COMBINATIONS OF A MUSCARINIC RECEPTOR ANTAGONIST AND A BETA-2 ADRENORECEPTOR AGONIST
Combinations of a muscarinic acetylcholine receptor antagonist and a beta 2 agonist for inhaled administration via the nose or mouth, and methods of using them are provided.
1 . A method of treating chronic obstructive pulmonary disease in a human comprising: the once per day administration to said human of a pharmaceutical combination product, comprising:
a) a compound of the formula:
wherein X − is a pharmaceutically acceptable anion, 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)) in the form of a dry powder;
wherein Compounds (I) and (II) are presented in a form adapted for simultaneous administration.
2 . The method 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 method according to claim 2 , wherein Compound (I) is 4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxyl]ethyl}-1-azoniabicyclo[2.2.2] octane bromide.
4 . The method 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 method 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 method according to claim 1 , wherein the pharmaceutical product is in a form suitable for administration by inhalation via a medicament dispenser, and 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 method 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 method according to claim 7 , wherein each separate dry powder composition or the admixed dry powder composition contains a carrier, which is lactose.
9 . The method according to claim 8 , wherein each separate or the admixed composition contains a ternary agent.
10 . The method according to claim 9 , wherein the ternary agent is magnesium stearate.
11 . The method 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 method 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 method 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 method 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 method 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 method 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 method 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 method according to claim 17 , wherein each separate dry powder composition or the admixed dry powder composition contains a carrier, which is lactose.
19 . The method according to claim 18 , wherein each separate or the admixed composition contains a ternary agent.
20 . The method according to claim 19 , wherein the ternary agent is magnesium stearate.
21 . The method 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 method of treating chronic obstructive pulmonary disease (COPD) in a human comprising:
simultaneously administering, via inhalation, to said human, once per day, a pharmaceutical combination product comprising:
a) a first dry powder composition comprising:
(i) 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) 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 method 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 method according to claim 23 , wherein for Compound (I) the pharmaceutically acceptable anion is bromide.
25 . The method 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 method 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 method 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) present in an amount of about 100 mcg/dose.
28 . The method 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) present in an amount of about 100 mcg/dose.
29 . The method 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) present in an amount of about 100 mcg/dose.
30 . The method 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) present in an amount of about 100 mcg/dose.
31 . The method according to claim 26 , wherein pharmaceutical combination product further comprises 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16a-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate) present in an amount of about 100 mcg/dose.
32 . A method of treating chronic obstructive pulmonary disease (COPD) in a human comprising:
simultaneously administering, via inhalation, to said human, once per day, a pharmaceutical combination product comprising:
a) a first dry powder composition comprising:
(i) a compound of the formula:
wherein X − is a pharmaceutically acceptable anion;
(ii) 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); and
(ii) carrier excipient.
33 . The method according to claim 32 , 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.
34 . The method according to claim 33 , wherein for Compound (I) the pharmaceutically acceptable anion is bromide.
35 . The method according to claim 32 , wherein Compound (II) is 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol triphenylacetate.
36 . The method according to claim 34 , wherein Compound (II) is 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol triphenylacetate.
37 . The method of claim 32 , wherein the carrier excipient comprises lactose, and the ternary agent comprises magnesium stearate.
38 . The method of claim 37 , 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.
39 . The method according to claim 38 , 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.
40 . The method of claim 36 , wherein the carrier excipient comprises lactose, and the ternary agent comprises magnesium stearate.
41 . The method of claim 40 , 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.
42 . The method according to claim 41 , 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.
43 . The method according to claim 10 , wherein the ternary agent is magnesium stearate, present in an amount of about 0.6% w/w of a composition of Compound (I).
44 . The method according to claim 10 , wherein the ternary agent is magnesium stearate, present in an amount of about 1.0% w/w of a composition of Compound (II).
45 . The method according to claim 10 , 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).
46 . The method according to claim 20 , wherein the ternary agent is magnesium stearate, present in an amount of about 0.6% w/w of a composition of Compound (I).
47 . The method according to claim 20 , wherein the ternary agent is magnesium stearate, present in an amount of about 1.0% w/w of a composition of Compound (II).
48 . The method according to claim 20 , 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).
49 . The method according to claim 20 , 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).
50 . The method according to claim 49 , wherein the fluticasone furoate is present in an amount of about 100 mcg/dose.
51 . The method of claim 49 , 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.
52 . The method according to claim 51 , wherein Compound (I) and Compound (II) are presented in (i) separate dry powder compositions or (ii) an admixed dry powder composition.
53 . The method according to claim 52 , wherein each separate dry powder composition or the admixed dry powder composition contains a carrier, which is lactose.
54 . The method according to claim 53 , wherein each separate or the admixed composition contains a ternary agent.
55 . The method according to claim 54 , wherein the ternary agent is magnesium stearate.
56 . The method according to claim 55 , 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).
57 . The method 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.