JP7361833B2 - Orally disintegrating tablet of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid - Google Patents

Description

The present invention relates to an orally disintegrating tablet of febuxostat, a drug for treating hyperuricemia, which has reduced drug-induced harshness, high tablet hardness, and excellent disintegration properties in the oral cavity.

In recent years, as the population continues to age, the number of cases of elderly people suffering from various diseases has increased, making it necessary for them to take multiple medications. Pharmaceuticals come in a variety of dosage forms, but the most common form is tablets, which are highly portable. Tablets are usually taken with water, but they can be painful for elderly people or small children because they are difficult to swallow and take. As one solution to this problem, orally disintegrating tablets have been developed that do not require water when taken and can be taken as they are by disintegrating the tablet in the oral cavity. Orally disintegrating tablets can improve patient compliance due to these characteristics.

On the other hand, problems with orally disintegrating tablets include the fact that they disintegrate in the oral cavity, resulting in unpleasant tastes such as acridness, bitterness, and irritation derived from pharmaceutical products. A certain degree of tablet hardness is required, but hardness is a property that is contradictory to disintegration. Generally, reducing the hardness of a tablet improves disintegration, but it also makes it easier for tablets to break or crack when maintaining their quality. , these tablets do not hold up as a product. In addition, increasing the hardness increases the disintegration time in the oral cavity, resulting in the problem that patients who take the drug are exposed to unpleasant tastes derived from the drug for a long time. For example, it is necessary to simultaneously avoid unpleasant taste.
These problems differ for each drug and require consideration each time during drug development, and therefore, multiple applications regarding orally disintegrating tablets have been reported.

For example, Patent Document 1 relates to pitavastatin having a bitter taste and includes particles containing pitavastatin, the particles have a coating layer covering pitavastatin, and the coating layer contains an ethyl acrylate/methyl methacrylate copolymer. Regarding orally disintegrating tablets with masked bitterness, Patent Document 2 describes atorvastatin having a bitter taste, which is prepared by granulating atorvastatin or a pharmaceutically acceptable salt thereof, an alkalizing agent, and a gastric soluble polymer. A technique related to an orally disintegrating tablet with suppressed bitter taste is disclosed.
Furthermore, Patent Document 3 discloses that an orally disintegrating tablet containing galantamine or its salt and sodium carboxymethyl starch as an additive exhibits good disintegrating properties and hardness, and Patent Document 4 discloses that an orally disintegrating tablet containing galantamine or its salt and sodium carboxymethyl starch as an additive exhibits good disintegrating properties and hardness, and Patent Document 4 discloses that risperidone, crystalline cellulose, and inorganic excipients By compression molding a powder containing carmellose and 0.8% by weight or less of a lubricant per tablet, it is possible to obtain orally disintegrating tablets that exhibit good disintegration properties and ensure tablet hardness. Disclosed.

2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid (generic name: febuxostat; hereinafter referred to as febuxostat) is a non-purine high xanthine compound. It is a drug with oxidase inhibitory activity, and has been manufactured and sold in the form of tablets by Teijin Pharma Co., Ltd. since 2011 as a treatment for gout and hyperuricemia under the brand name "Febryk (registered trademark) tablets." has been done. When considering the application of febuxostat to orally disintegrating tablets, since febuxostat itself has undesirable properties such as unpleasant taste such as acrid taste and irritation to the throat, it is necessary to Technical considerations were necessary.

As a technology related to orally disintegrating tablets containing febuxostat, Patent Document 5 discloses that a core particle containing febuxostat is coated with a layer containing a methacrylic acid copolymer, and further overcoated with a layer containing a water-soluble saccharide. Patent Document 6 discloses an intraorally rapidly disintegrating tablet comprising particles of which the core granules are coated with a disintegrant such as crospovidone, and which are made by compression molding core granules coated with a disintegrant such as crospovidone. In Example 1, an example using febuxostat is disclosed regarding an intraorally rapidly disintegrating tablet containing a disintegrant such as crospovidone and a drug inside and/or outside.

JP2013-237651A JP2013-231011A JP2012-188364A International Publication No. 2008/081774 pamphlet Patent No. 5000017 Patent No. 4934144

An object of the present invention is to provide an orally disintegrating tablet that has reduced astringency and irritation to the throat caused by febuxostat, has high tablet hardness, and has excellent disintegration properties in the oral cavity.

The present inventors have discovered that in granules containing febuxostat, the core particles of the granules contain febuxostat and a disintegrant, and the granules coated with a coating layer containing a cellulose derivative and an acrylic polymer are derived from febuxostat. It is confirmed that soreness and irritation to the throat are reduced, and that orally disintegrating tablets containing these granules have sufficient hardness and good disintegration properties in the oral cavity while retaining the characteristics of the granules. The present invention has been completed.

That is, the present invention provides granules in which the core particles contain febuxostat and a disintegrant, and the core particles are coated with a coating layer containing a cellulose derivative and an acrylic polymer.
The present invention also provides a method for producing the granules.
The present invention also provides an orally disintegrating tablet containing the granules.
The present invention also provides a method for producing the orally disintegrating tablet.

Granules of the present invention in which core particles containing febuxostat and a disintegrant are coated with a coating layer containing a cellulose derivative and an acrylic polymer, and orally disintegrating tablets containing these granules, are free from acrid irritation and throat irritation caused by febuxostat. It is highly suitable as an orally disintegrating tablet containing febuxostat because it has reduced hardness, sufficient hardness, and good disintegration properties.

The present invention will be explained in more detail below.
Examples of disintegrants used in the preparation of the core particles and orally disintegrating tablets of the present invention include crystalline cellulose, carboxymethylcellulose (carmellose), croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, crospovidone, Examples include hydroxypropyl starch, starch, partially pregelatinized starch, sodium starch glycolate, etc., preferably croscarmellose sodium, sodium starch glycolate, crospovidone, and more preferably crospovidone. Furthermore, the crospovidone used in the present invention includes Polyplasdone (registered trademark) XL, Polyplasdone (registered trademark) XL-10, Polyplasdone (registered trademark) INF-10 (all manufactured by Ashland), and Kollidone. (registered trademark) CL, Kollidon (registered trademark) CL-F, Kollidon (registered trademark) CL-SF, Kollidon (registered trademark) CL-M, etc., preferably Kollidon CL, Kollidon CL-F, Kollidon CL- SF, Kollidon CL-M (manufactured by BASF Japan), and particularly preferably Kollidon CL-F. The amount of the disintegrant used is preferably 5 to 30% by mass, more preferably 5 to 15% by mass in the core particles. When incorporated into orally disintegrating tablets, the amount is preferably 1 to 10% by weight, more preferably 2 to 6% by weight.

The excipient used in the present invention can be incorporated into the core particles and the orally disintegrating tablet, and examples thereof include sugar alcohols such as erythritol, D-sorbitol, xylitol, D-mannitol, and maltitol, and preferably D -Mannitol is mentioned. The content of the excipient in the core particles is preferably 1 to 50% by mass, more preferably 10 to 40% by mass. When incorporated into orally disintegrating tablets, it is preferably 10 to 80% by weight, more preferably 30 to 70% by weight.

The acrylic polymer used as the coating base in the coating layer of the present invention includes methacrylic acid copolymer L (e.g., Eudragit (registered trademark) L100, manufactured by Evonik), methacrylic acid copolymer S (e.g., Eudragit (registered trademark) S100, Evonik), aminoalkyl methacrylate copolymers (e.g. Eudragit® E100, Eudragit® EPO, Evonik), dry methacrylic acid copolymers LD (e.g. Eudragit® L100-55, Evonik) ), methacrylic acid copolymer LD (e.g., Eudragit® L30D-55, manufactured by Evonik), ethyl acrylate/methyl methacrylate copolymer dispersion (e.g., Eudragit® NE30D, manufactured by Evonik), ammonia Examples include polymers containing methacrylic acid derivatives such as oalkyl methacrylate copolymers (e.g., Eudragit® RL100/RLPO/RL30D, Eudragit® RS100/RSPO/RS30D, manufactured by Evonik), preferably methacrylic acid copolymers. An example is LD. The content of the acrylic polymer is from about 1 to about 30% by weight, preferably from about 3 to about 25%, more preferably from about 5 to about 20% by weight, based on the solid weight of the polymer in the coating layer.

The cellulose derivatives used in the preparation of the coating layer of the present invention include water-soluble cellulose derivatives such as methylcellulose, hypromellose, and hydroxypropylcellulose, and those having a viscosity of 1 to 100 mPa·s are particularly preferable, and more preferably Examples include those with a pressure of 1 to 50 mPa·s, more preferably 1 to 10 mPa·s, and methylcellulose is preferred. Examples of the methylcellulose used in the present invention include Metrose (registered trademark) SM-4, Metrose (registered trademark) SM-15, Metrose (registered trademark) SM-25, Metrose (registered trademark) SM-50, and more. Preferable examples include Metrose (registered trademark) SM-4, Metrose (registered trademark) SM-15, and Metrose (registered trademark) SM-25, and most preferred is Metrose (registered trademark) SM-4. The viscosity here refers to the viscosity in a 2% aqueous solution at 20°C. The content of the cellulose derivative is about 1 to about 30% by weight, preferably about 3 to about 25% by weight, more preferably about 5 to about 20% by weight, based on the solid weight of the polymer in the coating layer.

Examples of the plasticizer used in the present invention include glycerin, glycerin fatty acid ester, triethyl citrate, polyethylene glycol, diethyl phthalate, triacetin, sesame oil, castor oil, and preferably polyethylene glycol. The polyethylene glycol used in the present invention includes polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 11000, or Examples include polyethylene glycol 20000, preferably polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, and more. Preferred examples include polyethylene glycol 2000, polyethylene glycol 4000, and polyethylene glycol 6000. The content of the plasticizer is from about 1 to about 30% by weight, preferably from about 3 to about 25%, more preferably from about 5 to about 20% by weight, based on the solid weight of the polymer in the coating layer.

The fluidizing agents used in the preparation of the core particles and coating layer of the present invention include hydrous silicon dioxide, light anhydrous silicic acid, talc, synthetic aluminum silicate, titanium oxide, stearic acid, magnesium stearate, calcium stearate, and metasilicic acid. Examples include magnesium aluminate. Preferred are talc, hydrated silicon dioxide, and light anhydrous silicic acid, and talc is particularly preferred. These may be used alone or in a mixture of two or more. The content of the fluidizing agent is about 1 to about 50% by weight, preferably about 3 to about 40% by weight, more preferably about 5 to about 35% by weight, based on the weight of the polymer solids in the coating layer. The content in the core particles is preferably 0.01 to 10% by mass, more preferably 1 to 5% by mass.

The content of sodium chloride used in the present invention is preferably 0.1 to 10% by mass, more preferably 0.5 to 4% by mass in the granules and/or the orally disintegrating tablet.

The solubilizing agent used in the present invention can be blended with the core particles in the present invention, and examples thereof include sodium citrate, calcium oxide, magnesium oxide, magnesium chloride, sodium carbonate, sodium hydrogen carbonate, and sodium hydroxide. Preferably it is magnesium oxide. These may be used alone or in combination of two or more. The content of the solubilizing agent is preferably 0.01 to 10% by mass, more preferably 0.05 to 2% by mass in the core particles.

The granules and orally disintegrating tablets of the present invention may contain a binder, a lubricant, a flavoring agent, a flavoring agent, a coloring agent, and the like in appropriate combinations and amounts as necessary.

Examples of the binder include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, gelatin, agar, alginic acid, sodium alginate, partially saponified polyvinyl alcohol, pullulan, partially pregelatinized starch, dextrin, chitansan gum, gum arabic powder, etc. It will be done. Preferred are hydroxypropylcellulose, hypromellose, and polyvinylpyrrolidone. These may be used alone or in a mixture of two or more.

Examples of the lubricant include stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, light silicic anhydride, hydrogenated oil, glycerin fatty acid ester, and talc. Preferred are sodium stearyl fumarate, magnesium stearate, calcium stearate, and sucrose fatty acid ester. These may be used alone or in a mixture of two or more.

Examples of flavoring agents include sugar alcohols, aspartame, stevia, sodium saccharin, dipotassium glycyrrhizin, thaumatin, potassium acesulfame, and sucralose. These may be used alone or in a mixture of two or more.

Colorants include Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102, Food Blue No. 1 Aluminum Lake, Food Blue No. 2. No. aluminum lake, food yellow No. 4 aluminum lake, food yellow No. 5 aluminum lake, food red No. 2 aluminum lake, food red No. 3 aluminum lake, food red No. 102 aluminum lake, iron sesquioxide (red), titanium oxide, yellow Examples include iron sesquioxide, orange essence, caramel, talc, and green tea powder. These may be used alone or in a mixture of two or more.

Flavors include mint, lemon flavor, orange coaton, pineapple flavor, l-menthol, black tea micron, and the like. These may be used alone or in a mixture of two or more.

It is known that febuxostat used in the present invention has crystalline polymorphisms, and any crystalline form can be used in the present invention. , C crystal, G crystal and the like are preferred. Furthermore, these crystals may be made finer by crushing. Refinement by crushing the crystals can be performed, for example, by the method described in Patent No. 4084309 and International Publication No. 2015/063561 pamphlet.

Any shape can be adopted for forming the orally disintegrating tablet in the present invention, such as round, elliptical, spherical, polygonal plate, rod, donut shape, laminated tablet, and cored tablet. It may also be a lock or the like. Moreover, it can also be covered with a coating if necessary. It is also possible to print marks, characters, etc. to improve identification, and dividing lines may be added. The size of these preparations is preferably small, preferably about 5 to 12 mm in diameter and about 2 to 5 mm in thickness. The mass is preferably about 50 to 600 mg. Hardness is not particularly limited, but a certain degree of hardness is required to prevent tablets from being damaged during transportation. In the present invention, it is preferably 30 to 150N, more preferably 40 to 130N, and still more preferably 50 to 120N. The disintegration time is not particularly limited, but for example, when taken without water, it is about 5 to 60 seconds in the oral cavity, preferably about 10 to 40 seconds, and more preferably about 15 to 35 seconds.

The hardness of the orally disintegrating tablet of the present invention can be measured by a generally known method, and for example, a commercially available tablet hardness meter such as a load cell electric hardness meter or a Schleuniger tablet hardness meter can be used.

The granules and orally disintegrating tablets of the present invention can be produced, for example, by the following steps.
(Step 1: Preparation of core particles)
After febuxostat, an excipient, a solubilizing agent, a disintegrant, and a fluidizing agent are mixed in a tumbling fluidized bed granulator, core particles are prepared by spraying an aqueous solution containing a binder.
(Step 2: Preparation of coating liquid)
A coating liquid is prepared by adding acrylic polymer, cellulose derivative, polyethylene glycol, and talc to purified water and dissolving and dispersing them.
(Step 3: Preparation of granules)
The core particles prepared in Step 1 are coated with the coating liquid prepared in Step 2 using a tumbling fluidized bed granulator to prepare granules.
(Step 4: Preparation of orally disintegrating tablets)
After the granules obtained in step 3 are mixed with an excipient, a disintegrant, a fluidizing agent, sodium chloride, and a flavoring agent, a lubricant is further added and mixed. The resulting mixture is compressed using a rotary tablet machine to prepare orally disintegrating tablets.

The present invention will be explained in more detail below using Examples, Comparative Examples, and Test Examples, but the present invention is not limited thereto.

(Example 1-1)
Step 1 Production of core particles Febuxostat (prepared according to Example 5 described in paragraph number [0112] of International Publication No. 2015/063561 pamphlet) 240 g, D-mannitol (Mitsubishi Corporation Foodtech, Mannit C) 134.4 g , magnesium oxide (Tomita Pharmaceutical, XP103) 1 g, crospovidone (BASF Japan, Kollidon CL-F) 60 g, and light anhydrous silicic acid (Freund Sangyo, Ad Solider 101) 12 g were mixed in a tumbling fluidized bed granulator (Freund Sangyo, Spira). Flow SFC-MINI), and while controlling the air supply temperature at 70°C, 480g of 7% hydroxypropyl cellulose (Nippon Soda, HPC-SL) aqueous solution was sprayed at 5g/min. After the spraying was completed, the granules were dried until the temperature reached 45° C. to obtain febuxostat-containing core particles.

(Example 1-2) to (Example 1-8)
Core particles of (Example 1-2) to (Example 1-8) were obtained by the same process 1 as in (Example 1-1), and are summarized in Table 1.

(Example 2-1)
Step 2 Preparation of coating liquid Methacrylic acid copolymer LD (Evonik Japan, Eudragit L30D-55) 180g, methyl cellulose (Shin-Etsu Chemical, Metrose SM-4) 12g, Macrogol 6000 (Sanyo Chemical, PEG6000P) 6g, and talc (Matsumura A coating solution (864 g) was prepared by adding 24 g of Crown Talc (Industrial Industry) to an appropriate amount of water and stirring.

Step 3 Granule production The febuxostat-containing core particles obtained in Step 1 (Example 1-1) were put into a tumbling fluidized bed granulator (Freund Sangyo, Spiraflow SFC-MINI), and the supply air temperature was While controlling the temperature at 40° C., 864 g of the coating liquid obtained in Step 2 was sprayed at 5 g/min. After the spraying was completed, the supply air temperature was set to 70°C, and the granules were dried until the temperature of the granules reached 45°C to obtain febuxostat-containing granules.

(Example 2-2) to (Example 2-5)
Granules of (Example 2-2) to (Example 2-5) were obtained by the same steps 2 and 3 as in (Example 2-1), and are summarized in Table 2.

(Example 3-1)
Step 4 Production of orally disintegrating tablets 576 g of febuxostat-containing granules obtained in Step 3 (Example 2-1), 756 g of D-mannitol (Roquette Japan, PEARLITOL 160C), crospovidone (BASF Japan, Kollidon CL-) F) 72 g, aspartame (Ajinomoto) 27.6 g, light anhydrous silicic acid (Freund Sangyo, Ad Solider 101) 36 g, sodium chloride (Tomita Pharmaceutical) 9.6 g, and sodium stearyl fumarate (JRS Pharma, PRUV) 22.8 g. The mixture was mixed in a plastic bag, and then compressed into a rotary tablet machine (Kikusui Seisakusho, VELA-5) to produce tablets weighing 250 mg, having a diameter of 9 mm, and a hardness of approximately 75N.

(Example 3-2) to (Example 3-9)
Orally disintegrating tablets of (Example 3-2) to (Example 3-9) were obtained by the same step 4 as in (Example 3-1), and are summarized in Table 3.

(Comparative Example 1-1) to (Comparative Example 1-3)
Core particles of (Comparative Example 1-1) to (Comparative Example 1-3) were obtained by the same process 1 as in (Example 1-1), and are summarized in Table 4. Note that (Comparative Example 1-3) and (Example 1-1) are the same.

(Comparative Example 2-1) to (Comparative Example 2-4)
Granules of (Comparative Example 2-1) to (Comparative Example 2-4) were obtained by the same steps 2 and 3 as in (Example 2-1), and are summarized in Table 5. Note that (Comparative Example 2-1) and (Example 2-1) are the same.

(Comparative Example 3-1) ~ (Comparative Example 3-3)
Orally disintegrating tablets of (Comparative Example 3-1) to (Comparative Example 3-3) were obtained by the same step 4 as in (Example 3-1), and are summarized in Table 6.

(Comparative Example 3-4-A) and (Comparative Example 3-4-B)
Step 1 Production of orally disintegrating tablets (Comparative Example 2-1) 576 g of febuxostat-containing coated granules, 756 g of D-mannitol (Roquette Japan, PEARLITOL 160C), 90 g of croscarmellose sodium (Asahi Kasei, Kykkolate ND-200), Aspartame (Ajinomoto) 27.6g, light anhydrous silicic acid (Freund Sangyo, Ad Solider 101) 36g, sodium chloride (Tomita Pharmaceutical) 9.6g, and sodium stearyl fumarate (JRS Pharma, PRUV) 22.8g in a plastic bag. Mixed. The resulting mixture was compressed using a rotary tabletting machine (Kikusui Seisakusho, VELA-5), and tablets were prepared with a tablet weight of 250 mg, a tablet diameter of 9 mm, and a tablet thickness of 3.80 mm (Comparative Example 3-4). -A) and tablets prepared to exhibit a tablet weight of 250 mg, a tablet diameter of 9 mm, and a hardness of approximately 80N (Comparative Example 3-4-B) were manufactured, respectively.

(Comparative Example 3-1-A), (Comparative Example 3-5-A) ~ (Comparative Example 3-8-A) and (Comparative Example 3-1-B), (Comparative Example 3-5-B) ~ (Comparative Example 3-8-B)
In the same manner as (Comparative Example 3-4-A) and (Comparative Example 3-4-B), (Comparative Example 3-1-A), (Comparative Example 3-5-A) to (Comparative Example 3-8) -A), (Comparative Example 3-1-B), and (Comparative Example 3-5-B) to (Comparative Example 3-8-B) were produced and summarized in Table 7.

[Test Example 1-1]
(Example 3-1) - (Example 3-3), (Comparative example 3-1) - (Comparative example 3-3) and (Comparative example 3-4-A and B) - (Comparative example 3-8 -The masking properties of the tablets A and B) were evaluated. The evaluation method was carried out by five healthy adult males, and after the tablets were disintegrated in the oral cavity, the masking ability of the main drug against irritation was evaluated using the criteria shown below. The results are shown in Table 8.
0: There is a clear masking effect, and I do not feel any stimulation. 1: There is a masking effect, and I hardly feel any stimulation. 2: There is a masking effect, but I feel stimulation. 3: The masking effect is weak, and I feel the stimulation strongly (tolerable). possible)
4: No masking effect, strong stimulation felt (unacceptable)

[Test Example 2-1]
Regarding the tablets of (Example 3-1) to (Example 3-3) and (Comparative Example 3-1-A), (Comparative Example 3-4-A) to (Comparative Example 3-8-A), The implosion time and hardness were evaluated. The results are shown in Table 9. The hardness was measured using a portable hardness meter PC-30 (Okada Seiko). The hardness test was conducted using 10 tablets each, and the average value of the obtained results is shown.

[Test Example 3-1]
(Example 3-3), (Comparative Example 3-1-B), and (Comparative Example 3-4-B) to (Comparative Example 3-8-B) tablets prepared to have a hardness of approximately 80N were tested in the oral cavity. The disintegration time and hardness were evaluated. The results are shown in Table 10.

Comparing the Examples and Comparative Examples, the results in Table 8 show that the tablets that disintegrate in the oral cavity of the Comparative Examples show a good oral disintegration time, but the hardness of the tablets tends to decrease, and Table 9 shows that the hardness of the tablets tends to decrease when the hardness is increased. There was a tendency for the time to increase. From the above, it has not been possible to obtain an orally disintegrating tablet that satisfies both tablet disintegration properties and hardness. On the other hand, the orally disintegrating tablets of Examples exhibited high tablet hardness and good oral disintegration time, indicating that they exhibited excellent properties as orally disintegrating tablets.

(Example 1-9)
Febuxostat (prepared according to Example 5 described in paragraph number [0112] of WO 2015/063561 pamphlet) 240 g, D-mannitol (Mitsubishi Corporation Foodtech, Mannit C) 124.8 g, magnesium oxide (Tomita Pharmaceutical Co., Ltd.) , 480 g of 6% hydroxypropyl cellulose (Nippon Soda, HPC-L)/sodium chloride (Tomita Pharmaceutical, Pharmacopoeia sodium chloride) aqueous solution was sprayed at 5 g/min while controlling the air supply temperature at 80°C. After the spraying was completed, the granules were dried until the temperature reached 45° C. to obtain febuxostat-containing core particles.

(Example 1-10) to (Example 1-13)
Core particles of (Example 1-10) to (Example 1-13) were obtained by the same process 1 as in (Example 1-9), and are summarized in Table 11.

(Example 2-6) to (Example 2-11)
Granules of (Example 2-6) to (Example 2-11) were obtained by the same steps 2 and 3 as in (Example 2-1), and are summarized in Table 12.

(Example 3-10) to (Example 3-15)
Orally disintegrating tablets of (Example 3-10) to (Example 3-15) were obtained by the same step 4 as in (Example 3-1), and are summarized in Table 13.

[Test Example 1-2]
The masking properties of the tablets (Example 3-10) to (Example 3-15) were evaluated by five healthy adult men in the same manner as Test Example 1-1. The results are shown in Table 14. The evaluation method is as described above.

[Test Example 2-2]
The tablets of (Example 3-10) to (Example 3-15) were evaluated for oral disintegration time and hardness in the same manner as Test Example 2-27. The results are shown in Table 15.

From the results in Tables 14 and 15, the tablets manufactured according to Examples have both good disintegration properties and hardness while having a high masking effect, and exhibit excellent properties as orally disintegrating tablets. I understand.

Claims (14)

Granules coated with a coating layer, the core particles comprising (1) a core particle containing febuxostat and a disintegrant; (2) the core particle being coated with a coating layer containing methylcellulose and an acrylic polymer; Granules containing sodium chloride and no organic acids . The granule according to claim 1, wherein the disintegrant is crospovidone. Granules according to claim 1 or 2, wherein the acrylic polymer is a methacrylic acid copolymer. The granules according to claims 1 to 3, wherein the coating layer contains a plasticizer. Granules according to claim 4, wherein the plasticizer is polyethylene glycol. The granules according to claims 1 to 5, wherein the coating layer contains a fluidizing agent. Granules according to claim 6, wherein the plasticizing agent is talc. forming a core particle containing febuxostat and a disintegrant; coating the core particle with a coating layer containing methyl cellulose and an acrylic polymer; Production method. An orally disintegrating tablet comprising the granules according to claims 1 to 7. The orally disintegrating tablet according to claim 9, comprising the granules according to claims 1 to 7, a disintegrant, and an excipient. The granule according to claim 10, wherein the disintegrant is crospovidone. The orally disintegrating tablet according to claim 10 or 11, wherein the excipient is a sugar alcohol. The orally disintegrating tablet according to claims 9 to 12, which has a tablet hardness of 50N to 120N. forming core particles containing febuxostat and a disintegrant; coating the core particles with a coating layer containing methylcellulose and an acrylic polymer to produce granules; and mixing the granules with a disintegrant and an excipient. A method for manufacturing an orally disintegrating tablet containing (however, the tablet contains sodium chloride and does not contain an organic acid ).