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CN-116528852-B - Stable oral formulations containing 1- (3-cyano-1-isopropyl-indol-5-yl) pyrazole-4-carboxylic acid

CN116528852BCN 116528852 BCN116528852 BCN 116528852BCN-116528852-B

Abstract

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

Inventors

  • Liu Xiche
  • LI XUAN
  • YIN DEYI
  • Park Zhenghong
  • XUAN XIANZHI

Assignees

  • 株式会社LG 化学

Dates

Publication Date
20260512
Application Date
20211130
Priority Date
20201201

Claims (20)

  1. 1. A stable oral formulation comprising an Active Pharmaceutical Ingredient (API) and one or more excipients, said API being 1- (3-cyano-1-isopropyl-indol-5-yl) pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, and said API not being 1- (3-cyano-1-isopropyl-indol-5-yl) -1H-pyrazole-4-carboxylic acid crystalline particles comprising 0.02wt% of 1- (3-cyano-1-isopropyl-indol-5-yl) -1H-pyrazole-4-methyl ester, Wherein the formulation does not include a separate stabilizer as an excipient, and Wherein 90% by weight or more of the API is maintained at 40 ℃ and 75% relative humidity for 6 months, at 80 ℃ and 75% relative humidity for 12 days, or at 25 ℃ and 60% relative humidity for 1 year, Wherein the excipient is selected from the group consisting of diluents, disintegrants, binders, glidants, lubricants, and combinations thereof, Wherein the diluent is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, mannitol, dibasic calcium phosphate dihydrate, anhydrous dibasic calcium phosphate, silicified starch, powdered cellulose, starch, anhydrous lactose, and combinations thereof, Wherein the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, alginic acid, calcium carboxymethylcellulose, and combinations thereof, Wherein the binder is selected from the group consisting of copovidone, hydroxypropyl cellulose, hypromellose acetate succinate, povidone, sodium carboxymethyl cellulose, gelatin, and combinations thereof, Wherein the glidant is selected from the group consisting of colloidal silicon dioxide, hydrated silicon dioxide, talc, and combinations thereof, Wherein the lubricant is selected from the group consisting of magnesium stearate, zinc stearate, calcium stearate, sodium stearyl fumarate, and combinations thereof, Wherein the content of the API is 20 to 70 wt% based on 100 wt% of the formulation in total.
  2. 2. The stable oral formulation of claim 1, wherein the formulation is an oral tablet.
  3. 3. The stable oral formulation of claim 1 or 2, wherein 95% by weight or more of the API is maintained at 40 ℃ and 75% relative humidity for 6 months, at 80 ℃ and 75% relative humidity for 12 days, or at 25 ℃ and 60% relative humidity for 1 year.
  4. 4. The stable oral formulation of claim 3, wherein 99% by weight or more of the API is maintained at 40 ℃ and 75% relative humidity for 6 months, at 80 ℃ and 75% relative humidity for 12 days, or at 25 ℃ and 60% relative humidity for 1 year.
  5. 5. The stable oral formulation of claim 4, wherein 99.5% by weight or more of the API is maintained at 40 ℃ and 75% relative humidity for 6 months, at 80 ℃ and 75% relative humidity for 12 days, or at 25 ℃ and 60% relative humidity for 1 year.
  6. 6. The stable oral formulation of claim 1 or 2, wherein the oral formulation comprises a combination of diluents, disintegrants, glidants, and lubricants.
  7. 7. The stable oral formulation of claim 1 or 2, wherein the oral formulation comprises a combination of diluents, disintegrants, binders, glidants, and disintegrants.
  8. 8. The stable oral formulation of claim 1 or 2, wherein the content of the API is 30 to 50 wt% based on 100 wt% of the formulation in total.
  9. 9. The stable oral formulation of claim 7, wherein the content of the API is 40 to 50 wt% based on 100 wt% of the formulation in total.
  10. 10. The stable oral formulation of claim 1 or 2, wherein the diluent, when present, is in an amount ranging from 30 wt% to 50 wt%, the disintegrant is in an amount ranging from 1 wt% to 30 wt%, the binder is in an amount ranging from 1 wt% to 30 wt%, the glidant is in an amount ranging from 0.1 wt% to 10 wt%, and the lubricant is in an amount ranging from 0.1 wt% to 10 wt%, based on the total weight of the oral formulation.
  11. 11. The stable oral formulation of claim 10, wherein the diluent, when present, is in an amount ranging from 40 wt% to 50wt%, the disintegrant is in an amount ranging from 1 wt% to 5 wt%, the binder is in an amount ranging from 1 wt% to 5 wt%, the glidant is in an amount ranging from 0.5 wt% to 4 wt%, and the lubricant is in an amount ranging from 0.5 wt% to 4 wt%, based on the total weight of the oral formulation.
  12. 12. The stable oral formulation of claim 1 or 2, wherein when present, The diluent is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, and combinations thereof, The disintegrating agent is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone and combinations thereof, The binder is selected from the group consisting of copovidone, hydroxypropyl cellulose, hypromellose acetate succinate, povidone, and combinations thereof, The glidant is colloidal silicon dioxide, The lubricant is selected from magnesium stearate, sodium stearyl fumarate, and combinations thereof.
  13. 13. The stable oral formulation of claim 1 or 2, wherein when present, The diluent is microcrystalline cellulose and the diluent is a microcrystalline cellulose, The disintegrating agent is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone and combinations thereof, The binder is selected from the group consisting of copovidone, hydroxypropyl cellulose, povidone, and combinations thereof, The glidant is colloidal silicon dioxide, and The lubricant is selected from magnesium stearate, sodium stearyl fumarate, and combinations thereof.
  14. 14. The stable oral formulation of claim 2, wherein the oral formulation comprises, on a total weight basis: 45.5% of Active Pharmaceutical Ingredient (API), 47.6% of microcrystalline cellulose, 4.4% of crospovidone, 0.5% of colloidal silicon dioxide and 2% of sodium stearyl fumarate, or 45.5% Of Active Pharmaceutical Ingredient (API), 43.6% of microcrystalline cellulose, 4.5% of crospovidone, 4.5% of copovidone, 1% of colloidal silicon dioxide and 0.8% of magnesium stearate, or 45.5% Of Active Pharmaceutical Ingredient (API), 43.6% of microcrystalline cellulose, 4.5% of croscarmellose sodium, 4.5% of povidone, 1% of colloidal silicon dioxide and 0.8% of sodium stearyl fumarate, or 45.5% Active Pharmaceutical Ingredient (API), 43.6% microcrystalline cellulose, 4.5% sodium starch glycolate, 4.5% hydroxypropyl cellulose, 1% colloidal silicon dioxide, and 0.8% magnesium stearate; Wherein the API is 1- (3-cyano-1-isopropyl-indol-5-yl) pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, and the API is not 1- (3-cyano-1-isopropyl-indol-5-yl) pyrazole-4-carboxylic acid crystalline particles comprising 0.02wt% of 1- (3-cyano-1-isopropyl-indol-5-yl) -1H-pyrazole-4-methyl ester.
  15. 15. The stable oral formulation of claim 1 or 2, wherein the diluent when present is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, and combinations thereof, The disintegrating agent is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone and combinations thereof, The binder is selected from the group consisting of copovidone, hydroxypropyl cellulose, hypromellose acetate succinate, povidone, and combinations thereof, The lubricant is magnesium stearate.
  16. 16. The stable oral formulation of claim 15, 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.
  17. 17. The stable oral formulation of claim 1 or 2, wherein the content of the API is 50mg per formulation.
  18. 18. The stable oral formulation of claim 1 or 2, wherein the content of the API is 100mg per formulation.
  19. 19. The stable oral formulation of claim 1 or 2, wherein the content of the API is 200mg per formulation.
  20. 20. The stable oral formulation of claim 1 or 2, wherein the content of the API is 300mg per formulation.

Description

Stable oral formulations containing 1- (3-cyano-1-isopropyl-indol-5-yl) pyrazole-4-carboxylic acid Technical Field The present application claims the benefit of priority from korean patent application No. 10-2020-0166051, filed on 1 month 12 in 2020, the entire disclosure of which is incorporated herein by reference in its entirety. The present invention relates to an oral preparation comprising 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 uric acid from being deposited in vivo, as an Active Pharmaceutical Ingredient (API), and does not comprise a stabilizer, and a method for preparing the same. Background Xanthine oxidase is an enzyme that converts hypoxanthine to xanthine and also converts the xanthine formed to uric acid. It is known that when excessive uric acid is present in the body, it can cause various diseases including gout and the like. Gout is a disease in which uric acid crystals accumulate in cartilage, ligaments and surrounding tissues of joints, thereby causing severe inflammation and pain, and the incidence of gout has steadily increased over the past 40 years. Thus, substances inhibiting xanthine oxidase activity can be effective in the treatment of xanthine oxidase-related diseases, such as hyperuricemia, gout, heart failure, cardiovascular diseases, hypertension, diabetes, kidney diseases, inflammation, joint diseases, and inflammatory bowel diseases. Meanwhile, as for a substance capable of inhibiting xanthine oxidase activity, KR 10-1751325 (patent document 1) provides a compound 1- (3-cyano-1-isopropyl-indol-5-yl) pyrazole-4-carboxylic acid having the structure of the following formula 1 and a method for producing the compound, KR 10-1424013 (patent document 2) provides various types of crystal forms obtained by using various solvents and a method for producing the same. [ 1] In the case of pharmaceutical formulations, it generally comprises one or more excipients selected from diluents, disintegrants, stabilizers, binders, lubricants and glidants, and an API as active ingredient. In general, excipients included in pharmaceutical formulations should be stable ingredients and should not affect the efficacy of the formulation, but stability of the API itself is problematic, or reaction byproducts are generated between the API and the specific excipient, or reaction products generated depending on the combination between excipients may affect the stability of the formulation or the uniformity of the content of ingredients. That is, during the preparation process or storage process of the pharmaceutical formulation, there may be problems in terms of stability and uniformity of content of ingredients due to degradation products or reaction products of the API itself or by contact or combination with the API and excipients. Thus, in pharmaceutical formulations, it is necessary to properly select and combine excipients suitable for the API. Furthermore, since these excipients are very diverse in type and can be combined in many ways, selecting a particular excipient among the excipients and finding the appropriate combination to develop a stable pharmaceutical formulation is a very difficult and time-consuming step in drug development. Since the stability of the oral preparation containing formula 1 as an API is unknown, and in the case of the oral preparation, long-term storage for 1 year or more is common, it is required to improve the stability and uniformity of the content of the components of the oral preparation containing formula 1 as an API. [ Prior Art literature ] [ Patent literature ] KR 10-1751325 (2017, 6, 21) novel compounds effective as xanthine oxidase inhibitors, process for preparing the same and pharmaceutical compositions containing the same (Novel compounds effective as xanthine oxidase inhibitors,method for preparing the same,and pharmaceutical composition containing the same) KR 10-1424013 (22 th 2014), 1- (3-cyano-1-isopropyl-indol-5-yl) pyrazole-4-carboxylic acid crystal form and method for producing same (1-(3-cyano-1-isopropyl-indol-5-yl)pyrazol-4-carboxylic acid crystalline form and the producing method thereof) Disclosure of Invention Technical problem Accordingly, the present inventors have conducted various studies to solve the above-mentioned problems, as a result, have found that the use of 1- (3-cyano-1-isopropyl-indol-5-yl) pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an API does not produce decomposition products or reaction products due to contact or binding with an excipient, and have identified an oral preparation which does not contain a stabilizer in an excipient and which also has a stabilizing effect under any combination of excipients, as a result, have completed the present invention. It is therefore an object of the present invention to provide a stable oral formulation comprising an