Pharmaceutical compositions for inhalation containing an anticholinergic, corticosteroid and betamimetic

• US 7,244,742 B2
• Filed: 07/23/2003
• Issued: 07/17/2007
• Est. Priority Date: 08/17/2002
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim Pharma GmbH & Company Kg (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Pharma GmbH & Company Kg (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Pairet, Michel, Meade, Christopher John Montague, Pieper, Michael Paul
• Primary Examiner(s): Richter; Johann P.
• Assistant Examiner(s): ALSTRUM ACEVEDO, JAMES HENRY
• Application Number:
  US10/625,129
• Publication Number:
  US 20040228805A1
• Time in Patent Office: 1,455 Days
• Field of Search: 424/45, 424/46, 424/489, 514/291, 546/10, 546/80, 546/91
• US Class Current: 514/291
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/008 comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]

Abstract

A pharmaceutical composition comprising:

• • (a) an anticholinergic of formula 1

wherein X⁻ is an anion with a single negative charge;

• • (b) a corticosteroid; and
  • (c) a betamimetic,
    wherein each component (a), (b), and (c) are optionally in the form of the solvates or hydrates thereof, processes for preparing them, and their use in the treatment of respiratory diseases.

Claims

1. A pharmaceutical composition comprising:

(a) an anticholinergic of formula 1

2. The pharmaceutical composition according to claim 1, further comprising a physiologically acceptable excipient.

3. The pharmaceutical composition according to claim 2, wherein the physiologically acceptable excipient is a monosaccharide, disaccharide, oligo- or polysaccharide, polyalcohol, salt, or mixture thereof.

4. The pharmaceutical composition according to claim 1, wherein:

X⁻

is selected from the group consisting of;

chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, and p-toluenesulfonate.

5. The pharmaceutical composition according to claim 1, wherein:

X⁻

is selected from the group consisting of;

chloride, bromide, methanesulfonate, and p-toluenesulfonate.

6. The pharmaceutical composition according to claim 1, wherein X⁻

is bromide.

7. The pharmaceutical composition according to claim 1, wherein the corticosteroid is selected from flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW215864, KSR592, ST-126, dexamethasone, and mixtures thereof.

8. The pharmaceutical composition according to claim 1, wherein the corticosteroid is selected from flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, dexamethasone, and mixtures thereof.

9. The pharmaceutical composition according to claim 1, wherein the betamimetic is selected from bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoteri, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulfonterol, terbutaline, tolubuterol, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3 -oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino5ethanol, 1-[2H-5-hydroxy-3-oxo-4H- 1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino

ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H- 1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanol, 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol, and mixtures thereof.

10. The pharmaceutical composition according to claim 1, wherein the betamimetic is selected from formoterol, salmeterol, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2F1-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, and mixtures thereof.

11. The pharmaceutical composition according to one of claims 1 to 10, wherein the weight ratio of the anticholinergic in the form of its cation to the corticosteroid is in the range from 1:

250 to 250;

1.

12. The pharmaceutical composition according to one of claims 1 to 10, wherein the weight ratio of anticholinergic to the betamimetic is in the range from 1:

300 to 30;

1.

13. The pharmaceutical composition according to one of claims 1 to 10, wherein the total amount of the anticholinergic, the corticosteroid, and the betamimetic is 1 μ

g to 10000 μ

g.

14. The pharmaceutical composition according to claim 1, wherein the total amount of the anticholinergic, the corticosteroid, and the betamimetic is 10 μ

g to 2000 μ

g.

15. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is in a form suitable for inhalation.

16. The pharmaceutical composition according to claim 15, wherein the pharmaceutical composition is an inhalable powder, or a propellant-free inhalable solution or suspension.

17. The pharmaceutical composition according to one of claims 2 to 10, wherein the pharmaceutical composition is in a form suitable for inhalation.

18. The pharmaceutical composition according to one of claims 2 or 3, wherein the pharmaceutical composition is an inhalable powder and the physiologically acceptable excipient has a maximum average particle size of up to 250 μ

m.

19. The pharmaceutical composition according to claim 18, wherein the physiologically acceptable excipient has a maximum average particle size of between 10 μ

m and 150 μ

m.

20. A capsule containing inhalable powder according to claim 18.

21. A pharmaceutical composition consisting essentially of:

(a) an anticholinergic of formula 1