JP7744908B2 - Orally disintegrating tablets containing mirogabalin besilate - Google Patents

Description

The present invention relates to an orally disintegrating tablet containing mirogabalin besylate and having excellent stability.
The orally disintegrating tablet of the present invention disintegrates quickly when placed in the mouth or when placed in water, but has sufficient hardness for normal production, transportation and use.
The present invention also relates to a method for producing the same.

In the fields of pharmaceuticals and food, oral solid dosage forms known as tablets, capsules, granules, and powders are common, but there is hope for the development of orally disintegrating tablets that disintegrate quickly when placed in the mouth or immersed in water, as a dosage form that is easier to take for the elderly, children, and patients with swallowing difficulties.

In addition to the property of rapidly disintegrating in the mouth, orally disintegrating tablets, like regular tablets, must also have sufficient hardness to withstand physical impacts during manufacturing, transportation, and use. Furthermore, from the perspective of medication compliance, it is desirable for tablets to have a pleasant mouthfeel and suppress any unpleasant taste or irritation when placed in the mouth.

Regarding orally disintegrating tablets, Patent Document 1 describes an orally disintegrating tablet containing a drug, crystalline cellulose having a bulk density of 0.23 g/cm ^{or less} , a sugar alcohol, and pregelatinized starch. However, this document does not describe an orally disintegrating tablet containing mirogabalin besylate.

Patent Document 2 describes a pharmaceutical solid composition containing mirogabalin besylate, (i) one selected from the group consisting of D-mannitol, lactose, cornstarch, and crystalline cellulose, and (ii) carmellose calcium. However, this document does not describe orally disintegrating tablets containing mirogabalin besylate.

Patent Document 3 describes that in solid pharmaceutical formulations containing mirogabalin besylate, excipients, disintegrants, and specific antioxidants, stabilization of mirogabalin besylate is observed. However, this document does not describe orally disintegrating tablets containing mirogabalin besylate.

Patent Document 4 describes a pharmaceutical solid composition containing mirogabalin besylate, (i) one or more selected from the group consisting of D-mannitol, lactose, cornstarch, and crystalline cellulose, (ii) carmellose calcium, and (iii) titanium oxide as a colorant, and one or more other colorants. However, this document does not describe orally disintegrating tablets containing mirogabalin besylate.

US2015/0110880A1 US2015/0079166A1 US2018/0042878A1 US2018/0243223A1

An object of the present invention is to provide an orally disintegrating tablet containing mirogabalin besylate that is highly stable.
The orally disintegrating tablet of the present invention disintegrates quickly when placed in the mouth or when placed in water, but has sufficient hardness for normal production, transportation and use.
The present invention also has an excellent manufacturing method.

As a result of extensive research to solve the above-mentioned problems, the inventors discovered that by combining (A) mirogabalin besylate-containing granules with (B) drug-free granules containing crystalline cellulose or drug-free mixed powder containing crystalline cellulose, an orally disintegrating tablet with excellent properties can be produced, thereby solving the above-mentioned problems and completing the present invention.

In other words, the present invention is the invention described below.

[1]
An orally disintegrating tablet containing (A) mirogabalin besylate-containing granules and (B) drug-free granules containing crystalline cellulose or drug-free mixed powder containing crystalline cellulose.
[2]
The orally disintegrating tablet according to [1], wherein the average particle size of the mirogabalin besylate contained in (A) is 60 μm or less, and the content thereof, in terms of mirogabalin, is 0.5-10% by weight per 100% by weight of the orally disintegrating tablet.
[3]
The orally disintegrating tablet according to [1] or [2], wherein the bulk density of the crystalline cellulose contained in (B) is 0.10-0.26 g/ ^cm3 and the content thereof is 1.0-50 wt% per 100 wt% of the orally disintegrating tablet.
[4]
The orally disintegrating tablet according to any one of [1] to [3], wherein (A) is a mirogabalin besylate-containing granule further containing low-molecular-weight hydroxypropyl cellulose.
[5]
The orally disintegrating tablet according to [4], wherein the content of low molecular weight hydroxypropyl cellulose contained in (A) is 0.1 to 2.0% by weight per 100% by weight of the orally disintegrating tablet.
[6]
The orally disintegrating tablet according to any one of [1] to [3], wherein (A) is a mirogabalin besylate-containing granule further containing citric acid hydrate and tocopherol.
[7]
The orally disintegrating tablet according to [6], wherein the content of citric acid hydrate contained in (A) is 0.2-1.0 wt% per 100 wt% of the orally disintegrating tablet, and the content of tocopherol contained in (A) is 0.01-0.4 wt% per 100 wt% of the orally disintegrating tablet.
[8]
The orally disintegrating tablet according to [3], wherein (A) is a mirogabalin besylate-containing granule further containing D-mannitol and carmellose.
[9]
The orally disintegrating tablet according to any one of [6] to [8], wherein (A) is a mirogabalin besylate-containing granule further containing hydroxypropyl cellulose.
[10]
The orally disintegrating tablet according to [9], wherein the content of hydroxypropyl cellulose contained in (A) is 0.1 to 3.0% by weight per 100% by weight of the orally disintegrating tablet.
[11]
The orally disintegrating tablet according to any one of [6] to [10], wherein (B) is a drug-free granule further containing D-mannitol and pregelatinized starch.
[12]
The orally disintegrating tablet according to [11], wherein the content of D-mannitol contained in (B) is 20-55% by weight per 100% by weight of the orally disintegrating tablet, and the content of pregelatinized starch contained in (B) is 1.0-10% by weight per 100% by weight of the orally disintegrating tablet.
[13]
The orally disintegrating tablet according to [4] or [5], wherein (B) is a drug-free mixed powder further containing carmellose and acesulfame potassium.
[14]
The orally disintegrating tablet according to [13], wherein the content of carmellose contained in (B) is 2.0-20% by weight per 100% by weight of the orally disintegrating tablet, and the content of acesulfame potassium contained in (B) is 1.0-5.0% by weight per 100% by weight of the orally disintegrating tablet.
[15]
a step of mixing mirogabalin besylate, D-mannitol, and citric acid hydrate and spraying the mixture with a low molecular weight hydroxypropyl cellulose binder to produce granules;
a step of mixing the granules A, crystalline cellulose, carmellose, and acesulfame potassium, and then adding magnesium stearate to the mixed powder and mixing to obtain a mixture for tableting;
Obtaining tablets using a tablet press;
A method for producing an orally disintegrating tablet comprising the steps of:
[16]
mixing tocopherol with crystalline cellulose to obtain tocopherol trituration;
a step of mixing mirogabalin besylate, D-mannitol, carmellose, citric acid hydrate, tocopherol triturate, and magnesium aluminometasilicate, and spraying the mixture with a hydroxypropyl cellulose binding solution to produce granules;
a step of mixing D-mannitol and crystalline cellulose and spraying the mixture with a pregelatinized starch dispersion to produce granules;
a step of blending the two granules, crospovidone, and acesulfame potassium, and then blending magnesium stearate to obtain a mixture for tableting;
Obtaining tablets using a tablet press;
A method for producing an orally disintegrating tablet comprising the steps of:

According to the present invention, an orally disintegrating tablet containing mirogabalin besylate and having excellent stability can be provided.
The orally disintegrating tablet of the present invention is an orally disintegrating tablet that has good stability of mirogabalin besylate, particularly due to the inclusion of citric acid hydrate and tocopherol.
The orally disintegrating tablet of the present invention disintegrates quickly when placed in the mouth or when placed in water, exhibits excellent solubility, and has a pleasant texture.
The orally disintegrating tablet of the present invention has sufficient hardness for normal production, transportation and use, and is an orally disintegrating tablet with excellent storage stability.
The orally disintegrating tablet of the present invention can be produced by ordinary compression molding without requiring complicated steps or special equipment.

In the present invention, an "orally disintegrating tablet" refers to a compression-molded product that disintegrates and dissolves rapidly when placed in the mouth or in water. Specifically, this refers to a tablet that disintegrates in a time frame of typically 5-180 seconds, preferably 5-60 seconds, and more preferably 5-40 seconds, in a disintegration test using saliva in the mouth or a disintegration test using a device.

The orally disintegrating tablet of the present invention has sufficient hardness during normal manufacturing, transportation, and use. For example, in a hardness test, the orally disintegrating tablet typically has a hardness of 2 kg or more, preferably 3 kg or more, and more preferably 5 kg or more.

The orally disintegrating tablet of the present invention maintains dissolution properties suitable for pharmaceuticals. For example, in a dissolution test, the orally disintegrating tablet usually exhibits an average dissolution rate of 80% or more, preferably 85% or more, at 30 minutes.
Dissolution testing is the dissolution test described in Section 6.10, Dissolution Testing Methods, of the Japanese Pharmacopoeia, 18th Edition. This test is performed to determine whether oral dosage forms comply with the dissolution test specifications, and also aims to prevent significant bioequivalence. The sample in this test corresponds to the minimum dosage, which means one tablet for tablets, one capsule for capsules, or the specified amount for other dosage forms. The equipment used for this test includes rotating basket, paddle, and flow-through cell devices. Details are described in the Japanese Pharmacopoeia, 18th Edition.

The "mirogabalin" used in the present invention is a compound represented by the following formula (I):

It is a compound represented by the formula:

The "mirogabalin besylate" used in the present invention is a salt of mirogabalin and besylic acid, and is represented by the following formula (Ia):

represented by

Mirogabalin, used in the present invention, is thought to exert its analgesic effect by inhibiting calcium currents through binding to the α2δ subunit, which plays an auxiliary role in the function of voltage-dependent calcium channels in the nervous system.

Mirogabalin besylate used in the present invention has been approved for manufacture and sale as a peripheral neuropathic pain treatment based on clinical trials conducted both domestically and internationally, and is currently on sale.

For the treatment of peripheral neuropathic pain, adults usually begin with an initial dose of 5 mg of mirogabalin administered orally twice daily, followed by a gradual increase of 5 mg at intervals of at least one week to a total of 15 mg administered orally twice daily. The dose may be increased or decreased within the range of 10 mg to 15 mg twice daily depending on age and symptoms.

The method for producing the orally disintegrating tablet of the present invention is described below in both aspects (Aspect A and Aspect B).

Aspect A:
An orally disintegrating tablet obtained by compressing drug-free granules containing crystalline cellulose, D-mannitol, and pregelatinized starch, each having a bulk density of 0.26 g/cm3 or ^less , and mirogabalin besylate-containing granules.
In this embodiment, the drug-free granules function as a framework for a formulation that can impart the disintegration and moldability desired for orally disintegrating tablets. The drug-free granules exhibit excellent disintegration and moldability even when formulated with only ^three ingredients: crystalline cellulose with a bulk density of 0.26 g/cm or less, D-mannitol, and pregelatinized starch, but other additives may also be formulated as needed.
Furthermore, the orally disintegrating tablet in this embodiment exhibits excellent stability due to the addition of citric acid hydrate and tocopherol to the mirogabalin besylate-containing granules.
The method for producing the orally disintegrating tablet of embodiment A includes (1) a step of producing drug-free granules, (2) a step of producing mirogabalin besylate-containing granules, and (3) a step of blending the drug-free granules, mirogabalin besylate-containing granules, and other extragranular mixed powders, followed by compression molding.

(1) Step for Producing Drug-Free Granules Drug-free granules can be produced using the following method 1) or 2).
1) A method of wet granulating a mixture containing crystalline cellulose having a bulk density of 0.26 g/cm3 or ^less , D-mannitol, and pregelatinized starch with water.
2) A method of granulating a mixture containing crystalline cellulose having a bulk density of 0.26 g/cm3 or ^less and D-mannitol with a liquid in which pregelatinized starch is dissolved or dispersed in water or the like.
Here, for the granulation, a conventional extrusion granulation method, a mixing and stirring granulation method, a high speed stirring granulation method, a fluidized bed granulation method, a tumbling granulation method, or the like can be used.
Pregelatinized starch exhibits a viscosity suitable for granulation when dissolved or dispersed in a liquid, such as water. Granulation methods include mixing pregelatinized starch in powder form with other ingredients and granulating with water, and granulating with a liquid in which pregelatinized starch is dissolved or dispersed in water. Both methods produce tablets with the desired properties, but the latter method is preferred.
Furthermore, when granulation is performed using a liquid in which pregelatinized starch has been dissolved or dispersed, either high-speed agitation granulation or fluidized bed granulation can be used, but better orally disintegrating tablets can be obtained when granules are produced by fluidized bed granulation. When other additives such as conventional disintegrants are to be blended into the drug-free granules, they may be blended into the mixture before granulation.
The blending ratio of crystalline cellulose having a bulk density of 0.26 g/cm ³ or less and D-mannitol in the drug-free granules is 1 part crystalline cellulose to 1-3 parts by weight, preferably 1-2 parts by weight, of D-mannitol.

(2) Step of Producing Mirogabalin Besilate-Containing Granules Mirogabalin besilate can be mixed with drug-free granules either as a powder or, if desired, after granulation. Mirogabalin besilate-containing granules can be produced, for example, by conventional extrusion granulation, mixing and stirring granulation, high-speed stirring granulation, fluidized bed granulation, or tumbling granulation.
For example, a mixture of powdered or granular mirogabalin besilate, D-mannitol, carmellose, citric acid hydrate, 10x tocopherol powder (a mixture of tocopherol and crystalline cellulose having a bulk density of 0.26 g/cm or ^less ), and magnesium aluminometasilicate can be granulated with a solution or dispersion of hydroxypropyl cellulose in water to produce mirogabalin besilate-containing granules.
Alternatively, a powdered or granular mixture of mirogabalin besylate, D-mannitol, carmellose, citric acid hydrate, 10x tocopherol powder (a mixture of tocopherol and crystalline cellulose having a bulk density of 0.26 g/cm or ^less ), magnesium aluminometasilicate, and hydroxypropyl cellulose can be granulated with water to produce drug-containing granules.
For example, a powdered or granular mixed powder of mirogabalin besylate, D-mannitol, and citric acid hydrate can be granulated with a solution or dispersion of low-molecular-weight hydroxypropyl cellulose in water to produce mirogabalin besylate-containing granules.Furthermore, a powdered or granular mixed powder of mirogabalin besylate, D-mannitol, citric acid hydrate, and low-molecular-weight hydroxypropyl cellulose can be granulated with water to produce drug-containing granules.
Granules containing mirogabalin besylate can be coated to mask unpleasant tastes, such as bitterness or irritation, or to control dissolution. Coating agents and plasticizers can be used as appropriate for coating. Coating methods include, for example, using a fluidized bed granulator/coator, a tumbling fluidized bed granulator/coator, a centrifugal fluidized bed granulator/coator, or a Wurster fluidized bed granulator/coator.
When two or more drugs are used, they can be contained in the same granule or in separate granules depending on the compatibility of the drugs, and then subjected to compression molding.

(3) A step of blending and compressing drug-free granules, mirogabalin besylate-containing granules, and other extragranular mixed powders. The drug-free granules and mirogabalin besylate-containing granules, and optionally a disintegrant, lubricant, and other additives, are blended and compressed to form orally disintegrating tablets. Blending can be performed using, for example, a tumble mixer or a convection mixer.
The orally disintegrating tablets of the present invention can be compressed using a conventional tablet press. The compression pressure applied by the tablet press may be the same as that applied to conventional tablets, and although it depends on the shape and size of the tablet, it is preferably 2-20 kN, more preferably 4-14 kN.

The proportion of drug-free granules relative to the total weight of the tablet ingredients should be 30-90%. If the drug is in powder form, the proportion should be 30-80%, preferably 45-70%. If the drug is granulated for use, the proportion should be 30-80%, preferably 45-70%. Furthermore, if the drug is granulated for use, the weight ratio of drug-free granules to drug-containing granules is preferably 1 part drug-containing granules to 1.0-3.5 parts drug-free granules.

Aspect B:
An orally disintegrating tablet obtained by compressing a drug-free mixed powder containing crystalline cellulose, D-mannitol, and pregelatinized starch, or other extragranular mixed powder, with mirogabalin besylate-containing granules, having a bulk density of 0.26 g/cm3 or ^less .

In embodiment B, the drug-free mixed powder or other extragranular mixed powder provides the disintegration and compactibility desired for an orally disintegrating tablet.
The drug-free mixed powder exhibits excellent disintegration and moldability even when it is formulated with only three components: crystalline cellulose with a bulk density of 0.26 g/ ^cm3 or less, D-mannitol, and pregelatinized starch, but other additives may also be formulated as needed.
Furthermore, the other extragranular mixed powder exhibits excellent disintegration and moldability even when it is formulated with only the three components of crystalline cellulose, carmellose, and acesulfame potassium, but other additives may also be formulated as necessary.

The method for producing the orally disintegrating tablet of Aspect B optionally includes a step of producing mirogabalin besylate-containing granules, and a step of mixing the mirogabalin besylate-containing granules and other additives, followed by compression molding. The step for producing the mirogabalin besylate-containing granules is the same as (2) of Aspect A.

In the process of mixing and compressing mirogabalin besylate-containing granules and other additives, the mixing or compression molding process is the same as (3) of embodiment A.

The orally disintegrating tablet of the present invention obtained as described above has excellent disintegrability and solubility when placed in the oral cavity or in water, and also has excellent physical and chemical stability.

The disintegration or solubility of the orally disintegrating tablet of the present invention is such that the disintegration or dissolution time in the oral cavity (the time it takes for the tablet to completely disintegrate or dissolve in the oral cavity of a healthy adult male with only saliva, without any water in the mouth) is usually about 5 to 180 seconds, preferably about 5 to 60 seconds, and more preferably about 5 to 40 seconds.
The orally disintegrating tablet of the present invention gradually disintegrates or dissolves in saliva when placed in the mouth, but can be disintegrated or dissolved in a shorter time by pressure in the oral cavity, i.e., pressure from the upper jaw and tongue, or friction with the tongue, i.e., licking, etc. For people with dry mouths or those with little saliva, the tablet may be dissolved or disintegrated in the oral cavity using water or hot water, or may be taken directly with water in the same way as a normal tablet.

On the other hand, the orally disintegrating tablet of the present invention has sufficient hardness even after a stability test under certain temperature and humidity conditions (for example, a temperature of 25°C, a humidity of 75%, an open system, for one week).
Therefore, the formulation has a hardness that does not crumble during the manufacturing and distribution processes, has a practical hardness even when stored under certain temperature and humidity conditions, and is excellent in storage stability and disintegrability.

The orally disintegrating tablet of the present invention can be used to treat illnesses as a formulation that is easy to take for the elderly, children, and patients with swallowing difficulty, and as a safe formulation for general adults.

The "mirogabalin besylate" used in the present invention preferably has an average particle size of 60 μm or less (more preferably 40 μm or less). Note that the "average particle size" in the present invention refers to the particle size at 50% of the cumulative value in the particle size distribution determined by laser diffraction/scattering method.
The amount of mirogabalin besylate used in the present invention is preferably 0.5-40% by weight, more preferably 0.5-25% by weight, and particularly preferably 0.5-10% by weight, of mirogabalin per 100% by weight of the orally disintegrating tablet.

The "D-mannitol" used in the present invention can generally be that conforming to the Japanese, European, and American Pharmacopoeias. The crystalline form, particle size, and specific surface area of the D-mannitol to be incorporated are not particularly limited, but the crystalline form may be any of α-, β-, δ-, or amorphous. The particle size is preferably 10 μm or more and 250 μm or less, more preferably 20 μm or more and 150 μm or less. The specific surface area is preferably 0.1 m ² /g or more and 4 m ² /g or less, more preferably 0.1 ^{m 2} /g or more and 2 m ² /g or less. The crystalline form, particle size, and specific surface area can be measured, for example, by X-ray diffraction, laser diffraction particle size measurement, or BET specific surface area measurement (multipoint method). Commercially available D-mannitol includes, for example, D-mannitol from Merck, Roquette, Towa Kasei, and Kao Corporation.

When D-mannitol is used, it is usually 20-95% by weight, preferably 20-55% by weight, per 100% by weight of the orally disintegrating tablet.

D-mannitol may be mixed as a powder with other ingredients to form a tablet and then compressed, or it may be granulated using an appropriate binder and then compressed.

The amount of "carmellose" used in the present invention is typically 1-20% by weight, preferably 2-20% by weight, per 100% by weight of the orally disintegrating tablet.

The "citric acid hydrate" used in the present invention is citric acid hydrate that can be used as a pharmaceutical additive (e.g., a product conforming to the Japanese Pharmacopoeia), and is typically citric acid monohydrate. Citric acid anhydrate can also be used instead of citric acid hydrate.

The "citric acid hydrate" and "tocopherol" used in the present invention function as stabilizers. The content of the citric acid hydrate of the present invention is preferably 0.01-10 wt%, more preferably 0.1-5.0 wt%, and even more preferably 0.2-1.0 wt%, per 100 wt% of the orally disintegrating tablet.
The tocopherol content of the present invention is preferably 0.01-10% by weight, more preferably 0.01-1.0% by weight, and even more preferably 0.01-0.4% by weight, per 100% by weight of the orally disintegrating tablet.

The "crystalline cellulose" used in the present invention is usually a grade with a bulk density of 0.10-0.46 g/cm ³ , preferably 0.10-0.42 g/cm ³ , and more preferably 0.10-0.26 g/cm ^3. Commercially available products include, for example, Ceolus KG-1000 (bulk density 0.10-0.15 g/cm ³ ), Ceolus KG-802 (bulk density 0.13-0.23 g/cm ³ ), and Ceolus UF-711 (bulk density 0.20-0.26 g/cm ³ ) (all manufactured by Asahi Kasei Chemicals). It is also possible to combine two or more types of crystalline cellulose with different bulk densities to adjust the desired bulk density.

The amount of crystalline cellulose is preferably 1.0-50% by weight per 100% by weight of the orally disintegrating tablet. If it exceeds 50% by weight, fluidity may deteriorate and manufacturability may decrease. A more preferred amount is 5.0-30% by weight.

The blending ratio of the above crystalline cellulose and D-mannitol is 1.0-10 parts by weight, preferably 1.0-8.5 parts by weight, and more preferably 1.0-3.0 parts by weight, of D-mannitol to 1 part by weight of crystalline cellulose.

The orally disintegrating tablet of the present invention may contain an inorganic excipient, which may be one or a combination of two or more selected from synthetic hydrotalcite, precipitated calcium carbonate, hydrous silicon dioxide, light anhydrous silicic acid, magnesium aluminosilicate, and magnesium hydroxide.

The "hydroxypropyl cellulose" used in the present invention is not limited as long as it maintains the desired properties of an orally disintegrating tablet (disintegration time, hardness, dissolution property).

The content of hydroxypropyl cellulose in the orally disintegrating tablet of the present invention is typically, preferably 0.1-3.0% by weight per 100% by weight of the orally disintegrating tablet, from the viewpoints of moldability and disintegrability/suspension in water. If the hydroxypropyl cellulose content is too high, the time required for suspension will be extended, reducing its suitability as an orally disintegrating tablet.

The "low-molecular-weight hydroxypropyl cellulose" used in the present invention is hydroxypropyl cellulose having a molecular weight of 140,000 or less (GPS method). A plain tablet containing low-molecular-weight hydroxypropyl cellulose has desirable properties for an orally disintegrating tablet, such as inhibiting the production of related substances and inhibiting the extension of disintegration time.
The content of low-molecular-weight hydroxypropyl cellulose in the orally disintegrating tablet of the present invention is preferably 0.1 to 2.0% by weight per 100% by weight of the orally disintegrating tablet.

As used in this invention, "analogs" refers to lactamized forms of mirogabalin and other related substances whose structures have not yet been determined.

In addition to the above ingredients, the orally disintegrating tablet of the present invention further contains crospovidone (e.g., a product conforming to the Japanese Pharmacopoeia) and pregelatinized starch as "disintegrants."

The above-mentioned pregelatinized starch is starch that has been pregelatinized by heat treatment, and includes partially pregelatinized starch. Furthermore, the pregelatinized starch described in the Japanese Pharmaceutical Excipients Standards can be used. The average degree of pregelatinization is preferably 90% or less, and more preferably 70-80%. Commercially available products that can be used include pregelatinized starch SWELSTAR PD-1 (manufactured by Asahi Kasei Chemicals).

The amount of the above-mentioned pregelatinized starch is usually 1.0-15% by weight, preferably 1.0-10% by weight, per 100% by weight of the orally disintegrating tablet.

Pregelatinized starch may be mixed in its powder form with other ingredients to form tablet powder and then compressed, or it may be granulated with other ingredients and then compressed.

In the orally disintegrating tablets of the present invention, pregelatinized starch functions as a disintegrant. However, during production, it exhibits viscosity when dissolved or dispersed in a liquid, such as water, and can be sprayed onto powdered raw materials to promote granulation and produce granules. Taking advantage of this property, a solution or dispersion of pregelatinized starch dissolved or dispersed in water is sprayed onto a powdered mixture containing microcrystalline cellulose and D-mannitol having a bulk density of ^0.26 g/cm or less, followed by fluidized-bed granulation to produce granules. These granules can then be mixed with other ingredients as needed and compression-molded to produce tablets with good moldability and desired oral disintegration properties. This manufacturing advantage is a unique property of pregelatinized starch that is hardly obtained when conventional disintegrants such as low-substituted hydroxypropyl cellulose and crospovidone are used.

The amount of crospovidone blended is typically 0.5-20% by weight, preferably 2.0-20% by weight, per 100% by weight of the orally disintegrating tablet.

The orally disintegrating tablet of the present invention may contain various "additives" commonly used in tablet manufacturing, as long as they do not interfere with the effects of the invention.

Additives may include, for example, binders, lubricants, coating agents, plasticizers, colorants, flavoring agents, sweeteners, taste-masking agents, flow agents, foaming agents, and surfactants.

Examples of "binders" include one or a combination of two or more selected from gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, pullulan, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and macrogol.

Examples of the "lubricant" include one or a combination of two or more selected from magnesium stearate (e.g., a product conforming to the Japanese Pharmacopoeia), calcium stearate (e.g., a product conforming to the Japanese Pharmacopoeia), sodium stearyl fumarate (e.g., a product conforming to the Pharmaceutical Additives Standards), and talc (e.g., a product conforming to the Japanese Pharmacopoeia), and magnesium stearate is particularly preferred.
The amount of the lubricant to be added is preferably 0.1 to 5.0% by weight based on 100% by weight of the orally disintegrating tablet.

"Coating agents" are coating agents that coat the surface (crystal surface) of powdered drugs or the granule surface of granulated drugs, and can include one or a combination of two or more selected from ethyl cellulose, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer, polyvinyl acetal-diethylamino acetate, and polyvinyl acetate resin.

"Plasticizers" are typically used in combination with coating agents and include one or a combination of two or more selected from diethyl sebacate, dibutyl sebacate, triethyl citrate, stearic acid, polyethylene glycol, and triacetin.

"Coloring agents" include food dyes such as Food Yellow No. 5, Food Red No. 2, and Food Blue No. 2; food lake dyes, yellow ferric oxide, ferric oxide, titanium oxide, beta-carotene, and riboflavin; or a combination of two or more selected from the group consisting of:

"Flavoring agents" may include one or a combination of two or more selected from orange, lemon, strawberry, mint, menthol, menthol micron, and various fragrances.

"Sweetening agents" may include one or a combination of two or more selected from saccharin sodium, saccharin, aspartame, acesulfame potassium, dipotassium glycyrrhizinate, sucralose, stevia, and thaumatin.

"Flavoring agents" may include one or a combination of two or more selected from sodium chloride, magnesium chloride, disodium inosinate, monosodium L-glutamate, and honey.

"Gliding agents" may include one or a combination of two or more selected from hydrous silicon dioxide, light anhydrous silicic acid, and talc.

Examples of "foaming agents" include tartaric acid.

"Surfactants" may include one or a combination of two or more selected from polyoxyl 40 stearate, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polysorbate, glycerin monostearate, and sodium lauryl sulfate.

The present invention will be explained below by way of examples.
Example 1: Molecular weight of hydroxypropyl cellulose and formulation stability (1) Preparation of Granule A Mirogabalin besylate, D-mannitol, and citric acid monohydrate were weighed out in the proportions shown in Table 1, mixed in a PE bag for 3 minutes, and sieved at 1100 rpm using a Comil (U-10, Φ1.143 mm, QUADRO) to obtain sieved powder. The sieved powder was placed in a fluidized bed granulator (FL-labo2L, FREUND) and sprayed with low-molecular-weight hydroxypropyl cellulose binding solution (7 wt/wt%, dissolved in purified water) at approximately 8 g/min at an inlet air temperature of 77°C to obtain the proportions shown in Table 1. After spraying, the product was dried to a temperature of 50°C.
The mixture was granulated at 1100 rpm using a Comil (U-10, Φ1.143 mm, QUADRO) to obtain Granule A.
(2) Preparation of granules for tableting
Granule A, crystalline cellulose, carmellose, and acesulfame potassium were weighed out in the blending ratio shown in Table 1, and mixed in a V-type mixer (5 L) at 34 rpm for 10 minutes to obtain a mixed powder.
Next, magnesium stearate was weighed out in the blending ratio shown in Table 1, added to the mixed powder, and mixed for 10 minutes at 34 rpm using a V-type mixer (5 L) to prepare granules for tableting.
(3) Preparation of Tablets Using a tablet press (Virgo0524SS1AX, Kikusui Seisakusho), tablets were formed to a mass of 300 mg at a tableting pressure of 5.5 kN to obtain plain tablets (12.1 × 6.4 mm).

Comparative Example 1: Molecular weight of hydroxypropyl cellulose and formulation stability (1) Preparation of Granule A Mirogabalin besylate, D-mannitol, and citric acid monohydrate were weighed out in the proportions shown in Table 1, mixed for 3 minutes in a PE bag, and sieved at 1100 rpm using a Comil (U-10, Φ1.143 mm, QUADRO) to obtain sieved powder. The sieved powder was placed in a fluidized bed granulator (FL-labo2L, FREUND) and sprayed with hydroxypropyl cellulose binding solution (7 wt/wt%, dissolved in purified water) at approximately 8 g/min at an inlet air temperature of 80°C to obtain the proportions shown in Table 1. After spraying, the product was dried to a temperature of 50°C.
The mixture was granulated at 1100 rpm using a Comil (U-10, Φ1.143 mm, QUADRO) to obtain Granule A.
(2) Preparation of granules for tableting
Granule A, microcrystalline cellulose, carmellose, and acesulfame potassium were weighed out in the proportions shown in Table 1 and mixed for 10 minutes at 34 rpm in a V-type blender (5 L) to obtain a mixed powder. Next, magnesium stearate was weighed out in the proportions shown in Table 1, added to the mixed powder, and mixed for 10 minutes at 34 rpm in a V-type blender (5 L) to obtain granules for tableting.
(3) Preparation of Tablets Using a tablet press (Virgo0524SS1AX, Kikusui Seisakusho), tablets were formed to a mass of 300 mg at a tableting pressure of 6 kN to obtain plain tablets (12.1 × 6.4 mm).

(Evaluation method and results) Molecular weight of hydroxypropyl cellulose and stability of formulations The uncoated tablets of Example 1 and Comparative Example 1 were left in an aluminum bag at 40°C/75% RH for 1 month, and then the amounts of related substances produced were measured using HPLC (Agilent Infinity 1290) under the conditions shown in Table 2. In addition, a disintegration test was conducted in accordance with the disintegration test method of the Japanese Pharmacopoeia, 17th Edition, and the initial product without an auxiliary disc and the uncoated tablets after leaving them in an aluminum bag for 3 months at 40°C/75% RH were evaluated.
The results for the amount of related substances produced are shown in Table 3. It was found that the amount of related substances produced in uncoated tablets using low-molecular-weight hydroxypropyl cellulose (molecular weight 140,000 (GPS method) or less) was approximately half that of uncoated tablets using regular hydroxypropyl cellulose (molecular weight 1,000,000 (GPS method) or less).
The results of the disintegration test are shown in Table 4. For uncoated tablets using ordinary hydroxypropyl cellulose (molecular weight 1,000,000 or less (GPS method)), the disintegration time after 3 months at 40°C/75% RH increased by 38 seconds, whereas for uncoated tablets using low-molecular-weight hydroxypropyl cellulose (molecular weight 140,000 or less (GPS method)), the increase in disintegration time was only 12 seconds.
The above results demonstrate that uncoated tablets containing low-molecular-weight hydroxypropyl cellulose have desirable properties for orally disintegrating tablets, including the inhibition of the production of related substances and the inhibition of the extension of disintegration time.

(Example 2) Amount of crystalline cellulose and stability of formulation (1) Preparation of Granule A Tocopherol and crystalline cellulose were weighed out in the ratio shown in Table 5, and mixed for 15 minutes using a high-speed mixing granulator (VG-50, POWREX) with a blade rotation speed of 180 rpm and a chopper rotation speed of 3000 rpm to obtain a 10-fold dispersion of tocopherol.
Mirogabalin besilate, D-mannitol, carmellose, citric acid hydrate, 10x tocopherol powder, and magnesium aluminometasilicate were weighed out in the proportions shown in Table 5, mixed in a V-type blender (30 L) at 27 rpm for 5 minutes, and sieved at 600 rpm using a Comil (QC-194S, Φ1.143 mm, QUADRO) to obtain sieved powder. The sieved powder was placed in a fluidized bed granulator (FLO-5) and sprayed with hydroxypropyl cellulose binding solution (7 wt/wt%, dissolved in purified water) at approximately 40 g/min at an inlet air temperature of 80°C to obtain the proportions shown in Table 5. After spraying, the product was dried to a temperature of 55°C.
The mixture was granulated at 1400 rpm using a Comil (QC-194S, Φ1.143 mm, QUADRO) to obtain Granule A.
(2) Preparation of Granule B D-mannitol and microcrystalline cellulose were weighed out in the blending ratio shown in Table 5 and placed in a fluidized bed granulator (GPCG-15, POWREX). A pregelatinized starch dispersion (8 wt/wt%, dissolved in purified water) was sprayed at approximately 140 g/min at an inlet air temperature of 85°C to obtain the blending ratio shown in Table 5. After spraying, the mixture was dried until the exhaust temperature reached 45°C.
The mixture was granulated at 600 rpm using a Comil (QC-194S, Φ1.143 mm, QUADRO) to obtain Granule B.
(3) Preparation of granules for tableting
Granules A, Granules B, Crospovidone, and Acesulfame potassium were weighed out in the blending ratios shown in Table 5 and mixed for 5 minutes at 32 rpm in a V-type blender (10 L) to obtain a mixed powder. Next, magnesium stearate was weighed out in the blending ratios shown in Table 5, added to the mixed powder, and mixed for 10 minutes at 32 rpm in a V-type blender (10 L) to obtain granules for tableting.
(4) Preparation of Tablets Using a tablet press (Virgo0524SS1AX, Kikusui Seisakusho), tablets were formed to a mass of 300 mg at a tableting pressure of 8 kN to obtain plain tablets (φ10.0 mm).

(Comparative Example 2) Amount of Microcrystalline Cellulose and Stability of Preparation (1) Preparation of Granule A Tocopherol and microcrystalline cellulose were weighed out in the ratio shown in Table 5, and mixed for 15 minutes using a high-speed mixing granulator (VG-50, POWREX) with a blade rotation speed of 180 rpm and a chopper rotation speed of 3000 rpm to obtain a 10-fold dispersion of tocopherol.
Mirogabalin besilate, D-mannitol, carmellose, citric acid hydrate, 10x tocopherol powder, and magnesium aluminometasilicate were weighed out in the proportions shown in Table 5, mixed in a V-type blender (30 L) at 27 rpm for 5 minutes, and sieved at 600 rpm using a Comil (QC-194S, Φ1.143 mm, QUADRO) to obtain sieved powder. The sieved powder was placed in a fluidized-bed granulator (FLO-5, FREUND) and sprayed with hydroxypropyl cellulose binding solution (7 wt/wt%, dissolved in purified water) at approximately 40 g/min at an inlet air temperature of 80°C to obtain the proportions shown in Table 5. After spraying, the product was dried to a temperature of 55°C.
The mixture was granulated at 1400 rpm using a Comil (QC-194S, Φ1.143 mm, QUADRO) to obtain Granule A.
(2) Preparation of granules for tableting
Granule A, D-mannitol, crospovidone, and acesulfame potassium were weighed out in the blending ratios shown in Table 5 and mixed for 5 minutes at 32 rpm in a V-type blender (10 L) to obtain a mixed powder. Next, magnesium stearate was weighed out in the blending ratios shown in Table 5, added to the mixed powder, and mixed for 10 minutes at 32 rpm in a V-type blender (10 L) to obtain granules for tableting.
(3) Preparation of Tablets Using a tablet press (Vela5, Kikusui Seisakusho), tablets were formed to a mass of 300 mg at a tableting pressure of 7 kN to obtain plain tablets (φ9.5 mm).

(Evaluation method and results) Amount of crystalline cellulose and stability of formulation The uncoated tablets of Example 2 and Comparative Example 2 were left in a plastic bottle at 40°C/75% RH for 6 months, and then the amount of related substances produced was measured using HPLC (Agilent Infinity 1290) under the conditions shown in Table 2.
The results are shown in Table 6. It was revealed that the uncoated tablets (Example 2) in which D-mannitol, crystalline cellulose, and pregelatinized starch were used as granules B produced about one-third of the total amount of related substances compared to the uncoated tablets (Comparative Example 2) in which granules B, crystalline cellulose, and pregelatinized starch were not used.

(Example 3) Amount of crystalline cellulose blended and disintegration time, friability, and hardness of the formulation (1) Preparation of tablets Using the granules for tableting prepared in Example 2, tablets were formed into tablets with a mass of 300 mg using a tableting machine (Virgo0524SS1AX, Kikusui Seisakusho) at tableting pressures of 6, 8, and 10 kN to obtain plain tablets (φ10.0 mm).

(Comparative Example 3) Amount of Microcrystalline Cellulose Added and Disintegration Time, Friability, and Hardness of the Preparation (1) Preparation of Tablets Using the granules for tableting prepared in Comparative Example 2, tablets were formed into tablets with a mass of 300 mg using a tableting machine (Vela5, Kikusui Seisakusho) at tableting pressures of 6, 8, and 10 kN to obtain plain tablets (9.5 mm).

(Evaluation methods and results) Amount of crystalline cellulose blended and disintegration time, friability, and hardness of the formulation. The evaluation results of the manufactured uncoated tablets are shown in Tables 7 to 9. Tablet hardness was measured using a fully automatic tablet measuring device (Type WHT-2, PHARMA TEST APPRATEBAU GmbH). Disintegration tests were performed in accordance with the disintegration test method of the 17th Edition of the Japanese Pharmacopoeia, without an auxiliary disk. Friability tests were performed using a tablet friability tester (SZ-03, Rinkan Kogyo).
Although Example 3 had a lower hardness than Comparative Example 3, it was shown that the friability was lower and good friability was imparted. Furthermore, it was revealed that Example 3, when compared to Comparative Example 3, had a disintegration time that was approximately half that of uncoated tablets with almost the same hardness.
The above results demonstrate that the uncoated tablet containing D-mannitol, crystalline cellulose, and pregelatinized starch as granules B has both low friability and a short disintegration time, which are desirable properties for an orally disintegrating tablet.

(Example 4) Tocopherol and Stability of Preparations (1) Preparation of Granule A Tocopherol and crystalline cellulose were weighed out in the blending ratio shown in Table 10 and mixed for 15 minutes using a high-speed mixing granulator (VG-50, POWREX) with a blade rotation speed of 180 rpm and a chopper rotation speed of 3000 rpm to obtain a 10-fold dispersion of tocopherol.
Mirogabalin besylate, D-mannitol, carmellose, citric acid hydrate, 10x tocopherol powder, and magnesium aluminometasilicate were weighed out in the proportions shown in Table 10, mixed in a V-type blender (2 L) at 39 rpm for 5 minutes, and sieved at 2200 rpm using a Comil (U-10, Φ1.143 mm, QUADRO) to obtain sieved powder. The sieved powder was placed in a fluidized bed granulator (FLO-5) and sprayed with hydroxypropyl cellulose binding solution (7 wt/wt%, dissolved in purified water) at approximately 7 g/min at an inlet air temperature of 78°C to obtain the proportions shown in Table 10. After spraying, the product was dried to a temperature of 55°C.
The mixture was granulated at 2200 rpm using a Comil (U-10, Φ1.143 mm, QUADRO) to obtain Granule A.
(2) Preparation of Granule B D-mannitol and microcrystalline cellulose were weighed out in the blending ratio shown in Table 10 and placed in a fluidized bed granulator (NFLO-5, FREUND). A pregelatinized starch dispersion (8 wt/wt%, dissolved in purified water) was sprayed at approximately 45 g/min at an inlet air temperature of 85°C to obtain the blending ratio shown in Table 10. After spraying, the mixture was dried until the exhaust temperature reached 45°C.
The mixture was granulated at 800 rpm using a Comil (QC-197, Φ1.143 mm, QUADRO) to obtain Granule B.
(3) Preparation of granules for tableting
Granules A, Granules B, crospovidone, and acesulfame potassium were weighed out in the blending ratios shown in Table 10 and mixed for 5 minutes at 39 rpm in a V-type blender (2 L) to obtain a mixed powder. Next, magnesium stearate was weighed out in the blending ratios shown in Table 10, added to the mixed powder, and mixed for 5 minutes at 39 rpm in a V-type blender (2 L) to obtain granules for tableting.
(4) Preparation of Tablets Using a tablet press (Virgo0524SS1AX, Kikusui Seisakusho), tablets were formed to a mass of 300 mg at a tableting pressure of 6 kN to obtain plain tablets (12.1 × 6.4 mm).

Comparative Example 4: Tocopherol and Stability of Formulations (1) Preparation of Granule A Mirogabalin besylate, D-mannitol, carmellose, citric acid hydrate, and magnesium aluminometasilicate were weighed out in the proportions shown in Table 10, mixed in a V-type blender (5 L) at 34 rpm for 5 minutes, and sieved at 2200 rpm using a Comil (QC-197, Φ1.143 mm, QUADRO) to obtain sieved powder. The sieved powder was placed in a fluidized bed granulator (NFLO-5, FREUND) and sprayed with hydroxypropyl cellulose binding solution (7 wt/wt%, dissolved in purified water) at approximately 7 g/min at an inlet air temperature of 80°C to obtain the proportions shown in Table 10. After spraying, the product was dried to a temperature of 55°C.
The mixture was granulated at 2200 rpm using a Comil (QC-197, Φ1.143 mm, QUADRO) to obtain Granule A.
(2) Preparation of Granule B D-mannitol and microcrystalline cellulose were weighed out in the blending ratio shown in Table 10 and placed in a fluidized bed granulator (NFLO-5, FREUND). A pregelatinized starch dispersion (8 wt/wt%, dissolved in purified water) was sprayed at approximately 45 g/min at an inlet air temperature of 85°C to obtain the blending ratio shown in Table 1. After spraying, the mixture was dried until the exhaust temperature reached 45°C.
The mixture was granulated at 800 rpm using a Comil (QC-197, Φ1.143 mm, QUADRO) to obtain Granule B.
(3) Preparation of granules for tableting
Granules A, Granules B, crospovidone, and acesulfame potassium were weighed out in the blending ratios shown in Table 10 and mixed for 5 minutes at 34 rpm in a V-type blender (5 L) to obtain a mixed powder. Next, magnesium stearate was weighed out in the blending ratios shown in Table 10, added to the mixed powder, and mixed for 10 minutes at 34 rpm in a V-type blender (5 L) to obtain granules for tableting.
(4) Preparation of Tablets Using a tablet press (Virgo0524SS1AX, Kikusui Seisakusho), tablets were formed to a mass of 300 mg at a tableting pressure of 6 kN to obtain plain tablets (12.1 × 6.4 mm).

(Evaluation method and results) Stability of tocopherol and formulations The plain tablets of Example 4 and Comparative Example 4 were left unpackaged at 25°C/75% RH, and the amounts of related substances produced were then measured using HPLC (Agilent Infinity 1290) under the conditions shown in Table 2.
The results are shown in Table 11. It was revealed that the uncoated tablets containing tocopherol produced about half the total amount of related substances compared to the uncoated tablets not containing tocopherol.

Claims (13)

An orally disintegrating tablet comprising (A) mirogabalin besylate-containing granules and (B) drug-free granules containing crystalline cellulose or drug-free mixed powder containing crystalline cellulose,
An orally disintegrating tablet, wherein (A) is a mirogabalin besylate-containing granule further containing low-molecular-weight hydroxypropyl cellulose . The orally disintegrating tablet according to claim 1, wherein the mirogabalin besylate contained in (A) has an average particle size of 60 μm or less and contains 0.5-10% by weight of mirogabalin per 100% by weight of the orally disintegrating tablet. ^3. The orally disintegrating tablet according to claim 1, wherein the bulk density of the crystalline cellulose contained in (B) is 0.10-0.26 g/cm3 and the content thereof is 1.0-50 wt% per 100 wt% of the orally disintegrating tablet. 4. The orally disintegrating tablet according to claim 1 , wherein the content of the low-molecular-weight hydroxypropyl cellulose contained in (A) is 0.1 to 2.0% by weight per 100% by weight of the orally disintegrating tablet. The orally disintegrating tablet according to any one of claims 1 to 3, wherein (A) is a mirogabalin besylate-containing granule further containing citric acid hydrate and tocopherol. 6. The orally disintegrating tablet according to claim 5, wherein the content of citric acid hydrate contained in (A) is 0.2-1.0 wt % per 100 wt % of the orally disintegrating tablet, and the content of tocopherol contained in (A) is 0.01-0.4 wt % per 100 wt % of the orally disintegrating tablet. The orally disintegrating tablet according to claim 3, wherein (A) is a mirogabalin besylate-containing granule further containing D-mannitol and carmellose. 8. The orally disintegrating tablet according to claim 5 , wherein (A) is a mirogabalin besylate-containing granule further containing hydroxypropyl cellulose. 9. The orally disintegrating tablet according to claim 8 , wherein the content of hydroxypropyl cellulose contained in (A) is 0.1 to 3.0% by weight per 100% by weight of the orally disintegrating tablet. The orally disintegrating tablet according to any one of claims 5 to 9 , wherein (B) is a drug-free granule further containing D-mannitol and pregelatinized starch. 11. The orally disintegrating tablet according to claim 10, wherein the content of D-mannitol contained in (B) is 20 to 55% by weight per 100% by weight of the orally disintegrating tablet, and the content of pregelatinized starch contained in (B) is 1.0 to 10% by weight per 100 % by weight of the orally disintegrating tablet. 5. The orally disintegrating tablet according to claim 1 , wherein (B) is a drug-free mixed powder further containing carmellose and acesulfame potassium. 13. The orally disintegrating tablet according to claim 12, wherein the content of carmellose contained in (B) is 2.0-20% by weight per 100% by weight of the orally disintegrating tablet, and the content of acesulfame potassium contained in (B) is 1.0-5.0% by weight per 100 % by weight of the orally disintegrating tablet.