mPGES-1 inhibitor for the treatment of osteoarthritis pain

Patent metadata

Field	Value
Publication number	US-10758517-B2
Application number	US-201916282125-A
Country	US
Kind code	B2
Filing date	Feb 21, 2019
Priority date	Sep 20, 2017
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

Abstract

The present invention relates to a microsomal prostaglandin E synthases-1 (“mPGES-1”) inhibitor for the treatment of osteoarthritis pain in a subject. For example, the present invention relates to a method of treating moderate osteoarthritis pain in a subject in need thereof by orally administering to the subject a substituted triazolone compound as a mPGES-1 inhibitor. The present invention also relates to pharmaceutical compositions comprising the mPGES-1 inhibitor, and to processes for preparing such pharmaceutical compositions.

First claim

What is claimed is:

1. A method of treating osteoarthritis pain in a subject in need thereof, the method comprising orally administering to the subject from about 10 mg to about 1000 mg of a pharmaceutical composition per day, the composition comprising N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is a nanoparticulate composition.

2. The method according to claim 1 , wherein the method comprises orally administering a nanoparticulate pharmaceutical composition comprising about 10 mg of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide, or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 , wherein the method comprises orally administering a nanoparticulate pharmaceutical composition comprising about 25 mg of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide, or a pharmaceutically acceptable salt thereof.

4. The method according to claim 1 , wherein the method comprises orally administering a nanoparticulate pharmaceutical composition comprising about 75 mg of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide, or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1 , wherein the subject exhibits primary osteoarthritis of the hip or knee for at least 3 months in accordance with American College of Rheumatology (ACR) clinical and radiological criteria.

6. The method according to claim 1 , wherein the subject has moderate pain intensity defined as a minimum of 40 mm and a maximum of 74 mm on 0-100 Visual Analogue Scale (Pain Walking on a Flat Surface, WOMAC 3.1, Section A, Question 1) in the most severely affected joint.

7. The method according to claim 1 , wherein the subject exhibits more than a 30% reduction from baseline in the Western Ontario and McMaster's University Osteoarthritis Index 3.1 pain subscale (WOMAC-PS) upon treatment with N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide, or a pharmaceutically acceptable salt thereof.

8. The method according to claim 1 , wherein the subject exhibits a mean change from baseline in the Western Ontario and McMaster's University Osteoarthritis Index 3.1 pain subscale (WOMAC-PS) at the end of 12 weeks of treatment.

9. The method according to claim 1 , wherein the subject exhibits a mean change from baseline in overall WOMAC-3.1 index at the end of 2, 4, 8 and 12 weeks of treatment.

10. The method according to claim 1 , the method comprising orally administering a nanoparticulate pharmaceutical composition comprising about 10 mg to about 100 mg of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide, or a pharmaceutically acceptable salt thereof, wherein the subject has moderate pain intensity defined as a minimum of 40 mm and a maximum of 74 mm on 0-100 Visual Analogue Scale (Pain Walking on a Flat Surface, WOMAC 3.1, Section A, Question 1) in the most severely affected joint.

11. The method according to claim 1 , the method comprising orally administering a nanoparticulate pharmaceutical composition comprising about 10 mg, about 25 mg or about 75 mg of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide, or a pharmaceutically acceptable salt thereof, wherein the subject has moderate pain intensity defined as a minimum of 40 mm and a maximum of 74 mm on 0-100 Visual Analogue Scale (Pain Walking on a Flat Surface, WOMAC 3.1, Section A, Question 1) in the most severely affected joint.

12. The method according to claim 1 , the method comprising orally administering a nanoparticulate pharmaceutical composition comprising about 10 mg of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide, or a pharmaceutically acceptable salt thereof, wherein the subject has moderate pain intensity defined as a minimum of 40 mm and a maximum of 74 mm on 0-100 Visual Analogue Scale (Pain Walking on a Flat Surface, WOMAC 3.1, Section A, Question 1) in the most severely affected joint.

13. The method according to claim 1 , the method comprising orally administering a nanoparticulate pharmaceutical composition comprising about 25 mg of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide, or a pharmaceutically acceptable salt thereof, wherein the subject has moderate pain intensity defined as a minimum of 40 mm and a maximum of 74 mm on 0-100 Visual Analogue Scale (Pain Walking on a Flat Surface, WOMAC 3.1, Section A, Question 1) in the most severely affected joint.

14. The method according to claim 1 , the method comprising orally administering a nanoparticulate pharmaceutical composition comprising about 75 mg of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide, or a pharmaceutically acceptable salt thereof, wherein the subject has moderate pain intensity defined as a minimum of 40 mm and a maximum of 74 mm on 0-100 Visual Analogue Scale (Pain Walking on a Flat Surface, WOMAC 3.1, Section A, Question 1) in the most severely affected joint.

15. The method according to claim 1 , wherein the method comprises orally administering a nanoparticulate pharmaceutical composition comprising from about 10 to about 100 mg of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide, or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , wherein the nanoparticulate pharmaceutical composition is administered once or twice daily.

17. The method of claim 1 , wherein the osteoarthritis pain is moderate osteoarthritis pain.

Assignees

• Glenmark Pharmaceuticals Sa
• Ichnos Sciences SA

Inventors

• Tandon Monika
• Sant Sumit
• Khairatkar-Joshi Neelima
• Gudi Girish
• Menon Vinu C A
• Talluri Ravi

Classifications

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61K31/4196 Primary

  1,2,4-Triazoles · CPC title

• A61K9/14

  Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)} · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61K9/16

  Agglomerates; Granulates; Microbeadlets {; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction (A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51)} · CPC title