WO2022102457A1 - Linagliptin-containing orally disintegrating tablet - Google Patents

Linagliptin-containing orally disintegrating tablet Download PDF

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Publication number
WO2022102457A1
WO2022102457A1 PCT/JP2021/040258 JP2021040258W WO2022102457A1 WO 2022102457 A1 WO2022102457 A1 WO 2022102457A1 JP 2021040258 W JP2021040258 W JP 2021040258W WO 2022102457 A1 WO2022102457 A1 WO 2022102457A1
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Prior art keywords
linagliptin
orally disintegrating
disintegrating tablet
carmellose
tablet
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PCT/JP2021/040258
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French (fr)
Japanese (ja)
Inventor
康史 福原
克彦 尾曲
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沢井製薬株式会社
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Priority to JP2022561834A priority Critical patent/JPWO2022102457A1/ja
Publication of WO2022102457A1 publication Critical patent/WO2022102457A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3

Definitions

  • the present invention relates to an orally disintegrating tablet containing linagliptin and a method for producing the same.
  • Linagliptin (1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3- (R) -amino-piperidine-1-) Il) -xanthine) is a dipeptidyl peptidase-4 (DPP-IV) inhibitor and is used as a therapeutic agent for type II diabetes.
  • Patent Document 1 describes linagliptin or a salt thereof, a first diluent which is mannitol, a second diluent which is pregelatinized starch, a binder which is copovidone, a tablet decomposition substance which is corn starch, and magnesium stearate.
  • a pharmaceutical composition comprising a certain lubricant is disclosed.
  • the linagliptin-containing preparation be an orally disintegrating tablet which is an easy-to-drink dosage form for elderly people and patients who have difficulty swallowing.
  • the orally disintegrating tablet which is easy to take, will lead to the active participation of the patient in the treatment and the improvement of the medication behavior. Has been done.
  • the orally disintegrating tablet needs to have a good taste and other feeling of administration, and if the drug substance has a bitter taste or the like, it is required to mask the bitter taste or the like. Since linagliptin has a strong bitterness when the linagliptin-containing preparation is used as an orally disintegrating tablet, it is necessary to devise a method for masking the bitterness of linagliptin.
  • Patent Document 2 reports a technique of coating particles containing a drug substance with a poorly soluble substance.
  • Patent Document 3 describes a base by melting a mixture of a (meth) acrylate-polymer having an anionic group and a pharmaceutically active substance, extruding the mixture, and finely grinding the extruded product into granules or powder. Disclosed are methods of processing into taste-isolated granules or powders without the addition of sexually active substances.
  • Patent Document 4 by mixing a drug having an unpleasant taste with sucralose, which is a water-soluble sweetener, the discomfort of the drug exhibiting an unpleasant taste when taken is suppressed and the drug is made easier to take.
  • sucralose which is a water-soluble sweetener
  • the above-mentioned conventional bitterness masking method is complicated and time-consuming, such as coating of drug substance-containing fine particles and melting / extrusion / crushing steps, and requires special manufacturing equipment, so that bitterness is easily and efficiently masked. A method is required.
  • Patent No. 5478244 Special Table 6-502194 Gazette Japanese Patent Publication No. 2005-526731 Japanese Unexamined Patent Publication No. 2001-342151
  • One of the objects of the present invention is to provide a linagliptin-containing orally disintegrating tablet capable of sufficiently masking bitterness and a method for producing the same.
  • Orally disintegrating tablets are provided.
  • the additive may contain one or more selected from the group consisting of carmellose calcium, croscarmellose sodium, and carmellose.
  • the additive may be croscarmellose sodium.
  • the additive may contain 0.5 parts by weight or more with respect to 1 part by weight of linagliptin.
  • a linagliptin-containing orally disintegrating tablet capable of sufficiently masking bitterness and a method for producing the same are provided.
  • the linagliptin-containing orally disintegrating tablet according to the present invention and a method for producing the same will be described in detail.
  • the linagliptin-containing orally disintegrating tablet of the present invention and the method for producing the same are not construed as being limited to the contents of the embodiments and examples shown below.
  • the linagliptin-containing orally disintegrating tablet according to one embodiment of the present invention contains linagliptin and a disintegrating agent other than crospopidone.
  • the linagliptin of the present embodiment is 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino. -Piperidin-1-yl) -xanthine.
  • the present invention is not limited to this, and linagliptin or a salt thereof or a hydrate thereof may be used.
  • Linagliptin is contained, for example, 5 mg in one of the linagliptin-containing orally disintegrating tablets according to the present invention.
  • the disintegrant of the present embodiment preferably contains one or more selected from the group consisting of carmellose calcium, croscarmellose sodium, carmellose, and sodium starch glycolate. More preferably, the disintegrant comprises one or more selected from the group consisting of carmellose calcium, croscarmellose sodium, and carmellose. The additive is more preferably croscarmellose sodium.
  • the disintegrant of the present embodiment is preferably 0.5 parts by weight or more with respect to 1 part by weight of linagliptin.
  • the disintegrant is preferably contained in an amount of 0.9 parts by weight or more with respect to 1 part by weight of linagliptin.
  • the disintegrant is preferably contained in an amount of 1.8 parts by weight or more with respect to 1 part by weight of linagliptin. It is more preferable that the disintegrant is contained in an amount of 2 parts by weight or more with respect to 1 part by weight of linagliptin.
  • the disintegrant is preferably contained in an amount of 10 parts by weight or less with respect to 1 part by weight of linagliptin.
  • the disintegrant is preferably contained in an amount of 6 parts by weight or less with respect to 1 part by weight of linagliptin.
  • the linagliptin-containing orally disintegrating tablet of the present embodiment contains an additive necessary for forming the orally disintegrating tablet.
  • the additive include excipients, binders, disintegrants other than crospopidone, lubricants, surfactants, sweeteners, flavoring agents, fragrances, coloring agents and the like.
  • the additive one kind may be used alone, or two or more kinds may be used in combination. Further, in the case of two or more kinds, a so-called premix additive, which is granulated by mixing a plurality of additives in advance, may be contained.
  • the additives of the present embodiment are, for example, starches such as corn starch, lactose, sucrose, mannitol, xylitol, erythritol, sorbitol, martitol, calcium citrate, calcium phosphate, crystalline cellulose, magnesium carbonate, calcium carbonate, aluminic acid metasilicate. Excipients such as magnesium, light anhydrous silicic acid, anhydrous calcium hydrogen phosphate, etc .; sucrose, gelatin, gum arabic powder, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyethylene glycol, carmellose, crystalline cellulose carmellose.
  • starches such as corn starch, lactose, sucrose, mannitol, xylitol, erythritol, sorbitol, martitol, calcium citrate, calcium phosphate, crystalline cellulose, magnesium carbonate,
  • Excipients such as sodium, carmellose sodium, dextrin, purulan, tragant, sodium alginate, pregelatinized starch; magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, light anhydrous silicic acid, hydrous silicon dioxide, sucrose fatty acid ester , Glue such as hardened oil; interface of glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene hardened castor oil, polyoxyethylene alkyl ether, sodium lauryl sulfate, polyoxyethylene polyoxypropylene glycol, etc.
  • Sweeteners such as aspartame, saccharin, sodium saccharin, sodium acesulfam, sucralose, taumatin, lacanca extract, sorbitol, sucrose, glucose, martitol; citrate, sodium citrate, tartrate, DL-apple acid, glycine, DL -Excipients such as alanine; fragrances such as strawberry, lemon, lemon lime, orange, l-menthol, peppermint oil; and coloring agents such as yellow iron sesquioxide, iron sesquioxide, edible tar pigment, and natural pigment may be contained. ..
  • the linagliptin-containing orally disintegrating tablet contains linagliptin-derived bitterness by containing carmellose calcium, croscarmellose sodium, carmellose, or sodium starch glycolate as a disintegrant.
  • the linagliptin-containing orally disintegrating tablet can be produced according to a production method known in the pharmaceutical field.
  • the method for producing an orally disintegrating tablet containing linagliptin in the present embodiment is produced by first homogeneously mixing linagliptin and an additive selected from the above, and then tableting the obtained mixture.
  • a mixture containing linagliptin and an additive containing one or more selected from the group consisting of carmellose calcium, croscarmellose sodium, carmellose, and sodium starch glycolate is prepared in advance. Granulated ones may be used.
  • Additives such as excipients, binders, disintegrants capable of suppressing linagliptin-derived bitterness, surfactants, sweeteners, taste-masks, flavors, and colorants are added to the granulated products as needed. It may be contained. Further, a granulated product containing no linagliptin may be used.
  • the granulation method may be any method known in the pharmaceutical field, and may be a stirring granulation method, a fluidized bed granulation method, a rolling granulation method, a compression granulation method, an extrusion granulation method, a melt granulation method, or a spray granulation method. The granulation method and the like can be mentioned. As the granulation method, a stirring granulation method or a fluidized bed granulation method is simple and more preferable.
  • the linagliptin-containing orally disintegrating tablet can be produced by compression molding with a commonly used locking machine.
  • any shape can be adopted, and for example, it can be molded into a tablet shape, an elliptical shape, a spherical shape, or a rod shape.
  • the bitterness derived from linagliptin can be suppressed by adding carmellose calcium, croscarmellose sodium, carmellose, or sodium starch glycolate as a disintegrant.
  • Example 1 Per 5.0 g of linagliptin, anhydrous calcium hydrogen phosphate (GS: Kyowa Chemical Industry) 99.1 g, crystalline cellulose (Theoras PH102: Asahi Kasei) 84.0 g, carmellose calcium (ECG505: Nichirin Chemical Industry) 4.5 g, aspartame ( Ajinomoto) 15.0 g and light anhydrous silicic acid (Aerosil 200: Nippon Aerosil) 0.9 g were mixed in a polyethylene bag. The mixture was sieved through a No. 30 sieve and 1.5 g of magnesium stearate (Taipei Chemical Industry Co., Ltd.) was mixed to obtain a pre-tablet powder.
  • GS Kyowa Chemical Industry
  • the pre-locking powder was tableted with a rotary tableting machine (VELA5: Kikusui Seisakusho) to obtain an orally disintegrating tablet containing 210.0 mg of linagliptin and a thickness of 3.5 mm per tablet.
  • a rotary tableting machine VelA5: Kikusui Seisakusho
  • Example 2 In the oral cavity containing linagliptin at a thickness of 3.5 mm and 210.0 mg per tablet in the same manner as in Example 1 except that carmellose calcium was changed to croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry Co., Ltd.). Obtained a disintegrating tablet.
  • Comparative Example 1 210.0 mg per tablet, thickness 3 in the same manner as in Example 1 except that anhydrous calcium hydrogen phosphate (GS: Kyowa Chemical Industry) was added in place of carmellose calcium (ECG505: Nichirin Chemical Industry). An orally disintegrating tablet containing .5 mm linagliptin was obtained.
  • GS Kyowa Chemical Industry
  • ECG505 Nichirin Chemical Industry
  • Table 1 shows the disintegration time (sec), oral disintegration time (sec), and bitterness (sensory evaluation) of Examples 1 and 2 and Comparative Example 1.
  • the linagliptin-containing orally disintegrating tablets according to Examples 1 and 2 to which carmellose calcium or croscarmellose sodium was added as a disintegrant had a disintegration time, an oral disintegration time, and a sensory evaluation. It was good.
  • the linagliptin-containing orally disintegrating tablet according to Comparative Example 1 containing no disintegrant delayed the disintegration time and the orally disintegrating time, and could not suppress the bitterness.
  • Example 3 Per 5.0 g of linagliptin, anhydrous calcium hydrogen phosphate (GS: Kyowa Chemical Industry) 99.1 g, crystalline cellulose (Theoras PH102: Asahi Kasei) 84.0 g, carmellose calcium (ECG505: Nichirin Chemical Industry) 4.5 g, aspartame ( Ajinomoto) 15.0 g and light anhydrous silicic acid (Aerosil 200: Nippon Aerosil) 0.9 g were mixed in a polyethylene bag. The mixture was sieved through a No. 30 sieve and 1.5 g of magnesium stearate (Taipei Chemical Industry Co., Ltd.) was mixed to obtain a pre-tablet powder.
  • GS Kyowa Chemical Industry
  • the pre-locking powder was tableted with a rotary tableting machine (VELA5: Kikusui Seisakusho) to obtain an orally disintegrating tablet containing linagliptin having a thickness of 3.4 mm and 210.0 mg per tablet.
  • a rotary tableting machine VelA5: Kikusui Seisakusho
  • Example 4 An orally disintegrating tablet containing linagliptin having a thickness of 3.4 mm and 210.0 mg per tablet in the same manner as in Example 3 except that the amount of calcium hydrogen phosphate was changed to 9 g and the amount of anhydrous calcium hydrogen phosphate was reduced accordingly.
  • Example 5 An orally disintegrating tablet containing linagliptin having a thickness of 3.4 mm and 210.0 mg per tablet in the same manner as in Example 3 except that the amount of calcium hydrogen phosphate was changed to 20 g and the amount of anhydrous calcium hydrogen phosphate was reduced accordingly.
  • Example 6 Per 3.0 g of linagliptin, 60.36 g of anhydrous calcium hydrogen phosphate (GS: Kyowa Chemical Industry), 50.4 g of crystalline cellulose (Theoras PH102: Asahi Kasei), croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry) 1. 5 g, 9.0 g of aspartame (Ajinomoto) and 0.54 g of light anhydrous silicic acid (Aerosil 200: Nippon Aerosil) were mixed in a polyethylene bag. The mixture was sieved through a No.
  • Example 7 Same as Example 3 except that carmellose calcium was changed to croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry) and magnesium stearate was changed to 2.0 g, and anhydrous calcium hydrogen phosphate was reduced by that amount.
  • an orally disintegrating tablet containing linagliptin having a thickness of 3.4 mm and 210.0 mg per tablet was obtained.
  • Example 8 210.0 mg per tablet and 3.4 mm thick linagliptin-containing oral disintegration in the same manner as in Example 7, except that croscarmellose sodium was changed to 9 g and anhydrous calcium hydrogen phosphate was reduced by that amount. I got a lock.
  • Example 9 210.0 mg per tablet and 3.4 mm thick linagliptin-containing oral disintegration in the same manner as in Example 7, except that croscarmellose sodium was changed to 20 g and anhydrous calcium hydrogen phosphate was reduced by that amount. I got a lock.
  • Example 10 Per 5.0 g of linagliptin, anhydrous calcium hydrogen phosphate (GS: Kyowa Chemical Industry) 84.1 g, crystalline cellulose (Theoras PH102: Asahi Kasei) 73.0 g, croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry) 30. 0 g, 15.0 g of aspartame (Ajinomoto) and 0.9 g of light anhydrous silicic acid (Aerosil 200: Nippon Aerosil) were mixed in a polyethylene bag. The mixture was sieved through a No.
  • Example 2 An orally disintegrating tablet containing linagliptin having a thickness of 3.4 mm and 210.0 mg per tablet was obtained by the same method as in Example 3 except that the carmellose calcium was changed to sodium starch glycolate (Primogel: DFE pharma). rice field.
  • Example 11 210.0 mg per tablet and 3.4 mm thick linagliptin-containing oral disintegration in the same manner as in Comparative Example 2, except that sodium starch glycolate was changed to 10 g and anhydrous calcium hydrogen phosphate was reduced by that amount. I got a lock.
  • Example 12 210.0 mg per tablet and 3.4 mm thick linagliptin-containing oral disintegration in the same manner as in Comparative Example 2, except that sodium starch glycolate was changed to 20 g and anhydrous calcium hydrogen phosphate was reduced by that amount. I got a lock.
  • Example 13 A linagliptin-containing orally disintegrating tablet having a thickness of 3.4 mm and 210.0 mg per tablet was obtained by the same method as in Example 3 except that carmellose calcium was changed to carmellose (NS-300: Nichirin Chemical Industry Co., Ltd.). rice field.
  • Example 14 A linagliptin-containing orally disintegrating tablet having a thickness of 3.4 mm and 210.0 mg per tablet was obtained by the same method as in Example 13 except that carmellose was changed to 10 g and anhydrous calcium hydrogen phosphate was reduced by that amount. rice field.
  • Example 15 A linagliptin-containing orally disintegrating tablet having a thickness of 3.4 mm and 210.0 mg per tablet was obtained by the same method as in Example 13 except that carmellose was changed to 20 g and anhydrous calcium hydrogen phosphate was reduced by that amount. rice field.
  • Example 3 A linagliptin-containing orally disintegrating tablet having a thickness of 3.4 mm and 210.0 mg per tablet was obtained by the same method as in Example 3 except that carmellose calcium was changed to crolideon CL-F (BASF). rice field.
  • Comparative Example 4 A linagliptin-containing orally disintegrating tablet having a thickness of 3.4 mm and 210.0 mg per tablet was prepared in the same manner as in Comparative Example 3 except that the amount of crospopidone was changed to 20 g and the amount of anhydrous calcium hydrogen phosphate was reduced accordingly. Obtained.
  • Example 5 A linagliptin-containing orally disintegrating tablet having a thickness of 3.4 mm and 210.0 mg per tablet was obtained by the same method as in Example 3 except that anhydrous calcium hydrogen phosphate was increased by that amount without adding a disintegrant. rice field.
  • the amount of carmellose calcium added is preferably 0.9 parts by weight or more, more preferably 1.8 parts by weight or more with respect to 1 part by weight of linagliptin.
  • the amount of sodium croscarmellose added was preferably 0.5 part by weight or more, more preferably 0.9 part by weight or more with respect to 1 part by weight of linagliptin. 1.8 parts by weight or more is more preferable.
  • the amount of carmellose added is preferably 0.9 parts by weight or more, more preferably 2.0 parts by weight or more with respect to 1 part by weight of linagliptin.
  • the amount of sodium starch glycolate added is preferably 2.0 parts by weight or more with respect to 1 part by weight of linagliptin, and 4.0 parts by weight. The above is more preferable.
  • the linagliptin-containing orally disintegrating tablets according to Comparative Examples 3 and 4 containing crospopidone as a disintegrant had a good disintegration time, but could not suppress the bitterness.
  • the linagliptin-containing orally disintegrating tablet according to Comparative Example 5 containing no disintegrant delayed the disintegration time and could not suppress the bitterness.
  • Example 16 Per 5.0 g of linagliptin, D-mannitol (Mannit P: Mitsubishi Corporation Life Science) 135.7 g, crystalline cellulose (Theoras PH101: Asahi Kasei) 17.0 g, low substitution hydroxypropyl cellulose (NBD-022: Shin-Etsu Chemical) 8 .5 g, crospovidone (CL-F: BASF) 3.4 g, crospovidone (CL-M: BASF) 3.4 g, croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry) 20.0 g and aspartame (Ajinomoto) ) 15.0 g is mixed in a dairy pot, 50 g of purified water is added and kneaded, dried in a shelf-type dryer (MO-921: Toyama Sangyo), sieved with a No.
  • MO-921 Toyama Sangyo
  • Example 17 In the same method as in Example 16, linagliptin-containing oral disintegration of 210.0 mg and 4.0 mm in thickness, except that croscarmellose sodium was changed to carmellose calcium (ECG-505: Nichirin Chemical Industry). I got a lock.
  • Example 18 A linagliptin-containing orally disintegrating tablet having a thickness of 4.0 mm and 210.0 mg per tablet was prepared in the same manner as in Example 16 except that the sodium croscarmellose was changed to carmellose (NS-300: Nichirin Chemical Industry Co., Ltd.). Obtained.
  • Example 19 An orally disintegrating tablet containing linagliptin having a thickness of 4.1 mm and 210.0 mg per tablet in the same manner as in Example 16 except that croscarmellose sodium was changed to sodium starch glycolate (Primogel: DFE Pharma).
  • Example 6 A linagliptin-containing orally disintegrating tablet having a thickness of 4.1 mm and 210.0 mg per tablet was obtained by the same method as in Example 16 except that croscarmellose sodium was changed to crospovidone (CL-F: BASF). rice field.
  • CL-F crospovidone
  • Example 7 A linagliptin-containing orally disintegrating tablet having a thickness of 4.0 mm and 210.0 mg per tablet was obtained by the same method as in Example 16 except that D-mannitol was added in place of sodium croscarmellose.
  • Example 20 Per 10.0 g of linagliptin, D-mannitol (Mannit P: Mitsubishi Corporation Life Science) 271.4 g, crystalline cellulose (Theoras PH101: Asahi Kasei) 34.0 g, low substitution hydroxypropyl cellulose (NBD-022: Shin-Etsu Chemical) 17 0.0 g, crospovidone (CL-F: BASF) 6.8 g, crospovidone (CL-M: BASF) 6.8 g, croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry) 40.0 g, aspartame (Ajinomoto) ) 30.0 g is mixed with a fluidized layer granulator (MP-01: Paulec), then 300 g of purified water is sprayed to granulate, and after drying, it is sieved with a No.
  • MP-01 fluidized layer granulator
  • the linagliptin-containing orally disintegrating tablets according to Examples 16 to 20 to which croscarmellose sodium, carmellose calcium, carmellose, or sodium starch glycolate was added as a disintegrant were all in Example 5. Similar to 9, 12, and 15, the sensory evaluation was good. On the other hand, the linagliptin-containing orally disintegrating tablet according to Comparative Example 6 containing crospopidone as a disintegrant could not suppress the bitterness. Further, the linagliptin-containing orally disintegrating tablet according to Comparative Example 7 containing no disintegrant could not suppress the bitterness.
  • the method for producing the linagliptin-containing orally disintegrating tablet in the present embodiment can be obtained by the kneading method or the fluidized bed granulation method as well as the direct tableting method.
  • the disintegration time varied, but this is thought to be due to the fact that the amount of disintegrant used in the granulation method was larger than that of the disintegrant, and the formability was stronger than the disintegration property of the disintegrant.

Abstract

The present invention provides: a linagliptin-containing orally disintegrating tablet which is capable of sufficiently masking bitterness; and a method for producing the same. According to an embodiment of the present invention, provided is a linagliptin-containing orally disintegrating tablet containing: linagliptin; and an additive including at least one selected from the group consisting of carmellose calcium, crosscarmellose sodium, carmellose, and sodium starch glycolic acid. The additive may also include at least one selected from the group consisting of carmellose calcium, crosscalmellose sodium, and carmellose.

Description

リナグリプチン含有口腔内崩壊錠Orally disintegrating tablet containing linagliptin
　本発明は、リナグリプチン含有口腔内崩壊錠及びその製造方法に関する。 The present invention relates to an orally disintegrating tablet containing linagliptin and a method for producing the same.
　リナグリプチン（１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチン）は、ジペプチジルペプチダーゼ－４（ＤＰＰ－ＩＶ）阻害剤であり、ＩＩ型糖尿病の治療薬として用いられている。特許文献１には、リナグリプチン又はその塩、マンニトールである第一の希釈剤、アルファー化したデンプンである第二の希釈剤、コポビドンである結合剤、トウモロコシデンプンである錠剤分解物質及びステアリン酸マグネシウムである滑剤を含む医薬組成物が開示されている。 Linagliptin (1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3- (R) -amino-piperidine-1-) Il) -xanthine) is a dipeptidyl peptidase-4 (DPP-IV) inhibitor and is used as a therapeutic agent for type II diabetes. Patent Document 1 describes linagliptin or a salt thereof, a first diluent which is mannitol, a second diluent which is pregelatinized starch, a binder which is copovidone, a tablet decomposition substance which is corn starch, and magnesium stearate. A pharmaceutical composition comprising a certain lubricant is disclosed.
　一方、服用性向上等の目的から、リナグリプチン含有製剤を高齢者や嚥下困難な患者等に飲みやすい剤形である口腔内崩壊錠とすることが望まれている。特に、ＩＩ型糖尿病治療の場合は長期間に亘って服薬する必要があるため、服用が容易な口腔内崩壊錠は、患者の積極的な治療への参加、服薬行動の向上に繋がるものと期待されている。口腔内崩壊錠は、速やかな崩壊性に加え、味などの服用感が良いことが必要であり、原薬が苦味等を有する場合は苦味等をマスキングすることが求められる。リナグリプチン含有製剤を口腔内崩壊錠とするにあたり、リナグリプチンは強い苦味を有しているため、リナグリプチンの苦味をマスキングする工夫が必要である。 On the other hand, for the purpose of improving the ingestibility, it is desired that the linagliptin-containing preparation be an orally disintegrating tablet which is an easy-to-drink dosage form for elderly people and patients who have difficulty swallowing. In particular, in the case of type II diabetes treatment, it is necessary to take the drug for a long period of time, so it is expected that the orally disintegrating tablet, which is easy to take, will lead to the active participation of the patient in the treatment and the improvement of the medication behavior. Has been done. In addition to rapid disintegration, the orally disintegrating tablet needs to have a good taste and other feeling of administration, and if the drug substance has a bitter taste or the like, it is required to mask the bitter taste or the like. Since linagliptin has a strong bitterness when the linagliptin-containing preparation is used as an orally disintegrating tablet, it is necessary to devise a method for masking the bitterness of linagliptin.
　苦味をマスキングする手段の一つとして、例えば、特許文献２には、原薬を含む粒子を難溶解性物質でコーティングする技術が報告されている。例えば、特許文献３には、陰イオン基を有する（メタ）アクリレート－コポリマーと製薬学的作用物質との混合物を溶融し、混合物を押出し、押出物を顆粒または粉末に微粉砕することによって、塩基性作用物質の添加なしに味覚隔離された顆粒または粉末に加工する方法が開示されている。例えば、特許文献４には、不快な味を有する薬物と水溶性の甘味剤であるスクラロースを混合することによって、服用したときに不快な味を呈する薬物の不快感を抑え、服用しやすくすることが開示されている。上記従来の苦みマスキングの方法は、原薬含有微粒子のコーティングや、溶融・押出・粉砕工程など、煩雑で時間を要し、かつ特殊な製造機器を要するため、簡便かつ効率的に苦みをマスクする方法が求められている。 As one of the means for masking bitterness, for example, Patent Document 2 reports a technique of coating particles containing a drug substance with a poorly soluble substance. For example, Patent Document 3 describes a base by melting a mixture of a (meth) acrylate-polymer having an anionic group and a pharmaceutically active substance, extruding the mixture, and finely grinding the extruded product into granules or powder. Disclosed are methods of processing into taste-isolated granules or powders without the addition of sexually active substances. For example, in Patent Document 4, by mixing a drug having an unpleasant taste with sucralose, which is a water-soluble sweetener, the discomfort of the drug exhibiting an unpleasant taste when taken is suppressed and the drug is made easier to take. Is disclosed. The above-mentioned conventional bitterness masking method is complicated and time-consuming, such as coating of drug substance-containing fine particles and melting / extrusion / crushing steps, and requires special manufacturing equipment, so that bitterness is easily and efficiently masked. A method is required.
特許５４７８２４４号Patent No. 5478244 特表平６－５０２１９４号公報Special Table 6-502194 Gazette 特表２００５－５２６７３１号公報Japanese Patent Publication No. 2005-526731 特開２００１－３４２１５１号公報Japanese Unexamined Patent Publication No. 2001-342151
　本発明は、苦味を十分にマスキング可能なリナグリプチン含有口腔内崩壊錠及びその製造方法を提供することを目的の一つとする。 One of the objects of the present invention is to provide a linagliptin-containing orally disintegrating tablet capable of sufficiently masking bitterness and a method for producing the same.
　本発明の一実施形態によると、リナグリプチンと、カルメロースカルシウム、クロスカルメロースナトリウム、カルメロース、およびデンプングリコール酸ナトリウム、からなる群から選択される一つ以上を含む添加剤と、を含有するリナグリプチン含有口腔内崩壊錠が提供される。 According to one embodiment of the present invention, linagliptin containing linagliptin and an additive containing one or more selected from the group consisting of carmellose calcium, croscarmellose sodium, carmellose, and sodium starch glycolate. Orally disintegrating tablets are provided.
　添加剤は、カルメロースカルシウム、クロスカルメロースナトリウム、およびカルメロース、からなる群から選択される一つ以上を含んでもよい。 The additive may contain one or more selected from the group consisting of carmellose calcium, croscarmellose sodium, and carmellose.
　添加剤は、クロスカルメロースナトリウムであってもよい。 The additive may be croscarmellose sodium.
　添加剤は、リナグリプチン１重量部に対して０．５重量部以上含んでもよい。 The additive may contain 0.5 parts by weight or more with respect to 1 part by weight of linagliptin.
　本発明の一実施形態によると、苦味を十分にマスキング可能なリナグリプチン含有口腔内崩壊錠及びその製造方法が提供される。 According to one embodiment of the present invention, a linagliptin-containing orally disintegrating tablet capable of sufficiently masking bitterness and a method for producing the same are provided.
　以下、本発明に係るリナグリプチン含有口腔内崩壊錠及びその製造方法について詳細に説明する。ただし、本発明のリナグリプチン含有口腔内崩壊錠及びその製造方法は、以下に示す実施の形態及び実施例の記載内容に限定して解釈されるものではない。 Hereinafter, the linagliptin-containing orally disintegrating tablet according to the present invention and a method for producing the same will be described in detail. However, the linagliptin-containing orally disintegrating tablet of the present invention and the method for producing the same are not construed as being limited to the contents of the embodiments and examples shown below.
　本発明者らが検討した結果、特定の崩壊剤を含むリナグリプチン含有口腔内崩壊錠を製造したところ、リナグリプチン由来の苦味を抑制することができることを見出した。これは、特定の崩壊剤を選択して含有することで、製造方法に関わらず、リナグリプチン含有口腔内崩壊錠の、リナグリプチン由来の苦味を抑制することができることを見いだしたものである。 As a result of studies by the present inventors, it was found that when a linagliptin-containing orally disintegrating tablet containing a specific disintegrant was produced, the bitterness derived from linagliptin could be suppressed. It has been found that by selecting and containing a specific disintegrant, the bitterness derived from linagliptin can be suppressed in the orally disintegrating tablet containing linagliptin regardless of the production method.
　本発明の一実施形態に係るリナグリプチン含有口腔内崩壊錠は、リナグリプチンと、クロスポピドン以外の崩壊剤と、を含有する。 The linagliptin-containing orally disintegrating tablet according to one embodiment of the present invention contains linagliptin and a disintegrating agent other than crospopidone.
　本実施形態のリナグリプチンは、１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンである。しかしながらこれに限定されず、リナグリプチンまたはその塩もしくはその水和物であればよい。リナグリプチンは、本発明に係るリナグリプチン含有口腔内崩壊錠の１錠中に、例えば５ｍｇ含まれている。 The linagliptin of the present embodiment is 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino. -Piperidin-1-yl) -xanthine. However, the present invention is not limited to this, and linagliptin or a salt thereof or a hydrate thereof may be used. Linagliptin is contained, for example, 5 mg in one of the linagliptin-containing orally disintegrating tablets according to the present invention.
　本実施形態の崩壊剤は、カルメロースカルシウム、クロスカルメロースナトリウム、カルメロース、およびデンプングリコール酸ナトリウム、からなる群から選択される一つ以上を含むことが好ましい。崩壊剤は、カルメロースカルシウム、クロスカルメロースナトリウム、およびカルメロース、からなる群から選択される一つ以上を含むことがより好ましい。添加剤は、クロスカルメロースナトリウムであることがより好ましい。 The disintegrant of the present embodiment preferably contains one or more selected from the group consisting of carmellose calcium, croscarmellose sodium, carmellose, and sodium starch glycolate. More preferably, the disintegrant comprises one or more selected from the group consisting of carmellose calcium, croscarmellose sodium, and carmellose. The additive is more preferably croscarmellose sodium.
　本実施形態の崩壊剤は、リナグリプチン１重量部に対して０．５重量部以上であることが好ましい。崩壊剤は、リナグリプチン１重量部に対して０．９重量部以上含むことが好ましい。崩壊剤は、リナグリプチン１重量部に対して１．８重量部以上含むことが好ましい。崩壊剤は、リナグリプチン１重量部に対して２重量部以上含むことがより好ましい。崩壊剤は、リナグリプチン１重量部に対して１０重量部以下含むことが好ましい。崩壊剤は、リナグリプチン１重量部に対して６重量部以下含むことが好ましい。 The disintegrant of the present embodiment is preferably 0.5 parts by weight or more with respect to 1 part by weight of linagliptin. The disintegrant is preferably contained in an amount of 0.9 parts by weight or more with respect to 1 part by weight of linagliptin. The disintegrant is preferably contained in an amount of 1.8 parts by weight or more with respect to 1 part by weight of linagliptin. It is more preferable that the disintegrant is contained in an amount of 2 parts by weight or more with respect to 1 part by weight of linagliptin. The disintegrant is preferably contained in an amount of 10 parts by weight or less with respect to 1 part by weight of linagliptin. The disintegrant is preferably contained in an amount of 6 parts by weight or less with respect to 1 part by weight of linagliptin.
　本実施形態のリナグリプチン含有口腔内崩壊錠は、口腔内崩壊錠の形態とするために必要な添加剤を含有する。添加剤としては、賦形剤、結合剤、クロスポピドン以外の崩壊剤、滑沢剤、界面活性剤、甘味剤、矯味剤、香料、着色料等が挙げられる。添加剤は、１種を単独で、又は２種以上を組み合わせて使用することができる。また２種以上である場合、あらかじめ複数の添加剤を混合して造粒した、いわゆるプレミックス添加剤を含有していても良い。 The linagliptin-containing orally disintegrating tablet of the present embodiment contains an additive necessary for forming the orally disintegrating tablet. Examples of the additive include excipients, binders, disintegrants other than crospopidone, lubricants, surfactants, sweeteners, flavoring agents, fragrances, coloring agents and the like. As the additive, one kind may be used alone, or two or more kinds may be used in combination. Further, in the case of two or more kinds, a so-called premix additive, which is granulated by mixing a plurality of additives in advance, may be contained.
　本実施形態の添加剤は例えば、トウモロコシデンプンなどのデンプン類、乳糖、白糖、マンニトール、キシリトール、エリスリトール、ソルビトール、マルチトール、クエン酸カルシウム、リン酸カルシウム、結晶セルロース、炭酸マグネシウム、炭酸カルシウム、メタケイ酸アルミン酸マグネシウム、軽質無水ケイ酸、無水リン酸水素カルシウム等の賦形剤；ショ糖、ゼラチン、アラビアゴム末、メチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリエチレングリコール、カルメロース、結晶セルロース・カルメロースナトリウム、カルメロースナトリウム、デキストリン、プルラン、トラガント、アルギン酸ナトリウム、アルファー化デンプン等の結合剤；ステアリン酸マグネシウム、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、タルク、軽質無水ケイ酸、含水二酸化ケイ素、ショ糖脂肪酸エステル、硬化油等の滑沢剤；グリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンアルキルエーテル、ラウリル硫酸ナトリウム、ポリオキシエチレンポリオキシプロピレングリコール等の界面活性剤；アスパルテーム、サッカリン、サッカリンナトリウム、アセスルファムカリウム、スクラロース、タウマチン、ラカンカ抽出物、ソルビトール、白糖、ブドウ糖、マルチトール等の甘味剤；クエン酸、クエン酸ナトリウム、酒石酸、ＤＬ－リンゴ酸、グリシン、ＤＬ－アラニン等の矯味剤；ストロベリー、レモン、レモンライム、オレンジ、ｌ－メントール、ハッカ油等の香料；黄色三二酸化鉄、三二酸化鉄、食用タール色素、天然色素等の着色料等を含んでもよい。 The additives of the present embodiment are, for example, starches such as corn starch, lactose, sucrose, mannitol, xylitol, erythritol, sorbitol, martitol, calcium citrate, calcium phosphate, crystalline cellulose, magnesium carbonate, calcium carbonate, aluminic acid metasilicate. Excipients such as magnesium, light anhydrous silicic acid, anhydrous calcium hydrogen phosphate, etc .; sucrose, gelatin, gum arabic powder, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyethylene glycol, carmellose, crystalline cellulose carmellose. Excipients such as sodium, carmellose sodium, dextrin, purulan, tragant, sodium alginate, pregelatinized starch; magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, light anhydrous silicic acid, hydrous silicon dioxide, sucrose fatty acid ester , Glue such as hardened oil; interface of glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene hardened castor oil, polyoxyethylene alkyl ether, sodium lauryl sulfate, polyoxyethylene polyoxypropylene glycol, etc. Activators; Sweeteners such as aspartame, saccharin, sodium saccharin, sodium acesulfam, sucralose, taumatin, lacanca extract, sorbitol, sucrose, glucose, martitol; citrate, sodium citrate, tartrate, DL-apple acid, glycine, DL -Excipients such as alanine; fragrances such as strawberry, lemon, lemon lime, orange, l-menthol, peppermint oil; and coloring agents such as yellow iron sesquioxide, iron sesquioxide, edible tar pigment, and natural pigment may be contained. ..
　本実施形態においてリナグリプチン含有口腔内崩壊錠は、崩壊剤としてカルメロースカルシウム、クロスカルメロースナトリウム、カルメロース、またはデンプングリコール酸ナトリウムを含むことにより、リナグリプチン由来の苦味を抑制することができる。 In the present embodiment, the linagliptin-containing orally disintegrating tablet contains linagliptin-derived bitterness by containing carmellose calcium, croscarmellose sodium, carmellose, or sodium starch glycolate as a disintegrant.
　本実施形態においてリナグリプチン含有口腔内崩壊錠は、薬学分野において公知の製造方法に従って製造することができる。本実施形態におけるリナグリプチン含有口腔内崩壊錠の製造方法は、まずリナグリプチンと、上記から選択した添加剤を均質に混合し、得られた混合物を打錠することにより製造する。しかしながらこれに限定されず、リナグリプチンと、カルメロースカルシウム、クロスカルメロースナトリウム、カルメロース、およびデンプングリコール酸ナトリウム、からなる群から選択される一つ以上を含む添加剤と、を含む混合物は、前もって造粒したものを用いても良い。その造粒物には、賦形剤、結合剤、リナグリプチン由来の苦味を抑制することができる崩壊剤、界面活性剤、甘味剤、矯味剤、香料、着色料等の添加剤を必要に応じて含有してもよい。また、リナグリプチンを含有しない造粒物を用いても良い。造粒方法は、薬学分野において公知の方法であれば良く、撹拌造粒法、流動層造粒法、転動造粒法、圧縮造粒法、押出造粒法、溶融造粒法、噴霧造粒法などが挙げられる。造粒方法は、撹拌造粒法または流動層造粒法が簡便でより好ましい。 In the present embodiment, the linagliptin-containing orally disintegrating tablet can be produced according to a production method known in the pharmaceutical field. The method for producing an orally disintegrating tablet containing linagliptin in the present embodiment is produced by first homogeneously mixing linagliptin and an additive selected from the above, and then tableting the obtained mixture. However, but not limited to this, a mixture containing linagliptin and an additive containing one or more selected from the group consisting of carmellose calcium, croscarmellose sodium, carmellose, and sodium starch glycolate is prepared in advance. Granulated ones may be used. Additives such as excipients, binders, disintegrants capable of suppressing linagliptin-derived bitterness, surfactants, sweeteners, taste-masks, flavors, and colorants are added to the granulated products as needed. It may be contained. Further, a granulated product containing no linagliptin may be used. The granulation method may be any method known in the pharmaceutical field, and may be a stirring granulation method, a fluidized bed granulation method, a rolling granulation method, a compression granulation method, an extrusion granulation method, a melt granulation method, or a spray granulation method. The granulation method and the like can be mentioned. As the granulation method, a stirring granulation method or a fluidized bed granulation method is simple and more preferable.
　本実施形態においてリナグリプチン含有口腔内崩壊錠は、通常用いられる打錠機で圧縮成形することにより製造することができる。成形に関しては、どのような形状をも採用することができ、例えばタブレット型、楕円形、球形、棒状型の形状に成形することができる。 In the present embodiment, the linagliptin-containing orally disintegrating tablet can be produced by compression molding with a commonly used locking machine. As for molding, any shape can be adopted, and for example, it can be molded into a tablet shape, an elliptical shape, a spherical shape, or a rod shape.
　本実施形態におけるリナグリプチン含有口腔内崩壊錠の製造方法は、崩壊剤としてカルメロースカルシウム、クロスカルメロースナトリウム、カルメロース、またはデンプングリコール酸ナトリウムを加えることにより、リナグリプチン由来の苦味を抑制することができる。 In the method for producing an orally disintegrating tablet containing linagliptin in the present embodiment, the bitterness derived from linagliptin can be suppressed by adding carmellose calcium, croscarmellose sodium, carmellose, or sodium starch glycolate as a disintegrant.
　本発明に係るリナグリプチン含有口腔内崩壊錠の製造方法の一例を以下に示すが、この記載は一例にすぎず、これに限定されるものではない。 An example of a method for producing an orally disintegrating tablet containing linagliptin according to the present invention is shown below, but this description is merely an example and is not limited thereto.
（実施例１）
　リナグリプチン５．０ｇ当たり、無水リン酸水素カルシウム（ＧＳ：協和化学工業）９９．１ｇ、結晶セルロース（セオラスＰＨ１０２：旭化成）８４．０ｇ、カルメロースカルシウム（ＥＣＧ５０５：ニチリン化学工業）４．５ｇ、アスパルテーム（味の素）１５．０ｇ及び軽質無水ケイ酸（アエロジル２００：日本アエロジル）０．９ｇをポリエチレン袋で混合した。混合物は、３０号篩で篩過し、ステアリン酸マグネシウム（太平化学産業）１．５ｇを混合して打錠前粉末を得た。その後、打錠前粉末をロータリー打錠機（ＶＥＬＡ５：菊水製作所）にて打錠し、１錠あたり２１０．０ｍｇ、厚さ３．５ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 1)
Per 5.0 g of linagliptin, anhydrous calcium hydrogen phosphate (GS: Kyowa Chemical Industry) 99.1 g, crystalline cellulose (Theoras PH102: Asahi Kasei) 84.0 g, carmellose calcium (ECG505: Nichirin Chemical Industry) 4.5 g, aspartame ( Ajinomoto) 15.0 g and light anhydrous silicic acid (Aerosil 200: Nippon Aerosil) 0.9 g were mixed in a polyethylene bag. The mixture was sieved through a No. 30 sieve and 1.5 g of magnesium stearate (Taipei Chemical Industry Co., Ltd.) was mixed to obtain a pre-tablet powder. Then, the pre-locking powder was tableted with a rotary tableting machine (VELA5: Kikusui Seisakusho) to obtain an orally disintegrating tablet containing 210.0 mg of linagliptin and a thickness of 3.5 mm per tablet.
（実施例２）
　カルメロースカルシウムをクロスカルメロースナトリウム（キッコレートＮＤ－２ＨＳ：ニチリン化学工業）に変更したこと以外、実施例１と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ３．５ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 2)
In the oral cavity containing linagliptin at a thickness of 3.5 mm and 210.0 mg per tablet in the same manner as in Example 1 except that carmellose calcium was changed to croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry Co., Ltd.). Obtained a disintegrating tablet.
（比較例１）
　カルメロースカルシウム（ＥＣＧ５０５：ニチリン化学工業）の代わりに無水リン酸水素カルシウム（ＧＳ：協和化学工業）を追加したこと以外、実施例１と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ３．５ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Comparative Example 1)
210.0 mg per tablet, thickness 3 in the same manner as in Example 1 except that anhydrous calcium hydrogen phosphate (GS: Kyowa Chemical Industry) was added in place of carmellose calcium (ECG505: Nichirin Chemical Industry). An orally disintegrating tablet containing .5 mm linagliptin was obtained.
（リナグリプチン含有口腔内崩壊錠の製剤物性）
　上述のリナグリプチン含有口腔内崩壊錠は、崩壊時間および官能評価を測定することで製剤物性を評価した。崩壊時間は、第十七改正日本薬局方の崩壊試験法に準じて崩壊時間を測定し、６錠の測定値の結果を算出した。口腔内崩壊時間は、官能試験による口腔内崩壊時間を測定し、１錠の測定値の結果を算出した。官能評価は、官能試験による苦味を４段階（＋＋＋：非常に苦い、＋＋：苦い、＋：わずかに苦い、±：ほとんど苦くない）で評価し、２錠の測定値の結果を算出した。実施例１、２および比較例１の崩壊時間（ｓｅｃ）、口腔内崩壊時間（ｓｅｃ）、苦味（官能評価）を表１に示す。 (Physical properties of orally disintegrating tablets containing linagliptin)
The above-mentioned linagliptin-containing orally disintegrating tablets were evaluated for their physical properties by measuring the disintegration time and sensory evaluation. For the disintegration time, the disintegration time was measured according to the disintegration test method of the 17th revised Japanese Pharmacopoeia, and the results of the measured values of 6 tablets were calculated. For the oral disintegration time, the oral disintegration time was measured by a sensory test, and the result of the measured value of one tablet was calculated. In the sensory evaluation, the bitterness by the sensory test was evaluated in 4 stages (++++: very bitter, ++: bitter, +: slightly bitter, ±: almost not bitter), and the results of the measured values of 2 tablets were calculated. Table 1 shows the disintegration time (sec), oral disintegration time (sec), and bitterness (sensory evaluation) of Examples 1 and 2 and Comparative Example 1.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表１に示すように、崩壊剤としてカルメロースカルシウムまたはクロスカルメロースナトリウムを加えた実施例１および２に係るリナグリプチン含有口腔内崩壊錠はいずれも、崩壊時間、口腔内崩壊時間、および官能評価が良好であった。一方で、崩壊剤を含まない比較例１に係るリナグリプチン含有口腔内崩壊錠は、崩壊時間、口腔内崩壊時間が遅延し、苦味を抑制することができなかった。 As shown in Table 1, the linagliptin-containing orally disintegrating tablets according to Examples 1 and 2 to which carmellose calcium or croscarmellose sodium was added as a disintegrant had a disintegration time, an oral disintegration time, and a sensory evaluation. It was good. On the other hand, the linagliptin-containing orally disintegrating tablet according to Comparative Example 1 containing no disintegrant delayed the disintegration time and the orally disintegrating time, and could not suppress the bitterness.
（実施例３）
　リナグリプチン５．０ｇ当たり、無水リン酸水素カルシウム（ＧＳ：協和化学工業）９９．１ｇ、結晶セルロース（セオラスＰＨ１０２：旭化成）８４．０ｇ、カルメロースカルシウム（ＥＣＧ５０５：ニチリン化学工業）４．５ｇ、アスパルテーム（味の素）１５．０ｇ及び軽質無水ケイ酸（アエロジル２００：日本アエロジル）０．９ｇをポリエチレン袋で混合した。混合物は、３０号篩で篩過し、ステアリン酸マグネシウム（太平化学産業）１．５ｇを混合して打錠前粉末を得た。その後、打錠前粉末をロータリー打錠機（ＶＥＬＡ５：菊水製作所）にて打錠し、１錠あたり２１０．０ｍｇ、厚さ３．４ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 3)
Per 5.0 g of linagliptin, anhydrous calcium hydrogen phosphate (GS: Kyowa Chemical Industry) 99.1 g, crystalline cellulose (Theoras PH102: Asahi Kasei) 84.0 g, carmellose calcium (ECG505: Nichirin Chemical Industry) 4.5 g, aspartame ( Ajinomoto) 15.0 g and light anhydrous silicic acid (Aerosil 200: Nippon Aerosil) 0.9 g were mixed in a polyethylene bag. The mixture was sieved through a No. 30 sieve and 1.5 g of magnesium stearate (Taipei Chemical Industry Co., Ltd.) was mixed to obtain a pre-tablet powder. Then, the pre-locking powder was tableted with a rotary tableting machine (VELA5: Kikusui Seisakusho) to obtain an orally disintegrating tablet containing linagliptin having a thickness of 3.4 mm and 210.0 mg per tablet.
（実施例４）
　カルメロースカルシウムを９ｇに変更し、その分無水リン酸水素カルシウムを減らしたこと以外、実施例３と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ３．４ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 4)
An orally disintegrating tablet containing linagliptin having a thickness of 3.4 mm and 210.0 mg per tablet in the same manner as in Example 3 except that the amount of calcium hydrogen phosphate was changed to 9 g and the amount of anhydrous calcium hydrogen phosphate was reduced accordingly. Got
（実施例５）
　カルメロースカルシウムを２０ｇに変更し、その分無水リン酸水素カルシウムを減らしたこと以外、実施例３と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ３．４ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 5)
An orally disintegrating tablet containing linagliptin having a thickness of 3.4 mm and 210.0 mg per tablet in the same manner as in Example 3 except that the amount of calcium hydrogen phosphate was changed to 20 g and the amount of anhydrous calcium hydrogen phosphate was reduced accordingly. Got
（実施例６）
　リナグリプチン３．０ｇ当たり、無水リン酸水素カルシウム（ＧＳ：協和化学工業）６０．３６ｇ、結晶セルロース（セオラスＰＨ１０２：旭化成）５０．４ｇ、クロスカルメロースナトリウム（キッコレートＮＤ－２ＨＳ：ニチリン化学工業）１．５ｇ、アスパルテーム（味の素）９．０ｇ及び軽質無水ケイ酸（アエロジル２００：日本アエロジル）０．５４ｇをポリエチレン袋で混合した。混合物は、３０号篩で篩過し、ステアリン酸マグネシウム（太平化学産業）１．２ｇを混合して打錠前粉末を得た。その後、打錠前粉末をロータリー打錠機（ＶＥＬＡ５：菊水製作所）にて打錠し、１錠あたり２１０．０ｍｇ、厚さ３．４ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 6)
Per 3.0 g of linagliptin, 60.36 g of anhydrous calcium hydrogen phosphate (GS: Kyowa Chemical Industry), 50.4 g of crystalline cellulose (Theoras PH102: Asahi Kasei), croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry) 1. 5 g, 9.0 g of aspartame (Ajinomoto) and 0.54 g of light anhydrous silicic acid (Aerosil 200: Nippon Aerosil) were mixed in a polyethylene bag. The mixture was sieved through a No. 30 sieve and 1.2 g of magnesium stearate (Taipei Chemical Industry Co., Ltd.) was mixed to obtain a pre-tablet powder. Then, the pre-locking powder was tableted with a rotary tableting machine (VELA5: Kikusui Seisakusho) to obtain an orally disintegrating tablet containing linagliptin having a thickness of 3.4 mm and 210.0 mg per tablet.
（実施例７）
　カルメロースカルシウムをクロスカルメロースナトリウム（キッコレートＮＤ－２ＨＳ：ニチリン化学工業）に、ステアリン酸マグネシウムを２．０ｇに変更し、その分無水リン酸水素カルシウムを減らしたこと以外、実施例３と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ３．４ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 7)
Same as Example 3 except that carmellose calcium was changed to croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry) and magnesium stearate was changed to 2.0 g, and anhydrous calcium hydrogen phosphate was reduced by that amount. By the method, an orally disintegrating tablet containing linagliptin having a thickness of 3.4 mm and 210.0 mg per tablet was obtained.
（実施例８）
　クロスカルメロースナトリウムを９ｇに変更し、その分無水リン酸水素カルシウムを減らしたこと以外、実施例７と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ３．４ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 8)
210.0 mg per tablet and 3.4 mm thick linagliptin-containing oral disintegration in the same manner as in Example 7, except that croscarmellose sodium was changed to 9 g and anhydrous calcium hydrogen phosphate was reduced by that amount. I got a lock.
（実施例９）
　クロスカルメロースナトリウムを２０ｇに変更し、その分無水リン酸水素カルシウムを減らしたこと以外、実施例７と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ３．４ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 9)
210.0 mg per tablet and 3.4 mm thick linagliptin-containing oral disintegration in the same manner as in Example 7, except that croscarmellose sodium was changed to 20 g and anhydrous calcium hydrogen phosphate was reduced by that amount. I got a lock.
（実施例１０）
　リナグリプチン５．０ｇ当たり、無水リン酸水素カルシウム（ＧＳ：協和化学工業）８４．１ｇ、結晶セルロース（セオラスＰＨ１０２：旭化成）７３．０ｇ、クロスカルメロースナトリウム（キッコレートＮＤ－２ＨＳ：ニチリン化学工業）３０．０ｇ、アスパルテーム（味の素）１５．０ｇ及び軽質無水ケイ酸（アエロジル２００：日本アエロジル）０．９ｇをポリエチレン袋で混合した。混合物は、３０号篩で篩過し、ステアリン酸マグネシウム（太平化学産業）２．０ｇを混合して打錠前粉末を得た。その後、打錠前粉末をロータリー打錠機（ＶＥＬＡ５：菊水製作所）にて打錠し、１錠あたり２１０．０ｍｇ、厚さ３．５ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 10)
Per 5.0 g of linagliptin, anhydrous calcium hydrogen phosphate (GS: Kyowa Chemical Industry) 84.1 g, crystalline cellulose (Theoras PH102: Asahi Kasei) 73.0 g, croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry) 30. 0 g, 15.0 g of aspartame (Ajinomoto) and 0.9 g of light anhydrous silicic acid (Aerosil 200: Nippon Aerosil) were mixed in a polyethylene bag. The mixture was sieved through a No. 30 sieve and 2.0 g of magnesium stearate (Taipei Chemical Industry Co., Ltd.) was mixed to obtain a pre-tablet powder. Then, the pre-locking powder was tableted with a rotary tableting machine (VELA5: Kikusui Seisakusho) to obtain an orally disintegrating tablet containing 210.0 mg of linagliptin and a thickness of 3.5 mm per tablet.
（比較例２）
　カルメロースカルシウムをデンプングリコール酸ナトリウム（Ｐｒｉｍｏｊｅｌ：ＤＦＥ　ｐｈａｒｍａ）に変更したこと以外、実施例３と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ３．４ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Comparative Example 2)
An orally disintegrating tablet containing linagliptin having a thickness of 3.4 mm and 210.0 mg per tablet was obtained by the same method as in Example 3 except that the carmellose calcium was changed to sodium starch glycolate (Primogel: DFE pharma). rice field.
（実施例１１）
　デンプングリコール酸ナトリウムを１０ｇに変更し、その分無水リン酸水素カルシウムを減らしたこと以外、比較例２と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ３．４ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 11)
210.0 mg per tablet and 3.4 mm thick linagliptin-containing oral disintegration in the same manner as in Comparative Example 2, except that sodium starch glycolate was changed to 10 g and anhydrous calcium hydrogen phosphate was reduced by that amount. I got a lock.
（実施例１２）
　デンプングリコール酸ナトリウムを２０ｇに変更し、その分無水リン酸水素カルシウムを減らしたこと以外、比較例２と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ３．４ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 12)
210.0 mg per tablet and 3.4 mm thick linagliptin-containing oral disintegration in the same manner as in Comparative Example 2, except that sodium starch glycolate was changed to 20 g and anhydrous calcium hydrogen phosphate was reduced by that amount. I got a lock.
（実施例１３）
　カルメロースカルシウムをカルメロース（ＮＳ－３００：ニチリン化学工業）に変更したこと以外、実施例３と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ３．４ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 13)
A linagliptin-containing orally disintegrating tablet having a thickness of 3.4 mm and 210.0 mg per tablet was obtained by the same method as in Example 3 except that carmellose calcium was changed to carmellose (NS-300: Nichirin Chemical Industry Co., Ltd.). rice field.
（実施例１４）
　カルメロースを１０ｇに変更し、その分無水リン酸水素カルシウムを減らしたこと以外、実施例１３と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ３．４ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 14)
A linagliptin-containing orally disintegrating tablet having a thickness of 3.4 mm and 210.0 mg per tablet was obtained by the same method as in Example 13 except that carmellose was changed to 10 g and anhydrous calcium hydrogen phosphate was reduced by that amount. rice field.
（実施例１５）
　カルメロースを２０ｇに変更し、その分無水リン酸水素カルシウムを減らしたこと以外、実施例１３と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ３．４ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 15)
A linagliptin-containing orally disintegrating tablet having a thickness of 3.4 mm and 210.0 mg per tablet was obtained by the same method as in Example 13 except that carmellose was changed to 20 g and anhydrous calcium hydrogen phosphate was reduced by that amount. rice field.
（比較例３）
　カルメロースカルシウムをクロスポピドン（Ｋｏｌｌｉｄｏｎ　ＣＬ－Ｆ：ＢＡＳＦ）に変更したこと以外、実施例３と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ３．４ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Comparative Example 3)
A linagliptin-containing orally disintegrating tablet having a thickness of 3.4 mm and 210.0 mg per tablet was obtained by the same method as in Example 3 except that carmellose calcium was changed to crolideon CL-F (BASF). rice field.
（比較例４）
　クロスポピドンを２０ｇに変更し、その分無水リン酸水素カルシウムを減らしたこと以外、比較例３と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ３．４ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Comparative Example 4)
A linagliptin-containing orally disintegrating tablet having a thickness of 3.4 mm and 210.0 mg per tablet was prepared in the same manner as in Comparative Example 3 except that the amount of crospopidone was changed to 20 g and the amount of anhydrous calcium hydrogen phosphate was reduced accordingly. Obtained.
（比較例５）
　崩壊剤を加えずに、その分無水リン酸水素カルシウムを増やしたこと以外、実施例３と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ３．４ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Comparative Example 5)
A linagliptin-containing orally disintegrating tablet having a thickness of 3.4 mm and 210.0 mg per tablet was obtained by the same method as in Example 3 except that anhydrous calcium hydrogen phosphate was increased by that amount without adding a disintegrant. rice field.
（リナグリプチン含有口腔内崩壊錠の製剤物性）
　上述のリナグリプチン含有口腔内崩壊錠は、崩壊時間および官能評価を測定することで製剤物性を評価した。崩壊時間は、第十七改正日本薬局方の崩壊試験法に準じて崩壊時間を測定し、６錠の測定値の結果を算出した。官能評価は、官能試験による苦味を４段階（＋＋＋：非常に苦い、＋＋：苦い、＋：わずかに苦い、±：ほとんど苦くない）で評価し、２錠の測定値の結果を算出した。実施例３～１５および比較例２～５の崩壊時間（ｓｅｃ）、苦味（官能評価）を表２に示す。 (Physical properties of orally disintegrating tablets containing linagliptin)
The above-mentioned linagliptin-containing orally disintegrating tablets were evaluated for their physical properties by measuring the disintegration time and sensory evaluation. For the disintegration time, the disintegration time was measured according to the disintegration test method of the 17th revised Japanese Pharmacopoeia, and the results of the measured values of 6 tablets were calculated. In the sensory evaluation, the bitterness by the sensory test was evaluated in 4 stages (++++: very bitter, ++: bitter, +: slightly bitter, ±: almost not bitter), and the results of the measured values of 2 tablets were calculated. Table 2 shows the disintegration time (sec) and bitterness (sensory evaluation) of Examples 3 to 15 and Comparative Examples 2 to 5.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　表２に示すように、崩壊剤としてカルメロースカルシウム、クロスカルメロースナトリウム、デンプングリコール酸ナトリウム、またはカルメロースを加えた実施例３～１５に係るリナグリプチン含有口腔内崩壊錠はいずれも、崩壊時間、および官能評価が良好であった。カルメロースカルシウムを加えた実施例３～５を比較すると、カルメロースカルシウムの添加量は、リナグリプチン１重量部に対して０．９重量部以上が好ましく、１．８重量部以上がより好ましい。クロスカルメロースナトリウムを加えた実施例６～１０を比較すると、クロスカルメロースナトリウムの添加量は、リナグリプチン１重量部に対して０．５重量部以上が好ましく、０．９重量部以上がより好ましく、１．８重量部以上がより好ましい。カルメロースを加えた実施例１３～１５を比較すると、カルメロースの添加量は、リナグリプチン１重量部に対して０．９重量部以上が好ましく、２．０重量部以上がより好ましい。デンプングリコール酸ナトリウムを加えた実施例１１、１２および比較例２を比較すると、デンプングリコール酸ナトリウムの添加量は、リナグリプチン１重量部に対して２．０重量部以上が好ましく、４．０重量部以上がより好ましい。一方で、崩壊剤としてクロスポピドンを含む比較例３および４に係るリナグリプチン含有口腔内崩壊錠は、崩壊時間は良好であったが、苦味を抑制することができなかった。また崩壊剤を含まない比較例５に係るリナグリプチン含有口腔内崩壊錠は、崩壊時間が遅延し、苦味を抑制することができなかった。 As shown in Table 2, the linagliptin-containing orally disintegrating tablets according to Examples 3 to 15 to which carmellose calcium, croscarmellose sodium, sodium starch glycolate, or carmellose were added as disintegrants all had a disintegration time and disintegration time. The sensory evaluation was good. Comparing Examples 3 to 5 to which carmellose calcium was added, the amount of carmellose calcium added is preferably 0.9 parts by weight or more, more preferably 1.8 parts by weight or more with respect to 1 part by weight of linagliptin. Comparing Examples 6 to 10 to which sodium croscarmellose was added, the amount of sodium croscarmellose added was preferably 0.5 part by weight or more, more preferably 0.9 part by weight or more with respect to 1 part by weight of linagliptin. 1.8 parts by weight or more is more preferable. Comparing Examples 13 to 15 to which carmellose was added, the amount of carmellose added is preferably 0.9 parts by weight or more, more preferably 2.0 parts by weight or more with respect to 1 part by weight of linagliptin. Comparing Examples 11 and 12 to which sodium starch glycolate was added and Comparative Example 2, the amount of sodium starch glycolate added is preferably 2.0 parts by weight or more with respect to 1 part by weight of linagliptin, and 4.0 parts by weight. The above is more preferable. On the other hand, the linagliptin-containing orally disintegrating tablets according to Comparative Examples 3 and 4 containing crospopidone as a disintegrant had a good disintegration time, but could not suppress the bitterness. Further, the linagliptin-containing orally disintegrating tablet according to Comparative Example 5 containing no disintegrant delayed the disintegration time and could not suppress the bitterness.
（実施例１６）
リナグリプチン５．０ｇ当たり、Ｄ－マンニトール（マンニットＰ：三菱商事ライフサイエンス）１３５．７ｇ、結晶セルロース（セオラスＰＨ１０１：旭化成）１７．０ｇ、低置換度ヒドロキシプロピルセルロース（ＮＢＤ－０２２：信越化学）８．５ｇ、クロスポビドン（ＣＬ－Ｆ：ＢＡＳＦ）３．４ｇ、クロスポビドン（ＣＬ－Ｍ：ＢＡＳＦ）３．４ｇ、クロスカルメロースナトリウム（キッコレートＮＤ－２ＨＳ：ニチリン化学工業）２０．０ｇ及びアスパルテーム（味の素）１５．０ｇを乳鉢で混合後、精製水５０ｇを加えて練合し、棚式乾燥機（ＭＯ－９２１：富山産業）で乾燥した後、２２号篩で篩過し、ステアリン酸マグネシウム（太平化学産業）２．０ｇを混合して打錠前粉末を得た。その後、本粉末をロータリー打錠機（ＶＥＬＡ５：菊水製作所）にて打錠し、１錠あたり２１０．０ｍｇ、厚さ４．０ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 16)
Per 5.0 g of linagliptin, D-mannitol (Mannit P: Mitsubishi Corporation Life Science) 135.7 g, crystalline cellulose (Theoras PH101: Asahi Kasei) 17.0 g, low substitution hydroxypropyl cellulose (NBD-022: Shin-Etsu Chemical) 8 .5 g, crospovidone (CL-F: BASF) 3.4 g, crospovidone (CL-M: BASF) 3.4 g, croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry) 20.0 g and aspartame (Ajinomoto) ) 15.0 g is mixed in a dairy pot, 50 g of purified water is added and kneaded, dried in a shelf-type dryer (MO-921: Toyama Sangyo), sieved with a No. 22 sieve, and magnesium stearate (Taipei). Chemical industry) 2.0 g was mixed to obtain a pre-tablet powder. Then, this powder was tableted with a rotary tableting machine (VELA5: Kikusui Seisakusho) to obtain an orally disintegrating tablet containing linagliptin having a thickness of 4.0 mm and 210.0 mg per tablet.
（実施例１７）
クロスカルメロースナトリウムをカルメロースカルシウム（ＥＣＧ－５０５：ニチリン化学工業）に変更したこと以外、実施例１６と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ４．０ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 17)
In the same method as in Example 16, linagliptin-containing oral disintegration of 210.0 mg and 4.0 mm in thickness, except that croscarmellose sodium was changed to carmellose calcium (ECG-505: Nichirin Chemical Industry). I got a lock.
（実施例１８）
クロスカルメロースナトリウムをカルメロース（ＮＳ－３００：ニチリン化学工業）に変更したこと以外、実施例１６と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ４．０ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 18)
A linagliptin-containing orally disintegrating tablet having a thickness of 4.0 mm and 210.0 mg per tablet was prepared in the same manner as in Example 16 except that the sodium croscarmellose was changed to carmellose (NS-300: Nichirin Chemical Industry Co., Ltd.). Obtained.
（実施例１９）
クロスカルメロースナトリウムをデンプングリコール酸ナトリウム（プリモジェル：ＤＦＥ　Ｐｈａｒｍａ）に変更したこと以外、実施例１６と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ４．１ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 19)
An orally disintegrating tablet containing linagliptin having a thickness of 4.1 mm and 210.0 mg per tablet in the same manner as in Example 16 except that croscarmellose sodium was changed to sodium starch glycolate (Primogel: DFE Pharma). Got
（比較例６）
クロスカルメロースナトリウムをクロスポビドン（ＣＬ－Ｆ：ＢＡＳＦ）に変更したこと以外、実施例１６と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ４．１ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Comparative Example 6)
A linagliptin-containing orally disintegrating tablet having a thickness of 4.1 mm and 210.0 mg per tablet was obtained by the same method as in Example 16 except that croscarmellose sodium was changed to crospovidone (CL-F: BASF). rice field.
（比較例７）
クロスカルメロースナトリウムの代わりにＤ－マンニトールを追加したこと以外、実施例１６と同様の方法で、１錠あたり２１０．０ｍｇ、厚さ４．０ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Comparative Example 7)
A linagliptin-containing orally disintegrating tablet having a thickness of 4.0 mm and 210.0 mg per tablet was obtained by the same method as in Example 16 except that D-mannitol was added in place of sodium croscarmellose.
（実施例２０）
リナグリプチン１０．０ｇ当たり、Ｄ－マンニトール（マンニットＰ：三菱商事ライフサイエンス）２７１．４ｇ、結晶セルロース（セオラスＰＨ１０１：旭化成）３４．０ｇ、低置換度ヒドロキシプロピルセルロース（ＮＢＤ－０２２：信越化学）１７．０ｇ、クロスポビドン（ＣＬ－Ｆ：ＢＡＳＦ）６．８ｇ、クロスポビドン（ＣＬ－Ｍ：ＢＡＳＦ）６．８ｇ、クロスカルメロースナトリウム（キッコレートＮＤ－２ＨＳ：ニチリン化学工業）４０．０ｇ、アスパルテーム（味の素）３０．０ｇを流動層造粒機（ＭＰ－０１：パウレック）で混合後、精製水３００ｇを噴霧して造粒し、乾燥した後、２２号篩で篩過し、ステアリン酸マグネシウム（太平化学産業）４．０ｇを混合して打錠前粉末を得た。その後、本粉末をロータリー打錠機（ＶＥＬＡ５：菊水製作所）にて打錠し、１錠あたり２１０．０ｍｇ、厚さ４．１ｍｍのリナグリプチン含有口腔内崩壊錠を得た。 (Example 20)
Per 10.0 g of linagliptin, D-mannitol (Mannit P: Mitsubishi Corporation Life Science) 271.4 g, crystalline cellulose (Theoras PH101: Asahi Kasei) 34.0 g, low substitution hydroxypropyl cellulose (NBD-022: Shin-Etsu Chemical) 17 0.0 g, crospovidone (CL-F: BASF) 6.8 g, crospovidone (CL-M: BASF) 6.8 g, croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry) 40.0 g, aspartame (Ajinomoto) ) 30.0 g is mixed with a fluidized layer granulator (MP-01: Paulec), then 300 g of purified water is sprayed to granulate, and after drying, it is sieved with a No. 22 sieve and magnesium stearate (Taipei Chemicals). (Industry) 4.0 g was mixed to obtain a pre-tablet powder. Then, this powder was tableted with a rotary tableting machine (VELA5: Kikusui Seisakusho) to obtain an orally disintegrating tablet containing linagliptin having a thickness of 4.1 mm and 210.0 mg per tablet.
（リナグリプチン含有口腔内崩壊錠の製剤物性）
　上述のリナグリプチン含有口腔内崩壊錠は、崩壊時間および官能評価を測定することで製剤物性を評価した。崩壊時間は、第十七改正日本薬局方の崩壊試験法に準じて崩壊時間を測定し、６錠の測定値の結果を算出した。官能評価は、官能試験による苦味を４段階（＋＋＋：非常に苦い、＋＋：苦い、＋：わずかに苦い、±：ほとんど苦くない）で評価し、２錠の測定値の結果を算出した。実施例１６～２０および比較例６、７の崩壊時間（ｓｅｃ）、苦味（官能評価）を表３に示す。 (Physical properties of orally disintegrating tablets containing linagliptin)
The above-mentioned linagliptin-containing orally disintegrating tablets were evaluated for their physical properties by measuring the disintegration time and sensory evaluation. For the disintegration time, the disintegration time was measured according to the disintegration test method of the 17th revised Japanese Pharmacopoeia, and the results of the measured values of 6 tablets were calculated. In the sensory evaluation, the bitterness by the sensory test was evaluated in 4 stages (++++: very bitter, ++: bitter, +: slightly bitter, ±: almost not bitter), and the results of the measured values of 2 tablets were calculated. Table 3 shows the disintegration time (sec) and bitterness (sensory evaluation) of Examples 16 to 20 and Comparative Examples 6 and 7.
Figure JPOXMLDOC01-appb-T000003
  
Figure JPOXMLDOC01-appb-T000003
  
　表３に示すように、崩壊剤としてクロスカルメロースナトリウム、カルメロースカルシウム、カルメロース、またはデンプングリコール酸ナトリウムを加えた実施例１６～２０に係るリナグリプチン含有口腔内崩壊錠はいずれも、実施例５、９、１２、１５と同様に官能評価が良好であった。一方で、崩壊剤としてクロスポピドンを含む比較例６に係るリナグリプチン含有口腔内崩壊錠は、苦味を抑制することができなかった。また崩壊剤を含まない比較例７に係るリナグリプチン含有口腔内崩壊錠は、苦味を抑制することができなかった。本実施形態におけるリナグリプチン含有口腔内崩壊錠の製造方法は、練合法または流動層造粒法でも、直接打錠法と同様の結果が得られることがわかった。崩壊時間にはばらつきがあったが、これは造粒法において通常使用される崩壊剤の量よりも多く、崩壊剤の崩壊性よりも成形性が強く出ていることが原因と考えられる。
  As shown in Table 3, the linagliptin-containing orally disintegrating tablets according to Examples 16 to 20 to which croscarmellose sodium, carmellose calcium, carmellose, or sodium starch glycolate was added as a disintegrant were all in Example 5. Similar to 9, 12, and 15, the sensory evaluation was good. On the other hand, the linagliptin-containing orally disintegrating tablet according to Comparative Example 6 containing crospopidone as a disintegrant could not suppress the bitterness. Further, the linagliptin-containing orally disintegrating tablet according to Comparative Example 7 containing no disintegrant could not suppress the bitterness. It was found that the method for producing the linagliptin-containing orally disintegrating tablet in the present embodiment can be obtained by the kneading method or the fluidized bed granulation method as well as the direct tableting method. The disintegration time varied, but this is thought to be due to the fact that the amount of disintegrant used in the granulation method was larger than that of the disintegrant, and the formability was stronger than the disintegration property of the disintegrant.

Claims (4)

  1. 　リナグリプチンと、
    　カルメロースカルシウム、クロスカルメロースナトリウム、カルメロース、およびデンプングリコール酸ナトリウム、からなる群から選択される一つ以上を含む添加剤と、
    を含有するリナグリプチン含有口腔内崩壊錠。     With linagliptin,
    Additives comprising one or more selected from the group consisting of carmellose calcium, croscarmellose sodium, carmellose, and sodium starch glycolate, and
    Linagliptin-containing orally disintegrating tablet containing.
  2. 　前記添加剤は、カルメロースカルシウム、クロスカルメロースナトリウム、およびカルメロース、からなる群から選択される一つ以上を含む、請求項１に記載のリナグリプチン含有口腔内崩壊錠。 The linagliptin-containing orally disintegrating tablet according to claim 1, wherein the additive comprises one or more selected from the group consisting of carmellose calcium, croscarmellose sodium, and carmellose.
  3. 　前記添加剤は、クロスカルメロースナトリウムである、請求項１に記載のリナグリプチン含有口腔内崩壊錠。 The linagliptin-containing orally disintegrating tablet according to claim 1, wherein the additive is croscarmellose sodium.
  4. 　前記添加剤は、前記リナグリプチン１重量部に対して０．５重量部以上含む請求項２または３に記載のリナグリプチン含有口腔内崩壊錠。
          The linagliptin-containing orally disintegrating tablet according to claim 2 or 3, wherein the additive contains 0.5 part by weight or more with respect to 1 part by weight of the linagliptin.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022192036A (en) * 2021-06-16 2022-12-28 日本ジェネリック株式会社 Linagliptin-containing formulation and linagliptin-containing orally disintegrating tablet

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013161823A1 (en) * 2012-04-24 2013-10-31 第一三共株式会社 Orally disintegrating tablet and method for producing same
EP2848242A1 (en) * 2013-09-12 2015-03-18 Sanovel Ilac Sanayi ve Ticaret A.S. Orally disintegrating formulations of Linagliptin
CN105853382A (en) * 2016-05-19 2016-08-17 广州迈达康医药科技有限公司 Lige column dean orally-disintegrating tablet and preparing method thereof
JP2018530566A (en) * 2015-10-09 2018-10-18 ヘクサル・アクチェンゲゼルシャフトＨｅｘａｌ ＡＧ 8-[(3R) -3-Amino-1-piperidinyl] -7- (2-butyn-1-yl) -3,7-dihydro-3-methyl-1- [4-methyl-2-quinazolinyl) methyl ] -1H-purine-2,6-dione or a pharmaceutical composition containing a pharmaceutically acceptable salt thereof
JP2020158435A (en) * 2019-03-26 2020-10-01 エルメッド株式会社 Linagliptin-containing pharmaceutical composition and method for producing the same, and method for improving the quality of linagliptin-containing pharmaceutical composition

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013161823A1 (en) * 2012-04-24 2013-10-31 第一三共株式会社 Orally disintegrating tablet and method for producing same
EP2848242A1 (en) * 2013-09-12 2015-03-18 Sanovel Ilac Sanayi ve Ticaret A.S. Orally disintegrating formulations of Linagliptin
JP2018530566A (en) * 2015-10-09 2018-10-18 ヘクサル・アクチェンゲゼルシャフトＨｅｘａｌ ＡＧ 8-[(3R) -3-Amino-1-piperidinyl] -7- (2-butyn-1-yl) -3,7-dihydro-3-methyl-1- [4-methyl-2-quinazolinyl) methyl ] -1H-purine-2,6-dione or a pharmaceutical composition containing a pharmaceutically acceptable salt thereof
CN105853382A (en) * 2016-05-19 2016-08-17 广州迈达康医药科技有限公司 Lige column dean orally-disintegrating tablet and preparing method thereof
JP2020158435A (en) * 2019-03-26 2020-10-01 エルメッド株式会社 Linagliptin-containing pharmaceutical composition and method for producing the same, and method for improving the quality of linagliptin-containing pharmaceutical composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NAKAGAWA, TOMOYA ET AL.: "Drug Development Research with Taste Sensor, Part 2: Taste Masking and Formulation Development of Donepezil Hydrochloride OD Tablets", PHARM TECH JAPAN, vol. 28, no. 3, 1 January 2012 (2012-01-01), JP , pages 511 - 517, XP009536655, ISSN: 0910-4739 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022192036A (en) * 2021-06-16 2022-12-28 日本ジェネリック株式会社 Linagliptin-containing formulation and linagliptin-containing orally disintegrating tablet
JP7210794B2 (en) 2021-06-16 2023-01-23 日本ジェネリック株式会社 Preparations containing linagliptin and orally disintegrating tablets containing linagliptin

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