Novel tablet having improved dissolution rate comprising nintedanib or pharmaceutically acceptable salt thereof and preparation method therefor

Abstract

The present invention relates to an oral formulation comprising, as an active ingredient, nintedanib or a pharmaceutically acceptable salt thereof. Specifically, the present invention relates to a tablet having an improved dissolution rate, comprising nintedanib or a pharmaceutically acceptable salt thereof, and a preparation method therefor.

Description

Novel tablets having improved dissolution rate comprising nintedanib or a pharmaceutically acceptable salt thereof and a method for preparing the same

[0001] The present invention relates to an oral dosage form comprising nintedanib or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the present invention relates to a tablet comprising nintedanib or a pharmaceutically acceptable salt thereof with an improved dissolution rate, and a method for preparing the same.

[0002] Fibrosis refers to the transformation of normal tissue into fibrous connective tissue, resulting in the hardening of parts of an organ. Pulmonary fibrosis and liver fibrosis are prime examples. This type of fibrosis remains difficult to fundamentally treat.

[0003] Idiopathic pulmonary fibrosis (IPF) is a rare disease of unknown etiology characterized by chronic, progressive pulmonary fibrosis. Its prognosis is poor and its fundamental treatment is challenging. The clinical course of IPF varies widely, typically progressing slowly to respiratory failure due to a decline in lung function, and the survival rate is very low.

[0004] Nintedanib is a targeted therapy belonging to the tyrosine kinase inhibitor (TKI) family and is FDA-approved for the treatment of idiopathic pulmonary fibrosis (IPF). Nintedanib targets various growth factor receptors involved in the pathogenesis of pulmonary fibrosis, and is known to inhibit fibrosis by blocking signaling at the platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor receptor (VEGFR).

[0005] Nintedanib is used as a treatment for idiopathic pulmonary fibrosis and is currently administered orally in soft capsule form. However, soft capsules have the potential to stick to the mouth or esophagus, and some patients report discomfort when taking them. Furthermore, the capsule's capsule membrane can rupture under pressure, leading to leakage of the contents. Furthermore, the capsule's contents can leak out of the capsule membrane in high-temperature and high-humidity environments, and its high production cost is a drawback.

[0006] However, despite these various problems, the low solubility and dissolution rate of nintedanib make it difficult to manufacture into general tablets, and these characteristics make it difficult to manufacture granules and tablets. The present inventors have developed a tablet that improves the problem of nintedanib's low dissolution rate and has a dissolution rate equivalent to or higher than that of soft capsules, thereby completing the present invention.

[0007]

[0008] [Prior Art Literature]

[0009] [Patent Document]

[0010] (Patent Document 1) Republic of Korea Patent Publication No. 10-2021-0074027

[0011] (Patent Document 2) Republic of Korea Patent Publication No. 10-2011-0017872

[0012]

[0013] The present invention aims to provide a pharmaceutical composition having an improved dissolution rate by including an acidifying agent in nintedanib, a poorly soluble drug, or a pharmaceutically acceptable salt thereof.

[0014] The present invention aims to provide a pharmaceutical composition comprising nintedanib or a pharmaceutically acceptable salt thereof, an acidifying agent, and a dissolution regulator.

[0015] In addition, the present invention aims to provide a method for manufacturing a tablet comprising nintedanib or a pharmaceutically acceptable salt thereof, comprising the steps of mixing nintedanib or a pharmaceutically acceptable salt thereof and a dissolution regulator; and the steps of adding an acidifying agent to the mixture to manufacture granules.

[0016] The present invention relates to a pharmaceutical composition comprising nintedanib or a pharmaceutically acceptable salt thereof, and an acidifying agent.

[0017] In the present invention, nintedanib or a pharmaceutically acceptable salt thereof may be nintedanib esilate.

[0018] The acidifying agent of the present invention may be at least one selected from the group consisting of citric acid, fumaric acid, tartaric acid, ascorbic acid, glutamic acid, malic acid, formic acid, and maleic acid. Preferably, the acidifying agent of the present invention may be at least one selected from the group consisting of citric acid, fumaric acid, tartaric acid, and ascorbic acid, but is not limited thereto.

[0019] The acidifying agent of the present invention may have a weight ratio of 0.1 to 40, preferably a weight ratio of 0.1 to 30, more preferably a weight ratio of 0.1 to 25, even more preferably a weight ratio of 0.2 to 25, and most preferably a weight ratio of 0.3 to 25, relative to the weight of nintedanib included in the composition. Specifically, when the weight ratio of the acidifying agent is less than 0.1, a desired dissolution rate cannot be achieved, and when the weight ratio of the acidifying agent exceeds 40, the total weight of the tablet increases, which may cause problems in terms of convenience of administration and mass production.

[0020] The composition of the present invention may further comprise a release control agent. The release control agent of the present invention may be at least one selected from the group consisting of carbomer, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, sodium alginate, and Kollidone SR, and is preferably carbomer.

[0021] The release control agent of the present invention may have a weight ratio of 0.01 to 0.1, preferably 0.02 to 0.1, and most preferably 0.02 to 0.05, relative to the weight of nintedanib included in the composition.

[0022] The composition of the present invention may further comprise a lubricant. The lubricant of the present invention may be at least one selected from the group consisting of magnesium stearate, sodium stearyl fumarate, talc, and colloidal silicon dioxide, and preferably magnesium stearate.

[0023] The composition of the present invention may be in the form of a tablet, and may have a dissolution rate of 75% or more in 45 minutes in a dissolution test under purified water conditions.

[0024] The present invention relates to a tablet comprising granules comprising nintedanib or a pharmaceutically acceptable salt thereof, an acidifying agent, and a dissolution controlling agent.

[0025] The present invention relates to a method for manufacturing a tablet comprising nintedanib or a pharmaceutically acceptable salt thereof, comprising the steps of mixing nintedanib or a pharmaceutically acceptable salt thereof and a dissolution control agent; and the steps of adding an acidifying agent to the mixture to manufacture granules.

[0026] The present invention relates to a method for manufacturing a tablet, comprising the steps of mixing nintedanib or a pharmaceutically acceptable salt thereof and a dissolution regulator; adding an acidifying agent to the mixture to prepare granules; and adding an acidifying agent to the granules.

[0027] The tablet comprising nintedanib according to the present invention exhibits a dissolution rate equivalent to or higher than that of Ofev soft capsules, a commercially available formulation comprising nintedanib, including an acidifying agent, thereby possessing superior pharmaceutical properties. Therefore, the tablet comprising nintedanib according to the present invention can be widely used because it has superior physicochemical and pharmaceutical properties compared to existing commercial formulations in stages such as manufacturing, storage, and packaging.

[0028] Figure 1 shows the results of a dissolution test (Korean Pharmacopoeia Dissolution Test Method 2, 900 mL of purified water, 120 rpm, using a sinker) conducted on the coated tablet of Example 1 and the commercially available Ofev soft capsule.

[0029] Figure 2 shows the results of a dissolution test at pH 1.2 for the tablets of Examples 1 to 4 and the soft capsules of Opev.

[0030] Figure 3 shows the results of a dissolution test at pH 4.0 for the tablets of Examples 1 to 4 and the soft capsules of Opev.

[0031] Figure 4 shows the results of a dissolution test in purified water for the tablets of Examples 1 to 4 and the soft capsules of Opev.

[0032] Figure 5 shows the results of a dissolution test in purified water for the tablets of Examples 1, 5, and 6.

[0033] Figure 6 shows the results of a dissolution test in purified water for the tablets of Examples 1, 21, and 22.

[0034] Figure 7 shows the results of a dissolution test in purified water for the tablets of Examples 2, 7, and 8.

[0035] Figure 8 shows the results of a dissolution test in purified water for the tablets of Examples 3, 9, and 10.

[0036] Figure 9 shows the results of a dissolution test in purified water for the tablets of Examples 4, 11, and 12.

[0037] Figure 10 shows the results of a dissolution test at pH 1.2 for the tablets of Examples 1 and 13 to 17 and Comparative Example 2.

[0038] Figure 11 shows the results of a dissolution test at pH 4.0 for the tablets of Examples 1 and 13 to 17 and Comparative Example 2.

[0039] Figure 12 shows the results of a dissolution test in purified water for the tablets of Examples 1 and 13 to 17 and Comparative Example 2.

[0040] Figure 13 shows the results of a dissolution test at pH 1.2 for the tablets of Examples 1, 18 to 20, and Comparative Example 2.

[0041] Figure 14 shows the results of a dissolution test at pH 4.0 for the tablets of Examples 1, 18 to 20, and Comparative Example 2.

[0042] Figure 15 shows the results of a dissolution test in purified water for the tablets of Examples 1, 18 to 20, and Comparative Example 2.

[0043] The present invention relates to a pharmaceutical composition comprising nintedanib or a pharmaceutically acceptable salt thereof, and an acidifying agent.

[0044] The term "pharmaceutically acceptable salt" as used herein refers to an acid addition salt or base addition salt that is suitable or compatible with the treatment of a patient herein. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphoric acid and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids, such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic, and salicylic acids, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Mono- or diacid salts may be formed, and such salts may exist in hydrated, solvated, or substantially anhydrous form. In general, acid addition salts of the compounds of the present invention are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base forms. The selection of appropriate salts is well known to those skilled in the art.

[0045] The nintedanib or pharmaceutically acceptable salt thereof of the present invention may be nintedanib esilate.

[0046] The term "acidifying agent" as used herein means an excipient that has an acidifying effect or increases acidity, thereby reducing the pH of the gastrointestinal tract.

[0047] The term "release controlling agent" as used herein refers to an excipient that delays the dissolution rate or provides long-term release.

[0048] Hereinafter, with reference to the attached drawings, embodiments and examples of the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, the present invention may be implemented in various forms and is not limited to the embodiments and examples described herein.

[0049] Throughout this specification, whenever a part is said to "include" a component, this means that it may include other components, but not to the exclusion of other components, unless otherwise stated.

[0050] Hereinafter, the present invention will be described in more detail based on the following examples, but these are only for explaining the present invention and the scope of the present invention is not limited in any way by these examples.

[0051]

[0052] [Example 1]

[0053] Preparation of tablets containing nintedanib

[0054]

[0055] A core of a tablet containing nintedanib esilate as an active ingredient was manufactured with the ingredients and contents shown in Table 1 below.

[0056] Raw material name Content mg% Active ingredient Nintedanib esilate 180.6% (150 mg as Nintedanib) 38.0% Excipient Mannitol 141.6% 29.8% Binder Povidone 12.5% ​​2.6% Release regulator Carbomer 3.3% 0.7% Acidifier Citric acid 95.0% 20.0% Fluidizer Talc 4.0% 0.8% Disintegrant Crospovidone 35.0% 7.4% Lubricant Magnesium stearate 3.0% 0.6% Solvent Ethanol 90.0% - wt 475.0% 100.0%

[0057]

[0058] Carbomer, talc, and mannitol were mixed in a mixer to prepare mixture 1, and then crospovidone and nintedanib esilate were mixed with mixture 1 to prepare mixture 2. Afterwards, povidone was added to ethanol and stirred until the components were completely dissolved to prepare mixture 1. After adding mixture 1 to mixture 2, mixture was mixed in a mixer for 2 minutes, citric acid was added, and further mixing was performed for 1 minute.

[0059] The above mixture was placed in a fluidized bed granulator, dried, and granules were obtained. Citric acid was added to the granules, mixed, and then lubricated with magnesium stearate. The final mixture was compressed into tablets at 7 to 13 kp using a tablet press to obtain tablets containing nintedanib esilate (180.6 mg) (core weight 475 mg / tablet).

[0060]

[0061] [Examples 2 to 4]

[0062] Preparation of tablets containing nintedanib

[0063]

[0064] Tablets of Examples 2 to 4 were manufactured using the same manufacturing method as Example 1, with the types and contents of the remaining ingredients being the same and the type of acidifying agent being changed as shown in Table 2 below. However, the content of the excipients was adjusted so that the total amount of the tablets was the same by changing the content of the acidifying agent.

[0065] Raw material name Example 1 Example 2 Example 3 Example 4 mg % mg % mg % mg % Citric acid 95.063 --- Fumaric acid -- 95.063 -- Tartaric acid -- 95.063 -- Ascorbic acid -- 95.063

[0066] (The above content represents the weight % of acidifying agent for 150 mg of nintedanib)

[0067]

[0068] [Examples 5 to 12]

[0069] Preparation of tablets containing nintedanib

[0070]

[0071] Tablets of Examples 5 to 12 were manufactured using the same manufacturing method as Example 1, with the types and contents of the remaining ingredients being the same and the type of acidifying agent being changed as shown in Tables 3 and 4 below. However, the content of the excipients was adjusted so that the total amount of the tablets was the same by changing the content of the acidifying agent.

[0072]

[0073] Raw material name Example 5 Example 6 Example 7 Example 8 mg % mg % mg % mg % Citric acid 14.09 -------- 3,750 2,500 ---- Fumaric acid ---- 14.09 -------- 3,750 2,500

[0074] (The above content represents the weight % of acidifying agent for 150 mg of nintedanib)

[0075]

[0076] Raw material name Example 9 Example 10 Example 11 Example 12 mg % mg % mg % mg % Tartaric acid 14.09 -------- 3,750 2,500 ---- Ascorbic acid ---- 14.09 -------- 3,750 2,500

[0077] (The above content represents the weight % of acidifying agent for 150 mg of nintedanib)

[0078]

[0079] [Examples 13 to 17]

[0080] Preparation of tablets containing nintedanib

[0081]

[0082] Using the same manufacturing method as Example 1, the types and contents of the remaining ingredients were the same, and the type of the dissolution regulator was changed as shown in Tables 5 and 6 below to manufacture tablets of Examples 13 to 17 and Comparative Example 2 that did not include the dissolution regulator.

[0083]

[0084] Raw material name Example 13 Example 14 Example 15 mg % mg % mg % Kollidone SR 3.32 ---- Ethyl cellulose -- 3.32 -- Hydroxypropyl methyl cellulose -- 3.32

[0085] (The above content represents the weight % of the release regulator for 150 mg of nintedanib)

[0086]

[0087] Raw material name Example 16 Example 17 mg % mg % Hydroxypropyl methylcellulose phthalate 3.32 -- Sodium alginate -- 3.32

[0088] (The above content represents the weight % of the release regulator for 150 mg of nintedanib)

[0089]

[0090] [Examples 18 to 20]

[0091] Preparation of tablets containing nintedanib

[0092]

[0093] Tablets of Examples 18 to 20 were manufactured using the same manufacturing method as Example 1, with the types and contents of the remaining ingredients being the same and the type of dissolution regulator being changed as shown in Table 7 below. However, the content of the excipient was changed according to the content of the dissolution regulator to ensure that the total amount of the tablets was the same.

[0094]

[0095] Raw material name Example 18 Example 19 Example 20 mg % mg % mg % Carbomer 1.4 17.5 5 16.011

[0096] (The above content represents the weight % of the release regulator for 150 mg of nintedanib)

[0097]

[0098] [Examples 21 and 22]

[0099] Preparation of tablets containing nintedanib

[0100]

[0101] Tablets of Examples 5 to 12 were manufactured using the same manufacturing method as Example 1, with the types and contents of the remaining ingredients being the same and the type of acidifying agent being changed as shown in Table 8 below. However, the content of the excipients was adjusted to ensure that the total amount of the tablets was the same by changing the content of the acidifying agent.

[0102]

[0103] Raw material name Example 21 Example 22 mg% mg% Citric acid 30204530

[0104] (The above content represents the weight % of acidifying agent for 150 mg of nintedanib)

[0105]

[0106] [Comparative Example 1]

[0107] Preparation of tablets without acidifying agents

[0108]

[0109] Using the same manufacturing method as Example 1, a tablet of Comparative Example 1 was manufactured without an acidifying agent as shown in Table 9 below.

[0110]

[0111] Ingredient name Content Content mg% mg% Active ingredient Nintedanib esylate 180.638.0% 180.638.0% Excipient Mannitol 141.629.8% 236.649.8% Binder Povidone 12.52.6% 12.52.6% Release regulator Carbomer 3.30.7% 3.30.7% Acidifier Citric acid 95.020.0% -- Fluidizer Talc 4.00.8% 4.00.8% Disintegrant Crospovidone 35.07.4% 35.07.4% Lubricant Magnesium stearate 3.00.6% 3.00.6% Solvent Ethanol 90.0-90.0 wt 475.0100.0% 475.0100%

[0112]

[0113] [Experimental Example 1]

[0114] Dissolution comparison test

[0115]

[0116] The tablet of Example 1 was film-coated and photo-coated with a coating agent and a polishing agent having the compositions shown in Table 10 below, and a dissolution test was performed on the commercially available formulation, Opev soft capsule, using the following method.

[0117]

[0118] Ingredients for formulation purpose, name, quantity (mg), core tablet 475, coating agent tab shield brown 14.6, purified water 26.5, ethanol 105.0, film-coated tablet 489.6, gloss agent polyethylene glycol 6000, 0.4, purified water 3.8, ethanol 3.8, total weight of coating agent 490.0

[0119] The dissolution test was conducted according to the dissolution test method 2 (paddle test) of the general test methods of the Korean Pharmacopoeia. Specifically, the dissolution solution was 900 mL (purified water), the temperature was 37±0.5℃, the paddle speed was 120 rpm, and the dissolution solution was extracted using a sinker. The dissolution solution was collected at 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the start of the experiment, filtered through a 0.45 μm filter, and analyzed by HPLC.

[0120] As shown in Figure 1, it can be seen that the tablet of Example 1 shows an excellent dissolution test result that is equal to or better than that of the Opev soft capsule.

[0121]

[0122] [Experimental Example 2]

[0123] Dissolution test at pH 1.2 according to acidifying agent

[0124]

[0125] A dissolution test at pH 1.2 was performed on the tablets of Examples 1 to 2 and Comparative Example 1, and the Ofev soft capsules using the following method.

[0126] The dissolution test was conducted according to the dissolution test method 2 (paddle test) of the general test methods of the Korean Pharmacopoeia. Specifically, the dissolution solution was 900 mL (pH 1.2), the temperature was 37±0.5℃, and the paddle speed was 50 rpm. The dissolution solution was collected at 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the start of the experiment, filtered through a 0.45 μm filter, and analyzed by HPLC.

[0127]

[0128] The results of the above experiment are shown in Table 11 and Fig. 2 below.

[0129]

[0130]

[0131] As shown in Table 11 and Figure 2 above, the tablets of Examples 2 and 4 showed excellent dissolution rates, and the remaining tablets all showed dissolution rates equal to or higher than those of the Ofev soft capsules.

[0132]

[0133] [Experimental Example 3]

[0134] Dissolution test at pH 4.0 according to acidifying agent

[0135]

[0136] A dissolution test at pH 4.0 was performed on the tablets of Examples 1 to 2 and Comparative Example 1, and the Ofev soft capsules using the following method.

[0137] The dissolution test was conducted according to the dissolution test method 2 (paddle test) of the general test methods of the Korean Pharmacopoeia. Specifically, the dissolution solution was 900 mL (pH 4.0), the temperature was 37±0.5℃, and the paddle speed was 50 rpm. The dissolution solution was collected at 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the start of the experiment, filtered through a 0.45 μm filter, and analyzed by HPLC.

[0138]

[0139] The results of the above experiment are shown in Table 12 and Figure 3 below.

[0140]

[0141]

[0142] As shown in Table 12 and Figure 3 above, the tablets of Examples 1-4 all exhibited excellent dissolution rates, but Comparative Example 1 exhibited a very poor dissolution rate, and it was found that disintegration was not completed for 120 minutes.

[0143]

[0144] [Experimental Example 4]

[0145] Dissolution test in purified water according to acidifying agent

[0146]

[0147] A dissolution test in purified water was performed using the tablets of Examples 1 to 4 and Comparative Example 1, and the Ofev soft capsules, using the following method.

[0148] The dissolution test was conducted according to the dissolution test method 2 (paddle test) of the general test methods of the Korean Pharmacopoeia. Specifically, the dissolution solution was 900 mL (purified water), the temperature was 37±0.5℃, the paddle speed was 120 rpm, and the dissolution solution was extracted using a sinker. The dissolution solution was collected at 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the start of the experiment, filtered through a 0.45 μm filter, and analyzed by HPLC.

[0149] The results of the above experiment are shown in Table 13 and Fig. 4 below.

[0150]

[0151]

[0152] As shown in Table 13 and Fig. 4, the tablets of Examples 1-4 all exhibited excellent dissolution rates, but Comparative Example 1 exhibited a very poor dissolution rate. In particular, the tablets of Examples 1-4 exhibited a dissolution rate of 75% or more in 45 minutes.

[0153] From the above experimental results, it can be seen that the tablet of the present invention exhibits an excellent dissolution rate when it contains an acidifying agent.

[0154]

[0155] [Experimental Example 5]

[0156] Dissolution test in purified water according to citric acid content

[0157]

[0158] For Examples 1, 5, and 6, a dissolution test in purified water was performed using the following method.

[0159] The dissolution test was conducted according to the dissolution test method 2 (paddle test) of the general test methods of the Korean Pharmacopoeia. Specifically, the dissolution solution was 900 mL (purified water), the temperature was 37±0.5℃, the paddle speed was 120 rpm, and the dissolution solution was extracted using a sinker. The dissolution solution was collected at 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the start of the experiment, filtered through a 0.45 μm filter, and analyzed by HPLC.

[0160] The results of the above experiment are shown in Table 14 and Figure 5 below.

[0161]

[0162]

[0163] As shown in Table 14 and Figure 5 above, the tablets of Examples 1 and 6 both showed excellent dissolution rates, but the tablet of Example 5 showed a very poor dissolution rate.

[0164]

[0165] [Experimental Example 6]

[0166] Dissolution test in purified water according to citric acid content

[0167]

[0168] For Examples 1, 21, and 22, a dissolution test in purified water was performed using the following method.

[0169] The dissolution test was conducted according to the dissolution test method 2 (paddle test) of the general test methods of the Korean Pharmacopoeia. Specifically, the dissolution solution was 900 mL (purified water), the temperature was 37±0.5℃, the paddle speed was 120 rpm, and the dissolution solution was extracted using a sinker. The dissolution solution was collected at 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the start of the experiment, filtered through a 0.45 μm filter, and analyzed by HPLC.

[0170] The results of the above experiment are shown in Table 15 and Fig. 6 below.

[0171]

[0172]

[0173] As shown in Table 15 and Figure 6 above, the tablets of Examples 1 and 22 both showed excellent dissolution rates, but the tablet of Example 21 showed a very poor dissolution rate.

[0174] From the experimental results of Experimental Examples 5 and 6, it was confirmed that Examples 5 and 21, in which the weight ratio of the acidifying agent to nintedanib was 9% and 20%, respectively, showed inferior dissolution rates, and Examples 1, 6, and 22, in which the weight ratio of the acidifying agent was 30% or more, showed excellent dissolution rates.

[0175]

[0176] [Experimental Example 7]

[0177] Dissolution test in purified water according to fumaric acid content

[0178]

[0179] For Examples 2, 7 and 8, a dissolution test in purified water was performed using the following method.

[0180] The dissolution test was conducted according to the dissolution test method 2 (paddle test) of the general test methods of the Korean Pharmacopoeia. Specifically, the dissolution solution was 900 mL (purified water), the temperature was 37±0.5℃, the paddle speed was 120 rpm, and the dissolution solution was extracted using a sinker. The dissolution solution was collected at 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the start of the experiment, filtered through a 0.45 μm filter, and analyzed by HPLC.

[0181] The results of the above experiment are shown in Table 16 and Fig. 7 below.

[0182]

[0183]

[0184] As shown in Table 16 and Figure 7 above, the tablets of Examples 2 and 8 both showed excellent dissolution rates, but the tablet of Example 7 showed a very poor dissolution rate.

[0185]

[0186] [Experimental Example 8]

[0187] Dissolution test in purified water according to tartaric acid content

[0188]

[0189] For Examples 3, 9, and 10, a dissolution test in purified water was performed using the following method.

[0190] The dissolution test was conducted according to the dissolution test method 2 (paddle test) of the general test methods of the Korean Pharmacopoeia. Specifically, the dissolution solution was 900 mL (purified water), the temperature was 37±0.5℃, the paddle speed was 120 rpm, and the dissolution solution was extracted using a sinker. The dissolution solution was collected at 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the start of the experiment, filtered through a 0.45 μm filter, and analyzed by HPLC.

[0191] The results of the above experiment are shown in Table 17 and Fig. 8 below.

[0192]

[0193]

[0194] As shown in Table 17 and Figure 8 above, the tablets of Examples 3 and 10 both showed excellent dissolution rates, but the tablet of Example 9 showed a very poor dissolution rate.

[0195]

[0196] [Experimental Example 9]

[0197] Dissolution test in purified water according to ascorbic acid content

[0198]

[0199] For Examples 4, 11, and 12, a dissolution test in purified water was performed using the following method.

[0200] The dissolution test was conducted according to the dissolution test method 2 (paddle test) of the general test methods of the Korean Pharmacopoeia. Specifically, the dissolution solution was 900 mL (purified water), the temperature was 37±0.5℃, the paddle speed was 120 rpm, and the dissolution solution was extracted using a sinker. The dissolution solution was collected at 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the start of the experiment, filtered through a 0.45 μm filter, and analyzed by HPLC.

[0201] The results of the above experiment are shown in Table 18 and Fig. 9 below.

[0202]

[0203]

[0204] As shown in Table 18 and Figure 9 above, the tablets of Examples 4 and 12 both showed excellent dissolution rates, but the tablet of Example 11 showed a very poor dissolution rate.

[0205]

[0206] [Experimental Example 10]

[0207] Dissolution test according to dissolution control agent

[0208]

[0209] A dissolution test was performed using the following method for Examples 1 and 13 to 17 according to the type of dissolution regulator and Comparative Example 2 that did not include a dissolution regulator.

[0210] Dissolution tests were conducted according to the Dissolution Test Method 2 (Paddle Test) of the General Test Methods of the Korean Pharmacopoeia. Specifically, the dissolution solution was 900 mL, the temperature was 37±0.5℃, the paddle speed was 120 rpm, and the dissolution solution was extracted using a sinker. Dissolution solutions were collected at 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the start of the experiment, filtered through a 0.45 μm filter, and analyzed by HPLC.

[0211] Dissolution tests were performed under the conditions of pH 1.2, pH 4.0, and purified water, and the experimental results are shown in Tables 19 to 21 and Figures 10 to 12.

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218] As shown in Tables 19 to 21 above, Examples 1 and 13 to 17 containing a release regulator were confirmed to have appropriately controlled dissolution at an early stage, compared to Comparative Example 2 not containing a release regulator. If dissolution occurs too quickly at pH 1.2, side effects such as diarrhea, nausea, and abdominal pain may occur. To reduce these side effects, the release rate can be appropriately controlled at an early stage by using a release regulator, thereby reducing side effects.

[0219]

[0220] [Experimental Example 11]

[0221] Dissolution test according to the content of dissolution regulator

[0222]

[0223] A dissolution test was performed using the following method for Examples 1, 18 to 20, and Comparative Example 2 according to the content of the dissolution regulator.

[0224] Dissolution tests were conducted according to the Dissolution Test Method 2 (Paddle Test) of the General Test Methods of the Korean Pharmacopoeia. Specifically, the dissolution solution was 900 mL, the temperature was 37±0.5℃, the paddle speed was 120 rpm, and the dissolution solution was extracted using a sinker. Dissolution solutions were collected at 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the start of the experiment, filtered through a 0.45 μm filter, and analyzed by HPLC.

[0225] Dissolution tests were performed under the conditions of pH 1.2, pH 4.0, and purified water, and the experimental results are shown in Tables 22 to 24 and Figures 13 to 15.

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232] As shown in Tables 22 to 24 above, it can be seen that Examples 1 and 19, which contain 2% and 5% of the release regulator for nintedanib, respectively, have appropriately controlled initial dissolution. However, Example 18, which contains a small amount of 1% of the release regulator for nintedanib, exhibited a similar dissolution pattern to Comparative Example 2 under dissolution conditions in pH 4.0 and water, and Example 20, which contains an excessive amount of 11% of the release regulator for nintedanib, has an initial dissolution that is too low.

Claims

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

2. A pharmaceutical composition according to claim 1, wherein the acidifying agent is at least one selected from the group consisting of citric acid, fumaric acid, tartaric acid, ascorbic acid, glutamic acid, malic acid, formic acid, and maleic acid.

3. A pharmaceutical composition according to claim 1, wherein the acidifying agent is at least one selected from the group consisting of citric acid, fumaric acid, tartaric acid, and ascorbic acid.

4. A pharmaceutical composition according to claim 1, wherein the acidifying agent has a weight ratio of 0.1 to 40 with respect to the weight of nintedanib included in the composition.

5. A pharmaceutical composition according to claim 1, wherein the acidifying agent has a weight ratio of 0.1 to 30 with respect to the weight of nintedanib included in the composition.

6. A pharmaceutical composition according to claim 1, wherein the acidifying agent has a weight ratio of 0.1 to 25 with respect to the weight of nintedanib included in the composition.

7. A pharmaceutical composition according to claim 1, wherein the acidifying agent has a weight ratio of 0.2 to 25 with respect to the weight of nintedanib included in the composition.

8. A pharmaceutical composition according to claim 1, wherein the acidifying agent has a weight ratio of 0.3 to 25 with respect to the weight of nintedanib included in the composition.

9. A pharmaceutical composition according to claim 1, further comprising a release control agent.

10. A pharmaceutical composition according to claim 9, wherein the release control agent is at least one selected from the group consisting of carbomer, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, sodium alginate, and Kollidone SR.

11. A pharmaceutical composition according to claim 9, wherein the release control agent is a carbomer.

12. A pharmaceutical composition in claim 9, wherein the release regulator has a weight ratio of 0.01 to 0.1 with respect to the weight of nintedanib included in the composition.

13. A pharmaceutical composition in claim 9, wherein the release regulator has a weight ratio of 0.02 to 0.1 with respect to the weight of nintedanib included in the composition.

14. A pharmaceutical composition in claim 9, wherein the release regulator has a weight ratio of 0.02 to 0.05 with respect to the weight of nintedanib included in the composition.

15. A pharmaceutical composition according to claim 1, further comprising a lubricant.

16. A pharmaceutical composition according to claim 15, wherein the lubricant is at least one selected from the group consisting of magnesium stearate, sodium stearyl fumarate, talc, and colloidal silicon dioxide.

17. A pharmaceutical composition according to claim 15, wherein the lubricant is magnesium stearate.

18. A pharmaceutical composition according to any one of claims 1 to 17, wherein the composition is a tablet.

19. A pharmaceutical composition having a dissolution rate of 75% or more in 45 minutes in a dissolution test under purified water conditions in paragraph 18.

20. A tablet comprising granules containing nintedanib or a pharmaceutically acceptable salt thereof, an acidifying agent, and a dissolution regulator.

21. A tablet in claim 20, wherein the acidifying agent is at least one selected from the group consisting of citric acid, fumaric acid, tartaric acid, ascorbic acid, glutamic acid, malic acid, formic acid, and maleic acid.

22. A tablet in claim 20, wherein the acidifying agent is at least one selected from the group consisting of citric acid, fumaric acid, tartaric acid, and ascorbic acid.

23. A tablet in claim 20, wherein the release control agent is at least one selected from the group consisting of carbomer, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, sodium alginate, and Kollidone SR.

24. A tablet in claim 20, wherein the release control agent is a carbomer.

25. A step of mixing nintedanib or a pharmaceutically acceptable salt thereof and a release control agent; and A step of manufacturing granules by adding an acidifying agent to the above mixture A method for manufacturing a tablet comprising nintedanib or a pharmaceutically acceptable salt thereof.

26. A method for producing a tablet comprising nintedanib or a pharmaceutically acceptable salt thereof, further comprising a step of adding an acidifying agent to the granules in the 25th paragraph.

27. A pharmaceutical composition according to claim 1, wherein the nintedanib or a pharmaceutically acceptable salt thereof is nintedanib esilate.

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