Oral disintegrating tablets containing mirogabalin becilate.

Abstract

One objective of this invention is to deliver a disintegrating tablet orally. Mirogabalin basilate, which has excellent stability, is the solution to this invention; it is a tablet formulation. Oral administration of (A) granules containing mirogabalin becilate, and (B) drug-free granules containing cellulose. A drug-free crystalline or powder mixture containing crystalline cellulose;

Description

Orally disintegrating tablets containing mirogabalin besilate

[0001] 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 rapidly 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 tablet.

[0002] Tablets, capsules, granules, powders, etc. are known as oral solid dosage forms in the fields of pharmaceuticals and food. However, there is hope for the development of orally disintegrating tablets, which disintegrate quickly when placed in the mouth or when placed in water, as a dosage form that is easier to take for the elderly, children, and patients with swallowing difficulties.

[0003] Orally disintegrating tablets must not only disintegrate quickly in the oral cavity, but also have sufficient hardness to withstand physical shocks during manufacture, transportation, and use, just like regular tablets. Furthermore, it is desirable for oral disintegrating tablets to have a pleasant mouthfeel and suppress unpleasant tastes and irritation when placed in the mouth, in order to promote compliance with medication.

[0004] Regarding orally disintegrating tablets, Patent Document 1 describes a drug, a bulk density of 0.23 g / cm 3 An orally disintegrating tablet containing the following crystalline cellulose, sugar alcohol, and pregelatinized starch is described. However, this document does not describe an orally disintegrating tablet containing mirogabalin besylate.

[0005] 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 an orally disintegrating tablet containing mirogabalin besylate.

[0006] Patent Document 3 describes that stabilization of mirogabalin besylate is observed in a pharmaceutical solid formulation containing mirogabalin besylate, an excipient, a disintegrant, and a specific antioxidant. However, this document does not describe orally disintegrating tablets containing mirogabalin besylate.

[0007] 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.

[0008] US2015 / 0110880A1US2015 / 0079166A1US2018 / 0042878A1US2018 / 0243223A1

[0009] An object of the present invention is to provide an orally disintegrating tablet containing mirogabalin besylate and having excellent stability. The orally disintegrating tablet of the present invention disintegrates rapidly when placed in the mouth or when placed in water, but has sufficient hardness for normal production, transportation, and use. The present invention also provides an excellent production method.

[0010] As a result of intensive research to solve the above-mentioned problems, the present inventors have 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 have completed the present invention.

[0011] That is, the present invention is the invention described below.

[0012] [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 mirogabalin besylate contained in (A) has an average particle size of 60 μm or less and is contained in an amount of 0.5-10% by weight, as mirogabalin, per 100% by weight of the orally disintegrating tablet. [3] The bulk density of the crystalline cellulose contained in (B) is 0.10-0.26 g / cm 3and the content thereof is 1.0-50% by weight per 100% by weight of the orally disintegrating tablet. [4] The orally disintegrating tablet according to any one of [1] to [3], wherein (A) is mirogabalin besylate-containing granules 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 0.1-2.0% 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 mirogabalin besylate-containing granules 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% by weight per 100% by weight of the orally disintegrating tablet, and the content of tocopherol contained in (A) is 0.01-0.4% by weight per 100% by weight of the orally disintegrating tablet. [8] The orally disintegrating tablet according to [3], wherein (A) is mirogabalin besylate-containing granules further containing D-mannitol and carmellose. [9] The orally disintegrating tablet according to any one of [6] to [8], wherein (A) is mirogabalin besylate-containing granules further containing hydroxypropyl cellulose.

[10] The orally disintegrating tablet according to [9], wherein the content of hydroxypropyl cellulose contained in (A) is 0.1-3.0% 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 method for producing an orally disintegrating tablet, comprising the steps of: mixing mirogabalin besylate, D-mannitol, and citric acid hydrate, and spraying the mixture with a low-molecular-weight hydroxypropyl cellulose binding solution to produce granules; mixing granule A, crystalline cellulose, carmellose, and acesulfame potassium, and then adding magnesium stearate to the mixed powder and mixing to obtain a mixture for tableting; and obtaining tablets using a tablet press.

[16] A method for producing orally disintegrating tablets, comprising: a step of mixing tocopherol with crystalline cellulose to obtain tocopherol trituration; a step of mixing mirogabalin besylate, D-mannitol, carmellose, citric acid hydrate, tocopherol trituration, and magnesium aluminometasilicate, and spraying with a hydroxypropyl cellulose binding solution to produce granules; a step of mixing D-mannitol with crystalline cellulose, and spraying with a pregelatinized starch dispersion to produce granules; a step of mixing the above two granules, crospovidone, and acesulfame potassium, and then mixing with magnesium stearate to obtain a mixture for tableting; and a step of obtaining tablets using a tablet press.

[0013] The present invention provides an orally disintegrating tablet containing mirogabalin besylate and having excellent stability. The orally disintegrating tablet of the present invention is an orally disintegrating tablet having excellent stability of mirogabalin besylate, particularly due to the inclusion of citric acid hydrate and tocopherol. The orally disintegrating tablet of the present invention disintegrates rapidly when placed in the mouth or when placed in water, exhibits excellent solubility, and has a pleasant mouthfeel. The orally disintegrating tablet of the present invention has sufficient hardness for normal production, transportation, and use, and has excellent storage stability. The orally disintegrating tablet of the present invention can be produced by normal compression molding without requiring complicated processes or special equipment.

[0014] In the present invention, the term "orally disintegrating tablet" refers to a compression-molded product that has rapid disintegration and solubility when placed in the mouth or in water. Specifically, this refers to a tablet that disintegrates in a time period of typically 5 to 180 seconds, preferably 5 to 60 seconds, and more preferably 5 to 40 seconds in a disintegration test using saliva in the oral cavity or a disintegration test using a device.

[0015] The orally disintegrating tablet of the present invention has sufficient hardness during normal production, transportation, and use processes. For example, in a hardness test, the orally disintegrating tablet usually has a hardness of 2 kg or more, preferably 3 kg or more, and more preferably 5 kg or more.

[0016] The orally disintegrating tablets of the present invention maintain dissolution properties suitable for pharmaceutical use. For example, in dissolution tests, they typically exhibit an average dissolution rate of 80% or more at 30 minutes, preferably 85% or more. The dissolution test is described in Section 6.10, Dissolution Test, of the Japanese Pharmacopoeia, 18th Edition. This test is performed to determine whether oral formulations comply with the dissolution test specifications, while also aiming to prevent significant bioequivalence. The sample in this test corresponds to the minimum dosage, meaning one tablet for tablets, one capsule for capsules, or the specified amount for other formulations. Apparatuses used in this test include rotating basket, paddle, and flow-through cell apparatuses. Details are described in the Japanese Pharmacopoeia, 18th Edition.

[0017] The "mirogabalin" used in the present invention is a compound represented by the following formula (I):

[0018]

[0019] It is a compound represented by the formula:

[0020] The "mirogabalin besylate" used in the present invention is a salt of mirogabalin and besylic acid, and is represented by the following formula (Ia):

[0021]

[0022] It is expressed as:

[0023] 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.

[0024] Mirogabalin besylate used in the present invention has been approved for manufacture and sale as a peripheral neuropathic pain treatment agent based on clinical trials conducted both domestically and internationally, and is currently on the market.

[0025] For the treatment of peripheral neuropathic pain, adults usually start 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 adjusted within the range of 10 mg to 15 mg twice daily depending on age and symptoms.

[0026] The method for producing the orally disintegrating tablet of the present invention will be explained below in both of its embodiments (Aspect A and Aspect B).

[0027] Aspect A: Bulk density of 0.26 g / cm 3 An orally disintegrating tablet obtained by compression molding of drug-free granules containing crystalline cellulose, D-mannitol, and pregelatinized starch and mirogabalin besylate-containing granules. In this embodiment, the drug-free granules function as a framework for the formulation, which can impart the disintegration and moldability desired for an orally disintegrating tablet. The drug-free granules have a bulk density of 0.26 g / cm. 3 Although excellent disintegrability and moldability are exhibited by blending only the following three ingredients, crystalline cellulose, D-mannitol, and pregelatinized starch, other additives may be blended as necessary. Furthermore, the orally disintegrating tablet of this embodiment exhibits excellent stability by adding 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.

[0028] (1) Step of Producing Drug-Free Granules Drug-free granules can be produced using the following method 1) or 2). 1) Bulk density is 0.26 g / cm 3 A method of wet granulating a mixture containing the following: crystalline cellulose, D-mannitol, and pregelatinized starch with water. 2) A bulk density of 0.26 g / cm 3 This method granulates a mixture containing the following microcrystalline cellulose and D-mannitol with a liquid in which pregelatinized starch is dissolved or dispersed in water or the like. Conventional methods, such as extrusion granulation, mixing and stirring granulation, high-speed stirring granulation, fluidized bed granulation, and tumbling granulation, can be used for granulation. Pregelatinized starch exhibits a viscosity suitable for granulation when dissolved or dispersed in a liquid, such as water. Granulation methods include a method in which pregelatinized starch is mixed in its powder form with other ingredients and granulated with water, and a method in which pregelatinized starch is dissolved or dispersed in water. While both methods produce tablets with the desired properties, the latter method is preferred. Furthermore, when granulating using a liquid in which pregelatinized starch is dissolved or dispersed, both high-speed stirring granulation and fluidized bed granulation are applicable, 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 added to the drug-free granules, they may be added to the mixture before granulation. 3 The blending ratio of crystalline cellulose to D-mannitol below is 1 part by weight of crystalline cellulose to 1-3 parts by weight of D-mannitol, preferably 1-2 parts by weight.

[0029] (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 rolling granulation. For example, powdered or granulated mirogabalin besilate, D-mannitol, carmellose, citric acid hydrate, and 10x tocopherol powder (tocopherol has a bulk density of 0.26 g / cm) can be mixed with drug-free granules. 3 A mixture of the following crystalline cellulose and magnesium aluminometasilicate powders can be granulated with a solution of hydroxypropyl cellulose dissolved or dispersed in water to produce mirogabalin besilate-containing granules. Also, powdered or granular mirogabalin besilate, D-mannitol, carmellose, citric acid hydrate, and 10x tocopherol powder (tocopherol with a bulk density of 0.26 g / cm) can be used. 3Drug-containing granules can also be prepared by granulating a powder mixture of the following crystalline cellulose (a mixture), magnesium aluminometasilicate, and hydroxypropyl cellulose with water. For example, a powdered or granular mixture 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 prepare mirogabalin besylate-containing granules. Furthermore, a powdered or granular mixture of mirogabalin besylate, D-mannitol, citric acid hydrate, and low-molecular-weight hydroxypropyl cellulose can also be granulated with water to prepare drug-containing granules. Mirogabalin besylate-containing granules can also be coated to mask unpleasant tastes and odors, such as bitterness and irritation, or to control dissolution. Coating agents and plasticizers can be used as appropriate for the coating. Coating is carried out using, for example, a fluidized bed granulation / coating machine, a tumbling fluidized bed granulation / coating machine, a centrifugal fluidized bed granulation / coating machine, or a Wurster fluidized bed granulation / coating machine. When two or more drugs are used, they can be contained in the same granules or in separate granules, depending on the compatibility of the drugs with each other, and then subjected to compression molding.

[0030] (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 is carried out, for example, using a tumble mixer or 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 similar to that used for conventional tablets, and although it depends on the shape and size of the tablet, it is preferably about 2-20 kN, more preferably about 4-14 kN.

[0031] The blending ratio of drug-free granules to the total weight of the tablet ingredients may be 30-90%. When the drug is in powder form, the blending ratio is 30-80%, preferably 45-70%. When the drug is used in granulation, the blending ratio is 30-80%, preferably 45-70%. When the drug is used in granulation, the blending ratio is preferably 30-80%, preferably 45-70%. Furthermore, when the drug is used in granulation, the blending 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.

[0032] Aspect B: Bulk density is 0.26 g / cm 3 An orally disintegrating tablet obtained by compressing the following drug-free mixed powder containing crystalline cellulose, D-mannitol, and pregelatinized starch, or other extragranular mixed powder, with mirogabalin besylate-containing granules.

[0033] 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 has a bulk density of 0.26 g / cm 3 Although excellent disintegrability and moldability can be exhibited by blending only the following three components, crystalline cellulose, D-mannitol, and pregelatinized starch, other additives may be blended as needed. Furthermore, although excellent disintegrability and moldability can be exhibited by blending only the three components, crystalline cellulose, carmellose, and acesulfame potassium, other extragranular mixed powders may be blended as needed.

[0034] The method for producing the orally disintegrating tablet of Aspect B includes, if desired, 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.

[0035] In the step of mixing mirogabalin besylate-containing granules and other additives and compressing them, the mixing or compression-molding step is the same as that in (3) of embodiment A.

[0036] 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.

[0037] The orally disintegrating tablet of the present invention has a 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) of typically 5-180 seconds, preferably 5-60 seconds, and more preferably 5-40 seconds. The orally disintegrating tablet of the present invention gradually disintegrates or dissolves in the presence of 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. For people with dry oral cavities or those with little saliva, the tablet may be disintegrated or dissolved in the oral cavity using water or hot water, or may be taken directly with water in the same way as a normal tablet.

[0038] On the other hand, the orally disintegrating tablet of the present invention has a sufficient hardness even after a stability test under constant temperature and humidity conditions (for example, a temperature of 25°C, a humidity of 75%, an open system, for 1 week). Therefore, the orally disintegrating tablet has a hardness that does not crumble during the manufacturing process and distribution of the formulation, has a practical hardness even when stored under constant temperature and humidity conditions, and is also excellent in storage stability and disintegrability.

[0039] The orally disintegrating tablet of the present invention can be used for the treatment of diseases as a preparation that is easy to take even for the elderly, children, and patients with swallowing difficulties, and as a safe preparation for general adults.

[0040] The "mirogabalin besylate" used in the present invention preferably has an average particle size of 60 μm (more preferably 40 μm) or less. The "average particle size" in the present invention refers to the particle size at 50% cumulative value in the particle size distribution determined by laser diffraction / scattering. The mirogabalin besylate used in the present invention preferably accounts for 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.

[0041] The "D-mannitol" used in the present invention is generally one that complies with the Pharmacopoeias of Japan, Europe, and the United States. The crystalline form, particle size, and specific surface area of ​​the D-mannitol to be added are not particularly limited, but the crystalline form may be any of α-type, β-type, δ-type, and 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, and the specific surface area is 0.1 m 2 / g or more, 4m 2 / g or less is preferable, and 0.1m 2 / g or more, 2m 2 The crystal form, particle size, and specific surface area can be measured by, for example, X-ray diffraction, laser diffraction particle size measurement, or BET specific surface area measurement (multipoint method), respectively. Commercially available D-mannitol includes, for example, D-mannitol from Merck, Roquette, Towa Kasei, Kao, etc.

[0042] When D-mannitol is used, it is generally used in an amount of 20 to 95% by weight, preferably 20 to 55% by weight, per 100% by weight of the orally disintegrating tablet.

[0043] D-mannitol may be mixed in its powder form with other ingredients to form tablet powder, which may then be compressed, or may be granulated using a suitable binder and then subjected to compression molding.

[0044] The amount of "carmellose" used in the present invention is usually 1-20% by weight, preferably 2-20% by weight, per 100% by weight of the orally disintegrating tablet.

[0045] The "citric acid hydrate" used in the present invention is a citric acid hydrate that can be used as a pharmaceutical additive (e.g., a product conforming to the Japanese Pharmacopoeia), and is usually citric acid monohydrate. Citric acid anhydrate can also be used instead of citric acid hydrate.

[0046] The "citric acid hydrate" and "tocopherol" used in the present invention function as stabilizers. The content of 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 content of tocopherol of the present invention is preferably 0.01-10 wt%, more preferably 0.01-1.0 wt%, and even more preferably 0.01-0.4 wt%, per 100 wt% of the orally disintegrating tablet.

[0047] The "crystalline cellulose" used in the present invention usually has a bulk density of 0.10-0.46 g / cm 3 Preferably, the grade is 0.10-0.42 g / cm 3 and more preferably 0.10-0.26 g / cm 3 Commercially available products include Ceolus KG-1000 (bulk density 0.10-0.15 g / cm 3 ), Ceolus KG-802 (bulk density 0.13-0.23g / cm 3 ), Ceolus UF-711 (bulk density 0.20-0.26g / cm 3 ) (all manufactured by Asahi Kasei Chemicals Corporation). Two or more types of crystalline cellulose having different bulk densities may be combined and adjusted to have a desired bulk density.

[0048] 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, the fluidity may deteriorate and manufacturability may decrease. A more preferred amount is 5.0-30% by weight.

[0049] The blending ratio of the above crystalline cellulose to D-mannitol is 1.0 to 10 parts by weight, preferably 1.0 to 8.5 parts by weight, and more preferably 1.0 to 3.0 parts by weight, of D-mannitol to 1 part by weight of crystalline cellulose.

[0050] The orally disintegrating tablet of the present invention may contain an inorganic excipient, and examples of the inorganic excipient include 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.

[0051] The "hydroxypropyl cellulose" used in the present invention is not limited as long as it maintains the desired properties (disintegration time, hardness, dissolution property) of an orally disintegrating tablet.

[0052] The content of hydroxypropyl cellulose in the orally disintegrating tablet of the present invention is usually 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 content of hydroxypropyl cellulose is too high, the time required for suspension will be extended, and the suitability as an orally disintegrating tablet will decrease.

[0053] 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). An uncoated tablet containing low molecular weight hydroxypropyl cellulose has desirable properties for an orally disintegrating tablet, namely, 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 0.1-2.0% by weight per 100% by weight of the orally disintegrating tablet.

[0054] The term "analogs" as used in the present invention refers to lactamized products of mirogabalin and other related substances whose structures have not yet been determined.

[0055] In addition to the above ingredients, the orally disintegrating tablet of the present invention further contains crospovidone (for example, a product conforming to the Japanese Pharmacopoeia) and pregelatinized starch as "disintegrants".

[0056] The pregelatinized starch is starch that has been pregelatinized by heat treatment, and includes partially pregelatinized starch. The pregelatinized starch may be one specified in the Japanese Pharmaceutical Excipients Standards. The average degree of pregelatinization is preferably 90% or less, more preferably 70-80%. Commercially available pregelatinized starch is, for example, SWELSTAR PD-1 (manufactured by Asahi Kasei Chemicals).

[0057] The amount of the pregelatinized starch to be added is usually 1.0 to 15% by weight, preferably 1.0 to 10% by weight, per 100% by weight of the orally disintegrating tablet.

[0058] The pregelatinized starch may be mixed in its powder form with other ingredients to form tablet powder, which may then be compression molded, or it may be granulated together with other ingredients and then subjected to compression molding.

[0059] In the orally disintegrating tablet of the present invention, pregelatinized starch functions as a disintegrant. However, during production, when dissolved or dispersed in a liquid, such as water, it exhibits viscosity, and when sprayed onto a powdered raw material, it promotes granulation and can be made into granules. Utilizing this property, a bulk density of 0.26 g / cm 3 A solution or dispersion of pregelatinized starch dissolved or dispersed in water is sprayed onto a powdery mixture containing the following microcrystalline cellulose and D-mannitol, followed by fluidized bed granulation to produce granules, which are then mixed with other ingredients as needed and compression-molded to produce tablets with good moldability and desired oral disintegrability. Such advantages in manufacturing are unique to pregelatinized starch and are hardly obtained when conventional disintegrants such as low-substituted hydroxypropyl cellulose and crospovidone are used.

[0060] The amount of crospovidone blended is usually 0.5 to 20% by weight, preferably 2.0 to 20% by weight, per 100% by weight of the orally disintegrating tablet.

[0061] The orally disintegrating tablet of the present invention may contain various "additives" that are generally used in the production of tablets, as long as they do not impair the effects of the present invention.

[0062] Examples of the additives include binders, lubricants, coating agents, plasticizers, colorants, flavoring agents, sweeteners, taste-masking agents, fluidizing agents, foaming agents, and surfactants.

[0063] Examples of the "binder" 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.

[0064] Examples of "lubricants" 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), with magnesium stearate being particularly preferred. The amount of lubricant blended is preferably 0.1-5.0% by weight per 100% by weight of the orally disintegrating tablet.

[0065] The "coating agent" may be 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-diethylaminoacetate, and polyvinyl acetate resin, as a coating agent that coats the surface (crystal surface) of a powdered drug or the granule surface of a granulated drug.

[0066] The "plasticizer" is generally used in combination with a coating agent, and examples thereof include one or a combination of two or more selected from diethyl sebacate, dibutyl sebacate, triethyl citrate, stearic acid, polyethylene glycol, and triacetin.

[0067] Examples of the "coloring agent" include food dyes such as Food Yellow No. 5, Food Red No. 2, and Food Blue No. 2; and one or a combination of two or more selected from food lake dyes, yellow ferric oxide, ferric oxide, titanium oxide, β-carotene, and riboflavin.

[0068] The "flavoring agent" may include one or a combination of two or more selected from orange, lemon, strawberry, mint, menthol, menthol micron, and various flavors.

[0069] The "sweetening agent" may include one or a combination of two or more selected from saccharin sodium, saccharin, aspartame, acesulfame potassium, dipotassium glycyrrhizinate, sucralose, stevia, and thaumatin.

[0070] The "flavoring agent" may include one or a combination of two or more selected from sodium chloride, magnesium chloride, disodium inosinate, monosodium L-glutamate, and honey.

[0071] The "fluidizing agent" may include one or a combination of two or more selected from hydrous silicon dioxide, light anhydrous silicic acid, and talc.

[0072] Examples of "foaming agents" include tartaric acid.

[0073] The "surfactant" 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.

[0074] The present invention is described below with reference to examples. (Example 1) Molecular Weight of Hydroxypropylcellulose and Stability of Preparations (1) Preparation of Granule A Mirogabalin besylate, D-mannitol, and citric acid hydrate 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, Φ1.143mm, 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 mixture was dried until the product temperature reached 50°C. Granule A was obtained by sieving at 1100 rpm using a Comil (U-10, Φ1.143mm, QUADRO). (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 a granule for tableting. (3) Preparation of Tablets Tablets were formed using a tablet press (Virgo0524SS1AX, Kikusui Seisakusho) at a tableting pressure of 5.5 kN to obtain uncoated tablets (12.1 x 6.4 mm) with a tablet mass of 300 mg.

[0075] Comparative Example 1: Molecular Weight of Hydroxypropylcellulose and Stability of Formulations (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, Φ1.143mm, 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 mixture was dried until the product temperature reached 50°C. Granule A was obtained by sieving at 1100 rpm using a Comil (U-10, Φ1.143mm, QUADRO). (2) Preparation of Granules for Tableting Granule A, crystalline 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 a granule for tableting. (3) Preparation of Tablets Tablets were formed using a tablet press (Virgo0524SS1AX, Kikusui Seisakusho) at a tableting pressure of 6 kN to obtain uncoated tablets (12.1 x 6.4 mm) with a tablet mass of 300 mg.

[0076] (Evaluation Method and Results) Molecular Weight of Hydroxypropylcellulose and Stability of Formulations The uncoated tablets of Example 1 and Comparative Example 1 were left in aluminum bags at 40°C / 75% RH for 1 month, and the amount of related substances produced was measured using HPLC (Agilent Infinity 1290) under the conditions shown in Table 2. Furthermore, disintegration tests were conducted in accordance with the disintegration test method of the 17th Edition of the Japanese Pharmacopoeia. Initial tablets without an auxiliary disc and uncoated tablets left in aluminum bags at 40°C / 75% RH for 3 months were evaluated. The results of the amount of related substances produced are shown in Table 3. It was revealed that uncoated tablets using low molecular weight hydroxypropyl cellulose (molecular weight 140,000 or less (GPS method)) produced approximately half the amount of related substances compared to uncoated tablets using conventional hydroxypropyl cellulose (molecular weight 1,000,000 or less (GPS method)). 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 was extended by 38 seconds, but for uncoated tablets using low molecular weight hydroxypropyl cellulose (molecular weight 140,000 or less (GPS method)), the extension of disintegration time was only 12 seconds. These results demonstrate that uncoated tablets containing low molecular weight hydroxypropyl cellulose have desirable properties for orally disintegrating tablets, both inhibiting the production of related substances and inhibiting the extension of disintegration time.

[0077]

[0078]

[0079]

[0080]

[0081] Example 2: Amount of Microcrystalline Cellulose and Stability of Preparation (1) Preparation of Granule A: Tocopherol and microcrystalline cellulose were weighed out at the ratios shown in Table 5 and mixed for 15 minutes using a high-speed agitator granulator (VG-50, POWREX) at a blade rotation speed of 180 rpm and a chopper rotation speed of 3000 rpm to obtain a 10x powder of tocopherol. Mirogabalin besylate, D-mannitol, carmellose, citric acid hydrate, 10x powder of tocopherol, and magnesium aluminometasilicate were weighed out at the ratios shown in Table 5 and mixed for 5 minutes using a V-type blender (30 L) at a rotation speed of 27 rpm. The mixture was then sieved at 600 rpm using a Comil (QC-194S, Φ1.143 mm, QUADRO) to obtain a sieved powder. The sieved powder was placed in a fluidized-bed granulator (FLO-5) and sprayed with hydroxypropyl cellulose binder (7 wt / wt%, dissolved in purified water) at approximately 40 g / min at an inlet air temperature of 80°C to the blend ratio shown in Table 5. After spraying, the product was dried until the product temperature reached 55°C. Granules were sized at 1400 rpm using a Comil (QC-194S, Φ1.143 mm, QUADRO) to produce Granule A. (2) Preparation of Granule B: D-mannitol and microcrystalline cellulose were weighed out in the blend ratio shown in Table 5 and placed in a fluidized-bed granulator (GPCG-15, POWREX). 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 the blend ratio shown in Table 5. After spraying, the product was dried until the exhaust air temperature reached 45°C. Granules were sized at 600 rpm using a Comil (QC-194S, Φ1.143mm, QUADRO) to give Granule B. (3) Preparation of Granules for Tableting: Granules A, Granule B, crospovidone, and acesulfame potassium were weighed out in the proportions shown in Table 5 and mixed for 5 minutes at 32 rpm using a V-type blender (10L) to give a mixed powder. Next, magnesium stearate was weighed out in the proportions shown in Table 5 and added to the mixed powder. The mixture was then mixed for 10 minutes at 32 rpm using a V-type blender (10L) to give granules for tableting. (4) Preparation of Tablets: Tablets were formed using a tablet press (Virgo0524SS1AX, Kikusui Seisakusho) at a tableting pressure of 8 kN to give uncoated tablets (Φ10.0 mm) with a tablet mass of 300 mg.

[0082] Comparative Example 2: Amount of Microcrystalline Cellulose and Stability of Preparations (1) Preparation of Granule A: Tocopherol and microcrystalline cellulose were weighed out at the ratios shown in Table 5 and mixed for 15 minutes using a high-speed agitator granulator (VG-50, POWREX) at a blade rotation speed of 180 rpm and a chopper rotation speed of 3000 rpm to obtain a 10x powder of tocopherol. Mirogabalin besylate, D-mannitol, carmellose, citric acid hydrate, 10x powder of tocopherol, and magnesium aluminometasilicate were weighed out at the ratios shown in Table 5 and mixed for 5 minutes using a V-type blender (30 L) at a rotation speed of 27 rpm. The mixture was then sieved at 600 rpm using a Comil (QC-194S, Φ1.143 mm, QUADRO) to obtain a sieved powder. The sieved powder was placed in a fluidized bed granulator (FLO-5, FREUND) and sprayed with hydroxypropyl cellulose binder solution (7 wt / wt%, dissolved in purified water) at approximately 40 g / min at an inlet air temperature of 80°C to achieve the blending ratio shown in Table 5. After spraying, the product was dried until the product temperature reached 55°C. Granules were sized 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 ratio shown in Table 5 and blended for 5 minutes at 32 rpm using a V-type blender (10 L) to obtain the blended powder. Next, magnesium stearate was weighed out in the blending ratio shown in Table 5, added to the mixed powder, and mixed for 10 minutes at 32 rpm using a V-type mixer (10 L) to prepare 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).

[0083] (Evaluation method and results) Amount of crystalline cellulose blended and stability of formulation The uncoated tablets of Example 2 and Comparative Example 2 were left in plastic bottles 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 amount of total related substances produced in the uncoated tablets (Example 2) using D-mannitol, crystalline cellulose, and pregelatinized starch as granules B was about one-third of that in the uncoated tablets (Comparative Example 2) which did not use granules B and which did not use crystalline cellulose or pregelatinized starch.

[0084]

[0085]

[0086] (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).

[0087] (Comparative 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 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).

[0088] (Evaluation Method and Results) Microcrystalline Cellulose Amount 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 automated tablet measuring device (Type WHT-2, PHARMA TEST APPRATEBAU GmbH). Furthermore, 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). Despite having a lower hardness than Comparative Example 3, Example 3 also exhibited lower friability, demonstrating favorable friability. Furthermore, it was revealed that Example 3, despite having approximately the same hardness, had a disintegration time approximately half that of Comparative Example 3. These results demonstrate that uncoated tablets containing D-mannitol, microcrystalline cellulose, and pregelatinized starch as granule B possess both low friability and a short disintegration time, which are desirable properties for orally disintegrating tablets.

[0089]

[0090]

[0091]

[0092] Example 4: Stability of Tocopherol and Formulations (1) Preparation of Granule A Tocopherol and crystalline cellulose were weighed out at the blending ratios shown in Table 10 and mixed for 15 minutes using a high-speed agitation granulator (VG-50, POWREX) at a blade rotation speed of 180 rpm and a chopper rotation speed of 3000 rpm to obtain a 10x powder of tocopherol. Mirogabalin besylate, D-mannitol, carmellose, citric acid hydrate, 10x powder of tocopherol, and magnesium aluminometasilicate were weighed out at the blending ratios shown in Table 10 and mixed for 5 minutes using a V-type blender (2 L) at a rotation speed of 39 rpm. The mixture was then sieved at 2200 rpm using a Comil (U-10, Φ1.143 mm, QUADRO) to obtain a sieved powder. The sieved powder was placed in a fluidized-bed granulator (FLO-5) and sprayed with hydroxypropyl cellulose binder (7 wt / wt%, dissolved in purified water) at approximately 7 g / min at an inlet air temperature of 78°C to the blend ratio shown in Table 10. After spraying, the product was dried until the product temperature reached 55°C. Granules were sized at 2200 rpm using a Comil (U-10, Φ1.143 mm, QUADRO) to produce Granule A. (2) Preparation of Granule B: D-mannitol and microcrystalline cellulose were weighed out in the blend ratio shown in Table 10 and placed in a fluidized-bed granulator (NFLO-5, FREUND). 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 the blend ratio shown in Table 10. After spraying, the product was dried until the exhaust temperature reached 45°C. Granules were sized at 800 rpm using a Comil (QC-197, Φ1.143 mm, QUADRO) to give Granule B. (3) Preparation of Granules for Tableting: Granules A, Granule B, crospovidone, and acesulfame potassium were weighed out in the proportions shown in Table 10 and mixed for 5 minutes in a V-type blender (2 L) at 39 rpm to give a mixed powder. Next, magnesium stearate was weighed out in the proportions shown in Table 10, added to the mixed powder, and mixed for 5 minutes in a V-type blender (2 L) at 39 rpm to give granules for tableting. (4) Preparation of Tablets: Tablets were compressed to a mass of 300 mg using a tablet press (Virgo0524SS1AX, Kikusui Seisakusho) at a tableting pressure of 6 kN to give uncoated tablets (12.1 x 6.4 mm).

[0093] 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. Granules A were prepared by sieving the mixture at 2200 rpm using a Comyl (QC-197, Φ1.143mm, QUADRO). (2) Preparation of Granule B: D-mannitol and microcrystalline cellulose were weighed out in the proportions 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 proportions shown in Table 1. After spraying, the mixture was dried until the exhaust temperature reached 45°C. Granules B were prepared by sieving the mixture at 800 rpm using a Comyl (QC-197, Φ1.143mm, QUADRO). (3) Preparation of Granules for Tableting: Granules A, Granules B, crospovidone, and acesulfame potassium were weighed out in the proportions 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 proportions 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 a granule for tableting. (4) Preparation of Tablets: Tablets were formed using a tablet press (Virgo0524SS1AX, Kikusui Seisakusho) at a tableting pressure of 6 kN to obtain uncoated tablets (12.1 x 6.4 mm) with a tablet mass of 300 mg.

[0094] (Evaluation method and results) Stability of tocopherol and formulation The uncoated tablets of Example 4 and Comparative Example 4 were left unpackaged at 25°C / 75% RH, and the amount of related substances produced was 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 amount of total related substances produced in the uncoated tablets containing tocopherol was approximately half that of the uncoated tablets not containing tocopherol.

[0095]

[0096]

Claims

1. Oral disintegrating tablets comprising: (A) granules containing mirogabalin basalate; and (B) drug-free granules containing crystalline cellulose or drug-free powder mixtures containing crystalline cellulose.

2. Oral disintegrating tablets pursuant to claim 1. in which the average particle size of mirogabalin basalate contained in (A) is 60 µm or less, and the amount of this is 0.5 to 10 wt% in the form of mirogabalin relative to 100 wt% of this oral disintegrating tablet.

3. Tablets Oral disintegrating tablets under claim 1 or 2, in which the bulk density of crystalline cellulose contained in (B) is 0.10 to 0.26 g / cm3, and the amount of this is 10 to 50 wt%. compared to 100 wt%. of this oral disintegrating tablet.

4. Oral disintegrating tablets under one of claims 1 to 3, in which (A) is a granule containing mirogabalin basalate with additional low molecular weight cycloxypropyl cellulose.

5. Oral disintegrating tablets under claim 4,6. Oral disintegrating tablets under any of the claims 1 to 3, in which (A) is a granule containing bacilate with added citric acid hydrate and tocopherol.

7. Oral disintegrating tablets under claim 6, in which the amount of citric acid hydrate contained in (A) is 0.2 to 1.0 wt9% compared to 100 wt% of the oral disintegrating tablet.

8. Oral disintegrating tablet under claim 3, in which (A) is a granule containing mirogabalin bacilate with added D-mennitol and carmellose.

9. Oral disintegrating tablet under any one of claims 6 through 8, in which (A) is a granule containing mirogabalin bacilate with added hydroxypropyl cellulose.

10. Oral disintegrating tablet under claim 9,11. An oral disintegrating tablet under one of the claims 6 through 10, where(B) is a drug-free granule containing additional D-mannitol and pregelatinized starch.

12. An oral disintegrating tablet under claim 11, where the amount of D-mannitol contained in (B) is 20 through 55 wt%, compared to 100 wt% of the oral disintegrating tablet, and the amount of pregelatinized starch contained in (B) is 1.0 through 10 wt%, compared to 100 wt% of the oral disintegrating tablet.

13. Oral disintegrating tablets under claim 4 or 5, which (3) is a drug-free mixed powder containing additional carmellose and acesulfame potassium; 14. Oral disintegrating tablets under claim 13, in which the amount of carmellose contained in (B) is 2.0 to 20 wt%. relative to 100 wt% of this oral disintegrating tablet, and the amount of acesulfame potassium contained in (B) is 1.0 to 5.0 wt%. relative to 100 wt% of this oral disintegrating tablet; 15. Method for manufacturing oral disintegrating tablets, which consists of: a mixing procedure of mirogabalin becilate, D-mannitol,And citric acid hydrate and spray solution of low molecular weight hydroxypropyl cellulose binder, to produce granules; the mixing step of granule A, crystalline cellulose, carmellose, and acesulfame potassium, then adding magnesium stearate to this powder mixture, followed by mixing, to form a mixture for tablet making: and the tablet forming step using a tablet press, a method for the production of oral disintegrating tablets, which consists of: the mixing step of tocopherol and crystalline cellulose to obtain tocopherol powder; the mixing step of... Rogabalin becilate, D-mannitol, carmellose, citric acid hydrate, tocopherol powder, and magnesium aluminometasilicate are sprayed with a solution of hydroxypropyl cellulose binder to produce granules; the mixing of D-mannitol and crystalline cellulose and spraying of a pregelatinized starch dispersant are performed to produce granules; the mixing of these two granules, crospovidone, and acesulfame potassium are followed by the addition of magnesium stearate to form a tablet-forming mixture; and the tablet-forming process is carried out using a tablet press.