Oral preparations containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid

Abstract

The present invention relates to an oral formulation containing an API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof, the particle size (D(0.9)) of granules corresponding to 90% of the maximum particle size in a cumulative particle size distribution being 80 μm or more and 300 μm or less. The oral formulation according to the present invention has a low degree of wear and an increased dissolution rate despite containing a high content of API by adjusting the particle size of the API within a specific range.

Description

[Technical field]

[0001] This application claims the benefit of priority based on Korean Patent Application No. 10-2021-0049613 dated April 16, 2021, and incorporates all contents disclosed in the documents of that Korean patent application as part of this specification.

[0002] The present invention relates to an oral preparation which contains a high content of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid and yet has excellent physical properties. [Background technology]

[0003] Xanthine oxidase is an enzyme that converts hypoxanthine to xanthine and then converts the formed xanthine to uric acid. Substances that inhibit the activity of xanthine oxidase can effectively treat diseases associated with uric acid accumulation, such as hyperuricemia, gout, heart failure, and cardiovascular diseases.

[0004] Meanwhile, in relation to substances that inhibit the activity of xanthine oxidase, Korean Patent Publication No. 1751325 (Patent Document 1) provides 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (chemical formula 1 below) and a method for preparing the compound, and Korean Patent Publication No. 1424013 (Patent Document 2) provides various types of crystal forms obtained using various solvents and methods for preparing the same. [ka]

[0005] However, there has been no report on an oral formulation containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid of Formula 1 or a pharma- ceutically acceptable salt thereof as an active pharmaceutical ingredient (API), and in particular, there has been no report on an oral formulation containing the API at a high content.

[0006] Preparations containing a high content of API generally do not have excellent basic physical properties such as hardness and tabletability. To overcome these drawbacks, they are generally produced using a wet granulation or dry granulation method or by increasing the amount of excipients to reduce the proportion of API.

[0007] However, by carrying out a granulation process to improve the fluidity of the high-content formulation, not only may the manufacturing time and production cost increase, but also the total weight and volume of the formulation increase due to the increase in the amount of excipients, resulting in an increase in the production cost and a decrease in patient compliance.

[0008] In addition, when oral preparations are provided in the form of oral tablets in consideration of convenience of administration, production cost, etc., bioavailability is very important. An important factor affecting the bioavailability is the dissolution process of the drug in the body, which can be indirectly confirmed as the dissolution rate through a dissolution test in a laboratory.

[0009] However, since high-content formulations are inevitably required to have a lower excipient content than low-content formulations, the physical properties generally deteriorate.

[0010] Therefore, there is a need to develop an oral formulation that contains a high content of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutical acceptable salt thereof as an API, while having excellent physical properties and an excellent dissolution rate. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] Korean Patent Publication No. 1751325 (2017.06.21.), Novel compound effective as a xanthine oxidase inhibitor, its preparation method and pharmaceutical composition containing the same [Patent Document 2] Korean Patent Publication No. 1424013 (2014.07.22.), Crystalline form of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid and its preparation method Summary of the Invention [Problem to be solved by the invention]

[0012] The problem to be solved by the present invention is to provide an oral formulation that contains an excess amount of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof as an API, but has excellent physical properties and an excellent dissolution rate. [Means for solving the problem]

[0013] The present invention provides an oral formulation having excellent physical properties by containing an API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof, in particular an API having a particular particle size range, and a method for producing the oral formulation.

[0014] The API contained in the oral formulation of the present invention has a particle size (D(0.9)) of 90% of granules relative to the maximum particle size in the cumulative particle size distribution of 80 μm or more and 300 μm or less, or 120 μm or more and 270 μm or less.

[0015] When 900 ml of a pH 6.8 buffer solution is used as a dissolution medium and a paddle is used at a rotation speed of 50 rpm, the oral formulation of the present invention has a dissolution rate of 70% or more in 15 minutes, 85% or more in 30 minutes, and 89% or more in 60 minutes.

[0016] The content of the API contained in the oral preparation of the present invention is 30 to 50% by weight based on the total weight of the preparation.

[0017] The API content of the oral formulation of the present invention is 95-105%.

[0018] The oral preparation of the present invention is used for the treatment or prevention of a xanthine oxidase-related disease selected from the group consisting of hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation and joint disease, and inflammatory bowel disease. Effect of the Invention

[0019] The oral formulation according to the present invention containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof as an API has excellent physical properties despite a high API content by adjusting the particle size of the API within a specific range, and therefore it is possible to prevent problems that may occur during the manufacturing process.

[0020] In addition, the oral formulation according to the present invention contains a high content of the API, 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof, and is therefore not only economical but also expected to have increased bioavailability due to its high dissolution rate. [Brief description of the drawings]

[0021] [Figure 1] FIG. 1 shows the results of analyzing the degree of wear (%) of plain tablets according to the particle size distribution of API. [Diagram 2] FIG. 1 shows the results of analyzing the dissolution rate (%) of plain tablets according to the particle size distribution of API. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The present invention will now be described in more detail.

[0023] All technical terms used in the present invention are used in the same sense as commonly understood by those of ordinary skill in the art unless otherwise defined. In addition, although preferred methods and samples are described herein, similar or equivalent methods and samples are also included in the scope of the present invention. The contents of all publications referenced in this specification are incorporated herein by reference in their entirety.

[0024] The present inventors have continued to conduct research into various methods to increase the content of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof as an API in an oral formulation and maintain or improve its physical properties. As a result, they have developed an oral formulation that has excellent physical properties and an excellent dissolution rate when the particle size of the API is adjusted to a specific range.

[0025] In this case, by adjusting the particle size of the API within a specific range, while maintaining physical properties such as flowability, when formulated into tablets (plain tablets), the tablets have excellent physical properties such as hardness and abrasion resistance, which is economical. In addition, despite containing a high content of API, there is no need to increase the content of a separate excipient to improve physical properties, and the tablets have excellent content and uniformity and a high dissolution rate.

[0026] Therefore, the present invention provides an oral preparation having excellent physical properties and a high dissolution rate by adjusting the particle size of an API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof to a specific range.

[0027] In the present invention, the term "pharmaceutical acceptable salt" refers to a salt form of a compound that does not cause significant irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The API 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid contained in the oral formulation of the present invention can be converted to its salt by conventional methods.

[0028] In oral preparations such as tablets or granule-type capsules, it is common to minimize the size per unit dosage form even if a high content of API is contained in the preparation in order to make it easier to swallow. However, it is common general technical knowledge for a person having ordinary skill in the technical field to which this invention pertains that when an API is contained in a high content, not only are physical properties such as flowability and tabletability impaired, but also bioavailability represented by dissolution rate may be affected.

[0029] In fact, in an oral preparation containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid as an API, the allowable content of the API in an oral preparation (particularly, a tablet) having pharma- ceutically acceptable physical properties is only about 30%, and if the content exceeds this, there is a problem that physical properties such as tabletability are rapidly degraded.

[0030] In the present invention, extensive research was conducted on oral formulations that contain a high content of API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof, while also having excellent or good bioavailability, as represented by physical stability and dissolution rate.

[0031] The particle size distribution of an API is a factor that affects the compressibility during the tableting process and is known to be one of the important characteristics in the manufacturing process. In addition, the particle size distribution of an API is a factor that affects the solubility and is an important characteristic that affects the dissolution of the finished product. In order to ensure a desired dissolution pattern in the finished product, the particle size distribution of the API was adjusted in the present invention.

[0032] As a result, by adjusting the particle size distribution of the API, we developed an oral formulation that not only has excellent physical stability but also an excellent dissolution rate, despite containing a high content of API.

[0033] One embodiment of the present invention provides an oral formulation comprising: i) 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof as an API; and ii) a particle size (D(0.9)) of said API equal to or greater than 80 μm and equal to or less than 300 μm.

[0034] In the present invention, in the cumulative particle size distribution of the API, the particle size (D(0.9)) of granules corresponding to 90% of the maximum particle size is 80 μm or more and 300 μm or less, 90 μm or more and 300 μm or less, 100 μm or more and 300 μm or less, 110 μm or more and 300 μm or less, 120 μm or more and 300 μm or less, 130 μm or more and 300 μm or less, 140 μm or more and 300 μm or less, 150 μm or more and 300 μm or less, 80 μm or more and 270 μm or less, 90 μm or more and 270 μm or less, 100 μm or more and 270 μm or less, 110 μm or more and 270 μm or less, 120 μm or more and 270 μm or less, 130 μm or more and 270 μm or less, 140 μm or more and 270 μm or less, 150 μm or more and 300 μm or less. The thickness may be 270 μm or less, 80 μm or more and 250 μm or less, 90 μm or more and 250 μm or less, 100 μm or more and 250 μm or less, 110 μm or more and 250 μm or less, 120 μm or more and 250 μm or less, 130 μm or more and 250 μm or less, 140 μm or more and 250 μm or less, 150 μm or more and 250 μm or less, 80 μm or more and 230 μm or less, 90 μm or more and 230 μm or less, 100 μm or more and 230 μm or less, 110 μm or more and 230 μm or less, 120 μm or more and 230 μm or less, 130 μm or more and 230 μm or less, 140 μm or more and 230 μm or less, or 150 μm or more and 230 μm or less.

[0035] In addition, in the cumulative particle size distribution of the API, the particle size (D(0.5)) of the granules equivalent to 50% of the maximum particle size is 30 μm or more and 150 μm or less, 40 μm or more and 150 μm or less, 50 μm or more and 150 μm or less, 60 μm or more and 150 μm or less, 70 μm or more and 150 μm or less, 80 μm or more and 150 μm or less, 30 μm or more and 140 μm or less, 40 μm or more and 140 μm or less, 50 μm or more and 140 μm or less, 60 μm or more and 140 μm or less, 70 μm or more and 140 μm or less, 80 μm or more and 140 μm or less, 30 μm or more and 130 μm or less, 40 μm or more and 130 μm or less, 50 μm or more and 130 μm or less, 60 μm or more and 130 μm or less, 70 μm or more and 130 μm or less, or It may be 80 μm or more and 130 μm or less.

[0036] Furthermore, in the cumulative particle size distribution of the API, the particle size (D(0.1)) for granules corresponding to 10% of the maximum particle size may be 10 μm or more and 90 μm or less, 20 μm or more and 90 μm or less, 30 μm or more and 90 μm or less, 40 μm or more and 90 μm or less, 50 μm or more and 90 μm or less, 10 μm or more and 80 μm or less, 20 μm or more and 80 μm or less, 30 μm or more and 80 μm or less, 40 μm or more and 80 μm or less, or 50 μm or more and 80 μm or less.

[0037] The oral formulation of the present invention has excellent hardness and low abrasion because the API has a particle size of 80 μm or more and 300 μm or less in terms of D(0.9). As a result, when producing an oral formulation (tablet) containing the API with the particle size adjusted according to the present invention, there is an advantage in that the productivity of the oral formulation can be increased by reducing the possibility of tablet abrasion during handling and coating of the plain tablet.

[0038] The oral preparation of the present invention has excellent content and uniformity of 95% or more, and also has an excellent disintegration time.

[0039] When 900 ml of a pH 6.8 buffer solution is used as a dissolution medium and a paddle is used at a rotation speed of 50 rpm, the oral formulation of the present invention has a dissolution rate of 70% or more in 15 minutes, 85% or more in 30 minutes, and 89% or more in 60 minutes, which are superior to oral formulations having an API with a D(0.9) of 325 μm or more.

[0040] Furthermore, when 900 ml of a pH 6.8 buffer solution is used as the dissolution medium and a paddle is used at a rotation speed of 50 rpm, the oral preparation of the present invention has a dissolution rate of 89% or more in 60 minutes.

[0041] Therefore, since the oral preparation of the present invention has an excellent dissolution rate, it can be expected that the bioavailability will also be excellent, reflecting this.

[0042] In the present invention, the oral formulation further comprises at least one excipient selected from a pharma- ceutically acceptable diluent, disintegrant, glidant, lubricant, etc.

[0043] The excipients such as the diluent, disintegrant, flow agent, and lubricant may be any of those known to be commonly used in the art. The diluent may be used in an amount of 30-50 wt%, 40-50 wt%, or 45-50 wt%, based on the total weight of the oral formulation. The disintegrant may be used in an amount of 1-10 wt% or 1-5 wt%, based on the total weight of the oral formulation. The flow agent may be used in an amount of 0.1-5 wt%, 0.2-3 wt%, or 0.3-2 wt%, based on the total weight of the oral formulation. The lubricant may be used in an amount of 0.1-10 wt%, 0.3-5 wt%, or 0.5-4 wt%, based on the total weight of the oral formulation.

[0044] For example, the diluent may be selected from the group consisting of, but is not limited to, microcrystalline cellulose (MCC), lactose monohydrate, lactose anhydrous, lactose, starch, mannitol, carboxymethylcellulose, sorbitol, and combinations thereof. The disintegrant may be selected from the group consisting of, but is not limited to, low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, F-melt, and combinations thereof. The flow agent may be selected from the group consisting of, but is not limited to, talc, silicon dioxide, and combinations thereof. The lubricant may be selected from the group consisting of, but is not limited to, magnesium stearate, silicon dioxide, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof.

[0045] The oral formulations can be administered once a day and can be taken daily.

[0046] The content of the API contained in the oral formulation is 30 to 50 wt%, 35 to 50 wt%, 40 to 50 wt%, 45 to 50 wt%, 30 to 45 wt%, 35 to 45 wt%, 40 to 45 wt%, 30 to 40 wt%, or 35 to 40 wt%, based on the total weight of the oral formulation.

[0047] The API may comprise 50-500 mg, 50-400 mg, 50-300 mg, 50-200 mg, 50-100 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200-500 mg, 200-400 mg, 200-300 mg, 300-500 mg, or 300-400 mg per unit dosage form.

[0048] The API may comprise, for example, 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg or 455 mg per unit dosage form.

[0049] The content of the API contained in the formulation of the present invention may be 95% to 105%, 96% to 105%, 97% to 105%, 98% to 105%, 99% to 105%, 100% to 105%, 95% to 100%, 96% to 100%, 97% to 100%, 98% to 100%, or 99% to 100%. The content of the API may be 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more, or 105% or less, 104% or less, 103% or less, 102% or less, 101% or less, or 100% or less.

[0050] The oral formulation of the present invention can be prepared by any method known in the art, comprising an active pharmaceutical ingredient (API) selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof, having a particle size distribution of D(0.9) as described above.

[0051] The present invention provides a pharmaceutical composition for treating or preventing a human xanthine oxidase-related disease, comprising the 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutical acceptable salt thereof as an API and an oral formulation containing a fluidizing agent.

[0052] The present invention provides a method for treating or preventing a human xanthine oxidase-related disease using an oral formulation comprising the 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutical acceptable salt thereof as an API and a fluidizing agent.

[0053] The present invention provides a use of the 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof as an API for preparing a pharmaceutical composition for treating or preventing a human xanthine oxidase-related disease.

[0054] The "human xanthine oxidase-related disease" of the present invention refers to a disease that can be treated or prevented by inhibiting human xanthine oxidase, and examples thereof include, but are not limited to, hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, diabetes-related complications, kidney disease, joint disease, inflammatory bowel disease, etc. Examples of the diabetes-related complications include hyperlipidemia, arteriosclerosis, obesity, hypertension, retinopathy, renal failure, etc.

[0055] The term "treatment" means, when used on an object that exhibits symptoms of a disease, halting or slowing the progression of the disease, and the term "prevention" means, when used on an object that does not exhibit symptoms of a disease but is at high risk of becoming infected, halting or slowing the onset of the disease.

[0056] Unless otherwise indicated, all numbers used in the specification and claims, whether or not stated, should be understood to be modified in all cases by the term "about". It should also be understood that the precise numerical values ​​used in the specification and claims form additional embodiments of the present disclosure. Efforts have been made to ensure the accuracy of the numerical values ​​disclosed in the examples. However, all measured numerical values ​​may inherently contain certain errors resulting from the standard deviations observed in the respective measuring techniques.

[0057] Various evaluations in the examples and comparative examples were carried out as follows.

[0058] [Grain size analysis] The particle size distribution of the API used in the examples and comparative examples was measured by a dry method using a laser diffraction particle size analyzer, where D(0.1), D(0.5), and D(0.9) refer to the particle sizes of the particles that are 10%, 50%, and 90%, respectively, of the total number of particles when the measured particles are arranged in order from smallest to largest.

[0059] [Hardness and wear analysis] Hardness and abrasion are used as indicators for predicting tablet abrasion during handling of tablets (plain tablets) after tableting and during the coating process.

[0060] For the abrasion test, take a tablet of approximately 5g, remove any powder adhering to the tablet, measure the mass precisely, and then place it in the drum of the abrasion tester. After rotating the drum 100 times, take out the tablet, remove any powder adhering to the tablet in the same way as the first time, and measure the mass precisely. Wear rate (%) = (mass before test - mass after test) / (mass before test) x 100

[0061] For hardness testing, place one tablet in a table hardness tester to measure its hardness, repeat this method for 10 tablets, and use the average hardness.

[0062] [Analysis of collapse time] Disintegration time is an index that affects dissolution and absorption in the body after ingestion of a dosage form.

[0063] Fill the disintegration tester with purified water and adjust the temperature to 37±2℃. Place 4 test tablets in each glass tube of the disintegration tester and operate it in the specified manner to measure the time when the tablets completely disintegrate and disappear, and use the average value.

[0064] [Content Analysis] A content test was conducted to evaluate the content of the formulated drug product. Content is an important quality attribute of the final product, and the average API content of the uncoated tablets was measured.

[0065] <Analysis conditions> Preparation of mobile phase: acetonitrile (500 ml) + purified water (500 ml) + TFA (1 ml) Preparation of dilution solution: Methanol (900 ml) + purified water (100 ml) Preparation of standard and test solutions: After completely dissolving the standard and specimen in diluent, analyze them according to the UPLC analysis method below. Column: Waters CSH C18 (2.1 mm ID × 100 mm L, Particle size 1.7 μm) Column temperature: 40℃ Mobile phase: acetonitrile / H2O / TFA = 500 / 500 / 1 (v / v / v) Flow rate: 0.35ml / min Detection: 258 nm uv Sample volume: 1μl Analysis time: 6 minutes

[0066] [Dissolution rate analysis] The dissolution test of the plain tablets of the following Examples and Comparative Examples was carried out according to the dissolution test method of the Korean Pharmacopoeia, 10th edition. The paddle method was used for the dissolution test, and the stirring speed was 50 rpm and the dissolution temperature was 37±0.5° C. The dissolution solution was 900 ml of phosphate buffer solution at pH 6.8.

[0067] The analytical conditions were as follows: the solution obtained in the dissolution test was filtered through a 0.45 μm membrane filter, and the solution was analyzed for the concentration of the API, 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid, using the UPLC method.

[0068] <Analysis conditions> The analytical conditions were the same as those for the content analysis method.

[0069] [Examples and Comparative Examples] The tablets of the Examples and Comparative Examples were prepared as formulations (plain tablets) using the components shown in Table 1 below in the corresponding amounts.

[0070] 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (API) having each particle size distribution and a flow agent are mixed and milled to prepare a first mixture, and then a diluent, a disintegrant and a lubricant, which are components not included in the first mixture, are mixed and milled to prepare a second mixture.

[0071] After mixing the first mixture and the second mixture, tableting is carried out using a rotary tablet press (Modul P, GEA, Belgium) under conditions of a preload of 5.0 kN and a main load of 14 to 15 kN to produce plain tablets.

[0072] PRUV used as the lubricant is a trade name and is a sodium stearyl fumarate component.

[0073] [Table 1]

[0074] Test Example 1. Analysis of formulation characteristics based on particle size distribution In an oral formulation containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid as an API, the physical properties of the API based on particle size distribution were analyzed by the above-mentioned analytical method.

[0075] Specifically, the physical properties (hardness, abrasion, disintegration time, content, and dissolution rate) of the formulation (plain tablet) manufactured using the components listed in Table 1 at the corresponding contents were analyzed, and the results are summarized in the following Table 2 and Figures 1 and 2.

[0076] The hardness of the plain tablet increased as the particle size decreased, and the degree of abrasion increased as the particle size increased. Therefore, when D(0.9) was 325 μm or more (Comparative Example 1), taking into account the hardness and abrasion of the plain tablet, it was not suitable for formulation as a tablet (FIG. 1).

[0077] There was no difference in the average content due to particle distribution. However, in terms of dissolution rate, the average dissolution rates at 15 minutes, 30 minutes, and 60 minutes for the tablets of Comparative Example 1 were all lower than those of Examples 1 and 2 (46.1%, 59.4%, and 67.8%).

[0078] In addition, although both Examples 1 and 2 show relatively good dissolution rates, Examples 1 and 2 show slight differences depending on the time period. In the case of the average dissolution rate at 15 minutes, Example 1 shows 78.5% and Example 2 shows 71.8%, so that the tablet of Example 1, which has smaller particles, shows a somewhat higher average dissolution rate, but in the case of the dissolution rates at 30 minutes and 60 minutes, Example 2 shows a higher average dissolution rate.

[0079] [Table 2]

[0080] The present invention has been described above mainly with reference to the preferred embodiment. Those skilled in the art will understand that the present invention can be embodied in modified forms without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiment should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined in the claims, not in the above description, and all differences within the scope of the equivalents thereto should be construed as being included in the present invention.

Claims

1. A formulation for oral administration in the form of a tablet, comprising an active pharmaceutical ingredient (API) selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof, wherein the API has a particle size (D(0.9)) of 100 μm or more and 300 μm or less for 90% of the granules with respect to the maximum particle size in a cumulative particle size distribution; The oral formulation further comprises at least one excipient selected from a diluent, a disintegrant, a flow agent, and a lubricant; the diluent is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, lactose anhydrous, lactose, starch, mannitol, carboxymethylcellulose, sorbitol, and combinations thereof; the disintegrant is selected from the group consisting of low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, and combinations thereof; the glidant is selected from the group consisting of talc, silicon dioxide, and combinations thereof; The lubricant is selected from the group consisting of magnesium stearate, silicon dioxide, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof; The content of said API is 100 mg to 300 mg per unit dosage form for oral administration.

2. 2. The oral formulation of claim 1, wherein the API has a D(0.9) of 120 μm or more and 270 μm or less.

3. 2. The oral dosage form of claim 1, wherein the content of the API is 30-55% by weight based on the total weight of the formulation.

4. The oral formulation of claim 3, wherein the content of the API is 40-50% by weight based on the total weight of the formulation.

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