Pharmaceutical compositions with improved drug release and methods of making the same

Abstract

The present invention relates to a pharmaceutical composition comprising nintedanib or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition according to the present invention has an excellent dissolution rate at pH 4.0, thereby enabling nintedanib to be absorbed in gastric juice and the upper small intestine, thereby achieving excellent bioavailability. Accordingly, the pharmaceutical composition can be used as a solid preparation having improved medication compliance and storage convenience.

Description

Technical Field

[0001] This invention relates to pharmaceutical compositions comprising nintedanib or a pharmaceutically acceptable salt thereof and an alkalizing agent, and more particularly, to pharmaceutical compositions comprising nintedanib or a pharmaceutically acceptable salt thereof and an alkalizing agent, having an excellent dissolution rate at pH 4.0. Background Technology

[0002] Nintedanib is a small molecule tyrosine kinase inhibitor used as a treatment for idiopathic pulmonary fibrosis (IPF). The chemical name of nintedanib is (3Z)-3-{(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)aminomethylene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester.

[0003] Nintedanib has extremely low water solubility, so much so that it is considered insoluble. Therefore, it is used in the form of its salts, such as nintedanib isosulfonate, to improve solubility. The solubility of nintedanib isosulfonate is highly pH-dependent, especially increasing at acidic pH levels < 3.0. In solutions with pH 3.0 or higher, nintedanib isosulfonate aggregates and therefore tends to be insoluble, and even within the drug itself, drug release is often hindered due to the aggregation between nintedanib isosulfonate salts.

[0004] Related literature Non-patent literature Clinical Pharmacokinetics (2019) 58: 1131-1147 Invention Details Technical issues To address the drug release issues of nintedanib, the "Ofev soft capsule" formulation has been marketed, in which nintedanib ethanesulfonate is contained in liquid form within the capsule. However, the large volume and weight of this soft capsule reduce medication adherence, and its sensitivity to temperature and humidity due to its nature necessitates PTP (Al-Al) packaging, which reduces storage convenience. Therefore, there has been a need to develop an oral solid dosage form containing nintedanib that overcomes the shortcomings of such conventional products.

[0005] Technical solution The present invention provides a pharmaceutical composition comprising nintedanib as an active ingredient and an alkalizing agent, which has an excellent dissolution rate at pH 4.0.

[0006] The present invention provides a method for preparing tablets containing nintedanib, the tablets having an excellent dissolution rate at pH 4.0.

[0007] The specific implementation schemes of the present invention are as follows, but the scope of the present invention is not limited thereto.

[0008] (1) The pharmaceutical composition according to the invention comprises nintedanib or a pharmaceutically acceptable salt thereof; and an alkalizing agent.

[0009] (2) In (1) above, the pharmaceutically acceptable salt of nintedanib may include at least one selected from the following: hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, phosphate, acetate, lactate, maleate, fumarate, citrate, tartrate, hydrogen tartrate, succinate, gluconate, glycoside, methanesulfonate, ethanesulfonate, benzenesulfonate and toluenesulfonate.

[0010] (3) In (1) or (2) above, the pharmaceutically acceptable salt of nintedanib may be an ethanesulfonate.

[0011] (4) In any of (1) to (3) above, based on a total weight of 100% by weight of the pharmaceutical composition, the nintedanib or a pharmaceutically acceptable salt thereof may be contained in an amount of 10% to 60% by weight.

[0012] (5) In any one of (1) to (4) above, the composition can increase the dissolution rate at pH 4.0.

[0013] (6) In any of (1) to (5) above, the alkalizing agent may include at least one selected from the following: calcium hydroxide, magnesium hydroxide, sodium bicarbonate and L-arginine.

[0014] (7) In any of (1) to (6) above, the alkalizing agent may be calcium hydroxide or sodium bicarbonate.

[0015] (8) In any of (1) to (7) above, the alkalizing agent may be included in an amount of 1% to 30% by weight based on a total weight of 100% by weight of the pharmaceutical composition.

[0016] (9) In any of (1) to (8) above, the alkalizing agent may be calcium hydroxide, and may be contained in an amount of 3.5% to 10% by weight based on a total weight of 100% by weight of the pharmaceutical composition.

[0017] (10) In any of (1) to (9) above, the alkalizing agent may be sodium bicarbonate, and may be contained in an amount of 20% to 25% by weight based on a total weight of 100% by weight of the pharmaceutical composition.

[0018] (11) In any of (1) to (10) above, when tested at 50 rpm, 900 mL pH 4.0 solution and 37°C using apparatus 2 (paddle method) for dissolution testing in the Korean Pharmacopoeia, the pharmaceutical composition can have a dissolution rate of 40% or higher at 20 minutes and a dissolution rate of 60% or higher at 40 minutes.

[0019] (12) In any of (1) to (11) above, when tested at 50 rpm, 900 mL pH 4.0 solution and 37°C using apparatus 2 (paddle method) for dissolution testing in the Korean Pharmacopoeia, the pharmaceutical composition can have a dissolution rate of 60% or higher at 20 minutes and a dissolution rate of 85% or higher at 40 minutes.

[0020] (13) In any of (1) to (12) above, when tested at 50 rpm, 900 mL pH 4.0 solution and 37°C using apparatus 2 (paddle method) for dissolution testing in the Korean Pharmacopoeia, the pharmaceutical composition can have a dissolution rate of 70% or higher at 20 minutes and a dissolution rate of 90% or higher at 40 minutes.

[0021] (14) In any one of (1) to (13) above, the pharmaceutical composition may contain at least one additive selected from diluents, disintegrants and lubricants.

[0022] (15) In (14) above, the diluent may include lactose or its hydrate, starch, lactose-cellulose complex (cellactose), dextrin, microcrystalline cellulose, dipotassium hydrogen phosphate or its hydrate, calcium hydrogen phosphate or its hydrate, sugar, sugar alcohol, alginate, alkaline earth metal salt, clay, polyethylene glycol, or mixtures thereof.

[0023] (16) In (14) or (15) above, the diluent may include lactose or its hydrate, starch, lactose-cellulose complex, dextrin, microcrystalline cellulose, dipotassium hydrogen phosphate or its hydrate, calcium hydrogen phosphate or its hydrate, mannitol, glucose, alginate, alkaline earth metal salt, clay, polyethylene glycol, or mixtures thereof.

[0024] (17) In any of (14) to (16) above, the diluent may include microcrystalline cellulose, mannitol or a mixture thereof.

[0025] (18) In any one of (14) to (17) above, the disintegrant may include crospovidone, pregelatinized starch, corn starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl starch, sodium crospovidone carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, starch, alginate or its sodium salt, or mixtures thereof.

[0026] (19) In any of (14) to (18) above, the disintegrant may be crospovidone.

[0027] (20) In any of (14) to (19) above, the lubricant may include colloidal silica, stearic acid or its salt, talc, sodium benzoate, sodium acetate, sodium oleate, or mixtures thereof.

[0028] (21) In any of (14) to (20) above, the lubricant may be magnesium stearate.

[0029] (22) In any of (1) to (21) above, the pharmaceutical composition may be an oral formulation.

[0030] (23) In any of (1) to (22) above, the pharmaceutical composition may be a tablet or a capsule.

[0031] (24) In any one of (1) to (23) above, the pharmaceutical composition may comprise 10% to 60% by weight of the nintedanib or a pharmaceutically acceptable salt thereof, 20% to 75% by weight of the diluent, 1% to 15% by weight of the disintegrant, 1% to 10% by weight of the binder, 0.1% to 3% by weight of the lubricant, and 1% to 30% by weight of the alkalizing agent.

[0032] (25) In any of (1) to (24) above, the pharmaceutical composition may be used to treat or prevent idiopathic pulmonary fibrosis or cancer.

[0033] (26) A solid dosage form according to the invention comprises nintedanib or a pharmaceutically acceptable salt thereof; and at least one selected from calcium hydroxide, magnesium hydroxide, sodium bicarbonate and L-arginine as an alkalizing agent, wherein the solid dosage form has a dissolution rate of 40% or higher at 20 minutes and a dissolution rate of 60% or higher at 40 minutes when tested in apparatus 2 (paddle method) for dissolution testing according to the Korean Pharmacopoeia at 50 rpm, 900 mL pH 4.0 solution and 37°C.

[0034] (27) In (26) above, the alkalizing agent may be calcium hydroxide or sodium bicarbonate.

[0035] (28) In (26) or (27) above, the nintedanib or a pharmaceutically acceptable salt thereof may be nintedanib ethanesulfonate.

[0036] (29) In any of (26) to (28) above, the solid dosage form may further comprise microcrystalline cellulose or D-mannitol as a diluent, crospovidone as a disintegrant, and magnesium stearate as a lubricant.

[0037] (30) In any of (26) to (29) above, the solid dosage form may be a tablet or a capsule.

[0038] (31) In any of (26) to (30) above, the solid dosage form may be a tablet.

[0039] (32) In any of (26) to (31) above, the solid dosage form may comprise 10% to 60% by weight of the nintedanib or a pharmaceutically acceptable salt thereof, 20% to 75% by weight of a diluent, 1% to 15% by weight of a disintegrant, 0.1% to 3% by weight of a lubricant, and 1% to 30% by weight of the alkalizing agent.

[0040] (33) A method for preparing a tablet containing nintedanib according to the invention may include: (a) preparing granules containing nintedanib or a pharmaceutically acceptable salt thereof, a diluent and an alkalizing agent; (b) wet milling, drying and grinding the granules; and (c) mixing the milled product with at least one selected from a diluent, a disintegrant and a lubricant, and then compressing the resulting mixture into a tablet.

[0041] (34) In (33) above, step (a) may include: (a-1) preparing a mixture by mixing the nintedanib or a pharmaceutically acceptable salt thereof with the diluent; and (a-2) granulating the mixture with a binder solution containing the alkalizing agent.

[0042] (35) In (33) above, step (a) may include: (a-1) preparing a mixture by mixing the nintedanib or a pharmaceutically acceptable salt thereof, the diluent and the alkalizing agent; and (a-2) granulating the mixture with a binder solution.

[0043] (36) In (33) above, step (a) may include: (a-1) preparing a mixture by mixing the diluent and the alkalizing agent; and (a-2) granulating the mixture with a binder solution containing the nintedanib or a pharmaceutically acceptable salt thereof.

[0044] (37) A method for preparing a tablet comprising nintedanib according to the invention may include: (a) preparing granules comprising nintedanib or a pharmaceutically acceptable salt thereof and a diluent; (b) wet milling, drying and grinding the granules; and (c) mixing the milled product with an alkalizing agent, a disintegrant and a lubricant, and then compressing the resulting mixture into a tablet.

[0045] (38) In any of (33) to (37) above, the tablet may contain nintedanib ethanesulfonate, microcrystalline cellulose or D-mannitol as a diluent, crospovidone as a disintegrant, calcium hydroxide or sodium bicarbonate as an alkalizing agent, and magnesium stearate as a lubricant.

[0046] (39) In any of (33) to (38) above, the tablet may contain 10% to 60% by weight of the nintedanib or a pharmaceutically acceptable salt thereof, 20% to 75% by weight of the diluent, 1% to 15% by weight of the disintegrant, 1% to 10% by weight of the binder, 0.1% to 3% by weight of the lubricant, and 1% to 30% by weight of the alkalizing agent.

[0047] Beneficial effects The pharmaceutical composition of the present invention exhibits an excellent dissolution rate at pH 4.0, thereby enabling nintedanib to be absorbed in gastric juice and the upper small intestine, thus achieving excellent bioavailability. Therefore, the pharmaceutical composition can be used as a solid dosage form with improved medication adherence and storage convenience. Attached Figure Description

[0048] Figures 1 to 4 The results show the evaluation of the dissolution rate of tablets according to embodiments and comparative examples of the present invention at pH 4.0. Detailed Implementation

[0049] The pharmaceutical composition according to the invention comprises nintedanib or a pharmaceutically acceptable salt thereof as an active ingredient; and an alkalizing agent.

[0050] In this invention, nintedanib is a compound represented by the following formula 1: [Formula 1] According to an embodiment of the present invention, the pharmaceutical composition has an excellent dissolution rate at pH 4.0, thereby enabling nintedanib to be absorbed in gastric juice and the upper small intestine, thus achieving excellent bioavailability.

[0051] The pharmaceutical composition according to the invention is a pharmaceutical composition with an increased dissolution rate at pH 4.0, and therefore can be prepared as a solid dosage form, thus providing the advantages of superior medication adherence and storage convenience compared to conventional liquid soft capsules. Meanwhile, nintedanib soft capsules reach maximum plasma concentrations approximately 2 to 4 hours after oral administration, indicating that absorption occurs in the upper small intestine. In this regard, if the drug is not released at pH 4.0, there is a risk of reduced absorption in gastric juice and the upper small intestine, which may also lead to reduced bioavailability. Therefore, the dissolution rate at pH 4.0 is crucial in the development of solid dosage forms containing nintedanib. However, at pH 3.0 or higher, there is a tendency for drug release to be hindered due to the aggregation of nintedanib ethanesulfonate within the drug, which poses a challenge to the development of solid dosage forms. To date, solid dosage forms containing nintedanib with excellent dissolution rates at pH 4.0 are unknown, but the inventors have achieved excellent dissolution rates at pH 4.0 by including an alkalizing agent in the solid dosage form.

[0052] The pharmaceutical compositions of the present invention exhibit excellent dissolution rates at pH 4.0, and therefore also demonstrate sufficient bioavailability, thereby achieving excellent pharmacological effects. Furthermore, the pharmaceutical compositions of the present invention possess excellent stability.

[0053] In one embodiment of the invention, the pharmaceutically acceptable salt of nintedanib may include at least one selected from the following: hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, phosphate, acetate, lactate, maleate, fumarate, citrate, tartrate, hydrogen tartrate, succinate, gluconate, glycoside, methanesulfonate, ethanesulfonate, benzenesulfonate, and toluenesulfonate.

[0054] In one embodiment of the invention, the pharmaceutical composition may contain nintedanib ethanesulfonate as an active ingredient.

[0055] In one embodiment of the invention, based on a total weight of 100% by weight of the pharmaceutical composition, the nintedanib or a pharmaceutically acceptable salt thereof may be included in an amount of 10% to 60% by weight, specifically 12% to 55% by weight.

[0056] In one embodiment of the invention, the pharmaceutical composition may contain nintedanib or a pharmaceutically acceptable salt thereof in an amount of 100 mg to 150 mg based on the weight of nintedanib per unit dosage form, and specifically may contain nintedanib or a salt thereof in an amount of 100 mg or 150 mg based on the weight of nintedanib per tablet or capsule.

[0057] In one embodiment of the invention, the alkalizing agent may include at least one selected from the following: calcium hydroxide, magnesium hydroxide, sodium bicarbonate, and L-arginine.

[0058] In one embodiment of the invention, the alkalizing agent may be included in an amount of 1% to 30% by weight, specifically 1% to 25% by weight, based on a total weight of 100% by weight of the pharmaceutical composition.

[0059] In one embodiment of the invention, based on a total weight of 100% by weight of the pharmaceutical composition, the alkalizing agent may be included in amounts of 1% to 30% by weight, 1.5% to 29.5% by weight, 2% to 29% by weight, 2.3% to 28.5% by weight, 2.5% to 28% by weight, 2.6% to 27.5% by weight, 2.7% to 27% by weight, 2.8% to 26.5% by weight, 2.9% to 26% by weight, 3% to 25.5% by weight, 3.1% to 25% by weight, 3.2% to 24.5% by weight, 3.3% to 24% by weight, 3.4% to 23.5% by weight, 3.5% to 23% by weight, or 3.6% to 22.5% by weight.

[0060] In one embodiment of the invention, the alkalizing agent may be calcium hydroxide, magnesium hydroxide, sodium bicarbonate, L-arginine, or a mixture thereof, wherein the calcium hydroxide, magnesium hydroxide, sodium bicarbonate, L-arginine, or a mixture thereof may be contained in an amount of 1% to 30% by weight, specifically 1% to 25% by weight, based on a total weight of 100% of the pharmaceutical composition.

[0061] In one embodiment of the invention, the alkalizing agent may be calcium hydroxide, magnesium hydroxide, sodium bicarbonate, L-arginine, or a mixture thereof, wherein, based on the total weight of the pharmaceutical composition of 100% by weight, the calcium hydroxide, magnesium hydroxide, sodium bicarbonate, L-arginine, or a mixture thereof may be contained in amounts of 1% to 30% by weight, 1.5% to 29.5% by weight, 2% to 29% by weight, 2.3% to 28.5% by weight, 2.5% to 28% by weight, 2.6% to 27.5% by weight, 2.7% to 27% by weight, 2.8% to 26.5% by weight, 2.9% to 26% by weight, 3% to 25.5% by weight, 3.1% to 25% by weight, 3.2% to 24.5% by weight, 3.3% to 24% by weight, 3.4% to 23.5% by weight, 3.5% to 23% by weight, or 3.6% to 22.5% by weight.

[0062] In one embodiment of the invention, the alkalizing agent may be calcium hydroxide, wherein the calcium hydroxide may be contained in an amount of 3.5% to 10% by weight, specifically 3.5% to 8% by weight, based on a total weight of 100% by weight of the pharmaceutical composition.

[0063] In one embodiment of the invention, the alkalizing agent may be calcium hydroxide, wherein the calcium hydroxide may be contained in amounts of 3.5% to 10% by weight, 3.5% to 9.5% by weight, 3.5% to 9% by weight, 3.5% to 8.5% by weight, 3.5% to 8% by weight, 3.5% to 7.5% by weight, 3.5% to 7% by weight, 3.5% to 6.5% by weight, 3.5% to 6% by weight, 3.5% to 5.5% by weight, or 3.6% to 5.5% by weight, based on a total weight of 100% of the pharmaceutical composition. In another embodiment of the invention, the alkalizing agent may be calcium hydroxide, wherein the calcium hydroxide may be contained in amounts of 3.7% to 10% by weight, 3.7% to 9.5% by weight, 3.7% to 9% by weight, 3.7% to 8.5% by weight, 3.7% to 8% by weight, 3.7% to 7.5% by weight, 3.7% to 7% by weight, 3.7% to 6.5% by weight, 3.7% to 6% by weight, or 3.7% to 5.5% by weight, based on a total weight of 100% of the pharmaceutical composition. In another embodiment of the invention, the alkalizing agent may be calcium hydroxide, wherein the calcium hydroxide may be contained in amounts of 4.3 wt% to 10 wt%, 4.3 wt% to 9.5 wt%, 4.3 wt% to 9 wt%, 4.3 wt% to 8.5 wt%, 4.3 wt% to 8 wt%, 4.5 wt% to 7.5 wt%, 4.7 wt% to 7 wt%, 4.9 wt% to 6.5 wt%, 5.1 wt% to 6 wt%, or 5.3 wt% to 5.8 wt% based on the total weight of the composition. For example, the pharmaceutical composition may contain 3.6 wt%, 3.8 wt%, 4.1 wt%, or 5.5 wt% calcium hydroxide based on the total weight of the composition.

[0064] In one embodiment of the invention, the alkalizing agent may be sodium bicarbonate, wherein the sodium bicarbonate may be contained in an amount of 20% to 25% by weight, specifically 21% to 24% by weight, based on a total weight of 100% by weight of the pharmaceutical composition.

[0065] In one embodiment of the invention, the alkalizing agent may be sodium bicarbonate, wherein the sodium bicarbonate may be contained in amounts of 20% to 25% by weight, 20.5% to 24.5% by weight, 21% to 24% by weight, 21.5% to 23.5% by weight, or 22% to 23% by weight, based on a total weight of 100% by weight of the pharmaceutical composition. For example, the pharmaceutical composition may contain 22.5% by weight of sodium bicarbonate based on a total weight of 100% by weight of the composition.

[0066] In one embodiment of the invention, the total weight of the pharmaceutical composition may be from 300 mg to 450 mg, specifically from 320 mg to 420 mg. For example, the total weight of the pharmaceutical composition may be 338.2 mg, 366 mg, or 399.8 mg, but is not limited thereto.

[0067] The alkalizing agent according to the invention can improve the dissolution rate of the pharmaceutical composition at pH 4.0. In other words, compared with the case without the alkalizing agent, the pharmaceutical composition of the invention can have an improved dissolution rate at pH 4.0. The pharmaceutical composition containing the alkalizing agent according to the invention can have an excellent dissolution rate at pH 4.0, thereby enabling nintedanib to be absorbed in gastric juice and the upper small intestine, thus achieving excellent bioavailability.

[0068] Nintedanib is a drug that is only slightly soluble in water. Therefore, to improve solubility, it has been formulated in salt form, such as nintedanib isosulfonate. Furthermore, nintedanib is highly pH-dependent and difficult to release in solutions with pH 3.0 or higher, and has therefore been commercially available as soft capsules containing nintedanib isosulfonate in liquid form. However, commercially available Ofev soft capsules have the following drawbacks: the capsules are too large and heavy, reducing medication adherence, and the capsules are sensitive to temperature and humidity, leading to reduced storage convenience.

[0069] To address these issues, there is a need to develop nintedanib solid dosage forms. However, sufficient bioavailability cannot be achieved unless the solid dosage form dissolves at pH 4.0. Therefore, the dissolution rate at pH 4.0 is quite important in the development of nintedanib-containing solid dosage forms. The inventors have developed a nintedanib-containing solid dosage form that exhibits an excellent dissolution rate by incorporating an alkalizing agent, resulting in complete disintegration at pH 4.0. Therefore, compared to conventional Ofev soft capsules, the solid dosage form of the present invention offers improved medication adherence and increased storage convenience.

[0070] In one embodiment of the invention, when tested using apparatus 2 (paddle method) for dissolution testing according to the Korean Pharmacopoeia at 50 rpm, 900 mL pH 4.0 solution, and 37°C, the pharmaceutical composition can have a 20-minute dissolution rate of 40% or higher and a 40-minute dissolution rate of 60% or higher. As an example, when tested using apparatus 2 (paddle method) for dissolution testing according to the Korean Pharmacopoeia at 50 rpm, 900 mL pH 4.0 solution, and 37°C, the pharmaceutical composition according to the invention can have a 20-minute dissolution rate of 60% or higher and a 40-minute dissolution rate of 85% or higher. As another example, when tested using apparatus 2 (paddle method) for dissolution testing according to the Korean Pharmacopoeia at 50 rpm, 900 mL pH 4.0 solution, and 37°C, the pharmaceutical composition according to the invention can have a 20-minute dissolution rate of 70% or higher and a 40-minute dissolution rate of 90% or higher.

[0071] In one embodiment of the present invention, the pharmaceutical composition may be a solid dosage form, specifically a tablet or a capsule.

[0072] In one embodiment of the invention, the pharmaceutical composition according to the invention may contain pharmaceutically acceptable additives.

[0073] In one embodiment of the present invention, the pharmaceutically acceptable additive may include a carrier, a diluent (excipient), a binder, a disintegrant, a lubricant, or a mixture thereof, but the additives that can be used in the present invention are not limited thereto.

[0074] In one embodiment of the present invention, the diluents (excipients) used herein may include lactose or its hydrate, starch, lactose-cellulose complex, dextrin, microcrystalline cellulose, dipotassium hydrogen phosphate or its hydrate, calcium hydrogen phosphate or its hydrate, sugar, sugar alcohol, alginate, alkaline earth metal salt, clay, polyethylene glycol, etc., but the diluents used in the present invention are not limited thereto. They may be used alone or in combination of two or more.

[0075] In one embodiment of the present invention, the diluents (excipients) used herein may include lactose or its hydrate, starch, lactose-cellulose complex, dextrin, microcrystalline cellulose, dipotassium hydrogen phosphate or its hydrate, calcium hydrogen phosphate or its hydrate, mannitol, glucose, alginate, alkaline earth metal salts, clay, polyethylene glycol, etc., but the diluents used in the present invention are not limited thereto. They may be used alone or in combination of two or more.

[0076] In one embodiment of the invention, the diluent used herein may include microcrystalline cellulose, mannitol, etc., but the diluents that can be used in the invention are not limited thereto. They may be used alone or in combination.

[0077] In one embodiment of the present invention, the disintegrants used herein may include crospovidone, pregelatinized starch, corn starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl starch, sodium crospovidone carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, starch, alginate, or their sodium salts. They may be used alone or in combination of two or more.

[0078] In one embodiment of the present invention, crospovidone can be used as a disintegrant.

[0079] In one embodiment of the invention, the lubricant used herein may include colloidal silica, stearic acid or its salts, talc, sodium benzoate, sodium acetate, sodium oleate, etc. They may be used alone or in combination of two or more.

[0080] In one embodiment of the invention, magnesium stearate can be used as a lubricant.

[0081] Furthermore, if desired, the pharmaceutical compositions of the present invention may also include coating agents, swelling agents, surfactants, flow aids, pH adjusters, suspending agents, preservatives, flavoring agents, coloring agents, sweeteners, adsorbents, antioxidants, taste masking agents, etc. As these components, components known in the art may be used without limitation.

[0082] In one embodiment of the invention, the pharmaceutical composition may comprise nintedanib or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, a lubricant, and an alkalizing agent.

[0083] In one embodiment of the invention, the pharmaceutical composition may comprise 10% to 60% by weight of nintedanib or a pharmaceutically acceptable salt thereof, 20% to 75% by weight of a diluent, 1% to 15% by weight of a disintegrant, 0.1% to 3% by weight of a lubricant, and 1% to 30% by weight of an alkalizing agent, wherein the pharmaceutically acceptable salt of nintedanib, the diluent, the disintegrant, the lubricant, and the alkalizing agent may be substantially the same as described above.

[0084] In one embodiment of the invention, the pharmaceutical composition may comprise 12% to 55% by weight of nintedanib or a pharmaceutically acceptable salt thereof, 25% to 75% by weight of a diluent, 3% to 10% by weight of a disintegrant, 0.5% to 2% by weight of a lubricant, and 1% to 25% by weight of an alkalizing agent, wherein the diluent may be lactose or its hydrate, starch, lactose-cellulose complex, dextrin, microcrystalline cellulose, dipotassium hydrogen phosphate or its hydrate, calcium hydrogen phosphate or its hydrate, mannitol, glucose, alginate, or alkaline earth. The metal salt, clay, polyethylene glycol, or mixtures thereof, wherein the disintegrant may be crospovidone, pregelatinized starch, corn starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl starch, sodium crospovidone carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, starch, alginate or its sodium salt, or mixtures thereof, wherein the lubricant may be colloidal silica, stearic acid or its salt, talc, sodium benzoate, sodium acetate, sodium oleate, or mixtures thereof, and the alkalizing agent may be calcium hydroxide, magnesium hydroxide, sodium bicarbonate, L-arginine, or mixtures thereof.

[0085] In one embodiment of the present invention, the pharmaceutical composition may be an oral formulation.

[0086] In one embodiment of the invention, the pharmaceutical composition may be a solid dosage form. For example, the pharmaceutical composition may be a tablet or a capsule.

[0087] In one embodiment of the invention, the pharmaceutical composition may be a tablet, and the tablet may comprise particles containing nintedanib or a pharmaceutically acceptable salt thereof. In this case, the alkalizing agent may be contained within the particles, or the alkalizing agent may be contained outside the particles, or the alkalizing agent may be contained both within and outside the particles.

[0088] In one embodiment of the invention, the pharmaceutical composition may be a tablet, and the tablet may comprise particles containing nintedanib or a pharmaceutically acceptable salt thereof; and an alkalizing agent.

[0089] In one embodiment of the invention, the alkalizing agent can be used during the preparation of granules in the process of preparing tablets. For example, the alkalizing agent can be mixed with nintedanib or a pharmaceutically acceptable salt thereof to form granules, or the alkalizing agent can be mixed with a binder solution to form granules with nintedanib or a pharmaceutically acceptable salt thereof.

[0090] In one embodiment of the invention, the alkalizing agent can be post-mixed after the preparation of granules containing nintedanib or a pharmaceutically acceptable salt thereof. For example, the alkalizing agent can be mixed with granules containing nintedanib or a pharmaceutically acceptable salt thereof and extragranule additives (e.g., diluents, disintegrants, etc.). In this case, the mixture containing granules containing nintedanib or a pharmaceutically acceptable salt thereof, the alkalizing agent, and the extragranule additives can form final granules, and the final granules can be mixed with disintegrants, lubricants, etc., and then compressed to prepare tablets.

[0091] In one embodiment of the invention, during the preparation of tablets, taking into account the total content contained in the tablets, the alkalizing agent may be added to at least one or more of the following processes: the preparation of a mixture for preparing granules containing nintedanib, the mixing process with a binder solution during the preparation of granules containing nintedanib, and the mixing process with granules containing nintedanib and an extragranule additive, respectively.

[0092] The pharmaceutical compositions according to the present invention can treat or prevent idiopathic pulmonary fibrosis or cancer.

[0093] In one embodiment of the invention, a capsule can be prepared by mixing nintedanib or a pharmaceutically acceptable salt thereof with all pharmaceutical additives contained in the capsule and filling the capsule with the mixture. In this case, the pharmaceutical additives are as described above.

[0094] In one embodiment of the invention, the capsule may or may not contain a binder as a pharmaceutical additive.

[0095] The capsule can be a soft capsule or a hard capsule.

[0096] This invention provides a solid dosage form comprising: nintedanib or a pharmaceutically acceptable salt thereof as an active ingredient; and an alkalizing agent comprising calcium hydroxide, magnesium hydroxide, sodium bicarbonate, L-arginine, or a mixture thereof, wherein, when tested according to apparatus 2 (paddle method) for dissolution testing in the Korean Pharmacopoeia at 50 rpm, 900 mL of pH 4.0 solution and 37°C, the solid dosage form may have a 20-minute dissolution rate of 40% or higher and a 40-minute dissolution rate of 60% or higher.

[0097] The solid dosage form according to the invention is a pharmaceutical composition having an excellent dissolution rate at pH 4.0, and nintedanib can be absorbed in gastric juice and the upper small intestine, thereby achieving excellent bioavailability.

[0098] In one embodiment of the invention, when tested using apparatus 2 (paddle method) for dissolution testing according to the Korean Pharmacopoeia at 50 rpm, 900 mL pH 4.0 solution, and 37°C, the solid dosage form may have, for example: a 20-minute dissolution rate of 40% or higher and a 40-minute dissolution rate of 60% or higher; a 20-minute dissolution rate of 45% or higher and a 40-minute dissolution rate of 65% or higher; a 20-minute dissolution rate of 50% or higher and a 40-minute dissolution rate of 70% or higher; a 20-minute dissolution rate of 55% or higher and a 40-minute dissolution rate of 80% or higher; a 20-minute dissolution rate of 60% or higher and a 40-minute dissolution rate of 85% or higher; a 20-minute dissolution rate of 65% or higher and a 40-minute dissolution rate of 85% or higher; or a 20-minute dissolution rate of 70% or higher and a 40-minute dissolution rate of 90% or higher.

[0099] In one embodiment of the invention, based on a total weight of 100% by weight of the solid dosage form, the nintedanib or a pharmaceutically acceptable salt thereof may be contained in an amount of 10% to 60% by weight, specifically 12% to 55% by weight.

[0100] In one embodiment of the invention, the solid dosage form may contain nintedanib or a pharmaceutically acceptable salt thereof in an amount of 100 mg to 150 mg based on the weight of nintedanib, specifically, in an amount of nintedanib or a pharmaceutically acceptable salt thereof in an amount of 100 mg or 150 mg based on the weight of nintedanib.

[0101] In one embodiment of the invention, the solid dosage form may comprise a pharmaceutically acceptable salt of nintedanib, wherein the salt may comprise at least one selected from the group consisting of: hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, phosphate, acetate, lactate, maleate, fumarate, citrate, tartrate, hydrogen tartrate, succinate, gluconate, glycoside, methanesulfonate, ethanesulfonate, benzenesulfonate, and toluenesulfonate, and specifically the salt may be nintedanib ethanesulfonate.

[0102] In one embodiment of the present invention, the alkalizing agent in the solid dosage form may be calcium hydroxide or sodium bicarbonate.

[0103] In one embodiment of the invention, based on a total weight of 100% by weight of the solid dosage form, the content of calcium hydroxide, magnesium hydroxide, sodium bicarbonate, L-arginine, or mixtures thereof in the solid dosage form may be included in an amount from 1% to 30% by weight, specifically from 1% to 25% by weight.

[0104] In one embodiment of the invention, based on a total weight of 100% by weight of the solid dosage form, the solid dosage form may contain 1% to 30% by weight, 1.5% to 29.5% by weight, 2% to 29% by weight, 2.3% to 28.5% by weight, 2.5% to 28% by weight, 2.6% to 27.5% by weight, 2.7% to 27% by weight, 2.8% to 26.5% by weight, 2.9% to 26% by weight, 3% to 25.5% by weight, 3.1% to 25% by weight, 3.2% to 24.5% by weight, 3.3% to 24% by weight, 3.4% to 23.5% by weight, 3.5% to 23% by weight, or 3.6% to 22.5% by weight of calcium hydroxide, magnesium hydroxide, sodium bicarbonate, L-arginine, or mixtures thereof.

[0105] In one embodiment of the present invention, the solid dosage form may be a tablet or a capsule.

[0106] In one embodiment of the invention, the solid dosage form may comprise one or more additives selected from diluents, binders, disintegrants and lubricants, and specifically may comprise 10% to 60% by weight of nintedanib or a pharmaceutically acceptable salt thereof, 20% to 75% by weight of diluent, 1% to 15% by weight of disintegrant, 0.1% to 3% by weight of lubricant, and 1% to 30% by weight of alkalizing agent.

[0107] In one embodiment of the invention, the total weight of the solid dosage form can be from 300 mg to 450 mg, specifically from 320 mg to 420 mg. For example, the total weight of the solid dosage form can be 338.2 mg, 366 mg, or 399.8 mg, but is not limited thereto.

[0108] This invention provides a method for preparing tablets containing nintedanib. During tablet preparation, the alkalizing agent can be used concurrently during granulation, or the alkalizing agent can be post-mixed after granulation.

[0109] In one embodiment of the invention, a method for preparing a tablet comprising nintedanib may include: (a) preparing granules comprising nintedanib or a pharmaceutically acceptable salt thereof, a diluent, and an alkalizing agent; (b) wet milling, drying, and grinding the granules; and (c) mixing the ground product with at least one selected from a diluent, a disintegrant, and a lubricant, and then compressing the resulting mixture into a tablet.

[0110] Specifically, step (a) may include: (a-1) preparing a mixture by mixing the nintedanib or a pharmaceutically acceptable salt thereof and the diluent; and (a-2) granulating the mixture with a binder solution containing the alkalizing agent; or (a-1) preparing a mixture by mixing the nintedanib or a pharmaceutically acceptable salt thereof, the diluent, and the alkalizing agent; and (a-2) granulating the mixture with a binder solution; or (a-1) preparing a mixture by mixing the diluent and the alkalizing agent; and (a-2) granulating the mixture with a binder solution containing the nintedanib or a pharmaceutically acceptable salt thereof.

[0111] In one embodiment of the invention, a method for preparing a tablet comprising nintedanib may include: (a) preparing granules comprising nintedanib or a pharmaceutically acceptable salt thereof and a diluent; (b) wet milling, drying and grinding the granules; and (c) mixing the milled product with an alkalizing agent, a disintegrant and a lubricant, and then compressing the resulting mixture into a tablet.

[0112] Information such as additives and formulation preparation methods described in a pharmaceutical composition can be applied equally to the solid dosage form, provided they do not contradict each other.

[0113] Exemplary implementation details The present invention will now be described in more detail through exemplary embodiments. These embodiments are provided for illustrative purposes only and are therefore not intended to limit the scope of the invention.

[0114] Experimental Example 1: Based on the effect of alkalizing agents Example 1, Example 2 and Comparative Example 1 The aim is to confirm the effect of the composition comprising an alkalizing agent and nintedanib according to the present invention on improving the dissolution rate at pH 4.0.

[0115] Tablets for Examples 1, 2, and 1 (Comparative Example 1) were prepared according to the components and contents in Table 1 below.

[0116] [Table 1]

[0117] Specifically, the compositions of Examples 1, 2, and Comparative Example 1 were prepared into tablets by adding D-mannitol and microcrystalline cellulose as diluents, crospovidone as a disintegrant, and magnesium stearate as a lubricant. Nintanib isosulfonate, D-mannitol, and microcrystalline cellulose (PH101) were added to a high-shear mixer and mixed. Each alkalizing agent was dissolved in 30% ethanol as a binder solvent, and this binder solution was added to the high-shear mixer for granulation. The resulting granules were wet-milled, dried, and ground again. Crospovidone and magnesium stearate were then added to the resulting milled product, mixed, and compressed into tablets to prepare the tablets.

[0118] Disintegration test and dissolution test 1 Disintegration was measured according to the disintegration test method in the 12th revision of the Korean Pharmacopoeia. Specifically, the disintegration test was conducted by adding tablets to a disintegration tester (with 29 to 32 reciprocating motions per minute) using water as the test solution.

[0119] Dissolution tests were performed using apparatus 2 (paddle method) as described in the Korean Pharmacopoeia at 50 rpm, 900 mL of pH 4.0 solution, and 37°C. Eluents from each sample were collected at 10, 20, 30, 45, 60, 90, and 120 minutes, filtered, and used as test solutions. The solutions were then analyzed using liquid chromatography under the following analytical conditions.

[0120] <Analysis Conditions> Column: C18 (4.6 × 150 mm, 5 µm) or equivalent column, 40℃ Mobile phase: A – Water : Trifluoroacetic acid = 100 : 0.1 B – Acetonitrile: Trifluoroacetic acid = 100:0.1 Flow rate: 1.2 mL / min Injection volume: 10 µL (10℃) Detector: Ultraviolet absorption spectrophotometer (measurement wavelength: 285 nm) Detection wavelength: 286 nm [Table 2]

[0121] The results of the disintegration and dissolution tests of Examples 1, 2, and Comparative Example 1 are shown in Tables 3 and 4 below. Figure 1 middle.

[0122] [Table 3]

[0123] [Table 4]

[0124] Table 3 confirms that Comparative Example 1, which does not contain an alkalizing agent, did not disintegrate, while Example 1, which contains calcium hydroxide, and Example 2, which contains sodium bicarbonate, both disintegrated within five minutes. Furthermore, it was confirmed that Examples 1 and 2 exhibited superior dissolution rates at pH 4.0 compared to Comparative Example 1 (Table 4 and...). Figure 1 ).

[0125] The results above show that the solid dosage form containing nintedanib of the present invention exhibits rapid disintegration and excellent dissolution by including an alkalizing agent.

[0126] Experimental Example 2: Based on the effect of the preparation method Examples 3 to 6 For nintedanib solid dosage forms containing an alkalizing agent, to confirm the differences in preparation methods, the formulations of Examples 3 to 6 were prepared in a manner similar to that of Examples 1 and 2 above. The differences in preparation methods between the formulations of Examples 3 to 6 and the formulations of Examples 1 and 2 are as follows, and the components and contents are shown in Table 5 below.

[0127] Example 3: Nintanib ethanesulfonate, D-mannitol, and calcium hydroxide were added to a high-shear mixer and mixed. A binder solution (30% ethanol) was then added and granulation was performed. The resulting granules were wet-milled, dried, and ground. Cross-linked povidone and magnesium stearate were then added to the resulting milled product, mixed, and compressed into tablets to prepare tablets.

[0128] Example 4: D-mannitol and calcium hydroxide were added to a high-shear mixer and mixed. Nydananib ethanesulfonate was then dissolved in a binder solution (30% ethanol) and added to the high-shear mixer for granulation. The resulting granules were wet-milled, dried, and ground. Cross-linked povidone and magnesium stearate were then added to the resulting milled product, mixed, and compressed into tablets to prepare tablets.

[0129] Example 5: Nintanib ethanesulfonate and D-mannitol were added to a high-shear mixer and mixed. Calcium hydroxide was then dissolved in a binder solution (30% ethanol) and added to the high-shear mixer for granulation. The resulting granules were wet-milled, dried, and ground. Cross-linked povidone and magnesium stearate were then added to the resulting milled product, mixed, and compressed into tablets to prepare tablets.

[0130] Example 6: Nintanib ethanesulfonate and D-mannitol were added to a high-shear mixer and mixed, then a binder solution (30% ethanol) was added and granulation was performed. The resulting granules were wet-milled, dried, and ground, then crospovidone, calcium hydroxide, and magnesium stearate were added to the resulting milled product, mixed, and compressed to prepare tablets.

[0131] [Table 5]

[0132] Disintegration test and dissolution test 2 For the tablets of Examples 3 to 6, the improvement effect according to the preparation method was confirmed in essentially the same manner as in the disintegration test and dissolution test 1.

[0133] [Table 6]

[0134] [Table 7]

[0135] As can be confirmed from Table 6, there are some differences in disintegration times among the formulations of each example due to differences in preparation methods. However, Comparative Example 1, which does not contain an alkalizing agent, did not disintegrate, while Examples 3 to 6, which contain an alkalizing agent, disintegrated completely regardless of the preparation method. Furthermore, it was confirmed that Examples 3 to 6 exhibited superior dissolution rates at pH 4.0 compared to Comparative Example 1 (Table 7 and...). Figure 2 ).

[0136] Experiment Example 3: Effects based on the proportion of calcium hydroxide Examples 7 to 13 The tablets of Examples 7 to 13 were prepared according to the composition ratios (wt%) shown in Table 8 below. Nintanib isosulfonate, D-mannitol, and microcrystalline cellulose (PH101) were added to a high-shear mixer and mixed, then a binder solution (30% ethanol) containing dissolved calcium hydroxide was added and granulation was performed. The resulting granules were wet-milled, dried, and ground, then microcrystalline cellulose (PH102), crospovidone, and magnesium stearate were added to the resulting milled product, mixed, and compressed to prepare tablets.

[0137] [Table 8]

[0138] Disintegration test and dissolution test 3 For the tablets of Examples 7 to 13, the improvement effect based on the calcium hydroxide content was confirmed in essentially the same manner as in the disintegration test and dissolution test 1.

[0139] [Table 9]

[0140] [Table 10]

[0141] As can be confirmed from Table 9, despite the differences in calcium hydroxide content, there was no significant difference in disintegration time among the formulations of Examples 7 to 13. Furthermore, it was confirmed that the formulations of Examples 7 to 10 exhibited significantly superior dissolution rates at pH 4.0 compared to Comparative Example 1 (Table 10 and...). Figure 3 ).

[0142] Experiment Example 4: Effects based on principal component ratios Examples 14 to 17 The tablets of Examples 14 to 17 were prepared in substantially the same manner as the tablets of Examples 7 to 13, except that the tablets were prepared according to the composition ratios (weight %) shown in Table 11 below.

[0143] [Table 11]

[0144] Dissolution test 4 For the tablets of Examples 14 to 17, the improvement effect based on the content of the main component was confirmed in essentially the same manner as in Dissolution Test 1.

[0145] [Table 12]

[0146] Examples 14 to 16 were confirmed to exhibit superior dissolution rates at pH 4.0 compared to Comparative Example 1 (Table 12 and 16). Figure 4 ).

[0147] Based on the above description, those skilled in the art will understand that the present invention can be implemented in other specific forms without altering its technical concept or essential features. In this regard, it should be understood that the exemplary embodiments described above are illustrative in all respects and not intended to limit the scope of the invention. It should be understood that the scope of the invention includes all modifications or alterations derived from the meaning and scope of the claims described below and their equivalents, and not the detailed description above.

Claims

1. A pharmaceutical composition comprising nintedanib or a pharmaceutically acceptable salt thereof; and an alkalizing agent.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of nintedanib is selected from at least one of the following: hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, phosphate, acetate, lactate, maleate, fumarate, citrate, tartrate, hydrogen tartrate, succinate, gluconate, glycoside, methanesulfonate, ethanesulfonate, benzenesulfonate, and toluenesulfonate.

3. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of nintedanib is an ethanesulfonate.

4. The pharmaceutical composition of claim 1, wherein the nintedanib or a pharmaceutically acceptable salt thereof is contained in an amount of 10% to 60% by weight, based on a total weight of 100% by weight of the pharmaceutical composition.

5. The pharmaceutical composition according to claim 1, wherein the composition improves the dissolution rate at pH 4.

0.

6. The pharmaceutical composition according to claim 1, wherein the alkalizing agent is selected from at least one of the following: calcium hydroxide, magnesium hydroxide, sodium bicarbonate and L-arginine.

7. The pharmaceutical composition according to claim 1, wherein the alkalizing agent is calcium hydroxide or sodium bicarbonate.

8. The pharmaceutical composition according to claim 1, wherein the alkalizing agent is contained in an amount of 1% to 30% by weight based on a total weight of 100% by weight of the pharmaceutical composition.

9. The pharmaceutical composition of claim 1, wherein the alkalizing agent is calcium hydroxide, and the alkalizing agent is contained in an amount of 3.5% to 10% by weight based on a total weight of 100% by weight of the pharmaceutical composition.

10. The pharmaceutical composition of claim 1, wherein the alkalizing agent is sodium bicarbonate, and the alkalizing agent is contained in an amount of 20% to 25% by weight based on a total weight of 100% by weight of the pharmaceutical composition.

11. The pharmaceutical composition according to claim 1, wherein, when tested according to the apparatus 2 (paddle method) for dissolution testing in the Korean Pharmacopoeia at 50 rpm, 900 mL pH 4.0 solution and 37°C, the pharmaceutical composition has a dissolution rate of 40% or higher at 20 minutes and a dissolution rate of 60% or higher at 40 minutes.

12. The pharmaceutical composition according to claim 1, wherein, when tested according to the apparatus 2 (paddle method) for dissolution testing in the Korean Pharmacopoeia at 50 rpm, 900 mL pH 4.0 solution and 37°C, the pharmaceutical composition has a dissolution rate of 60% or higher at 20 minutes and a dissolution rate of 85% or higher at 40 minutes.

13. The pharmaceutical composition according to claim 1, wherein, when tested according to the apparatus 2 (paddle method) for dissolution testing in the Korean Pharmacopoeia at 50 rpm, 900 mL pH 4.0 solution and 37°C, the pharmaceutical composition has a dissolution rate of 70% or higher at 20 minutes and a dissolution rate of 90% or higher at 40 minutes.

14. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises at least one additive selected from diluents, disintegrants and lubricants.

15. The pharmaceutical composition of claim 14, wherein the diluent comprises lactose or its hydrate, starch, lactose-cellulose complex, dextrin, microcrystalline cellulose, dipotassium hydrogen phosphate or its hydrate, calcium hydrogen phosphate or its hydrate, sugar, sugar alcohol, alginate, alkaline earth metal salt, clay, polyethylene glycol, or mixtures thereof.

16. The pharmaceutical composition of claim 14, wherein the diluent comprises lactose or its hydrate, starch, lactose-cellulose complex, dextrin, microcrystalline cellulose, dipotassium hydrogen phosphate or its hydrate, calcium hydrogen phosphate or its hydrate, mannitol, glucose, alginate, alkaline earth metal salt, clay, polyethylene glycol, or mixtures thereof.

17. The pharmaceutical composition of claim 14, wherein the diluent comprises microcrystalline cellulose, mannitol, or a mixture thereof.

18. The pharmaceutical composition of claim 14, wherein the disintegrant comprises crospovidone, pregelatinized starch, corn starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl starch, sodium crospovidone carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, starch, alginate or its sodium salt, or mixtures thereof.

19. The pharmaceutical composition of claim 14, wherein the disintegrant is crospovidone.

20. The pharmaceutical composition of claim 14, wherein the lubricant comprises colloidal silica, stearic acid or a salt thereof, talc, sodium benzoate, sodium acetate, sodium oleate, or mixtures thereof.

21. The pharmaceutical composition of claim 14, wherein the lubricant is magnesium stearate.

22. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an oral formulation.

23. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a tablet or capsule.

24. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition comprises 10% to 60% by weight of the nintedanib or a pharmaceutically acceptable salt thereof, 20% to 75% by weight of the diluent, 1% to 15% by weight of the disintegrant, 1% to 10% by weight of the binder, 0.1% to 3% by weight of the lubricant, and 1% to 30% by weight of the alkalizing agent.

25. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is used to treat or prevent idiopathic pulmonary fibrosis or cancer.

26. A solid dosage form comprising nintedanib or a pharmaceutically acceptable salt thereof; and at least one selected from calcium hydroxide, magnesium hydroxide, sodium bicarbonate and L-arginine as an alkalizing agent, wherein, when tested according to apparatus 2 (paddle method) for dissolution testing in the Korean Pharmacopoeia at 50 rpm, 900 mL of pH 4.0 solution and 37°C, the solid dosage form has a dissolution rate of 40% or higher at 20 minutes and a dissolution rate of 60% or higher at 40 minutes.

27. The solid dosage form according to claim 26, wherein the alkalizing agent is calcium hydroxide or sodium bicarbonate.

28. The solid dosage form according to claim 26, wherein the nintedanib or a pharmaceutically acceptable salt thereof is nintedanib ethanesulfonate.

29. The solid dosage form according to claim 26, wherein the solid dosage form further comprises microcrystalline cellulose or D-mannitol as a diluent, crospovidone as a disintegrant, and magnesium stearate as a lubricant.

30. The solid dosage form according to any one of claims 26 to 29, wherein the solid dosage form is a tablet or capsule.

31. The solid dosage form according to any one of claims 26 to 29, wherein the solid dosage form is a tablet.

32. The solid dosage form according to any one of claims 26 to 29, wherein the solid dosage form comprises 10% to 60% by weight of the nintedanib or a pharmaceutically acceptable salt thereof, 20% to 75% by weight of a diluent, 1% to 15% by weight of a disintegrant, 0.1% to 3% by weight of a lubricant, and 1% to 30% by weight of the alkalizing agent.

33. A method for preparing a tablet comprising nintedanib, the method comprising: (a) Preparing granules containing nintedanib or a pharmaceutically acceptable salt thereof, a diluent, and an alkalizing agent; (b) Wet grinding, drying, and milling of the particles; and (c) The ground product is mixed with at least one selected from diluents, disintegrants and lubricants, and the resulting mixture is then compressed into tablets.

34. The method of claim 33, wherein step (a) comprises: (a-1) The mixture is prepared by mixing the nintedanib or a pharmaceutically acceptable salt thereof with the diluent; as well as (a-2) The mixture is granulated using a binder solution containing the alkalizing agent.

35. The method of claim 33, wherein step (a) comprises: (a-1) A mixture is prepared by mixing the nintedanib or a pharmaceutically acceptable salt thereof, the diluent and the alkalizing agent; as well as (a-2) Granulate the mixture using an adhesive solution.

36. The method of claim 33, wherein step (a) comprises: (a-1) A mixture is prepared by mixing the diluent and the alkalizing agent; and (a-2) The mixture is granulated using a binder solution containing the nintedanib or a pharmaceutically acceptable salt thereof.

37. A method for preparing a tablet comprising nintedanib, the method comprising: (a) Preparing granules containing nintedanib or a pharmaceutically acceptable salt thereof and a diluent; (b) Wet grinding, drying, and milling of the particles; and (c) The ground product is mixed with an alkalizing agent, a disintegrant and a lubricant, and then the resulting mixture is compressed into tablets.

38. The method according to any one of claims 33 to 37, wherein the tablet comprises nintedanib ethanesulfonate, microcrystalline cellulose or D-mannitol as a diluent, crospovidone as a disintegrant, calcium hydroxide or sodium bicarbonate as an alkalizing agent, and magnesium stearate as a lubricant.

39. The method according to any one of claims 33 to 37, wherein the tablet comprises 10% to 60% by weight of the nintedanib or a pharmaceutically acceptable salt thereof, 20% to 75% by weight of the diluent, 1% to 15% by weight of the disintegrant, 1% to 10% by weight of the binder, 0.1% to 3% by weight of the lubricant, and 1% to 30% by weight of the alkalizing agent.

Images