Stable oral formulations containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid

Abstract

The present invention relates to stable oral formulations comprising 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API. The stable oral formulation according to the present invention has the characteristic of maintaining stability even without the inclusion of a stabilizer as an excipient, and has an increased API content instead of the absence of a stabilizer, thereby increasing the convenience of administration.

Description

Technical Field

[0001] This application claims the benefit of priority based on Korean Patent Application No. 10-2020-0166051 filed on December 1, 2020, and all the contents disclosed in the literature of the Korean Patent Application are included as part of this specification.

[0002] The present invention relates to an oral formulation containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API), which is useful as a xanthine oxidase inhibitor capable of preventing in vivo uric acid deposition, and does not contain a separate stabilizer, and a method for producing the same.

Background Art

[0003] Xanthine oxidase is an enzyme that converts hypoxanthine to xanthine and the formed xanthine to uric acid. When there is an excessive amount of uric acid transiently present in the body, it is known to cause various diseases including gout.

[0004] Gout refers to a state in which uric acid crystals accumulate in joint cartilage, ligaments, and surrounding tissues, inducing severe inflammation and pain, and the incidence rate has been steadily increasing over the past 40 years.

[0005] Therefore, substances that inhibit the activity of xanthine oxidase can effectively treat xanthine oxidase-related diseases such as hyperuricemia, gout, heart failure, cardiovascular diseases, hypertension, diabetes, kidney diseases, inflammation, joint diseases, and inflammatory bowel diseases.

[0006] On the other hand, in relation to substances that inhibit the activity of xanthine oxidase, Korean Patent Publication No. 1751325 (Patent Document 1) provides a compound having the structure of the following chemical formula 1, namely 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid, and a method for producing the compound, while Korean Patent Publication No. 1424013 (Patent Document 2) provides various types of crystalline forms obtained using various solvents and methods for producing the same. [ka]

[0007] In the case of pharmaceutical formulations, it is common for them to contain one or more excipients selected from diluents, disintegrants, stabilizers, binders, lubricants, and glidants, in addition to the active ingredient API. Generally, the excipients included in pharmaceutical formulations should be stable components that do not affect the efficacy of the formulation. However, problems with the stability of the API itself, the generation of reaction byproducts between the API and certain excipients, or reaction products that may be generated by combinations of excipients may affect the stability of the formulation. In other words, problems with stability and uniformity of content may occur during the manufacturing or storage process of the pharmaceutical formulation due to degradation products or reaction products resulting from contact or binding of the API with excipients, etc.

[0008] Therefore, in pharmaceutical formulations, it is essential to appropriately select and combine excipients suitable for APIs. Furthermore, since there is a wide variety of excipients and a wide range of possible combinations, selecting specific excipients from among them, finding appropriate combinations, and developing stable pharmaceutical formulations is an extremely difficult and time-consuming stage in drug development.

[0009] The stability of oral formulations containing chemical formula 1 as an API is currently unknown. Since oral formulations are typically stored for long periods of more than one year, improvements are needed to ensure the stability and uniformity of content of oral formulations containing chemical formula 1 as an API. [Prior art documents] [Patent Documents]

[0010] [Patent Document 1] Korean Patent Publication No. 1751325 (June 21, 2017), Novel compound effective as a xanthine oxidase inhibitor, method for producing the same, and pharmaceutical composition containing the same. [Patent Document 2] Korean Patent Publication No. 1424013 (July 22, 2014), Crystalline form of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid and method for producing the same. [Overview of the project] [Problems that the invention aims to solve]

[0011] Therefore, the inventors conducted multifaceted research to solve the aforementioned problems and, through stability tests with various excipients using 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API, confirmed that no decomposition products or reaction products are generated upon contact with or binding to excipients. This led to the development of an oral formulation that not only does not contain stabilizers in the excipients but also exhibits stable effects with any combination of excipients, thus completing the present invention.

[0012] Therefore, the object of the present invention is to provide a stable oral formulation and a method for producing the same, comprising an API and excipient of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, but without any additional stabilizers in the excipient. [Means for solving the problem]

[0013] The present invention provides a stable oral formulation comprising an API and excipient of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, but without any additional stabilizers in the excipient.

[0014] The present invention provides a stable oral formulation that contains 20% to 60% by weight of the API of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, based on the total weight of the oral formulation, and does not contain any stabilizers.

[0015] The oral formulation of the present invention contains, in addition to an API of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, diluents, disintegrants, binders, fluidizers and lubricants as excipients, but does not contain stabilizers.

[0016] The oral formulation of the present invention is used for the treatment or prevention of xanthine oxidase-related disorders selected from the group consisting of hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, renal disease, inflammation, joint disease, and inflammatory bowel disease. [Effects of the Invention]

[0017] An oral formulation containing 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof according to the present invention can maintain or improve stability and uniformity of content in combination with any excipient, even without containing a stabilizer in the excipient.

[0018] Therefore, the oral formulation of the present invention provides excellent storage stability regardless of storage conditions, even without containing a stabilizer in the excipient.

[0019] Furthermore, the oral preparation according to the present invention does not contain a stabilizer, and by containing a high content of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid, which is an API, or a pharmaceutically acceptable salt thereof, it is not only economical but also can increase the convenience of administration.

Mode for Carrying Out the Invention

[0020] Hereinafter, the present invention will be described in more detail.

[0021] All technical terms used in the present invention are used with the same meaning as generally understood by those having ordinary knowledge in the relevant field of the present invention, unless otherwise defined. Also, although preferred methods and samples are described in this specification, those similar or equivalent to these are also included in the scope of the present invention. The contents of all publications described as references in this specification are incorporated herein by reference in their entirety.

[0022] The present inventors have continued research on oral preparations in which the stability of the above API is maintained in various ways for the development of a stable oral preparation containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API and containing pharmaceutically acceptable excipients. As a result, an oral preparation has been developed in which the stability and content uniformity are maintained with any combination of excipients and which has excellent stability even without a stabilizer.

[0023] In this case, since the oral preparation does not contain a stabilizer to be contained therein, the content of the API can be increased, and thereby, a high-content oral preparation with increased convenience of administration can be prepared without increasing the size of the oral preparation, and it also has a secondary effect of being more economical than other preparations containing a stabilizing agent.

[0024] Therefore, the present invention provides an oral formulation containing a high content of API of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, and free of stabilizers in the excipients.

[0025] In the present invention, "pharmaceutically acceptable salt" means a salt form of the compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid, an API contained in the oral formulation of the present invention, can be converted to its salt by conventional methods.

[0026] In oral formulations, it is common technical knowledge for those with ordinary knowledge in the field of pharmaceuticals that when an API comes into contact with excipients, particularly disintegrants, the API may generate degradation products or reaction products, which can impair the stability of the formulation and potentially reduce the API content. Therefore, it is common technical knowledge for those with ordinary knowledge in the art to which this invention belongs to to include a stabilizer, which is any pharmaceutically acceptable additive (excipient), in the formulation in order to increase the stability of the API and maintain the uniformity of the API content, thereby suppressing the generation of degradation products that may be generated when the API is mixed with and in contact with additives such as excipients.

[0027] In this invention, in order to suppress the formation of degradation products or reaction products upon contact between the API, 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, and an excipient, and to ensure stability during oral administration, research was conducted on oral formulations including various excipients and combinations of excipients.

[0028] As a result, we confirmed that even without including stabilizers as excipients, it is possible to inhibit the degradation or reaction products of the API that may occur during the manufacturing or storage process of the formulation, thereby ensuring stability during oral administration and simultaneously ensuring uniformity of content. Thus, we developed an oral formulation that is stable and does not contain the aforementioned stabilizers.

[0029] Therefore, one embodiment of the present invention provides an oral formulation that i) uses 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API, and ii) does not contain a stabilizer as an excipient.

[0030] In the present invention, "stabilization" means suppressing any changes in the API by increasing its stability, and includes suppressing the generation of flexible substances (decomposition products or reaction products) that may occur during the manufacturing process of the formulation. Therefore, the oral formulation of the present invention exhibits stability and / or improved stability compared to other oral formulations.

[0031] In this invention, the terms "stability," "stable," and their variations mean that in a formulation, 90% or more of the total weight of API is maintained without decomposition for 6 months under test conditions of 40°C and 75% relative humidity, or 12 days under test conditions of 80°C and 75% relative humidity, or 1 year under 25°C and 60% relative humidity. In this case, the API content measured after storage under certain conditions and for a certain period, based on the initial API content in the formulation, is called the "residual content." In various embodiments, for example, it means that 90% or more, 92% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 99.5% or more of API is maintained without decomposition under the aforementioned conditions. The stability of compounds, formulations, etc., can be measured within the capabilities of those skilled in the art using methods generally accepted in the industry. For example, the amount of API or compound can be measured by any suitable method, such as HPLC.

[0032] Decomposition is a chemical process consisting of one or more reactions, such as oxidation, reduction, or hydrolysis, which, during the decomposition of a substance, cause chemical changes and produce one or more novel compounds. These novel compounds or impurities can generate a reduced and / or variable amount of API in a given formulation, reducing its efficacy and potentially leading to undesirable and / or harmful side effects for the patient.

[0033] In this invention, "impurity" means any novel compound present in the composition and / or formulation in an amount of less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 1% by weight, or less than 0.5% by weight of the API. Therefore, the change in total impurities in the formulation under the conditions and period presented in this invention may also be an indicator of a stable formulation, which can be measured by a suitable method, such as HPLC.

[0034] Furthermore, stability is, for example, - Test conditions after one year: 25°C and 75% relative humidity (room temperature conditions) - Test conditions after 6 months: 40°C and 75% relative humidity (accelerated conditions) - Testing can be performed under various conditions, including 12 days of testing at 80°C and 75% relative humidity (harsh conditions).

[0035] Furthermore, stability can be measured by appearance. In this invention, "visual stability" and its variations mean non-substantial changes in the color, integrity (e.g., non-collapse), form, and / or size of the formulation.

[0036] In this invention, "improved stability," "enhanced stability," and their variations mean that the amount of degradation of one or more APIs in a given formulation, and / or the increase in impurities in the given formulation, is less than the increase in impurities in the formulation exposed to the test conditions.

[0037] The oral formulation of the present invention, when subjected to flexibility testing under harsh conditions of 80°C, maintained a residual API content of 99.5% by weight or more even after 12 days without the presence of a stabilizer. It also maintained a residual API content of 99.5% by weight or more even after 1 year of storage under conditions of 25°C and 75% relative humidity without the presence of a stabilizer. The formulation showed no substantial changes in color, form, size, etc., confirming its excellent stability.

[0038] In the present invention, the oral formulation further comprises one or more excipients selected from pharmaceutically acceptable diluents, disintegrants, binders, glidants, and lubricants.

[0039] The diluent, disintegrant, binder, fluidizer, and lubricant may be any excipients commonly used or known in the art. The diluent may be used in an amount of 30-50% by weight, 40-50% by weight, or 40-45% by weight, based on the total weight of the oral formulation. The disintegrant may be used in an amount ranging from 1-30% by weight, 1-20% by weight, 1-10% by weight, or 1-5% by weight, based on the total weight of the oral formulation. The binder may be used in an amount ranging from 1-30% by weight, 1-20% by weight, 1-10% by weight, or 1-5% by weight, based on the total weight of the oral formulation. The fluidizer may be used in an amount ranging from 0.1-10% by weight, 0.3-5% by weight, or 0.5-4% by weight, 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 preparation.

[0040] For example, the diluent may be selected from the group consisting of microcrystalline cellulose, 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, polyvinylacetic acid, 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 acacia gum, gelatin, cellulose derivatives such as ethylcellulose, and mixtures thereof, but is not limited thereto. The fluidizing agent may be selected from, but is not limited to, colloidal silicon dioxide, hydrated silicon dioxide, and combinations thereof. The lubricant may be selected from, but is not limited to, magnesium stearate, silicon dioxide, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof.

[0041] In one embodiment, the oral formulation may contain the API, 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid, in the form of crystalline granules. In one example, the crystalline granules of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid can be produced by a commonly used method for producing crystalline granules.

[0042] The aforementioned oral formulation can be administered once a day and taken daily.

[0043] The amount of API contained in the oral preparation may be 20-70% by weight, 20-60% by weight, 20-50% by weight, 20-45% by weight, 30-70% by weight, 30-60% by weight, 30-50% by weight, 30-45% by weight, 40-70% by weight, 40-60% by weight, 40-50% by weight, or 40-45% by weight, based on the total weight of the oral preparation.

[0044] Furthermore, the API may contain, for example, 50mg-500mg, 50mg-400mg, 50mg-300mg, 50mg-200mg, 50mg-100mg, 100mg-500mg, 100mg-400mg, 100mg-300mg, 100mg-200mg, 200mg-500mg, 200mg-400mg, 200mg-300mg, 300mg-500mg, or 300mg-400mg per unit formulation.

[0045] Furthermore, the API may contain 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, or 455 mg per unit formulation.

[0046] The present invention provides a method for producing an oral formulation comprising the steps of: mixing an API selected from 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, and excipients including a diluent, disintegrant, binder, fluidizer, and lubricant that does not contain a stabilizer; and forming the mixture into a dosage form.

[0047] The oral formulation can be manufactured according to any manufacturing method for formulations known in the art, and a tablet, which is one embodiment of the oral formulation, can also be manufactured according to any manufacturing method for tablets known in the art.

[0048] Furthermore, the present invention provides a method for treating or preventing human xanthine oxidase-related diseases using an oral formulation containing 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically usable salt thereof as an API.

[0049] The "human xanthine oxidase-related diseases" of the present invention refer to diseases that can be treated or prevented by inhibiting human xanthine oxidase, and include, but are not limited to, hyperuricemia, gout, heart failure, cardiovascular diseases, hypertension, diabetes, diabetes-related complications, kidney diseases, inflammation, joint diseases, and inflammatory bowel diseases. Examples of diabetes-related complications include hyperlipidemia, arteriosclerosis, obesity, hypertension, retinopathy, and renal failure.

[0050] The term "treatment" as used on an object exhibiting symptoms of the disease means interrupting or delaying the progression of the disease, and the term "prevention" as used on an object that does not exhibit symptoms of the disease but is at high risk of doing so means interrupting or delaying the onset of symptoms.

[0051] Unless otherwise indicated, all figures used herein and in the claims, whether mentioned or not, should be understood to be modifiable in all cases by the term “about.” Furthermore, the precise figures used herein and in the claims should be understood to form additional embodiments of the content of this disclosure. Efforts have been made to ensure the accuracy of the figures disclosed in the examples. However, all measured figures may inherently contain certain errors arising from the standard deviation measured by the respective measurement method.

[0052] <Examples and Test Examples> One or more embodiments will be described in more detail based on the following examples and test examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited thereto.

[0053] Test Example 1: Stability analysis of the mixture of the API 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid and each excipient. As shown in Table 1 below, mixtures were prepared by combining the API 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid with various excipients such as microcrystalline cellulose. The residual content of the API was then measured under accelerated conditions (40°C, 75% RH; relative humidity) at initial, 1 month, 2 months, and 3 months of storage using the analytical methods and processes described below. Table 1 shows only the residual content at initial and 3 months of storage.

[0054] [Table 1-1] [Table 1-2]

[0055] <Analysis Methods and Processes> The HPLC analysis conditions are as follows: Column: Inertsil ODS-2 (4.6 x 150mm, 5μm, GL Science) Detector: 254nm, UV Flow Rate: 1.0 ml / min Injection Volume: 5 μl Column Temperature: 40℃ Eluent A: Acetonitril / purified water / TFA (Trifluoroacetic acid) =40 / 60 / 0.1(v / v / v) B: Acetonitril / purified water / TFA=80 / 20 / 0.1(v / v / v)

[0056] [Table 2]

[0057] According to the stability analysis results in Table 1, when 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid alone is stored under accelerated conditions, it exhibits excellent stability even after 3 months (Comparative Example 1). Furthermore, when 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid is mixed with various types of excipients and stored under accelerated conditions, it exhibits excellent stability similar to that of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid alone (Examples 1-15).

[0058] Test Example 2. Stability analysis of tablets compressed from a mixture of the API 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid and each excipient. As disclosed in Table 3 below, 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid, an API, was mixed with various types of excipients such as microcrystalline cellulose. The mixture was then compressed into tablets using a tablet press to produce oral tablets (uncoated tablets) for Comparative Example 2 and Examples 16-27.

[0059] Each manufactured oral tablet was initially stored under harsh conditions (80°C, 75% RH), and the residual content of the API was measured through the aforementioned method and process after 12 days under these harsh conditions.

[0060] [Table 3-1] [Table 3-2]

[0061] According to the stability analysis results in Table 3, it can be seen that tablets of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid alone exhibited excellent stability even after 12 days when stored under harsh conditions (Comparative Example 2). Furthermore, it can be seen that tablets manufactured by mixing 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid with various types of excipients also exhibited excellent stability similar to that of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid alone when stored under harsh conditions (Examples 16-27). We confirmed that there were no substantial changes in the appearance of the tablets, such as color, shape, or size, indicating excellent tablet stability.

[0062] Test Example 3. Stability analysis of a mixture of the API 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid and each excipient. As disclosed in Table 4 below, the mixtures of Examples 28 to 47 were prepared by mixing the API 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid with various types of excipients such as microcrystalline cellulose.

[0063] The prepared mixtures were stored under harsh conditions (80°C, 75% RH) for an initial period, and the residual content of the API was measured through the aforementioned method and process after 12 days under harsh conditions.

[0064] [Table 4-1] [Table 4-2]

[0065] According to the stability analysis results in Table 4, when 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid is mixed with various types of excipients and stored under harsh conditions, the API is hardly degraded, and the initial residual content is almost maintained, similar to the results under accelerated conditions (Examples 28-47).

[0066] Test Example 4. Stability analysis of tablets containing the API 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid and each excipient. When a mixture of APIs and excipients such as diluents, disintegrants, and binders is formed into an orally administered tablet, even if each component of the API and individual excipients is stable in its raw material state, stability problems may arise during the dosage form process, such as the formation of degradation products of the API when the API is mixed with or comes into contact with the excipients. Therefore, to confirm this, oral tablets with various combinations of APIs and excipients were manufactured and their stability was analyzed (each tablet weighed 220 mg, and the content ratios of each component listed in Table 5 are based on one tablet (220 mg)).

[0067] As disclosed in Table 5 below, the oral tablets of Examples 48-51 were produced by mixing the API 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid with various types of excipients such as microcrystalline cellulose, and then finally forming them into tablets using a tablet press.

[0068] The residual content of the API in each manufactured tablet was measured using the aforementioned method and process after initialization under harsh conditions (80°C, 75%RH), storage for 12 days, or after initialization under accelerated conditions (40°C±2°C, 75%±5%RH), storage for 3 months or 6 months, or after initialization under room temperature conditions (25°C±2°C, 60%±5%RH), and long-term storage for 1 year or 2 years or more.

[0069] [Table 5]

[0070] According to the stability analysis results in Table 6 below, when oral tablets were manufactured by mixing 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid (API) with various combinations of excipients, even without the inclusion of stabilizers, virtually no flexible material was generated after 12 days of storage under harsh conditions (80°C, 75%RH), 6 months of storage under accelerated conditions (40°C±2°C, 75%±5%RH), or 12 months of storage under normal temperature conditions (25°C±2°C, 60%±5%RH). The residual content of API remained almost unchanged compared to the initial state, confirming its stable form. Furthermore, there was no substantial change in the appearance of the tablets, such as color, shape, or size, confirming the excellent stability of the tablets.

[0071] [Table 6]

Claims

1. The present invention relates to a pharmaceutical composition comprising an active pharmaceutical ingredient (API) that is 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharma- ceutically acceptable salt thereof, and one or more excipients; 1. A stable oral formulation, wherein at least 90% by weight of the API is maintained at 40° C. and 75% relative humidity for 6 months, at 80° C. and 75% relative humidity for 12 days, or at 25° C. and 60% relative humidity for 1 year; the excipient is selected from the group consisting of a diluent, a disintegrant, a binder, a glidant, a lubricant, and combinations thereof; the diluent is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, lactose anhydrous, pregelatinized starch, mannitol, dicalcium phosphate dihydrate, dicalcium phosphate anhydrous, silicified starch, powdered cellulose, lactose anhydrous, and combinations thereof; the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, low-substituted hydroxypropylcellulose (L-HPC), alginic acid, calcium carboxymethylcellulose, and combinations thereof; the binder is selected from the group consisting of copovidone, hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate, povidone, sodium carboxymethylcellulose, gelatin, and combinations thereof; The flow agent is colloidal silicon dioxide, hydrous silicon dioxide, talc, and combinations thereof; the lubricant is selected from the group consisting of magnesium stearate, zinc stearate, calcium stearate, sodium stearyl fumarate, and combinations thereof; The content of said API is 100 mg to 300 mg per formulation; A stable oral formulation, wherein the API content is 20-70% by weight, based on 100% by weight of the total formulation.

2. 2. The stable oral formulation of claim 1, wherein at least 95% by weight of the API is maintained at 40° C. and 75% relative humidity for 6 months, at 80° C. and 75% relative humidity for 12 days, or at 25° C. and 60% relative humidity for 1 year.

3. 3. The stable oral formulation of claim 2, wherein at least 99% by weight of the API is maintained at 40° C. and 75% relative humidity for 6 months, at 80° C. and 75% relative humidity for 12 days, or at 25° C. and 60% relative humidity for 1 year.

4. 4. The stable oral formulation of claim 3, wherein at least 99.5% by weight of the API is maintained at 40° C. and 75% relative humidity for 6 months, at 80° C. and 75% relative humidity for 12 days, or at 25° C. and 60% relative humidity for 1 year.

5. 2. The stable oral formulation of claim 1, wherein the content of the API is 30-50% by weight, based on 100% by weight of the total formulation.

6. 2. The stable oral formulation of claim 1, wherein the content of the API is 40-50% by weight, based on 100% by weight of the total formulation.

7. 2. The stable oral formulation of claim 1, wherein the content of the API is 100 mg per formulation.

8. 2. The stable oral formulation of claim 1, wherein the content of the API is 200 mg per formulation.

9. 2. The stable oral formulation of claim 1, wherein the content of the API is 300 mg per formulation.

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