Rapidly disintegrating oral tablet for treatment of diabetes

Abstract

To provide a rapidly disintegrating oral tablet containing a high concentration of teneligliptin and having sufficient hardness for handling.SOLUTION: The present invention relates to a rapidly disintegrating oral tablet comprising: a teneligliptin granule containing a high concentration of teneligliptin or a salt thereof, or a solvate thereof, a binder, and an aggregation inhibitor; and a drug-excluded part including a pharmaceutically acceptable additive.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an orally disintegrating tablet containing teneligliptin or a salt thereof, or a solvate thereof as an active ingredient.

Background Art

[0002] Providing a formulation that is easy to take for the elderly and patients with difficulty in swallowing is considered to lead to an improvement in Quality of Life and an improvement in medication compliance. In particular, orally disintegrating tablets not only are easy to take, but also the possibility of launching new products is increased by demonstrating biological equivalence with already approved formulations, and thus many products are being developed. In addition, since orally disintegrating tablets also have the advantage of reducing dispensing operations such as grinding and suspension in the clinical field, it leads to the need for orally disintegrating tablets.

[0003] Teneligliptin (chemical name: {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone) or a salt thereof has been reported to exhibit DPP-IV inhibitory activity and be useful in the treatment or prevention of diabetes and the like (see Patent Documents 1 and 2).

[0004] As a formulation method of a solid preparation containing teneligliptin or a salt thereof, or a solvate thereof (hereinafter sometimes abbreviated as a teneligliptin-containing solid preparation), it is known to mix teneligliptin or a salt thereof, or a solvate thereof with a general pharmaceutical carrier and formulate it (see Patent Documents 1 and 2). However, there are no reported examples of formulation methods for orally disintegrating tablets containing teneligliptin or a salt thereof, or a solvate thereof.

[0005] Patent Document 3 discloses an orally disintegrating tablet produced by mixing and molding soluble particles containing a highly soluble drug at a high concentration with a fast-disintegrating component. However, information on the soluble particles containing a highly soluble drug is limited, and no formulation or manufacturing method for obtaining high-concentration particles of teneligliptin or its salt, or its solvate, is disclosed.

[0006] Regarding particles containing a high concentration of teneligliptin, Patent Document 4 discloses a teneligliptin-containing solid preparation that independently contains a teneligliptin-containing portion containing teneligliptin hydrobromide monohydrate at a content rate of 30 to 80% by weight and one or more excipients selected from D-mannitol, sorbitol, and xylitol in a portion other than the teneligliptin-containing portion, and the teneligliptin-containing solid preparation in which the teneligliptin-containing portion is granular or particulate. However, Patent Document 4 states that when the teneligliptin content rate in the granular or particulate solid that is the teneligliptin-containing portion is higher than 80% by weight, there is a concern about insufficient strength for maintaining a solid shape such as a particulate state, and it cannot be denied that manufacturing problems may occur.

[0007] While the development of orally disintegrating tablets that improve patient convenience is desired, the development of orally disintegrating tablets containing teneligliptin or its salt, or its solvate, is similarly desired.

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0009] An object of the present invention is to provide an orally disintegrating tablet that contains teneligliptin or a salt thereof, or a solvate thereof as an active ingredient, contains teneligliptin at a high concentration, and has sufficient hardness for handling.

Means for Solving the Problems

[0010] The present inventors conducted studies to obtain an orally disintegrating tablet containing teneligliptin or a salt thereof, or a solvate thereof as an active ingredient. However, due to the properties of this compound that prevent the penetration of moisture into the tablet interior, a problem was found that the disintegration time was significantly delayed. Therefore, in order to solve this problem, the inventors focused on reducing the properties of this compound and conducted intensive research. However, with the conventional method of uniformly mixing this compound in the tablet, the inventors faced the problem that the desired disintegration time could not be achieved due to the properties of this compound. One way to solve this problem is to reduce the concentration of this compound in the tablet, but this may lead to an increase in the size of the tablet and a new problem of reducing the usability of the preparation.

[0011] As a result of intensive studies, the present inventors tried to obtain granules containing this compound at a high concentration in order to reduce the properties of this compound. However, during the production of the granules, aggregation of the powder occurred due to the adhesion and aggregation properties of this compound, and the desired granules could not be produced. Therefore, as a result of intensive studies, the inventors found a combination of formulations containing an aggregation inhibitor that suppresses the aggregation tendency of the powder derived from the adhesion and aggregation properties of this compound, and found that the problem can be solved by incorporating the granules containing a high content of this compound into the tablet. In addition, as a method for further reducing the properties of this compound and improving the disintegration property of the tablet, the inventors found that the problem can also be solved by coating the granules containing this compound at a high concentration and including them in the tablet.

[0012] As a result, an orally disintegrating tablet having an increased concentration of this compound in the tablet and a desired disintegration time was found.

[0013] That is, the present invention is as follows. [1] An orally disintegrating tablet comprising teneligliptin granules containing teneligliptin or a salt thereof, or a solvate thereof, a binder, and an aggregation inhibitor, and a drug-free portion containing a pharmaceutically acceptable additive. [2] The orally disintegrating tablet according to [1] above, wherein the teneligliptin granules contain teneligliptin or a salt thereof, or a solvate thereof, in a mass not containing a coating base, in an amount of 45% by mass to 99% by mass. [3] The orally disintegrating tablet according to [1] or [2] above, wherein the teneligliptin granules contain teneligliptin or a salt thereof, or a solvate thereof, in a mass not containing a coating base, in an amount of 80% by mass to 99% by mass. [4] The orally disintegrating tablet according to any one of [1] to [3] above, wherein the binder is one or more selected from hydroxypropyl cellulose, ethyl cellulose, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, hypromellose, isomalt, and aminomethacrylate copolymer. [5] The orally disintegrating tablet according to any one of [1] to [4] above, wherein the aggregation inhibitor is one or more selected from lubricants, suspending agents, brightening agents, antistatic agents, dispersants, and fluidizing agents. [6] The orally disintegrating tablet according to [5] above, wherein the aggregation inhibitor is a fluidizing agent. [7] The orally disintegrating tablet according to [6] above, wherein the fluidizing agent is one or more selected from light anhydrous silicic acid and hydrous silicon dioxide. [8] The orally disintegrating tablet according to any one of [1] to [7] above, wherein the teneligliptin granules in the orally disintegrating tablet are in an amount of 10% by mass to 60% by mass per tablet of the orally disintegrating tablet in a mass not containing a coating base. [9] The orally disintegrating tablet according to any one of [1] to [8] above, wherein the teneligliptin granules further contain a coating base.

[10] The orally disintegrating tablet according to [9] above, wherein the teneligliptin granules are coated with a coating base.

[11] The orally disintegrating tablet according to [9] or

[10] above, wherein the coating base is a water-insoluble polymer.

[12] The orally disintegrating tablet according to

[11] above, wherein the water-insoluble polymer is at least one selected from ethyl cellulose, polyvinyl acetal diethylaminoacetate, and aminomethacrylate copolymer.

[13] The orally disintegrating tablet according to any one of [1] to

[12] above, wherein the drug-free portion contains at least an excipient, a disintegrant, or a lubricant.

[14] The orally disintegrating tablet according to

[13] above, wherein the disintegrant is at least one selected from low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, and sodium carboxymethyl starch.

[15] The orally disintegrating tablet according to any one of [1] to

[14] above, wherein the drug-free portion contains a sweetening agent or a flavoring agent.

[16] An orally disintegrating tablet comprising teneligliptin or a salt thereof, or a solvate thereof, in a mass not containing a coating base of 70% by mass to 99% by mass, a binder and an aggregation inhibitor, and further teneligliptin granules coated with a coating base, and a drug-free portion containing a disintegrant and a pharmaceutically acceptable additive.

[17] The orally disintegrating tablet according to

[16] above, wherein the teneligliptin granules contain teneligliptin or a salt thereof, or a solvate thereof, in a mass not containing a coating base of 80% by mass to 99% by mass.

[18] A method for producing an orally disintegrating tablet, comprising: 1) A step of obtaining teneligliptin granules by mixing teneligliptin or a salt thereof, or a solvate thereof, in a mass not containing a coating base of 45% by mass to 99% by mass, a binder, and an aggregation inhibitor, and granulating; 2) A step of mixing the granules with a pharmaceutically acceptable additive to obtain granules for tableting; and 3) Compressing and molding the granules for tableting to obtain an orally disintegrating tablet; The method for producing an orally disintegrating tablet according to any one of the above [1] to

[17] , comprising the above steps.

[19] The step of obtaining the teneligliptin granules comprises granulating teneligliptin or a salt thereof, or a solvate thereof, in a mass not containing a coating base, in an amount of 45% by mass to 99% by mass, a binder, an aggregation inhibitor, and a coating base, and mixing them. The method for producing an orally disintegrating tablet according to the above

[18] .

[20] The step of obtaining the teneligliptin granules comprises granulating teneligliptin or a salt thereof, or a solvate thereof, in a mass not containing a coating base, in an amount of 45% by mass to 99% by mass, a binder, and an aggregation inhibitor, and then coating with a coating base. The method for producing an orally disintegrating tablet according to the above

[19] . [Advantages of the Invention]

[0014] An orally disintegrating tablet containing teneligliptin or a salt thereof, or a solvate thereof as an active ingredient and rapidly disintegrating in the oral cavity has not been found so far, and its formulation and production method have not been known. According to the present invention, it is possible to provide a teneligliptin-containing orally disintegrating tablet containing teneligliptin granules containing a high concentration of an active ingredient, having sufficient hardness for handling, and rapidly disintegrating in the oral cavity. [Embodiments for Carrying out the Invention]

[0015] Hereinafter, the present invention will be described in detail.

[0016] The present invention is an orally disintegrating tablet comprising teneligliptin granules containing teneligliptin or a salt thereof, or a solvate thereof, in a mass not containing a coating base, in an amount of 45% by mass to 99% by mass, a binder, and an aggregation inhibitor, and a drug-free portion containing a pharmaceutically acceptable additive.

[0017] The teneligliptin granules of the present invention are granular or particulate solids containing at least teneligliptin or a salt thereof, or a solvate thereof, a binder, and an aggregation inhibitor. The content of teneligliptin or a salt thereof, or a solvate thereof, is 45 to 99% by mass, preferably 70 to 99% by mass, more preferably 80 to 99% by mass, still more preferably 95 to 99% by mass, based on 100% by mass of the granules, excluding the coating base.

[0018] Teneligliptin or a salt thereof, or a solvate thereof, contained in the teneligliptin granules is a known compound described in International Publication No. 2002 / 014271 (Patent Document 1) and International Publication No. 2006 / 088129 (Patent Document 2), and can be synthesized by the methods described in these documents. Teneligliptin or a salt thereof, or a solvate thereof, used in the orally disintegrating tablets of the present invention is preferably teneligliptin hydrobromide hydrate, more preferably teneligliptin 5 / 2 hydrobromide hydrate, and still more preferably 1.0 to 2.0 hydrates of teneligliptin 5 / 2 hydrobromide.

[0019] The binder that can be formulated in the teneligliptin granules of the present invention is not particularly limited as long as granules containing teneligliptin or a salt thereof, or a solvate thereof, can be obtained, and is any binder generally used in pharmaceutical preparations. Specific examples of such binders include, for example, hydroxypropyl cellulose, polyvinyl alcohol, povidone, hypromellose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, polyvinyl acetal diethylaminoacetate, methacrylic acid copolymer, isomalt, aminomethacrylate copolymer, and the like. Preferred are hydroxypropyl cellulose, polyvinyl alcohol, hypromellose, ethylcellulose, polyvinyl acetal diethylaminoacetate, isomalt, or aminomethacrylate copolymer, and more preferred are polyvinyl alcohol or ethylcellulose.

[0020] In the teneligliptin granules, the binder can be formulated in the range of, for example, 0.5% by mass to 20% by mass, preferably in the range of 0.5% by mass to 10% by mass, more preferably in the range of 0.5% by mass to 5% by mass, based on 100% by mass of the granules.

[0021] The anti-aggregation agent that can be formulated in the teneligliptin granules of the present invention is not particularly limited as long as it can suppress the adhesion and aggregation of teneligliptin or its salt, or its solvate, that is, adhesion to manufacturing equipment and aggregation of the powder. Examples thereof include lubricants, suspending agents, brightening agents, antistatic agents, dispersants, fluidizing agents, and the like. The anti-aggregation agent is preferably a lubricant, an antistatic agent, a dispersant, or a fluidizing agent, and more preferably a fluidizing agent.

[0022] In the teneligliptin granules, the anti-aggregation agent can be formulated in the range of, for example, 0.1% by mass to 10% by mass, preferably in the range of 0.1% by mass to 7.5% by mass, more preferably in the range of 0.1% by mass to 5% by mass, based on 100% by mass of the granules.

[0023] Among the anti-aggregation agents that can be formulated in the teneligliptin granules of the present invention, examples of the lubricant include sodium stearyl fumarate, talc, alkaline earth metal stearates (e.g., magnesium stearate, calcium stearate, etc.), sucrose higher fatty acid esters, glycerin higher fatty acid esters, hydrogenated oils, and the like. Preferably, it is magnesium stearate, calcium stearate, sodium stearyl fumarate, or talc, and more preferably sodium stearyl fumarate.

[0024] Among the aggregation inhibitors that can be formulated in the teneligliptin granules of the present invention, suspending agents include, for example, gum arabic, gum arabic powder, alkylbenzene sulfonate type powder, sodium alginate, propylene glycol alginate, sodium erythorbate, calcium chloride hydrate, sodium chloride, oleic acid, kaolin, carrageenan, carnauba wax, carboxyvinyl polymer, carmellose, carmellose calcium, carmellose sodium, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, citric acid hydrate, glycine, glycerin, glycerin fatty acid ester, magnesium aluminum silicate, crystalline cellulose, crystalline cellulose - carmellose sodium, hydrogenated oil, white beeswax, titanium oxide, dioctyl sodium sulfosuccinate, dimethyl polysiloxane - silicon dioxide mixture, sucrose fatty acid ester, potassium hydroxide, sodium hydroxide, stearyl alcohol, aluminum stearate, polyoxyl stearate, purified gelatin, cetyl alcohol, cetomacrogol 1000, sorbitan fatty acid ester, sorbitan sesquioleate, p - sorbitol, soybean lecithin, simple syrup, tragacanth, tragacanth powder, sorbitan trioleate, lactose hydrate, veegum neutral, hydroxypropyl cellulose, propylene glycol, propylene glycol fatty acid ester, pectin, benzalkonium chloride, benzyl alcohol, bentonite, povidone (K25), povidone (K30), povidone (K90), polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene nonylphenyl ether, polyoxyethylene nonylphenyl ether - calcium alkylbenzene sulfonate mixture, polyoxyethylene (160) polyoxypropylene (30) glycol, sodium polystyrene sulfonate, polysorbate 20, polysorbate 60, polysorbate 80, sodium polyphosphate, macrogol 4000, macrogol 6000, D - mannitol, beeswax, isopropyl myristate, magnesium aluminum metasilicate, methyl cellulose, methylene - β - naphthalene sulfonate sodium copolymer, ethylene glycol monostearate, sorbitan monostearate,Examples include polyoxyethylene sorbitol monostearate, peanut oil, liquid paraffin, phosphoric acid, calcium hydrogen phosphate hydrate, etc.

[0025] Among the anti-aggregation agents that can be formulated in the teneligliptin granules of the present invention, the brightening agents include, for example, candelilla wax, carnauba wax, carboxymethyl cellulose calcium, fish scale foil, light anhydrous silicic acid, light liquid paraffin, hard wax, beeswax, titanium oxide, dimethylpolysiloxane, dimethylpolysiloxane - silicon dioxide mixture, stearic acid, calcium stearate, polyoxyl stearate, magnesium stearate, purified shellac, purified sugar, purified paraffin - carnauba wax mixed wax, cetyl alcohol, gelatin, talc, gold leaf, paraffin, isopropyl palmitate, hydroxypropyl cellulose, castor oil, polyethylene glycol 8000, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, beeswax, isopropyl myristate, medicinal charcoal, sodium lauryl sulfate, liquid paraffin, rosin, etc.

[0026] Among the anti-aggregation agents that can be formulated in the teneligliptin granules of the present invention, the antistatic agents include, for example, light anhydrous silicic acid, hydrated silicon dioxide, talc, etc. Preferably, it is light anhydrous silicic acid or hydrated silicon dioxide.

[0027] Among the aggregation inhibitors that can be formulated in the teneligliptin granules of the present invention, examples of the dispersant include gum arabic, powdered gum arabic, alkylbenzene sulfonate type emulsifier, propylene glycol alginate, ammonioalkyl methacrylate copolymer, oleic acid, carboxyvinyl polymer, sodium carboxymethylcellulose, dried egg white, agar powder, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light aluminum oxide, crystalline cellulose, crystalline cellulose - sodium carboxymethylcellulose, hydrogenated oil, synthetic aluminum silicate, choline phosphate, safflower oil, white beeswax, zinc oxide, titanium oxide, dioctyl sodium sulfosuccinate, sucrose fatty acid ester, lipophilic glycerol monostearate, sodium hydroxide, stearic acid, zinc stearate, polyoxyl stearate, magnesium stearate, purified oleic acid, purified soy lecithin, sodium cetyl sulfate, hydrophobic light anhydrous silicic acid, sorbitan fatty acid ester, sorbitan sesquioleate, p - sorbitol, soybean oil, soy lecithin, low - degree - substitution hydroxypropyl cellulose, dextrin, sodium starch glycolate, corn starch, tragacanth powder, sorbitan trioleate, lactose hydrate, concentrated glycerin, potato starch, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose (2910), propylene glycol, propylene glycol fatty acid ester, Peru balsam, benzethonium chloride, bentonite, povidone (K25), povidone (K30), povidone (K90), polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene nonylphenyl ether polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene lanolin alcohol ether (5E.O.) Microcrystalline wax, Macrogol 300, Macrogol 4000, Macrogol 6000, Isopropyl myristate, Sodium citrate anhydrous, Sodium pyrophosphate anhydrous, Lauryl methacrylate, Magnesium aluminometasilicate, Sodium metaphosphate, Mocrowax, Glycerin monooleate, Sorbitan monooleate, Aluminum monostearate, Glycerin monostearate, Sorbitan monostearate, Polyoxyethylene sorbitan monostearate, Sorbitan monopalmitate, Sorbitan monolaurate, Sodium lauryl sulfate, Lauromacrogol, Lanolin alcohol, Egg yolk oil, Egg yolk phospholipid, Sodium lignin sulfonate, Zinc sulfate hydrate, Liquid paraffin, Calcium hydrogen phosphate hydrate, Sodium polyoxyethylene lauryl ether phosphate, etc. can be mentioned.

[0028] Among the anti-aggregation agents that can be formulated in the teneligliptin granules of the present invention, fluidizing agents include, for example, light anhydrous silicic acid, hydrous silicon dioxide, talc, crystalline cellulose, synthetic aluminum silicate, titanium oxide, heavy anhydrous silicic acid, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, corn starch, magnesium aluminometasilicate, calcium hydrogen phosphate granule, sodium stearyl fumarate, sucrose fatty acid ester, glycerin fatty acid ester, hydrogenated castor oil, hydrogenated rapeseed oil, carnauba wax, etc. Preferably, it is light anhydrous silicic acid or hydrous silicon dioxide.

[0029] The teneligliptin granules can contain pharmaceutically acceptable additives (hereinafter sometimes referred to as "additives in the granules"). Additives that can be formulated in the granules include, in addition to binders and anti-aggregation agents, sweeteners, plasticizers, flavoring agents, fragrances, disintegrants, excipients, etc.

[0030] The sweeteners that can be formulated in the teneligliptin granules of the present invention are specifically, for example, aspartame, saccharin, sodium saccharin, acesulfame potassium, sucralose, stevia, thaumatin, etc. Preferably, it is acesulfame potassium. In the teneligliptin granules, the sweetener can be formulated in the range of 0.1% by mass to 10% by mass, preferably 0.5% by mass to 8% by mass, more preferably 1% by mass to 5% by mass, based on 100% by mass of the granules.

[0031] The plasticizers that can be formulated in the teneligliptin granules of the present invention are specifically, for example, polyethylene glycol, triacetin, triethyl citrate, etc. Preferably, it is triethyl citrate. In the teneligliptin granules, the plasticizer can be formulated in the range of 0.5% by mass to 12.5% by mass, preferably 1.5% by mass to 10% by mass, more preferably 2.5% by mass to 7.5% by mass, based on 100% by mass of the granules.

[0032] The flavor correctives that can be formulated in the teneligliptin granules of the present invention are specifically, for example, l-menthol, sodium chloride, sodium citrate, monosodium glutamate, sodium bicarbonate, Venecote (registered trademark), malic acid, etc. In the teneligliptin granules, the flavor corrective can be formulated in the range of 0.1% by mass to 15% by mass, preferably 0.5% by mass to 10% by mass, more preferably 1% by mass to 5% by mass, based on 100% by mass of the granules.

[0033] The flavors that can be incorporated into the teneligliptin granules of the present invention are specifically, for example, peppermint oil, orange oil, yuzu flavor, strawberry flavor, lemon flavor, menthol flavor, orange flavor, and the like. In the teneligliptin granules, the flavor can be incorporated in an amount of 0.01% by mass to 5% by mass, preferably 0.01% by mass to 3% by mass, more preferably 0.01% by mass to 1% by mass, based on 100% by mass of the granules.

[0034] The disintegrants that can be incorporated into the teneligliptin granules of the present invention are specifically, for example, celluloses such as calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium, and crystalline cellulose; starches such as corn starch, pregelatinized starch, and sodium carboxymethyl starch; and crospovidone and the like. Preferably, they are croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone, sodium carboxymethyl starch, or carboxymethylcellulose, and more preferably, they are croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, or crospovidone. In the teneligliptin granules, the disintegrant can be incorporated in an amount of 0.1% by mass to 20% by mass, preferably 0.5% by mass to 15% by mass, more preferably 1% by mass to 10% by mass, based on 100% by mass of the granules.

[0035] The teneligliptin granules of the present invention are preferably further coated with a coating base. The coating base that can be blended in the teneligliptin granules is not particularly limited as long as it is pharmaceutically acceptable and has the property of suppressing the elution of the drug in the oral cavity and suppressing bitterness by coating the drug. Specifically, water-insoluble polymers can be mentioned. Specific examples of the water-insoluble polymer preferably include ethyl cellulose, methyl cellulose, polyvinyl acetal diethylaminoacetate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, or an amino methacrylate copolymer, and more preferably ethyl cellulose. In the teneligliptin granules, the coating base can be blended in an amount in the range of, for example, 10% by mass to 50% by mass, preferably 20% by mass to 40% by mass, based on 100% by mass of teneligliptin or a salt thereof, or a solvate thereof contained in the granules.

[0036] In addition to coating the teneligliptin granules, the coating base may also be contained in the granules. Further, the plasticizer may be contained together with the coating base.

[0037] The volume average particle diameter (hereinafter referred to as "D50") of the teneligliptin granules of the present invention preferably maintains dispersibility in an orally rapidly disintegrating tablet. Specifically, those having a D50 of 350 μm or less and a particle size of 90% or more of the particles being 500 μm or less are preferred, and more preferably those having a D50 of 250 μm or less and a particle size of 90% or more of the particles being 350 μm or less.

[0038] As used herein, the term "volume average particle diameter" refers to the average particle diameter of the volume conversion value of particles. In principle, particles of a certain volume are sieved in ascending order of size, and it means the particle diameter at the time when the particles corresponding to 50% of the volume are separated. The measurement of the volume average particle diameter can be carried out according to the usual methods in the relevant technical field. For example, actual measurement by microscopic observation, methods using electrical or optical particle diameter measuring devices, etc. can be mentioned. In particular, for the measurement of the volume average particle diameter of powders with a particle diameter of several tens to several hundreds of μm, mainly, methods such as sieving method, or methods of measuring by using diffracted light or scattered light after dispersing in a medium are used. The sieving method is a method in which a plurality of sieves with different mesh sizes are used, stacked so that the sieve with the larger mesh size is on the upper layer, the powder to be measured is put into the uppermost layer, vibration is applied manually or mechanically, the amount of powder remaining on each sieve is measured, and the weight fraction is calculated.

[0039] The teneligliptin granules of the present invention are contained in, for example, the range of 10 mass percent to 60 mass percent, preferably in the range of 15 mass percent to 45 mass percent, and more preferably in the range of 20 mass percent to 35 mass percent per orally disintegrating tablet.

[0040] In the orally disintegrating tablet of the present invention, the teneligliptin granules are contained, and the teneligliptin granules and the other part (hereinafter, may be referred to as "drug-free part") are not mixed, and the teneligliptin granules and the drug-free part exist independently.

[0041] The drug-free part preferably has a faster disintegration rate than the teneligliptin granules and disintegrates without delay in the administration subject.

[0042] The drug-free portion of the present invention does not contain teneligliptin or its salt, or its solvate, and has the property of rapidly disintegrating in the oral cavity, which is a characteristic of the orally disintegrating tablets of the present invention. Without impairing the physical strength required to prevent breakage during the processes of manufacture, distribution, and dispensing, as long as the content rate of teneligliptin or its salt, or its solvate can be adjusted to a desired level, there are no particular restrictions. Examples of the components constituting such a drug-free portion include pharmaceutically acceptable additives. Examples of pharmaceutically acceptable additives include disintegrants, excipients, binders, lubricants, fluidizing agents, sweeteners, flavoring agents, fragrances, coloring agents, etc. Preferably, they are disintegrants, excipients, binders, lubricants, sweeteners, fragrances, or coloring agents.

[0043] The disintegrant that can be incorporated into the drug-free portion of the present invention is any disintegrant generally used in pharmaceutical preparations. Incorporating a disintegrant in addition to the orally disintegrating tablets helps to impart the effect of more rapid disintegration of the tablets in the oral cavity. Examples of such disintegrants include celluloses such as calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium, and crystalline cellulose; starches such as corn starch, pregelatinized starch, and sodium carboxymethyl starch; and crospovidone. Preferably, they are croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone, or carboxymethylcellulose, and more preferably, they are croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, or crospovidone. The disintegrant can be incorporated in an amount, for example, in the range of 0.1% by mass to 40% by mass, preferably in the range of 1% by mass to 30% by mass, and more preferably in the range of 1% by mass to 20% by mass, based on 100% by mass of the orally disintegrating tablets.

[0044] The excipients that can be formulated in the drug-free part of the present invention are any excipients generally used in pharmaceutical preparations. Such excipients include, for example, sugar alcohols or saccharides such as mannitol, xylitol, erythritol, maltitol, sorbitol, lactose, sucrose, maltose, trehalose, crystalline cellulose, and starches. Mannitol, erythritol, and lactose are preferred, and mannitol is more preferred. Also, as the excipient, an excipient with good wettability in water can preferably be used. Here, the excipients corresponding to the following definition correspond to excipients with good wettability in water. That is, when the wetting time of the tablet obtained by compressing and molding the excipient with a flat pestle with a diameter of 10 mm under a tableting pressure of 1000 kgf / pestle is measured by the operation described in International Publication No. 2010 / 061846, if the wetting time is within 300 seconds, the excipient corresponds to an excipient with good wettability in water. Examples of the excipient with good wettability in water include one or more sugar alcohols or saccharides selected from the group consisting of mannitol, erythritol, and xylitol, and mannitol is preferred. The excipient can be formulated in the range of, for example, 20% to 80% by mass, preferably 25% to 75% by mass, and more preferably 30% to 70% by mass, based on 100% by mass of the orally disintegrating tablet.

[0045] The binder that can be formulated in the drug-free portion of the present invention is any binder generally used in pharmaceutical preparations, and is preferable for enhancing the hardness of the orally disintegrating tablets and imparting sufficient hardness for handling. Examples of such binders include hydroxypropyl cellulose, polyvinyl alcohol, povidone, hypromellose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, isomalt, and the like. Preferably, it is hydroxypropyl cellulose, ethyl cellulose, polyvinyl alcohol, or povidone, and more preferably, it is ethyl cellulose or polyvinyl alcohol. The binder can be formulated in the range of, for example, 0.01% by mass to 15% by mass, preferably 0.05% by mass to 10% by mass, and more preferably 0.1% by mass to 5% by mass with respect to 100% by mass of the orally disintegrating tablets.

[0046] The lubricant that can be formulated in the drug-free portion of the present invention is any lubricant generally used in pharmaceutical preparations, and is preferable for enhancing the manufacturability during tableting of the orally disintegrating tablets. Examples of such lubricants include sodium stearyl fumarate, talc, alkaline earth metal stearates (e.g., magnesium stearate, calcium stearate, etc.), sucrose higher fatty acid esters, glycerin higher fatty acid esters, hydrogenated oils, and the like. Preferably, it is magnesium stearate, calcium stearate, sodium stearyl fumarate, or talc, and more preferably, it is sodium stearyl fumarate. The lubricant can be formulated in the range of, for example, 0.1% by mass to 15% by mass, preferably 0.1% by mass to 10% by mass, and more preferably 0.5% by mass to 5% by mass with respect to 100% by mass of the orally disintegrating tablets.

[0047] The fluidizing agents that can be formulated in the drug-free portion of the present invention are preferred for improving the fluidity of granules. Specifically, for example, light anhydrous silicic acid, hydrous silicon dioxide, talc, crystalline cellulose, synthetic aluminum silicate, titanium oxide, heavy anhydrous silicic acid, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, corn starch, magnesium aluminometasilicate, calcium hydrogen phosphate granules, sodium stearyl fumarate, sucrose fatty acid ester, glycerin fatty acid ester, hydrogenated castor oil, hydrogenated rapeseed oil, carnauba wax, etc. may be mentioned. Preferably, they are light anhydrous silicic acid or hydrous silicon dioxide. The fluidizing agent can be formulated in the range of, for example, 0.1% by mass to 10% by mass, preferably 0.1% by mass to 7.5% by mass, more preferably 0.1% by mass to 5% by mass, based on 100% by mass of the orally disintegrating tablets.

[0048] The sweetening agent that can be formulated in the drug-free portion of the present invention is not particularly limited as long as it is usually used for imparting sweetness to pharmaceutical compositions. For example, aspartame, saccharin, sodium saccharin, acesulfame potassium, sucralose, stevia, thaumatin, etc. can be mentioned. The sweetening agent can be formulated in the range of, for example, 0.1% by mass to 10% by mass, preferably 0.3% by mass to 7.5% by mass, more preferably 0.5% by mass to 5% by mass, based on 100% by mass of the orally disintegrating tablets.

[0049] The flavoring agent that can be formulated in the drug-free part of the present invention is not particularly limited as long as it is usually used for reducing the bitterness of the active ingredient. For example, l-menthol, sodium chloride, sodium citrate, sodium glutamate, sodium bicarbonate, Benecote (registered trademark), malic acid, etc. can be mentioned. The flavoring agent can be formulated in the range of, for example, 0.1% by mass to 10% by mass, preferably 0.3% by mass to 7.5% by mass, more preferably 0.5% by mass to 5% by mass with respect to 100% by mass of the orally disintegrating tablet.

[0050] The fragrance that can be formulated in the drug-free part of the present invention includes, for example, peppermint oil, orange oil, yuzu flavor, strawberry flavor, lemon flavor, menthol flavor, orange flavor, etc. The fragrance can be formulated in the range of, for example, 0.01% by mass to 10% by mass, preferably 0.01% by mass to 5% by mass, more preferably 0.01% by mass to 1% by mass with respect to 100% by mass of the orally disintegrating tablet.

[0051] The coloring agent that can be formulated in the drug-free part of the present invention includes, for example, Food Red No. 2, No. 3, Food Yellow No. 4, No. 5, Food Blue No. 1, No. 2, their aluminum lakes, iron sesquioxide, yellow iron sesquioxide, titanium oxide, etc. The coloring agent can be formulated in the range of, for example, 0.01% by mass to 10% by mass, preferably 0.01% by mass to 5% by mass, more preferably 0.01% by mass to 1% by mass with respect to 100% by mass of the orally disintegrating tablet.

[0052] As an additive that can be incorporated into the drug-free portion of the present invention, a premix product sold by an additive manufacturer can also be used. The additives contained in the premix product include, for example, a disintegrant, an excipient or a binder. Specifically, the disintegrant includes low-substituted hydroxypropyl cellulose, the excipient includes D-mannitol, and the binder includes polyvinyl alcohol. Examples of the premix product include Smart EX sold by Shin-Etsu Chemical Co., Ltd. The premix product is, for example, 50 mass percent to 85 mass percent, preferably 55 mass percent to 80 mass percent, more preferably 60 mass percent to 75 mass percent, based on 100 mass percent of the orally disintegrating tablets.

[0053] Furthermore, it is also preferable that the drug-free portion further contains a water-insoluble polymer in order to enhance the hardness of the orally disintegrating tablet. The water-insoluble polymer refers to any water-insoluble polymer having functions such as acting as a binder for tablets to impart sufficient hardness for handling and not reducing the wettability of excipients in parts other than granules in the tablets. For example, those described in International Publication No. 2010 / 061846 can be used. Examples of such water-insoluble polymers include hydroxypropyl methylcellulose acetate succinate (e.g., HPMC-AS / Shin-Etsu Chemical), methacrylic acid copolymer S (e.g., Eudragit® S / Röhm), methacrylic acid copolymer L (e.g., Eudragit® L / Röhm), carboxymethyl ethyl cellulose (e.g., CMEC / Sanyo Chemical Industries), ethyl cellulose (e.g., Ethocel® / Dow Chemical), hydroxypropyl methylcellulose phthalate (e.g., HP-50 / Shin-Etsu Chemical), polyvinyl acetal diethylaminoacetate, amino methacrylate copolymer (e.g., Eudragit® RS or RL / Röhm), and the like. Preferably, it is ethyl cellulose, polyvinyl acetal diethylaminoacetate, or amino methacrylate copolymer, and more preferably ethyl cellulose. The water-insoluble polymer can be blended in the range of, for example, 1 mass percent to 20 mass percent, preferably 1 mass percent to 15 mass percent, and more preferably 1 mass percent to 10 mass percent based on 100 mass percent of the orally disintegrating tablet.

[0054] As described above, the drug-free portion of the present invention is not particularly limited, but other additives can also be further blended. Examples of such additives include pH adjusters such as citrate and carbonate; solubilizers such as sodium lauryl sulfate and sorbitan monostearate; and dissolution aids such as arginine and lysine.

[0055] The orally disintegrating tablet of the present invention contains teneligliptin or a salt thereof, or a solvate thereof, a teneligliptin granule containing a binder and an aggregation inhibitor, and a drug-free portion, and can be produced by a usual method for producing tablets without using special tablet production equipment but with ordinary tablet production equipment.

[0056] The orally disintegrating tablet of the present invention can be produced, for example, by the following steps: 1) A step of obtaining teneligliptin granules by mixing teneligliptin or a salt thereof, or a solvate thereof (e.g., teneligliptin hydrobromide hydrate) in a mass not containing a coating base at 45% by mass to 99% by mass, a binder, and an aggregation inhibitor and granulating; 2) A step of mixing the granules with a pharmaceutically acceptable additive to obtain granulation for tableting; and 3) A step of compression molding the granulation for tableting to obtain an orally disintegrating tablet. It can be produced by a method including the above steps.

[0057] Also, the step of obtaining the teneligliptin granules can be produced by a method including mixing teneligliptin or a salt thereof, or a solvate thereof in a mass not containing a coating base at 45% by mass to 99% by mass, a binder, an aggregation inhibitor, and a coating base and granulating.

[0058] Also, the step of obtaining the teneligliptin granules can be produced by a method including mixing teneligliptin or a salt thereof, or a solvate thereof in a mass not containing a coating base at 45% by mass to 99% by mass, a binder, and an aggregation inhibitor, granulating, and then coating with a coating base.

[0059] The step of obtaining the teneligliptin granules is carried out according to a method known in the technical field of pharmaceutical preparations, and includes at least teneligliptin or its salt, or its solvate, a binder, and an aggregation inhibitor. For example, wet granulation can be carried out using a fluidized bed granulation method, and the obtained granules can be dried to be produced in a granular form or the like. The teneligliptin granules thus obtained have a strength that can exist independently in the orally disintegrating tablets of the present invention, and the teneligliptin granules can be dispersed and present in the orally disintegrating tablets of the present invention.

[0060] Regarding the step of obtaining the teneligliptin granules, for example, a dry granulation method, a wet granulation method, or the like can be used. In the case of the dry granulation method, a desired granule can be obtained by granulating a powder mixture containing at least teneligliptin or its salt, or its solvate, a binder, and an aggregation inhibitor using, for example, a roller compactor, a roll granulator, or the like. In the case of the wet granulation method, for example, using a fluidized bed granulator, a high-speed stirring granulator, or the like, while flowing, water is added to a powder mixture containing at least teneligliptin or its salt, or its solvate, a binder, and an aggregation inhibitor by means such as spraying, and granulation is carried out. By drying the obtained granulated product, the desired teneligliptin granules can be obtained. As another method in the case of the wet granulation method, for example, using a fluidized bed granulator, a high-speed stirring granulator, or the like, while flowing, a solution of a binder (for example, an aqueous solution, an ethanol solution, an ethanol / aqueous solution, etc.) is added to a powder mixture containing teneligliptin or its salt, or its solvate, and an aggregation inhibitor by means such as spraying, and granulation is carried out. By drying the obtained granulated product, the desired teneligliptin granules can be obtained. Also, as the spraying method, any of a top spray method, a tangent spray method, or a bottom spray method can be adopted.

[0061] The teneligliptin granules may contain a coating base. For the step of obtaining teneligliptin granules containing a coating base, according to a method known in the technical field of pharmaceutical preparations, for example, at least teneligliptin or a salt thereof, or a solvate thereof, a binder, an aggregation inhibitor, and a coating base are included, and for example, wet granulation is carried out using a fluidized bed granulation method, and the obtained granulated product is dried to be produced in a granular form or the like.

[0062] The teneligliptin granules may be coated with a coating base. For the step of obtaining teneligliptin granules coated with a coating base, it can be produced according to a method known in the technical field of pharmaceutical preparations. For example, at least teneligliptin or a salt thereof, or a solvate thereof, a binder, and an aggregation inhibitor are included, and for example, wet granulation is carried out using a fluidized bed granulation method, and the obtained granulated product is dried to be in a granular form or the like, and then, under fluidization, a liquid containing at least a coating base (for example, an aqueous dispersion, an ethanol solution, an ethanol / aqueous solution, an ethanol / aqueous dispersion, etc.) is added and coated, for example, by means such as spraying, and the obtained coated product is dried to obtain the desired teneligliptin granules. Also, as the spraying method, any of a top spray method, a tangential spray method, or a bottom spray method can be adopted.

[0063] The step of obtaining the tableting granules is a step of obtaining tableting granules by mixing the obtained teneligliptin granules with a drug-free portion containing a pharmaceutically acceptable additive selected from at least a disintegrant, an excipient, a binder, a lubricant, a sweetening agent, a flavoring agent, or a coloring agent. As the mixing method, any method can be used. For example, a conventional method using a container rotation type mixer such as a double cone mixer, a fluidized bed granulator, a high-speed stirring granulator, or the like can be used. After mixing, if necessary, the mixture can be sieved, for example, using a 22-mesh sieve of the Japanese Pharmacopoeia.

[0064] The step of compression-molding the granule for tableting can be carried out using a conventional tableting machine such as a single-punch tableting machine or a rotary tableting machine. The tableting pressure can be appropriately selected according to the properties such as the hardness of the target tablet, but it can be about 10 to 5000 kgf / punch, preferably about 20 to 4000 kgf / punch, and particularly preferably about 100 to 2000 kgf / punch. When using, for example, a Compaction Analyzer manufactured by Kikusui Seisakusho as the tableting machine, when using a punch with a diameter of 9.5 mm, for example, it is preferable to tablet at a tableting pressure of 200 to 1000 kgf / punch.

[0065] For the orally disintegrating tablet of the present invention, when the diameter of the tablet is about 3 to 20 mm, preferably about 4 to 15 mm, and more preferably about 5 to 13 mm, it is advantageous for taking and handling.

[0066] The orally disintegrating tablet of the present invention has the property of rapidly disintegrating in the oral cavity and exhibits physical strength that does not break during each process of manufacturing, distribution, and dispensing. The disintegration time of the orally disintegrating tablet (the time until the orally disintegrating tablet is completely disintegrated when performing a disintegration test using the disintegration test apparatus described in the pharmacopoeia, using water as the test solution, and at a liquid temperature of 37 ± 2°C) is within about 60 seconds, preferably within about 50 seconds, and most preferably within about 40 seconds. In addition, the orally disintegrating tablet of the present invention has an appropriate hardness such that it does not break during the formulation process and the distribution process. The strength of the orally disintegrating tablet (the measured value by a tablet hardness tester) is usually about 20 to 80 N, and more preferably about 20 to 70 N.

[0067] The dosage of the orally disintegrating tablets of the present invention is determined according to age, body weight, general health condition, sex, diet, administration time, administration method, excretion rate, combination of drugs, or the degree of the disease state being treated by the patient at that time, taking these or other factors into consideration. The solid preparation of the present invention has low toxicity and can be safely used. The daily dosage thereof varies depending on the patient's condition, body weight, etc. For example, as teneligliptin, which is the active ingredient, it is preferably administered at 0.01 to 100 mg / kg body weight / day, more preferably 0.05 to 50 mg / kg body weight / day, in one to several divided doses per day.

[0068] In the orally disintegrating tablets of the present invention, when teneligliptin is formulated as teneligliptin or its salt, or its solvate, teneligliptin can be formulated in a desired amount. For example, 1 mg to 100 mg, preferably 10 mg to 50 mg, more preferably 20 mg or 40 mg can be formulated per tablet of the orally disintegrating tablets. Further, teneligliptin or its salt, or its solvate can be formulated in an amount of 10 mass percent to 50 mass percent, preferably 15 mass percent to 30 mass percent, based on 100 mass percent of one tablet of the orally disintegrating tablets.

Example

[0069] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the examples.

[0070] Example 1 (1) 62 parts by mass of teneligliptin hydrobromide hydrate and 0.62 parts by mass of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by Powrex, MP-01 / SFP), and granulation was carried out while spraying 35.4 parts by mass of a 3.5% (W / W) aqueous polyvinyl alcohol solution over about 30 minutes at an intake air temperature of 70°C. Granulated particles were obtained by drying until the temperature of the granulated product reached 40°C or higher. (2) 63.86 parts by mass of the granulated particles obtained in (1) above, 252.3 parts by mass of a premix excipient (Smart EX (registered trademark), grade; QD-50), 17 parts by mass of crospovidone, and 6.8 parts by mass of sodium stearyl fumarate were mixed to obtain granules for tableting. Using the said granules for tableting, they were compression-molded with a rotary tablet press (manufactured by Kikusui Seisakusho, VELAII, pestle diameter: 9.5 mm, tableting pressure: 400 kgf / pestle) so as to be 340 mg per tablet, thereby obtaining orally disintegrating tablets (hardness: 64 N, disintegration time: 26 seconds).

[0071] Example 2 (1) 62 parts by mass of teneligliptin hydrobromide hydrate and 0.62 parts by mass of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by Powrex, MP-01 / SFP), and at an intake air temperature of 70°C, a solution in which 12.4 parts by mass of ethyl cellulose, 2.48 parts by mass of triacetin, and 2.48 parts by mass of talc were dispersed in 164.7 parts by mass of an 80% (W / W) ethanol aqueous solution was sprayed over about 300 minutes while granulating. The granulated particles were obtained by drying until the temperature of the granulated product reached 40°C or higher. (2) 80 parts by mass of the granulated particles obtained in (1) above, 236.3 parts by mass of a premix excipient (Smart EX (registered trademark), grade; QD-50), 17 parts by mass of crospovidone, and 6.8 parts by mass of sodium stearyl fumarate were mixed to obtain granules for tableting. Using the said granules for tableting, they were compression-molded with a compaction analyzer (manufactured by Kikusui Seisakusho, pestle diameter: 9 mm, tableting pressure: 400 kgf / pestle) so as to be 340 mg per tablet, thereby obtaining orally disintegrating tablets (hardness: 47 N, disintegration time: 30 seconds).

[0072] Example 3 (1) 62 parts by mass of teneligliptin hydrobromide hydrate and 0.62 parts by mass of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by Powrex, MP-01 / SFP), and at an intake air temperature of 70°C, 35.429 parts by mass of a 3.5% polyvinyl alcohol (W / W) aqueous solution was sprayed over about 60 minutes while granulating. The granulated particles were obtained by drying until the temperature of the granulated product reached 35°C or higher. (2) Charge 63.86 parts by mass of the granulated particles obtained in (1) above into a fluidized bed granulator (manufactured by Powrex, MP-01 / SFP), and while spraying a liquid in which 91.85 parts by mass of an ethyl cellulose aqueous dispersion (Aquacoat (registered trademark), grade: ECD) (24.8 parts by weight as ethyl cellulose) and 6.612 parts by mass of triacetin are dispersed in 129.328 parts by mass of water at an intake air temperature of 60°C, perform coating. The coated granules were obtained by drying until the temperature of the coated material reached 55°C or higher. (3) Mix 98.03 parts by mass of the coated granules obtained in (2) above, 218.2 parts by mass of a premix excipient (Smart EX (registered trademark), grade: QD-50), 17 parts by mass of croscarmellose sodium, and 6.8 parts by mass of sodium stearyl fumarate to obtain granules for tableting. Using the granules for tableting, compression molding was performed with a compaction analyzer (manufactured by Kikusui Seisakusho, pestle diameter: 9.5 mm, tableting pressure: 400 kgf / pestle) so that it would be 340 mg per tablet, thereby obtaining orally disintegrating tablets (hardness: 39 N, disintegration time: 28 seconds).

[0073] Example 4 (1) Charge 62 parts by mass of teneligliptin hydrobromide hydrate, 0.93 parts by mass of acesulfame potassium, and 0.62 parts by mass of light anhydrous silicic acid into a fluidized bed granulator (manufactured by Powrex, MP-01 / SFP), and while spraying 20.67 parts by mass of a 6% polyvinyl alcohol (W / W) aqueous solution over about 40 minutes at an intake air temperature of 70°C, perform granulation. The granulated granules were obtained by drying until the temperature of the granulated material reached 35°C or higher. (2) Charge 64.79 parts by mass of the granulated particles obtained in (1) above into a fluidized bed granulator (manufactured by Powrex, MP-01 / SFP), and while spraying a liquid in which 91.85 parts by mass of an ethyl cellulose aqueous dispersion (Aquacoat (registered trademark), grade: ECD) (24.8 parts by weight as ethyl cellulose) and 6.612 parts by mass of triethyl citrate are dispersed in 144.85 parts by mass of water at an intake air temperature of 60°C, perform coating. Sampling was carried out when 18.6 parts by mass of ethyl cellulose (coating amount is 30% with respect to the active ingredient), and the coating granules were obtained by drying until the temperature of each coated product reached 55°C or higher. (3) Mix 98.96 parts by mass of the coating granules obtained in (2) above, 163.6 parts by mass of a premix excipient (Smart EX (registered trademark), grade: QD-50), 8.4 parts by mass of croscarmellose sodium, 2.8 parts by mass of sucralose, 0.39 parts by mass of flavoring, 0.28 parts by mass of yellow iron oxide and 5.6 parts by mass of sodium stearyl fumarate to obtain granules for tableting. Using the said granules for tableting, compression molding was carried out with a rotary tablet press (manufactured by Kikusui Seisakusho, VERAII, punch diameter: 9 mm, tableting pressure: 400 kgf / punch) so that it became 280 mg per tablet, and an orally disintegrating tablet was obtained. Also for the granules with coating amounts of 0% and 30%, by mixing 64.79 parts by mass and 90.45 parts by mass of the granulated particles and 197.8 parts by mass and 172.1 parts by mass of the premix excipient (Smart EX (registered trademark), grade: QD-50) respectively, an orally disintegrating tablet of 280 mg per tablet was obtained. (4) The hardness and disintegration time obtained are shown in Table 1 below.

[0074]

Table 1

[0075] Example 5 (1) 62 parts by mass of teneligliptin hydrobromide hydrate and 0.62 parts by mass of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by Powrex, MP-01 / SFP). While maintaining an intake air temperature of 70°C, a solution prepared by dispersing 24.8 parts by mass of ethyl cellulose, 4.96 parts by mass of triacetin, and 4.96 parts by mass of talc in 329.5 parts by mass of an 80% (W / W) ethanol aqueous solution was sprayed over approximately 600 minutes to perform granulation. The granulated product was dried until its temperature reached 40°C or higher to obtain granulated particles. (2) 97.34 parts by mass of the granulated particles obtained in (1) above, 218.86 parts by mass of a premix excipient (Smart EX (registered trademark), grade; QD-50), 17 parts by mass of crospovidone (Kollidon (registered trademark), grade; CL-F), and 6.8 parts by mass of sodium stearyl fumarate were mixed to obtain granules for tableting. Using these granules for tableting, compression molding was performed with a rotary tablet press (manufactured by Kikusui Seisakusho, VERAII, punch diameter: 9 mm, tableting pressure: 400 kgf / punch) to obtain orally disintegrating tablets such that each tablet weighed 340 mg (hardness: 60 N, disintegration time: 30 seconds).

[0076] Comparative Example 1 (1) 62 parts by mass of teneligliptin hydrobromide hydrate was charged into a fluidized bed granulator (manufactured by Powrex, MP-01 / SFP). While maintaining an intake air temperature of 70°C, 20.7 parts by mass of a 6% (W / W) polyvinyl alcohol aqueous solution was sprayed over approximately 40 minutes to perform granulation. However, inside the lower part of the can body, the internal powder formed agglomerates (blocking), and it was not possible to obtain the desired granules.

[0077] From the results of Comparative Example 1, it was shown that powder aggregation occurred due to the adhesion and aggregation properties of teneligliptin hydrobromide hydrate during production, and it was not possible to produce the desired teneligliptin granules.

[0078] Comparative Example 2 (1) 62 parts by mass of teneligliptin hydrobromide hydrate and 244 parts by mass of mannitol were charged into a fluidized bed granulator (manufactured by Powrex, MP-01 / SFP). While maintaining an intake air temperature of 70°C, granulation was carried out by spraying 340 parts by mass of an 80% (W / W) ethanol solution of 3% (W / W) ethyl cellulose (grade; 10P) over approximately 30 minutes. The granulated product was dried until the temperature of the granulated product reached 40°C or higher to obtain granulated particles. (2) 316.2 parts by mass of the granulated particles obtained in (1) above, 17 parts by mass of crospovidone, and 6.8 parts by mass of sodium stearyl fumarate were mixed to obtain granulated tablets for tableting. Using the granulated tablets for tableting, tablets were obtained by compression molding with a rotary tablet press (manufactured by Kikusui Seisakusho, VELAII, punch diameter: 9.5 mm, tableting pressure: 400 kgf / punch) so that each tablet had a mass of 340 mg (hardness: 90 N, disintegration time: 60 seconds or more).

[0079] From the results of Comparative Example 2, it was shown that with the conventional method of uniformly mixing teneligliptin hydrobromide hydrate in tablets, due to the properties of this compound that prevent the penetration of moisture into the tablets, it is impossible to obtain orally disintegrating tablets with a desired disintegration time.

Industrial Applicability

[0080] The orally rapidly disintegrating tablet containing teneligliptin of the present invention can provide a formulation that is easy to administer to the elderly and patients with difficulty in swallowing, and the present invention is useful for the production of therapeutic agents for type 2 diabetes containing teneligliptin and the like.

[0081] This application is based on Japanese Patent Application No. 2019-076376 filed in Japan on April 12, 2019, the content of which is incorporated herein in its entirety.

Claims

1. An intraorally rapidly disintegrating tablet comprising teneligliptin granules containing teneligliptin or a salt thereof, or a solvate thereof, a binder and an aggregation inhibitor, and a drug-free portion containing a pharma- ceutical acceptable additive.

2. 2. The intraorally rapidly disintegrating tablet according to claim 1, wherein the teneligliptin granules contain 45 to 99 percent by mass of teneligliptin or a salt thereof, or a solvate thereof, not including a coating base.

3. 3. The intraorally rapidly disintegrating tablet according to claim 1, wherein the teneligliptin granules contain 80 to 99 percent by mass of teneligliptin or a salt thereof, or a solvate thereof, not including a coating base.

4. The intraoral rapid disintegration tablet according to any one of claims 1 to 3, wherein the binder is one or more selected from hydroxypropyl cellulose, ethyl cellulose, polyvinyl acetal diethyl amino acetate, polyvinyl alcohol, hypromellose, isomalt and amino methacrylate copolymer.

5. The intraorally rapidly disintegrating tablet according to any one of claims 1 to 4, wherein the aggregation inhibitor is one or more selected from a lubricant, a suspending agent, a glossing agent, an antistatic agent, a dispersing agent and a fluidizing agent.

6. The tablet according to claim 5, wherein the aggregation inhibitor is a glidant.

7. The tablet according to claim 6, wherein the glidant is one or more selected from the group consisting of light anhydrous silicic acid, hydrous silicon dioxide and talc.

8. The tablet according to any one of claims 1 to 7, wherein the mass of the teneligliptin granules in the tablet, not including a coating base, is 10% by mass to 60% by mass of one tablet of the tablet.

9. The intraorally rapidly disintegrating tablet according to any one of claims 1 to 8, wherein the teneligliptin granules further comprise a coating base.

10. The intraorally rapidly disintegrating tablet according to claim 9, wherein the teneligliptin granules are coated with a coating base.

11. The intraorally rapidly disintegrating tablet according to claim 9 or 10, wherein the coating base is a water-insoluble polymer.

12. The tablet according to claim 11, wherein the water-insoluble polymer is one or more selected from the group consisting of ethyl cellulose, polyvinyl acetal diethyl amino acetate and amino methacrylate copolymer.

13. The intraorally rapidly disintegrating tablet according to any one of claims 1 to 12, wherein the drug-free portion contains at least an excipient, a disintegrant, or a lubricant.

14. The tablet rapidly disintegrating in the oral cavity according to claim 13, wherein the disintegrant is one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium and sodium carboxymethyl starch.

15. The intraorally rapidly disintegrating tablet according to any one of claims 1 to 14, wherein the drug-free portion contains a sweetener or a flavoring.

16. A tablet that rapidly disintegrates in the oral cavity, comprising teneligliptin granules that contain 70 to 99 mass percent of teneligliptin or a salt thereof, or a solvate thereof, a binder and an aggregation inhibitor, not including the coating base, and are further coated with a coating base, and a drug-free portion that contains a disintegrant and a pharma- ceutical acceptable additive.

17. 17. The intraorally rapidly disintegrating tablet according to claim 16, wherein the teneligliptin granules contain 80 to 99 percent by mass of teneligliptin or a salt thereof, or a solvate thereof, not including a coating base.

18. A method for producing an intraorally rapidly disintegrating tablet, comprising: 1) A step of granulating teneligliptin granules by mixing 45% by mass to 99% by mass of teneligliptin or a salt thereof, or a solvate thereof, not including a coating base, with a binder and an aggregation inhibitor; 2) mixing the granules with a pharma- ceutically acceptable additive to obtain granules for tableting; and 3) A step of compressing the granules to obtain an intraorally rapidly disintegrating tablet; The method for producing the intraorally rapidly disintegrating tablet according to any one of claims 1 to 17, comprising:

19. 19. The method for producing an intraorally rapidly disintegrating tablet according to claim 18, wherein the step of obtaining teneligliptin granules comprises mixing and granulating 45% by mass to 99% by mass of teneligliptin or a salt thereof, or a solvate thereof, not including the coating base, with a binder, an aggregation inhibitor and a coating base.

20. 20. The method for producing an intraorally rapidly disintegrating tablet according to claim 19, wherein the step of obtaining teneligliptin granules comprises mixing and granulating teneligliptin or a salt thereof, or a solvate thereof in an amount of 45 mass percent to 99 mass percent, not including the coating base, with a binder and an aggregation inhibitor, and then coating the mixture with the coating base.

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