Composite formulation for oral administration comprising 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazol-4-carboxyl acid and a process for the preparation thereof

Abstract

This invention relates to an oral formulation of tranquilizer, comprising 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API). The oral formulation of tranquilizer according to this invention maintains stability even without containing a tranquilizer as an excipient, and has an increased API content despite not containing a tranquilizer, thus increasing dosing 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-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API) and does not contain a tranquilizer, wherein the 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof is a xanthine oxidase inhibitor that can prevent the deposition of uric acid in the body. [Previous Technology]

[0003] Xanthine oxidase is an enzyme that converts hypoxanthine into xanthine and also converts the resulting xanthine into uric acid. It is known that when there is too much uric acid in the body, this excess uric acid can cause a variety of diseases, including gout and similar conditions.

[0004] Gout refers to the symptoms caused by the accumulation of uric acid crystals in cartilage, ligaments and periarticular tissues, which causes severe inflammation and pain. The incidence of gout has been increasing over the past 40 years.

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

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

[0007] Regarding pharmaceutical formulations, pharmaceutical formulations generally contain one or more excipients selected from diluents, disintegrants, stabilizers, binders, lubricants, and slip agents, in addition to the active ingredient (API). Typically, the excipients included in pharmaceutical formulations should be stable components and should not affect the effectiveness of the formulation. However, if the stability of the API itself is problematic, or if reaction byproducts are generated between the API and specific excipients, or if reaction products dependent on the combination of these excipients may occur, these may affect the stability or detection uniformity of the formulation. In other words, during the preparation or storage of the pharmaceutical formulation, problems with stability and detection uniformity may arise due to the API itself or degradation products or reaction products generated through contact or bonding with the API or excipients.

[0008] Therefore, for pharmaceutical formulations, it is important to appropriately select and combine excipients suitable for the API. In addition, because there is a great variety of excipients and it is possible to combine many different excipients, selecting specific excipients from a variety of excipients and finding appropriate combinations to develop stable pharmaceutical formulations is an extremely difficult and time-consuming step in drug development.

[0009] Because the stability of oral formulations containing compounds of Formula 1 as APIs is unknown, and the long-term storage period of oral formulations is generally one year or more, there is a need to improve the stability and detection uniformity of oral formulations containing compounds of Formula 1 as APIs. [Prior Art Documents] [Patent Documents]

[0010] 1. KR 10-1751325 (June 21, 2017): Novel compound effective as a xanthine oxidase inhibitor, method for its preparation and pharmaceutical composition comprising the compound.

[0011] 2. KR 10-1424013 (July 22, 2014): Crystal form of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid and method for its preparation. [Summary of the Invention]

[0012] [Technical Problem] Therefore, the inventors of the present invention have conducted various studies to solve the above-mentioned problems, and thus, through safety tests on various excipients, it has been found that the use of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or its pharmaceutically acceptable salt as an API does not produce decomposition products or reaction products due to contact or bonding with such excipients, and oral formulations that do not contain stabilizers and exhibit stabilizing effects in any combination with excipients have been identified, thereby completing the present invention.

[0013] Therefore, the object of the present invention is to provide a tranquilizing oral formulation and a method for preparing the oral formulation, the oral formulation comprising 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API and an excipient, but not comprising any separate tranquilizer in the excipient. [Technical Solution]

[0014] The present invention provides an oral formulation of tranquilizer, comprising 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API and an excipient, but not comprising any individual tranquilizer in the excipient.

[0015] The present invention provides an oral preparation of tranquilizer, comprising an API, wherein the API is 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, in a content of 20% or more and 60% or less of the total weight of the oral preparation, and does not contain a tranquilizer.

[0016] The oral formulation of the present invention comprises a diluent, a disintegrant, a binder, a lubricant and a slurry as excipients and contains 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API, but does not contain a stabilizer.

[0017] The oral formulation of the present invention is used to treat or prevent diseases related to xanthine oxidase, which are selected from the group consisting of hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, joint disease, and inflammatory bowel disease. [Excellent Efficacy]

[0018] According to the present invention, in the absence of a variety of excipients containing a stabilizer, even in any combination with such excipients, the 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) can maintain or improve stability and detection uniformity.

[0019] Thus, in the case where various excipients do not contain stabilizers, the oral formulation of the present invention provides excellent storage stability regardless of storage conditions.

[0020] Furthermore, by not containing a stabilizer, the oral formulation according to the present invention contains a high content of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof (which is an API), and thus is not only economically practical, but also increases the convenience of administration.

Implementation Method

[0021] [Best Embodiment] The present invention will now be described in more detail.

[0022] Unless otherwise defined, all technical terms used in this invention have the same meaning as commonly understood by those skilled in the art related to this invention. Furthermore, while preferred methods and embodiments are described herein, the scope of this invention also includes similar or equivalent methods. All disclosures in publications incorporated herein by reference are incorporated herein by reference in their entirety.

[0023] Through various methods, the inventors of this invention have been continuously researching oral formulations that maintain the stability of APIs in order to develop stable oral formulations containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API and a pharmaceutically acceptable excipient. As a result, oral formulations with excellent stability have been developed even without the presence of a stabilizer and even in any combination of various excipients by maintaining stability and detection uniformity.

[0024] In this regard, since the oral formulation does not contain a tranquilizer, the content of the API can be increased. Therefore, it is possible to create a high-content oral formulation that increases administration convenience without increasing the size of the oral formulation. Compared with formulations containing other tranquilizers, the oral formulation also has the additional benefit of being economically practical.

[0025] Therefore, the present invention provides an oral formulation containing a high amount of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API, but without a stabilizer in the excipients.

[0026] As used herein, "medically acceptable salt" refers to the 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-indole-5-yl)pyrazole-4-carboxylic acid of the API contained in the oral formulation of this invention can be converted to its salt using conventional methods.

[0027] For oral formulations, it is common knowledge among those skilled in the art of pharmaceutical technology that when an API comes into contact with an excipient (especially a disintegrant), degradation products or reaction products of the API may be generated, thereby inhibiting the stability of the formulation and potentially reducing the detectability of the API. Accordingly, to increase the stability of the API and maintain the uniformity of its detection, it is common knowledge among those skilled in the art of pharmaceutical technology that when the API is mixed and contacted with an additive (such as an excipient), the formulation contains a stabilizer of any pharmaceutically acceptable additive (excipient) to inhibit the formation of any degradation products that may be generated.

[0028] In this invention, in order to suppress the decomposition products or reaction products generated by contact between 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or its pharmaceutically acceptable salt (which is an API) and excipients, and thus ensure the stability of oral administration, oral formulations containing a variety of different excipients and combinations of multiple excipients are studied.

[0029] As a result, it has been confirmed that even without the inclusion of a stabilizer as an excipient, it is possible to ensure stability during oral administration and at the same time ensure detection uniformity by inhibiting the degradation products or reaction products of the API that may occur during the preparation or storage of the modifier, and to develop oral modifiers that do not include the stabilizer but have excellent stability.

[0030] Therefore, one aspect of the present invention provides an oral formulation which (1) contains 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API; but (2) does not contain a stabilizer as an excipient.

[0031] The term "stabilization" as used herein refers to the suppression of any alteration of an API by increasing its stability, including the suppression of the formation of product-related substances (decomposition products or reaction products) that may occur during the preparation of the modifier. Therefore, the oral modifier of the present invention is stable and / or has improved stability compared to other oral modifiers.

[0032] The terms "stability," "stable," and their variations as used in this invention refer to: maintaining 90% or more of the total weight of the API relative to the modifier without decomposition for 6 months under test conditions of 40°C and 75% relative humidity; or maintaining 90% or more of the total weight of the API relative to the modifier without decomposition for 12 days under test conditions of 80°C and 75% relative humidity; or maintaining 90% or more of the total weight of the API relative to the modifier without decomposition for 1 year under test conditions of 25°C and 60% relative humidity. In this case, the API test measured based on the initial API test of the modifier after storage for a certain period under certain conditions is called "residual test." In several different embodiments, residual detection indicates that the API maintained, for example, at 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 without decomposition under the aforementioned conditions. By using methods conventionally accepted in this art, those skilled in the art can determine the stability of the compound, modifier, etc. For example, the amount of the API or compound can be determined by any suitable method (such as HPLC).

[0033] Decomposition is a chemical process consisting of one or more reactions such as oxidation, reduction, or hydrolysis, in which the decomposition of a substance causes a chemical change to produce one or more new compounds. In a given modifier, such novel compounds or impurities can cause a reduction and / or change in the amount of API, thereby reducing the efficacy of the modifier and causing undesirable and / or harmful side effects to the patient.

[0034] As used in this invention, the term "impurity" refers to any novel compound present in the composition and / or modifier at a concentration 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 the concentration of all impurities in the modifier during the conditions and time period described herein can also be used to characterize the stabilizing modifier, and the variation in the concentration of all impurities can be determined by a suitable method (e.g., HPLC).

[0035] Furthermore, this stability can be tested under various other test conditions, including, for example:

[0036] - Test conditions at 25℃ and 75% relative humidity (room temperature) after 1 year;

[0037] - Test conditions at 40℃ and 75% relative humidity (accelerated conditions) after 6 months; or

[0038] - Test conditions at 80℃ and 75% relative humidity (severe conditions) after 12 days.

[0039] The stability can also be determined by appearance. The term "visual stability" and its variation as used herein are intended to indicate that the color, overall (e.g., unbroken), shape and / or size of the modifier are not substantially changed.

[0040] The terms “increased stability”, “improved stability” and variations thereof as used herein indicate that in a given modifier, the amount of degradation of one or more APIs and / or the amount of increase in impurities is lower than the amount of increase in impurities of the modifier when exposed to the test conditions.

[0041] It has been confirmed that, for the oral formulation of the present invention, when a flexibility test is performed under severe conditions at 80°C, even without the inclusion of a stabilizer, the residual detection of the API measured after 12 days remains at or above 99.5% by weight compared to the total weight of the API. Furthermore, even under conditions of 25°C and 75% relative humidity, even without the inclusion of a stabilizer, the residual detection of the API measured after 1 year of storage remains at or above 99.5% by weight compared to the total weight of the API. Moreover, the color, shape, size, etc. of the formulation do not change substantially. Therefore, the stability of the formulation is excellent.

[0042] In this invention, the oral preparation further comprises one or more excipients selected from pharmaceutically acceptable diluents, disintegrants, binders, lubricants and slurries as excipients.

[0043] The diluent, disintegrant, binder, lubricant, and slip agent may be any known excipient conventionally used in this art. The amount of the diluent may be 30 to 50% by weight, 40 to 50% by weight, or 40 to 45% by weight based on the total weight of the oral preparation. The amount of the disintegrant may be 1 to 30% by weight, 1 to 20% by weight, 1 to 10% by weight, or 1 to 5% by weight based on the total weight of the oral preparation. The amount of the binder may be 1 to 30% by weight, 1 to 20% by weight, 1 to 10% by weight, or 1 to 5% by weight based on the total weight of the oral preparation. The amount of the slip agent may be 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. The amount of the lubricant may be 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.

[0044] For example, the diluent may be selected from, but is not limited to, the group consisting of microcrystalline cellulose, lactose monohydrate, anhydrous lactose, lactose, starch, mannitol, carboxymethyl cellulose, sorbitol, and combinations thereof. The disintegrant may be selected from, but is not limited to, the group consisting of, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, croscarmellose sodium, carboxymethyl starch sodium, F-melt®, and combinations thereof. The adhesive may be selected from, but is not limited to, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, polyvinyl acetate, polyvinylpyrrolidone, polyvinylhydropyrrolidone, copolyvinylpyrrolidone, polyethylene glycol, sodium lauryl sulfate, light anhydrous silicate, synthetic aluminum silicate, calcium silicate or silicate derivatives (such as magnesium aluminum metasilicate), 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 combinations thereof. The lubricant may be selected from, but is not limited to, colloidal silica, hydrated silica, and combinations thereof. The lubricant may be selected from, but is not limited to, magnesium stearate, silica, talc, light anhydrous silica, sodium stearate fumarate, and combinations thereof.

[0045] In one embodiment, the 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, the 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.

[0046] This oral preparation can be administered once a day or taken daily.

[0047] The content of API contained in the oral preparation 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 preparation.

[0048] In addition, the API contained therein may be, for example, 50 to 500 mg, 50 to 400 mg, 50 to 300 mg, 50 to 200 mg, 50 to 100 mg, 100 to 500 mg, 100 to 400 mg, 100 to 300 mg, 100 to 200 mg, 200 to 500 mg, 200 to 400 mg, 200 to 300 mg, 300 to 500 mg or 300 to 400 mg per unit of modulator.

[0049] In addition, the amount of the API contained may be 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg or 455 mg per unit of modulator.

[0050] The present invention provides a method for preparing an oral formulation, 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 an excipient, a diluent, a disintegrant, a binder, a lubricant, and a stabilizer, wherein the excipient does not contain a stabilizer; and preparing the mixture.

[0051] The oral preparation can be prepared by any preparation method known in this art, and can also be prepared as a type of tablet of the oral preparation by any tablet preparation method known in this art.

[0052] The present invention also provides a method for treating or preventing human diseases related to xanthine oxidase using an oral modifier, the oral modifier comprising 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API.

[0053] The term "human diseases related to xanthine oxidase" as used in this invention refers to diseases that can be treated or prevented by inhibiting human xanthine oxidase, and may include, for example, hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, diabetes-related complications, kidney disease, inflammation, joint diseases, inflammatory bowel disease, and the like, but is not limited thereto. Examples of diabetes-related complications may include hyperlipidemia, arteriosclerosis, obesity, hypertension, retinopathy, renal failure, and the like.

[0054] When used for an individual exhibiting symptoms of a disease, the term "treatment" means to stop or delay the progression of the disease, and when used for an individual who does not exhibit symptoms of a disease but is at high risk of developing the disease, the term "prevention" means to stop or delay the symptoms of the disease.

[0055] Unless otherwise specified, it should be understood that all figures used in the specification and claims, whether or not mentioned, may be modified by the term "about" in all cases. It should also be understood that the precise figures used in the specification and claims form other embodiments of this disclosure. Every effort has 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 individual measurement techniques.

[0056] [Example and Experimental Examples]

[0057] Subsequently, one or more specific embodiments will be described in more detail through the following examples and experimental examples. However, these embodiments are only intended to illustrate these embodiments, and the scope of the present invention is not limited to these embodiments.

[0058] Experimental Example 1. Stability analysis of API (1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid) mixed with each excipient

[0059] As shown in Table 1 below, after preparing a mixture by mixing API (1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid) with various types of excipients (such as microcrystalline cellulose), the residual detection of the API was measured at the initial stage and after storage for 1 month, 2 months, and 3 months under accelerated conditions of 40°C and 75% relative humidity (RH) using the analytical methods and procedures described below. Table 1 only shows the residual detection at the initial stage and after 3 months of storage.

[0060]

[0061] [Analysis Methods and Procedures]

[0062] HPLC analysis conditions are described below:

[0063] Column: Inertsil ODS-2 (4.6×150 mm, 5 μm, GL Science)

[0064] Detector: 254 nm, UV

[0065] Flow rate: 1.0 ml / min

[0066] Injection volume: 5 μl

[0067] Tube temperature: 40℃

[0068] Separation solution:

[0069] A: Acetonitrile / Purified water / TFA (trifluoroacetic acid) = 40 / 60 / 0.1 (v / v / v)

[0070] B: Acetonitrile / Purified water / TFA = 80 / 20 / 0.1 (v / v / v)

[0071]

[0072] Based on the stability analysis results shown in Table 1, it can be seen that when 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid is stored alone under accelerated conditions, it still exhibits excellent stability even after 3 months (Comparative Example 1). Furthermore, it can be seen that even when 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid is mixed with various different excipients and stored under accelerated conditions, it exhibits the same excellent stability as 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid alone (Examples 1 to 15).

[0073] Experimental Example 2. Stability analysis of tablets prepared by mixing API (1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid) with each excipient and then compressing them into tablets.

[0074] As shown in Table 3 below, 1-(3-cyano-1-isopropyl-indole-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 Examples 2 and 16 to 27.

[0075] For each prepared oral tablet, the residual detection of the API was measured during the initial storage phase and after 12 days of storage under severe conditions (80°C and 75%RH) using the methods and procedures described above.

[0076]

[0077] Based on the stability analysis results shown in Table 3, it can be seen that when 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid tablets are stored alone under severe conditions, the tablets still exhibit excellent stability even after 12 days (Comparative Example 2). Furthermore, it can be seen that even when tablets prepared by mixing 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid with various types of excipients are stored under severe conditions, these tablets exhibit the same excellent stability as 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid alone (Examples 16 to 27).

[0078] Regarding the appearance, it has been confirmed that the color, shape, size, etc. of the tablet have not been substantially changed, and the tablet has excellent stability.

[0079] Experimental Example 3. Stability analysis of a mixture of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid (which is an API) and excipients.

[0080] As shown in Table 4 below, 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid (which is an API) was mixed with various types of excipients (such as microcrystalline cellulose) to prepare the mixtures of Examples 28 to 47.

[0081] For each prepared mixture, the residual detection of the API was measured during the initial storage phase and after 12 days of storage under severe conditions (80°C and 75%RH) using the methods and procedures described above.

[0082]

[0083] Based on the stability analysis results shown in Table 4, it can be seen that even when 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid is mixed with various types of excipients and stored under severe conditions, the API hardly decomposes and, as shown in the results obtained under accelerated conditions, almost maintains the initial residual detection (Examples 28 to 47).

[0084] Experimental Example 4. Stability analysis of tablets containing 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid (which is an API) and each excipient.

[0085] When a mixture of API and excipients (such as diluents, disintegrants, or binders) is formulated into an oral tablet, even if each of the API and each of the individual excipient components is stable in its raw state, stability problems may arise when the API is mixed or comes into contact with the excipients during formulation, such as the formation of degradation products of the API. Therefore, to confirm this, oral tablets of API combined with various different excipients were prepared and their stability was analyzed (each tablet weighs 220 mg, and the content ratios of each component shown in Table 5 are based on one tablet (220 mg)).

[0086] As shown in Table 5 below, the oral tablets of Examples 48 to 51 were prepared by mixing 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid (which is an API) with various types of excipients (such as microcrystalline cellulose) and then finally compressing them using a tableting machine.

[0087] For each tablet, the residual detection of the API was measured by the methods and procedures described above during the initial storage phase under severe conditions (80°C and 75% RH) and after 12 days of storage, or during the initial storage phase under accelerated conditions (40°C ± 2°C and 75% ± 5% RH) and after 3 months and 6 months of storage, or during the initial storage phase under room temperature conditions (25°C ± 2°C and 60% ± 5% RH) and after long-term storage for 1 year, 2 years or longer.

[0088]

[0089] Based on the stability analysis results shown in Table 6 below, it can be confirmed that when 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid (API) is mixed with various excipients to prepare oral tablets, even without stabilizers, and even after storage under severe conditions (80°C and 75% RH) for 12 days, under accelerated conditions (40°C ± 2°C and 75% ± 5% RH) for 6 months, or under room temperature conditions (25°C ± 2°C and 60% ± 5% RH) for 12 months, almost no product-related substances are generated, and the residual detection of the API is stable and almost maintained compared with the initial stage. Furthermore, it has been confirmed that even considering appearance, the color, shape, and size of the tablets do not change substantially, and the tablets have excellent stability.

[0090]

Claims

1. An oral formulation of tranquilizer comprising an active pharmaceutical ingredient (API) and one or more excipients, wherein the API is 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the formulation does not include individual tranquilizers as excipients, and wherein 90% by weight or 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, wherein the oral formulation comprises at least one excipient selected from diluents, disintegrants, binders, lubricants, and precipitants, wherein the diluent is selected from microcrystalline cellulose, lactose monohydrate, anhydrous lactose, pregelatinized starch, mannitol, calcium hydrogen phosphate dihydrate, anhydrous calcium hydrogen phosphate, silicified starch, cellulose powder, starch, and combinations thereof. The disintegrant is selected from sodium carboxymethyl starch, croscarmellose sodium, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, alginate, calcium carboxymethyl cellulose, and combinations thereof; the adhesive is selected from polyvinylpyrrolidone, copolyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, sodium carboxymethyl cellulose, gelatin, and combinations thereof; the lubricant is selected from colloidal silica, hydrated silica, talc, and combinations thereof; and the lubricant is selected from magnesium stearate, sodium stearyl fumarate, glyceryl docosanoate, glyceryl palmitate, stearic acid, zinc stearate, calcium stearate, hydrogenated vegetable oil, and combinations thereof.

2. The oral preparation of diazepam as claimed in claim 1, wherein the oral preparation is an oral tablet.

3. An oral formulation of diazepam as requested in item 1 or 2, wherein 95% by weight or more than 95% by weight of the API is maintained at 40°C and 75% relative humidity for 6 months, or at 80°C and 75% relative humidity for 12 days, or at 25°C and 60% relative humidity for 1 year.

4. An oral formulation of diazepam as claimed in claim 3, wherein 99% by weight or more than 99% by weight of the API is maintained at 40°C and 75% relative humidity for 6 months, or at 80°C and 75% relative humidity for 12 days, or at 25°C and 60% relative humidity for 1 year.

5. An oral formulation of diazepam as claimed in claim 4, wherein 99.5% by weight or more than 99.5% by weight of the API is maintained at 40°C and 75% relative humidity for 6 months, or at 80°C and 75% relative humidity for 12 days, or at 25°C and 60% relative humidity for 1 year.

6. An oral preparation of diazepam as claimed in claim 1 or 2, wherein the oral preparation comprises a diluent, a disintegrant, a lubricant, and a slurry.

7. An oral preparation of diazepam as claimed in claim 1 or 2, wherein the oral preparation comprises a diluent, a disintegrant, a binder, a lubricant, and a slurry.

8. An oral preparation of diazepam as claimed in item 1 or 2, wherein the content of the API is 20 to 70% by weight based on 100% of the total weight of the preparation.

9. The oral preparation of diazepam as claimed in claim 8, wherein the content of the API is 30 to 50% by weight based on 100% by weight of the total preparation.

10. The oral preparation of diazepam as claimed in claim 9, wherein the content of the API is 40 to 50% by weight based on 100% by weight of the total preparation.

11. The oral preparation of tranquilizer according to claim 1 or 2, wherein, based on the total weight of the oral preparation, when present, the amount of the diluent is 30 to 50% by weight, the amount of the disintegrant is 1 to 30% by weight, the amount of the adhesive is 1 to 30% by weight, the amount of the lubricant is 0.1 to 10% by weight, and the amount of the lubricant is 0.1 to 10% by weight.

12. The oral preparation of tranquilizer according to claim 11, wherein, based on the total weight of the oral preparation, when present, the amount of the diluent is 40 to 50% by weight, the amount of the disintegrant is 1 to 5% by weight, the amount of the adhesive is 1 to 5% by weight, the amount of the lubricant is 0.5 to 4% by weight, and the amount of the lubricant is 0.5 to 4% by weight.

13. The oral preparation of diazepam 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, carboxymethyl starch sodium, polyvinylpyrrolidone, and combinations thereof; the binder is selected from copolyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone, and combinations thereof; the gliding agent is colloidal silica; and the lubricant is selected from magnesium stearate, sodium stearyl fumarate, and combinations thereof.

14. The oral preparation of diazepam according to claim 1 or 2, wherein, when present, the diluent is microcrystalline cellulose, the disintegrant is selected from croscarmellose sodium, carboxymethyl starch sodium, polyvinylpyrrolidone and combinations thereof, the binder is selected from copolyvinylpyrrolidone, hydroxypropyl cellulose, polyvinylpyrrolidone and combinations thereof, the gliding agent is colloidal silica, and the lubricant is selected from magnesium stearate, sodium stearyl fumarate and combinations thereof.

15. The oral formulation of diazepam according to claim 2, wherein the oral formulation comprises, by total weight: 45.5% of the active pharmaceutical ingredient (API), 47.6% of microcrystalline cellulose, 4.4% of polyvinylpyrrolidone, 0.5% of colloidal silica, and 2% of sodium stearate; or 45.5% of the active pharmaceutical ingredient (API), 43.6% of microcrystalline cellulose, 4.5% of polyvinylpyrrolidone, 4.5% of copolyvinylpyrrolidone, 1% of colloidal silica, and 0.8% of magnesium stearate; or 45.5% of the active pharmaceutical ingredient (API), 43.6% of microcrystalline cellulose, 4.5% of polyvinylpyrrolidone, 4.5% of copolyvinylpyrrolidone, 1% of colloidal silica, and 0.8% of magnesium stearate; or 45.5% of the active pharmaceutical ingredient (API). The active pharmaceutical ingredient (API) comprises 43.6% microcrystalline cellulose, 4.5% croscarmellose sodium, 4.5% polyvinylpyrrolidone, 1% colloidal silica, and 0.8% sodium stearate; or 45.5% active pharmaceutical ingredient (API), 43.6% microcrystalline cellulose, 4.5% sodium carboxymethyl starch, 4.5% hydroxypropyl cellulose, 1% colloidal silica, and 0.8% magnesium stearate; wherein, The API is 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

16. The oral preparation of diazepam 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, carboxymethyl starch sodium, polyvinylpyrrolidone, and combinations thereof; the binder is selected from copolyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone, and combinations thereof; and the lubricant is magnesium stearate.

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

10.

18. An oral formulation of diazepam as requested in item 1 or 2, wherein the content of the API is 50 mg per formulation.

19. An oral formulation of diazepam as claimed in item 1 or 2, wherein the content of the API is 100 mg per formulation.

20. An oral formulation of diazepam as requested in item 1 or 2, wherein the content of the API is 200 mg per formulation.

21. An oral formulation of diazepam as requested in item 1 or 2, wherein the content of the API is 300 mg per formulation.