tablet, including mixing:.

The manufacturing method for a tablet according to the item <NUM>, in which the functional particles are at least one kind of component selected from the group consisting of bitterness-masking particles and sustained-release particles.

The manufacturing method for a tablet according to the item <NUM> or <NUM>, further including adding and mixing a lubricant.

The manufacturing method for a tablet according to any one of the items <NUM> to <NUM>, in which the tablet is an orally disintegrating tablet.

A composite granulated product, which is manufactured by the manufacturing method for a composite granulated product of any one of the items <NUM> to <NUM>.

A granule for tableting, which is manufactured by the manufacturing method for a granule for tableting of the item <NUM> or <NUM>.

A composite granulated product, including a sugar or a sugar alcohol, a swelling binder, a disintegrating agent, and a highly absorbent excipient.

The composite granulated product according to the item <NUM>, in which the compositing is treatment involving the following steps:.

The composite granulated product according to the item <NUM> or <NUM>, in which the sugar or the sugar alcohol is at least one kind of component selected from the group consisting of D-mannitol, trehalose, xylitol, erythritol, lactose, and sucrose.

The composite granulated product according to any one of the items <NUM> to <NUM>, in which the swelling binder is at least one kind of component selected from the group consisting of a polyvinyl alcohol-based polymer, partially pregelatinized starch, hydroxypropyl cellulose, and crystalline cellulose.

The composite granulated product according to any one of the items <NUM> to <NUM>, in which the disintegrating agent is at least one kind of component selected from the group consisting of hydroxypropyl cellulose, crospovidone, starch, croscarmellose sodium, carmellose calcium, carmellose, and partially pregelatinized starch.

The composite granulated product according to any one of the items <NUM> to <NUM>, in which the highly absorbent excipient is at least one kind of component selected from the group consisting of light anhydrous silicic acid, hydrated silicon dioxide, calcium silicate, and magnesium aluminometasilicate.

The composite granulated product according to any one of the items <NUM> to <NUM>, in which the swelling binder has an average particle diameter of from <NUM> to <NUM>.

A granule for tableting, including the composite granulated product of any one of the items <NUM> to <NUM>, and at least one kind of hardness modifier selected from the group consisting of crystalline cellulose, a D-mannitol granulated product, and isomalt.

The composite granulated product according to any one of the items <NUM> to <NUM>, in which the composite granulated product is a composite granulated product for an orally disintegrating tablet.

The granule for tableting according to the item <NUM>, in which the granule for tableting is a granule for tableting for an orally disintegrating tablet.

The tablet according to the item <NUM>, in which the functional particles are at least one kind of component selected from the group consisting of bitterness-masking particles and sustained-release particles.

The tablet according to the item <NUM> or <NUM>, in which the tablet is an orally disintegrating tablet.

A manufacturing method for a composite granulated product including a sugar or a sugar alcohol, a swelling binder, a disintegrating agent, and a highly absorbent excipient,
the manufacturing method including the steps of:.

A manufacturing method for a granule for tableting, further including (<NUM>) a step of adding and mixing at least one kind of hardness modifier selected from the group consisting of crystalline cellulose, a D-mannitol granulated product, and isomalt into a composite granulated product obtained in the item <NUM>.

When an OD tablet is produced using the composite granulated product of the present invention, the OD tablet is excellent in disintegrability and has proper hardness.

In addition, when an OD tablet is produced using the composite granulated product of the present invention, the following OD tablet can be obtained: the OD tablet maintains its high hardness and disintegrability even under high temperature and increased humidity, and hence is excellent in storage stability.

A composite granulated product of the present invention includes a sugar or a sugar alcohol, a swelling binder, a disintegrating agent, and a highly absorbent excipient.

The compositing of a composite granulated product is treatment involving the following steps:.

The composite granulated product of the present invention is preferably used for an orally disintegrating tablet (OD tablet).

When an OD tablet is produced using the composite granulated product of the present invention, the following OD tablet can be obtained:.

The sugar or the sugar alcohol is at least one kind of component selected from the group consisting of D-mannitol, trehalose, xylitol, erythritol, lactose, and sucrose.

The average particle diameter of the sugar or the sugar alcohol is preferably from about <NUM> to about <NUM>, more preferably from about <NUM> to about <NUM>. A case in which the average particle diameter of the sugar or the sugar alcohol falls within the above-mentioned range is preferred because disintegrability and formability are improved, and mouth feeling is improved.

The average particle diameter of the sugar or the sugar alcohol is a volume-based particle diameter, and may be measured by a powder particle diameter measurement method using a laser diffraction method.

The content of the sugar or the sugar alcohol in the composite granulated product is preferably from about <NUM> mass% to about <NUM> mass%, more preferably from about <NUM> mass% to about <NUM> mass%. When the content of the sugar or the sugar alcohol falls within the above-mentioned range, hygroscopicity, stability of a formulation, formability, disintegrability, mouth feeling, and the like are improved.

The swelling binder is at least one kind of component selected from the group consisting of a polyvinyl alcohol-based polymer (PVA-based polymer), partially pregelatinized starch, hydroxypropyl cellulose (HPC), and crystalline cellulose.

For example, when the polyvinyl alcohol-based polymer is used, the size of granulated particles can be satisfactorily controlled. With regard to the size of the granulated particles, particles having an average particle diameter of about <NUM> or less are preferred.

The polyvinyl alcohol-based polymer (PVA-based polymer) is at least one kind of PVA-based polymer selected from polyvinyl alcohol (PVA) and derivatives thereof, and a PVA-based copolymer obtained by polymerizing at least one kind selected from PVA and derivatives thereof and at least one kind of polymerizable vinyl monomer.

The PVA-based polymer includes: PVA; derivatives of PVA (modified products of PVA); a PVA copolymer obtained by polymerizing PVA and another polymerizable vinyl monomer; a PVA-based copolymer obtained by polymerizing a derivative of PVA and another polymerizable vinyl monomer; and a PVA-based copolymer obtained by polymerizing PVA, a derivative of PVA, and another polymerizable vinyl monomer.

Herein, those polymers are collectively referred to as PVA-based polymer.

For the PVA and the derivatives thereof included in the PVA-based polymer, known ones may be used, and it is desired that commercially available products be easily available.

The polymerization degree of each of the PVA and the derivatives thereof is not particularly limited, and a polymerization degree optimal for concentration and viscosity that are suited to an intended use may be selected. The polymerization degree is, for example, from about <NUM> to about <NUM>,<NUM>, preferably from about <NUM> to about <NUM>,<NUM>.

In addition, it is preferred to use partially saponified PVA in which the saponification degree of each of the PVA and the derivatives thereof is preferably from about <NUM> mol% to about <NUM> mol%, more preferably from about <NUM> mol% to about <NUM> mol%, still more preferably from about <NUM> mol% to about <NUM> mol%.

Such saponified PVA may be manufactured by radically polymerizing vinyl acetate, and saponifying the obtained vinyl acetate as appropriate. The manufacture of desired PVA is achieved by appropriately controlling the polymerization degree and the saponification degree by a method known per se.

The PVA is a fully saponified product of polyvinyl acetate. As the derivatives of PVA, for example, there may be used various modified PVAs, such as amine-modified PVA, ethylene-modified PVA, and terminal thiol-modified PVA as well as an intermediately saponified product and partially saponified product of PVA.

As a commercially available derivative of PVA, there is given, for example, JP-<NUM> manufactured by Japan VAM & Poval Co. (partially saponified PVA, polymerization degree: <NUM>, saponification degree: <NUM>%).

In the PVA-based polymer, a polymerizable vinyl monomer may be bonded to or polymerized with part of a straight chain of each of the PVA and the derivatives thereof. In the PVA-based polymer, a polymerizable vinyl monomer may be bonded to part or all of hydroxy groups of the PVA and the derivatives thereof by an ester bond. The polymerizable vinyl monomer bonded to each of the PVA and the derivatives thereof may be further polymerized.

In the present invention, examples of the polymerizable vinyl monomer include:.

acrylonitrile, acrylamide, dimethylacrylamide, styrene, vinyl acetate, hydroxyethyl methacrylate, hydroxyethyl acrylate, an ester of polyethylene glycol and methacrylic acid, an ester of polyethylene glycol and acrylic acid, an ester of polypropylene glycol and methacrylic acid, an ester of polypropylene glycol and acrylic acid, N-vinylpyrrolidone, acryloylmorpholine, N,N-dimethylaminoethyl methacrylate, and methacryloyloxyethyl trimethylammonium chloride.

A preferred example of the polymerizable vinyl monomer is a compound represented by the following general formula (A):.

where R<NUM> represents a hydrogen atom or a methyl group, and R<NUM> represents a hydrogen atom or an alkyl group having <NUM> to <NUM> carbon atoms.

The polymerizable vinyl monomers may be used alone or as a mixture thereof. When two or more kinds of polymerizable vinyl monomers are used as a mixture, the polymerizable vinyl monomers preferably include a compound in which R<NUM> represents a hydrogen atom and a compound in which R<NUM> represents an alkyl group having <NUM> to <NUM> carbon atoms among compounds represented by the general formula (A).

The use ratios of the compound in which R<NUM> in the general formula (A) represents a hydrogen atom and the compound in which R<NUM> represents an alkyl group having <NUM> to <NUM> carbon atoms in the PVA-based polymer, that is,.

A preferred combination of polymerizable vinyl monomers is combined use of at least one kind of the monomers described above in (<NUM>) and (<NUM>) and at least one kind of the monomers described above in (<NUM>). A more preferred combination of polymerizable vinyl monomers is combined use of acrylic acid or methacrylic acid and methyl methacrylate, that is, a combination of acrylic acid and methyl methacrylate, or a combination of methacrylic acid and methyl methacrylate.

A combination of acrylic acid and methyl methacrylate is particularly preferred. Further, the polymerizable vinyl monomers preferably include at least one kind selected from the group consisting of acrylic acid and methyl methacrylate, and it is particularly preferred that only acrylic acid and methyl methacrylate be used as the polymerizable vinyl monomers.

The use ratios of acrylic acid and methyl methacrylate in the PVA-based polymer, that is, with respect to <NUM> mass% of the total amount of at least one kind selected from PVA and derivatives thereof and the polymerizable vinyl monomer are preferably about <NUM> mass% to about <NUM> mass% of acrylic acid and about <NUM> mass% to about <NUM> mass% of methyl methacrylate, more preferably about <NUM> mass% to about <NUM> mass% of at least one kind selected from the group consisting of acrylic acid and methacrylic acid and about <NUM> mass% to about <NUM> mass% of methyl methacrylate.

In particular, a polyvinyl alcohol-based copolymer obtained by polymerizing <NUM> wt% to <NUM> wt% of acrylic acid, <NUM> to <NUM> wt% of methyl methacrylate, and <NUM> wt% to <NUM> wt% of PVA with respect to the total amount of acrylic acid, methyl methacrylate, and PVA is preferred, and a PVA-based copolymer obtained by polymerizing <NUM> wt% to <NUM> wt% of acrylic acid, <NUM> to <NUM> wt% of methyl methacrylate, and <NUM> wt% to <NUM> wt% of PVA is more preferred.

A copolymer obtained by polymerizing acrylic acid and methyl methacrylate in the presence of PVA is commercially available, and is available under the name of POVACOAT from Daido Chemical Corporation. In the present invention, the commercially available product may be used.

An example of the PVA-based polymer is a polymer obtained by graft-polymerizing a polymerizable vinyl monomer to PVA (chain). Such polymer is preferably a PVA-based polymer obtained by graft-polymerizing at least one kind selected from the group consisting of acrylic acid and methyl methacrylate to at least one kind selected from PVA and derivatives thereof.

The weight-average molecular weight of the PVA-based polymer is preferably from about <NUM>,<NUM> to about <NUM>,<NUM>, more preferably from about <NUM>,<NUM> to about <NUM>,<NUM>.

For the PVA-based polymer, a commercially available product may be used. When the commercially available product is used, for example, POVACOAT (trademark: manufactured by Daido Chemical Corporation) may be used. POVACOAT (polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer) is a synthetic polymer obtained by copolymerizing partially saponified polyvinyl alcohol with acrylic acid and methyl methacrylate. The PVA-based polymer is represented by the following structural formula as a general formula. <CHM>
<CHM>.

In the structural formula, about <NUM>% to about <NUM>% of k, about <NUM>% to about <NUM>% of l, about <NUM>% to about <NUM> of m, and about <NUM>% to about <NUM>% of n are preferably included in <NUM>% of the sum of k, l, m, and n.

The average molecular weight (Mw) of such PVA-based polymer is preferably from about <NUM>,<NUM> to about <NUM>,<NUM>.

The average polymerization degree of such PVA-based polymer is preferably from about <NUM> to about <NUM>,<NUM>.

The labeled viscosity of such PVA-based polymer is preferably from about <NUM> mPA·s to about <NUM> mPA·s.

For example, POVACOAT Type F having an average molecular weight (Mw) of about <NUM>,<NUM>, or POVACOAT Type MP, POVACOAT Type FM, and POVACOAT Type SP each having an average molecular weight (Mw) of about <NUM>,<NUM> but having different average particle diameters, or POVACOAT Type R having an average molecular weight (Mw) of about <NUM>,<NUM> may be used.

POVACOAT Type MP is a pulverized product of POVACOAT Type F (average particle diameter: about <NUM> pm).

POVACOAT Type FM is a pulverized product of Type F (average particle diameter: about <NUM>), and is a frozen and pulverized product.

POVACOAT Type SP is a pulverized product prepared by pulse combustion drying (average particle diameter: about <NUM>).

The PVA and the derivatives thereof may be used alone or as a mixture thereof.

Other than the PVA-based polymer, the swelling binder is partially pregelatinized starch, hydroxypropyl cellulose (HPC), crystalline cellulose. HPC is more preferably low-substituted HPC (L-HPC).

As another binder, for example, polyvinylether, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxyvinyl polymer, cellulose powder, crystalline cellulose, carmellose sodium, methyl cellulose, ethyl cellulose, potassium phosphate, gum arabic powder, pullulan, pectin, dextrin, hydroxypropyl starch, gelatin, xanthan gum, carrageenan, tragacanth, tragacanth powder, polyethylene glycol, carboxymethylcellulose sodium, methyl cellulose, or sodium alginate may be used in combination with the above-mentioned swelling binder.

The average particle diameter of the swelling binder is preferably from about <NUM> to about <NUM> pm, more preferably from about <NUM> to about <NUM>. When the average particle diameter of the swelling binder falls within the above-mentioned range, the swelling binder shows proper swellability and solubility to improve fluidity, disintegrability, formability, and the like.

When the swelling binder has the preferred average particle diameter, an optimal composite granulated product to be used for an OD tablet can be prepared. The average particle diameter is a volume-based particle diameter, and may be measured by a powder particle diameter measurement method using a laser diffraction method.

The content of the swelling binder in the composite granulated product is preferably from about <NUM> mass% to about <NUM> mass%, more preferably from about <NUM> mass% to about <NUM> mass%. When the content of the swelling binder falls within the above-mentioned range, hygroscopicity, stability of a formulation, binding property, disintegrability, and the like are improved.

The The first disintegrating agent is hydroxypropyl cellulose (HPC, preferably low-substituted HPC), and the second disintegrating agent is at least one kind of component selected from the group consisting of starch, crospovidone, and croscarmellose sodium.

The hydroxypropyl cellulose contains cellulose as a basic backbone, and is preferably low-substituted hydroxypropyl cellulose (L-HPC) obtained by introducing a small amount of hydroxypropoxy groups into the basic backbone. The L-HPC is a water-insoluble polymer and has a characteristic of swelling by absorbing water, and its degree of hydroxypropoxy substitution is preferably from about <NUM> mass% to about <NUM> mass%, more preferably from about <NUM> mass% to about <NUM> mass%.

When the degree of hydroxypropoxy substitution falls within the above-mentioned range, swellability after water absorption, disintegrability, binding property, water solubility, and the like are improved. When the L-HPC is used, the stability of a tablet (preferably an OD tablet) is improved. In addition, the L-HPC has good compatibility with the PVA-based polymer, and hence improves the stability of a tablet (preferably an OD tablet).

The use of crospovidone, starch (corn starch or the like), croscarmellose sodium, carmellose calcium, carmellose, partially pregelatinized starch, or the like provides the following effect: the disintegrability of the prepared OD tablet is excellent.

As another disintegrating agent, starch, dry starch, carboxymethyl starch sodium, sodium starch glycolate, agar powder, sodium hydrogen carbonate, calcium carbonate, or the like may be used in combination with the above-mentioned disintegrating agent.

The average particle diameter of the disintegrating agent is preferably from about <NUM> to about <NUM>, more preferably from about <NUM> to about <NUM>. When the average particle diameter of the disintegrating agent falls within the above-mentioned range, water absorption swellability, disintegrability, binding property, and the like are improved.

The average particle diameter is a volume-based particle diameter, and may be measured by a powder particle diameter measurement method using a laser diffraction method.

The content of the disintegrating agent in the composite granulated product is preferably from about <NUM> mass% to about <NUM> mass%, more preferably from about <NUM> mass% to about <NUM> mass%. When the content of the disintegrating agent falls within the above-mentioned range, disintegrability and the like are improved.

The highly absorbent excipient is at least one kind of component selected from the group consisting of light anhydrous silicic acid, hydrated silicon dioxide, calcium silicate, and magnesium aluminometasilicate. When any of those components is used, the average particle diameter of the composite granulated product can be made sharper.

As another excipient, for example, allose, talose, gulose, glucose, altrose, mannose, galactose, idose, ribose, lyxose, xylose, arabinose, apiose, erythrose, threose, glyceraldehyde, sedoheptulose, coriose, psicose, fructose, sorbose, tagatose, ribulose, xylulose, erythrulose, dihydroxyacetone, isotrehalose, kojibiose, sophorose, nigerose, laminaribiose, maltose, cellobiose, isomaltose, gentiobiose, lactose, sucrose, sodium chloride, starch, reduced palatinose,.

The average particle diameter of the highly absorbent excipient is preferably from about <NUM> to about <NUM>, more preferably from about <NUM> to about <NUM>. When the average particle diameter of the disintegrating agent falls within the above-mentioned range, water absorption swellability, disintegrability, binding property, and the like are improved.

The content of the highly absorbent excipient in the composite granulated product is preferably from about <NUM> mass% to about <NUM> mass%, more preferably from about <NUM> mass% to about <NUM> mass%. When the content of the highly absorbent excipient falls within the above-mentioned range, the average particle diameter of the composite granulated product can be made sharper.

The present invention is directed to the composite granulated product including the sugar or the sugar alcohol, the swelling binder, the disintegrating agent, and the highly absorbent excipient as defined in the claims.

A hardness modifier is preferably added to the composite granulated product including the above-mentioned components. Through the addition of the hardness modifier to the composite granulated product, a granule for tableting may be prepared.

The hardness modifier is an additive for increasing hardness without sacrificing disintegration time, by being further added to the composite granulated product including the above-mentioned components.

The hardness modifier is preferably at least one kind of hardness modifier selected from the group consisting of crystalline cellulose, a D-mannitol granulated product, and isomalt. D-mannitol is preferably a D-mannitol granulated product prepared by spray drying or the like. Isomalt is a sugar alcohol using sucrose as a raw material.

When any of those components is used, the hardness of a prepared OD tablet can be increased.

The average particle diameter of the hardness modifier is preferably from about <NUM> to about <NUM> pm, more preferably from about <NUM> to about <NUM>. When the average particle diameter of the hardness modifier falls within the above-mentioned range, the prepared OD tablet shows proper hardness, and fluidity, disintegrability, formability, and the like are improved.

When the hardness modifier has the preferred average particle diameter, an optimal composite granulated product to be used for an OD tablet can be prepared. The average particle diameter is a volume-based particle diameter, and may be measured by a powder particle diameter measurement method using a laser diffraction method.

The content of the hardness modifier in the composite granulated product is preferably from about <NUM> mass% to about <NUM> mass%, more preferably from about <NUM> mass% to about <NUM> mass%. When the content of the hardness modifier falls within the above-mentioned range, the following effect is obtained in the prepared OD tablet: its hardness is increased without sacrificing its disintegration time.

A tablet of the present invention contains a medicinal component, functional particles, and the like in addition to the above-mentioned composite granulated product.

The above-mentioned composite granulated product may be used.

The average particle diameter of the composite granulated product is preferably from about <NUM> to about <NUM>, more preferably from about <NUM> to about <NUM>. When the average particle diameter of the composite granulated product falls within the above-mentioned range, the prepared OD tablet shows proper hardness, and is improved in water absorption swellability, disintegrability, binding property, and the like.

The content of the composite granulated product in the tablet is preferably from about <NUM> mass% to about <NUM> mass%, more preferably from about <NUM> mass% to about <NUM> mass%. When the content of the composite granulated product falls within the above-mentioned range, hygroscopicity, stability of a formulation, binding property, disintegrability, and the like are improved.

The medicinal component may be selected from a wide range of fields, such as pharmaceutical compounds (pharmaceutical compounds including animal drugs), medical materials (medical materials including regenerative medical materials, such as artificial skin), pesticide compounds, fertilizers, cosmetics, perfumes, food materials, feeds, germicides, fungicides, insect repellents, insecticides, corrosion inhibitors, absorbents, and coating materials.

The following components are preferred as the pharmaceutical compounds.

It is preferred that at least one kind of component selected from these components be used.

Adrenaline, noradrenaline, etilefrine, naphazoline, phenylephrine, methoxamine, midodrine, isoprenaline, isoproterenol, dobutamine, denopamine, trimetoquinol, salbutamol, terbutaline, tulobuterol, fenoterol, procaterol, clenbuterol, salmeterol, mabuterol, ritodrine, isoxsuprine, tyramine, amphetamine, methamphetamine, ephedrine, methylephedrine, dopamine, docarpamine, amezinium, or salts thereof, and the like.

Ergotamine, ergometrine, phentolamine, tolazoline, prazosin, bunazosin, terazosin, urapidil, doxazosin, tamsulosin, silodosin, naftopidil, alprenolol, oxprenolol, propranolol, bufetolol, pindolol, carteolol, timolol, nadolol, nipradilol, atenolol, metoprolol, bisoprolol, labetalol, amosulalol, arotinolol, carvedilol, reserpine, guanethidine, α-methyldopa, clonidine, guanabenz, or salts thereof, and the like.

Acetylcholine, bethanechol, carbachol, methacholine, pilocarpine, muscarine, physostigmine, neostigmine, distigmine, pyridostigmine, ambenonium, edrophonium, pilocarpine, carpronium, cevimeline, or salts thereof, and the like.

Homatropine, tropicamide, cyclopentolate, propantheline, butylscopolamine, mepenzolate, prifinium, pirenzepine, ipratropium, oxitropium, piperidolate, propiverine, oxybutynin, trihexyphenidyl, biperiden, piroheptine, mazaticol, profenamine, metixene, or salts thereof, and the like.

Hexamethonium, trimethaphan, nicotine, or salts thereof, and the like.

Cocaine, procaine, oxybuprocaine, tetracaine, ethyl aminobenzoate, lidocaine, dibucaine, mepivacaine, oxethazaine, xylocaine, or salts thereof, and the like.

Tubocurarine, pancuronium, vecuronium, suxamethonium, dantrolene, pridinol, mephenesin, chlorzoxazone, phenprobamate, methocarbamol, chlormezanone, pridinol mesylate, afloqualone, chlorphenesin, tizanidine, tolperisone, eperisone, baclofen, or salts thereof, and the like.

Thiopental, thiamylal, propofol, midazolam, droperidol, ketamine, or salts thereof, and the like.

Flurazepam, haloxazolam, quazepam, nitrazepam, flunitrazepam, estazolam, nimetazepam, brotizolam, rilmazafone, lormetazepam, triazolam, zolpidem, zopiclone, bromovalerylurea, barbital, phenobarbital, amobarbital, secobarbital, pentobarbital, thiopental, thiamylal, ramelteon, or salts thereof, and the like.

Morphine, codeine, papaverine, noscapine, dihydrocodeine, oxycodone, diacetylmorphine, pethidine, methadone, levorphanol, fentanyl, remifentanil, pentazocine, butorphanol, buprenorphine, naloxone, levallorphan, dextromethorphan, tipepidine, guaifenesin, pentoxyverine, benzonatate, oxymorphone, cloperastine, or salts thereof, and the like.

Phenobarbital, primidone, phenytoin, carbamazepine, ethosuximide, trimethadione, diazepam, clonazepam, nitrazepam, valproic acid, gabapentin, sultiame, zonisamide, or salts thereof, and the like.

Levodopa, carbidopa, benserazide, entacapone, bromocriptine, pergolide, cabergoline, talipexole, pramipexole, amantadine, selegiline, trihexyphenidyl, biperiden, profenamine, piroheptine, metixene, mazaticol, droxidopa, or salts thereof, and the like.

Donepezil, galantamine, rivastigmine, memantine, or salts thereof, and the like.

Chlorpromazine, fluphenazine, thioridazine, haloperidol, bromperidol, spiperone, haloperidol decanoate, sulpiride, risperidone, perospirone, olanzapine, quetiapine, clozapine, aripiprazole, prochlorperazine, trifluoperazine, zotepine, or salts thereof, and the like.

Etizolam, diazepam, oxazolam, ethyl loflazepate, clotiazepam, lorazepam, tandospirone, hydroxyzine, oxazepam, medazepam, temazepam, fludiazepam, meprobamate, chlordiazepoxide, or salts thereof, and the like.

Imipramine, clomipramine, amitriptyline, nortriptyline, desipramine, amoxapine, maprotiline, mianserin, setiptiline, trazodone, fluvoxamine, paroxetine, sertraline, milnacipran, duloxetine, mirtazapine, noxiptiline, phenelzine, or salts thereof, and the like.

Dimenhydrinate, difenidol, betahistine, or salts thereof, and the like.

Digitoxin, digoxin, metildigoxin, deslanoside, dobutamine, denopamine, dopamine, docarpamine, colforsin daropate, aminophylline, milrinone, olprinone, pimobendan, bucladesine, trans-n-oxocamphor, terephyllol, etilefrine, or salts thereof, and the like.

Quinidine, procainamide, disopyramide, ajmaline, cibenzoline, pirmenol, lidocaine, mexiletine, aprindine, phenytoin, propafenone, flecainide, pilsicainide, propranolol, alprenolol, bufetolol, oxprenolol, pindolol, carteolol, nadolol, atenolol, acebutolol, metoprolol, bisoprolol, amiodarone, sotalol, nifekalant, verapamil, diltiazem, bepridil, or salts thereof, and the like.

Nitroglycerin, isosorbide nitrate, nicorandil, nifedipine, amlodipine, nitrendipine, nicardipine, felodipine, cilnidipine, manidipine, diltiazem, captopril, lisinopril, alacepril, enalapril, temocapril, imidapril, losartan, valsartan, candesartan cilexetil, olmesartan medoxomil, azilsartan, aliskiren, hydralazine, bosentan, ethyl icosapentate, nicomol, niceritrol, isoxsuprine, tolazoline, hexobendine, bamethan, nilvadipine, trapidil, dilazep, beraprost, alprostadil, or salts thereof, and the like.

Phenylephrine, midodrine, methoxamine, etilefrine, ephedrine, dihydroergotamine, amezinium, or salts thereof, and the like.

Acetazolamide, furosemide, bumetanide, torsemide, azosemide, piretanide, hydrochlorothiazide, trichlormethiazide, spironolactone, canrenoic acid, eplerenone, triamterene, isosorbide, methyclothiazide, hydroflumethiazide, ethiazide, cyclopenthiazide, chlorothiazide, ethacrynic acid, or salts thereof, and the like.

Tamsulosin, silodosin, naftopidil, prazosin, terazosin, urapidil, bethanechol, neostigmine, distigmine, oxendolone, chlormadinone acetate, allylestrenol, gestonorone caproate, or salts thereof, and the like.

Propiverine, oxybutynin, solifenacin, imidafenacin, tolterodine, imipramine, clomipramine, amitriptyline, clenbuterol, mirabegron, flavoxate, terodiline, or salts thereof, and the like.

Bromhexine, acetylcysteine, ethylcysteine, methylcysteine, carbocysteine, ambroxol, senega, polygala root, platycodon root, chlophedianol, picoperidamine, or salts thereof, and the like.

Theophylline, aminophylline, ipratropium, oxitropium, beclomethasone propionate, fluticasone propionate, dexamethasone, prednisolone, budesonide, trimetoquinol, salbutamol, terbutaline, procaterol, salmeterol, fenoterol, tulobuterol, mabuterol, clenbuterol, formoterol, indacaterol, methoxyphenamine, or salts thereof, and the like.

Pirenzepine, propantheline, butylscopolamine, cimetidine, ranitidine, famotidine, nizatidine, roxatidine acetate, proglumide, oxethazaine, omeprazole, lansoprazole, rabeprazole, sucralfate, teprenone, cetraxate, rebamipide, gefarnate, ecabet, azulene, sulpiride, misoprostol, enprostil, irsogladine, roxatidine acetate, magnesium oxide, synthetic aluminum silicate, or salts thereof, and the like.

Metoclopramide, domperidone, mosapride, sennoside, picosulfate, bisacodyl, gentian, swertia herb, coptis rhizome, phellodendron bark, fennel, cinnamon bark, ginger, Japanese zanthoxylum peel, carmellose, dioctyl sodium sulfosuccinate, lactulose, magnesium oxide, magnesium sulfate, magnesium hydroxide, or salts thereof, and the like.

Atropine, loperamide, trimebutine, opium, mepenzolate, albumin tannate, bismuth subnitrate, natural aluminum silicate, berberine, nalidixic acid, or salts thereof, and the like.

Chlorpromazine, sulpiride, domperidone, metoclopramide, granisetron, ondansetron, azasetron, oxethazaine, dimenhydrinate, promethazine, aprepitant, apomorphine, ipecac (emetine or cephaeline), or salts thereof, and the like.

Interferon preparations, lamivudine, glycyrrhizin, protoporphyrin, saikosaponin, lactulose, dehydrocholic acid, ursodeoxycholic acid, flopropione, chenodeoxycholic acid, nafamostat, ulinastatin, gabexate, camostat, trepibutone, or salts thereof, and the like.

Sildenafil, vardenafil, tadalafil, udenafil, mirodenafil, ergometrine, methylergometrine, oxytocin, dinoprostone, dinoprost, gemeprost, ritodrine, isoxsuprine, piperidolate, or salts thereof, and the like.

Pilocarpine, distigmine, latanoprost, isopropyl unoprostone, bunazosin, acetazolamide, dorzolamide, timolol, carteolol, levobunolol, nipradilol, dipivefrine, or salts thereof, and the like.

Phenylephrine, homatropine, tropicamide, cyclopentolate, pilocarpine, or salts thereof, and the like.

Tacalcitol, etretinate, urea, methoxsalen, lysozyme, alprostadil, alprostadil alfadex, tretinoin tocoferil, trafermin, or salts thereof, and the like.

Corticotropin releasing hormone, thyrotropin-releasing hormone, gonadotropin-releasing hormone, luteinizing hormone-releasing hormone, growth hormone-releasing hormone, prolactin-releasing hormone, prolactin-release-inhibiting hormone, adrenocorticotropic hormone, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, growth hormone,.

Insulin preparations, tolbutamide, acetohexamide, chlorpropamide, gliclazide, glibenclamide, glimepiride, nateglinide, mitiglinide, metformin, buformin, pioglitazone, acarbose, voglibose, miglitol, sitagliptin, vildagliptin, alogliptin, liraglutide, exenatide, epalrestat, or salts thereof, and the like.

Pravastatin, simvastatin, fluvastatin, atorvastatin, cholestyramine, colestimide, ezetimibe, γ-oryzanol, soy sterol, probucol, clofibrate, bezafibrate, fenofibrate, nicomol, niceritrol, dextran sulfate, ethyl icosapentate, ethyl <NUM>-chloro-<NUM>-[<NUM>-(<NUM>-methyl-<NUM>-phenylpropoxy)phenyl]propanoate [<NPL>)], clinofibrate, soy sterol, or salts thereof, and the like.

Colchicine, allopurinol, febuxostat, probenecid, benzbromarone, bucolome, or salts thereof, and the like.

Estradiol, raloxifene, elcatonin, salmon calcitonin, ipriflavone, calcitriol, α-calcidol, menatetrenone, etidronic acid, alendronic acid, risedronic acid, teriparatide, or salts thereof, and the like.

Phytonadione, menatetrenone, thrombin, hemocoagulase, tranexamic acid, carbazochrome, or salts thereof, and the like.

Heparin, dalteparin, danaparoid, warfarin, argatroban, urokinase, alteplase, monteplase, aspirin, ozagrel, ethyl icosapentate, sarpogrelate, ticlopidine, clopidogrel, beraprost, cilostazol, dipyridamole, or salts thereof, and the like.

Cideferron, cyanocobalamin, hydroxocobalamin, mecobalamin, folic acid, metenolone, nandrolone, erythropoietin preparations, pyridoxal phosphate, pyridoxine, filgrastim, lenograstim, nartograstim, mirimostim, or salts thereof, and the like.

Aspirin, salicylamide, indometacin, indometacin farnesil, acemetacin, sulindac, piroxicam, ampiroxicam, tenoxicam, meloxicam, diclofenac, felbinac, ibuprofen, naproxen, loxoprofen, flurbiprofen, flurbiprofen axetil, ketoprofen, mefenamic acid, flufenamic acid, etodolac, celecoxib, tiaramide,
epirizole, salicylic acid, sulpyrine, aminopyrine, phenacetin, phenylbutazone, ketophenylbutazone, benzydamine, mepirizole, tinoridine, isopropylantipyrine, sazapyrine, clofezone, or salts thereof, and the like.

Cyclosporine, tacrolimus, azathioprine, mizoribine, mycophenolate mofetil, cyclophosphamide, gusperimus, muromonab-CD3, basiliximab, or salts thereof, and the like.

Gold thiomalate, auranofin, D-penicillamine, bucillamine, methotrexate, leflunomide, actarit, lobenzarit, salazosulfapyridine, or salts thereof, and the like.

Cromoglicic acid, tranilast, pemirolast, amlexanox, diphenhydramine, chlorpheniramine, clemastine, promethazine, cyproheptadine, azelastine, ketotifen, oxatomide, mequitazine, epinastine, fexofenadine, cetirizine, ebastine, olopatadine, loratadine, ozagrel, seratrodast, ramatroban, pranlukast, montelukast, zafirlukast, ibudilast, suplatast, tripelennamine, methdilazine, clemizole, diphenylpyraline, alimemazine, or salts thereof, and the like.

Benzylpenicillin, sultamicillin, phenethicillin, cloxacillin, ampicillin, bacampicillin, amoxicillin, piperacillin, cephalothin, cefazolin, cefalexin, cefaclor, cefotiam, cefuroxime axetil, cefsulodin, cefotaxime, cefmenoxime, ceftizoxime, cefoperazone, ceftriaxone, cefuzonam, ceftazidime,.

Quinine, mefloquine, sulfadoxine, pyrimethamine, metronidazole, tinidazole, spiramycin acetate, pentamidine, santonin, pyrantel, mebendazole, ivermectin, diethylcarbamazine, praziquantel, albendazole, levamisole, or salts thereof, and the like.

Amphotericin B, nystatin, itraconazole, clotrimazole, ketoconazole, fluconazole, miconazole, micafungin, terbinafine, butenafine, flucytosine, griseofulvin, or salts thereof, and the like.

Acyclovir, valaciclovir, ganciclovir, vidarabine, foscarnet, amantadine, oseltamivir, zanamivir, laninamivir octanoate, peramivir, zidovudine, didanosine, lamivudine, sanilvudine, abacavir, nevirapine, efavirenz, delavirdine, saquinavir, ritonavir, indinavir, nelfinavir, fosamprenavir, lopinavir, raltegravir, interferon preparations, ribavirin, or salts thereof, and the like.

Cyclophosphamide, ifosfamide, busulfan, thiotepa, melphalan, nimustine, ranimustine, lomustine, carmustine, mercaptopurine, fludarabine, fluorouracil, tegafur, doxifluridine, capecitabine, cytarabine, cytarabine ocfosfate, enocitabine, gemcitabine, methotrexate, folinate, levofolinate, doxorubicin,.

Imatinib, gefitinib, erlotinib, dasatinib, lapatinib, nilotinib, sorafenib, sunitinib, crizotinib, axitinib, temsirolimus, everolimus, bortezomib, tamibarotene, tretinoin, vandetanib, and the like.

Amidotrizoic acid, meglumine, iotalamic acid, meglumine iothalamate, meglumine iotroxate, iopromide, iomeprol, iopamidol, iohexol, ioxilan, iotrolan, iodixanol, gadodiamide, sulfobromophthalein, indocyanine green, indigo carmine, p-aminohippuric acid, phenolsulfonphthalein, inulin, creatinine, Evans blue, tetragastrin, tuberculin, edrophonium, o-tolidine, or salts thereof, and the like.

Dimercaprol, edetic acid, D-penicillamine, trientine, deferoxamine, amyl nitrite, thiosulfuric acid, pralidoxime, atropine, nalorphine, naloxone, levallorphan, flumazenil, dimorpholamine, folinate, protamine, phytonadione, acetylcysteine, mesna, dimesna, pyridoxine, pyridoxal phosphate, disulfiram, cyanamide, or salts thereof, and the like.

Asinus gelatin, clematis root, Artemisia capillaris flower, fennel, lindera root, corydalis tuber, astragalus root, scutellaria root, phellodendron bark, cherry bark, coptis rhizome, polygala root, Artemisia leaf, polygonum root, pueraria root, aluminum silicate hydrate with silicon dioxide,.

Vitamin A, vitamin D, vitamin E, vitamin K, vitamin B1, vitamin B2, vitamin B6, vitamin B12, folic acid, niacin, biotin, pantothenic acid, vitamin C, and derivatives thereof, and the like.

Glycine, alanine, serine, threonine, valine, leucine, asparagine, aspartic acid, isoleucine, proline, glutamine, glutamic acid, phenylalanine, tryptophan, histidine, arginine, tyrosine, methionine, cysteine, lysine, and derivatives thereof, and the like.

Aivlosin, spiramycin, aspoxicillin, amoxicillin, oxytetracycline, ampicillin, erythromycin, kitasamycin, cloxacillin, chloramphenicol, dicloxacillin, josamycin, sedecamycin, cefazolin, cefalonium, ceftiofur, cefuroxime, tylosin, tiamulin, tilmicosin, destomycin A,
terdecamycin, nystatin, nanafrocin, nafcillin, novobiocin, hygromycin B, bicozamycin, tetracycline, benzylpenicillin, fosfomycin, oleandomycin, mirosamicin, mecillinam, monensin, chlortetracycline, spectinomycin, doxycycline, lincomycin, dexamethasone, apramycin, kanamycin, streptomycin, gentamycin, colistin, fradiomycin, pyromidic acid, or derivatives thereof, and salts thereof, and the like.

Meclofenoxate, tiapride, ifenprodil, nicergoline, fasudil, sumatriptan, dutasteride, oxyfedrine, protokylol, alloclamide, cinepazide maleate, cyclandelate, cinnarizine, pentoxifylline, ifenprodil, rotenone, Amytal, antimycin A, valinomycin, gramicidin A, oligomycin, edaravone, citicoline,.

Poorly soluble drugs, such as griseofulvin, hydrochlorothiazide, probucol, tolbutamide, fenofibrate, flurbiprofen, naproxen, piroxicam, albendazole, phenytoin, dipyridamole, acyclovir, indomethacin, and furosemide.

The following components are preferred as the pesticide compounds that are poorly water-soluble components.

The content of the medicinal component in the tablet is preferably from about <NUM> mass% to about <NUM> mass%, more preferably from about <NUM> mass% to about <NUM> mass%. When the content of the medicinal component falls within the above-mentioned range, hygroscopicity, stability of a formulation, binding property, disintegrability, and the like are improved.

The functional particles are preferably at least one kind of component selected from the group consisting of bitterness-masking particles and sustained-release particles.

The bitterness-masking particles are preferably polymer-coated particles, drug matrix particles having imparted thereto a bitterness-masking function, bitterness-masked drug granulated particles, or the like.

The sustained-release particles are preferably polymer-coated sustained-release particles, enteric polymer-coated particles, or the like.

It is preferred that at least one kind of component selected from those components be used.

The content of the functional particles in the tablet is preferably from about <NUM> mass% to about <NUM> mass%, more preferably from about <NUM> mass% to about <NUM> mass%. When the content of the functional particles falls within the above-mentioned range, hygroscopicity, stability of a formulation, binding property, disintegrability, and the like are improved.

The composite granulated product and tablet of the present invention may include other additives in addition to the above-mentioned components.

Plasticizers, for example: polyhydric alcohols, such as glycerin, ethylene glycol, and propylene glycol; various waxes, such as monostearin, PEG <NUM>, PEG <NUM>, and PEG <NUM>; organic fatty acids, such as stearic acid and magnesium stearate; surfactants, such as triethyl citrate, Tween <NUM>, HCO-<NUM>, and triacetin; and viscosity modifiers, such as simple syrup, a glucose solution, a starch solution, and a gelatin solution.

Absorption promoters, such as a quaternary ammonium salt and sodium lauryl sulfate.

Adsorbents, such as starch, lactose, kaolin, bentonite, and colloidal silicic acid.

Lubricants, such as magnesium stearate, calcium stearate, talc, magnesium oxide, colloidal silica, boric acid powder, and polyethylene glycol.

Dispersants, such as sucrose fatty acid ester, sorbitan fatty acid ester, and saponin.

Antioxidants, such as ascorbic acid and tocopherol.

Acidulants, such as lactic acid, citric acid, gluconic acid, and glutamic acid.

Sweeteners, such as sucralose, acesulfame potassium, aspartame, and glycyrrhizin.

Flavors, such as mint oil, eucalyptus oil, cinnamon oil, fennel oil, clove oil, orange oil, lemon oil, rose oil, fruit flavor, mint flavor, peppermint powder, d,l-menthol, and l-menthol.

A stabilizer, a surfactant, a modifier, a lubricant, a capsule coating, a solubilizer, a reducing agent, a buffer, a sweetener, a base, a volatilizing aid, a taste masking agent, a synergist, a suspending agent, an antioxidant, a glossing agent, an efficacy enhancer, a coating agent, a coating,.

The tablet of the present invention is preferably an OD tablet.

In a balance between disintegrability and hardness, when the disintegrability is rapid (rapid disintegrability), the hardness generally tends to lower. This relationship is manifested in a relationship among the tableting pressure, hardness, and disintegration time of a tablet. The tablet of the present invention maintains disintegrability and hardness in good balance as an OD tablet.

For example, in a comparison between Comparative Example <NUM> and Example <NUM> to be described below, when the disintegration time is shortened, the hardness tends to be slightly low. The addition of <NUM> of PH101 in additional Examples can achieve both rapid disintegration and proper hardness (high hardness).

In pharmaceutical approval and licensing, the disintegration time and hardness of a rapidly disintegrating tablet are not standardized in Japan.

An 8ϕ and <NUM> tablet is a rapidly disintegrating tablet when its disintegration time is about <NUM> seconds or less.

A hardness of <NUM> N or more is a general hardness. According to an orally disintegrating tablet handbook, a <NUM> to <NUM> tablet needs to have a tablet hardness of from <NUM> kgf to <NUM> kgf or more (<NUM> N to <NUM> N).

That is, in the case of 8ϕ, a hardness of <NUM> N or more is an appropriate hardness, and is a recent design target (<NPL>).

The present invention is directed to a composite granulated product including a sugar or a sugar alcohol, a swelling binder, a disintegrating agent, and a highly absorbent excipient and is defined in the claims.

The composite granulated product includes a sugar or a sugar alcohol, a swelling binder, a disintegrating agent (first disintegrating agent), and a highly absorbent excipient, and is manufactured by a manufacturing method including the steps of:.

The composite granulated product includes a sugar or a sugar alcohol, a swelling binder, a disintegrating agent, and a highly absorbent excipient, and is manufactured by a manufacturing method including the steps of:.

The first disintegrating agent is hydroxypropyl cellulose, and the second disintegrating agent is at least one kind of component selected from the group consisting of starch, crospovidone, and croscarmellose sodium.

The granulation composition (ratio to total mass) of the sugar or the sugar alcohol (D-mannitol or the like) is preferably from about <NUM> mass% to about <NUM> mass%, more preferably from about <NUM> mass% to about <NUM> mass%.

The granulation composition (ratio to total mass) of the swelling binder (PVA-based polymer or the like) is preferably from about <NUM> mass% to about <NUM> mass%, more preferably from about <NUM> mass% to about <NUM> mass%.

The granulation composition (ratio to total mass) of the first disintegrating agent (L-HPC or the like) is preferably from about <NUM> mass% to about <NUM> mass%, more preferably from about <NUM> mass% to about <NUM> mass%.

The amount of the binding solution is preferably from about <NUM> mass% to about <NUM> mass%, more preferably from about <NUM> mass% to about <NUM> mass%.

With regard to the conditions of the wet granulation, agitation granulation is preferably used because of a simple manufacturing process.

The period of time for which the wet granulation is performed is preferably from about <NUM> minutes to about <NUM> minutes.

In the manufacturing method for a composite granulated product, as the sugar or the sugar alcohol, at least one kind of component selected from the group consisting of D-mannitol, trehalose, xylitol, erythritol, lactose, and sucrose is preferably used.

In the manufacturing method for a composite granulated product, as the swelling binder, at least one kind of component selected from the group consisting of a polyvinyl alcohol-based polymer, partially pregelatinized starch, hydroxypropyl cellulose, and crystalline cellulose is preferably used.

In the manufacturing method for a composite granulated product, the average particle diameter of the swelling binder is preferably from <NUM> to <NUM>.

The steps (<NUM>) and (<NUM>) involve performing granulation with addition of the highly absorbent excipient to the granulated product obtained in the above-mentioned step (step (<NUM>)), and.

These steps constitute the compositing of the composite granulated product.

In the manufacturing method for a composite granulated product, at least one kind of component selected from the group consisting of light anhydrous silicic acid, hydrated silicon dioxide, calcium silicate, magnesium aluminometasilicate, starch, calcium carbonate, kaolin, silicic acid, potassium hydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, dipotassium phosphate, disodium phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, calcium lactate, magnesium aluminosilicate, calcium silicate, and magnesium silicate is preferably used as the highly absorbent excipient.

The step (<NUM>) is a step of subjecting the composite granulated product to layering granulation.

The granulation composition (ratio to total mass) of the highly absorbent excipient (light anhydrous silicic acid, hydrated silicon dioxide, or the like) is preferably from about <NUM> mass% to about <NUM> mass%, more preferably from about <NUM> mass% to about <NUM> mass%.

With regard to the conditions of the layering granulation, the highly absorbent excipient is preferably added as powder, and an agitation granulator is preferably used to facilitate the powder addition.

A granulation time is preferably from about <NUM> minutes to about <NUM> minutes. The following effect is obtained: the progress of the granulation (increase in particle diameter) is suppressed, the size of the granulated product is maintained at about <NUM> or less, and the granulated product does not increase in size.

The step (<NUM>) is a step of layering granulation.

The granulation composition (ratio to total mass) of the second disintegrating agent (starch (corn starch or the like), crospovidone, croscarmellose sodium, or the like) is preferably from about <NUM> mass% to about <NUM> mass%, more preferably from about <NUM> mass% to about <NUM> mass%.

With regard to the conditions of the layering granulation, the second disintegrating agent is preferably added as powder, and an agitation granulator is preferably used to facilitate the powder addition.

The period of time for which the wet granulation is performed is preferably from <NUM> minutes to <NUM> minutes.

When the second disintegrating agent is allowed to adhere to the surface of the granulated product, the following effect is obtained with a small addition amount thereof when the granulated product is tableted: the capacity for water absorption into the inside of the tablet is enhanced (water-conducting effect).

In the manufacturing method for a composite granulated product, hydroxypropyl cellulose is preferably used as the first disintegrating agent, and at least one kind of component selected from the group consisting of starch, crospovidone, and croscarmellose sodium is preferably used as the second disintegrating agent.

A composite granulated product may be manufactured by the manufacturing method for a composite granulated product.

In the manufacturing method for a composite granulated product, the composite granulated product is preferably a composite granulated product for an orally disintegrating tablet.

When an OD tablet is produced using the obtained composite granulated product, the following OD tablet can be obtained:.

When an OD tablet is produced using the composite granulated product manufactured by the manufacturing method for a composite granulated product of the present invention, the OD tablet has high hardness and is also excellent in disintegrability.

The OD tablet maintains its high hardness and disintegrability even under high temperature and increased humidity, and hence is excellent in storage stability.

As described above, the manufacturing method can produce a composite granulated product optimal for producing an excellent OD tablet.

The manufacturing method has a feature of including.

The manufacturing method includes the first step (<NUM>) of performing wet granulation using the first disintegrating agent,
and includes, as the subsequent steps (<NUM>) and (<NUM>), layering granulation steps for the granulated product, of performing granulation with addition of the highly absorbent excipient to the obtained granulated product, and further performing granulation with addition of the second disintegrating agent to the obtained granulated product.

Those steps constitute the compositing of the composite granulated product.

The steps (<NUM>) and (<NUM>) are referred to as layering granulation.

In the manufacturing method, a granulated product including the first disintegrating agent is formed, and is granulated with the highly absorbent excipient, and a granulated product in which the resultant is further composited with the second disintegrating agent is produced.

Through such layering granulation (surface-modifying granulation), the surface of the granulated product is modified.

In addition, in the manufacturing method, the second disintegrating agent is allowed to adhere to the surface of the granulated product including the first disintegrating agent (step (<NUM>)) and obtained by being granulated with the addition of the highly absorbent excipient (step (<NUM>)), and hence,
with a smaller addition amount thereof, there can be produced a composite granulated product having the following effect when tableted: the capacity for water absorption into the inside of the tablet is enhanced (water-conducting effect).

That is, an OD tablet produced using the composite granulated product is excellent in hardness, disintegrability, and storage stability.

The effect achieved by the layering granulation steps included in the manufacturing method for a composite granulated product has been demonstrated through a dissolution test and a stability test in Examples to be described later.

In the manufacturing method for a composite granulated product of the present invention, it is important that the composite granulated product having a modified surface be produced by forming layers on the granulated product through.

It is important that the manufacturing method involve the layering granulation steps of adding the first disintegrating agent and the second disintegrating agent in two separate stages.

In the manufacturing method for a composite granulated product, the invention is clear even when a difference between the first disintegrating agent and the second disintegrating agent is not specified.

The preferred mode of the manufacturing method for a composite granulated product is as follows:.

The disintegrating agents to be used in the manufacturing method for a composite granulated product are specified.

The use of the first disintegrating agent and the second disintegrating agent in the manufacturing method for a composite granulated product is utilized and effective also in a manufacturing method for a granule for tableting or a manufacturing method for a tablet.

A granule for tableting may be manufactured by including (<NUM>) a step of adding and mixing at least one kind of hardness modifier selected from the group consisting of crystalline cellulose, a D-mannitol granulated product, and isomalt into a composite granulated product obtained by the above-mentioned manufacturing method for a composite granulated product.

A granule for tableting may be manufactured by adding and mixing a hardness modifier into the composite granulated product.

It is preferred that the granule for tableting be manufactured by a manufacturing method including
(<NUM>) a step of adding and mixing at least one kind of hardness modifier selected from the group consisting of crystalline cellulose (microcrystalline cellulose), a D-mannitol granulated product, and isomalt into the composite granulated product obtained in the step (<NUM>).

The granule for tableting is one mode of the composite granulated product.

The amount of the hardness modifier (microcrystalline cellulose or the like) is preferably from about <NUM> mass% to about <NUM> mass%, more preferably from about <NUM> mass% to about <NUM> mass%.

A period of time may be adjusted in accordance with an implementation scale and a mixer, and is generally preferably from about <NUM> minutes to about <NUM> minutes.

The following effect is obtained: the tablet hardness at the same tableting pressure is increased.

The obtained composite granulated product is a wet mass, and is preferably dried.

It is preferred that: an additive and functional particles be added to the composite granulated product or the granule for tableting; then about <NUM>% of a lubricant (magnesium stearate or the like) be added and mixed into the mixture; and then tableting be performed with a tableting machine.

As a binding solution, water, an aqueous solution of a PVA copolymer, an aqueous solution of PVA, an aqueous solution of hydroxypropyl cellulose, an aqueous solution of polyvinylpyrrolidone, or the like may be used. Of those, water is preferred.

Those binding solutions may be used in combination thereof. As the binding solution, an aqueous solution having low concentration, such as <NUM> mass% of a PVA-based copolymer, may be used.

In the manufacturing method for a granule for tableting, the granule for tableting is preferably a granule for tableting for an orally disintegrating tablet.

A tablet may be manufactured by mixing a medicinal component and functional particles, and a composite granulated product obtained by the above-mentioned manufacturing method for a composite granulated product, or the above-mentioned granule for tableting.

The tablet is preferably manufactured by a method including the steps of:
adding and mixing drug functional particles and a lubricant (magnesium stearate or the like, about <NUM>%) into the composite granulated product; and then performing tableting.

In the manufacturing method for a tablet, as the functional particles, at least one kind of component selected from the group consisting of bitterness-masking particles and sustained-release particles is preferably used.

The manufacturing method for a tablet preferably further includes adding and mixing a lubricant.

In the manufacturing method for a tablet, the tablet is preferably an orally disintegrating tablet.

In the tableting step, the compositional ratio of the composite granulated product in the tablet is preferably from about <NUM> wt% to about <NUM> wt%.

The ratio of the functional particles in the tablet is preferably from about <NUM> wt% to about <NUM> wt%.

The ratio of the lubricant in the tablet is preferably from about <NUM> wt% to about <NUM> wt%.

The tablet is preferably manufactured by a method including the steps of:.

The ratio of the hardness modifier in the tablet is preferably from about <NUM> wt% to about <NUM> wt%.

The tablet is preferably manufactured by a manufacturing method including the steps of:.

The composite granulated product manufactured by the above-mentioned manufacturing method for a composite granulated product, and the granule for tableting manufactured by the above-mentioned manufacturing method for a granule for tableting are prepared through the layering granulation steps of adding the first disintegrating agent and the second disintegrating agent in two stages.

The OD tablet produced using such composite granulated product or granule for tableting is excellent in hardness, disintegrability, and storage stability.

This effect is due to the granulated product having a modified surface, which is provided by the layering granulation steps included in the manufacturing method therefor, and can be identified on the basis of the process (production process) for obtaining the surface-modified granulation product.

As a product of a manufacturing method, the composite granulated product or the granule for tableting is different from the related art in consideration of its materials and manufacturing process, and the difference can be distinguished on the basis of the manufacturing process.

Now, the present invention is described in more detail by way of Examples. However, the present invention is not limited to these Examples.

In the following Examples and Comparative Examples, investigations were performed using materials and test methods described below.

The compositing of a composite granulated product was treatment involving the following steps:.

Shelf-type forced-air drying: <NUM>, <NUM> hours.

Granules loaded into a die (<NUM>. 3ϕ) were formed with S-<NUM>-<NUM> manufactured by Riken Kiki Co. (pressure receiving area: <NUM><NUM>). For example, a pressure of <NUM>/cm<NUM> corresponds to <NUM> kN on the basis of <NUM>×<NUM>×<NUM>.

This corresponds to about <NUM> kN in the case of an 8ϕ tablet, which serves as a standard in a formability evaluation method.

The resultant formed plate was evaluated for its hardness (hardness meter manufactured by Okada Seiko Co. ) and disintegration time (the Japanese Pharmacopoeia) with a disintegration tester manufactured by Toyama Sangyo Co. and purified water at <NUM>.

<NUM>% each of a placebo (containing no model particles), vitamin C-granulated product (VC97: BASF), and EUDRAGIT-coated bitterness-masking model particles (functional particles, RSPO-FC: manufactured by Pharma Polytech Inc. ) were mixed, and an 11ϕ and <NUM> flat tablet was prepared with a hydraulic press (manufactured by Rigaku) and was evaluated.

<NUM>% each of a placebo (containing no model particles), vitamin C-granulated product (VC <NUM>: BASF), and EUDRAGIT-coated bitterness-masking model particles (functional particles, RSPO-FC: manufactured by Pharma Polytech Inc. ) were mixed, and an 11ϕ and <NUM> flat tablet was prepared with a hydraulic press (manufactured by Rigaku) and was evaluated.

Fluidized bed dryer (MDG-<NUM>: Fuji Paudal Co. ) <NUM>, <NUM> minutes.

Including continuous tableting results of Example <NUM> and Comparative Example <NUM>.

Continuous tableting sample: <NUM>) Aero/XL-<NUM> layering granulation product, high-speed agitation granulation product (VG) Placebo,.

Tableting results: Punch sticking or the like was not found in each case.

A comprehensive comparison with Comparative Example <NUM> (no layering granulation), Comparative Example <NUM> (commercially available product A), and Comparative Example <NUM> (commercially available product B) was performed.

Contained model drugs (<NUM> wt% in all cases) are as follows:.

A preparation method was performed in accordance with the following reference: <NPL>).

<NUM>% each of a placebo (containing no model particles), vitamin C-granulated product (VC <NUM>: BASF), and EUDRAGIT-coated bitterness-masking model particles (RSPO-FC: manufactured by Pharma Polytech Inc. ) were mixed, and an 11ϕ and <NUM> flat tablet was prepared with a hydraulic press (manufactured by Rigaku) and was evaluated.

Example <NUM> (Aero/XL-<NUM> layering granulation product: high-speed agitation granulation product (VG)) was mixed with <NUM>% of microcrystalline cellulose (CEOLUS PH101: Asahi Kasei Corporation), and the resultant was mixed with <NUM> wt% each of a vitamin C-granulated product (VC <NUM>: BASF) and EUDRAGIT-coated bitterness-masking model particles (RSPO-FC: manufactured by Pharma Polytech Inc. ) to produce a granule for tableting.

The compositing of a composite granulated product (Example <NUM>) was treatment involving the following steps:.

A granule for tableting was prepared through (<NUM>) a step of adding and mixing microcrystalline cellulose (hardness modifier) into the composite granulated product.

Each product was mixed with <NUM>% of bitterness-masking model particles (RSPO-FC: manufactured by Pharma Polytech Inc. ), and an 11ϕ and <NUM> flat tablet was prepared with a hydraulic press (manufactured by Rigaku) and evaluated for its effectiveness.

In order to confirm whether there was no adverse influence on the rupture of a film of the functional particles, the following test was performed using the Example <NUM> (Aero/XL-<NUM>) layering granulation particles.

Bitterness-masking model particles (RSPO-FC: manufactured by Pharma Polytech Inc. ), the bitterness-masking model particles (functional particles) containing carbazochrome sodium sulfonate as a model drug.

The premix particles (Example <NUM> (Aero/XL-<NUM>) layering granulation product) and <NUM>% of RSPO-FC were mixed, and <NUM>% of a lubricant: magnesium stearate (St-Mg: manufactured by Taihei Chemical Industrial Co. ) was mixed.

Tableting was performed with a rotary tableting machine (VEL5: Kikusui Seisakusho Ltd. ), 8ϕ12R (target weight; <NUM>) at a tableting pressure of <NUM> kN.

The dissolution rate was not changed by tableting, and hence it was confirmed that there was no rupture of the film of the functional drug particles.

Into each sample, <NUM> wt% of spherical microcrystalline cellulose (CELPHERE CP102, Asahi Kasei Corporation) was incorporated as OD tablet functional model particles and <NUM>% of St-Mg was incorporated as a lubricant, and an 8ϕ12R and <NUM> tablet was prepared with a rotary tableting machine (VEL5: Kikusui Seisakusho Ltd.

The tableting pressure was adjusted so that the tablet hardness of each tablet was around <NUM> N.

Those test tablets were subjected to one-month evaluation at <NUM>/<NUM>%RH (Tables <NUM> and <NUM>).

Hardness measurement: hardness meter manufactured by Okada Seiko Co.

Claim 1:
A manufacturing method for a composite granulated product including a sugar or a sugar alcohol, a swelling binder, a disintegrating agent, and a highly absorbent excipient,
the manufacturing method comprising the steps of:
(<NUM>) performing wet granulation by mixing a sugar or a sugar alcohol, a swelling binder, and a first disintegrating agent using a binding solution;
(<NUM>) performing granulation with addition of a highly absorbent excipient to the granulated product obtained in the step (<NUM>); and
(<NUM>) performing granulation with addition of a second disintegrating agent to the granulated product obtained in the step (<NUM>),
wherein the first disintegrating agent is hydroxypropyl cellulose, and the second disintegrating agent is at least one kind of component selected from the group consisting of starch, crospovidone, and croscarmellose sodium,
wherein the sugar or the sugar alcohol is at least one kind of component selected from the group consisting of D-mannitol, trehalose, xylitol, erythritol, lactose and sucrose,
wherein the swelling binder is at least one kind of component selected from the group consisting of a polyvinyl alcohol-based polymer, partially pregelatinized starch, hydroxypropyl cellulose, and crystalline cellulose, and
wherein the highly absorbent excipient is at least one kind of component selected from the group consisting of light anhydrous silicic acid, hydrated silicon dioxide, calcium silicate, magnesium aluminometasilicate, starch, calcium carbonate, kaolin, silicic acid, potassium hydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, dipotassium phosphate, disodium phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, calcium lactate, magnesium aluminosilicate, calcium silicate, and magnesium silicate.