Combinations of a muscarinic receptor antagonist and a β-2 adrenoreceptor agonist

Patent metadata

Field	Value
Publication number	US-12396986-B2
Application number	US-202318485799-A
Country	US
Kind code	B2
Filing date	Oct 12, 2023
Priority date	Dec 1, 2009
Publication date	Aug 26, 2025
Grant date	Aug 26, 2025

Abstract

Combinations of a muscarinic acetylcholine receptor antagonist and a beta 2 agonist for inhaled administration via the nose or mouth, compositions thereof, and methods of using them are provided.

First claim

The invention claimed is:

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-fura

Assignees

• Glaxo Group Ltd

Inventors

• Baker Darrell
• Bruce Mark
• Crater Glenn
• Noga Brian
• Thomas Marian
• Wire Patrick

Classifications

• B65D75/36

  one sheet or blank being recessed and the other formed of relatively stiff flat sheet material, e.g. blister packages {, the recess or recesses being preformed (B65D73/0057, B65D73/0092 take precedence)} · CPC title

• A61K9/0075

  for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles · CPC title

• C07H15/26

  Acyclic or carbocyclic radicals, substituted by hetero rings · CPC title

• C07H15/203

  Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems · CPC title

• A61K31/7052

  having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides · CPC title