JP2019147798A - Method for producing solid preparation with crystalline form of dasatinib anhydride stably maintained - Google Patents

Abstract

To provide technical means useful for producing a solid preparation by stably maintaining a crystalline form of dasatinib.SOLUTION: The present invention provides a method for producing a tablet through a wet granulation step using dasatinib in a crystalline form as an anhydride, or a method for producing a tablet by direct tableting using the dasatinib. A preferable system of the wet granulation is fluidized bed granulation; and also preferably, the wet granulation is performed by dropping an aqueous solution containing a binder onto powder containing a dasatinib anhydride in crystalline form.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a solid preparation containing dasatinib as a drug substance, and is expected to stably maintain its crystal form.

  Dasatinib is a compound used to treat chronic myeloid leukemia and relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia. Drugs containing dasatinib are widely available worldwide. (Nonpatent literature 1 etc. reference).

  Dasatinib is currently being provided to medical sites in the form of tablets. The prescription and production method of a solid preparation containing dasatinib have been introduced in documents such as Patent Document 1 below, but currently there are few known knowledge for reference.

  It is important from the viewpoint of ensuring the effectiveness of a drug to stably maintain the crystal form of the drug substance in the manufacturing process of the drug. Therefore, the present inventor aimed to newly develop a method for producing tablets while stably maintaining the crystal form of dasatinib anhydride.

Patent No. 517397

"Sprycel (registered trademark) 20 mg, Splicel (registered trademark) 50 mg" pharmaceutical interview form revised in January 2018 (12th edition)

  An object of the present invention is to provide useful technical means for producing a solid preparation while maintaining a stable crystal form of dasatinib anhydride.

  As a result of intensive studies on the formulation and manufacturing method of solid preparations in order to solve the above-mentioned problems, the present inventor conducted a step of performing wet granulation using crystal form (N-6 type) of dasatinib which is an anhydride. It was found that the crystal form was stably maintained in the solid preparation (granule or tablet) obtained through the method. Based on the above findings, the present inventor has conducted further intensive studies and has completed the following invention.

Preferred embodiments of the present invention are described in the following (1) to (9).
(1) A method for producing a solid preparation containing dasatinib in crystalline form,
A method for producing a solid preparation (granules or tablets) comprising a step of granulating (dry granulation or wet granulation) using dasatinib in a crystalline form which is an anhydride.
(2) The method for producing a solid preparation according to (1), wherein the granulation is wet granulation.
(3) It is characterized by passing through a step of wet granulation by adding a granulation liquid in which a binder is dissolved in a solvent containing water to a powder containing dasatinib anhydride in crystalline form (dropping or spraying). The manufacturing method of the solid formulation as described in said (2).
(4) The method for producing a solid preparation according to (2) or (3), wherein the wet granulation is fluidized bed granulation.
(5) The binder or coating agent used in wet granulation is hydroxypropylcellulose, hypromellose, methylcellulose, povidone, polyvinyl alcohol, aminoalkyl methacrylate copolymer, polyvinyl alcohol / polyethylene glycol / graft copolymer, and polyvinyl alcohol / acrylic acid / methacrylic. The manufacturing method of the solid formulation in any one of said (2)-(4) chosen from an acid methyl copolymer.
(6) The manufacturing method of the solid formulation in any one of said (2)-(4) whose binder or coating agent used in the case of wet granulation is aminoalkyl methacrylate copolymer E.
(7) Any of the above (2) to (6), comprising a step of mixing the granules obtained by wet granulation with other additives (such as a lubricant) and then tableting to produce an uncoated tablet The manufacturing method of the solid formulation as described in 1 ..
(8) A method for producing a solid preparation containing dasatinib in crystalline form,
A method for producing a solid preparation (tablet), wherein a direct compression method is performed using dasatinib in crystalline form which is an anhydride.
(9) The excipient according to any one of (1) to (8) above, wherein the excipient is lactose hydrate and crystalline cellulose, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate. A method for producing a solid preparation.

  The present invention makes it possible to produce a solid preparation while stably maintaining the crystal form of dasatinib anhydride.

FIG. 1 shows the result of analyzing the crystalline form of dasatinib anhydride (N-6 type) by powder X-ray diffraction measurement. FIG. 2 shows the result of analyzing the crystal form of dasatinib monohydrate by powder X-ray diffraction measurement. FIG. 3 shows the granule of Examples 3 to 5 and Comparative Examples 1 and 2, and the crystal form of dasatinib anhydride (type N-6) and the crystal form of dasatinib monohydrate by powder X-ray diffractometry. The result is shown.

  Hereinafter, the formulation and production method of a solid preparation containing crystalline form of dasatinib anhydride according to the present invention will be described in detail. However, the following description is an example for explaining the present invention, and is not intended to specifically limit the present invention to this description range.

<Form of solid preparation>
As dosage forms of solid preparations according to the present invention, granules and uncoated tablets (refer to tablets that are not covered with a film coating layer, a sugar coating layer, etc., and are formed by tableting, etc. The same shall apply hereinafter), film coated tablets, etc. The tablet is preferably a granule or a plain tablet. The uncoated tablet according to the present invention can be formed into a film-coated tablet by applying a film coating layer to the periphery. The granule according to the present invention can be contained in an uncoated tablet. Examples of the shape of the tablet according to the present invention include circular tablets {circular flat tablets (including corner locks, etc.), circular R locks (including corner locks, 2-stage R locks, etc.)}, deformed tablets, and the like.

<Physical properties of API>
The crystalline form of dasatinib used in the manufacture of the solid dosage form of the present invention is anhydrous. The median diameter (d ₅₀ ) of dasatinib anhydride is preferably 10.0 to 60.0 μm. The dasatinib anhydride can be adjusted to an arbitrary particle size by appropriately performing dry or wet pulverization as necessary. The particle diameter can be measured (volume basis) by a laser diffraction / scattering method. Dasatinib is contained in the uncoated tablet part (desirably inside the granules contained in the uncoated tablet), and preferably 10.0 to 50.0% by weight, more preferably 15.0 to 30%, based on the total weight of the uncoated tablet. It is contained in the uncoated tablet in the range of 0.0% by weight. Dasatinib is desirably contained in 20 mg or 50 mg per tablet.

<Wet granulation>
The method for producing a solid preparation of the present invention preferably includes a step of granulating using crystalline form of dasatinib anhydride, and particularly preferably includes a step of wet granulation. Examples of the wet granulation method include a fluidized bed granulation method and a stirring granulation method, and a fluidized bed granulation method is particularly preferable. In the agitation granulation, a granulation liquid (an aqueous solution or the like) containing a binder is dropped to a powder containing dasatinib anhydride in crystal form (during stirring). In fluidized bed granulation, a granulating liquid (such as an aqueous solution) containing a binder is sprayed on a powder containing dasatinib anhydride in crystal form (during fluidization). The granulating liquid used in wet granulation is particularly preferably a granulating liquid (including an aqueous solution) in which a binder is dissolved in a solvent containing water (a solvent made of water is most preferable). The granulating liquid preferably does not contain an alcohol (particularly ethanol) solvent.

<Pharmaceutical additives that can be used in the manufacture of uncoated tablets>
The pharmaceutically acceptable pharmaceutical additives used for the production of the uncoated tablet according to the solid preparation of the present invention include commonly used excipients, disintegrants, binders, coating agents, plasticizers, lubricants. Agents, flavoring agents, surfactants, colorants and the like can be used. In addition, in this specification, the interpretation of the terms of various additives (excipients, binders, disintegrants, lubricants, etc.) is essential to exhibit their role as additives in formulation. It is preferable to understand that it is used in anticipation of the above, and as a result, its role as an additive is exhibited. Of course, the drug substance is not included in the interpretation of the term additive in this specification.

<Excipient>
Examples of the excipient according to the present invention include lactose (lactose hydrate, anhydrous lactose, etc.), maltose, sucrose, sucrose, glucose, sugar alcohol (D-mannitol, erythritol, xylitol, sorbitol, isomalt, maltitol, etc. ), Starch (corn starch, potato starch, rice starch, wheat starch, etc.), crystalline cellulose, hydroxypropyl starch, pregelatinized starch, partially pregelatinized starch, etc., preferably lactose hydrate or crystalline cellulose. More preferred are lactose hydrate and crystalline cellulose. The excipient is preferably contained in the uncoated tablet in the range of 40.0 to 90.0% by weight, more preferably 50.0 to 75.0% by weight, based on the total weight of the uncoated tablet.

<Disintegrant>
Disintegrants according to the present invention include, for example, carmellose, carmellose calcium, carmellose potassium, carmellose sodium, croscarmellose sodium, sodium carboxymethyl starch, partially pregelatinized starch, crospovidone, and low-substituted hydroxypropylcellulose. Preferred is croscarmellose sodium. The disintegrant is preferably contained in the uncoated tablet in an amount of 1.0 to 20.0% by weight, more preferably 2.0 to 10.0% by weight, based on the total weight of the uncoated tablet.

<Binder>
Examples of the binder according to the present invention include hydroxypropylcellulose, hypromellose, methylcellulose, povidone, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol / graft copolymer, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, aminoalkyl methacrylate copolymer ( Aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, etc.) and the like, preferably aminoalkyl methacrylate copolymer or hydroxypropyl cellulose, and most preferably aminoalkyl methacrylate copolymer E. The above binder can be used as a coating agent for the purpose of coating the core particles. The binder and the coating agent are contained in the uncoated tablet in an amount of 0.1 to 20.0% by weight, preferably 2.0 to 15.0% by weight, based on the total weight of the uncoated tablet.

<Fluidizer>
Specific examples of the fluidizing agent include light anhydrous silicic acid, fatty acid ester, hydrous silicon dioxide, hydrogenated oil, and the like, and light anhydrous silicic acid is preferable. The fluidizing agent is preferably contained in the uncoated tablet in the range of 0.1 to 3.0% by weight based on the total weight of the uncoated tablet.

<Lubricant>
The lubricant according to the present invention is selected from, for example, magnesium stearate, calcium stearate, sodium stearyl fumarate, etc., preferably magnesium stearate. The lubricant is preferably contained in the uncoated tablet in the range of 0.1 to 3.0% by weight based on the total weight of the uncoated tablet.

<Structure and production method of granules>
The granule according to the present invention is contained in the uncoated tablet in an amount of preferably 25.0% by weight or more, more preferably 25.0 to 80.0% by weight based on the total weight of the uncoated tablet. Dasatinib anhydride is contained in the granulated product, preferably in the range of 60.0 to 95.0 parts by weight with respect to 100.0 parts by weight of the granulated product. The binder and the coating agent are preferably contained in the granulated product in an amount of 5.0 to 50.0 parts by weight with respect to 100.0 parts by weight of the granulated product. The granule according to the present invention is preferably produced by spraying a binder or a coating agent on a dasatinib anhydride or a granule containing the same by a fluidized bed granulation method.

<Manufacturing method of uncoated tablet>
The uncoated tablet according to the present invention can be prepared by a general manufacturing method, for example, by the following manufacturing method.
[Wet granule compression method]
First, powder of dasatinib, excipient, disintegrant, etc. is put into a fluidized bed granulator and fluidized, and a granulated product is produced by spraying a solution (granulating liquid) in which a binder is dissolved. To do. The granulated product is dried and sized, mixed with a lubricant and the like, and then compressed by a tableting machine to form tablets (plain tablets). The striking pressure when compressing the tablets is preferably 400 to 1500 kgf.
[Direct tableting method]
After first mixing powders such as dasatinib, excipient, disintegrant, and fluidizing agent, a lubricant is added to the powder, followed by secondary mixing, followed by compression molding with a tableting machine. Lock). The striking pressure when compressing the tablets is preferably 400 to 1500 kgf.
[Dry granule compression method]
First, after mixing powders such as dasatinib, excipients, disintegrants, fluidizers and lubricants, it is put into a dry granulator to apply a strong pressure to agglomerates, and further pulverized and granulated Manufacturing. The granulated product is sized, mixed with a lubricant and the like, and then compressed by a tableting machine to form a tablet (plain tablet).

EXAMPLES The present invention will be described below with reference to examples and the like, but the present invention is not limited to these examples and the like. The dasatinib anhydride (type N-6) used in the production of the solid preparations described in Examples 1 to 5 and Comparative Examples 1 and 2 below is a crystalline form in advance, and the particle size distribution is d ₁₀ = 2. _8, d 50 _{= 24.0,} it was confirmed that the d 90 = 90.5.

In a mixture of dasatinib anhydride, lactose hydrate (Pharmacato (registered trademark) 200M / DFE Pharma), crystalline cellulose (CEOLUS (registered trademark) PH-101 / Asahi Kasei Chemical) and croscarmellose sodium in a mortar On the other hand, a solution obtained by dissolving hydroxypropylcellulose (HPC-SL / manufactured by Nippon Soda Co., Ltd.) in purified water was added dropwise and mixed to perform wet granulation. After wet granulation, it was dried and sized to obtain granules containing dasatinib.
The granules, crystalline cellulose and magnesium stearate obtained above were mixed together to obtain a mixed powder for tableting. The mixed powder is first tableted with a punching pressure of 600 kgf to obtain a circular tablet α (uncoated tablet, containing 20 mg of dasatinib) with a mass of 80.0 mg and a diameter of 6.0 mm, and further tableted with a punching pressure of 700 kgf. One tablet mass 200.0 mg and 8.0 mm diameter round tablet β (uncoated tablet, containing 50 mg dasatinib) were obtained. The drug substance and each additive were used in the above production in such an amount that each tablet had the formulation shown in Table 1 below.

    Dasatinib anhydride, lactose hydrate (Dilactose (registered trademark) F / Freund Sangyo Co., Ltd.), crystalline cellulose (CEOLUS (registered trademark) UF-711 / manufactured by Asahi Kasei Chemical), croscarmellose sodium and light anhydrous silicic acid ( AdSolider (registered trademark) 101 / manufactured by Freund Sangyo Co., Ltd.) was first mixed, and then magnesium stearate was added and mixed to obtain a mixed powder for tableting. The mixed powder is first tableted with a punching pressure of 600 kgf to obtain a circular tablet α (uncoated tablet, containing 20 mg of dasatinib) with a mass of 80.0 mg and a diameter of 6.0 mm, and further tableted with a punching pressure of 700 kgf. One tablet mass 200.0 mg and 8.0 mm diameter round tablet β (uncoated tablet, containing 50 mg dasatinib) were obtained. The drug substance and each additive were used in the above production in such an amount that each tablet had the formulation shown in Table 1 below.

  The formulation of each tablet obtained in Examples 1 and 2 is listed in Table 1 below (the content of the drug substance and each additive and the numerical unit of the tablet weight are in mg).

[Test Example 1]
The tablets obtained in Examples 1 and 2 were analyzed by powder X-ray diffraction measurement. The main points of the analysis results are shown in Table 2 below.

  From the results in Table 2, a characteristic peak was confirmed in the crystal form of dasatinib anhydride (type N-6) from each tablet of Examples 1 and 2, so that the crystal form remained stable before and after production. It was suggested that.

  Add 600.0 g of dasatinib anhydride to a spouted fluidized bed granulator (MP-01 / manufactured by POWREC) and fluidize it, and 240.0 g of aminoalkyl methacrylate copolymer E (manufactured by Eudragit EPO / Evonik Japan) 960 g of ethanol The liquid dissolved in was sprayed and dried to obtain a granulated product. This was sieved with a 30-mesh sieve to obtain sized granules.

  To 50.0 g of dasatinib anhydride in the mortar, 4.0 g of aminoalkyl methacrylate copolymer E (Eudragit EPO / Evonik Japan), 0.4 g of sodium lauryl sulfate (NIKKOL SLS / Nikko Chemicals) and stearic acid (Parteck LUB) A solution obtained by dissolving 0.6 g (STA50 / Merck) in 25 g of purified water was dropped and mixed to obtain a granulated product. This was sieved with a 30-mesh sieve to obtain sized granules.

  Dasatinib anhydride (525.0 g) was put into a fluidized bed fluidized bed granulator (MP-01 / Paulec) and fluidized, and aminoalkyl methacrylate copolymer E (Eudragit EPO / Evonik Japan) (210.0 g), lauryl sulfate. A solution obtained by dissolving 21.0 g of sodium (manufactured by Nikko Kol SLS / Nikko Chemicals) and 31.5 g of stearic acid (Parteck LUB STA50 / manufactured by Merck) in 1210 g of purified water is sprayed and dried to obtain a granulated product. Obtained. This was sieved with a 30-mesh sieve to obtain sized granules.

[Comparative Example 1]
200.0 g of dasatinib anhydride and 4.0 g of calcium silicate (FLORITE RE / manufactured by Tomita Pharmaceutical Co., Ltd.) were charged into an agitation granulator (VG-01 / manufactured by Paulek), and aminoalkyl methacrylate copolymer E (eudragit EPO / (Evonik Japan Co., Ltd.) A solution obtained by dissolving 48.0 g of ethanol in 72 g of ethanol was added dropwise and stirred (blade rotation speed: 370 rotations / minute, cross screw rotation speed: 3,500 rotations / minute) to obtain a granulated product. . This was sieved with a 30-mesh sieve to obtain sized granules.

[Comparative Example 2]
A granulated product was obtained by adding dropwise a solution of 12.0 g of aminoalkyl methacrylate copolymer E (Eudragit EPO / Evonik Japan) in 18 g of ethanol to 50.0 g of anhydrous dasatinib in a mortar and mixing them. This was sieved with a 30-mesh sieve to obtain sized granules.

  A list of the formulations of the granules obtained in Examples 3 to 5 and Comparative Examples 1 and 2 is shown in Table 4 below (the content of the drug substance and each additive and the numerical units of the weight of the granules are mg).

[Test Example 2]
The granules obtained in each of Examples 3 to 5 and Comparative Examples 1 and 2 were analyzed by a powder X-ray diffraction measurement method. The details of the analysis result are as shown in FIG.

  From FIG. 3, the granules obtained in Comparative Examples 1 and 2 are clearly different from the crystalline form of dasatinib anhydride (type N-6) (Journal of Pharmaceutical Sciences 105 (2016) 1489-1495). In contrast, it was confirmed that the granules obtained in Examples 3 to 5 showed the same peak as the crystalline form of dasatinib anhydride (however, in Example 3) It is confirmed that dasatinib in the obtained granule shows a slight but ethanol ethanol peak). Therefore, it is shown that dasatinib in the granules obtained in Examples 3 to 5 maintains the crystal form stably or almost stably before and after production. Therefore, in the wet granulation in the present invention, it is particularly preferable that the method is fluidized bed granulation, and it is considered that the granulation liquid containing the binder is more preferably an aqueous solution.

  What can be considered as a specific method for producing a tablet of the present invention is described below as a reference example.

[Reference Example 1]
Circular tablets α and β are obtained in the same manner as in the tablet production method of Example 1 except that “lactose hydrate” is replaced with “D-mannitol”.

[Reference Example 2]
Circular tablets α and β are obtained in the same manner as the tablet production method of Example 1 except that “hydroxypropylcellulose” is replaced with “hypromellose”.

[Reference Example 3]
Circular tablets α and β are obtained in the same manner as in the tablet production method of Example 1 except that “hydroxypropyl cellulose” is replaced with “polyvinyl alcohol”.

[Reference Example 2]
Circular tablets α and β are obtained in the same manner as the tablet production method of Example 1 except that “hydroxypropylcellulose” is replaced with “hypromellose”.

[Reference Example 4]
Circular tablets α and β are obtained in the same manner as the tablet production method of Example 1 except that “hydroxypropylcellulose” is replaced with “povidone”.

[Reference Example 4]
The circular tablets α and β obtained in Example 1 were put into a coating machine and stirred, and hypromellose, talc, titanium oxide, and a plasticizer (any one listed in Table 3) were added to purified water. Then, the uniformly dissolved and dispersed liquid is sprayed and dried to obtain film-coated tablets α′β ′.
Each additive is used in the production in such an amount that the film-coated tablet has a formulation shown in Table 3 below (the content unit of each additive and the numerical unit of the tablet weight is mg).

[Reference Example 5]
Film-coated tablets α′β ′ were prepared in the same manner as in the method for producing film-coated tablets of Reference Example 4 except that the “plasticizer (any of Table 3)” was not used and the contents of hypromellose and talc were used. obtain.

[Reference Example 6]
After mixing the crystalline form of dasatinib anhydride, lactose hydrate, crystalline cellulose, light anhydrous silicic acid, magnesium stearate and croscarmellose sodium, it is put into a dry granulator and applied with high pressure to form a lump. Dry granulation is performed by grinding. After dry granulation, the granules are sized to obtain granules containing dasatinib.
The above-obtained granule, crystalline cellulose, light anhydrous silicic acid and magnesium stearate are mixed together to obtain a mixed powder for tableting. The mixed powder is first tableted with a punching pressure of 600 kgf to obtain a circular tablet α (uncoated tablet, containing 20 mg of dasatinib) with a mass of 80.0 mg and a diameter of 6.0 mm, and further tableted with a punching pressure of 700 kgf. One tablet mass 200.0 mg, 8.0 mm diameter round tablet β (uncoated tablet, containing dasatinib 50 mg) is obtained. The drug substance and each additive are produced in such an amount that each tablet has the formulation shown in the following Table 4 (the content of drug substance and each additive, and the numerical unit of the tablet weight is mg). Used for.

[Reference Example 7]
A film was prepared in the same manner as the film-coated tablet production method of Reference Example 4 except that “the circular tablets α and β obtained in Example 1” were replaced with “the circular tablets α and β obtained in Reference Example 6”. Coated tablets α′β ′ are obtained respectively.

[Reference Example 8]
The film-coated tablets α′β ′ were respectively prepared in the same manner as in the method for producing the film-coated tablets of Reference Example 7 except that the “plasticizer (any of Table 3)” was not used and the contents of hypromellose and talc were not used. obtain.

[Reference Example 9]
The granule, lactose hydrate, crystalline cellulose, croscarmellose sodium and magnesium stearate obtained in Example 5 are mixed to obtain a mixture. The mixed powder is first tableted with a punching pressure of 600 kgf to obtain a circular tablet α (uncoated tablet, containing 20 mg of dasatinib) with a mass of 80.0 mg and a diameter of 6.0 mm, and further tableted with a punching pressure of 700 kgf. One tablet mass 200.0 mg, 8.0 mm diameter round tablet β (uncoated tablet, containing dasatinib 50 mg) is obtained. The drug substance and each additive are used in the above production in such an amount that the tablet has a formulation shown in Table 6 below (the content of the drug substance and each additive and the numerical unit of the tablet weight is mg). .

The present invention contributes to industrial production of a solid preparation by stably maintaining the crystal form of dasatinib anhydride.

Claims (8)

A method for producing a solid dosage form containing dasatinib in crystalline form,
A method for producing a solid preparation comprising a step of wet granulation using a crystalline form of dasatinib which is an anhydride. The method for producing a solid preparation according to claim 1, further comprising a step of wet granulating the powder containing dasatinib anhydride in a crystalline form by adding an aqueous solution containing a binder. The method for producing a solid preparation according to claim 2, wherein the wet granulation is fluidized bed granulation. The binder used in wet granulation is hydroxypropylcellulose, hypromellose, methylcellulose, povidone, polyvinyl alcohol, aminoalkyl methacrylate copolymer, polyvinyl alcohol / polyethylene glycol / graft copolymer and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. The manufacturing method of the solid formulation of Claim 2 or 3 selected. The manufacturing method of the solid formulation of Claim 2 or 3 whose binder used in the case of wet granulation is the aminoalkyl methacrylate copolymer E. The manufacturing method of the solid formulation in any one of Claims 2-4 including the process of tableting, after mixing the granule obtained by wet granulation with another additive, and manufacturing an uncoated tablet. A method for producing a solid dosage form containing dasatinib in crystalline form,
A method for producing a solid preparation, characterized in that a direct compression method is performed using dasatinib in crystalline form which is an anhydride. The manufacturing method of the solid formulation in any one of Claims 1-7 using the excipient | filler which is lactose hydrate and crystalline cellulose, the disintegrating agent which is croscarmellose sodium, and the lubricant agent which is magnesium stearate.