JP7579091B2 - Pharmaceutical tablets containing axitinib as an active ingredient and their manufacturing method - Google Patents

Description

The present invention relates to a pharmaceutical tablet containing axitinib as an active ingredient and capable of suppressing the dissolution of axitinib, and a method for producing the same.

Axitinib is a compound with the chemical name N-methyl-2-({3-[(1E)-2-(pyridin-2-yl)ethen-1-yl]-1H-indazol-6-yl}sulfanyl)benzamide and the structure shown in formula (1).

Axitinib is a selective kinase inhibitor targeting vascular endothelial growth factor receptors (VEGFR-1, -2 and -3). VEGFRs are major receptor tyrosine kinases that regulate angiogenesis and lymphangiogenesis and are involved in tumor growth and metastasis. Axitinib is available under the trade name Inlyta®.

Axitinib is available in the form of a film-coated pharmaceutical tablet. Non-Patent Document 1 describes a pharmaceutical tablet obtained by dry granulating a mixture of axitinib (XLI type), lactose hydrate, crystalline cellulose, and croscarmellose sodium, adding magnesium stearate to the mixture, and compressing the mixture into tablets. These tablets are prepared as a film-coated pharmaceutical tablet using a coating agent containing titanium oxide (Opadry (registered trademark) Red).

EUROPEAN MEDICINES AGENCY CHMP assessment report Inlyta

The object of the present invention is to provide a pharmaceutical tablet containing axitinib as an active ingredient, and to provide a tablet capable of suppressing dissolution and a method for producing the same.

The present inventors have discovered that a pharmaceutical tablet containing axitinib as an active ingredient can have a dissolution suppression effect by using a manufacturing method that includes a step of adding an aqueous solvent and granulating the tablet, and have completed the present invention. That is, the gist of the present invention is as follows: [1] to [15].

[1] A method for producing a pharmaceutical tablet containing axitinib as an active ingredient, comprising:
(1) mixing axitinib, an excipient, and a disintegrant to prepare a composition;
(2) adding an aqueous solvent to the composition to prepare a granule;
(3) forming the granulated material into a pharmaceutical tablet;
A method for producing a pharmaceutical tablet comprising the steps of:
The method for producing pharmaceutical tablets of axitinib includes a step of adding an aqueous solvent and granulating, which makes it possible to produce pharmaceutical tablets in which the dissolution property of axitinib is suppressed and controlled.
[2] The method according to [1], wherein the composition contains a binder.
In the present invention, by including a binder, it becomes possible to further suppress elution.
[3] The method according to [1] or [2], wherein the aqueous solvent contains a binder.
[4] The method according to any one of [1] to [3], wherein axitinib is a IV type polymorph.
The IV crystal polymorph of axitinib exhibits relatively rapid dissolution. Therefore, the present invention is suitable for use in cases where the IV crystal polymorph of axitinib is used as an active ingredient.
[5] The method according to any one of [1] to [4], wherein the pharmaceutical tablet has a moisture content of 1% by mass or more and 6% by mass or less.
[6] The method according to any one of [1] to [5], wherein the granules have a bulk density of 0.2 to 0.4 g/mL and an average particle size of 50 to 250 μm.

The axitinib tablet obtained by the manufacturing method described in [1] to [6] above has a clearly different dissolution property from the axitinib tablet prepared by the so-called dry granulation method, which is granulated without using an aqueous solvent. This suggests that the association state between axitinib and excipients and disintegrants in the tablet is different, and it is difficult to express it in terms of chemical structure, characteristics, etc. Therefore, it is appropriate to express the present invention as an axitinib tablet specified by the manufacturing method shown in [1] above, and it is considered that the requirement of clarity of the invention is satisfied.
[7] A pharmaceutical tablet containing axitinib as an active ingredient,
(1) mixing axitinib, an excipient, and a disintegrant to prepare a composition;
(2) adding an aqueous solvent to the composition to prepare a granule;
(3) forming the granulated material into a pharmaceutical tablet;
A pharmaceutical tablet obtained by a manufacturing method comprising the steps of:
[8] The pharmaceutical tablet of [7], further comprising a binder.
[9] The pharmaceutical tablet according to [7] or [8], wherein axitinib is a type IV polymorph.
[10] The pharmaceutical tablet according to any one of [7] to [9], wherein the pharmaceutical tablet has a moisture content of 1% by mass or more and 6% by mass or less.

The present application also includes an invention relating to a pharmaceutical tablet using the Form IV polymorph of axitinib.
[11] A pharmaceutical tablet containing axitinib as an active ingredient,
A pharmaceutical tablet comprising a granulation material containing the IV crystal polymorph of axitinib, an excipient, and a disintegrant.
[12] The pharmaceutical tablet according to [11], which contains a binder.
[13] The pharmaceutical tablet according to [11] or [12], which contains water and has a water content of 1% by mass or more and 6% by mass or less.
[14] The pharmaceutical tablet according to any one of [11] to [13], wherein axitinib is contained as a granule containing an excipient and a disintegrant.
[15] The pharmaceutical tablet according to any one of [11] to [13], wherein axitinib is contained as a granule containing an excipient, a disintegrant and a binder.

By using a manufacturing method including a step of adding an aqueous solvent according to the present invention and granulating the resulting pharmaceutical tablet, it is possible to provide a pharmaceutical tablet in which the dissolution of axitinib is suppressed and a manufacturing method for the pharmaceutical tablet.

The details of the present invention are described below.

The pharmaceutical tablet of the present invention uses axitinib as an active ingredient. Axitinib is a compound with the chemical name N-methyl-2-({3-[(1E)-2-(pyridin-2-yl)ethen-1-yl]-1H-indazol-6-yl}sulfanyl)benzamide. This compound is disclosed in Japanese Patent No. 3878849, and can be synthesized by the method described therein.

Axitinib may be used in the form of anhydrous axitinib, axitinib hydrate, an organic solvent solvate, or a pharma- ceutically acceptable salt thereof. For example, anhydrous axitinib, axitinib hydrate, ethanol solvate, THF solvate, and isopropanol solvate are all disclosed in Japanese Patent No. 5869197, and can be prepared by the method described therein. Axitinib is preferably used as a compound of a quality level that can be used as an active ingredient of pharmaceuticals.
In the present invention, it is preferable to use axitinib anhydrate as the tablet.
Axitinib anhydride has multiple crystal polymorphs. Representative examples include the XLI type crystal polymorph and the IV type crystal polymorph, which are disclosed in Japanese Patent No. 5869197 and Japanese Translation of PCT International Publication No. 2008-518904. The XLI polymorph is characterized by peaks at 2θ (°) of approximately 6.0, 11.5, 11.9, 12.5, 12.9, 14.9, 15.6, 16.2, 16.5, 17.9, 19.9, 20.7, 21.0, 21.6, 22.4, 22.8, 23.1, 24.2, 24.5, 25.0, 25.3, 25.6, 25.9, 26.4, 26.9, 27.7, 28.0, 28.1, 28.5, 29.9, 30.9, 31.5, 32.9, 33.2, 34.8, 35.0, and 36.1 in powder X-ray diffraction (XRD). The Form IV polymorph is characterized by powder X-ray diffraction (XRD) peaks at approximately 8.9, 12.0, 14.6, 15.2, 15.7, 17.8, 19.2, 20.5, 21.6, 23.2, 24.2, 24.8, 26.2, and 27.5 degrees 2θ.
In the present invention, the active ingredient, axitinib anhydride, can be used without any problem as long as it has the quality required for use as a pharmaceutical drug. In addition, the crystal polymorphism is not particularly limited and can be applied. Preferably, the IV type crystal polymorphism is applied.
The active ingredient, axitinib, is preferably used in an amount of 0.1% by mass to 10% by mass, more preferably 0.2% by mass to 5% by mass, based on the total amount of the pharmaceutical tablet.

In the present invention, the excipient may be cellulose such as crystalline cellulose, sugars such as lactose, mannitol, maltose, sucrose, sorbitol, xylitol, inositol, or starches such as corn starch, and it is preferable to use these alone or in combination of two or more. Preferred are crystalline cellulose, lactose, and mannitol, and the excipient contains one or more of these. The excipient is preferably a combination of crystalline cellulose and sugar, and preferably a combination of crystalline cellulose and lactose and/or mannitol. In the case of a combination excipient of crystalline cellulose and sugar, it is preferable that the crystalline cellulose is in excess of the sugar, and it is preferable that the crystalline cellulose is 1.1 to 5 parts by mass per part by mass of sugar. More preferably, it is 1.2 to 3 parts by mass of crystalline cellulose per part by mass of sugar. When an excipient is used, it is preferable to use it in an amount of 10% by mass or more and 95% by mass or less with respect to the total amount of the pharmaceutical tablet. It is preferably 40% by mass or more and 95% by mass or less.

In the present invention, examples of disintegrants include croscarmellose sodium, carboxymethylstarch sodium, crospovidone, carmellose, carmellose calcium, low-substituted carboxymethylstarch sodium, etc., and it is preferable to use these alone or in combination of two or more kinds. Preferred are croscarmellose sodium, carboxymethylstarch sodium, and crospovidone. More preferred is croscarmellose sodium.
When a disintegrant is used, it is preferably used in an amount of 1% by mass to 20% by mass, more preferably 2% by mass to 10% by mass, based on the total weight of the pharmaceutical tablet.

The method for producing pharmaceutical tablets of the present application includes a first step of (1) preparing a composition by mixing axitinib, an excipient, and a disintegrant. The composition may contain other additives such as binders, lubricants, colorants, solubilizers, flow agents, stabilizers, preservatives, and flavoring agents in addition to the above-mentioned components.

Examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, carmellose sodium, methylcellulose, partially pregelatinized starch, polyvinyl alcohol, etc., and these are preferably used alone or in combination of two or more. Preferred are hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, carmellose sodium, and methylcellulose.
When a binder is used, it is preferably used in an amount of 0.5% by mass to 20% by mass, more preferably 1% by mass to 10% by mass, based on the total weight of the pharmaceutical tablet.

Hydroxypropyl cellulose is generally regulated by its molecular weight according to the GPS method and the viscosity of a 2% aqueous solution at 20°C. It is preferable to use one with a molecular weight of 40,000 or more according to the GPS method. Alternatively, it is preferable to use one with a viscosity of 2 or more in a 2% aqueous solution at 20°C. Examples of the above hydroxypropyl cellulose include NISSO HPC (Nippon Soda Co., Ltd.), and grades SSL (molecular weight 40,000, viscosity 2-2.9 mPa·s), SL (molecular weight 100,000, viscosity 3-5.9 mPa·s), L (molecular weight 140,000, viscosity 6-10 mPa·s), M (molecular weight 700,000, viscosity 150-400 mPa·s), and H (molecular weight 910,000, viscosity 1,000-4,000 mPa·s), which can be used. It is preferable to use one with a molecular weight of 140,000 or more according to the GPS method. It is also preferable that the viscosity of a 2% aqueous solution at 20°C is 6 to 10 mPa·s or more. In other words, it is preferable to use grade L (molecular weight 140,000, viscosity 6 to 10 mPa·s), grade M (molecular weight 700,000, viscosity 150 to 400 mPa·s), or grade H (molecular weight 910,000, viscosity 1,000 to 4,000 mPa·s).

Hydroxypropyl methylcellulose is generally rated according to the viscosity of a 2% aqueous solution at 20°C. It is preferable to use one with a viscosity of 3 or more when the solution is 2% at 20°C. Examples of the above hydroxypropyl methylcellulose include TC-5 (Shin-Etsu Chemical Co., Ltd.), and there are grades E (viscosity 3 mPa·s), M (viscosity 4.5 mPa·s), R (viscosity 6 mPa·s), and S (viscosity 15 mPa·s), which are preferably used. It is preferable that the viscosity of a 2% aqueous solution at 20°C is 6 mPa·s or more. In other words, it is preferable to use grades R (viscosity 6 mPa·s) and S (viscosity 15 mPa·s).

Povidone is generally rated according to its molecular weight and viscosity as determined by light scattering. It is preferable to use one with a molecular weight of 44,000 or more as determined by light scattering. Alternatively, it is preferable to use one with a viscosity of 5.5 mPa·s or more. Examples of the povidone include Kollidon (BASF Corporation), which includes grade 30 (molecular weight 44,000-54,000, viscosity 5.5 mPa·s) and grade 90F (molecular weight 1,000,000-1,500,000, viscosity 300-700 mPa·s), and it is preferable to use these.

The standard for carmellose sodium is generally determined by the degree of etherification (degree of substitution) and the viscosity at 25°C, 60 rpm. It is preferable to use one with a degree of etherification (degree of substitution) of 0.6 to 0.8. Alternatively, it is preferable that the 2% viscosity at 25°C, 60 rpm is 100 to 200 mPa·s, and the 1% viscosity at 25°C, 60 rpm is 20 mPa·s or more. Examples of the above carmellose sodium include CMC Daicel (Daicel Miraize Co., Ltd.), and grades 1110 (2% viscosity at 25°C, 60 rpm is 100 to 200 mPa·s), 1120 (1% viscosity at 25°C, 60 rpm is 20 to 50 mPa·s), 1130 (1% viscosity at 25°C, 60 rpm is 50 to 100 mPa·s), 1140 (1% viscosity at 25°C, 60 rpm is 100 to 200 mPa·s), 1150 (1% viscosity at 25°C, 60 rpm is 100 to 200 mPa·s), 1160 (1% viscosity at 25°C, 60 rpm is 100 to 200 mPa·s), 1170 (1% viscosity at 25°C, 60 rpm is 100 to 200 mPa·s), 1180 (1% viscosity at 25°C, 60 rpm is 100 to 200 mPa·s), 1190 (1% viscosity at 25°C, 60 rpm is 100 to 200 mPa·s), 1200 (1% viscosity at 25°C, 60 rpm is 100 Grade 50 (1% viscosity at 25°C, 60 rpm is 200-300 mPa·s), Grade 1160 (1% viscosity at 25°C, 60 rpm is 300-500 mPa·s), Grade 1170 (1% viscosity at 25°C, 60 rpm is 500-800 mPa·s), Grade 1180 (1% viscosity at 25°C, 60 rpm is 1000-1300 mPa·s), Grade 1190 (1% viscosity at 25°C, 60 rpm is 1300-2000 mPa·s), etc. are available, and it is preferable to use these.

Methylcellulose is generally rated according to the viscosity of a 2% aqueous solution at 20°C. It is preferable to use methylcellulose with a viscosity of 4 or more when the solution is 2% at 20°C. Examples of the methylcellulose include METOLOSE SM (Shin-Etsu Chemical Co., Ltd.), and there are grades 4 (viscosity 4 mPa·s), 4VF (viscosity 4 mPa·s), 15 (viscosity 15 mPa·s), 25 (viscosity 25 mPa·s), 100 (viscosity 100 mPa·s), 400 (viscosity 400 mPa·s), 1500 (viscosity 1500 mPa·s), and 4000 (viscosity 4000 mPa·s), which are preferably used.

Examples of lubricants include magnesium stearate, stearic acid, zinc stearate, aluminum stearate, glycerin monostearate, sodium stearyl fumarate, calcium stearate, talc, carnauba wax, and the like. These are preferably used alone or in combination of two or more kinds.
When a lubricant is used, it is preferably used in an amount of 0.1% by mass to 10% by mass, more preferably 0.2% by mass to 5% by mass, based on the total weight of the pharmaceutical tablet.

Examples of colorants include titanium oxide, ferric oxide, talc, yellow ferric oxide, yellow ferric oxide, black ferric oxide, zinc oxide, brown ferric oxide, edible yellow dyes, edible blue dyes, edible red dyes, etc. Preferred are titanium oxide and ferric oxide.
When a colorant is used, it is preferably used in an amount of 0.1% by mass to 20% by mass, more preferably 0.2% by mass to 10% by mass, based on the total weight of the pharmaceutical tablet.

Examples of solubilizers include sodium lauryl sulfate, soybean lecithin, refined soybean lecithin, sorbitan fatty acid ester, soybean oil, lauromacrogol, and the like.
The fluidizing agent includes light anhydrous silicic acid, talc, hydrous silicon dioxide, and the like.
The stabilizer may include dibutylhydroxytoluene, tocopherol, sulfite, and the like.
Examples of preservatives include paraoxybenzoic acid esters.
Examples of flavoring agents include sucrose, D-sorbitol, and xylitol.

These additives can be used without any particular restrictions as long as they have a purity acceptable for use in pharmaceutical formulations. These additives may be used alone or as a mixture. They are used optionally when preparing the pharmaceutical composition or pharmaceutical formulation.

In the first step of the present invention, a composition is prepared by mixing axitinib, excipients, disintegrants, and any other additives. The mixing method may be V-type mixing, W-type mixing, drum-type mixing, ribbon mixing, conical screw mixing, etc., and mixing is terminated when the degree of bulk loss becomes small.

The method for producing pharmaceutical tablets of the present application includes a second step of (2) adding an aqueous solvent to the composition to prepare a granulation product.
The aqueous solvent is a solvent containing water, and may be water alone or a mixed solvent of water and a water-miscible organic solvent. Examples of the water-miscible organic solvent include volatile organic solvents having a boiling point of 100° C. or less, such as ethanol and acetone. When a water-miscible organic solvent is used, it is applied in an amount of 0.1 to 1 part by volume per 1 part by volume of water. The aqueous solvent is preferably water alone.
The aqueous solvent may contain a binder. The binder is as described above, and the amount of the binder added is 0.5% by mass to 20% by mass, preferably 1% by mass to 10% by mass, based on the total weight of the pharmaceutical tablet.
The aqueous solvent can be used in any amount, preferably from 5% by mass to 100% by mass, more preferably from 10% by mass to 80% by mass, and even more preferably from 20% by mass to 60% by mass, based on the total amount of the composition.

In the second step, an aqueous solvent is added to the composition to prepare a granulated product. The method for preparing the granulated product is characterized by the procedure of mixing axitinib and the additives, adding an aqueous solvent thereto, granulating, drying, sizing if necessary, and then sieving appropriately if necessary to obtain a granulated product, which is carried out by a so-called wet granulation method. Specific wet granulation methods include agitation granulation, fluidized bed granulation, and extrusion granulation.

The bulk density of the granulated product is preferably 0.2 to 0.4 g/mL, more preferably 0.25 to 0.35 g/mL, and the average particle size of the granulated product is preferably 50 to 250 μm, more preferably 75 to 225 μm.
The moisture content of the granulated product is preferably 10% by mass or less, more preferably 1% by mass or more and 6% by mass or less, and even more preferably 3% by mass or more and 6% by mass or less.
The bulk density of a granulated product is a value obtained by measuring the volume of a certain weight of the granulated product. The bulk density can be measured by precisely weighing the granulated product, then putting it into a container with a volume scale, and measuring the volume of the granulated product, or by precisely weighing the granulated product after putting it into a container with a volume scale and measuring the volume of the granulated product. In the present application, the bulk density is measured by precisely weighing 10 g of the granulated product, putting it into a 50 mL container, and measuring the volume of the granulated product without tapping.
The average particle size of the granulated product is the particle size at which the cumulative mass is 50% when the particle size distribution of the granulated product is measured, and indicates the so-called median diameter (d50). The particle size distribution can be measured by the sieving method of the Particle Size Measurement Method 2 described in the 17th Revised Japanese Pharmacopoeia, and the average particle size is measured using sieves with openings of 500 μm, 355 μm, 250 μm, 180 μm, 150 μm, 125 μm, 106 μm, and 75 μm.
The moisture content of the granulated material is a value obtained by the loss on drying method, in which the granulated material is precisely weighed, spread on a baking sheet, and dried at atmospheric pressure at 80° C. for 15 minutes or more until a constant weight is reached, at which the loss in weight is regarded as the moisture content.

The method for producing a pharmaceutical tablet of the present application includes a third step (3) of molding the granulated material into a pharmaceutical tablet. That is, the granulated material is mixed with any other additives, and the mixture is molded into a pharmaceutical tablet.
The other additives include excipients, disintegrants, binders, lubricants, colorants, solubilizers, flow agents, stabilizers, preservatives, flavoring agents, etc. The types and amounts of these additives are as described above. The amount to be applied should take into account the total amount through the first to third steps, and is the content relative to the total amount of the pharmaceutical tablet.
These additives can be used without any particular limitation as long as they have a purity acceptable for use in pharmaceutical preparations. These additives may be used alone or in combination. They are optionally used when preparing the pharmaceutical composition or pharmaceutical preparation.

Methods for forming the pharmaceutical tablets include rotary tableting and single shot tableting, and the pharmaceutical tablets are prepared by forming the pharmaceutical tablets using these methods. The dosage form may be any of the following: plain tablets, film-coated tablets, dispersible tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, etc.

The pharmaceutical tablet may be further coated with a coating agent and any plasticizer, light-blocking agent, colorant, etc. to form a film-coated tablet.

Examples of coating agents include hydroxypropyl methylcellulose, polyvinyl alcohol, hydroxypropyl cellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, hydroxypropyl methylcellulose phthalate, ethyl cellulose, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, ethyl acrylate-methyl methacrylate copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like. It is preferable to use these alone or in combination of two or more kinds.
The coating agent is preferably used in an amount of 0.1% by mass to 20% by mass, more preferably 0.2% by mass to 10% by mass, based on the total weight of the pharmaceutical tablet.

Examples of the plasticizer include triacetin, triethyl citrate, glycerin, propylene glycol, polyethylene glycol, polysorbate, D-sorbitol, and liquid paraffin. It is preferable to use these alone or in combination of two or more kinds.
When a plasticizer is used, it is preferably used in an amount of 0.1% by mass to 20% by mass, more preferably 0.2% by mass to 10% by mass, based on the total weight of the pharmaceutical tablet.

Examples of light-shielding agents and colorants include titanium oxide, ferric oxide, talc, yellow ferric oxide, yellow ferric oxide, black ferric oxide, zinc oxide, brown ferric oxide, edible yellow dyes, edible blue dyes, edible red dyes, etc. Titanium oxide and ferric oxide are preferred.
When a light shielding agent or coloring agent is used, it is preferable to use it in an amount of 0.1% by mass to 20% by mass, and more preferably 0.2% by mass to 10% by mass, based on the total amount of the pharmaceutical tablet.

The manufacturing process for film-coated tablets can involve dissolving or suspending the coating agent and any plasticizer, light-blocking agent, colorant, etc. in an aqueous solvent to prepare an aqueous solution of the coating agent, which is then applied to the tablet surface by spraying or the like, and then blowing hot air to remove the solvent from the tablet surface and dry it.
The aqueous solvent is a solvent containing water, and may be water alone or a mixed solvent of water and a water-miscible organic solvent, such as ethanol or acetone.

The pharmaceutical tablet of the present invention contains water because a wet granulation method is used in the manufacturing process. The pharmaceutical tablet has a moisture content of 1% by mass or more and 6% by mass or less. More specifically, the moisture content is 2% by mass or more and 5% by mass or less, and more specifically, 3% by mass or more and 5% by mass or more.
The moisture content in the present invention is a value measured by the loss on drying method. In the present invention, the measurement conditions of the loss on drying method are as follows: the pharmaceutical tablet is precisely weighed, spread on a baking sheet, and dried at atmospheric pressure at 80° C. for 15 minutes or more, and the weight loss at the time of a constant weight is calculated as the moisture content.

The present application also includes an invention relating to a pharmaceutical tablet containing axitinib as an active ingredient, which contains the IV-type polymorph of axitinib, an excipient, and a disintegrant. That is, the pharmaceutical tablet is a pharmaceutical tablet obtained by molding a composition containing the IV-type polymorph of axitinib as an active ingredient, an excipient, and a disintegrant. The types and suitable contents of the IV-type polymorph of axitinib, the excipient, and the disintegrant are as described above.
The pharmaceutical tablet preferably contains a binder, the type and preferred content of which are as described above.

The pharmaceutical tablet containing the IV-type polymorph of axitinib as an active ingredient is preferably a tablet containing a granulated material containing the IV-type polymorph of axitinib, an excipient, and a disintegrant. Alternatively, it is preferably a tablet containing a granulated material containing the IV-type polymorph of axitinib, an excipient, a disintegrant, and a binder. The granulated material is preferably a granulated material prepared by a wet granulation method. The wet granulation method and the granulated material are the same as those described above.

In addition to the above ingredients, the pharmaceutical tablet may contain typical pharmaceutical additives for preparing pharmaceutical preparations, such as lubricants, colorants, solubilizers, flow agents, stabilizers, preservatives, flavoring agents, etc. The types and suitable contents of the additives are as described above.
The pharmaceutical tablet may be a film-coated tablet coated with a coating agent and an optional plasticizer, light-shielding agent, colorant, etc. The types and suitable contents of the additives are as described above.

The pharmaceutical tablet containing the axitinib IV crystal polymorph as an active ingredient contains water. The water content is 1% by mass or more and 6% by mass or less. More specifically, the water content is 2% by mass or more and 5% by mass or less, and more specifically, 3% by mass or more and 5% by mass or less.
The moisture content of the pharmaceutical tablet is calculated by the loss on drying method.

The pharmaceutical tablet containing axitinib as an active ingredient obtained by the present invention can suppress and control the dissolution of axitinib. In particular, the pharmaceutical tablet can control the dissolution at pH 3.0, and can provide a pharmaceutical tablet that provides appropriate pharmacokinetics of axitinib.
The dissolution of the pharmaceutical tablet of the present invention can be confirmed by a normal dissolution test method. As an example of the dissolution test method, it is preferable to use a diluted McIlvaine's buffer solution as the aqueous solution of pH 3.0 in the dissolution test. Then, using 900 mL of the test solution, the active ingredient is dissolved from the pharmaceutical tablet prepared according to the present invention into the test solution by the dissolution test method according to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method), and the dissolution rate into the test solution is evaluated using an ultraviolet-visible spectrophotometer or liquid chromatography, thereby confirming the excellent dissolution inhibition effect that is a feature of the present invention.

The present invention will be further explained below with reference to examples. However, the present invention is not limited to these examples.

[Example 1]
The contents per tablet were 5 mg of axitinib (IV type), 58.8 mg of lactose hydrate, 96.3 mg of crystalline cellulose, 8.7 mg of croscarmellose sodium, and 5.2 mg of hydroxypropylcellulose (NISSO HPC L FP, manufactured by Nippon Soda Co., Ltd., with a molecular weight of 140,000 by GPS method and a viscosity of 2% aqueous solution at 20 ° C. of 6 to 10 mPa · s). 50 μL of purified water was added to this ratio, and stirred and granulated. The obtained granules were dried at 60 ° C. for 1 hour. The obtained granules were granules with a bulk density of 0.291 g / mL and an average particle size of 140 μm. The loss on drying of the obtained granules was 3.10%. The tablets according to Example 1 were prepared by mixing and tableting at a ratio of 1.8 mg of magnesium stearate to 174 mg of this granules. The loss on drying of the resulting tablets was 3.11%.

[Example 2]
In Example 1, 5.2 mg of hydroxypropyl cellulose (NISSO HPC L FP) was changed to 5.2 mg of hydroxypropyl cellulose (NISSO HPC M FP, manufactured by Nippon Soda Co., Ltd., molecular weight measured by the GPS method is 700,000, and viscosity of a 2% aqueous solution at 20°C is 150 to 400 mPa·s), and otherwise the tablet of Example 2 was prepared in the same manner.
The obtained granules had a bulk density of 0.284 g/mL and an average particle size of 186 μm. The loss on drying of the obtained granules was 3.33%. The loss on drying of the obtained tablets was 3.35%.

[Example 3]
In Example 1, 5.2 mg of hydroxypropyl cellulose (NISSO HPC L FP) was changed to 5.2 mg of hydroxypropyl cellulose (NISSO HPC H FP, manufactured by Nippon Soda Co., Ltd., molecular weight as measured by the GPS method is 1,000,000, viscosity of a 2% aqueous solution at 20°C is 1,000 to 4,000 mPa·s), and otherwise the tablet of Example 3 was prepared in the same manner.
The obtained granules had a bulk density of 0.292 g/mL and an average particle size of 186 μm. The loss on drying of the obtained granules was 3.35%. The loss on drying of the obtained tablets was 3.34%.

[Example 4]
In Example 1, 5.2 mg of hydroxypropyl cellulose (NISSO HPC L FP) was changed to 5.2 mg of hydroxypropyl methylcellulose (TC-5 R, manufactured by Shin-Etsu Chemical Co., Ltd., substitution type 2910, viscosity of 2% aqueous solution at 20°C is 6 mPa·s), and otherwise the tablet of Example 4 was prepared in the same manner.
The obtained granules had a bulk density of 0.289 g/mL and an average particle size of 137 μm. The loss on drying of the obtained granules was 3.42%. The loss on drying of the obtained tablets was 3.41%.

[Example 5]
In Example 1, 5.2 mg of hydroxypropyl cellulose (NISSO HPC L FP) was changed to 5.2 mg of povidone (Kollidon 30, manufactured by BASF Corporation, molecular weight measured by light scattering method is 44,000 to 54,000, viscosity of 2% aqueous solution at 20°C is 5.5 mPa·s), and otherwise the tablet of Example 5 was prepared in the same manner.
The obtained granules had a bulk density of 0.310 g/mL and an average particle size of 153 μm. The loss on drying of the obtained granules was 3.50%. The loss on drying of the obtained tablets was 3.49%.

[Example 6]
In Example 1, 5.2 mg of hydroxypropyl cellulose (NISSO HPC L FP) was changed to 5.2 mg of sodium carboxymethyl cellulose (CMC Daicel 1110, manufactured by Daicel Miraize Co., Ltd., degree of etherification (degree of substitution) 0.6 to 0.8, viscosity of a 2% aqueous solution at 25°C and 60 revolutions is 100 to 200 mPa·s), and the rest was prepared in the same manner as in Example 6.
The obtained granules had a bulk density of 0.320 g/mL and an average particle size of 171 μm. The loss on drying of the obtained granules was 3.57%. The loss on drying of the obtained tablets was 3.55%.

[Example 7]
In Example 1, 5.2 mg of hydroxypropyl cellulose (NISSO HPC L FP) was changed to 5.2 mg of methyl cellulose (METOLOSE SM 4VF, manufactured by Shin-Etsu Chemical Co., Ltd., 26 to 33% methoxy group, viscosity of 2% aqueous solution at 20°C is 4 mPa·s), and otherwise the tablet of Example 7 was prepared in the same manner.
The obtained granules had a bulk density of 0.312 g/mL and an average particle size of 149 μm. The loss on drying of the obtained granules was 3.19%. The loss on drying of the obtained tablets was 3.20%.

[Example 8]
The tablet of Example 8 was prepared in the same manner as in Example 1, except that 5.2 mg of hydroxypropyl cellulose (NISSO HPC L FP, manufactured by Nippon Soda Co., Ltd., having a molecular weight of 140,000 by the GPS method and a viscosity of a 2% aqueous solution at 20° C. of 6 to 10 mPa·s) that had been mixed before adding 50 μL of purified water was dissolved in 50 μL of purified water to achieve this ratio and then added.
The obtained granules had a bulk density of 0.271 g/mL and an average particle size of 138 μm. The loss on drying of the obtained granules was 3.37%. The loss on drying of the obtained tablets was 3.36%.

[Example 9]
The tablets of Example 9 were prepared in the same manner as in Example 1, except that 50 μL of purified water was changed to 75 μL of purified water.
The obtained granules had a bulk density of 0.329 g/mL and an average particle size of 202 μm. The loss on drying of the obtained granules was 3.40%. The loss on drying of the obtained tablets was 3.39%.

[Example 10]
The tablet of Example 10 was prepared in the same manner as in Example 1, except that 96.3 mg of crystalline cellulose and 5.2 mg of hydroxypropyl cellulose (NISSO HPC L FP) were changed to 92.8 mg of crystalline cellulose and 8.7 mg of hydroxypropyl cellulose (NISSO HPC L FP).
The obtained granules had a bulk density of 0.276 g/mL and an average particle size of 194 μm. The loss on drying of the obtained granules was 3.24%. The loss on drying of the obtained tablets was 3.26%.

[Example 11]
A tablet of Example 11 was prepared in the same manner as in Example 1, except that 96.3 mg of crystalline cellulose and 5.2 mg of hydroxypropyl cellulose (NISSO HPC LF) in Example 1 were changed to 101.5 mg of crystalline cellulose.
The obtained granules had a bulk density of 0.306 g/mL and an average particle size of 101 μm. The loss on drying of the obtained granules was 3.40%. The loss on drying of the obtained tablets was 3.39%.

[Reference Example 1]
The contents per tablet were mixed to a ratio of 5 mg axitinib (IV type), 83 mg lactose hydrate, 83 mg crystalline cellulose, and 9.1 mg croscarmellose sodium, and dry granulated using a roller compactor. The obtained granules were sized using a speed mill and a 16M screen. The obtained granules had a bulk density of 0.510 g/mL and an average particle size of 209 μm. The loss on drying of the obtained granules was 2.97%. The tablets according to Reference Example 1 were prepared by mixing and tableting the dry granules to a ratio of 1.8 mg magnesium stearate to 180.1 mg of the dry granules. The loss on drying of the obtained tablets was 2.97%.

[Test Example 1]
The dissolution rates of the tablets of Examples 1 to 11 and Reference Example 1 were evaluated using an aqueous solution of pH 3.0 prepared with diluted McIlvaine's buffer solution according to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method).
The dissolution rate was evaluated using a dissolution tester (NTR-6200A, manufactured by Toyama Sangyo Co., Ltd.) and an ultraviolet-visible spectrophotometer (UV-1700, manufactured by Shimadzu Corporation) with a test liquid volume of 900 mL, a test liquid temperature of 37±0.5° C., and a paddle rotation speed of 50 rpm.
The axitinib dissolution rates at each time point for each tablet sample are summarized in Table 1.

The pharmaceutical tablet of the present invention has a dissolution rate of 30% or less in the first 15 minutes of dissolution, and 50% or less in 60 minutes, and is able to suppress and control the dissolution of axitinib. In other words, it is possible to provide a pharmaceutical tablet with suppressed dissolution of axitinib.

Claims (3)

A method for producing a pharmaceutical tablet containing axitinib as an active ingredient, comprising:
(1) mixing axitinib, an excipient , a disintegrant and a binder to prepare a composition;
(2) adding an aqueous solvent to the composition to prepare a granule;
(3) forming the granulated material into a pharmaceutical tablet;
Including,
The binder is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, carmellose sodium, and methylcellulose;
The moisture content of the pharmaceutical tablet is 1% by mass or more and 6% by mass or less;
Manufacturing method of pharmaceutical tablets. The method of claim 1 , wherein axitinib is a type IV polymorph. The method according to claim 1 or 2 , wherein the granules have a bulk density of 0.2 to 0.4 g/mL and an average particle size of 50 to 250 μm.