Oral preparations containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazol-4-carboxylic

Abstract

The invention relates to a mixed oral preparation containing an active ingredient (API) selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazol-4-carboxylic acid or its pharmaceutical salt, wherein the API has a particle size corresponding to 90% of the maximum particle size in the cumulative particle size distribution (D(0,9)) which is between 80 µm or greater and 300 µm or less. By adjusting the particle size of the API to a certain range, the mixed oral preparation according to the invention has high hardness and increased average dissolution rate even when containing API at high concentrations.

Description

Oral preparation containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid

[0001] This application claims the benefit of priority to Korean Patent Application No. 10-2021-0049613, filed April 16, 2021, which is incorporated herein by reference in its entirety.

[0002] The present invention relates to an oral preparation containing a high content of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid, while having excellent physical properties.

[0003] Xanthine oxidase is an enzyme that converts hypoxanthine into xanthine and also converts the formed xanthine into uric acid. A substance that inhibits the activity of xanthine oxidase can effectively treat diseases related to uric acid accumulation, such as hyperuricemia, gout, heart failure, and cardiovascular disease.

[0004] Meanwhile, with regard to substances that inhibit the activity of xanthine oxidase, Korean Patent Publication No. 1751325 (Patent Document 1) provides 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (chemical formula 1 below) and a method for preparing the compound, and Korean Patent Publication No. 1424013 (Patent Document 2) provides various types of crystal forms obtained using various solvents and a method for preparing the same.

[0005] [Chemical Formula 1]

[0006]

[0007] However, there has been no report on an oral preparation containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid of the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API), and in particular, there has been no report on an oral preparation containing a high content of the API.

[0008] Formulations containing a high content of API generally do not have excellent basic physical properties such as hardness and tabletability, so to overcome these shortcomings, they are generally manufactured using wet granulation or dry granulation methods, or by increasing the amount of excipients to lower the proportion of API.

[0009] However, by performing a granulation process to improve the fluidity of the high-content formulation, not only can the manufacturing time and production cost increase, but there is also a problem of increasing the total weight and volume of the formulation by increasing the amount of excipients, thereby increasing the production cost and reducing patient compliance.

[0010] Furthermore, for oral formulations, bioavailability is crucial when providing oral tablets for ease of administration and production costs. A key factor influencing bioavailability is the drug's in vivo dissolution process, which can be indirectly determined through dissolution rate testing in the laboratory.

[0011] However, since high-content formulations inevitably have lower excipient content than low-content formulations, their physical properties are usually deteriorated.

[0012] Therefore, there is a need to develop an oral formulation 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, while having excellent physical properties and a high dissolution rate.

[0013] [Prior Art Literature]

[0014] (Patent Document 1) 1. Republic of Korea Patent Publication No. 1751325 (June 21, 2017), Novel compound effective as xanthine oxidase inhibitor, method for preparing same, and pharmaceutical composition containing same

[0015] (Patent Document 2) 2. Korean Patent Publication No. 1424013 (July 22, 2014), Crystalline form of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid and its preparation method

[0016] The problem to be solved by the present invention is to derive an oral formulation having excellent physical properties and a high dissolution rate while containing an excess amount of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as API.

[0017] The present invention provides an oral preparation having excellent physical properties and a method for producing the oral preparation, by including an API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, particularly an API having a specific particle size range.

[0018] The API included in the oral preparation of the present invention has a particle size (D(0.9)) for granules corresponding to 90% of the maximum particle size in the particle size cumulative distribution of 80 ㎛ or more and 300 ㎛ or less, or 120 ㎛ or more and 270 ㎛ or less.

[0019] The oral preparation of the present invention uses 900 ml of a pH 6.8 buffer as a dissolution medium, and when a paddle with a rotation speed of 50 rpm is used, the dissolution rate at 15 minutes is 70% or more, the dissolution rate at 30 minutes is 85% or more, and the dissolution rate at 60 minutes is 89% or more.

[0020] The content of API included in the oral preparation of the present invention is 30 to 50 wt% based on the total weight of the preparation.

[0021] The API content of the oral preparation of the present invention is 95 to 105%.

[0022] The oral formulation of the present invention is used for the treatment or prevention of xanthine oxidase-related diseases selected from the group consisting of hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammatory and joint disease, and inflammatory bowel disease.

[0023] The oral preparation comprising 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as API according to the present invention has excellent physical properties despite a high API content by adjusting the particle size of the API to a specific range, thereby preventing problems that may occur during the manufacturing process.

[0024] In addition, the oral preparation according to the present invention contains a high content of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, which is an API, and is therefore not only economical but also expected to have increased bioavailability due to a high dissolution rate.

[0025] Figure 1 shows the results of analyzing the wear rate (%) of the tablet according to the particle size distribution of the API.

[0026] Figure 2 shows the results of analyzing the dissolution rate (%) of the tablet according to the particle size distribution of the API.

[0027] Hereinafter, the present invention will be described in more detail.

[0028] Unless otherwise defined, all technical terms used in this invention have the same meaning as commonly understood by those of ordinary skill in the relevant field. Furthermore, while preferred methods and samples are described herein, similar or equivalent methods are also included within the scope of the present invention. The contents of all publications cited as references herein are incorporated herein by reference in their entirety.

[0029] The present inventors have conducted research on various methods to increase the content of API and maintain or increase the physical properties of an oral preparation containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as API, and as a result, have developed an oral preparation having excellent physical properties and excellent dissolution rate when the particle size of the API is controlled within a specific range.

[0030] In this case, by adjusting the particle size of the API to a specific range, the physical properties such as flowability are maintained, and when formulated as a tablet (tablet), the physical properties such as hardness and friability are excellent, so it is not only economical, but also does not require increasing the content of a separate excipient to improve the physical properties even though it contains a high content of API, and the tablet has the advantage of having excellent content and uniformity and a high dissolution rate.

[0031] Accordingly, the present invention provides an oral preparation having excellent physical properties and a high dissolution rate by adjusting the particle size of an API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof to a specific range.

[0032] In the present invention, "pharmaceutically acceptable salt" refers to a salt form of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid, the API included in the oral formulation of the present invention, can be converted into its salt by conventional methods.

[0033] In oral formulations such as tablets or granular capsules, it is common to try to minimize the size per unit dosage form even if it contains a high content of API for easy swallowing. However, it is common knowledge of a person having ordinary skill in the art to which this invention pertains that when API is contained in a high content, not only are physical properties such as fluidity and tabletability generally impaired, but also bioavailability represented by the dissolution rate may be affected.

[0034] In fact, in oral preparations containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid as API, the acceptable content of API in oral preparations (especially tablets) with pharmaceutically acceptable properties is only about 30%, and when the content exceeds that, there is a problem that physical properties such as tabletability rapidly deteriorate.

[0035] In the present invention, a multi-faceted study was conducted on an oral formulation containing a high content of API selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, while having excellent or good bioavailability represented by physical stability and dissolution rate.

[0036] The particle size distribution of API is known to be an important characteristic in the manufacturing process, affecting compressibility during the tableting process. Furthermore, the particle size distribution of API is a critical characteristic that influences solubility and thus the dissolution of the finished product. To ensure the desired dissolution pattern in the finished product, the particle size distribution of the API was adjusted in the present invention.

[0037] As a result, by adjusting the particle size distribution of the API, an oral formulation was developed that not only had excellent physical stability but also had an excellent dissolution rate despite containing a high content of API.

[0038] 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 API, and ii) a particle size (D(0.9)) of the API of 80 ㎛ or more and 300 ㎛ or less.

[0039] In the present invention, the particle size (D(0.9)) for granules corresponding to 90% of the maximum particle size in the cumulative particle size distribution of API is 80 ㎛ or more and 300 ㎛ or less, 90 ㎛ or more and 300 ㎛ or less, 100 ㎛ or more and 300 ㎛ or less, 110 ㎛ or more and 300 ㎛ or less, 120 ㎛ or more and 300 ㎛ or less, 130 ㎛ or more and 300 ㎛ or less, 140 ㎛ or more and 300 ㎛ or less, 150 ㎛ or more and 300 ㎛ or less, 80 ㎛ or more and 270 ㎛ or less, 90 ㎛ or more and 270 ㎛ or less, 100 ㎛ or more and 270 ㎛ or less, 110 ㎛ or more and 270 ㎛ or less, 120 ㎛ or more and 270 ㎛ or less, 130 ㎛ or more and 270 ㎛ Below, 140 ㎛ or more and 270 ㎛ or less, 150 ㎛ or more and 270 ㎛ or less, 80 ㎛ or more and 250 ㎛ or less, 90 ㎛ or more and 250 ㎛ or less, 100 ㎛ or more and 250 ㎛ or less, 110 ㎛ or more and 250 ㎛ or less, 120 ㎛ or more and 250 ㎛ or less, 130 ㎛ or more and 250 ㎛ or less, 140 ㎛ or more and 250 ㎛ or less, 150 ㎛ or more and 250 ㎛ or less, 80 ㎛ or more and 230 ㎛ or less, 90 ㎛ or more and 230 ㎛ or less, 100 ㎛ or more and 230 ㎛ or less, 110 ㎛ or more and 230 ㎛ or less, 120 ㎛ or more and 230 ㎛ or less, 130 ㎛ or more and 230 ㎛ or less, 140 ㎛ or more It may be 230 ㎛ or less, or 150 ㎛ or more and 230 ㎛ or less.

[0040] In addition, in the cumulative particle size distribution of API, the particle size (D(0.5)) for the granules corresponding to 50% of the maximum particle size is 30 ㎛ or more and 150 ㎛ or less, 40 ㎛ or more and 150 ㎛ or less, 50 ㎛ or more and 150 ㎛ or less, 60 ㎛ or more and 150 ㎛ or less, 70 ㎛ or more and 150 ㎛ or less, 80 ㎛ or more and 150 ㎛ or less, 30 ㎛ or more and 140 ㎛ or less, 40 ㎛ or more and 140 ㎛ or less, 50 ㎛ or more and 140 ㎛ or less, 60 ㎛ or more and 140 ㎛ or less, 70 ㎛ or more and 140 ㎛ or less, 80 ㎛ or more and 140 ㎛ or less, 30 ㎛ or more and 130 ㎛ or less, 40 ㎛ or more and 130 ㎛ or less, 50 ㎛ or more and 130 It may be ㎛ or less, 60 ㎛ or more and 130 ㎛ or less, 70 ㎛ or more and 130 ㎛ or less, or 80 ㎛ or more and 130 ㎛ or less.

[0041] In addition, the particle size (D(0.1)) for granules corresponding to 10% of the maximum particle size in the cumulative particle size distribution of the API may be 10 ㎛ or more and 90 ㎛ or less, 20 ㎛ or more and 90 ㎛ or less, 30 ㎛ or more and 90 ㎛ or less, 40 ㎛ or more and 90 ㎛ or less, 50 ㎛ or more and 90 ㎛ or less, 10 ㎛ or more and 80 ㎛ or less, 20 ㎛ or more and 80 ㎛ or less, 30 ㎛ or more and 80 ㎛ or less, 40 ㎛ or more and 80 ㎛ or less, or 50 ㎛ or more and 80 ㎛ or less.

[0042] The oral formulation of the present invention has excellent hardness and low friability because the API has a particle size of D(0.9) of 80 ㎛ or more and 300 ㎛ or less. As a result, there is an advantage in that the productivity of the oral formulation (tablet) containing the particle size-controlled API of the present invention can be increased by reducing the possibility of tablet wear during the handling and coating processes of the tablet.

[0043] The oral preparation of the present invention has excellent content and uniformity of 95% or more and also has excellent disintegration time.

[0044] The oral preparation of the present invention uses 900 ml of a pH 6.8 buffer as a dissolution medium and, when using a paddle with a rotation speed of 50 rpm, has a dissolution rate of 70% or more at 15 minutes, a dissolution rate of 85% or more at 30 minutes, and a dissolution rate of 89% or more at 60 minutes, showing a dissolution rate superior to that of an oral preparation having an API of D(0.9) 325 μm or more.

[0045] In addition, the oral preparation of the present invention uses 900 ml of a pH 6.8 buffer as a dissolution medium and has a dissolution rate of 89% or more in 60 minutes when using a paddle with a rotation speed of 50 rpm.

[0046] Therefore, since the oral formulation of the present invention has an excellent dissolution rate, it can be expected that the bioavailability will also be excellent reflecting this.

[0047] In the present invention, the oral preparation further includes one or more excipients selected from pharmaceutically acceptable diluents, disintegrants, glidants, lubricants, etc.

[0048] Any excipients commonly known to be used in the art, such as the diluent, disintegrant, fluidizing agent, and lubricant, may be used. The diluent may be used in an amount of 30 to 50 wt%, 40 to 50 wt%, or 45 to 50 wt%, based on the total weight of the oral formulation. The disintegrant may be used in an amount of 1 to 10 wt% or 1 to 5 wt%, based on the total weight of the oral formulation. The fluidizing agent may be used in an amount of 0.1 to 5 wt%, 0.2 to 3 wt%, or 0.3 to 2 wt%, based on the total weight of the oral formulation. The lubricant may be used in an amount of 0.1 to 10 wt%, 0.3 to 5 wt%, or 0.5 to 4 wt%, based on the total weight of the oral formulation.

[0049] For example, the diluent may be selected from the group consisting of microcrystalline cellulose (MCC), lactose monohydrate, lactose anhydrous, lactose, starch, mannitol, carboxymethylcellulose, sorbitol, and combinations thereof, but is not limited thereto. The disintegrant may be selected from the group consisting of low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, F-melt, and combinations thereof, but is not limited thereto. The fluidizing agent may be selected from the group consisting of talc, silicon dioxide, and mixtures thereof, but is not limited thereto. The glidant may be selected from the group consisting of magnesium stearate, silicon dioxide, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof, but is not limited thereto.

[0050] The above oral preparation can be administered once a day and can be taken daily.

[0051] The content of API included in the oral preparation is 30 to 50 wt%, 35 to 50 wt%, 40 to 50 wt%, 45 to 50 wt%, 30 to 45 wt%, 35 to 45 wt%, 40 to 45 wt%, 30 to 40 wt%, or 35 to 40 wt% based on the total weight of the oral preparation.

[0052] The API may comprise 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.

[0053] The above API may contain, for example, 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg or 455 mg per unit dosage form.

[0054] The API content included in the formulation of the present invention may be included as 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%, 98% to 100%, or 99% to 100%. In addition, the API content may be included as 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more, and may be included as 105% or less, 104% or less, 103% or less, 102% or less, 101% or less, or 100% or less.

[0055] The oral formulation of the present invention can be prepared by any method known in the art, wherein the active pharmaceutical ingredient (API) is selected from 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof having a particle size distribution of D(0.9).

[0056] The present invention provides a pharmaceutical composition for treating or preventing a human xanthine oxidase-related disease using an oral formulation comprising the above-mentioned 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API and a fluidizing agent.

[0057] The present invention provides a method for treating or preventing a human xanthine oxidase-related disease using an oral formulation comprising the above-mentioned 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API and a fluidizing agent.

[0058] The present invention provides a use for preparing a pharmaceutical composition for treating or preventing a human xanthine oxidase-related disease using the above 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API.

[0059] The “human xanthine oxidase-related disease” of the present invention refers to a disease that can be treated or prevented by inhibiting human xanthine oxidase, and includes, for example, hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, diabetes-related complications, kidney disease, joint disease, inflammatory bowel disease, etc., but is not limited to the diseases mentioned above. Examples of the diabetes-related complications include hyperlipidemia, arteriosclerosis, obesity, hypertension, retinopathy, renal failure, etc.

[0060] The above “treatment” means stopping or delaying the progression of a disease when used on a subject showing symptoms of the disease, and the above “prevention” means stopping or delaying the signs of the disease when used on a subject not showing symptoms of the disease but at a high risk of such.

[0061] Unless otherwise indicated, all numbers used in this specification and claims, whether stated or not, should be understood as being modified by the term "about" in all instances. Furthermore, it should be understood that the precise numbers used in this specification and claims form additional embodiments of the present disclosure. Efforts have been made to ensure the accuracy of the numbers set forth in the examples. However, all measured numbers may inherently contain certain errors resulting from the standard deviation inherent in their respective measurement techniques.

[0062] Various evaluations in the examples and comparative examples were conducted as follows.

[0063]

[0064] [Particle size analysis]

[0065] The particle size distribution of the API used in the examples and comparative examples was measured by a dry method using a laser diffraction particle size analyzer. Here, D(0.1), D(0.5), and D(0.9) represent the particle sizes of particles that rank 10%, 50%, and 90% of the total number of particles, respectively, when the measured particles are arranged in order of smallest to largest particle size.

[0066]

[0067] [Hardness and wear analysis]

[0068] Hardness and friability are used as indicators to predict tablet wear and tear in the handling and coating fixation of tablets after tableting.

[0069] For the friability test, take an amount close to 5g, remove any powder attached to the tablet, precisely measure the mass, and place it in the drum of the friability tester. After rotating the drum 100 times, remove the tablet, and, as before, remove any powder attached to the tablet, and precisely measure the mass.

[0070] Friability (%) = (mass before test - mass after test) / (mass before test) X 100

[0071] For the hardness test, place one tablet in a table hardness meter to measure the hardness, and repeat this method for 10 tablets to use the average hardness.

[0072]

[0073] [Disintegration Time Analysis]

[0074] Disintegration time is an indicator that affects the dissolution and absorption in the body after ingestion of the formulation.

[0075] After filling the disintegration tester with sufficient purified water, adjust the temperature to 37±2℃. Place four test tablets in each glass tube of the disintegration tester, operate it according to the prescribed method, and measure the time until the tablets completely disintegrate and disappear, and use the average value.

[0076]

[0077]

[0078] [Content Analysis]

[0079] A content test was conducted to evaluate the content of the formulated formulation. Content is a key quality characteristic of the final product, and the average API content of the tablet was measured.

[0080] <Analysis Conditions>

[0081] Preparation of mobile phase: Acetonitrile (500 ml) + purified water (500 ml) + TFA (1 ml)

[0082] Preparation of diluted solution: Methanol (900 ml) + purified water (100 ml)

[0083] Preparation of standard and test solutions: Completely dissolve the standard and test solution in the diluent and then analyze according to the UPLC analysis method below.

[0084] Column: Waters CSH C18 (2.1 ㎜ ID

[0085] Column temperature: 40℃

[0086] Mobile phase: Acetonitrile / H2O / TFA = 500 / 500 / 1 (v / v / v)

[0087] Flow rate: 0.35 ml / min

[0088] Detection: 258 nm UV

[0089] Sample volume: 1 μl

[0090] Analysis time: 6 minutes

[0091]

[0092] [Dissolution rate analysis]

[0093] The following examples and comparative examples were tested for dissolution according to the dissolution test method of the 10th revision of the Korean Pharmacopoeia. The dissolution test method used was the paddle method, the stirring speed was 50 rpm, and the dissolution temperature was 37±0.5 o It was performed in C. The elution was performed in 900 ml of pH 6.8 phosphate buffer.

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

[0095] <Analysis Conditions>

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

[0097]

[0098] [Examples and Comparative Examples]

[0099] The tablets of the examples and comparative examples were manufactured into preparations (tablets) using the ingredients listed in Table 1 below in the corresponding amounts.

[0100] A first mixture is prepared by mixing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (API) and a fluidizing agent having respective particle size distributions and milling them. Thereafter, a diluent, a disintegrant, and a lubricant, which are not included in the first mixture, are mixed and milled to prepare a second mixture.

[0101] After mixing the first mixture and the second mixture, tableting is performed using a rotary tablet press (Modul P, GEA, Belgium) under the conditions of preload: 5.0 kN and main pressure: 14 to 15 kN to manufacture a tablet.

[0102] PRUV®, used as a lubricant, is a trade name and contains the ingredient sodium stearyl fumarate.

[0103] Classification Ingredients Example 1 Example 2 Comparative Example 1 Content (mg / T) Content Ratio (%) Content (mg / T) Content Ratio (%) Content (mg / T) Content Ratio (%) API 100.045.5 100.045.5 100.045.5 D (0.1) 1470 118 D (0.5) 47 126 203 D (0.9) 10 123 1325 Diluent MCC 102 (microcrystalline cellulose) 104.847.6 104.847.6 104.847.6 Disintegrant Crospovidone 9.7 4.4 9.7 4.4 9.7 4.4 Fluidizing agent Colloidal silicon dioxide (SiO2) 1.10.5 1.10.5 1.10.5 Lubricant PRUV® 4.4 2.0 4.4 2.0 4.4 2.0 Total tablet weight (mg) 220.0 100.0 220.0 100.0 220.0 100.0

[0104]

[0105] Test Example 1. Analysis of formulation characteristics according to particle size distribution

[0106] In an oral formulation containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid as an API, the physical properties according to the particle size distribution of the API were analyzed using the aforementioned analysis method.

[0107] Specifically, the physical properties (hardness, friability, disintegration time, content, and dissolution rate) of the preparation (tablet) manufactured using the ingredients listed in Table 1 at the corresponding contents were analyzed, and the results are summarized in Table 2 and Figures 1 and 2 below.

[0108] The hardness of the tablet increased as the particle size decreased, and conversely, the friability increased as the particle size increased. Therefore, when D(0.9) was 325 ㎛ or more (Comparative Example 1), the tablet was unsuitable for formulation into tablets considering the hardness and friability of the tablet (Fig. 1).

[0109] No difference in average content was observed according to particle distribution. However, in terms of dissolution rate, the tablet of Comparative Example 1 showed a lower average dissolution rate at 15 minutes, 30 minutes, and 60 minutes than those of Examples 1 and 2 (46.1%, 59.4%, and 67.8%).

[0110] In addition, although both Examples 1 and 2 show relatively good dissolution rates, Examples 1 and 2 show slight differences depending on the time zone. In the case of the average dissolution rate at 15 minutes, Example 1 is 78.5%, and Example 2 is 71.8%, so the tablet of Example 1 with smaller particles shows a somewhat higher average dissolution rate, but in the dissolution rates at 30 minutes and 60 minutes, Example 2 shows a higher average dissolution rate.

[0111] Note Example 1 Example 2 Comparative Example 1 Hardness (kP) 10.2 7.3 6.2 Friability (%) 0.07 0.05 0.12 Disintegration time (s) 14 10 13 Content Average content (%) 99.4 99.4 99.1 Dissolution rate Average dissolution rate (15 minutes) (%) 78.5 71.8 46.1 Average dissolution rate (30 minutes) (%) 87.2 88.6 59.4 Average dissolution rate (60 minutes) (%) 89.4 95.8 67.8

[0112] The present invention has been described above, focusing on preferred embodiments. Those skilled in the art will appreciate that the present invention can be implemented in modified forms without departing from its essential characteristics. Therefore, the disclosed embodiments should be considered illustrative rather than limiting. The scope of the present invention is set forth in the claims, not the foregoing description, and all differences within the scope equivalent thereto should be construed as being encompassed by the present invention.

Claims

An oral formulation comprising an active pharmaceutical ingredient (API) selected from 1.1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the API has a particle size (D(0.9)) for granules corresponding to 90% of the maximum particle size in a particle size cumulative distribution of 80 ㎛ or more and 300 ㎛ or less.

2. An oral preparation according to claim 1, wherein D(0.9) of the API is 120 ㎛ or more and 270 ㎛ or less.

3. In paragraph 1, An oral preparation further comprising one or more excipients selected from a diluent, a disintegrant, a fluidizing agent and a glidant.

4. In paragraph 1, An oral preparation having the content of the above API in an amount of 30 to 55 wt% based on the total weight of the preparation.

5. In paragraph 4, An oral preparation containing the above API in an amount of 40 to 50 wt% based on the total weight of the preparation.

6. In paragraph 1, An oral formulation containing the above API in a dosage form of 50 mg, 100 mg, 200 mg or 300 mg.

Images