Extended release formulation of pudafensine

Abstract

The present invention relates to extended release formulations comprising the compound pudafensine or a pharmaceutically acceptable salt thereof as disclosed herein.

Description

This invention relates to sustained-release formulations comprising the compound pudafensine or a pharmaceutically acceptable salt thereof, as disclosed herein. Abstract

Claims

Claims1 . A composition comprising pellets, said pellets comprising or consisting of: a) a pellet core; b) a drug layer covering the core, the drug layer comprising a compound of formula (I)OO formula (I), or a pharmaceutically acceptable salt thereof, c) a barrier coating layer comprising a film forming agent, wherein said layer covers the drug layer in b), and d) an extended release layer comprising one or more extended release polymer(s); wherein said extended release layer covers the barrier coating in c).

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

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 to 3, wherein the binder is HPMC.

5. The composition according to claim 4, 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 stabilizer is sodium sulphite.

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

9. The composition according to any one of the preceding claims, wherein the drug layer further comprises sodium sulphite is present 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 consists of or comprises spheres made of a material selected from: 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 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 drug layer comprises the compound of formula I in an amount of from about 2.5% to 3.5% by weight of the pellets.

14. The composition according to any one of the preceding claims, wherein the barrier coating layer comprises the film forming agent in an amount between 0.5% and 5% by weight of the pellets.

15. The composition according to any one of the preceding claims, wherein the film forming agent is selected from hydroxypropyl methyl cellulose (HPMC), cellulose derivatives, polyacrylates, polymethacrylates and copolymers of acrylate and methacrylate and polyvinylalcohol (PVA).

16. The composition according to any one of the preceding claims, wherein the film forming agent is HPMC.

17. The composition according to any one of the preceding claims, wherein the barrier coating layer comprises HPMC in an amount of about 0.5% to about 5 % by weight of the pellets.

18. The composition according to any one of the preceding claims, wherein the barrier coating layer comprises HPMC in an amount from about 1 % to 4% by weight of the pellets.

19. The composition according to any one of the preceding claims, wherein the one or more extended release polymer(s) is present in an amount of about 0.5% to about 10 % by weight of the pellets.

20. The composition according to any one of the preceding claims, wherein the one or more extended release polymer(s) is selected from: cellulose derivatives that have been modified with hydrophobic groups, such as short alkyl groups; or other hydrophobic polymers, such as synthetic polyacrylates derivatives with hydrophobic groups such as short alkyl groups.

21. The composition according to any one of the preceding claims, wherein the extended release polymer is ethylcellulose.

22. The composition according to any one of the preceding claims, wherein the extended release layer comprises ethylcellulose in an amount from about 0.5% to about 10% by weight of the pellets.

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

24. The composition according to any one of the preceding claims, wherein the extended release layer further comprises a film forming agent.

25. The composition according to claim 24, wherein the extended release layer comprises the film forming agent in an amount from 0.5% to about 5% by weight of the pellets.

26. The composition according to any one of claims 24 to 25, wherein the film forming agent is HPMC.

27. The composition according to any one of the preceding claims, wherein the extended release layer further comprises HPMC.

28. The composition according to any one of the preceding claims, wherein the extended release layer further comprises HPMC in an amount from 0.5% to about 5% by weight of the pellets.

29. The composition according to any one of the preceding claims, wherein the extended release layer further comprises HPMC in an amount from 1 % to about 4% by weight of the pellets.

30. The composition according to any one of the preceding claims, wherein the extended release layer further comprises a plasticizer.

31. The composition according to any one of the preceding claims, wherein the extended release layer further comprises a plasticizer selected from: esters derived from citric acid, such as triethyl citrate or tributyl citrate; acetylated monoglycerides; esters of phthalic acid; polyethylene glycol or derivatives thereof; and sorbitol or mixtures thereof.

32. The composition according to any one of claims 30 to 31 , wherein the plasticizer is triethyl citrate.

33. The composition according to any one of the preceding claims, wherein the extended release layer further comprises triethyl citrate.

34. The composition according to any one of the preceding claims, wherein the extended release layer further comprises an antitacking agent.

35. The composition according to claim 34, wherein the antitacking agent is selected from: stearates or fatty acid salts of calcium or magnesium, talc, silica, and silicates or combinations thereof.

36. The composition according to claim 35, wherein the antitacking agent is magnesium stearate.

37. The composition according to any one of the preceding claims, wherein the extended release layer further comprises magnesium stearate.

38. The composition according to any one of the preceding claims, wherein the extended release layer further comprises one or more additional excipients selected from: i. a film forming agent according to claims 24 to 26; and / or ii. a plasticiser according to claims 30 to 33; and / or ill. an antitacking agent according to claims 34 to 37.

39. The composition according to any one of the preceding claims, wherein the compound of formula I is according to formula laor a pharmaceutically acceptable salt thereof.

40. 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.41 . The composition according to any one of the preceding claims, wherein the composition is an extended release (ER) composition of the compound of formula I.

42. The composition according to any one of the preceding claims, wherein the composition is an extended 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;c) a barrier layer comprising HPMC in an amount of about 0.5% to about 5% by weight of the pellets, wherein the barrier coating layer covers the drug layer in b); and d) an extended release layer comprising ethyl cellulose in an amount of about 0.5 to 10% by weight of the pellets, wherein the extended release layer covers the barrier coating layer in c).

43. The composition according to claim 42, wherein the drug layer further comprises sodium sulphite.

44. The composition according to any one of claims 42 to 43, wherein the extended release layer further comprises one or more additional excipients selected from:: i. a film forming agent according to claims 24 to 26; and / or ii. a plasticiser according to claims 30 to 33; and / or ill. an antitacking agent according to claims 34 to 37.

45. The composition according to any one of the preceding claims, wherein the composition comprises the compound of formula I in an amount of about 0.5 mg to 30 mg.

46. 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.

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

48. The composition according to claim 46, wherein the unit dosage form or pharmaceutical dosage form is a capsule.

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

50. The composition according to any one of the preceding claims, wherein the composition reduces the Cmax of the compound of formula I, wherein the Cmax is reduced by at least 10%, such as at least 20% compared to an aqueous solution of an equivalent amount of the compound of formula I after oral administration.

51. The composition according to any one of the preceding claims, wherein the composition provides for a Cmax of the compound of formula I upon oral administration from 5.0 ng / mL to 12.0 ng / mL, such as from 6.0 ng / mL to 10.0 ng / mL, such as from 6.0 ng / mL to 8.0 ng / mL.

52. 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 an equivalent amount of the compound of formula I after oral administration.

53. The composition according to any one of the preceding claims, wherein the tmax of the compound of formula I is increased by at least 60 minutes, such as 90 minutes, such as 120 minutes, such as 180 minutes, such as 210 minutes upon oral administration compared to an aqueous solution of an equivalent amount of the compound of formula I after oral administration.

54. The composition according to any one of the preceding claims, wherein the tmax of the compound of formula I is from about 4 to 12 hours, such as from 5.5 to 8.5 hours after oral administration.

55. The composition according to any one of the preceding claims, wherein the composition provides for an AUC0-72 of the compound of formula I upon oral administration of at least 85% of the AUC0-72 of an aqueous solution of an equivalent amount of the compound of formula I after oral administration.

56. 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 of at least 85% of the AUCo-inf of an aqueous solution of the compound of formula I after oral administration.

57. 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 100 to 500 h-ng / mL, such as AUCo-inf from 160 to 460 h-ng / mL, or AUCo-inf from 250 to 350 h-ng / mL, such as AUCo-inf of about 300 h-ng / mL.

58. The composition according to any one of the preceding claims, wherein after oral administration the composition provides: a) an AUC0-72 or an AUCo-inf of the compound of formula I upon oral administration of at least 85% of the AUC0-72 or AUCo-inf of an aqueous solution of an equivalent amount of a compound of formula I after oral administration, and b) a tmax of the compound of formula I from about 5.5 to 8.5 hours.

59. The composition according to any one of the preceding claims, wherein the composition releases the compound of formula I at a rate of: i. 35-70% within the first 2 hours, such as 40-65% release within the first 2 hours; ii. 60-95% released after 4 hours, such as 75-85% released after 4 to 6 hours, such as after 4 hours, 5 hours or 6 hours; and ill. full release after 8 hours as measured in a USP-I or a USP-II apparatus at pH 6.8 at 37 °C.

60. The composition according to any one of the preceding claims, wherein the composition comprises from about 0.5 mg to about 25 mg of the compound of formula (I).

61. The composition according to any one of the preceding claims, wherein the composition comprises from about 0.5 mg to 25 mg, such as about 0.5 mg, such as about 1 mg, 1.5 mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11 mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21 mg, 22mg, 23mg, 24mg or 25 mg of the compound of formula (I).

62. The composition according to any one of the preceding claims, wherein the composition comprises 5 mg or 10mg of the compound of formula (I).

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

64. 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 4 and 12 hours, said method comprising oral administration of a composition according to any one of claims 1 to 62.

65. The method according to claim 64, wherein the subject is a human.

66. The method according to claims 64 to 65, wherein the AUC0-72 or the AUCo-inf of the compound of formula I upon oral administration is of at least 85%, such as at least 90%, of the AUCo-72 or the AUCo-inf of an aqueous solution of an equivalent amount of a compound of formula I upon oral administration.

67. 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; c) coating the drug layer solution onto the pellet core to form a drug layer; d) providing a barrier coating solution comprising a film forming agent; e) coating the barrier coating solution on top of the drug layer in c) to obtain a barrier coating layer; f) providing an extended release solution comprising one or more extended release polymer(s); g) coating the extended release solution on to the barrier coating layer in e) to obtain an extended release layer.

68. The method according to claim 67, wherein the pellet core is as described in any one of claims 10 to 1 1 , the drug layer is as described in any one of claims 1 -9 or 12- 13, the barrier coating layer is as described in any one of claims 14 to 18, or the extended release layer is as described in any one of claims 19 to 38.

69. The method according to any one of claims 67-68, wherein the drug layer solution comprises a binder as described in any one of claims 2 to 5, or a pH modifier and / or a stabilizer as described in any one of claims 6 to 9.

70. The method according to any one of claims 67-69, wherein the drug layer solution comprises a solvent or dispersant, wherein said solvent or dispersant comprises or consist of an aqueous solution.

71. The method according to any one of claims 67-70, wherein the barrier coating solution comprises a solvent or dispersant, wherein said solvent or dispersant comprises or consists of an aqueous solution.

72. The method according to any one of claims 67-71 , wherein the extended release layer solution comprises a film forming agent as described in any one of claims 24 to 26 or a plasticizer as described in any one of claims 30 to 33 or an antitacking agent as described in any one of claims 34 to 37.

73. The method according to any one of claims 67-72, wherein the extended release layer solution comprises a solvent or dispersant, wherein said solvent or dispersant comprises or consists of an aqueous solution comprising an organic solvent, such as isopropanol.

74. The method according to any one of claims 67 to 73, wherein the composition is as defined in any one of claims 1 to 59.

75. A composition obtained by the method according to any one of claims 1 to 74.

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