Oral formulations comprising 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid and methods of preparing the same

Abstract

The present invention relates to an oral formulation comprising a high content of an API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof. The oral formulation according to the present invention has a high content as well as excellent physical properties by including a glidant in the excipient, and thus can increase economic efficiency and administration convenience.

Description

TECHNICAL FIELD

[0001] This application claims the priority benefit of Korean Patent Application No. 10-2020-0165790, filed on December 1, 2020, the entire disclosure of which is incorporated herein by reference in its entirety.

[0002] The present application relates to an oral preparation having excellent physical properties, which comprises a high content of an active pharmaceutical ingredient (API) selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, which is useful as a xanthine oxidase inhibitor capable of preventing the deposition of uric acid in the body, and a preparation method thereof. BACKGROUND

[0003] Xanthine oxidase is an enzyme that converts hypoxanthine into xanthine and also converts the formed xanthine into uric acid. It is known that when excessive uric acid is present in the body, it causes various diseases, including gout and the like.

[0004] Accordingly, a substance that inhibits the activity of xanthine oxidase can be effective in treating xanthine oxidase-related diseases, such as hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, joint disease, and inflammatory bowel disease.

[0005] Meanwhile, with respect to a substance that inhibits the activity of xanthine oxidase, KR 10-1751325 (Patent Document 1) provides 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid and a method of preparing the same, and KR 10-1424013 (Patent Document 2) provides different types of crystal forms obtained by using different solvents and a method of preparing the same.

[0006] [Formula 1]

[0007]

[0008] However, an oral preparation comprising 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API) has not been reported, and in particular, an oral preparation comprising a high content of the API has not been reported.

[0009] A preparation comprising a high content of an API in general cannot be said to have excellent flowability and tableting properties. Therefore, in order to overcome these disadvantages, a wet granulation method or a dry granulation method is generally used or the amount of an excipient is increased to reduce the API ratio.

[0010] However, there is a problem in that the granulation process for improving flowability increases the manufacturing time and production cost of the high content formulation, and increasing the amount of excipient increases the total weight and volume of the formulation. Thus, the conventional high content formulation increases the production cost and reduces the convenience of patient administration. In addition, even if the granulation process or the amount of excipient is added to prepare a high content formulation, the content of the formulation ingredients is affected by the imbalance between the excipient and the high content API, which is common knowledge in the art.

[0011] Therefore, it is necessary to develop an oral formulation having excellent physical properties when containing 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.

[0012] [Prior Art Documents]

[0013] [Patent Documents]

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

[0015] 2. KR 10-1424013 (July 22, 2014), 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid crystalline form and the producing method thereof SUMMARY

[0016] Technical problem

[0017] An object of the present application is to provide an oral formulation having excellent physical properties, which contains an excess amount of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API.

[0018] Technical solution

[0019] The present application provides an oral preparation having excellent physical properties and a method of preparing the same, the oral preparation comprising an API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof and excipients, particularly a glidant in the excipients.

[0020] The glidant contained in the oral preparation of the present application is SiO2 selected from colloidal silicon dioxide, hydrated silicon dioxide, and combinations thereof, and the content of the glidant in the preparation is 0.2 to 1% by weight or 0.2 to 0.8% by weight based on the total weight of the preparation.

[0021] The content of the API contained in the oral preparation of the present application is 30 to 50% by weight based on the total weight of the preparation.

[0022] The content of the API component of the oral preparation of the present application is 95% or more.

[0023] The oral preparation of the present application is used for the treatment or prevention of xanthine oxidase-related diseases selected from hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, joint disease, and inflammatory bowel disease.

[0024] Beneficial effects

[0025] The oral preparation comprising 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API according to the present application has excellent physical properties, and maintains a high preparation component content with a glidant in the excipient despite a high API content.

[0026] In addition, the oral preparation according to the present application 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, and thus is not only economical but also increases the convenience of administration. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 The API component content per unit tablet is shown as a function of the glidant (SiO2) content. DETAILED DESCRIPTION

[0028] The present application will be described in greater detail hereinafter.

[0029] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art associated with the present application. In addition, although preferred methods and samples are described herein, similar or equivalent alternatives are also encompassed within the scope of the present application. The disclosures of all publications referred to herein are incorporated by reference herein in their entirety.

[0030] The inventors of the present application have continuously researched in various ways to increase the API content in an oral formulation containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API and to maintain or increase the physical properties of the oral formulation. Accordingly, the inventors of the present application have developed an oral formulation having a high API content and excellent physical properties, which contains a glidant in an excipient.

[0031] In this case, even though it contains an excess of API compared to an oral formulation not containing a glidant, since the physical properties are maintained when formulated as a non-coated tablet, there is no need to increase the excipient content according to the increase in the API content, and thus it has the advantages of being economical and enabling the manufacture of a high content oral formulation and increasing the convenience of administration without increasing the size of the formulation. In addition, there is also the advantage that since it has a high API content, the quality of the final product is also excellent.

[0032] Accordingly, the present application provides an oral formulation containing a high content of an API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof and a glidant in an excipient.

[0033] As used herein, "pharmaceutically acceptable salt" refers to a salt form of a compound that does not cause significant irritation to an organism to which the compound is administered and does not abrogate the biological activity and physical properties of the compound. 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid, which is an API contained in the oral formulation of the present application, can be converted into a salt thereof by a conventional method.

[0034] As used herein, the term "API content" or "content" refers to the amount of an active ingredient in a formulation or tablet. The content is an important quality characteristic of the final product.

[0035] In an oral formulation such as a tablet or a granular capsule, even though a high content API is included, it is generally desirable to minimize the size of the unit dosage form so as to be easily swallowed. However, when a high content of API is included, not only are the physical properties such as flowability and tabletting properties generally impaired, but also the imbalance between the high content API and each excipient affects the content of the formulation, which is common technical knowledge to one of ordinary skill in the art.

[0036] In fact, in oral formulations containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid as an API, the acceptable content of the API in oral formulations (especially tablets) with pharmaceutically acceptable physical properties is only about 30%. When the content exceeds 30%, there is a problem of rapid deterioration of physical properties such as tableting performance.

[0037] In this invention, different studies are conducted on oral formulations that, despite containing high amounts of an API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, exhibit excellent or good physical stability by combining different excipients.

[0038] Therefore, oral formulations with high component content and excellent physical stability, including gliding agents as excipients, have been developed.

[0039] Therefore, one aspect of the present invention provides an oral formulation comprising i) 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API; and ii) a gliding agent in an excipient.

[0040] In this invention, the amount of the gliding agent contained in the total weight of the formulation may be greater than 0% by weight and less than 1% by weight, greater than 0.1% by weight and less than 1% by weight, greater than 0.2% by weight and less than 1% by weight, greater than 0% by weight and less than 0.9% by weight, greater than 0.1% by weight and less than 0.9% by weight, greater than 0.2% by weight and less than 0.9% by weight, greater than 0% by weight and less than 0.8% by weight, greater than 0.1% by weight and less than 0.8% by weight, or greater than 0.2% by weight and less than 0.8% by weight. Furthermore, the amount of the gliding agent contained in the total weight of the formulation may be 0.1% by weight, 0.2% by weight, 0.3% by weight, 0.4% by weight, 0.5% by weight, 0.6% by weight, 0.7% by weight, 0.8% by weight, or 0.9% by weight.

[0041] In this invention, the gliding agent may be selected from colloidal silica, hydrated silica, talc, and combinations thereof, but is not limited thereto. However, when talc is used as a gliding agent, since the hardness tends to decrease and the brittleness tends to increase when formulated into tablets, it is preferable to use SiO2 series such as colloidal silica, hydrated silica, or combinations thereof as gliding agents.

[0042] In this invention, the oral formulation further comprises one or more excipients selected from pharmaceutically acceptable diluents, disintegrants, binders, stabilizers, lubricants, etc.

[0043] The diluent, disintegrant, binder, stabilizer, lubricant, etc., can be any of those commonly known in the art. The amount of diluent used, based on the total weight of the oral formulation, can be 30% to 50% by weight, 40% to 50% by weight, or 45% to 50% by weight. The amount of disintegrant used, based on the total weight of the oral formulation, can range from 1% to 30% by weight, 1% to 20% by weight, 1% to 10% by weight, or 1% to 5% by weight. The amount of binder used, based on the total weight of the oral formulation, can range from 1% to 30% by weight, 1% to 20% by weight, 1% to 10% by weight, or 1% to 5% by weight. The amount of stabilizer 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. The amount of lubricant used, based on the total weight of the oral formulation, can be in the range of 0.1% to 10% by weight, 0.3% to 5% by weight, or 0.5% to 4% by weight.

[0044] For example, the diluent may be selected from microcrystalline cellulose (MCC), 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. The binder may be selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate, povidone, polyvinylpyrrolidone, copovidone, polyethylene glycol, sodium lauryl sulfate, light anhydrous silicate, 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 not limited to these. The stabilizer may be selected from BHT, BHA, ascorbic acid, tocopherol, EDTA, and mixtures thereof, but not limited to these. The lubricant may be selected from magnesium stearate, silica, talc, light anhydrous silicate, sodium stearoyl fumarate, and combinations thereof, but not limited to these.

[0045] The oral preparation can be administered once daily and can be taken daily.

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

[0047] Further, the amount of the contained API can 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 dosage form.

[0048] The amount of the contained API can be, for example, 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, or 455 mg per unit dosage form.

[0049] The API ingredient content in the formulation of the present application can be 95% to 105%, 96% to 105%, 97% to 105%, 98% to 105%, 99% to 105%, 100% to 105%, 95% to 100%, 96% to 100%, 97% to 100%, 97% to 100%, or 99% to 100%. Further, the API ingredient content can be 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more, and can be 105% or less, 104% or less, 103% or less, 102% or less, 101% or less, or 100% or less.

[0050] The "API ingredient content" refers to the content of pure API excluding impurities among the content of the API contained per unit dosage form. Specifically, it can have a similar meaning to the API purity.

[0051] The present application provides a method of preparing an oral formulation containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, the method comprising the steps of: i) mixing an API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof and a glidant to prepare a first mixture; ii) mixing a pharmaceutically acceptable excipient to prepare a second mixture; and iii) formulating the first mixture and the second mixture into an oral formulation.

[0052] In the preparation method of the present application, the step of preparing each of the first mixture and the second mixture includes a step of performing milling after mixing.

[0053] In the manufacturing method of the present application, the glidant in the first mixture includes SiO2 selected from colloidal silicon dioxide, hydrated silicon dioxide, and a combination thereof.

[0054] In the preparation method of the present application, the pharmaceutically acceptable excipient in the second mixture optionally includes the above excipient.

[0055] The API ingredient content and the ingredient content of the preparation prepared by the preparation method of the present application are the same as the above API ingredient content and the ingredient content of the oral preparation of the present application, respectively.

[0056] The oral preparation can be formulated according to any tablet preparation method or granule preparation method known in the art.

[0057] In addition, the present application provides a method for treating or preventing a human xanthine oxidase-related disease in a human by administering an oral preparation comprising 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API and a glidant.

[0058] As used in the present application, the term "human xanthine oxidase-related disease" means a disease that can be treated or prevented by inhibiting human xanthine oxidase, and can be, for example, hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, diabetes-related complications, kidney disease, inflammation, joint disease, inflammatory bowel disease, etc., but is not limited thereto. Examples of diabetes-related complications can be hyperlipidemia, arteriosclerosis, obesity, hypertension, retinopathy, renal failure, etc.

[0059] The term "treatment" means termination or delay of progression of a disease when used in a subject showing symptoms of the disease, and the term "prevention" means termination or delay of symptoms of a disease when administered to a subject not showing symptoms of the disease but at high risk of suffering from the disease.

[0060] Unless otherwise indicated, it will be understood that all numbers used herein to describe embodiments are approximate and can vary by the term "about." It is also to be understood that the terminology used herein is for the purpose of describing only the particular embodiments. It is not intended to be limiting. Any numerical values found in the specification and claims are approximations and can vary. Unless otherwise stated, the numerical values set forth in the specification and claims are approximations that can vary depending on the numerical values of the numerical values.

[0061] [Examples and Experimental Examples]

[0062] Each evaluation of the examples and comparative examples was performed as follows.

[0063] [Flowability Analysis]

[0064] The bulk and tap densities of the mixtures (powders) used to prepare the uncoated tablets of the Examples and Comparative Examples were measured. The bulk density is the volume of about 50 g of granular powder when placed in a graduated cylinder, while the tap density is measured when the volume no longer changes after the graduated cylinder is tapped 100 times on a floor at a constant height. The bulk density refers to the volume occupied by a certain mass of powder, meaning the sum of the volume of the powder and the volume of the inter-particle voids, i.e. the total volume.

[0065] The flowability of the mixtures was calculated as the Carr Index in equation (1) using the bulk and tap densities measured according to the method of Jinapong et al. (2008).

[0066] Equation (1):

[0067] The Carr Index is a measure of the compressibility of a powder, defined as the percentage of (tap density - bulk density) / tap density. A higher index means that the powder is more compact and has poor flowability.

[0068] The following table shows the classification of powder flowability according to the Carr Index.

[0069] Table 1:

[0070] Karl index (% of flowability) Flowability <10 Excellent 11～15 Good 16～20 Fair 21～25 Average 26～31 Poor 32～38 Very poor >38 Very, very poor

[0071] [Hardness and friability analysis]

[0072] Hardness and friability were used as indices that can predict tablet attrition during handling and coating of uncoated tablets after compression.

[0073] For the friability test, an amount of tablets close to about 5 g were used, the powder adhering to the tablets was removed, the mass was accurately measured, and then the tablets were placed in the rotating drum of the friability tester. After the drum was rotated 100 times, the tablets were removed, the powder adhering to the tablets was removed as at the start, and the mass was accurately measured.

[0074] Friability (%) = (mass before test - mass after test) / (mass before test) x 100

[0075] In the case of the hardness test, one tablet was placed in a benchtop hardness tester to measure the hardness, and this was repeated for 10 tablets to measure the average hardness.

[0076] [Disintegration time analysis]

[0077] Disintegration time is an index that affects in vivo dissolution and absorption after ingestion of a preparation.

[0078] After the disintegration tester was sufficiently filled with purified water, it was adjusted to 37 ± 2℃. Four sample tablets were placed in the square glass tube of the disintegration tester, it was operated in a prescribed manner, and the time for the tablet to completely disintegrate and disappear was measured to obtain an average value.

[0079] [Component Content Analysis]

[0080] The component content test was performed to evaluate the component content of the prepared formulation. The component content is an important quality characteristic of the final product, which measures the average component content of the API of the uncoated tablet.

[0081] <Analysis Conditions>

[0082] Preparation of mobile phase: acetonitrile (500 ml) + purified water (500 ml) + TFA (1 ml)

[0083] Preparation of diluent: methanol (900 ml) + purified water (100 ml)

[0084] Preparation of standard solution and test solution: After the standard and sample were completely dissolved in the diluent, they were analyzed according to the following UPLC analysis method.

[0085] Column: Waters CSH C18 (2.1 mm I.D. x 100 mm L, particle size 1.7 μm

[0086] Column temperature: 40℃

[0087] Mobile phase: acetonitrile / H2O / TFA = 500 / 500 / 1 (v / v / v)

[0088] Flow rate: 0.35 ml / min

[0089] Detection: 258 nm uv

[0090] Sample amount: 1 μl

[0091] Analysis time: 6 minutes

[0092] [Rate of Dissolution Analysis]

[0093] The dissolution of the uncoated tablets of the following examples and comparative examples was tested according to the dissolution test method of the 10th revised edition of the Korean Pharmacopoeia. The dissolution method was the paddle method, the stirring speed was 50 rpm, and the dissolution temperature was 37 ± 0.5℃. The eluent was 900 ml of pH 6.8 phosphate buffer.

[0094] For the analysis conditions, the solution obtained from the above dissolution test was filtered through a 0.45 μm filter, and the concentration of 1-(3-cyano-1-isopropyl-indol-5-yl) pyrazole-4-carboxylic acid as the API was analyzed using the UPLC method.

[0095] <Analysis Conditions>

[0096] The analysis conditions were the same as the composition content analysis method.

[0097] [Examples 1 to 8 and Comparative Example 1]

[0098] The formulations of Examples 1 to 8 and Comparative Example 1 were prepared as uncoated tablets using the ingredients shown in Tables 2 to 4 below at the respective contents.

[0099] Specifically, 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (API) and a glidant were mixed and milled to prepare a first mixture. A diluent, a disintegrant, and a lubricant, i.e., components not included in the first mixture, were mixed and milled to prepare a second mixture.

[0100] In the case of Examples 1 to 8 including a glidant, after the first mixture was mixed with the second mixture, the mixture was tabletted using a rotary tablet press (Modul P, GEA, Belgium) under conditions of a pre-pressure of 5.0 kN and a main pressure of 14 to 15 kN to obtain uncoated tablets. In the case of Comparative Example 1 not including a glidant, the process of preparing mixture 1 was omitted, 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (API) and all excipients were mixed and milled, and then tabletted in the same manner as Example 1 to prepare uncoated tablets.

[0101] (If colloidal silicon dioxide is used as a glidant, it is expressed as "SiO2". MCC 102 used as a diluent is a microcrystalline cellulose component. Magnesium stearate used as a lubricant is a commercial name, and is a sodium stearyl fumarate component).

[0102] Table 2:

[0103]

[0104] Table 3:

[0105]

[0106] Table 4:

[0107]

[0108] Experimental Example 1: Analysis of the properties of formulations with changes in the content of a glidant

[0109] ​The physical properties of oral formulations containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid as an API with or without and with varying contents of SiO2glidant as an excipient were analyzed by the above-mentioned analysis methods.

[0110] Specifically, the physical properties of the pre-formulation mixture state (bulk density, tapped density, and Carr index) and the physical properties of the uncoated tablet state after tableting the mixture (hardness, friability, disintegration time, ingredient content, and dissolution rate) were analyzed. The results are summarized in Table 5 below.

[0111] The bulk density, tapped density, and Carr index did not show any significant difference with or without and with varying contents of glidant (SiO2) in the mixture state before preparing the uncoated tablet.

[0112] It is known that when a glidant is added to a conventional pharmaceutical formulation, the flowability is improved. However, in the case of the API (1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid) of the present application, even when the glidant is contained, the flowability is not significantly increased.

[0113] However, as a result of measuring the hardness and friability of the uncoated tablet, when SiO2was contained (Examples 1 to 4), the hardness was 6.7 kP or more, which satisfied the target hardness of 6.0 kP for the uncoated tablet. On the other hand, in the case of Comparative Example 1, it was only 5.4 kP, which did not reach the target hardness of the uncoated tablet, making it unsuitable for formulation into a tablet (Table 5).

[0114] In addition, as a result of measuring the API ingredient content of the uncoated tablet, as shown in Table 5 and Figure 1 below, in Comparative Example 1, the average ingredient content was 95.3%, when 0.2 to 0.8 wt% SiO2was contained, it increased to 98.8 to 99.4% (Examples 1 to 3). However, in Example 4 containing 1 wt% SiO2, like Comparative Example 1, it decreased to 94.8%, indicating that the preferred content range of SiO2was 0.2 to 0.8 wt% based on the total weight of the formulation.

[0115] Further, in the case of the dissolution rate, Comparative Example 1 had low hardness, so it showed early dissolution, but then showed a constant dissolution rate. However, when SiO2was contained, the slope showed a constant increase, and in particular, Example 2 (containing 0.5 wt% SiO2) showed the highest tendency for the 60-minute dissolution rate (Table 5).

[0116] Table 5

[0117]

[0118] Experimental Example 2: Analysis of properties of formulations according to flow agent type

[0119] To analyze the properties according to flow agent type, the physical properties of Example 2 and Example 5 were analyzed. In Table 5, Example 2 showed the best physical properties, while Example 5 was prepared by changing SiO2 to talc while maintaining the flow agent content (0.5 wt%) of Example 2.

[0120] As shown in Table 6 below, in the case of Example 5 in which talc was included as a flow agent in the state of a mixture before preparing a non-coated tablet, the bulk density did not show a difference compared to Example 2 and Comparative Example 1, but the Carr index was calculated as 28%. Thus, in the case of Example 5, the Carr index was in the "poor" category, and it was not suitable for direct tableting. In addition, in the case of Example 5, the hardness of the non-coated tablet was 5.1 kP, which did not reach the target hardness of 6.0 kP, and the friability was also three times that of Example 2, so it had physical properties that were not suitable as a tablet.

[0121] As can be seen, the average ingredient content of Example 5 was also reduced compared to Example 2.

[0122] Thus, as can be seen, when SiO2 is used as a flow agent, the overall physical properties are improved compared to talc.

[0123] Table 6:

[0124]

[0125] Experimental Example 3: Analysis of properties according to API content

[0126] To prepare a non-coated tablet containing 50 wt% or more of an API, the properties were analyzed according to an increase in the API content (Examples 6 to 8) based on the content of Example 2 (45.5 wt%).

[0127] According to Table 7, because the density of the API increases compared to the diluent as the API content increases, the bulk density tends to slightly increase as the API content increases, but the flowability itself does not show a significant difference.

[0128] However, as the API content increases, the hardness of the non-coated tablet is weakened, and the friability increases due to a decrease in tableting performance (a decrease in tablet compressibility), and in particular, Example 8 (API content: 60 wt%) showed a hardness of 3.0 kP and a friability of 0.2% or more, so it was not suitable for formulation into a tablet (Table 7).

[0129] Furthermore, as a result of measuring the API content of the uncoated tablets, Examples 2, 6, and 7 showed an average component content of over 99%, while Example 8 showed an average component content of 94.6% (Table 7).

[0130] In summary, when the API content is below 55% by weight, the average component content is above 99%. However, when the API content is 60% by weight, the average component content drops significantly to 94.6%. When the API content exceeds 50% by weight, although the content is excellent, the hardness of the uncoated tablets decreases and the brittleness increases. Therefore, it is evident that when the API content is above 55% by weight, formulation into tablets is not ideal.

[0131] Table 7:

[0132]

[0133] So far, the preferred embodiments of the present invention have been examined. Those skilled in the art will understand that the present invention can be implemented in modified forms without departing from its essential characteristics. Therefore, the embodiments disclosed above should be considered illustrative rather than restrictive. The scope of the present invention is specified in the claims rather than in the foregoing description, and all differences within their equivalents should be considered to be included within the present invention.

Claims

1. An oral formulation comprising an active pharmaceutical ingredient (API) selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof; a gliding agent; and one or more excipients selected from diluents, disintegrants, binders, and lubricants. The flow aid is selected from colloidal silica, hydrated silica, and combinations thereof. The content of the gliding agent, based on the total weight of the formulation, is greater than 0.2% by weight and less than 0.8% by weight. The API content is 30% to 50% by weight, based on the total weight of the formulation, and The API content mentioned therein is 97% or higher. in, The oral formulation is prepared by a method comprising the following steps: i) Mix the API with the gliding agent to prepare a first mixture; ii) Mixing the excipients to prepare a second mixture; and iii) The first mixture and the second mixture are mixed and formulated into the oral preparation.

2. The oral formulation according to claim 1, wherein the content of the gliding agent is 0.5% by weight based on the total weight of the formulation.

3. The oral formulation according to claim 1, wherein the content of the API is 40% to 50% by weight, based on the total weight of the formulation.

4. The oral formulation according to claim 1, wherein the content of the API is 50 mg, 100 mg, 200 mg or 300 mg per unit dosage form.

5. The oral formulation according to any one of claims 1 to 4, wherein The diluent is selected from microcrystalline cellulose, lactose, starch, mannitol, carboxymethyl cellulose, sorbitol, and combinations thereof. The disintegrants are selected from low-substituted hydroxypropyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, sodium glycolate starch, etc. and its combinations, The adhesive is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate, polyvinylpyrrolidone, copovidone, polyethylene glycol, sodium lauryl sulfate, light anhydrous silicate, synthetic aluminum silicate, calcium silicate, magnesium metaaluminate, dicalcium phosphate, calcium carbonate, pregelatinized starch, gum arabic, gelatin, ethyl cellulose, and mixtures thereof, and / or The lubricant is selected from magnesium stearate, silicon dioxide, talc, sodium stearoyl fumarate and combinations thereof.

6. The oral formulation according to claim 5, wherein the diluent lactose is lactose monohydrate or anhydrous lactose, and / or the lubricant silica is light anhydrous silicic acid.

7. The oral formulation according to any one of claims 1 to 4, wherein, Based on the total weight of the oral formulation, The amount of diluent used is in the range of 40% to 50% by weight or 45% to 50% by weight. The amount of disintegrant used is in the range of 1% to 5% by weight. The amount of adhesive used is in the range of 1% to 5% by weight, and / or The amount of lubricant used is in the range of 0.5% to 4% by weight.

8. The oral formulation according to any one of claims 1 to 4, wherein, in addition to the gliding agent, it further comprises a diluent, a disintegrant, and a lubricant.

9. The oral formulation according to claim 8, wherein, Based on the total weight of the oral formulation, The amount of diluent used is in the range of 45% to 50% by weight. The amount of disintegrant used ranges from 1% to 5% by weight, and The amount of lubricant used is in the range of 0.5% to 4% by weight.

10. The oral formulation according to claim 8, wherein the diluent is microcrystalline cellulose, the disintegrant is crospovidone, and the lubricant is sodium stearoyl fumarate.

11. The oral formulation according to claim 1, comprising a composition selected from the following:

12. A method for preparing an oral formulation comprising 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, the method comprising the steps of: i) Prepare a first mixture by mixing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, which is an API, with a gliding agent; ii) mixing pharmaceutically acceptable excipients to prepare a second mixture; and iii) Formulate the first mixture and the second mixture into an oral formulation. The flow aid is selected from colloidal silica, hydrated silica, and combinations thereof. The content of the gliding agent, based on the total weight of the formulation, is greater than 0.2% by weight and less than 0.8% by weight. The API content is 30% to 50% by weight, based on the total weight of the formulation, and The API content is above 97%.

13. The method for preparing an oral formulation according to claim 12, wherein the content of the gliding agent is 0.5% by weight based on the total weight of the formulation.

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

15. The method for preparing an oral formulation according to claim 12, wherein the pharmaceutically acceptable excipient is a diluent, a disintegrant, or a lubricant.

16. The method for preparing an oral formulation according to claim 15, wherein, Based on the total weight of the oral formulation, The amount of diluent used is in the range of 45% to 50% by weight. The amount of disintegrant used ranges from 1% to 5% by weight, and The amount of lubricant used is in the range of 0.5% to 4% by weight.

17. The method for preparing an oral formulation according to claim 15 or 16, wherein the diluent is microcrystalline cellulose, the disintegrant is crospovidone, and the lubricant is sodium stearoyl fumarate.

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