Granted Patent B2

US 12,396,986 · App. 18/485,799 · Granted Aug 26, 2025

Inventors: Darrell Baker (Uxbridge, GB); Mark Bruce (Stevenage, GB); Glenn Crater (Mississauga, CA); Brian Noga (Durham, NC); Marian Thomas (Ware, GB); Patrick Wire (Durham, NC)

Assignee: Glaxo Group Limited

A61K31/439A61K9/0075A61K31/138A61K31/7052A61K45/06A61P31/04B65D75/36C07H15/203C07H15/26

Abstract

Claims (81)

1. A pharmaceutical combination product comprising

a) a compound of the formula

wherein

X − is a pharmaceutically acceptable anion wherein Compound (I) is in an amount of about 62.5 mcg/dose in the combination product, and is in the form of a dry powder; and b) 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol,

or a pharmaceutically acceptable salt thereof (Compound II),

wherein Compound (II) is in an amount of about 25 mcg/dose in the combination product, and is in the form of a dry powder,

wherein said pharmaceutical combination product is suitable for once daily administration, and

wherein compounds (a) and (b) are presented in a form adapted for simultaneous administration.

2. The combination product according to claim 1 , wherein for Compound (I) the pharmaceutically acceptable anion is selected from the group consisting of chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate or p-toluenesulfonate.

3. The combination product according to claim 2 , wherein Compound (I) is 4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane bromide.

4. The combination product according to claim 1 , wherein Compound (II) is 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol triphenylacetate.

5. The combination product according to claim 3 , wherein Compound (II) is 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol triphenylacetate.

6. The combination product according to claim 1 , wherein the pharmaceutical product is in a form suitable for administration by inhalation via a medicament dispenser, wherein said medicament dispenser is selected from the group consisting of a reservoir dry powder inhaler, a unit-dose dry powder inhaler, and a pre-metered multi-dose dry powder inhaler.

7. The combination product according to claim 6 , wherein Compound (I) and Compound (II) are presented in (i) separate dry powder compositions or (ii) an admixed dry powder composition.

8. The combination product according to claim 7 , wherein each separate dry powder composition or the admixed dry powder composition contains a carrier, which is lactose.

9. The combination product according to claim 8 , wherein each separate or the admixed composition contains a ternary agent.

10. The combination product according to claim 9 , wherein the ternary agent is magnesium stearate.

11. The combination product according to claim 7 , wherein said separate or admixed composition is in unit dose form, and further wherein the unit dose form is selected from the group consisting of a capsule, a cartridge and a blister.

12. The combination product according to claim 1 , wherein the pharmaceutical combination product further comprises 6α, 9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate).

13. The combination product according to claim 12 , wherein the 6α, 9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate) is present in an amount of about 100 mcg/dose.

14. The combination product according to claim 5 , wherein the pharmaceutical combination product further comprises 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate).

15. The combination product according to claim 14 , wherein the 6α, 9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate) is present in an amount of about 100 mcg/dose.

16. The combination product according to claim 5 , wherein the pharmaceutical product is in a form suitable for administration by inhalation via a medicament dispenser, wherein said medicament dispenser is selected from the group consisting of a reservoir dry powder inhaler, a unit-dose dry powder inhaler, and a pre-metered multi-dose dry powder inhaler.

17. The combination product according to claim 16 , wherein Compound (I) and Compound (II) are presented in (i) separate dry powder compositions or (ii) an admixed dry powder composition.

18. The combination product according to claim 17 , wherein each separate dry powder composition or the admixed dry powder composition contains a carrier, which is lactose.

19. The combination product according to claim 18 , wherein each separate or the admixed composition contains a ternary agent.

20. The combination product according to claim 19 , wherein the ternary agent is magnesium stearate.

21. The combination product according to claim 17 , wherein said separate or admixed compositions is in unit dose form, and further wherein the unit dose form is selected from the group consisting of a capsule, a cartridge and a blister.

22. A pharmaceutical combination product comprising

a) a first dry powder composition comprising:

(i) about 62.5 mcg/dose of a compound of the formula:

wherein X − is a pharmaceutically acceptable anion;

(ii) lactose; and

(iii) magnesium stearate in an amount of about 0.6% w/w of said first dry powder composition; and

b) a second dry powder composition comprising:

(i) about 25 mcg/dose of 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol, or a pharmaceutically acceptable salt thereof (Compound (II));

(ii) lactose; and

(iii) magnesium stearate in an amount of about 1.0% w/w of said second dry powder composition.

23. The combination product according to claim 22 , wherein for Compound (I), the pharmaceutically acceptable anion is selected from the group consisting of chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate or p-toluenesulfonate.

24. The combination product according to claim 23 , wherein for Compound (I) the pharmaceutically acceptable anion is bromide.

25. The combination product according to claim 22 , wherein Compound (II) is 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol triphenylacetate.

26. The combination product according to claim 24 , wherein Compound (II) is 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol triphenylacetate.

27. The combination product according to claim 22 , wherein pharmaceutical combination product further comprises 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate).

28. The combination product according to claim 23 , wherein pharmaceutical combination product further comprises 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate).

29. The combination product according to claim 24 , wherein pharmaceutical combination product further comprises 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate).

30. The combination product according to claim 25 , wherein pharmaceutical combination product further comprises 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate).

31. A pharmaceutical combination product comprising

a) a first dry powder composition comprising:

(i) about 62.5 mcg/dose of a compound of the formula:

wherein X − is a pharmaceutically acceptable anion;

(ii) about 25 mcg/dose of 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol, or a pharmaceutically acceptable salt thereof (Compound (II));

(iii) carrier excipient; and

(iv) a ternary agent, and

(b) a second dry powder composition comprising:

(i) 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate), present in an amount of about 100 mcg/dose; and

(ii) carrier excipient.

32. The combination product according to claim 31 , wherein for Compound (I), the pharmaceutically acceptable anion is selected from the group consisting of chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate or p-toluenesulfonate.

33. The combination product according to claim 32 , wherein for Compound (I) the pharmaceutically acceptable anion is bromide.

34. The combination product according to claim 31 , wherein Compound (II) is 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol triphenylacetate.

35. The combination product according to claim 33 , wherein Compound (II) is 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol triphenylacetate.

36. The combination product of claim 31 , wherein the carrier excipient comprises lactose, and the ternary agent comprises magnesium stearate.

37. The combination product of claim 36 , wherein the pharmaceutical combination product is administered via a medicament dispenser, wherein said medicament dispenser is selected from the group consisting of a reservoir dry powder inhaler, a unit-dose dry powder inhaler, and a pre-metered multi-dose dry powder inhaler.

38. The combination product according to claim 37 , wherein each of said first and second dry powder compositions is in unit dose form, wherein said unit dose forms are independently selected from the group consisting of a capsule, a cartridge and a blister.

39. The combination product of claim 35 , wherein the carrier excipient comprises lactose, and the ternary agent comprises magnesium stearate.

40. The combination product of claim 39 , wherein the pharmaceutical combination product is administered via a medicament dispenser, wherein said medicament dispenser is selected from the group consisting of a reservoir dry powder inhaler, a unit-dose dry powder inhaler, and a pre-metered multi-dose dry powder inhaler.

41. The combination product according to claim 40 , wherein each of said first and second dry powder compositions are in unit dose form, wherein said unit dose forms are independently selected from the group consisting of a capsule, a cartridge and a blister.

42. The combination product according to claim 9 , wherein the ternary agent is magnesium stearate, present in an amount of about 0.6% w/w of a composition of Compound (I).

43. The combination product according to claim 9 , wherein the ternary agent is magnesium stearate, present in an amount of about 1.0% w/w of a composition of Compound (II).

44. The combination product according to claim 9 , wherein the ternary agent is magnesium stearate, present in an amount of about 0.6% w/w of a composition of Compound (I) and in an amount of about 1.0% w/w of a composition of Compound (II).

45. The combination product according to claim 19 , wherein the ternary agent is magnesium stearate, present in an amount of about 0.6% w/w of a composition of Compound (I).

46. The combination product according to claim 19 , wherein the ternary agent is magnesium stearate, present in an amount of about 1.0% w/w of a composition of Compound (II).

47. The combination product according to claim 19 , wherein the ternary agent is magnesium stearate, present in an amount of about 0.6% w/w of a composition of Compound (I) and in an amount of about 1.0% w/w of a composition of Compound (II).

48. The combination product according to claim 19 , wherein the pharmaceutical combination product further comprises 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate).

49. The combination product according to claim 48 , wherein the fluticasone furoate is present in an amount of about 100 mcg/dose.

50. The combination product of claim 48 , wherein the pharmaceutical combination product is administered via a medicament dispenser, wherein said medicament dispenser is selected from the group consisting of a reservoir dry powder inhaler, a unit-dose dry powder inhaler, and a pre-metered multi-dose dry powder inhaler.

51. The combination product according to claim 50 , wherein Compound (I) and Compound (II) are presented in (i) separate dry powder compositions or (ii) an admixed dry powder composition.

52. The combination product according to claim 51 , wherein each separate dry powder composition or the admixed dry powder composition contains a carrier, which is lactose.

53. The combination product according to claim 52 , wherein each separate or the admixed composition contains a ternary agent.

54. The combination product according to claim 53 , wherein the ternary agent is magnesium stearate.

55. The combination product according to claim 54 , wherein the magnesium stearate is present in a composition comprising Compound (II), in an amount of about 1.0% w/w of the composition comprising Compound (II).

56. The combination product according to claim 50 , wherein said dry powder compositions are in unit dose form, wherein each of said unit dose forms are independently selected from the group consisting of a capsule, a cartridge or a blister.

Assignments (1)

Priority Claims (1)

Continuity (6)

References Cited (400)