JP2024076228A - Nintedanib Ethanesulfonate Tablets - Google Patents

Abstract

The present invention provides a tablet containing nindenib ethanesulfonate, which has a dosage form and size that are easy to take, and has sufficient hardness and disintegrability for packaging and distribution.
[Solution] A nintedanib ethanesulfonate tablet comprising nintedanib ethanesulfonate, an excipient, a disintegrant and a lubricant.
[Selection diagram] None

Description

The present invention relates to a tablet containing nintedanib ethanesulfonate and a method for producing the same.

Nintedanib ethanesulfonate is a compound represented by the following formula, and is sold in the form of soft capsules as a treatment for idiopathic pulmonary fibrosis, interstitial lung disease associated with systemic sclerosis, and interstitial lung disease associated with progressive fibrosis due to its tyrosine kinase inhibitory effect (Non-Patent Document 1). The shape of the soft capsules is generally oblong, and the size of a 100 mg capsule of Nintedanib ethanesulfonate is approximately 16.3 mm in major axis, approximately 6.2 mm in diameter, and approximately 440 mg in weight, and a 150 mg capsule is approximately 17.6 mm in major axis, approximately 7.1 mm in diameter, and approximately 620 mg in weight.

The solubility of nintedanib ethanesulfonic acid in water depends on the pH, being approximately 10 mg/mL at pH 1 and less than 0.001 mg/mL at pH 7, and its BCS class is 2 to 4. Patent Document 1 discloses a soft capsule filled with nintedanib ethanesulfonic acid suspended in a solution of medium-chain fatty acid triglyceride, hard fat, and lecithin in order to make it into a fast-release formulation (Patent Document 1), but the soft capsule shown here has a problem in that it is difficult to take orally because it is large, weighing more than 620 mg with a drug content of 150 mg. In addition, soft capsules cannot be manufactured using general-purpose solid formulation manufacturing equipment, and dedicated equipment is required.

Patent Document 2 discloses a tablet in which nintedanib ethanesulfonate is melt-granulated together with a carrier such as sugar alcohol, hypromellose esters, or (meth)acrylic acid polymers to obtain a solid dispersion of drug particles, which is then mixed with pharmaceutical additives and compressed into tablets. However, this method involves melt-granulation at 130°C or higher for several minutes, which causes a problem of increased impurities. In particular, when nintedanib ethanesulfonate is made amorphous, the impurity content exceeds a threshold value, making it impractical. In addition, a carrier such as hardened oil or sugar alcohol must be added to form a solid dispersion, so a tablet containing 180.6 mg of nintedanib ethanesulfonate weighs 630 mg, making the tablet large and problematic in terms of ease of administration.

International Publication No. WO 2009/147220 International Publication No. 2022/138549

"Ofeb (registered trademark) Capsules 100 mg, Ofeb (registered trademark) Capsules 150 mg" Pharmaceutical Interview Form, Revised March 2022 (10th edition)

The present invention relates to providing a tablet containing nindenib ethanesulfonate that has a dosage form and size that is easy to take, and has sufficient hardness and disintegrability for packaging and distribution.

As a result of intensive research into solving the problems, the present inventors have found that nintedanib sulfonate tablets that satisfy the above-mentioned problems can be obtained by a method that includes a step of mixing and compression-molding nintedanib ethanesulfonate, an excipient, a disintegrant, and a lubricant, or a step of granulating nintedanib ethanesulfonate, an excipient, and a disintegrant, and then mixing and compression-molding a lubricant.

That is, the present invention relates to the following 1) to 10).
1) A nintedanib ethanesulfonate tablet comprising nintedanib ethanesulfonate, an excipient, a disintegrant and a lubricant.
2) The tablet of 1), further comprising a binder and/or a surfactant.
3) A tablet according to 1), in which the content of nintedanib ethanesulfonate is 35% by mass or more as nintedanib relative to the total mass of the tablet.
4) The tablet of 1), having a mass of 250-500 mg and a hardness of 4-20 kg.
5) The tablet of 1), wherein the excipient is one or more selected from lactose and crystalline cellulose.
6) The tablet according to 1), wherein the disintegrant is one or more selected from low-substituted hydroxypropylcellulose, crospovidone and sodium starch glycolate.
7) The tablet of 1), wherein the average particle size of nintedanib ethanesulfonate is 0.1 to 50 μm.
8) A method for producing a nintedanib ethanesulfonate tablet, comprising the steps of mixing nintedanib ethanesulfonate, an excipient, a disintegrant and a binder in the presence of a liquid and granulating the mixture.
9) A method for producing nintedanib ethanesulfonate tablets, comprising the steps of mixing nintedanib ethanesulfonate, an excipient and a disintegrant to obtain a mixed powder, and mixing the mixed powder with a lubricant to obtain tablets.
10) A method for producing nintedanib ethanesulfonate tablets, comprising the steps of mixing and compressing nintedanib ethanesulfonate, an excipient, a disintegrant and a binder to obtain a granulated powder, and mixing the granulated powder with a lubricant and a disintegrant to obtain tablets.

According to the present invention, it is possible to obtain nindenib ethanesulfonate tablets that are easy to take in terms of dosage form and size, and have sufficient hardness and disintegrability for packaging and distribution.

The present invention will be described in detail below.
Unless otherwise specified in the present invention, the use of each pharmaceutical additive is in accordance with the use of pharmaceutical additives in the Pharmaceutical Additives Dictionary.
The nintedanib ethanesulfonate tablet of the present invention (hereinafter also referred to as "the tablet of the present invention") contains an excipient, a disintegrant and a lubricant, and further contains a binder and/or a surfactant as necessary.

In the present invention, nintedanib ethanesulfonate is an ethanesulfonate salt of (chemical name: methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate), which is a compound represented by the following formula:
The compound may also be in the form of a solvate, and examples of the solvate include hydrates and alcohol solvates.

The solubility of nintedanib ethanesulfonate is pH-dependent, and is about 10 mg/mL at low pH, but is poorly soluble at 0.001 mg/mL or less at neutral pH. Therefore, the particle size should be small within a range that does not cause problems in production, and the particle size can be, for example, an average particle size of 0.1 to 50 μm, preferably 1 to 30 μm, more preferably 7 to 21 μm. The average particle size means the median diameter (D ₅₀ : particle size equivalent to 50% of the cumulative distribution curve), and is calculated based on the volume. The average particle size can be measured using known methods and measuring instruments, for example, by laser light scattering particle size distribution measurement or dynamic light scattering particle size distribution measurement.

In the nintedanib ethanesulfonate tablet of the present invention, the content of nintedanib ethanesulfonate can be increased to reduce the tablet size. The amount of nintedanib ethanesulfonate is 25 to 70% by mass, preferably 30 to 60% by mass, and more preferably 35 to 50% by mass, of the total mass of the tablet. The content of nintedanib ethanesulfonate is 60 to 250 mg, preferably 120.4 mg or 180.6 mg, of nintedanib per tablet.

Examples of excipients used in the tablets of the present invention include sugars such as lactose, sucrose, and glucose; sugar alcohols such as mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, and xylitol; starches such as corn starch, potato starch, wheat starch, rice starch, and tapioca starch; dextrin, crystalline cellulose, anhydrous calcium hydrogen phosphate, magnesium aluminometasilicate, and the like, with lactose and crystalline cellulose being preferred.
The amount of the excipient to be added is 1 to 70% by mass, preferably 5 to 60% by mass, more preferably 10 to 60% by mass, and even more preferably 20 to 60% by mass, based on the total mass of the tablet.

The disintegrant used in the tablet of the present invention is not particularly limited, and examples thereof include cellulose-based disintegrants such as carmellose calcium, carmellose, croscarmellose, croscarmellose sodium, and low-substituted hydroxypropyl cellulose; starch-based disintegrants such as sodium starch glycolate, corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and sodium carboxymethyl starch; and crospovidone. Preferred examples include croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, and crospovidone, and more preferred examples include crospovidone.
The amount of the disintegrant to be added is 0.5 to 20% by mass, preferably 0.5 to 15% by mass, and more preferably 1 to 10% by mass, based on the total mass of the tablet.

The lubricant used in the tablet of the present invention is not particularly limited, but examples thereof include magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, sucrose fatty acid esters, sodium stearyl fumarate, etc., and preferably magnesium stearate.
The amount of the lubricant to be added is 0.01 to 5% by mass, preferably 0.05 to 3% by mass, and more preferably 0.1 to 2% by mass, based on the total mass of the tablet.
This also includes the case where the lubricant is localized on the surface of the uncoated tablet by external lubrication.

The binder used in the tablet of the present invention is not particularly limited, and examples thereof include cellulose-based binders such as hydroxypropyl cellulose, hypromellose phthalate, hydroxypropyl methylcellulose acetate succinate, crystalline cellulose, powdered cellulose, low-substituted hydroxypropyl cellulose, carmellose sodium, ethyl cellulose, methyl cellulose, and hypromellose; starch-based binders such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, and pregelatinized starch; silicic acid-based binders such as magnesium aluminometasilicate, synthetic aluminum silicate, light anhydrous silicic acid, and calcium silicate; gum arabic, sodium alginate, dextrin, gelatin, pullulan, povidone, and carboxyvinyl polymers; preferably, cellulose-based binders, and particularly preferably, hydroxypropyl cellulose.
The amount of the binder is 1 to 15% by mass, preferably 1 to 10% by mass, and more preferably 1.5 to 7% by mass, based on the total mass of the tablet.

Surfactants used in the tablets of the present invention include lecithin, sodium lauryl sulfonate, sodium lauryl sulfate, sodium laurylbenzenesulfonate, polysorbate, polysorbate 80, polyoxyethylene glycol esters, sucrose fatty acid esters, etc. Preferred are lecithin, polysorbate 80, and sodium laurylbenzenesulfonate.

When the above excipients, disintegrants, binders and lubricants are blended, a premix excipient containing some or all of these can be added instead. Examples of premix excipients that can be used include F-MELT (manufactured by Fuji Chemical Industry Co., Ltd.), Kollitab DC87L (manufactured by BASF), GRANFILLER-D (manufactured by Daicel Corporation), HiSIRAD (manufactured by Daicel Corporation), ODIFUL (manufactured by Daido Chemical Industries Co., Ltd.), PROSOLV EASTtab (manufactured by JRS Pharma Co., Ltd.), and PROSOLV ODT G2 (manufactured by JRS Pharma Co., Ltd.).

Pharmaceutical additives other than the above-mentioned excipients, binders, disintegrants, lubricants, and surfactants that can be used to manufacture the tablets of the present invention include, for example, colorants, sweeteners, and flavors, and are specifically as follows:

Examples of coloring agents include Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Red No. 2, Food Red No. 3, Food Blue No. 1 Aluminum Lake, Food Blue No. 2 Aluminum Lake, Food Red No. 2 Aluminum Lake, titanium oxide, ferric oxide, yellow ferric oxide, caramel, talc, etc.

Examples of sweeteners include one or more sweeteners selected from sugar, oligosaccharides, maltitol, erythritol, sorbitol, xylitol, aspartame, acesulfame potassium, sucralose, and stevia.

Flavors include, for example, those with the flavors of lemon, orange, grapefruit, bergamot, yuzu, kabosu, sudachi, strawberry, apple, peach, yogurt, and almond jelly.

In order to prevent nintedanib ethanesulfonate from being absorbed or taken by anyone other than the patient, the tablet of the present invention is preferably a film-coated tablet. For the film coating, film coating agents, plasticizers, flow agents, dyes, and solvents for dissolving/suspending these, which are also used in ordinary pharmaceuticals, can be used.

Here, the film coating agent is not particularly limited, but examples thereof include cellulose-based film coating agents such as carmellose, carmellose sodium, carmellose calcium, hydroxypropyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose, and carboxymethyl cellulose, powdered acacia, gelatin, pullulan, dextrin, sodium carboxymethyl starch, sodium alginate, polyvinylpyrrolidone, and polyvinyl alcohol, among which cellulose-based film coating agents are preferred, and hypromellose is more preferred.

The plasticizer is not particularly limited, but examples thereof include polyethylene glycol (e.g., polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, etc.), triethyl citrate, glycerin, castor oil, poloxyethylene hydrogenated castor oil, polysorbate 80, macrogol, lauromacrogol, triacetin, etc., preferably triacetin.

Lubricants for film coating are not particularly limited, but examples include talc, hydrous silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, sodium stearyl fumarate, stearic acid, calcium stearate, and magnesium stearate, and preferably magnesium stearate or sodium stearyl fumarate.

As the pigment for film coating, the above-mentioned colorants can be used, and from the viewpoint of distinguishability, preferred are ferric oxide, yellow ferric oxide, and titanium oxide.

The tablet size of the tablet of the present invention varies depending on the content of nintedanib ethanesulfonate. For example, in the case of 120.4 mg or 180.6 mg nintedanib ethanesulfonate tablets, the tablet size is a normal round tablet with a diameter of 5 to 12 mm and a thickness of 1 to 6 mm. In addition, the tablet may be an irregularly shaped tablet such as a caplet or oval tablet, with a major axis of about 8 to 20 mm and a minor axis of about 3 to 8 mm.

In the tablet of the present invention, the dissolution rate of nintedanib after 60 minutes using the first dissolution solution and 50 rotations of the paddle method according to the Japanese Pharmacopoeia is 70% or more, preferably 75% or more, and more preferably 85% or more. Furthermore, under the same conditions, the time for 85% dissolution of nintedanib is within 60 minutes, preferably within 45 minutes, and more preferably within 30 minutes.

The tablets of the present invention are manufactured under conditions of low temperature, low shear, etc., so there is little formation of related substances such as decomposition products, oxides, and combinations derived from the drug. The amount of related substances is 2.0% or less of the total related substances and 0.5% or less of each related substance relative to the drug. Preferably, the amount of related substances is 1.0% or less and each related substance is 0.25% or less. The amount of related substances here is the amount of related substances relative to the amount of drug, as measured by HPLC or the like.

The tablet of the present invention has excellent stability. Here, stability means that the decrease in disintegration and dissolution properties due to changes over time is suppressed, the increase in related substances is suppressed, and the decrease in drug content is suppressed.

The method for producing the tablet of the present invention will now be described.
The tablets of the present invention can be prepared either by direct compression, dry granulation or wet granulation.
The direct compression method can be carried out by a known method, for example, nintedanib ethanesulfonate, excipient, disintegrant, binder, lubricant, etc. are appropriately mixed and compressed. The excipient, disintegrant, binder, etc. can be used as previously granulated excipients. Also, a premix excipient containing components such as excipient, disintegrant, binder, etc. can be used. This granulation method can be carried out by a known method in the pharmaceutical field, for example, under the conditions of dry granulation or wet granulation described below.

As the dry granulation method, a method that is usually used in the pharmaceutical field may be used, which is a granulation method in which the cohesive force of the raw materials is increased to granulate the material without using any liquid components during granulation. As the wet granulation method, manufacturing methods such as agitation granulation, tumbling granulation, and fluidized bed granulation may be used, and production by fluidized bed granulation or agitation granulation is more preferable.
In the wet granulation method, nintedanib ethanesulfonate, excipients, disintegrants and binders are mixed in the presence of a liquid such as water or ethanol, and granulation is carried out.
In the case of fluidized bed granulation, for example, nintedanib ethanesulfonate, excipients, disintegrants, etc. are mixed uniformly, then charged into a fluidized bed granulator, granulated by spraying a binder solution, and granulated and dried. Fluidized bed dryer conditions - heat input temperature, exhaust heat temperature, spray speed, etc. - are appropriately set depending on the equipment used.

In the case of agitation granulation, for example, nintedanib ethanesulfonate, excipients, disintegrants, etc. are put into an agitation granulator, a binder solution is added, granulation is performed, and then drying is performed. The drying method may be shelf drying, fluidized bed drying, etc. Drying conditions are a drying temperature of about 20 to 100°C, and a drying time of about 10 minutes to 20 hours, and it is preferable to dry until the desired moisture content is achieved.

The resulting dried granules are sieved through a sieve and sized as required.
The granulated product is mixed uniformly with a lubricant and, if necessary, a disintegrant, a surfactant, etc. to prepare a powder mixture for tableting, which is then compression molded.

In the dry granulation method, nintedanib ethanesulfonate, excipients, disintegrants and binders are compacted and crushed to form granules without the intentional addition of water.
As the method of dry granulation, a dry granulation method commonly used in the field of pharmaceuticals can be adopted, such as the slug method and the roller compactor method. Conditions of the roller compactor: roll pressure, roll rotation speed, powder supply screw rotation speed, etc. vary depending on the device. For example, in the case of TFmini and TF-208 manufactured by Freund Corporation, the roll pressure is preferably 2 to 15 MPa, the roll rotation speed is preferably 2 to 15 rpm, and the powder supply screw rotation speed is preferably 5 to 30 rpm.
The flakes obtained by the roller compactor are pulverized and sized to a predetermined particle size using a pulverizer or disintegrator such as an oscillator, a Comil, a Quick Mill, a Power Mill, etc. The particle size of the granulated product is preferably as small as possible in terms of fine powder, for example, as small as possible below 200 mesh, in order to facilitate tableting.

The resulting granules are mixed with a disintegrant and, if desired, a lubricant, a surfactant and other pharmaceutical additives appropriately selected, and then compressed to produce tablets.
The mixing can be carried out by a commonly used mixing method, such as mixing, kneading, granulation, etc. The mixing can be carried out, for example, by using a high-speed stirring mixer, a universal kneader, a fluidized bed granulator, a V-type mixer, a tumbler mixer, a double cone mixer, a ribbon type mixer, a revolving screw type mixer, manual mixing in a bag, etc.

The manufacturing process of the uncoated tablets may further include a process of crushing or drying the granulated material. Compression molding can be performed using a rotary tablet press or the like that is commonly used in pharmaceuticals. The molding pressure during tableting varies depending on the size of the tablet, but for example, for a tablet with a diameter of 9.0 mm, it is 2 to 22 kN, preferably 5 to 17 kN. At this time, the set tablet hardness is 2.0 to 30 kg, preferably 3.0 to 25 kg, more preferably 4.0 to 20 kg.
In addition, the tablet of the present invention can be compressed by an external lubrication method. When using the external lubrication method, the dry granulation, disintegrant, binder, etc. are mixed, and then compressed to obtain a base formulation of nintedanib ethanesulfonate. The mixing method and compression molding conditions are the same as the manufacturing method of the base tablet described above.

Examples of solvents for dissolving/suspending the film coating agent include alcohols such as methanol, ethanol, and isopropyl alcohol, acetone, toluene, hexane, methyl ethyl ketone, and water, or mixed solvents of these, with ethanol and water being preferred, and water being more preferred.

Film coating can be carried out using equipment normally used for aqueous or non-aqueous coating of tablets, such as a pan-coating type coating device.

In the film-coated tablets, there is no clear limit to the amount of coating of the film coating portion, but for example, it is preferable that an uncoated tablet having a mass of 300 mg/tablet is coated with a coating amount in the range of 2 to 20 mg/tablet, and more preferably in the range of 4 to 12 mg/tablet, and it is preferable that an uncoated tablet having a mass of 450 mg/tablet is coated with a coating amount in the range of 3 to 30 mg/tablet, and more preferably in the range of 6 to 18 mg/tablet.

The present invention will be described in more detail below with reference to examples, comparative examples, and test examples, but the present invention is not limited to these.

Example 1
[Tablet manufacturing by direct compression method]
Nintedanib ethanesulfonate (D ₅₀ : 10 μm) 120.4 parts by weight, lactose hydrate 89.6 parts by weight, crystalline cellulose 60.0 parts by weight, low-substituted hydroxyprocellulose 15.0 parts by weight, hydroxyprocellulose 9.0 parts by weight and light anhydrous silicic acid 3.0 parts by weight were mixed and sieved through a sieve with an opening of 500 μm to obtain a mixed powder. Mixed powder 297.0 parts by weight and magnesium stearate 3.0 parts by weight were mixed and compressed using a rotary tablet press at a rotation speed of 30 rpm with a tablet diameter of 9.0 mm and a molding pressure of 11 kN to obtain a plain tablet of 300 mg per tablet. The tablet hardness was 92 N and the disintegration time was 56 seconds.
A coating liquid containing 5.5% hypromellose, 0.9% triacetin, 2.67% titanium dioxide, 0.03% ferric oxide and 0.9% talc was sprayed onto the uncoated tablets in a coating device at an inlet air temperature of 60°C and an exhaust air temperature of 43 to 46°C to obtain film-coated tablets weighing 310 mg each.

(Example 2) to (Example 4)
Film-coated tablets of nintedanib ethanesulfonate were prepared in the same manner as in Example 1 using the tablet ingredients and amounts shown in Table 1.

[Tablet manufacturing by wet granulation method]
Example 5
9.0 parts by mass of hydroxyprocellulose was dissolved in water to prepare a 10% binding solution. 120.4 parts by mass of nintedanib ethanesulfonate (D ₅₀ : 10 μm), 92.6 parts by mass of lactose hydrate, 45.0 parts by mass of crystalline cellulose, and 30.0 parts by mass of low-substituted hydroxyprocellulose were mixed, put into a high-speed stirring granulator, and the binding solution was added while stirring to obtain a granulated product. The granulated product was dried at 70° C. for 2 hours, then sieved through a sieve with an opening of 850 μm, mixed with magnesium stearate at a ratio of 3.0 parts by mass, and compressed with a rotary tablet press at a rotation speed of 30 rpm and a molding pressure of 11 kN with a tablet diameter of 9.0 mm to obtain a plain tablet of 300 mg per tablet. The tablet hardness was 92 N and the disintegration time was 51 seconds.
A coating liquid containing 5.5% hypromellose, 0.9% triacetin, 2.67% titanium dioxide, 0.03% ferric oxide and 0.9% talc was sprayed onto the uncoated tablets in a coating device at an inlet air temperature of 60°C and an exhaust air temperature of 43 to 46°C to obtain film-coated tablets weighing 310 mg each.

(Example 6) to (Example 7)
Film-coated tablets of nintedanib ethanesulfonate were prepared in the same manner as in Example 5 according to the tablet ingredients and formulation amounts shown in Table 2.

[Tablet production by dry granulation method]
(Example 8)
Mix 120.4 parts by weight of nintedanib ethanesulfonate ( _D50 : 10μm), 92.6 parts by weight of lactose, 21.0 parts by weight of low-substituted hydroxyprocellulose, 25.0 parts by weight of crystalline cellulose, 6.0 parts by weight of hydroxyprocellulose, 3.0 parts by weight of anhydrous silicic acid and 2.0 parts by weight of magnesium stearate, and perform tableting, then disintegrate and sieve through a 20Mesh sieve to obtain granules. Mix 270 parts by weight of this granule with 20.0 parts by weight of crystalline cellulose, 9.0 parts by weight of low-substituted hydroxyprocellulose and 1.0 parts by weight of magnesium stearate, and use a rotary tablet press with a rotation speed of 30 rpm, tablet diameter of 9.0 mm and molding pressure of 11 kN to obtain plain tablets of 300 mg per tablet.

Claims (10)

A nintedanib ethanesulfonate tablet comprising nintedanib ethanesulfonate, an excipient, a disintegrant and a lubricant. The tablet of claim 1, further comprising a binder and/or a surfactant. The tablet according to claim 1, wherein the content of nintedanib ethanesulfonate is 35% by mass or more as nintedanib based on the total mass of the tablet. The tablet according to claim 1, wherein the tablet has a mass of 250 to 500 mg and a hardness of 4 to 20 kg. The tablet according to claim 1, wherein the excipient is one or more selected from lactose and crystalline cellulose. The tablet according to claim 1, wherein the disintegrant is one or more selected from low-substituted hydroxypropyl cellulose, crospovidone, and sodium starch glycolate. The tablet according to claim 1, wherein the average particle size of nintedanib ethanesulfonate is 0.1 to 50 μm. A method for producing nintedanib ethanesulfonate tablets, comprising the steps of mixing nintedanib ethanesulfonate, an excipient, a disintegrant and a binder in the presence of a liquid, and granulating the mixture. A method for producing nintedanib ethanesulfonate tablets, comprising the steps of mixing nintedanib ethanesulfonate, an excipient, and a disintegrant to obtain a mixed powder, and mixing the mixed powder with a lubricant to obtain tablets. A method for producing nintedanib ethanesulfonate tablets, comprising the steps of mixing and compressing nintedanib ethanesulfonate, an excipient, a disintegrant and a binder to obtain a granulated powder, and mixing the granulated powder with a lubricant and a disintegrant to obtain tablets.