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

Abstract

The present invention relates to a stable oral preparation 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 preparation according to the present invention has a property of maintaining stability even without a stabilizer as an excipient, and instead of containing a stabilizer has an increased API content, and thus can increase administration convenience.

Description

Technical Field

[0001] This application claims priority to Korean Patent Application No. 10-2020-0166051, filed on December 1, 2020, the entire disclosure of which is incorporated herein by reference.

[0002] This invention relates to an oral formulation and its preparation method, wherein the oral formulation comprises 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 can be used as a xanthine oxidase inhibitor that can prevent uric acid deposition in the body, and does not contain a stabilizer. Background Technology

[0003] Xanthine oxidase is an enzyme that converts hypoxanthine into xanthine and then converts the resulting xanthine into uric acid. It is known that excessive uric acid in the body can lead to various diseases, including gout.

[0004] Gout is a condition caused by the accumulation of uric acid crystals in the cartilage, ligaments, and surrounding tissues of joints, resulting in severe inflammation and pain. The incidence of gout has been steadily increasing over the past 40 years.

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

[0006] Meanwhile, regarding substances that can inhibit xanthine oxidase activity, KR 10-1751325 (Patent Document 1) provides a compound 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid having the structure of Formula 1 and a method for preparing said compound, and KR 10-1424013 (Patent Document 2) provides various types of crystal forms obtained by using various solvents and methods for preparing them.

[0007] [Formula 1]

[0008]

[0009] In the case of pharmaceutical formulations, they typically contain one or more excipients selected from diluents, disintegrants, stabilizers, binders, lubricants, and flow aids, as well as an API (active ingredient). Generally, the excipients included in pharmaceutical formulations should be stable components and should not affect the efficacy of the formulation. However, issues with the stability of the API itself, the formation of reaction byproducts between the API and specific excipients, or reaction products that may depend on the combination of excipients can affect the stability or uniformity of the formulation's composition. That is, during the preparation or storage of pharmaceutical formulations, problems with stability and uniformity of composition may arise due to degradation products or reaction products generated by the API itself or through contact or combination with APIs and excipients.

[0010] Therefore, in pharmaceutical formulations, it is essential to correctly select and combine excipients suitable for the API. Furthermore, because these excipients are highly diverse and can be combined in numerous ways, selecting specific excipients and finding appropriate combinations to develop stable pharmaceutical formulations is a very difficult and time-consuming step in drug development.

[0011] Since the stability of oral formulations containing Formula 1 as an API is unknown, and long-term storage of more than one year is common in the case of oral formulations, there is a need to improve the stability and uniformity of component content of oral formulations containing Formula 1 as an API.

[0012] [Existing technical documents]

[0013] [Patent Literature]

[0014] 1. KR 10-1751325 (June 21, 2017), Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same.

[0015] 2. KR 10-1424013 (July 22, 2014), 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazol-4-carboxylicacid crystalline form and the producing method thereof. Summary of the Invention

[0016] Technical issues

[0017] Therefore, the inventors of this invention have conducted various studies to solve the above-mentioned problems. As a result, through stability tests on various excipients, it has been found that using 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API does not produce decomposition products or reaction products due to contact or binding with excipients. Furthermore, oral formulations that do not contain stabilizers in the excipients and have a stable effect in any combination of excipients have been identified, thus completing this invention.

[0018] Therefore, an object of the present invention is to provide a stable oral formulation and a method for preparing the same, the oral formulation comprising an API of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof and an excipient, but not comprising a separate stabilizer in the excipient.

[0019] Technical solution

[0020] The present invention provides a stable oral formulation comprising an API of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, and an excipient, but not comprising a separate stabilizer in the excipient.

[0021] The present invention provides a stable oral formulation comprising an amount of API of 20% to 60% by weight, based on the total oral formulation, wherein the API is 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof; and does not contain a stabilizer.

[0022] The oral formulation of the present invention comprises a diluent, a disintegrant, a binder, a flow aid, and a lubricant as excipients, and 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API, but does not contain a stabilizer.

[0023] The oral formulation of the present invention is used to treat or prevent xanthine oxidase-related diseases, which are selected from hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, joint disease, and inflammatory bowel disease.

[0024] Beneficial effects

[0025] Even without a stabilizer in the excipients, oral formulations according to the present invention containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API) can maintain or improve stability and uniformity of ingredient content, even in any combination with excipients.

[0026] Therefore, even without stabilizers in the excipients, the oral formulations of the present invention provide excellent storage stability regardless of storage conditions.

[0027] Furthermore, by being free of stabilizers, the oral formulation according to the invention contains a high content of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API, thus not only being economical but also increasing ease of administration. Detailed Implementation

[0028] The invention will be described in more detail below.

[0029] Unless otherwise defined, all technical terms used in this invention are used in the same sense as commonly understood by one of ordinary skill in the art related to this invention. Furthermore, while preferred methods and embodiments are described herein, analogues or equivalents are also included within the scope of this invention. All disclosures of publications incorporated herein by reference are incorporated herein in their entirety.

[0030] The inventors of this invention have continued to study oral formulations that maintain the stability of APIs through various methods in order to develop a stable oral formulation comprising 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as the API, and a pharmaceutically acceptable excipient. As a result, an oral formulation with excellent stability even without a stabilizer has been developed by maintaining stability and uniformity of component content even in any combination with excipients.

[0031] In this case, because it does not contain the stabilizers found in oral formulations, the API content can be increased, resulting in a high-content oral formulation that increases ease of administration without increasing the size of the oral dosage form. It also offers the added benefit of being more economical and practical compared to formulations containing other stabilizers.

[0032] Therefore, the present invention provides an oral formulation containing a high content of an API of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, but without a stabilizer in the excipients.

[0033] As used herein, the term "pharmaceutically acceptable salt" refers to a salt form of a compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the compound's biological activity and physical properties. The 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid contained in the oral formulation of this invention can be converted to its salt using conventional methods.

[0034] In oral formulations, it is common knowledge among those skilled in the art in the pharmaceutical field that when an API comes into contact with excipients, especially disintegrants, degradation products or reaction products of the API are generated, thereby inhibiting the stability of the formulation and potentially reducing the API content. Therefore, to increase API stability and maintain uniform API content, it is common knowledge among those skilled in the art in the pharmaceutical field that the formulation contains stabilizers, i.e., any pharmaceutically acceptable additives (excipients), to inhibit the formation of decomposition products that may occur when the API mixes with and comes into contact with excipients and other additives.

[0035] In this invention, in order to suppress the formation of decomposition products or reaction products by contact between 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or its pharmaceutically acceptable salt as an API and excipients, and thus ensure stability after oral administration, oral formulations containing various excipients and combinations of excipients were investigated.

[0036] The results have confirmed that even without stabilizers as excipients, stability during oral administration can be ensured by inhibiting API degradation products or reaction products that may occur during formulation preparation or storage, while ensuring uniformity of component content, and a stabilizer-free oral formulation with excellent stability has been developed.

[0037] Therefore, one aspect of the present invention provides an oral formulation i) containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API; but ii) not containing a stabilizer as an excipient.

[0038] As used herein, the term "stable" means suppressing any changes in the API by increasing its stability, and includes suppressing the generation of product-related substances (decomposition products or reaction products) that may occur during formulation preparation. Therefore, the oral formulations of the present invention are stable and / or exhibit improved stability compared to other oral formulations.

[0039] As used in this invention, the terms "stability," "stable," and variations thereof mean that an API representing 90% or more of the total API weight in the formulation remains undecomposed for up to 6 months under test conditions of 40°C and 75% relative humidity, or for up to 12 days under test conditions of 80°C and 75% relative humidity, or for up to 1 year under test conditions of 25°C and 60% relative humidity. In this case, the API content measured after storage under certain conditions for a certain period of time, based on the initial API content in the formulation, is referred to as the "residual content." In various embodiments, it means, for example, 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 the API remains undecomposed under the aforementioned conditions. The stability of compounds, formulations, etc., can be determined using methods generally accepted in the art, to the extent possible by those skilled in the art. For example, the amount of an API or compound can be determined by any suitable method such as HPLC.

[0040] Decomposition is a chemical process consisting of one or more reactions such as oxidation, reduction, or hydrolysis, which cause chemical changes after a substance is broken down, resulting in one or more novel compounds. Such novel compounds or impurities may produce reduced and / or variable levels of API in a given formulation, thereby reducing its efficacy and causing undesirable and / or adverse side effects in patients.

[0041] The term "impurity" in this invention 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 relative to the API. Therefore, the variation in total impurities in the formulation under the conditions and time periods set forth herein can also characterize a stable formulation, and can be determined by suitable methods, such as HPLC.

[0042] Furthermore, stability can be tested under various other test conditions, including, for example...

[0043] - One year later, under test conditions of 25°C and 75% relative humidity (room temperature conditions),

[0044] - After 6 months, under test conditions of 40°C and 75% relative humidity (accelerated conditions), or

[0045] -12 days later, test conditions at 80°C and 75% relative humidity (harsh conditions).

[0046] Stability can also be measured by appearance. As used herein, “visual stability” and its variations are intended to mean no substantial change in the color, integrity (e.g., unbroken), shape, and / or size of the formulation.

[0047] As used herein, the terms “enhanced stability,” “improved stability,” and variations thereof mean that the degradation of one or more APIs in a given formulation and / or the increase in impurities in a given formulation is less than the increase in impurities when the formulation is exposed to the test conditions.

[0048] It has been confirmed that, in the case of the oral formulation of the present invention, when subjected to a flexibility test under harsh conditions of 80°C, even without the stabilizer, the residual content of the API remains above 99.5% by weight compared to the total weight of the API when measured after 12 days. Even under conditions of 25°C and 75% relative humidity, even without the stabilizer, the residual content of the API remains above 99.5% by weight when measured after one year of storage, and there are no substantial changes in the color, shape, size, etc. of the formulation. Therefore, the formulation is excellent in terms of stability.

[0049] In this invention, the oral formulation further comprises one or more excipients selected from pharmaceutically acceptable diluents, disintegrants, binders, flow aids and lubricants as excipients.

[0050] Diluents, disintegrants, binders, gliding agents, and lubricants can be any excipient known to be commonly used in the art. The amount of diluent may be 30% to 50%, 40% to 50%, or 40% to 45% by weight of the total weight of the oral formulation. The amount of disintegrant may be 1% to 30%, 1% to 20%, 1% to 10%, or 1% to 5% by weight of the total weight of the oral formulation. The amount of binder may be 1% to 30%, 1% to 20%, 1% to 10%, or 1% to 5% by weight of the total weight of the oral formulation. The amount of gliding agent may be 0.1% to 10%, 0.3% to 5%, or 0.5% to 4% by weight of the total weight of the oral formulation. The amount of lubricant used, based on the total weight of the oral formulation, can range from 0.1% to 10% by weight, 0.3% to 5% by weight, or 0.5% to 4% by weight.

[0051] For example, the diluent may be selected from microcrystalline cellulose, lactose monohydrate, anhydrous lactose, lactose, starch, mannitol, carboxymethyl cellulose, sorbitol, and combinations thereof, but is not limited thereto. The disintegrant may be selected from low-substituted hydroxypropyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, sodium glycolate starch, etc. Adhesives may be selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate, povidone, polyvinylpyrrolidone, copovidone, polyethylene glycol, sodium lauryl sulfate, light anhydrous silica, synthetic aluminum silicate, calcium silicate or silicate derivatives such as magnesium aluminosilicate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, pregelatinized starch, gums such as gum arabic, gelatin, cellulose derivatives such as ethyl cellulose, and mixtures thereof, but are not limited to these. Gliders may be selected from colloidal silica, hydrated silica, and combinations thereof, but are not limited to these. Lubricants may be selected from magnesium stearate, silica, talc, light anhydrous silica, sodium stearoyl fumarate, and combinations thereof, but are not limited to these.

[0052] In one embodiment, 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid, contained in the oral formulation as an API, may be in the form of crystalline particles. In one embodiment, crystalline particles of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid may be prepared by conventional methods for preparing crystalline particles.

[0053] Oral preparations can be administered once daily and can be taken daily.

[0054] The content of API in the oral formulation may be 20% to 70% by weight, 20% to 60% by weight, 20% to 50% by weight, 20% to 45% by weight, 30% to 70% by weight, 30% to 60% by weight, 30% to 50% by weight, 30% to 45% by weight, 40% to 70% by weight, 40% to 60% by weight, 40% to 50% by weight, or 40% to 45% by weight, based on the total weight of the oral formulation.

[0055] In addition, the API contained may be in the range of, for example, 50 mg to 500 mg, 50 mg to 400 mg, 50 mg to 300 mg, 50 mg to 200 mg, 50 mg to 100 mg, 100 mg to 500 mg, 100 mg to 400 mg, 100 mg to 300 mg, 100 mg to 200 mg, 200 mg to 500 mg, 200 mg to 400 mg, 200 mg to 300 mg, 300 mg to 500 mg, or 300 mg to 400 mg per unit dosage.

[0056] In addition, the content of API can be 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg or 455 mg per unit of formulation.

[0057] The present invention provides a method for preparing an oral formulation, the method comprising the following steps: mixing an API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof with excipients such as diluents, disintegrants, binders, flow aids and lubricants, wherein the excipients are free of stabilizers; and formulating the mixture.

[0058] Oral formulations can be prepared according to any preparation method known in the art, and tablets, as a form of oral formulation, can also be prepared according to any tablet preparation method known in the art.

[0059] The present invention also provides a method for treating or preventing human xanthine oxidase-related diseases using an oral formulation, said oral formulation comprising 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API.

[0060] As used in this invention, the term "human xanthine oxidase-related disease" refers to a disease that can be treated or prevented by inhibiting human xanthine oxidase, and can include, but is not limited to, hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, diabetes-related complications, kidney disease, inflammation, joint disease, inflammatory bowel disease, etc. Examples of diabetes-related complications may include hyperlipidemia, arteriosclerosis, obesity, hypertension, retinopathy, kidney failure, etc.

[0061] The term "treatment" when used for subjects exhibiting disease symptoms means to stop or delay disease progression, while the term "prevention" when used for subjects who do not exhibit disease symptoms but are at high risk of developing the disease means to stop or delay disease symptoms.

[0062] Unless otherwise specified, it should be understood that all figures used in the specification and claims, whether or not mentioned, are in all cases modified by the term "about". It should also be understood that the precise figures used in the specification and claims form other embodiments of this disclosure. Efforts have been made to ensure the accuracy of the numerical values ​​disclosed in the embodiments. However, all measurements may inherently contain some error values ​​resulting from the standard deviation measured by their respective measurement techniques.

[0063] <Examples and Experimental Examples>

[0064] The following examples and experimental cases will describe one or more specific implementations in more detail. However, these examples are for illustrative purposes only, and the scope of the invention is not limited thereto.

[0065] Experimental Example 1. Stability analysis of API 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid mixed with each excipient

[0066] As disclosed in Table 1 below, the residual content of API under accelerated conditions (40°C, 75% RH; relative humidity) was measured in the initial stage and after storage for 1 month, 2 months, and 3 months, respectively, using the analytical methods and procedures described below, after preparing a mixture by mixing API 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid with various types of excipients such as microcrystalline cellulose. Table 1 only lists the residual content in the initial stage and after 3 months of storage.

[0067] Table 1:

[0068]

[0069]

[0070] <Analysis Methods and Procedures>

[0071] The HPLC analysis conditions are as follows:

[0072] Column: Inertsil ODS-2 (4.6×150mm, 5μm, GL Science) Detector: 254nm, UV

[0073] Flow rate: 1.0 ml / min

[0074] Injection volume: 5 μl

[0075] Column temperature: 40℃

[0076] Elution solution

[0077] A: Acetonitrile / Purified water / TFA (trifluoroacetic acid) = 40 / 60 / 0.1 (v / v / v)

[0078] B: Acetonitrile / Purified Water / TFA = 80 / 20 / 0.1 (v / v / v)

[0079] Table 2: Gradient Table

[0080] Time (minutes) A(％) B(％) initial 100 0 9 100 0 15 0 100 20 100 0 30 100 0

[0081] Based on the stability analysis results in Table 1, it is evident that 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid alone exhibits excellent stability even after 3 months of accelerated storage (Comparative Example 1). Furthermore, it is also evident that even when 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid is mixed with various excipients and stored under accelerated conditions, it possesses the same excellent stability as 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid alone (Examples 1 to 15).

[0082] Experimental Example 2. Stability analysis of tablets prepared by mixing and compressing 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid (as an API) with each excipient.

[0083] As disclosed in Table 3 below, 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid, as an API, was mixed with various types of excipients such as microcrystalline cellulose, and then finally compressed using a tableting machine to prepare oral tablets (uncoated tablets) of Comparative Example 2 and Examples 16 to 27.

[0084] In each prepared oral tablet, the residual API content was measured under harsh conditions (80°C, 75% RH) during the initial storage phase and after 12 days under harsh conditions, using the methods and procedures described above.

[0085] Table 3:

[0086]

[0087]

[0088] Based on the stability analysis results in Table 3, it is evident that when tablets of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid alone are stored under harsh conditions, they exhibit excellent stability even after 12 days (Comparative Example 2). Furthermore, it is evident that even when tablets prepared by mixing various excipients with 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid are stored under harsh conditions, they exhibit the same excellent stability as 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid alone (Examples 16 to 27).

[0089] It has been confirmed that, in terms of appearance, there are no substantial changes in the color, shape, or size of the tablets, and the tablets exhibit excellent stability.

[0090] Experimental Example 3: Stability analysis of a mixture of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid as an API and excipients.

[0091] As disclosed in Table 4 below, 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid, as an API, was mixed with various types of excipients such as microcrystalline cellulose to prepare mixtures of Examples 28 to 47.

[0092] In each of the prepared mixtures, the residual content of API was measured under harsh conditions (80°C, 75% RH) during the initial storage phase and after 12 days under harsh conditions, using the methods and procedures described above.

[0093] Table 4:

[0094]

[0095]

[0096] Based on the stability analysis results in Table 4, it can be seen that even when 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid is mixed with various excipients and stored under harsh conditions, the API hardly decomposes and almost retains the initial residual content, as in the case of accelerated conditions (Examples 28 to 47).

[0097] Experimental Example 4: Stability Analysis of Tablets Containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic Acid as an API and Various Excipients

[0098] When APIs are formulated into oral tablets with mixtures of excipients such as diluents, disintegrants, and binders, even if the API and each excipient component are stable in their individual raw material states, the API will mix or come into contact with the excipients during formulation, which may lead to stability issues, such as the formation of API degradation products. Therefore, to confirm this, oral tablets of APIs in combination with various excipients were prepared and their stability was analyzed (each tablet weighed 220 mg, and the content ratio of each component listed in Table 5 is based on one tablet (220 mg)).

[0099] As disclosed in Table 5 below, 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid, as an API, was mixed with various types of excipients such as microcrystalline cellulose, and then finally compressed using a tableting machine to prepare oral tablets of Examples 48 to 51.

[0100] The residual API content of the prepared tablets was measured under harsh conditions (80℃, 75% RH) during the initial storage phase and after 12 days of storage, or under accelerated conditions (40℃±2℃, 75%±5% RH) during the initial storage phase and after 3 and 6 months of storage, or under room temperature conditions (25℃±2℃, 60%±5% RH) during the initial storage phase and after long-term storage of 1 year and more than 2 years, using the methods and procedures described above.

[0101] Table 5:

[0102]

[0103]

[0104] Based on the stability analysis results in Table 6 below, it can be confirmed that when 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (API) is mixed with various excipients to prepare oral tablets, even without stabilizers, and even after storage under harsh conditions (80°C, 75% RH) for 12 days, under accelerated conditions (40°C ± 2°C, 75% ± 5% RH) for 6 months, or under room temperature conditions (25°C ± 2°C, 60% ± 5% RH) for 12 months, very few product-related substances are generated, and the residual content of API remains stable, almost unchanged compared to the initial stage. Furthermore, it has been confirmed that there are no substantial changes in the color, shape, and size of the tablets, even in terms of appearance, and the tablet stability is excellent.

[0105] Table 6:

[0106]

Claims

1. A stable oral formulation comprising an active pharmaceutical ingredient (API) and one or more excipients, said API being 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, and said API not being crystalline particles of 1-(3-cyano-1-isopropyl-indole-5-yl)-1H-pyrazole-4-methyl ester comprising 0.02 wt% of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid. The formulation described herein does not include a separate stabilizer as an excipient, and Of which more than 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 excipients are selected from diluents, disintegrants, binders, flow aids, lubricants, and combinations thereof. The diluent is selected from microcrystalline cellulose, lactose monohydrate, pregelatinized starch, mannitol, dicalcium phosphate dihydrate, anhydrous dicalcium phosphate, silicified starch, powdered cellulose, starch, anhydrous lactose, and combinations thereof. The disintegrants mentioned above are selected from croscarmellose sodium, starch glycolate sodium, croscarmellose, alginate, calcium carboxymethyl cellulose, and combinations thereof. The adhesive is selected from copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, povidone, sodium carboxymethyl cellulose, gelatin, and combinations thereof. The flow aid is selected from colloidal silica, hydrated silica, talc, and combinations thereof. The lubricant mentioned is selected from magnesium stearate, zinc stearate, calcium stearate, sodium stearoyl fumarate, and combinations thereof. The content of the API is 20% to 70% by weight, based on a total of 100% by weight of the formulation.

2. The stable oral formulation according to claim 1, wherein the formulation is an oral tablet.

3. The stable oral formulation according to claim 1 or 2, wherein more than 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.

4. The stable oral formulation according to claim 3, wherein more than 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.

5. The stable oral formulation according to claim 4, wherein more than 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.

6. The stable oral formulation according to claim 1 or 2, wherein the oral formulation comprises a combination of a diluent, a disintegrant, a flow aid, and a lubricant.

7. The stable oral formulation according to claim 1 or 2, wherein the oral formulation comprises a combination of a diluent, a disintegrant, a binder, a flow aid, and a disintegrant.

8. The stable oral formulation according to claim 1 or 2, wherein the content of the API is 30% to 50% by weight, based on a total of 100% by weight of the formulation.

9. The stable oral formulation according to claim 7, wherein the content of the API is 40% to 50% by weight, based on a total of 100% by weight of the formulation.

10. The stable oral formulation according to claim 1 or 2, wherein, based on the total weight of the oral formulation, the amount of diluent is 30% to 50% by weight, when present; the amount of disintegrant is in the range of 1% to 30% by weight; the amount of binder is in the range of 1% to 30% by weight; the amount of glidant is in the range of 0.1% to 10% by weight; and the amount of lubricant is in the range of 0.1% to 10% by weight.

11. The stable oral formulation of claim 10, wherein, based on the total weight of the oral formulation, the amount of diluent is 40% to 50% by weight, when present; the amount of disintegrant is in the range of 1% to 5% by weight; the amount of binder is in the range of 1% to 5% by weight; the amount of glidant is in the range of 0.5% to 4% by weight; and the amount of lubricant is in the range of 0.5% to 4% by weight.

12. The stable oral formulation according to claim 1 or 2, wherein, when present, The diluent is selected from microcrystalline cellulose, lactose monohydrate, pregelatinized starch, and combinations thereof. The disintegrant is selected from croscarmellose sodium, sodium starch glycolate, croscarmellose, and combinations thereof. The adhesive is selected from copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, povidone, and combinations thereof. The flow aid is colloidal silica. The lubricant is selected from magnesium stearate, sodium stearoyl fumarate, and combinations thereof.

13. The stable oral formulation according to claim 1 or 2, wherein, when present, The diluent is microcrystalline cellulose. The disintegrant is selected from croscarmellose sodium, sodium starch glycolate, croscarmellose, and combinations thereof. The adhesive is selected from copovidone, hydroxypropyl cellulose, povidone, and combinations thereof. The flow aid is colloidal silica, and The lubricant is selected from magnesium stearate, sodium stearoyl fumarate, and combinations thereof.

14. The stable oral formulation of claim 2, wherein the oral formulation comprises, by total weight: 45.5% active pharmaceutical ingredient (API), 47.6% microcrystalline cellulose, 4.4% crospovidone, 0.5% colloidal silica, and 2% sodium stearoyl fumarate; or 45.5% active pharmaceutical ingredient (API), 43.6% microcrystalline cellulose, 4.5% crospovidone, 4.5% copovidone, 1% colloidal silica, and 0.8% magnesium stearate; or 45.5% active pharmaceutical ingredient (API), 43.6% microcrystalline cellulose, 4.5% croscarmellose sodium, 4.5% povidone, 1% colloidal silica, and 0.8% sodium stearoyl fumarate; or 45.5% active pharmaceutical ingredient (API), 43.6% microcrystalline cellulose, 4.5% sodium starch glycolate, 4.5% hydroxypropyl cellulose, 1% colloidal silica and 0.8% magnesium stearate; in, The API is 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, and the API is not crystalline particles of 1-(3-cyano-1-isopropyl-indol-5-yl)-1H-pyrazole-4-methyl ester comprising 0.02 wt% of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid.

15. The stable oral formulation according to claim 1 or 2, wherein, when present, the diluent is selected from microcrystalline cellulose, lactose monohydrate, pregelatinized starch, and combinations thereof. The disintegrant is selected from croscarmellose sodium, sodium starch glycolate, croscarmellose, and combinations thereof. The adhesive is selected from copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, povidone, and combinations thereof. The lubricant is magnesium stearate.

16. The stable oral formulation according to claim 15, wherein the API:diluent ratio (w / w) is 1:1; the API:disintegrant ratio (w / w) is 1:10; the API:binder ratio (w / w) is 1:10; and / or the API:lubricant ratio (w / w) is 1:

10.

17. The stable oral formulation according to claim 1 or 2, wherein the API content is 50 mg per dose.

18. The stable oral formulation according to claim 1 or 2, wherein the API content is 100 mg per dose.

19. The stable oral formulation according to claim 1 or 2, wherein the API content is 200 mg per dose.

20. The stable oral formulation according to claim 1 or 2, wherein the API content is 300 mg per dose.

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