JP2018127416A - Febuxostat-containing tablet production method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide febuxostat-containing tablet production methods in which the crystal transition of febuxostat is suppressed in production processes.SOLUTION: Provided is a febuxostat-containing tablet production method comprising obtaining a febuxostat-containing pharmaceutical composition by dry granulation, and tableting the mixture of the obtained granule and an additive composition. The dry granulation is typically a roller compaction dry granulation. A crystal form II, crystal form C, or crystal form 10 of febuxostat can be used suitably.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a method for producing febuxostat-containing tablets in which the crystal transition of febuxostat is suppressed.

  Febuxostat, a therapeutic agent for hyperuricemia, has many crystal forms such as A, B, C, D, G, F1, F2, F10, and II Is known (Patent Documents 1, 2, and 3, Non-Patent Document 1). Depending on the crystal form, febuxostat may undergo crystal transition upon long-term storage. It is known that A and C types are relatively stable, B and D types undergo crystal transition after long-term storage, and G type is stable for storage but undergoes crystal transition upon heating under reduced pressure. (Patent Document 1). In addition, it is known that F1 type, F2 type, and F10 type are difficult to undergo crystal transition (Patent Document 2). In addition, for type II crystals of febuxostat, a reproducible production method for preparing a high yield and high purity is known (Patent Document 3). It is not clear.

  Thus, febuxostat may undergo a crystal transition not only during long-term storage, but also in the preparation process of the preparation, resulting in a preparation containing an unplanned crystal form. For this reason, in formulating febuxostat, stable crystal forms have been studied, which is a very laborious operation. Therefore, there is a need for a method for producing a febuxostat-containing preparation that does not undergo crystal transition during the preparation of the preparation regardless of the crystal form.

Japanese Patent No. 3547707 Patent No. 5215505 Special table No. 2013-531021

Journal of Pharmaceutical Sciences, 104, 3722-3730, 2015

  An object of the present invention is to provide a method for producing a tablet containing febuxostat, wherein the crystal transition of febuxostat during the production process is suppressed.

The present inventor repeated researches to solve the above-described problems, and obtained the following knowledge.
(i) Tablets containing febuxostat are prone to tableting problems such as sticking during tableting, but after granulating a pharmaceutical composition containing febuxostat, it can be mixed with the additive composition and tableted. Occurrence of tableting troubles is suppressed.
(ii) Although febuxostat is particularly susceptible to crystal transition in the granulation process, crystal transition is effectively suppressed by employing a dry granulation method.

This invention is completed based on the said knowledge, and provides the manufacturing method of the following febuxostat containing tablet.
Item 1. A method for producing a febuxostat-containing tablet comprising a step of dry granulating a pharmaceutical composition comprising febuxostat and a step of tableting a mixture of the obtained granule and additive composition.
Item 2. The pharmaceutical composition comprises carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, citric acid and its salt, tartaric acid and its salt, malic acid and its salt, succinic acid The manufacturing method of claim | item 1 containing at least 1 sort (s) of additive chosen from the group which consists of a salt and oxalic acid and its salt, and ascorbic acid and its salt.
Item 3. When the compound selected from the group consisting of carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, and crospovidone is contained, the total content is 0.01 to the total amount of the pharmaceutical composition containing febuxostat. 10% by weight, and when the compound selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinyl alcohol is included, the total content is 0. 0% relative to the total amount of the pharmaceutical composition containing febuxostat. 01 to 10% by weight of a compound selected from the group consisting of citric acid and salts thereof, tartaric acid and salts thereof, malic acid and salts thereof, succinic acid and salts thereof, oxalic acid and salts thereof, and ascorbic acid and salts thereof The total content of Based on the total amount of the pharmaceutical composition comprising Kisosutatto method according to claim 2 which is 0.01 to 10 wt%.
Item 4. Item 4. The production method according to any one of Items 1 to 3, wherein the dry granulation is pressure plate granulation.
Item 5. Item 5. The method according to any one of Items 1 to 4, wherein the febuxostat is a type II crystal, a C type crystal, or an F10 type crystal.
Item 6. Item 6. A febuxostat-containing tablet obtained by the production method according to any one of Items 1 to 5.
Item 7. Item 7. The febuxostat-containing tablet according to Item 6, which is contained in a packaging container including a polyvinyl chloride and / or polypropylene containing member and a metal foil lid together with a calcium chloride desiccant and / or a zeolite desiccant.

  Febuxostat is very unstable depending on the crystal form, and is particularly prone to crystal transition during granulation. However, according to the production method of the present invention, the crystal transition due to granulation is remarkably suppressed by dry granulation. Further, according to the present invention, it has been found that type II crystals are very easy to undergo a crystal transition. However, even in the case of type II crystals that are relatively unstable in this way, if dry granulation is performed, Almost no crystal transition. Therefore, it is not necessary to study a stable crystal form, and labor can be reduced, and the degree of freedom in designing febuxostat-containing tablets becomes very high.

A comparison between the powder X-ray diffraction pattern of a granulated product obtained by subjecting a type II crystal to dry granulation and the powder X-ray diffraction pattern of a granulated product obtained by subjecting a type II crystal to wet granulation is there. A comparison between the powder X-ray diffraction pattern of the granulated product obtained by subjecting the F10 type crystal to dry granulation and the powder X-ray diffraction pattern of the granulated product obtained by subjecting the type II crystal to wet granulation. is there. FIG. 2 is a graph comparing a powder X-ray diffraction pattern of a granulated product obtained by subjecting a C-type crystal to dry granulation and a powder X-ray diffraction pattern of a granulated product obtained by subjecting a type II crystal to wet granulation. is there.

Hereinafter, the present invention will be described in detail.
The method for producing a febuxostat-containing tablet of the present invention comprises a step of dry granulating a pharmaceutical composition containing febuxostat and a step of tableting a mixture of the obtained granulated product and additive composition. It is a manufacturing method including.

Febuxostat is a compound whose chemical name is 2- [3-cyano-4- (2-methylpropoxy) phenyl] -4-methylthiazole-5-carboxylic acid. Either R-form or S-form can be used, but usually a racemate may be used. Also, any of hydrate, hemihydrate, anhydride and the like can be used.
As the febuxostat, for example, a powder can be used.
Febuxostat may be used so that about 1 to 100 mg is contained in one tablet, and for example, 10 mg, 20 mg, or 40 mg may be used in one tablet.

Febuxostat may be used in any crystal form. Crystal forms include A type, B type, C type, D type, G type, F1 type, F2 type, F3 type, F4 type, F5 type, F6 type, F7 type, F8 type, F9 type, F10 type, Examples include F11 type, F12 type, F13 type, F14 type, and II type. Among them, type II crystals are very unstable and are suitable targets for the method of the present invention. Moreover, it has been found that the C-type crystal is easily transferred during granulation according to the present invention, and the C-type crystal is also a suitable subject of the method of the present invention. F10 crystals are also a suitable subject of the method of the present invention.
A type, B type, C type, D type, and G type can be obtained, for example, by the method described in Japanese Patent No. 3547707 (Patent Document 1). Moreover, F1-F14 type | mold can be obtained by the method of patent 5215505 (patent document 2), for example. Moreover, type II can be obtained by the method as described in Japanese translations of PCT publication No. 2013-531021 (patent document 3), for example.
Febuxostat may be used in one crystal form, or two or more different crystal forms may be used in combination.

In the powder X-ray diffraction pattern, type A is represented by a reflection angle 2θ of 6.6 ° ± 0.2 °, 7.2 ° ± 0.2 °, 12.8 ° ± 0.2 °, 13. It has characteristic peaks at 3 ° ± 0.2 °, 16.5 ° ± 0.2 °, 19.6 ° ± 0.2 °, and 25.8 ° ± 0.2 °.
B type is 6.8 ° ± 0.2 °, 8.1 ° ± 0.2 °, 11.5 ° ± 0.2 °, 19. It has characteristic peaks at 4 ° ± 0.2 °, 21.6 ° ± 0.2 °, 23.2 ° ± 0.2 °, and 29.4 ° ± 0.2 °.
In the powder X-ray diffraction pattern, the C type is expressed by a reflection angle 2θ of 6.5 ± 0.2 °, 10.8 ° ± 0.2 °, 13.3 ° ± 0.2 °, 15.5. It has characteristic peaks at ° ± 0.2 °, 17.3 ° ± 0.2 °, 25.1 ° ± 0.2 °, and 27.0 ° ± 0.2 °.
In the powder X-ray diffraction pattern, the D type is expressed by a reflection angle 2θ of 8.3 ° ± 0.2 °, 9.7 ° ± 0.2 °, 12.9 ° ± 0.2 °, 17. It has characteristic peaks at 3 ° ± 0.2 °, 19.4 ° ± 0.2 °, 26.0 ° ± 0.2 °, and 40.3 ° ± 0.2 °.
In the powder X-ray diffraction pattern, the G type is represented by a reflection angle 2θ of 4.9 ° ± 0.2 °, 7.0 ° ± 0.2 °, 8.5 ° ± 0.2 °, 9. Characterized by 7 ° ± 0.2 °, 11.9 ° ± 0.2 °, 13.9 ° ± 0.2 °, 16.1 ° ± 0.2 °, and 17.7 ° ± 0.2 ° Has a typical peak.
In the powder X-ray diffraction pattern, the F2 type is represented by a reflection angle 2θ of 3.0 ° ± 0.2 °, 5.9 ° ± 0.2 °, 8.8 ° ± 0.2 °, 11. It has characteristic peaks at 8 ° ± 0.2 ° and 12.5 ° ± 0.2 °.
In the powder X-ray diffraction pattern, the F10 type is expressed by a reflection angle 2θ of 6.3 ° ± 0.2 °, 7.4 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13. It has characteristic peaks at 0 ° ± 0.2 °, 13.4 ° ± 0.2 °, 16.0 ° ± 0.2 °, and 16.4 ° ± 0.2 °.
In the powder X-ray diffraction pattern, type II is represented by a reflection angle 2θ of 5.9 ° ± 0.2 °, 8.1 ° ± 0.2 °, 11.8 ° ± 0.2 °, 12. It has characteristic peaks at 9 ° ± 0.2 °, 17.0 ° ± 0.2 °, and 17.7 ° ± 0.2 °.
The F1, F3, F4, F5, F6, F7, F8, F9, F11, F12, F13, and F14 types are disclosed in, for example, Japanese Patent No. 5215505 (Patent Document 2). The peak of the powder X-ray diffraction pattern described in 1.

Pharmaceutical composition containing febuxostat The pharmaceutical composition containing febuxostat may contain an excipient as an additive in addition to febuxostat. Furthermore, it is generally used for tablets such as binders, disintegrants, lubricants, fluidizers, brighteners, colorants, corrigents, pH adjusters, sweeteners, fragrances and preservatives. Optional additives can be included.
An additive can be used individually by 1 type or in combination of 2 or more types.

(Excipient)
Excipients include, for example, lactose hydrate, sucrose, maltose, fructose, glucose (dextrose), sugars such as trehalose; mannitol (particularly D-mannitol), maltitol, sorbitol, xylitol, erythritol, lactitol Sugar alcohols such as starch; starches such as pregelatinized starch and partially pregelatinized starch; celluloses such as crystalline cellulose; dextrin and the like.

(Disintegrant)
Examples of disintegrants include crospovidone; carboxymethylcellulose (carmellose), carmellose sodium, carmellose calcium, low-substituted hydroxypropylcellulose, cellulose such as croscarmellose sodium; starch, pregelatinized starch, partially pregelatinized Starch, starches such as sodium carboxymethyl starch (sodium starch glycolate); dextrin; calcium silicate and the like.

Among them, crospovidone, carmellose, carmellose sodium, and / or carmellose calcium are preferable, and crospovidone is more preferable in that the crystal transition can be more effectively suppressed.
When crospovidone, carmellose, carmellose sodium, and / or carmellose calcium are blended, the total amount used is preferably about 0.01 to 10% by weight based on the total amount of the pharmaceutical composition containing febuxostat. About 1 to 10% by weight, more preferably about 0.1 to 1% by weight.

(Binder)
Examples of the binder include celluloses such as methylcellulose, ethylcellulose, carmellose, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), croscarmellose sodium; popidone; starch; gelatin; tragacanth gum;

Among these, polyvinyl alcohol, hydroxypropyl cellulose, hypromellose, and / or carmellose are preferable, and polyvinyl alcohol, hydroxypropyl cellulose, and / or hypromellose are more preferable in that the crystal transition can be more effectively suppressed.
When blending polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and / or carboxymethyl cellulose, the total amount used is about 0.01 to 10% by weight based on the total amount of the pharmaceutical composition containing febuxostat. Preferably, about 0.1-2% by weight is more preferred, and about 0.1-1% by weight is even more preferred.

(lubricant)
Examples of lubricants include stearic acid, stearates (magnesium stearate, calcium stearate, aluminum stearate, zinc stearate, etc.), stearate esters (sodium stearyl fumarate, glyceryl monostearate, palmitostearate). Acid glycerin, etc.), sodium lauryl sulfate, polyethylene glycol, talc, sucrose fatty acid ester, sodium potassium tartrate and the like.

(Fluidizer)
Examples of the fluidizing agent include light anhydrous silicic acid and magnesium aluminate metasilicate.

(Flavoring agent / pH adjuster)
In addition, by adding a compound selected from citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, ascorbic acid, and the like, which are generally used as a corrigent and pH adjuster, and a salt thereof, the crystal transition is more effective Can be suppressed.
When one or more selected from citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, and ascorbic acid and their salts are added, the total amount used is the total amount of the pharmaceutical composition including febuxostat. On the other hand, it is preferably about 0.01 to 10% by weight, preferably about 0.05 to 5% by weight, and more preferably about 0.1 to 1% by weight.

Additive composition not containing febuxostat The additive composition not containing febuxostat includes excipients, binders, disintegrants, lubricants, fluidizing agents, brighteners, colorants, flavoring agents, Any additive commonly used in tablets can be included, such as sweetening, flavoring, preservatives and the like. As the additive, for example, those exemplified above can be used.
An additive can be used individually by 1 type or in combination of 2 or more types.

Manufacturing Process A pharmaceutical composition containing febuxostat is subjected to dry granulation. The dry granulation method is not limited, and examples thereof include a pressure granulation method, a briquette granulation method, and a melt granulation method. Among these, the pressed-plate granulation method is preferable in that the crystal transition of febuxostat can be more effectively suppressed.

  The mixing ratio of the pharmaceutical composition containing febuxostat and the additive composition not containing febuxostat was such that the pharmaceutical composition containing febuxostat was about 3 to 70 based on the total amount of both compositions. What is necessary is just to make it become weight%.

  The compression pressure can be 300 kgf or more, 500 kgf or more, or 800 kgf or more, and can be 1200 kgf or less, 1000 kgf or less, or 700 kgf or less. Within this range, practically sufficient moldability and tablet strength can be obtained, and good disintegration can be obtained.

Tablets The thus-obtained febuxostat-containing tablet of the present invention has suppressed crystal transition of the raw material febuxostat.
The tablets may be orally disintegrating tablets, chewable tablets and the like in addition to ordinary tablets. Further, it may be a sublingual tablet, buccal tablet, troche tablet or the like absorbed from the oral cavity. In the present invention, the orally disintegrating tablet refers to a tablet having a disintegration time of 30 seconds or less measured using an orally disintegrating tablet tester (Toyama Sangyo Co., Ltd., ODT-101). This disintegration time is preferably within 25 seconds.

The tablets obtained by the production method of the present invention can be more effectively suppressed from crystal transition during storage by packaging with a desiccant. Examples of the desiccant include calcium chloride (for example, ID Sheet; Hishie Chemical Co., Ltd.) and zeolite. A desiccant can be used individually by 1 type or in combination of 2 or more types.
Since the tablet of the present invention is also suppressed in crystal transition during storage, it is not necessary to package it in an expensive ultra-high moisture-proof container. Therefore, it can be packaged in a container formed of a general plastic housing member such as polyvinyl chloride or polypropylene and a lid made of a sheet such as an aluminum sheet.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these.
(1) Examination of granulation method
Example 1 (Type II crystal / dry granulation)
Weigh febuxostat 4.00 g, D-mannitol 4.50 g, croscarmellose sodium 1.00 g, hydroxypropylcellulose 0.30 g, light anhydrous silicic acid 0.10 g, and magnesium stearate 0.10 g in a polyethylene bag. And mixed to obtain a powder mixed powder. Subsequently, the obtained powder mixture is put into a dry granulator (TF-LABO Freund Kogyo Co., Ltd.) and compressed under the conditions of a roller pressure of 5.0 MPa, a roller rotation speed of 3.0 rpm, and a screw rotation speed of 8.0 rpm. I got flakes.
Next, the obtained flakes were sieved and sized, and granulated granules were obtained.

Comparative Example 1 (Type II crystal / wet granulation)
Febuxostat 4.00 g, D-mannitol 4.50 g, croscarmellose sodium 1.00 g, and hydroxypropylcellulose 0.30 g were put into a stainless steel container and mixed with a polyethylene stirring rod for 5 minutes. Subsequently, granulation was performed for 5 minutes with a polyethylene stirring rod while dropping 4 mL of purified water to obtain granulated granules.
Next, the obtained granulated granules were put into a shelf type dryer (DKN811 manufactured by Yamato Kagaku Co., Ltd.) set at 60 ° C. and dried for 16 hours to obtain dry granules.

Example 2 (F10 crystal / dry granulation)
In Example 1, granules containing febuxostat were obtained in the same manner as in Example 1 except that F10 type crystals were used instead of type II crystals as febuxostats.

Comparative Example 2 (F10 crystal / wet granulation)
In Comparative Example 1, granules containing febuxostat were obtained in the same manner as in Comparative Example 1, except that F10-type crystals were used instead of II-type crystals as febuxostats.

Example 3 (C-type crystal / dry granulation)
In Example 1, granules containing febuxostat were obtained in the same manner as in Example 1 except that C-type crystals were used instead of II-type crystals as febuxostats.

Comparative Example 3 (C-type crystal / wet granulation)
In Comparative Example 1, granules containing febuxostat were obtained in the same manner as in Comparative Example 1, except that C-type crystals were used instead of II-type crystals as febuxostats.

(Evaluation of stability)
A powder X-ray diffraction analysis was performed on the granulated product immediately after preparation in Examples 1 to 3 and Comparative Examples 1 to 3. The results are shown in FIGS.
As is clear from FIG. 1, in wet granulation, a peak of 2θ = 4.9 ° and a peak of 2θ = 7.0 ° characteristic of the transition type II crystal were observed (upper pattern). In dry granulation, these peaks did not appear (lower pattern).
In addition, as is apparent from FIG. 2, in wet granulation, a peak of 2θ = 4.9 ° characteristic of the transition product of F10 type crystal was observed (upper pattern), but in dry granulation, No peak was expressed (lower pattern).
In addition, as is apparent from FIG. 3, in wet granulation, a peak of 2θ = 4.9 ° characteristic of the transition product of C-type crystals was observed (upper pattern), but in dry granulation, No peak was expressed (lower pattern).
From the above, it can be seen that by performing dry granulation, crystal transition due to granulation is suppressed regardless of the crystal form of febuxostat. Of particular note is that the transition of very unstable type II crystals is strongly suppressed.

(2) Examination of additives
Example 4
Febuxostat type II crystals and D-mannitol were mixed at a weight ratio of 1: 9, and placed in a glass bottle to prepare a sample.

Examples 5-12
Febuxostat type II crystals, D-mannitol, crystalline cellulose, corn starch, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, croscarmellose sodium, partially pregelatinized starch, or sodium starch glycolate, The sample was mixed at a weight ratio of 1: 8: 1 and placed in a glass bottle to obtain a sample.

Examples 13-17
Mix febuxostat type II crystals, D-mannitol, crospovidone, hydroxypropylcellulose, hypromellose, polyvinyl alcohol, or polyvinylpyrrolidone in a weight ratio of 1: 8.8: 0.2 and place in a glass bottle. A sample was used.

Examples 18-24
A febuxostat type II crystal, D-mannitol, citric acid, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, sucrose fatty acid ester, or light anhydrous silicic acid, 1: 8.9: The sample was mixed at a weight ratio of 0.1 and placed in a glass bottle to obtain a sample.

Example 25
Febuxostat type II crystals were put into a glass bottle without any additives and used as samples.

(Evaluation of stability)
The samples prepared in Examples 4 to 25 were allowed to stand for 2 weeks under harsh conditions of 55 ° C. and a relative humidity of 75%, and then powder X-ray diffraction analysis was performed.
Example 8 (carmellose), Example 9 (carmellose calcium), Example 10 (croscarmellose sodium), Example 13 (crospovidone), Example 14 (hydroxypropylcellulose), Example 15 (hypromellose), Only the granulated product obtained in Example 16 (polyvinyl alcohol) and Example 18 (citric acid) had a 2θ = 5.9 ° peak and a 2θ = 8.1 ° peak characteristic of type II crystals. It was recognized that In other examples, these peaks specific to type II crystals disappeared and were not detected (peak residual ratio 0%).
The ratio (peak residual ratio) to the sum of the peak areas of 2θ = 5.9 ° and 2θ = 8.1 ° of the granulated product in which the peak was detected and the peak area before standing under severe conditions is shown. It is shown in 1.

It can be seen that crystal transformation is more effectively suppressed by dry granulating febuxostat with the additives listed in Table 1.

According to the production method of the present invention, crystal granulation due to granulation of febuxostat is remarkably suppressed by dry granulation. Therefore, it becomes unnecessary to study a stable crystal form, and labor can be reduced, and the degree of freedom in designing febuxostat-containing tablets is increased.

Claims (5)

  A method for producing a febuxostat-containing tablet comprising a step of dry granulating a pharmaceutical composition comprising febuxostat and a step of tableting a mixture of the obtained granule and additive composition.   The pharmaceutical composition comprises carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, citric acid and its salt, tartaric acid and its salt, malic acid and its salt, succinic acid And a salt thereof, oxalic acid and a salt thereof, and at least one additive selected from the group consisting of ascorbic acid and a salt thereof.   When the compound selected from the group consisting of carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, and crospovidone is contained, the total content is 0.01 to the total amount of the pharmaceutical composition containing febuxostat. 10% by weight, and when the compound selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinyl alcohol is included, the total content is 0. 0% relative to the total amount of the pharmaceutical composition containing febuxostat. 01 to 10% by weight of a compound selected from the group consisting of citric acid and salts thereof, tartaric acid and salts thereof, malic acid and salts thereof, succinic acid and salts thereof, oxalic acid and salts thereof, and ascorbic acid and salts thereof The total content of Based on the total amount of the pharmaceutical composition comprising Kisosutatto method of claim 2 wherein 0.01 to 10 wt%.   The production method according to any one of claims 1 to 3, wherein the dry granulation is pressure plate granulation.   The manufacturing method according to any one of claims 1 to 4, wherein the febuxostat is a type II crystal, a type C crystal, or a type F10 crystal.