JP7628020B2 - A pharmaceutical tablet containing axitinib as the active ingredient - Google Patents

Description

The present invention relates to a pharmaceutical tablet that contains axitinib as an active ingredient and can suppress the dissolution of axitinib.

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). VEGFR is a major receptor tyrosine kinase that regulates angiogenesis and lymphangiogenesis and is involved in tumor growth and metastasis. Axitinib is available under the trade name Inlyta® tablets.
It is known that axitinib has multiple types of crystalline polymorphism. Patent Document 1 discloses axitinib polymorphs I, II, III, IV, VI, VII and VIII. Patent Document 2 also describes polymorphism XLI, crystalline polymorphisms including multiple types of solvates, and amorphous forms. Different crystalline polymorphs have different physical properties such as water solubility, and therefore different dissolution and absorption properties in pharmaceuticals. Among these, existing axitinib formulations are provided as film-coated pharmaceutical tablets using anhydrous XLI crystalline polymorphism as an active ingredient. Non-Patent Document 1 describes a pharmaceutical tablet obtained by dry granulating a mixture of axitinib (XLI), lactose hydrate, crystalline cellulose and croscarmellose sodium, adding magnesium stearate to the mixture and tableting the mixture, and a pharmaceutical tablet film-coated with a coating agent containing titanium oxide (Opadry (registered trademark) Red).

Special Publication No. 2008-518904 Patent No. 5869197

EUROPEAN MEDICINES AGENCY CHMP assessment report Inlyta

In pharmaceutical tablets, rapid dissolution of the active ingredient can cause side effects, so it is desirable that the dissolution be appropriately controlled. The present inventors have found that the solubility varies greatly depending on the crystalline polymorphism of the axitinib drug substance, and that the dissolution varies greatly when pharmaceutical tablets are prepared using drug substances with different crystalline polymorphisms. The object of the present invention is to provide a pharmaceutical tablet containing axitinib as an active ingredient, which can suppress dissolution. In particular, the object of the present invention is to provide a pharmaceutical tablet in which the dissolution is suppressed and controlled, regardless of the crystalline polymorphism of the axitinib drug substance.

The present inventors have discovered that it is possible to impart a dissolution suppression effect to pharmaceutical tablets containing axitinib as an active ingredient by adding polyvinyl acetate, and have completed the present invention. That is, the present invention is summarized as follows: [1] to [11].

[1] A pharmaceutical tablet containing axitinib and polyvinyl acetate.
By incorporating polyvinyl acetate into a pharmaceutical tablet of axitinib, it is possible to obtain a pharmaceutical tablet in which the dissolution property of axitinib is suppressed and controlled.
[2] The pharmaceutical tablet according to [1], containing 0.5 to 15 parts by mass of polyvinyl acetate per part by mass of axitinib.
[3] The pharmaceutical tablet according to [1] or [2], which contains a water-soluble polymer.
[4] The pharmaceutical tablet according to any one of [1] to [3], wherein the polyvinyl acetate is a granule containing polyvinyl acetate and a water-soluble polymer.
[5] The pharmaceutical tablet according to any one of [1] to [4], further comprising a poorly water-soluble excipient.
By using a poorly water-soluble excipient, the dissolution rate can be adjusted, and a pharmaceutical tablet of axitinib having the desired dissolution property can be prepared.
[6] The pharmaceutical tablet according to [5], containing 50 to 95% by mass of the poorly water-soluble excipient.
[7] The pharmaceutical tablet according to any one of [1] to [6], further comprising a disintegrant.
Even in the case of a pharmaceutical tablet of axitinib containing a disintegrant, it is possible to obtain a pharmaceutical tablet having a suppressed and controlled dissolution property.
[8] The pharmaceutical tablet according to any one of [1] to [7], comprising a granule containing axitinib, polyvinyl acetate and a poorly water-soluble excipient.
[9] The pharmaceutical tablet according to any one of [1] to [8], containing 0.1 to 10% by mass of axitinib.

[10] A method for producing a pharmaceutical tablet containing axitinib as an active ingredient, comprising:
(1) mixing axitinib and polyvinyl acetate in the absence of a solvent to prepare a composition;
(2) molding the composition into a pharmaceutical tablet;
A method for producing a pharmaceutical tablet comprising the steps of:
[11] A method for producing a pharmaceutical tablet containing axitinib as an active ingredient, comprising:
(1) mixing axitinib and polyvinyl acetate in the absence of a solvent to prepare a composition;
(2) compressing 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:

In pharmaceutical tablets containing axitinib as an active ingredient, the application of polyvinyl acetate can effectively control the dissolution of axitinib. In particular, dissolution in the acidic range, such as pH 1.2, can be suppressed, and pharmaceutical tablets with the desired dissolution characteristics can be provided.

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 anhydrous axitinib, hydrated axitinib, an organic solvent solvate, or a pharma- ceutically acceptable salt thereof. For example, anhydrous axitinib, hydrated axitinib, 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 a compound of a quality level that can be used as an active ingredient of pharmaceuticals.
In the tablet of the present invention, it is preferable to use axitinib anhydrate as axitinib.
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.

The present invention is characterized by using polyvinyl acetate. It is preferable to use polyvinyl acetate having a molecular weight of 300,000 to 600,000. The molecular weight is preferably 400,000 to 500,000.
The polyvinyl acetate is preferably used in an amount of 0.5 parts by mass or more and 15 parts by mass or less, more preferably 0.6 parts by mass or more and 13 parts by mass or less, and even more preferably 0.7 parts by mass or more and 11 parts by mass or less, relative to 1 part by mass of axitinib.
In addition, polyvinyl acetate is preferably used in an amount of 0.5% by mass to 50% by mass, more preferably 1% by mass to 40% by mass, more preferably 1.5% by mass to 35% by mass, and even more preferably 2% by mass to 30% by mass, based on the total amount of the pharmaceutical tablet.

The present invention preferably contains a water-soluble polymer. Examples of the water-soluble polymer include povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carmellose sodium, methylcellulose, partially pregelatinized starch, polyvinyl alcohol, etc., and it is preferable to use these alone or in combination of two or more. Povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carmellose sodium, and methylcellulose are preferable. Povidone is more preferable.
When a water-soluble polymer is used, it is preferably used in an amount of 0.1% by mass to 15% by mass, more preferably 0.3% by mass to 10% by mass, based on the total weight of the pharmaceutical tablet.

As the polyvinyl acetate, it is preferable to use a granulated product with the water-soluble polymer. A granulated product containing polyvinyl acetate, the water-soluble polymer, and a solubilizing agent may be used. Alternatively, a granulated product containing polyvinyl acetate, the water-soluble polymer, a solubilizing agent, and a fluidizing agent may be used.
The granules containing polyvinyl acetate and a water-soluble polymer may be granules obtained by mixing these components and dry granulating them without using a solvent, or may be granules obtained by mixing these components and wet granulating them with a solvent, or may be granules prepared by spray drying.

Examples of solubilizing agents used in granules containing polyvinyl acetate include sodium lauryl sulfate, soybean lecithin, refined soybean lecithin, sorbitan fatty acid ester, soybean oil, lauromacrogol, etc., and these are preferably used alone or in combination of two or more kinds. Sodium lauryl sulfate is preferred.
When a solubilizer is used, it is preferably used in an amount of 0.005% by mass to 0.5% by mass, more preferably 0.01% by mass to 0.4% by mass, based on the total weight of the pharmaceutical tablet.
Examples of the fluidizing agent used in the granulation material containing polyvinyl acetate include silicon dioxide, light anhydrous silicic acid, talc, etc., and it is preferable to use these alone or in combination of two or more of them. Silicon dioxide is preferable.
When a fluidizing agent is used, it is preferably used in an amount of 0.001% by mass to 0.2% by mass, more preferably 0.0025% by mass to 0.15% by mass, based on the total weight of the pharmaceutical tablet.

As the polyvinyl acetate, it is preferable to use a premix type additive prepared by previously mixing polyvinyl acetate and an additive containing a water-soluble polymer and granulating the mixture.
Preferably, the polyvinyl acetate used is a premix type additive prepared by previously mixing and granulating additives including polyvinyl acetate, a water-soluble polymer, a solubilizer, and a fluidizer.
More preferably, the polyvinyl acetate used is a premix type additive prepared by previously mixing and granulating additives containing polyvinyl acetate, povidone, sodium lauryl sulfate, and silicon dioxide.
When a granulated product made of polyvinyl acetate, povidone, sodium lauryl sulfate, and silicon dioxide is used, it is preferable to use 75 to 85% by mass of polyvinyl acetate, 18 to 21% by mass of povidone, 0.1 to 1% by mass of sodium lauryl sulfate, and 0.1 to 1% by mass of silicon dioxide. For example, a premixed additive (Kollidon (registered trademark) SR BASF) made of polyvinyl acetate, povidone, sodium lauryl sulfate, and silicon dioxide is known and available. Kollidon (registered trademark) SR is a granular additive containing 80.0% by mass of polyvinyl acetate (molecular weight about 450,000), 19.0% by mass of povidone (molecular weight about 50,000), 0.8% by mass of sodium lauryl sulfate, and 0.2% by mass of silicon dioxide, with an average particle size of 80 to 100 μm and a bulk density of about 0.45 g/mL. In the present invention, it is preferable to use Kollidon (registered trademark) SR.

In the present invention, it is preferable to use a poorly water-soluble excipient. Examples of poorly water-soluble excipients include celluloses such as crystalline cellulose, starches such as corn starch, magnesium aluminometasilicate, anhydrous calcium hydrogen phosphate, etc., and it is preferable to use these alone or in combination of two or more. Preferred are crystalline cellulose and corn starch, and the excipient contains one or more of these.
When a poorly water-soluble excipient is used, it is preferable to use it in an amount of 40% by mass or more and 95% by mass or less, and more preferably 50% by mass or more and 95% by mass or less, based on the total weight of the pharmaceutical tablet.

The disintegrant in the present invention includes croscarmellose sodium, carboxymethyl starch sodium, crospovidone, carmellose, carmellose calcium, low-substituted carboxymethyl starch sodium, etc., and it is preferable to use these alone or in combination of two or more kinds. Preferred are croscarmellose sodium, carboxymethyl starch sodium, and crospovidone. More preferred is croscarmellose sodium.
When a disintegrant is used, it is preferably used in an amount of 0.1% by mass to 7% by mass, more preferably 0.2% by mass to 6% by mass, based on the total weight of the pharmaceutical tablet. In addition, the pharmaceutical tablet of the present invention may not contain the disintegrant.

The pharmaceutical tablet of the present invention may contain excipients, binders, lubricants, solubilizers, flow agents, colorants, etc. that are used in preparing pharmaceutical tablets.
Examples of excipients include sugars such as lactose, mannitol, maltose, sucrose, sorbitol, xylitol, and inositol, which can be used alone or in combination of two or more. Lactose and mannitol are preferred, and one or more of these may be included. When using the sugars as excipients, it is preferable to use them in an amount of 5% by mass to 60% by mass based on the total amount of the pharmaceutical tablet. The amount is preferably 5% by mass to 40% by mass.
Examples of binders include povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carmellose sodium, methylcellulose, partially pregelatinized starch, polyvinyl alcohol, etc., and these can be used alone or in combination of two or more. Povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carmellose sodium, and methylcellulose are preferred. Povidone is more preferred. When a binder is used, it is preferably used in an amount of 0.1% by mass or more and 15% by mass or less based on the total weight of the pharmaceutical tablet. It is preferably 0.3% by mass or more and 10% by mass or less.

Examples of lubricants include magnesium stearate, stearic acid, zinc stearate, aluminum stearate, glycerin monostearate, sodium stearyl fumarate, calcium stearate, talc, carnauba wax, etc., which can be used alone or in combination of two or more. Magnesium stearate is preferred. When using a lubricant, it is preferred to use it in an amount of 0.1% by mass or more and 10% by mass or less based on the total amount of the pharmaceutical tablet. It is preferably 0.2% by mass or more and 5% by mass or less.
Examples of solubilizers include sodium lauryl sulfate, soybean lecithin, refined soybean lecithin, sorbitan fatty acid ester, soybean oil, lauromacrogol, etc., and these can be used alone or in combination of two or more.Preferably, sodium lauryl sulfate.When using a solubilizer, it is preferable to use it in an amount of 0.1% by mass or more and 15% by mass or less based on the total amount of the pharmaceutical tablet.Preferably, it is 0.1% by mass or more and 10% by mass or less.
Examples of the fluidizing agent include silicon dioxide, light anhydrous silicic acid, talc, etc., which can be used alone or in combination of two or more. Silicon dioxide is preferred. When a fluidizing agent is used, it is preferably used in an amount of 0.1% by mass or more and 15% by mass or less based on the total amount of the pharmaceutical tablet. Preferably, it is 0.1% by mass or more and 10% by mass or less.
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 pigments, edible blue pigments, edible red pigments, etc., and these can be used alone or in combination of two or more. Titanium oxide and ferric oxide are preferred. When a colorant is used, it is preferably used in an amount of 0.1% by mass or more and 20% by mass or less based on the total amount of the pharmaceutical tablet. Preferably, it is 0.2% by mass or more and 10% by mass or less.
These optional additives can be used without any particular limitation as long as they have a purity acceptable for use in pharmaceutical formulations. These additives may be used alone or in combination.

The pharmaceutical tablet is prepared by molding the mixture of the above-mentioned formulation components. Examples of the molding method include rotary tableting and single shot tableting, and the pharmaceutical tablet is prepared by molding using these methods. The formulation may be in any form, such as a bare tablet, a film-coated tablet, a dispersible tablet, an orally disintegrating tablet, a chewable tablet, or an effervescent tablet.

The pharmaceutical tablet may be a film-coated tablet prepared by coating with a coating agent and an optional plasticizer, light-shielding agent, colorant, and the like.
Examples of coating agents include hydroxypropylmethylcellulose, polyvinyl alcohol, hydroxypropylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, hydroxypropylmethylcellulose phthalate, ethylcellulose, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, ethyl acrylate-methyl methacrylate copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc., and these can be used alone or in combination of two or more.Preferably, hydroxypropylmethylcellulose.When using a coating agent, it is preferable to use it in an amount of 0.1% by mass or more and 20% by mass or less with respect to the total amount of the pharmaceutical tablet.Preferably, it is 0.2% by mass or more and 10% by mass or less.

Examples of plasticizers include triacetin, triethyl citrate, glycerin, propylene glycol, polyethylene glycol, polysorbate, D-sorbitol, liquid paraffin, etc., which may be used alone or in combination of two or more. Triacetin is preferred. When a plasticizer is used, it is preferably used in an amount of 0.1% by mass or more and 20% by mass or less based on the total weight of the pharmaceutical tablet. Preferably, it is 0.2% by mass or more and 10% by mass or less.
Examples of light-shielding agents and coloring agents include titanium oxide, ferric oxide, talc, yellow ferric oxide, yellow ferric oxide, black ferric oxide, zinc oxide, brown ferric oxide, edible yellow pigments, edible blue pigments, edible red pigments, etc., and these can be used alone or in combination of two or more. Titanium oxide and ferric oxide are preferred. When a light-shielding agent and coloring agent are used, it is preferred to use them in an amount of 0.1% by mass or more and 20% by mass or less based on the total amount of the pharmaceutical tablet. It is preferably 0.2% by mass or more and 10% by mass or less.

Film-coated tablets can be prepared by a manufacturing method in which a coating agent and any plasticizer, light-blocking agent, colorant, etc. are dissolved or suspended 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 hot air is blown 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 axitinib of the present invention may be a tablet containing a granulation containing axitinib, polyvinyl acetate, and a poorly water-soluble excipient. The granulation is preferably a granulation prepared by a dry granulation method. The granulation may further contain a water-soluble polymer. Alternatively, the tablet may contain a granulation containing axitinib and a poorly water-soluble excipient, in which the polyvinyl acetate is a pre-prepared granular additive containing polyvinyl acetate, a water-soluble polymer, a solubilizer, and a flow agent. The granulation may further contain a disintegrant. The pharmaceutical tablet is prepared by mixing the granulation with the above-mentioned additive and molding.

The pharmaceutical tablet of the present invention can be produced by mixing axitinib and the above-mentioned formulation additive components in the absence of a solvent and molding the mixture by a direct compression method. Alternatively, the pharmaceutical tablet can be produced by preparing a granulated material containing axitinib by a dry granulation method and molding the granulated material.
When the pharmaceutical tablet of the present invention is produced by direct compression, in the first step, axitinib, polyvinyl acetate, and any other additives are mixed to prepare a composition. The mixing method includes 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.
In the second step, the composition is molded into a pharmaceutical tablet, i.e., the composition is mixed with any other additives and molded into a pharmaceutical tablet.
The pharmaceutical tablet can be prepared by molding using rotary tableting, single shot tableting, etc. The pharmaceutical tablet can be prepared in any form such as a plain tablet, a film-coated tablet, a dispersible tablet, an orally disintegrating tablet, a chewable tablet, or an effervescent tablet, etc.

When the pharmaceutical tablet of the present invention is produced by dry granulation, in the first step, axitinib, polyvinyl acetate, and any other additives are mixed to prepare a composition. The mixing method includes 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.
In the second step, the composition is compressed to prepare a granulated product. The method for preparing the granulated product is a procedure in which the composition is compressed to granulate, the granules are sized, and then, if necessary, the granulated product is obtained by appropriately screening the granulated product.
In the third step, the granulated material is molded into a pharmaceutical tablet, i.e., the composition is mixed with any other additives and molded into a pharmaceutical tablet.
The pharmaceutical tablet can be prepared by molding using rotary tableting, single shot tableting, etc. The pharmaceutical tablet can be prepared in any form such as a plain tablet, a film-coated tablet, a dispersible tablet, an orally disintegrating tablet, a chewable tablet, or an effervescent tablet, etc.

Pharmaceutical tablets prepared by direct compression or dry granulation may be film-coated tablets prepared by coating with a coating agent and any plasticizer, light-blocking agent, colorant, etc. The types and suitable contents of various additives for film coating are as described above.

The pharmaceutical tablet containing axitinib as an active ingredient obtained by the present invention can suppress and control the dissolution of axitinib. In particular, it is characterized by being able to control the initial dissolution at pH 1.2, and can provide a pharmaceutical tablet that brings about appropriate pharmacokinetics of axitinib.
The dissolution of the pharmaceutical tablet of the present invention can be confirmed by a conventional dissolution test method. As an example of the dissolution test method, an aqueous solution of pH 1.2 in the dissolution test can be prepared by the method described in the Japanese Pharmacopoeia. Then, using 900 mL of the test solution, the active ingredient is dissolved from the pharmaceutical tablet of the present invention into the test solution by 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), 42.3 mg of Kollidon (registered trademark) SR (a granular additive containing polyvinyl acetate; 80.0% by mass, povidone; 19.0% by mass, sodium lauryl sulfate; 0.8% by mass, and silicon dioxide; 0.2% by mass, BASF), and 126.7 mg of crystalline cellulose. The mixture was mixed at a ratio of 174 mg to 1.8 mg of magnesium stearate, and compressed to prepare the tablet according to Example 1.

[Example 2]
The contents per tablet were 5 mg of axitinib (IV type), 10.6 mg of Kollidon (registered trademark) SR (BASF), and 158.4 mg of crystalline cellulose. The mixture was mixed at a ratio of 174 mg to 1.8 mg of magnesium stearate, and compressed into tablets to prepare tablets according to Example 2.

[Example 3]
The contents per tablet were 5 mg of axitinib (IV type), 5.3 mg of Kollidon (registered trademark) SR (BASF), and 163.7 mg of crystalline cellulose. The mixture was mixed at a ratio of 174 mg to 1.8 mg of magnesium stearate, and compressed into tablets to prepare the tablet according to Example 3.

[Example 4]
The contents per tablet were 5 mg of axitinib (IV type), 42.3 mg of Kollidon (registered trademark) SR (BASF), 125.0 mg of crystalline cellulose, and 1.7 mg of croscarmellose sodium. The mixture was mixed at a ratio of 174 mg to 1.8 mg of magnesium stearate, and compressed into tablets to prepare the tablet according to Example 4.

[Example 5]
The contents per tablet were 5 mg of axitinib (IV type), 21.1 mg of Kollidon (registered trademark) SR (BASF), and 147.9 mg of microcrystalline cellulose, which were mixed and dry granulated, and the resulting granules were sized. The dry granules were mixed and compressed to a ratio of 1.8 mg of magnesium stearate per 174 mg of the dry granules, to prepare the tablets according to Example 5.

[Example 6]
The contents per tablet were 5 mg of axitinib (IV type), 5.3 mg of Kollidon (registered trademark) SR (BASF), and 163.7 mg of microcrystalline cellulose, which were then mixed and dry granulated, and the resulting granules were sized. The dry granules were mixed and compressed to a ratio of 1.8 mg of magnesium stearate per 174 mg of the dry granules, to prepare the tablets according to Example 6.

[Example 7]
The contents per tablet were mixed to give a ratio of 5 mg axitinib (IV type), 63.4 mg Kollidon (registered trademark) SR (BASF), 100.4 mg microcrystalline cellulose, and 5.2 mg croscarmellose sodium, and then dry granulated. The resulting granules were sized. The dry granules were mixed to give a ratio of 174 mg to 1.8 mg magnesium stearate, and then compressed to give the tablet according to Example 7.

[Example 8]
The contents per tablet were mixed and dry granulated to give a ratio of 5 mg axitinib (IV type), 42.3 mg Kollidon (registered trademark) SR (BASF), 125.8 mg microcrystalline cellulose, and 0.9 mg croscarmellose sodium. The resulting granules were sized. The dry granules were mixed and compressed to give a ratio of 1.8 mg magnesium stearate per 174 mg of the dry granules, to give the tablet according to Example 8.

[Example 9]
The content per tablet was 5 mg of axitinib (IV type), 63.4 mg of Kollidon (registered trademark) SR (BASF), and 96.9 mg of crystalline cellulose, which were mixed and dry granulated, and the resulting granules were sized. The dry granules were mixed at a ratio of 8.7 mg of croscarmellose sodium to 165.3 mg of the dry granules. The mixture was mixed at a ratio of 1.8 mg of magnesium stearate to 174 mg of the mixture, and tableted to prepare the tablet according to Example 9.

[Example 10]
The content per tablet was 5 mg of axitinib (IV type), 63.4 mg of Kollidon (registered trademark) SR (BASF), and 100.4 mg of crystalline cellulose, which were mixed and dry granulated, and the resulting granules were sized. The dry granules were mixed at a ratio of 5.2 mg of croscarmellose sodium to 168.8 mg of the dry granules. The mixture was mixed at a ratio of 1.8 mg of magnesium stearate to 174 mg of the mixture, and tableted to prepare the tablet according to Example 10.

[Example 11]
The content per tablet was 5 mg of axitinib (IV type), 42.3 mg of Kollidon (registered trademark) SR (BASF), and 125.8 mg of crystalline cellulose, which were mixed and dry granulated, and the resulting granules were sized. The dry granules were mixed at a ratio of 0.9 mg of croscarmellose sodium to 173.1 mg of the dry granules. The mixture was mixed at a ratio of 1.8 mg of magnesium stearate to 174 mg of the mixture, and tableted to prepare the tablet according to Example 11.

[Comparative Example 1]
The contents per tablet were 5 mg axitinib (IV type), 83 mg lactose hydrate, 83 mg crystalline cellulose, and 9.1 mg croscarmellose sodium, mixed and dry granulated, and the resulting granules were sized. The dry granules were mixed and compressed to a ratio of 180.1 mg to 1.8 mg magnesium stearate, to prepare the tablet according to Comparative Example 1.

[Test Example 1]
The dissolution rates were evaluated by the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method) using the tablets of Examples 1 to 11 and Comparative Example 1, and Inlyta (registered trademark) tablets, which are existing axitinib formulations, and a test solution of pH 1.2 prepared by the method described in the Japanese Pharmacopoeia.
The dissolution rate was evaluated using a dissolution tester (NTR-6600A, manufactured by Toyama Sangyo Co., Ltd.) and an ultraviolet-visible spectrometer (UV-1900, 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 dissolution rate at 15 minutes after the start of the test was used to judge similarity, and a dissolution rate within ±15% of the Inlyta (registered trademark) tablet was judged to be similar.
The axitinib dissolution rate of each tablet sample is summarized in Table 1.

The pharmaceutical tablet of the present invention had a dissolution rate of 75% or less at the beginning of the dissolution period of 5 minutes, 90% or less at 10 minutes, and 90% or less at 15 minutes, and was able to suppress and control the dissolution of axitinib. In addition, the pharmaceutical tablet of the present invention was judged to be similar to Inlyta (registered trademark) tablets at 15 minutes after the start of the test. On the other hand, Comparative Example 1 was unable to suppress and controlled the initial dissolution, and showed a dissolution rate of 90% or more at 5 minutes and 95% or more at 10 minutes. In other words, the present invention can provide axitinib tablets with suppressed and controlled dissolution, particularly in the early stages, and can provide a pharmaceutical tablet that shows a dissolution behavior similar to that of an existing formulation, even when a different crystalline polymorphic drug substance from that of the existing formulation, Inlyta (registered trademark) tablets, is used.

Claims (7)

A pharmaceutical tablet comprising axitinib, a granule containing polyvinyl acetate and a water-soluble polymer, and microcrystalline cellulose,
A pharmaceutical tablet comprising 50 to 95% by mass of crystalline cellulose. The pharmaceutical tablet according to claim 1, containing 0.5 to 15 parts by mass of polyvinyl acetate per part by mass of axitinib. 3. The pharmaceutical tablet of claim 1 or 2, comprising a disintegrant. The pharmaceutical tablet according to any one of claims 1 to 3 , comprising a granule containing axitinib, polyvinyl acetate and a water-soluble polymer, and a granule containing crystalline cellulose . The pharmaceutical tablet according to any one of claims 1 to 4 , containing 0.1 to 10% by mass of axitinib. A method for producing a pharmaceutical tablet containing axitinib as an active ingredient, comprising:
(1) A step of preparing a composition by mixing a granule containing axitinib, polyvinyl acetate and a water-soluble polymer, and microcrystalline cellulose in the absence of a solvent;
(2) molding the composition into a pharmaceutical tablet;
Including,
A method for producing a pharmaceutical tablet containing 50 to 95% by mass of crystalline cellulose . A method for producing a pharmaceutical tablet containing axitinib as an active ingredient, comprising:
(1) A step of preparing a composition by mixing a granule containing axitinib, polyvinyl acetate and a water-soluble polymer, and microcrystalline cellulose in the absence of a solvent;
(2) compressing the composition to prepare a granule;
(3) forming the granulated material into a pharmaceutical tablet;
Including,
A method for producing a pharmaceutical tablet containing 50 to 95% by mass of crystalline cellulose .