Low dose compositions of Aramachol salts

• US 10,849,911 B2
• Filed: 06/08/2016
• Issued: 12/01/2020
• Est. Priority Date: 06/10/2015
• Status: Active Grant

• Current Assignee: Galmed Research & Development Ltd. (Galmed Pharmaceuticals Ltd.)
• Original Assignee: Galmed Research & Development Ltd. (Galmed Pharmaceuticals Ltd.)
• Inventors: Baharaff, Allen, Eshkar-Oren, Idit
• Primary Examiner(s): Shiao, Rei Tsang
• Application Number:
  US15/580,611
• Publication Number:
  US 20190328751A1
• Time in Patent Office: 1,637 Days
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07J 41/0005 the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton

Abstract

The present invention relates to salts of arachidyl amido cholanoic acid (Aramchol), pharmaceutical compositions comprising Aramchol salts, methods for their preparation, and methods of use thereof in medical treatment.

Claims

1. A pharmaceutical composition in unit dosage form comprising a therapeutically effective amount of a salt comprising 3β

-arachidylamido-7α

,12α

-dihydroxy-5β

-cholan-24-oic acid (Aramchol) and an amine wherein the ratio between the Aramchol and the amine is about 1;

1, in which the Aramchol component is present in an amount of about 10 to 400 mg based on the weight of Aramchol free acid; and

optionally at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient.

2. The pharmaceutical composition of claim 1, wherein the amount of said Aramchol component is selected from the group consisting of (i) 10 to 25 mg;

(ii) 10 to 100 mg;

(iii) 30 to 100 mg;

(iv) 30 to 200 mg;

(v) 100 to 200 mg;

(vi) 30 to 300 mg;

(vii) 100 to 300 mg; and

(viii) 200 to 300 mg.

3. The pharmaceutical composition according to claim 1, wherein said amine component is selected from the group consisting of ammonia, a primary amine, a secondary amine, a tertiary amine, a quaternary ammonium compound, an amino alcohol, an amino sugar and an amino acid.

4. The pharmaceutical composition according to claim 2, wherein said amine component is selected from the group consisting of an amino alcohol, an amino sugar and an amino acid.

9. The pharmaceutical composition of claim 1, wherein said composition is in a form suitable for oral administration to a human subject.

10. The pharmaceutical composition of claim 9, wherein said composition is formulated in solid oral dosage form.

11. The pharmaceutical composition of claim 1, wherein said composition is formulated in a form selected from the group consisting of tablets, pills, capsules, pellets, granules, powders, lozenges, sachets, cachets, patches, elixirs, suspensions, dispersions, emulsions, solutions, syrups, aerosols, ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

12. The pharmaceutical composition of claim 1, wherein the amount of said Aramchol component is 10 to 25 mg.

13. The pharmaceutical composition of claim 1, wherein the amount of said Aramchol component is 10 to 100 mg.

14. The pharmaceutical composition of claim 1, wherein the amount of said Aramchol component is 30 to 100 mg.

15. The pharmaceutical composition of claim 1, wherein the amount of said Aramchol component is 30 to 200 mg.

16. The pharmaceutical composition of claim 1, wherein the amount of said Aramchol component is 100 to 200 mg.

17. The pharmaceutical composition of claim 1, wherein the amount of said Aramchol component is 30 to 300 mg.

18. The pharmaceutical composition of claim 1, wherein the amount of said Aramchol component is 100 to 300 mg.

19. The pharmaceutical composition of claim 1, wherein the amount of said Aramchol component is 200 to 300 mg.

20. A method of treating a condition associated with fatty liver in a human subject in need thereof, comprising the step of administering to the subject the pharmaceutical composition of claim 1.

21. The method of claim 20, wherein the amount of said Aramchol component is selected from the group consisting of (i) 10 to 25 mg;

(ii) 10 to 100 mg;

(iii) 30 to 100 mg;

(iv) 30 to 200 mg;

(v) 100 to 200 mg;

(vi) 30-300 mg;

(vii) 100-300 mg;

(viii) 200 to 300 mg; and

(ix) 300 to 400 mg.

22. The method of claim 20, wherein said pharmaceutical composition is administered to said subject in a dosage regimen selected from the group consisting of:

(i) once a day;

(ii) 2 to 4 separate administrations per day;

(iii) 2 to 4 separate administrations per week; and

(iv) 2 to 4 separate administrations per month.

23. The method of claim 20, wherein said pharmaceutical composition delivers a therapeutically effective amount of the salt in which the Aramchol component is present in an amount of 200 to 300 mg is administered daily to said subject.

24. The method of claim 20, wherein said pharmaceutical composition delivers a therapeutically effective amount of the salt in which the Aramchol component is present in an amount of about 260 mg is administered daily to said subject.

25. The method of claim 20, wherein said pharmaceutical composition delivers a therapeutically effective amount of the salt in which the Aramchol component is present in an amount of 300 to 400 mg is administered daily to said subject.

26. The method of claim 20, wherein said pharmaceutical composition delivers a therapeutically effective amount of the salt in which the Aramchol component is present in an amount of about 400 mg is administered daily to said subject.

27. The method of claim 20, for treating non-alcoholic steatohepatitis (NASH) in said subject.

28. The method of claim 19, wherein said composition is formulated as a solid oral dosage form.

30. The method of claim 20, wherein the amine is N-methylglucamine (meglumine).

31. The method of claim 27, wherein the amine is N-methylglucamine (meglumine).

5. A pharmaceutical composition in unit dosage form comprising a therapeutically effective amount of a salt comprising 3β

-arachidylamido-7α

,12α

-dihydroxy-5β

-cholan-24-oic acid (Aramchol) and an amine wherein the ratio between the Aramchol and the amine is about 1;

1, in which the Aramchol component is present in an amount of about 10 to 400 mg based on the weight of Aramchol free acid; and

optionally at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient;

wherein said amine component of said salt is selected from the group consisting of ammonium, benzathine, trimethylglycine (betaine), ethanolamine, diethanolamine, diethylamine, arginine, lysine, choline, deanol, 2-diethylaminoethanol, N-methylglucamine (meglumine), N-ethylglucamine (eglumine), and tromethamine.

6. The pharmaceutical composition according to claim 5, comprising the 3β

-arachidylamido-7α

,12α

-dihydroxy-5β

-cholan-24-oic acid lysine salt.

7. The pharmaceutical composition according to claim 5, comprising the 3β

-arachidylamido-7α

,12α

-dihydroxy-5β

-cholan-24-oic acid tromethamine salt.

8. A pharmaceutical composition in unit dosage form comprising a therapeutically effective amount of a salt comprising 3β

-arachidylamido-7α

,12α

-dihydroxy-5β

-cholan-24-oic acid (Aramchol) and an amine wherein the ratio between the Aramchol and the amine is about 1;

1, in which the Aramchol component is present in an amount of about 10 to 400 mg based on the weight of Aramchol free acid; and

optionally at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient;

wherein said amine component of said salt is N-methylglucamine (meglumine).

29. A method of treating a disease or condition amenable for treatment by 3β

-arachidylamido-7α

,12α

-dihydroxy-5β

-cholan-24-oic acid (Aramchol) in a human subject in need thereof, comprising the step of administering to the subject a pharmaceutical composition in unit dosage form comprising a therapeutically effective amount of a salt comprising Aramchol and an amine wherein the ratio between the Aramchol and the amine is about 1;

1, in which the Aramchol component is present in an amount of about 10 to 400 mg, based on the weight of Aramchol free acid; and

optionally at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient;

wherein said disease or condition is selected from the group consisting of conditions associated with fatty liver, high cholesterol levels in the blood, altered glucose metabolism, gallstones, amyloid plaque deposits and arteriosclerosis.

32. The method of claim 29, wherein said disease is Non Alcoholic SteatoHepatitis (NASH).

33. The method of claim 29, wherein the amine is N-methylglucamine (meglumine).

34. The method of claim 32, wherein the amine is N-methylglucamine (meglumine).