Solid oral formulation of pudafensine

Abstract

The present invention relates to solid formulations of pudafensine as disclosed herein or a pharmaceutically acceptable salt thereof.

Description

This invention relates to solid dosage forms of pudafensine or its pharmaceutically acceptable salts as described herein. Abstract

Claims

Claims1 . A composition comprising pellets, said pellets comprising or consisting of: a. a pellet core; and b. a drug layer covering the core, the drug layer comprising a compound of formula (I)(I) or a pharmaceutically acceptable salt thereof.

2. The composition according to claim 1 , wherein the drug layer further comprises a binder selected from cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC),or hydroxypropyl cellulose (HPC); gelatin; polyalkylene glycols, such as PEO; and polyvinyl pyrrolidone (PVP).

3. The composition according to claim 2, wherein the drug layer comprises the binder in an amount from 0.5 to 10% by weight of the pellets.

4. The composition according to any one of claims 2-3, wherein the binder is HPMC.

5. The composition according to any one of the preceding claims, wherein the drug layer comprises HPMC in an amount from about 1 % to 5% by weight of the pellets.

6. The composition according to any one of the preceding claims, wherein the drug layer further comprises additional excipients selected from: pH modifiers and / or stabilizers.

7. The composition according to claim 6, wherein the pH modifier and / or stabilizer is present in an amount from 0.05% to 1% by weight of the pellets.

8. The composition according to any one of claims 6-7, wherein the stabilizer is sodium sulphite.

9. The composition according to any one of the preceding claims, wherein the drug layer comprises sodium sulphite in an amount from 0.05 % to 1% by weight of the pellets.

10. The composition according to any one of the preceding claims, wherein the pellet core comprises or consists of spheres made of a material selected form: microcrystalline cellulose (MCC); sugars, such as sucrose, xylitol, mannitol, and lactose; starch, silica, tartaric acid and calcium carbonate.1 1 . The composition according to any one of the preceding claims, wherein the pellet core comprises or consists of microcrystalline cellulose (MCC).

12. The composition according to any one of the preceding claims, wherein the drug layer comprises the compound of formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 0.5% to about 5% by weight of the pellets.

13. The composition according to any one of the preceding claims, wherein the binder is present in an amount between 0.5% and 5% by weight of the pellets.

14. The composition according to any one of the preceding claims, wherein the compound of formula I is according to formula laformula (la), or a pharmaceutically acceptable salt thereof.

15. The composition according to any one of the preceding claims, wherein the compound is exo-7-[(8-azabicyclo[3.2.1 ]octan-3-yl)oxy]-3-methoxy-chromen-2- one or a pharmaceutically acceptable salt thereof.

16. The composition according to any one of the preceding claims, wherein the composition is an immediate release (IR) composition of the compound of formula I.

17. The composition according to any one of the preceding claims, wherein said composition is an immediate release composition of an active ingredient consisting of a compound of formula I,(I), or a pharmaceutically acceptable salt thereof, the composition comprising pellets, said pellets comprising or consisting of: a) an inert pellet core comprising microcrystalline cellulose (MCC); b) a drug layer comprising: the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.5% to about 5% by weight of the pellets and HPMC in an amount of 0.5% to about 5% by weight of the pellets, wherein the drug layer covers the inert core.

18. The composition according to claim 17, wherein the drug layer further comprises additional excipients selected from: pH modifiers and / or stabilizers.

19. The composition according to any one of claims 17-18, wherein the drug layer further comprises sodium sulphite.

20. The composition according to any one of claims 17-19, wherein the drug layer comprises sodium sulphite in an amount from 0.05 % to 1% by weight of the pellets.21 . The composition according to any one of the preceding claims, wherein the composition comprises an amount of the compound of formula I of about 0.5 mg to 10 mg.

22. The composition according to any one of the preceding claims, wherein the composition is in the form of a pharmaceutical dosage form or a unit dosage form.

23. The composition according to any one of the preceding claims, wherein the composition is in the form of a solid dosage form.

24. The composition according to any one of claims 22-23, wherein the unit dosage form or pharmaceutical dosage form is a capsule.

25. The composition according to any one of the preceding claims, wherein the composition is for oral administration.

26. The composition according to any one of the preceding claims, wherein the composition provides a pharmacokinetic profile having a single mean average plasma concentration peak upon oral administration.

27. The composition according to any one of the preceding claims, wherein the composition provides a Cmax after oral administration of 80% to 125% of the Cmax provided by an equivalent amount of the compound of formula I administered orally as an aqueous solution.

28. The composition according to any one of the preceding claims, wherein the composition provides a Cmax of the compound of formula I upon oral administration from 5.0 ng / mL to 12.5 ng / mL, such as from 6.0 ng / mL to 10.0 ng / mL, such as from 7 ng / mL to 9 ng / mL.

29. The composition according to any one of the preceding claims, wherein the composition increases the tmax of the compound of formula I compared to an aqueous solution of the compound of formula I after oral administration by at the most 150 minutes.

30. The composition according to any one of the preceding claims, wherein the composition provides a tmax of the compound of formula I from about 2 to 8 hours, such as from 3 to 5 hours after oral administration.

31. The composition according to any one of the preceding claims, wherein the composition provides a tmax of the compound of formula I from about 2 to 8 hours after oral administration.

32. The composition according to any one of the preceding claims, wherein the composition provides a tmax of the compound of formula I from about 3 to 5 hours after oral administration.

33. The composition according to any one of the preceding claims, wherein the composition releases the compound of formula I at a rate of more than 90% released in the first hour as measured in a USP-I or a USP-II apparatus at pH 1 .0 at 37 °C.

34. The compositions according to any one of the preceding claims, wherein the composition releases the compound of formula I at a rate of more than 90% release in the first 0.5 hours, such as more than 90% release in the first 10 minutes, such as more than 90% release in the first 5 minutes as measured in a USP-I or a USP-II apparatus at pH 1 .0 at 37 °C.

35. The composition according to any one of the preceding claims, wherein the composition releases the compound of formula I at a rate of 100% release in the first 5 minutes as measured in a USP-I or a USP-II apparatus at pH 1 .0 at 37 °C.

36. The composition according to any one of the preceding claims, wherein the composition provides for an AUC0-72 of the compound of formula I of at least 90% of the AUCo-72 of an aqueous solution of an equivalent amount of the compound of formula I after oral administration.

37. The composition according to any one of the preceding claims, wherein the composition provides for an AUCo-inf of the compound of formula I of at least 90% of the AUCo-inf of an aqueous solution of an equivalent amount of the compound of formula I after oral administration.

38. The composition according to any one of the preceding claims, wherein the composition provides for an AUCo-inf of the compound of formula I upon oral administration from 180 to 480 h-ng / mL, such as AUCo-inf from 250 to 350 h-ng / mL, such as AUCo-inf of about 300 h-ng / mL.

39. The composition according to any one of the preceding claims, wherein the composition comprises from about 0.1 mg to about 10 mg of the compound of formula (I).

40. The composition according to any one of the preceding claims, wherein the composition comprises 5mg of the compound of formula (I).

41. A unit dosage form comprising the composition according to any one of the preceding claims.

42. A method of obtaining a therapeutically effective plasma concentration of a compound of formula (I)in a subject, wherein the tmax of the compound of formula I is between 3 and 5 hours, said method comprising oral administration of a composition according to any one of the preceding claims.

43. The method according to claim 42, wherein the subject is a human.

44. A method of preparing a composition comprising pellets, the method comprising: a) providing pellet core, b) providing a drug layer solution comprising a compound of formula (I)(I), or a pharmaceutically acceptable salt thereof; and c) coating the drug layer solution on to the pellet core to form a drug layer.

45. The method according to claim 44, wherein: a. the pellet core is as described in any one of claims 10-11 , and / or b. the drug layer solution comprises a binder, a pH modifier or stabilizer, and / or the compound of formula I as described in any one of claims 1 -10 and 12-15.

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