Oral formulation comprising 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid and method for preparing the same

Abstract

To provide an oral formulation comprising a high content of an API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazol-4-carboxylic acid or a pharmaceutically acceptable salt thereof.SOLUTION: An oral formulation according to the present invention, which includes a glidant in an excipient, has a high content and excellent physical properties. As a result, it offers improved economic efficiency and convenience of administration.SELECTED DRAWING: None

Description

[Technical field]

[0001] This application claims the benefit of priority based on Korean Patent Application No. 10-2020-0165790 filed on December 1, 2020, and all contents disclosed in the documents of said Korean patent application are incorporated herein by reference.

[0002] The present invention relates to an oral preparation having excellent physical properties while containing a high content of 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, which is useful as a xanthine oxidase inhibitor capable of preventing deposition of uric acid in the body, and a method for producing the same. [Background technology]

[0003] Xanthine oxidase is an enzyme that converts hypoxanthine to xanthine and then converts the resulting xanthine to uric acid. Excessive levels of uric acid in the body are known to cause various diseases, including gout.

[0004] Therefore, substances that inhibit the activity of xanthine oxidase can effectively treat xanthine oxidase-related diseases such as hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, joint disease, inflammatory bowel disease, etc.

[0005] 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 and a method for preparing said 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]

[0006] However, there has been no report on an oral formulation containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid 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 a high content of the API.

[0007] Since formulations containing a high content of API generally do not have excellent flowability or tabletability, in order to overcome such drawbacks, they are generally manufactured using a wet granulation or dry granulation method, or by increasing the amount of excipients to reduce the proportion of API.

[0008] However, the high-content formulation may have a problem that the manufacturing time and production cost may increase due to the granulation process for improving the flowability, and that the total weight and volume of the formulation may increase due to the increase in the amount of excipients, resulting in an increase in the production cost and a decrease in the patient's ability to take the formulation. In addition, even if a granulation process is added or the amount of excipients is increased to produce the high-content formulation, it is common technical knowledge of a person having ordinary skill in the art that the formulation content may be affected due to an imbalance between the excipients and the high-content API.

[0009] 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- ceutically acceptable salt thereof as an API and has excellent physical properties. [Prior art documents] [Patent documents]

[0010] [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 manufacturing method Summary of the Invention [Problem to be solved by the invention]

[0011] The problem to be solved by the present invention is to provide an oral formulation having excellent physical properties while containing an excessive amount of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutical acceptable salt thereof as an API. [Means for solving the problem]

[0012] The present invention provides an oral formulation having excellent physical properties, comprising an API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma-ceutically acceptable salt thereof and an excipient, in particular by including a flow agent in the excipient, and a method for producing the oral formulation.

[0013] The fluidizing agent contained in the oral preparation of the present invention is SiO2 selected from the group consisting of colloidal silicon dioxide, hydrous silicon dioxide, and combinations thereof, and the content of the fluidizing agent per production is 0.2 to 1 wt %, or 0.2 to 0.8 wt %, based on the total weight of the preparation.

[0014] 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.

[0015] The oral formulation of the present invention has an API content of 95% or more.

[0016] 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

[0017] The oral formulation according to the present invention comprising 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 its high API content, and maintains a high formulation content, by including a flow agent in the excipient.

[0018] 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, making it not only economical but also convenient to administer. [Brief description of the drawings]

[0019] [Figure 1] FIG. 1 is a diagram showing API content per unit tablet according to the content of fluidizer (SiO2). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The present invention will now be described in more detail.

[0021] 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.

[0022] The present inventors have continued to conduct research using various methods to increase the content of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutical acceptable salt thereof as an API and maintain or improve its physical properties in an oral formulation. As a result, they have developed an oral formulation having a high API content while having excellent physical properties and containing a flow agent in the excipient.

[0023] In this case, even if an excessive amount of API is contained compared to an oral formulation not containing a flow agent, the physical properties are maintained when the tablet (plain tablet) is formulated, so there is no need to increase the excipient content due to the increase in API content, and therefore it is possible to prepare a high-content oral formulation that is convenient to take without increasing the size of the formulation, and is also economical. In addition, the high API content has the advantage that the quality of the final product is excellent.

[0024] Accordingly, the present invention provides an oral formulation comprising a high content of an API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof, and a flow agent in an excipient.

[0025] 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.

[0026] In the present invention, "API content" refers to the amount of API in a formulation or tablet.

[0027] 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 so as to make it easy to swallow. However, it is common general technical knowledge of a person having ordinary skill in the art to which the present invention pertains that when an API is contained in a high content, not only are physical properties such as flowability and tabletability generally impaired, but also the content of the preparation may be affected due to an imbalance between the high content of API and each excipient.

[0028] 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 amount, there is a problem in that physical properties such as tabletability are rapidly degraded.

[0029] In the present invention, a multi-faceted study was conducted to combine various excipients to develop an oral formulation having a high content of an API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof and excellent or good physical stability. As a result, when a flow agent was included as an excipient, an oral formulation was developed that not only had excellent physical stability but also a high content of API, regardless of the high content of API.

[0030] Thus, 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 flow agent in the excipient.

[0031] In the present invention, the fluidizing agent may be contained in an amount of more than 0 wt% and less than 1 wt%, 0.1 wt% or more and less than 1 wt%, 0.2 wt% or more and less than 1 wt%, more than 0 wt% and less than 0.9 wt%, more than 0.1 wt% and less than 0.9 wt%, more than 0 wt% and less than 0.9 wt%, more than 0 wt% and less than 0.8 wt%, more than 0.1 wt% and less than 0.8 wt%, or more than 0.2 wt% and less than 0.8 wt%, based on the total weight of the formulation. The fluidizing agent may also be contained in an amount of 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, or 0.9 wt% based on the total weight of the formulation.

[0032] In the present invention, the glidant may be selected from the group consisting of colloidal silicon dioxide, hydrous silicon dioxide, talc, and combinations thereof, but is not limited thereto. However, when talc is used as the glidant, it shows a tendency that the hardness decreases and the friability increases when it is formulated into a tablet, so it is preferable to use SiO2-based glidants such as colloidal silicon dioxide, hydrous silicon dioxide, or combinations thereof.

[0033] In the present invention, the oral formulation further comprises one or more excipients selected from a pharma- ceutically acceptable diluent, disintegrant, binder, stabilizer, lubricant, and the like.

[0034] The excipients such as the diluent, disintegrant, binder, stabilizer and lubricant may be any one 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 1-30 wt%, 1-20 wt%, 1-10 wt%, or 1-5 wt%, based on the total weight of the oral formulation. The binder may be used in an amount of 1-30 wt%, 1-20 wt%, 1-10 wt%, or 1-5 wt%, based on the total weight of the oral formulation. The stabilizer 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. The lubricant may be used in an amount ranging from 0.1 to 10% by weight, 0.3 to 5% by weight, or 0.5 to 4% by weight, based on the total weight of the oral formulation.

[0035] For example, the diluent may be selected from the group consisting of microcrystalline cellulose (MCC), lactose monohydrate, lactose anhydrous, lactose, starch, mannitol, carboxymethylcellulose, sorbitol, and combinations thereof, but is not limited thereto. The disintegrant may be selected from the group consisting of low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, F-melt®, and combinations thereof, but is not limited thereto. The binder may be selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose, polyvinyl acetate, povidone, polyvinylpyrrolidone, copovidone, macrogol, sodium lauryl sulfate, light anhydrous silicic acid, synthetic aluminum silicate, silicate derivatives such as calcium silicate or magnesium metasilicate aluminate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, pregelatinized starch, gums such as gum acacia, gelatin, cellulose derivatives such as ethyl cellulose, and mixtures thereof, but is not limited thereto. The stabilizer may be selected from the group consisting of, but is not limited to, BHT, BHA, ascorbic acid, tocopherol, EDTA, and mixtures 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.

[0036] The oral formulations can be administered once a day and can be taken daily.

[0037] 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.

[0038] The API may also contain, for example, 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.

[0039] 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.

[0040] The API content in the formulation of the present invention may be 95%-105%, 96%-105%, 97%-105%, 98%-105%, 99%-105%, 100%-105%, 95%-100%, 96%-100%, 97%-100%, or 99%-100%. The API content 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.

[0041] The term "API content" refers to the content of pure API excluding impurities among the API content contained in a unit dosage form. Specifically, it may be the same as the purity of API.

[0042] The present invention provides a method for preparing an oral formulation comprising 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof, comprising the steps of: i) mixing an API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof, and a flow agent to prepare a first mixture; ii) mixing a pharma- ceutically acceptable excipient to prepare a second mixture; and iii) formulating the first and second mixtures into an oral formulation.

[0043] In the manufacturing method of the present invention, the steps of manufacturing each of the first mixture and the second mixture include a mixing step and a milling step.

[0044] In the manufacturing method of the present invention, the fluidizing agent contained in the first mixture contains SiO2 selected from the group consisting of colloidal silicon dioxide, hydrous silicon dioxide, and combinations thereof.

[0045] In the production method of the present invention, the pharma- ceutically acceptable excipient contained in the second mixture selectively includes the excipients described above.

[0046] The API content and content of the formulation prepared by the preparation method of the present invention are the same as the API content and content of the oral formulation of the present invention described above.

[0047] The oral preparation can be formulated by any tablet or granule manufacturing method known in the art.

[0048] The present invention also provides a method for treating or preventing a human xanthine oxidase-related disease using an oral formulation containing 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.

[0049] 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, and inflammatory bowel disease. Examples of the diabetes-related complications include hyperlipidemia, arteriosclerosis, obesity, hypertension, retinopathy, and renal failure.

[0050] The term "treatment" means, when used on an object that exhibits symptoms of 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 disease but is at high risk of becoming so, halting or slowing the onset of the disease.

[0051] 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.

[0052] [Examples and Test Examples] Various evaluations in the examples and comparative examples were carried out as follows.

[0053] [Liquidity analysis] The bulk density and tapped density of the mixture (powder) for producing the plain tablets of the Examples and Comparative Examples were measured. The bulk density was the volume when about 50 g of granular powder was placed in a graduated cylinder, and the tapped density was the volume when the graduated cylinder was lightly tapped 100 times against the bottom at a certain height and there was no further change in volume. The bulk density means the volume occupied by a certain mass of powder, and the total volume means the combined volume of the powder volume and the volume of the voids between the particles.

[0054] The flowability of the mixture was calculated by the Carr index of formula (1) using the bulk density and tap density measured above according to the method of Jinapong et al. (2008).

[0055]

number

[0056] The Carr index is a measure of the compressibility of a powder and is defined as (tapped density - bulk density) / percentage of tapped density. The higher the index, the more compressible and less flowable the powder is.

[0057] The table below shows the flowability classification of powders according to the Carr index.

[0058] [Table 1]

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

[0060] For friability testing, take a tablet of approximately 5g, remove any powder adhering to the tablet, measure its mass precisely, and then place it in the drum of the friability tester. After rotating the drum 100 times, take out the tablet, remove any powder adhering to the tablet in the same way as before, and measure its mass precisely. Friability (%) = (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 the hardness, and repeat this method for 10 tablets to 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] Add sufficient purified water to the disintegration tester 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 analytical method below.

[0066] Column: Waters CSH C18 (2.1mm ID x 100mm L, Particle size 1.7μm) Column temperature: 40°C Mobile phase: acetonitrile / H2O / TFA = 500 / 500 / 1 (v / v / v) Flow rate: 0.35ml / min Detection: 258nm uv Sample volume: 1μl Analysis time: 6 minutes

[0067] [Dissolution rate analysis] The dissolution test was carried out on the plain tablets of the following Examples and Comparative Examples according to the Korean Pharmacopoeia, 10th Edition. The dissolution test was carried out using the paddle method, with a stirring speed of 50 rpm and a dissolution temperature of 37±0.5° C. The dissolution solution used was 900 ml of pH 6.8 phosphate buffer solution.

[0068] 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, by UPLC.

[0069] <Analysis conditions> The analytical conditions were the same as those for the content analysis method.

[0070] [Examples 1 to 8 and Comparative Example 1] The preparations of Examples 1 to 8 and Comparative Example 1 were produced into tablets (plain tablets) using the components in the amounts shown in Tables 2 to 4 below.

[0071] Specifically, 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (API) and a flow agent are mixed and milled to produce a first mixture, and a diluent, a disintegrant, and a lubricant, which are not included in the first mixture, are mixed and milled to produce a second mixture.

[0072] In the case of Examples 1 to 8 containing a fluidizer, the first mixture and the second mixture were mixed, and then tableting was 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. In Comparative Example 1 containing no fluidizer, the step of producing mixture 1 was omitted, and 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (API) and all excipients were mixed, milled, and tableted in the same manner as in Example 1 to produce plain tablets. (When colloidal silicon dioxide was used as the fluidizer, it is indicated as "SiO2". MCC 102 used as a diluent is a microcrystalline cellulose component. PRUV (registered trademark) used as a lubricant is a trade name and is a sodium stearyl fumarate component.)

[0073] [Table 2]

[0074] [Table 3]

[0075] [Table 4]

[0076] Test Example 1. Analysis of formulation characteristics based on fluidizer content In oral preparations containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid as the API, the physical properties depending on the presence or absence and amount of SiO2 fluidizing agent as an excipient were analyzed by the analytical method described above.

[0077] Specifically, the physical properties (bulk density, tap density, and Curl index) of the mixture before formulation and the physical properties (hardness, brittleness, disintegration time, content, and dissolution rate) of the uncoated tablets after tableting of the mixture were analyzed, and the results are shown in Table 5 below.

[0078] In the state of the mixture before manufacturing the plain tablets, there was no significant difference in bulk density, tap density, and curl index depending on the presence or absence of a fluidizer (SiO2) and the amount of the fluidizer (SiO2).

[0079] That is, although it was known that the addition of a flow agent to a conventional pharmaceutical formulation would improve the fluidity, the inclusion of a flow agent in the API of the present invention (1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid) did not significantly increase the fluidity.

[0080] However, as a result of measuring the hardness and friability of the plain tablets, when SiO2 was included (Examples 1 to 4), the hardness was 6.7 kP or more, and all of them met the target hardness of 6.0 kP for the plain tablets, compared with the case where SiO2 was not included (Comparative Example 1). On the other hand, in the case of Comparative Example 1, the hardness was only 5.4 kP, which was not enough to meet the target hardness of the plain tablets, and was not suitable for formulation into tablets (Table 5).

[0081] In addition, as a result of measuring the API content of the plain tablets, as shown in Table 6 and FIG. 1 below, in the case of Comparative Example 1, the average content was 95.3%, and when SiO2 was contained at 0.2 to 0.8 wt% (Examples 1 to 3), it increased to a maximum of 98.8 to 99.4%, but in the case of Example 4 containing 1 wt% SiO2, it decreased to 94.8%, which is similar to Comparative Example 1, and therefore it can be seen that the preferred SiO2 content range is 0.2 to 0.8 wt% based on the total weight of the formulation.

[0082] Next, in the case of the dissolution rate, Comparative Example 1 shows a rapid dissolution in the early stage due to its low hardness, but thereafter shows a constant dissolution rate. However, when SiO2 is included, a constant increasing slope is shown, and in particular, in the case of Example 2 (0.5 wt% SiO2), the dissolution rate at 60 minutes tends to be the highest (Table 5).

[0083] [Table 5]

[0084] Test Example 2. Analysis of formulation characteristics by type of fluidizer In order to analyze the characteristics depending on the type of superplasticizer, the properties of Example 5 were analyzed in which the content of superplasticizer (0.5 wt%) was kept the same as in Example 2, which showed the best physical properties, but SiO2 was replaced with Talc.

[0085] As shown in Table 6 below, in the case of Example 5, in which talc was used as a fluidizer in the mixture before manufacturing the plain tablets, the bulk density showed no difference compared to Example 2 and Comparative Example 1, but the curl index was calculated to be 28%. Therefore, in the case of Example 5, the curl index is in the "Poor" category and is not suitable for the direct compression process. In addition, in the case of Example 5, the hardness of the plain tablets is 5.1 kP, which does not meet the target hardness of 6.0 kP, and the friability is also about three times higher than that of Example 2, so that the physical properties are not suitable for tablets.

[0086] It can be seen that the average content of Example 5 was also decreased compared to Example 2.

[0087] Therefore, when SiO2 is used as a fluidizing agent, the overall physical properties are improved compared to talc.

[0088] [Table 6]

[0089] Test Example 3. Characterization by API content In order to produce tablets containing 50 wt% or more of API, the properties of increasing API contents (Examples 6 to 8) were analyzed based on the content in Example 2 (45.5 wt%).

[0090] According to Table 7, as the API content increases, the density of the API becomes higher compared to the diluent, so there is a tendency for the bulk density to increase slightly as the API content increases, but there is no significant difference in the fluidity itself.

[0091] However, as the API content increases, the tableting ability decreases (tablet compressibility decreases), resulting in a decrease in the hardness of the bare tablet and an increase in friability. In particular, Example 8 (API content: 60% by weight) exhibited a hardness of 3.0 kP and a friability of 0.2% or more, making it unsuitable for formulation into tablets (Table 7).

[0092] Furthermore, the API content of the plain tablets was measured, and as a result, Examples 2, 6, and 7 showed an average content of 99% or more, whereas Example 8 showed an average content of 94.6% (Table 7).

[0093] In summary, when the API content is 55 wt% or less, the average content is 99% or more, but when it is 60 wt%, the average content drops significantly to 94.6%. When the API content is 50% or more, even if the content is excellent, the hardness of the bare tablet decreases and the friability increases, so it is not desirable to formulate the API into tablets when the API content is 55 wt% or more.

[0094] [Table 7]

[0095] 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. An oral dosage form 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; and a flow agent.

2. 2. The oral formulation of claim 1, wherein the flow agent is selected from the group consisting of colloidal silicon dioxide, hydrous silicon dioxide, and combinations thereof.

3. 3. The oral formulation according to claim 2, wherein the content of the fluidizing agent is greater than 0% by weight and less than 1% by weight based on the total weight of the formulation.

4. The oral formulation according to claim 3, wherein the content of the fluidizing agent is 0.2 to 0.8% by weight based on the total weight of the formulation.

5. 10. The oral formulation of claim 1, further comprising one or more excipients selected from diluents, disintegrants, binders and lubricants.

6. 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.

7. The oral formulation of claim 6, wherein the content of the API is 40-50% by weight based on the total weight of the formulation.

8. 2. The oral dosage form of claim 1, wherein the content of the API is 50 mg, 100 mg, 200 mg, or 300 mg per unit dosage form.

9. The oral dosage form according to any one of claims 1 to 8, wherein the content of the API is 97% or more.

10. i) 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof as an API; and SiO as a superplasticizer. 2 to produce a first mixture; ii) mixing a pharma- ceutically acceptable excipient to produce a second mixture; and iii) A method for producing an oral formulation comprising 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof, comprising the step of formulating the first mixture and the second mixture into an oral formulation.

11. The method for producing an oral formulation according to claim 10, wherein the content of the fluidizing agent is 0.2 to 0.8% by weight based on the total weight of the formulation.

12. The method for producing an oral formulation according to claim 10, wherein the content of the API is 40-50% by weight based on the total weight of the formulation.

13. 13. A dosage form for oral administration, produced by the process according to any one of claims 10 to 12, wherein the content of the API is 97% or more.

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