JP2019142814A - Production method of febuxostat-containing tablet - Google Patents

Abstract

To provide production methods of febuxostat-containing tablets with excellent elution.SOLUTION: Provided is a production method of a tablet containing as an active ingredient 2-(3-cyano 4-isobutyloxy phenyl)-4-methyl-5-thiazole carboxylic acid, the method comprising a fluid layer granulation step using C type crystal of 2-(3-cyano 4-isobutyloxy phenyl)-4-methyl-5-thiazole carboxylic acid having an average particle diameter of 1.0 to 30.0 μm. Preferably, the production method uses polyvinyl alcohol as a binder.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing febuxostat-containing tablets having excellent dissolution properties.

  Febuxostat (chemical name: (2- (3-cyano-4-isobutyloxyphenyl) -4-methyl-5-thiazolecarboxylic acid) is used in living organisms as described in WO 92/09279. It is a compound that has strong xanthine oxidase inhibitory activity or uric acid lowering action and is expected as a therapeutic agent for gout or hyperuricemia.

  Febuxostat is marketed in Japan as a therapeutic agent for gout, hyperuricemia and hyperuricemia associated with cancer chemotherapy, under the product name “Febrix tablets 10 mg, 20 mg, 40 mg”.

As for febuxostat, a plurality of crystal polymorphs are known. For example, as described in Patent Document 1, the following six types have been reported. That is, the powder X-ray diffraction pattern represented by the reflection angle 2θ is approximately 6.62 °, 7.18 °, 12.80 °, 13.26 °, 16.48 °, 19.58 °, 21.92 °, Having characteristic peaks at 22.68 °, 25.84 °, 26.70 °, 29.16 °, and 36.70 ° (crystal A),
Similarly, approximately 6.76 °, 8.08 °, 9.74 °, 11.50 °, 12.22 °, 13.56 °, 15.76 °, 16.20 °, 17.32 °, 19 .38 °, 21.14 °, 21.56 °, 23.16 °, 24.78 °, 25.14 °, 25.72 °, 26.12 °, 26.68 °, 27.68 °, and Having a characteristic peak at 29.36 ° (crystal B),
Similarly, approximately 6.62 °, 10.82 °, 13.36 °, 15.52 °, 16.74 °, 17.40 °, 18.00 °, 18.70 °, 20.16 °, 20 Those having characteristic peaks at .62 °, 21.90 °, 23.50 °, 24.78 °, 25.18 °, 34.08 °, 36.72 °, and 38.04 ° (C crystal ),
Similarly, approximately 8.32 °, 9.68 °, 12.92 °, 16.06 °, 17.34 °, 19.38 °, 21.56 °, 24.06 °, 26.00 °, 30 Having characteristic peaks at .06 °, 33.60 °, and 40.34 ° (crystal D),
Similarly, approximately 6.86 °, 8.36 °, 9.60 °, 11.76 °, 13.74 °, 14.60 °, 15.94 °, 16.74 °, 17.56 °, 20 0.00, 21.26, 23.72, 24.78, 25.14, 25.74, 26.06, 26.64, 27.92, 28.60, 29 Those having characteristic peaks at .66 ° and 29.98 ° (G crystal), and amorphous (sometimes referred to as “E crystal”).

  As a method for producing tablets containing these crystal forms, Patent Document 1 discloses a method including a step of mixing fluidized granulation with febuxostat and an additive.

  In Patent Document 1, a method for producing a tablet containing A-type crystals is disclosed as an example on the assumption that A-type crystals are suitable for formulation, but among febuxostat crystal forms, C It has been reported that crystals are useful from the viewpoint of maintaining a crystal shape by long-term storage (for example, Patent Document 2).

  This Patent Document 2 describes a tablet manufacturing method including a step of mixing pulverized febuxostat C-type crystals with an additive and stirring granulation.

Japanese Patent No. 4084309 International Publication No. 2015/063561

  In order to obtain an effective medicine, it is important to improve the bioavailability of the active ingredient. However, in order to provide an oral preparation having a high bioavailability, a high solubility of the active ingredient is required.

  In this regard, Patent Document 2 reports that febuxostat C-type crystals composed only of crystals having a major axis length of about 200 μm or less are excellent in elution and the like.

  However, it has been found by the present inventors that sufficient elution cannot be obtained by simply pulverizing. That is, it was considered that in addition to fine powdering, it was necessary to further improve the dissolution properties of febuxostat C-type crystal-containing tablets.

  This invention is made | formed in view of said point, and makes it a main objective to provide the manufacturing method of the febuxostat containing tablet provided with the further outstanding dissolution property than before.

  The inventors of the present invention have made extensive studies and found that the above problems can be solved by a preparation having the following constitution. Based on the knowledge, the inventors have further studied and completed the following invention.

  In the method for producing a tablet containing 2- (3-cyano-4-isobutyloxyphenyl) -4-methyl-5-thiazolecarboxylic acid as an active ingredient according to one embodiment of the present invention, the average particle size is 1.0 to 30. It includes at least a step of granulating a fluidized bed using a C-type crystal of 2- (3-cyano-4-isobutyloxyphenyl) -4-methyl-5-thiazolecarboxylic acid which is 0.0 μm.

  Moreover, it is preferable to use polyvinyl alcohol as a binder in the fluidized bed granulation step.

  Furthermore, it is preferable to include a step of mixing the C-type crystal and an additive before the fluidized bed granulation step.

  Moreover, it is preferable that the C-type crystal further satisfies d10: 3.0 to 6.0 μm, d50: 8.0 to 18.0 μm, and d90: 20.0 to 38.0 μm.

  Furthermore, in the manufacturing method of the said tablet, it is preferable that the said C-type crystal | crystallization is a solvate.

  Moreover, in the manufacturing method of the said tablet, it is preferable that a tablet is a film coating agent.

  ADVANTAGE OF THE INVENTION According to this invention, the manufacturing method of the febuxostat containing tablet which was further excellent in the dissolution property than before can be provided.

  Hereinafter, although the embodiment concerning the present invention is described, the present invention is not limited to these.

  The manufacturing method of the tablet containing 2- (3-cyano-4-isobutyloxyphenyl) -4-methyl-5-thiazolecarboxylic acid as an active ingredient according to this embodiment has an average particle size of 1.0 to 30.0 μm. At least a step of granulating a fluidized bed using a C-type crystal of 2- (3-cyano-4-isobutyloxyphenyl) -4-methyl-5-thiazolecarboxylic acid (hereinafter also referred to as “febuxostat”) It is characterized by including.

  The inventors of the present invention have found that the dissolution properties are remarkably improved by fluidized bed granulation of finely divided febuxostat C-type crystals having the above-described configuration, that is, a predetermined average particle size. I found it.

(Active ingredient)
Febuxostat, which is an active ingredient in the oral preparation of this embodiment, is a compound having the chemical name of-(3-cyano-4-isobutyloxyphenyl) -4-methyl-5-thiazolecarboxylic acid.

  Further, C type crystal of febuxostat (hereinafter, also simply referred to as “C type crystal”) is a powder X-ray diffraction pattern expressed by a reflection angle 2θ of approximately 6.62 °, 10.82 °, 13 .36 °, 15.52 °, 16.74 °, 17.40 °, 18.00 °, 18.70 °, 20.16 °, 20.62 °, 21.90 °, 23.50 °, 24 It means a crystalline form with characteristic peaks at .78 °, 25.18 °, 34.08 °, 36.72 °, and 38.04 °. This C-type crystal is a substance that can be identified from a powder X-ray diffraction diagram (FIG. 4), an infrared absorption spectrum (FIG. 15) and the like described in Japanese Patent No. 3547707. For example, Journal of Chemical Engineering of Japan, Vol. 35, no. 11, pp. It can be produced according to the crystallization method described in “2.3. Crystallization” in 1116-1222, 2002.

  The febuxostat used in the production method of the present embodiment is a C-type crystal having an average particle diameter of 1.0 to 30.0 μm. In the present embodiment, the “average particle diameter” means a volume average diameter on a volume basis, and is a value obtained by measurement by a laser diffraction / scattering method.

  When the average particle size is in the range of 1.0 to 30.0 μm, a tablet with good drug dissolution when produced using a fluidized bed granulation method is obtained. When the average particle size of C-type crystals is less than 1.0 μm, there is a concern that aggregation of drug substances during fluidized bed granulation is promoted. On the other hand, when the average particle size exceeds 30.0 μm, sufficient drug dissolution is achieved. It is a problem because it becomes a situation that cannot be obtained. A more preferable range of the average particle diameter of the C-type crystal is 3.0 to 9.0 μm.

  The average particle size of the C-type crystal can be adjusted by a conventionally known method, and is not particularly limited. For example, it can be adjusted to the above range by means of a jet mill, a hammer mill, a ball mill, a pin mill, or the like. Is possible.

Further, the C-type crystal preferably has a d10 of 3.0 to 6.0 μm, a d50 of 8.0 to 18.0 μm, and a d90 of 20.0 to 38.0 μm. If d10, d50, and d90 of C-type crystals are within the above ranges, there is an advantage that a tablet with good drug elution can be obtained when produced using a fluidized bed granulation method.

In the present embodiment, the average particle diameter of the C-type crystal and the measurements of d10, d50, and d90 are not particularly limited, but can be performed using, for example, a laser diffraction / scattering method (volume basis) or the like.

  Furthermore, the C-type crystal of this embodiment is preferably a solvate.

  The content of the C-type crystals in the tablet of the present embodiment is not particularly limited as long as it is an amount showing its medicinal effect, but the content of febuxostat C-type crystals is relative to the total weight of the tablet. Preferably it is 4.0-25.0 weight%, More preferably, it is 7.0-17.0 weight%.

  The tablet of this embodiment may contain a pharmaceutically acceptable additive. Specifically, commonly used binders, excipients, disintegrants, lubricants, colorants and the like can be used.

(Excipient)
Examples of excipients that can be used in this embodiment include lactose hydrate, partially pregelatinized starch, sugar alcohol, crystalline cellulose, anhydrous lactose, corn starch, and calcium hydrogen phosphate. Preferably, lactose hydrate, partially pregelatinized starch and the like can be used. These may be used individually by 1 type and may use 2 or more types together. Although not particularly limited, the excipient is preferably contained in the range of 50.0 to 80.0% by weight based on the total weight of the tablet.

(Disintegrant)
Examples of disintegrants that can be used in this embodiment include croscarmellose sodium, crystalline cellulose, corn starch, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, crospovidone, Examples include partially pregelatinized starch. More preferred is carmellose, carmellose calcium, croscarmellose sodium, crospovidone, and most preferred is croscarmellose sodium. These may be used individually by 1 type and may use 2 or more types together. Although not particularly limited, the disintegrant is preferably contained in the range of 1.0 to 20.0% by weight based on the total weight of the tablet.

(Binder)
Examples of the binder that can be used in the present embodiment include polyvinyl alcohol, povidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, methyl cellulose, ethyl cellulose, polyvinyl alcohol / polyethylene glycol / graft copolymer. And polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. These may be used individually by 1 type and may use 2 or more types together. Preferably it contains polyvinyl alcohol. Although not particularly limited, the binder is preferably contained in the range of 0.5 to 5.0% by weight based on the total weight of the tablet.

(lubricant)
Examples of lubricants that can be used in this embodiment include magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, and the like. Preferably it is magnesium stearate. These may be used individually by 1 type and may use 2 or more types together. The lubricant is preferably contained in the range of 0.5 to 2.5% by weight based on the total weight of the tablet.

(Production method)
The method for producing the febuxostat-containing tablet of the present embodiment is at least 2- (3-cyano-4-isobutyloxyphenyl) -4-methyl-5-thiazole having an average particle size of 1.0 to 30.0 μm. At least the step of fluidized bed granulation using C-type crystals of carboxylic acid.

  In the manufacturing method in the present embodiment, first, as the C-type crystal, a pulverized product (primary particles) having an average particle size of 1.0 to 30.0 μm is used. The pulverization method is not particularly limited. Desirable by dry pulverization (rotary impact mill (pin mill, hammer mill, etc.), jet mill, ball mill, etc.) or wet pulverization (rotor-stator mixing, ball mill, high pressure homogenizer, etc.). Can be pulverized to a particle size of.

  More preferably, the average particle diameter is 1.0 to 30.0 μm, and d10: 3.0 to 6.0 μm, d50: 8.0 to 18.0 μm, and d90: 20.0 to 38.0 μm. It is preferable to use pulverized C-type crystals so as to satisfy the above.

  In the present embodiment, the fluidized bed granulation step can be performed by a known method. For example, a mixture of the C-type crystal and an additive (excipient, disintegrant, etc.) is charged into a fluidized bed granulator. The granules can be obtained by spraying and granulating a binder dissolved in purified water, followed by drying and sizing.

  Thereafter, a lubricant or the like is further mixed with the obtained granules as necessary to obtain a mixed powder, which can be compressed by tableting to form an uncoated tablet. For tableting, for example, a hydraulic hand press, a single-shot tableting machine, or a rotary tableting machine can be used. The tableting pressure can be appropriately set according to the tablet weight as the tablet to be produced.

  In this embodiment, by performing fluidized bed granulation using the C-type crystals having the average particle diameter as described above, an excellent dissolution rate even when a tablet is produced using the fluidized bed granulation method Can be provided.

  Moreover, you may crush the mixture of the said C-type crystal | crystallization and an additive before performing fluid bed granulation. In this embodiment, crushing can be performed with a crushing and sizing machine in order to pass through a sieve having an opening of 100 to 5000 μm, for example.

  However, although febuxostat crystals have a crystal form in which primary particles tend to aggregate into secondary agglomerates, the crushing process is in principle performed because the C-type crystals are used in the manufacturing method of the present embodiment. There is an advantage that it is unnecessary.

  The shape of the tablet of the present embodiment is not particularly limited, but a round tablet {circular flat lock (including corner locks, etc.), round R lock (including corner locks, two-stage R locks, etc.)} or deformed tablet (elliptical) A lock, etc.).

(Film coated tablets)
The tablet of this embodiment is good also as a film coating tablet by forming a film layer on the surface of an uncoated tablet as masking for bitterness suppression. The film coating layer contains a colorant for the purpose of laser printing, and examples of usable colorants include titanium oxide, yellow iron sesquioxide, iron sesquioxide, and talc, with titanium oxide being preferred. The colorant is preferably contained in the range of 0.05 to 0.5% by weight with respect to the total weight of the tablet. Examples of the coating agent for forming the film coating layer include hypromellose, polyethylene glycol, lactose hydrate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol, etc., preferably hypromellose, polyethylene Glycol, lactose hydrate and the like. These can be used alone or in combination of two or more. The coating agent is preferably contained in the range of 1.0 to 10.0% by weight with respect to the total weight of the tablet.

(Indication / dose)
The febuxostat-containing tablet of this embodiment can be used effectively for the treatment or prevention of gout, hyperuricemia and hyperuricemia associated with cancer chemotherapy.

  The amount of febuxostat C-type crystals in the tablet of this embodiment is such that the daily dose of febuxostat for human patients is usually about 10 mg, 20 mg or 40 mg (once) per day. It is preferable. The present invention will be described more specifically with reference to the following examples. However, the scope of the present invention is not limited to these examples.

  First, the febuxostat crystals used are C-type crystals and III-type crystals shown in Table 1 below.

  The average particle diameters d10, d50 and d90 in the above table were dry measured by a laser diffraction / scattering method using a wet / dry particle size distribution measuring device (LS 13 320).

(Example 1)
A mixture of 80.0 g of febuxostat (C-type crystal), 334.8 g of lactose hydrate, 80.0 g of partially pregelatinized starch and 10.0 g of croscarmellose sodium was pulverized and granulated (Comil QC-197S type / And was crushed and obtained after passing through a screen having an opening of 0.991 mm.

  The obtained mixture after pulverization was put into a fluidized bed granulator (MP-01-SPC type / manufactured by POWREC Co., Ltd.) and fluidized. A liquid (granulating liquid) dissolved in 0 g was sprayed and dried to granulate, and sieved with a 30 mesh (aperture 500 μm) sieve to obtain granules.

  257.4 g of the obtained granule was mixed with 2.6 g of magnesium stearate and tableted with a pressure of 1000 kgf to give a tablet with a mass of 260.0 mg, a diameter of 9.0 mm, and a thickness of 4.0 mm (two-stage R circular secant Tablet).

(Example 2)
A mixture of 80.0 g of febuxostat (C-type crystal), 334.8 g of lactose hydrate, 80.0 g of partially pregelatinized starch and 10.0 g of croscarmellose sodium was fluidized bed granulator (MP-01-SPC type) / Paurek Co., Ltd.) and fluidized, sprayed and dried with a solution (granulated solution) of 10.0 g of polyvinyl alcohol (partially saponified product) in 190.0 g of purified water, and granulated. The granules were obtained by sieving with a mesh (aperture 500 μm) sieve.

  257.4 g of the obtained granule was mixed with 2.6 g of magnesium stearate and tableted with a pressure of 1000 kgf to give a tablet with a mass of 260.0 mg, a diameter of 9.0 mm, and a thickness of 4.0 mm (two-stage R circular secant Tablet).

(Comparative Example 1)
A mixture of 80.0 g of febuxostat (type III crystal), 324.8 g of lactose hydrate, 80.0 g of partially pregelatinized starch, 10.0 g of croscarmellose sodium and 4.0 g of light anhydrous silicic acid is crushed and sized. A machine (Comil QC-197S type / manufactured by POWREC) was crushed and obtained by passing through a screen having an aperture of 0.991 mm.

  The obtained mixture after pulverization was put into a fluidized bed granulator (MP-01-SPC type / manufactured by POWREC) and fluidized, and 16.0 g of polyvinyl alcohol (partially saponified product) was purified into 297. A liquid (granulating liquid) dissolved in 0 g was sprayed and dried to granulate, and sieved with a 30 mesh (aperture 500 μm) sieve to obtain granules.

  257.4 g of the obtained granule was mixed with 2.6 g of magnesium stearate and tableted with a pressure of 1000 kgf to give a tablet with a mass of 260.0 mg, a diameter of 9.0 mm, and a thickness of 4.0 mm (two-stage R circular secant Tablet).

(Comparative Example 2)
Fluidized bed granulation of a mixture of febuxostat (type III crystal) 80.0 g, lactose hydrate 324.8 g, partially pregelatinized starch 80.0 g, croscarmellose sodium 10.0 g and light anhydrous silicic acid 4.0 g A machine (MP-01-SPC type / manufactured by POWREC Co., Ltd.) is allowed to flow, and a liquid (granulated liquid) in which 16.0 g of polyvinyl alcohol (partially saponified product) is dissolved in 297.0 g of purified water is sprayed. The granules were dried and granulated, and sieved with a 30 mesh (aperture 500 μm) sieve to obtain granules.

  257.4 g of the obtained granule was mixed with 2.6 g of magnesium stearate and tableted with a pressure of 1000 kgf to give a tablet with a mass of 260.0 mg, a diameter of 9.0 mm, and a thickness of 4.0 mm (two-stage R circular secant Tablet).

(Evaluation test)
About the obtained febuxostat containing tablet of each Example, the dissolution test with respect to febuxostat was done on condition of the following.
-Dissolution test method: 17th revised Japanese Pharmacopoeia-Dissolution test method of general test method (paddle method)
Test solution: second solution for dissolution test (pH 6.8)
-Test liquid volume: 900 mL
Test liquid temperature: 37 ° C ± 0.5 ° C
-Paddle rotation speed: 50 times per minute And elution rate (%) of what crushed (Example 1, Comparative Example 1) and what was not crushed (Example 2, Comparative Example 2) The difference was calculated.

  The results are shown in Table 2.

  From the results in Table 2, it was shown that in the examples using C-type crystals having a predetermined particle diameter based on the production method of the present invention, an excellent dissolution rate was obtained without crushing. On the other hand, in the comparative example using the type III crystal, it was shown that the dissolution rate was considerably inferior when crushing was not performed. Thus, according to the production method of the present invention, it was confirmed that a febuxostat crystal-containing tablet excellent in dissolution was obtained.

(Production example: film-coated tablets)
The uncoated tablets obtained in Examples 1 and 2 were put into a coating machine (manufactured by Paulek, Inc .: DRC-200 type). To this, 21.0 g of hypromellose, 5.0 g of lactose hydrate, 3.0 g of Macrogol 6000 And a liquid in which 1.0 g of titanium oxide was added to 270.0 g of purified water and uniformly dispersed was sprayed and dried to obtain a film-coated tablet having a tablet weight of 266.0 mg.

Claims (6)

A method for producing a tablet comprising 2- (3-cyano-4-isobutyloxyphenyl) -4-methyl-5-thiazolecarboxylic acid as an active ingredient,
The step of fluidized bed granulation using C-type crystals of 2- (3-cyano-4-isobutyloxyphenyl) -4-methyl-5-thiazolecarboxylic acid having an average particle size of 1.0 to 30.0 μm The manufacturing method of the said tablet containing at least.   The manufacturing method of the tablet of Claim 1 which uses polyvinyl alcohol as a binder in the said fluidized-bed granulation process.   The manufacturing method of the tablet of Claim 1 or 2 including the process of mixing the said C-type crystal | crystallization and an additive before the said fluidized bed granulation process.   The C-type crystal further satisfies d10: 3.0 to 6.0 μm, d50: 8.0 to 18.0 μm, and d90: 20.0 to 38.0 μm. Tablet manufacturing method.   The manufacturing method of the tablet in any one of Claims 1-4 whose said C-type crystal | crystallization is a solvate. The manufacturing method of the tablet in any one of Claims 1-5 whose tablet is a film coating agent.