Compositions and Methods for Treating Centrally Mediated Nausea and Vomiting

• US 20120064153A1
• Filed: 03/31/2011
• Published: 03/15/2012
• Est. Priority Date: 11/18/2009
• Status: Active Grant

• Current Assignee: Helsinn Healthcare SA
• Original Assignee: Helsinn Healthcare SA
• Inventors: Cannella, Roberta, Bonadeo, Daniele, Braglia, Riccardo, Trento, Fabio, Cantoreggi, Sergio, Rossi, Giorgia
• Granted Patent: US 8,623,826 B2
• Time in Patent Office: Days
• US Class Current: 424/452
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics

Abstract

Provided are compositions and methods for treating or preventing nausea and vomiting in patients undergoing chemotherapy, radiotherapy, or surgery.

Claims

1. ) A method of treating nausea and vomiting for five consecutive days in a patient in need thereof, comprising:

a) administering to said patient on day one netupinant or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount which is effective to treat nausea and vomiting during the acute and delayed phases of emesis, and which enters the systemic circulation, crosses the blood brain barrier and occupies at least 70% of NK₁ receptors in the striatum seventy-two hours after said administration;

b) administering to said patient on day one a therapeutically effective amount of a 5-HT₃ antagonist or a pharmaceutically acceptable salt thereof, which is effective to treat nausea and vomiting during the acute and delayed phases; and

c) administering to said patient on day one a first dose of dexamethasone which is ineffective against nausea and vomiting when administered alone, but effective against nausea and vomiting when administered in combination with said netupitant, wherein said first dose comprises from 50 to 70% of a minimum effective dose when administered alone.

2. ) The method of claim 1, further comprising:

d) administering to said patient, on days two, three and four, a second dose of dexamethasone which is ineffective against nausea and vomiting when administered alone, but effective against nausea and vomiting when administered in combination with said netupitant, wherein said second dose comprises from 40 to 60% of a minimum effective dose when administered alone.

3. ) The method of claim 1 or 2, wherein said netupitant occupies at least 80% of NK₁ receptors in the striatum seventy-two hours after said administration.

4. ) The method of any one of claims 1 to 3, wherein only one dose of netupitant or a pharmaceutically acceptable salt thereof is administered during said five days.

5. ) The method of any one of claims 1 to 4, wherein only one dose of netupitant or a pharmaceutically acceptable salt thereof is administered during said five days, and said one dose is administered orally.

6. ) The method of any one of claims 1 to 5, wherein said therapeutically effective amount of netupitant comprises from about 200 to about 400 mg. of netupitant or a pharmaceutically acceptable salt thereof.

7. ) The method of any one of claims 1 to 6, wherein said therapeutically effective amount of netupitant comprises about 300 mg. of netupitant as a free base.

8. ) The method of any one of claims 1 to 7, wherein said therapeutically minimum effective dose of dexamethasone when administered alone comprises from about 16 mg to about 20 mg of dexamethasone.

9. ) The method of any one of claims 1 to 8, wherein only one dose of 5-HT₃ antagonist or a pharmaceutically acceptable salt thereof is administered during said five days.

10. ) The method of any one of claims 1 to 9, wherein the 5-HT₃ antagonist is ondansetron or palonosetron.

11. ) The method of any one of claims 1 to 10, wherein said therapeutically effective amount of 5-HT₃ antagonist comprises from about 0.25 to about 0.75 mg. of palonosetron or a pharmaceutically acceptable salt thereof.

12. ) The method of any one of claims 1 to 11, wherein said therapeutically effective amount of 5-HT₃ antagonist comprises about 0.56 mg. of palonosetron hydrochloride, corresponding to about 0.5 mg of palonosetron as a free base.

13. ) The method of any one of claims 1 to 12, wherein said palonosetron is administered orally.

14. ) The method of any one of claims 1 to 13, comprising orally administering:

a) about 300 mg. of netupitant as a free base on day one;

b) about 0.56 mg. of palonosetron hydrochloride, corresponding to about 0.5 mg of palonosetron as a free base, on day one; and

c) about 12 mg. of dexamethasone on day one.

15. ) The method of any one of claims 1 to 14, comprising orally administering:

a) about 300 mg. of netupitant as a free base on day one;

b) about 0.56 mg. of palonosetron hydrochloride (corresponding to about 0.5 mg of palonosetron as a free base) on day one;

c) about 12 mg. of dexamethasone on day one; and

d) about 8 mg. of dexamethasone on days two, three and four.

23. ) The method of any one of claims 1-22, wherein said nausea and vomiting is chemotherapy induced nausea and vomiting (“

CINV”

), radiation therapy induced nausea and vomiting (“

RINV”

), or post-operative nausea and vomiting (“

PONV”

).

24. ) The method of any one of claims 1-22, wherein said nausea and vomiting is induced by moderately or highly emetogenic chemotherapy.

25. ) The method of any one of claims 1-24, comprising administering moderately or highly emetogenic chemotherapy within from about one hour to about two hours of said administration of said netupitant or pharmaceutically acceptable salt thereof.

26. ) The method of any one of claims 1-25, comprising treating nausea and vomiting in response to highly emetogenic chemotherapy during the acute phase, or in response to highly emetogenic chemotherapy during the delayed phase, or in response to moderately emetogenic chemotherapy during the acute phase, or in response to moderately emetogenic chemotherapy during the delayed phase.

32. ) The method of any one of claims 1-31, wherein netupitant potentiates the therapeutic effect of dexamethasone.

33. ) The method of any one of claims 1-32, wherein netupitant promotes bioavailability of palonosetron.

16. ) A method of treating nausea and vomiting for a period of five consecutive days in a patient in need thereof, comprising administering to said patient netupinant or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount which is effective to treat nausea and vomiting during the acute and delayed phases of emesis, and which enters the systemic circulation, crosses the blood brain barrier and occupies at least 70% of NK₁ receptors in the striatum seventy-two hours after said administration.

17. ) The method of claim 16, wherein said netupitant occupies at least 80% of NK₁ receptors in the striatum seventy-two hours after said administration

18. ) The method of claim 16 or 17, further comprising:

a) administering to said patient on day one a first dose of dexamethasone which is ineffective against nausea and vomiting when administered alone, but effective against nausea and vomiting when administered in combination with said netupitant, wherein said first dose comprises from 50 to 70% of a minimum effective dose when administered alone; and

b) if said patient is subject to highly emetogenic chemotherapy, administering to said patient, on days two, three and four, a second dose of dexamethasone which is ineffective against nausea and vomiting when administered alone, but effective against nausea and vomiting when administered in combination with said netupitant, wherein said second dose comprises from 40 to 60% of a minimum effective dose when administered alone.

19. ) The method of any one of claims 16 to 18, further comprising administering a therapeutically effective amount of a 5-HT₃ antagonist.

20. ) The method of any one of claims 16-19, wherein said therapeutically effective amount of netupitant comprises from about 200 to about 400 mg. of netupitant or a pharmaceutically acceptable salt thereof, said therapeutically effective amount of 5-HT₃ antagonist comprises from about 0.25 to about 0.75 mg. of palonosetron or a pharmaceutically acceptable salt thereof, and said therapeutically minimum effective dose of dexamethasone when administered alone comprises from about 16 mg to about 20 mg of dexamethasone.

21. ) The method of any one of claims 16-20, wherein:

a) only one dose of netupitant is administered during said five days on day one, comprising about 300 mg. of netupitant as the free base; and

b) administering about 12 mg. of dexamethasone on day one; and

c) if said patient is undergoing highly emetogenic chemotherapy, administering about 8 mg. of dexamethasone on days two, three and four.

22. ) The method of claim 21, further comprising administering only one dose of a 5-HT₃ antagonist during said five days on day one, comprising about 0.56 mg. of palonosetron hydrochloride, corresponding to about 0.5 mg of palonosetron as a free base.

27. ) A method of treating nausea and vomiting in a human subject in need thereof, during the acute and/or delayed phases of CINV in response to moderately or highly emetogenic chemotherapy, comprising administering a therapeutically effective amount of netupitant, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of palonosetron, or a pharmaceutically acceptable salt thereof, before said chemotherapy.

28. ) The method of claim 27, comprising orally administering from about 200 to about 400 mg. of netupitant or a pharmaceutically acceptable salt thereof, and from about 0.25 to about 0.75 mg. of palonosetron or a pharmaceutically acceptable salt thereof.

29. ) The method of claim 27 or 28, comprising orally administering about 300 mg. of netupitant as the free base, and about 0.56 mg. of palonosetron hydrochloride.

30. ) The method of any one of claims 27-29, further comprising, if said patient is subject to highly emetogenic chemotherapy, administering a sub-therapeutic dose of dexamethasone on days one, two, three and four.

31. ) The method of any one of claims 27-30, further comprising, if said patient is undergoing highly emetogenic chemotherapy, orally administering 12 mg. of dexamethasone on day one, and 8 mg. of dexamethasone on days two, three and four.

34. ) An orally administered dosage form comprising a combination of palonosetron and an NK1 antagonist, or a pharmaceutically acceptable salt or prodrug thereof, comprising:

a) an outer shell;

b) one or more NK1 antagonist units housed within said outer shell, each comprising said netupitant or pharmaceutically acceptable salt or prodrug thereof and one or more pharmaceutically acceptable excipients; and

c) one or more palonosetron units housed within said outer shell, each comprising said palonosetron or pharmaceutically acceptable ester or prodrug thereof and one or more pharmaceutically acceptable excipients;

wherein said dosage form comprises (3S)-3-[(3aS)-1-oxo-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinoline-2-yl]-1-azoniabicyclo[2.2.2]octan-1-olate in an amount that does not exceed 3 wt. %.

35. ) The dosage form of claim 34, comprising about 0.56 mg. of palonosetron hydrochloride and from about 100 to about 500 mg, or from about 200 to about 400 mg, or about 300 mg of netupitant or a pharmaceutically acceptable salt thereof.

36. ) The dosage form of claim 34 or 35, wherein said one or more NK1 antagonist units are in the form of one or more orally administered tablets, and said palonosetron units are in the form of one or more orally administered soft-gel capsules.

37. ) The dosage form of any one of claims 34 to 36, wherein each of said tablets comprises from about 50 to about 200 mg, or from about 100 to about 150 mg, or about 100 mg of netupitant.

38. ) The capsule of any one of claims 34 to 37, wherein said outer shell of said capsule has an oxygen permeability of less than 1.0×

10<sup>−

3</sup> ml·

cm/(cm²·

24 hr. atm).

39. ) The capsule of any one of claims 34 to 38, wherein each of said soft-gel capsules comprises an inner fill composition comprising from 0.1 to 2.0 mg. of palonosetron hydrochloride.

40. ) The capsule of any one of claims 34 to 39, wherein each of said soft-gel capsules comprises an inner fill composition comprising from 75 to 98 wt. % of one or more lipophilic components.

41. ) The capsule of any one of claims 34 to 40, wherein each of said soft-gel capsules comprises an outer shell having an oxygen permeability of less than 1.0×

10<sup>−

3</sup> ml·

cm/(cm²·

24 hr. atm).

49. ) The dosage form or capsule of any one of claims 34 to 48, wherein netupitant and palonosetron are formulated in separate form and then combined in one dosage.

50. ) A method of treating emesis comprising administering to a human in need thereof the dosage form of any one of claims 34-51.

51. ) The method of claim 50 wherein said emesis is delayed-onset emesis.

42. ) An orally administered capsule dosage form comprising:

a) an outer shell;

b) one or more tablets housed within said outer shell, each comprising an NK1 antagonist or a pharmaceutically acceptable salt or prodrug thereof and one or more pharmaceutically acceptable excipients; and

c) one or more soft-gel capsules housed within said outer shell, each comprising palonosetron or a pharmaceutically acceptable ester or prodrug thereof and one or more pharmaceutically acceptable excipients;

wherein said dosage form comprises (3S)-3-[(3aS)-1-oxo-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinoline-2-yl]-1-azoniabicyclo[2.2.2]octan-1-olate in an amount that does not exceed 3 wt. %.

43. ) The capsule of claim 42 comprising about 0.56 mg. of palonosetron hydrochloride and from about 100 to about 500 mg, or from about 200 to about 400 mg, or about 300 mg of netupitant.

44. ) The capsule of claim 42 or 43, wherein said outer shell of said capsule has an oxygen permeability of less than 1.0×

10<sup>−

3</sup> ml·

cm/(cm²·

24 hr. atm).

45. ) The capsule of any one of claims 42 to 44, wherein each of said tablets comprises from about 50 to about 200 mg, or from about 100 to about 150 mg, or about 100 mg of netupitant or a pharmaceutically acceptable salt thereof.

46. ) The capsule of any one of claims 42 to 45, wherein each of said soft-gel capsules comprises an outer shell having an oxygen permeability of less than 1.0×

10<sup>−

3</sup> ml·

cm/(cm²·

24 hr. atm).

47. ) The capsule of any one of claims 42 to 46, wherein said soft-gel capsule comprises an inner fill composition comprising from 0.1 to 2.0 mg. of palonosetron hydrochloride.

48. ) The capsule of any one of claims 42 to 47, wherein said soft-gel capsule comprises an inner fill composition comprising from 75 to 98 wt. % of one or more lipophilic components.