Medicaments comprising betamimetics and a novel anticholinergic

• US 20040010003A1
• Filed: 03/24/2003
• Published: 01/15/2004
• Est. Priority Date: 04/12/2002
• 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, Pieper, Michael P., Konetzki, Ingo, Meade, Christopher John Montague, Meissner, Helmut, Banholzer, Rolf, Speck, Georg, Pohl, Gerald, Morschhaeuser, Gerd, Reichl, Richard
• Granted Patent: US 7,417,051 B2
• Time in Patent Office: Days
• US Class Current: 514/291
• 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 31/537 spiro-condensed or forming part of bridged ring systems
• 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) a salt of formula 1

wherein:

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

(b) a betamimetic 2,

or a solvate or hydrate thereof, optionally in the form of the enantiomers, mixtures of the enantiomers, or in the form of the racemates thereof, processes for preparing them and their use in the treatment of respiratory complaints.

Claims

1. A pharmaceutical composition comprising:

(a) a salt of formula 1

wherein;

X⁻

is an anion with a single negative charge; and

(b) a betamimetic 2,

or a solvate or hydrate thereof, optionally in the form of the enantiomers, mixtures of the enantiomers, or in the form of the racemates thereof.

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

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

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

4. The pharmaceutical composition according to claim 1, wherein pharmaceutical composition comprises more than one betamimetic 2.

5. The pharmaceutical composition according to claim 1, wherein the betamimetic 2 is a salmeterol salt, formoterol salt, or acid addition salt of a compound of formula 2a′

6. The pharmaceutical composition of claim 1, wherein the betamimetic 2 is a salt of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1-hydroxy-2-naphthalenecarboxylic acid, 4-phenylcinnamic acid, 5-(2,4-difluorophenyl)salicylic acid, or maleic acid.

7. The pharmaceutical composition of claim 1, wherein the betamimetic 2 is salmeterol xinafoate, salmeterol-4-phenylcinnamate, or salmeterol-5-(2,4-difluorophenyl)salicylate.

8. The pharmaceutical composition according to claim 1, wherein the betamimetic 2 is an acid addition salt of a compound of formula 2a′

9. The pharmaceutical composition according to claim 8, wherein:

R¹ and R², which are identical or different, are each hydrogen or ethyl; and

R³ and R⁴, which are identical or different, are each hydrogen, methyl, ethyl, propyl, butyl, or methoxyethyl, or

R³ and R⁴ together are butylene or —

O-ethylene-O—

.

10. The pharmaceutical composition according to claim 8, wherein the betamimetic 2 is a salt of the compound of formula 2a′

wherein;

(a) R¹ and R² are each hydrogen and R³ and R⁴ are each ethyl;

(b) R¹ and R² are each hydrogen and R³ and R⁴ are each methyl;

(c) R¹ and R² are each ethyl and R³ and R⁴ are each hydrogen;

(d) R¹ and R² are each hydrogen and R³ and R⁴ together are butylene;

(e) R¹ and R² are each hydrogen and R³ and R⁴ together are —

O-ethylene-O—

;

(f) R¹ and R² are each hydrogen and R³ and R⁴ are each tert-butyl;

(g) R¹ and R² are each hydrogen and R³ and R⁴ are each isopropyl;

or

(h) R¹ and R² are each hydrogen and R³ and R⁴ are each methoxymethyl.

11. The pharmaceutical composition according to claim 1, wherein the betamimetic 2 is salmeterol and the weight ratio of 1′

to the salmeterol 2 is in a range from about 1;

30 to 400;

1.

12. The pharmaceutical composition according to claim 1, wherein the weight ratio of 1′

to the salmeterol 2 is in a range from about 1;

25 to 200;

1.

13. The pharmaceutical composition according to claim 1, wherein the betamimetic 2 is formoterol hydrochloride, formoterol sulfate, or formoterol fumarate.

14. The pharmaceutical composition according to claim 13, wherein the weight ratio of 1′

to the formoterol 2′

is in a range from about 1;

10 to 300;

1.

15. The pharmaceutical composition according to claim 14, wherein the weight ratio of 1′

to the formoterol 2′

is in a range from about 1;

5 to 200;

1.

16. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an inhalable powder, a propellant-containing metered-dose aerosol, or a propellant-free inhalable solution or suspension.

17. The pharmaceutical composition according to claim 16, wherein the pharmaceutical composition is an inhalable powder comprising the salt of formula 1′

and the betamimetic 2 in admixture with a physiologically acceptable excipient selected from monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts, or mixtures thereof.

18. The pharmaceutical composition according to claim 17, wherein the excipient has a maximum average particle size of 250 μ

m or less.

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

m and 150 μ

m.

21. The pharmaceutical composition according to claim 16, wherein the pharmaceutical composition is a propellant-containing metered-dose aerosol comprising the salt of formula 1′

and the steroid 2 in dissolved or dispersed form.

22. The pharmaceutical composition according to claim 21, wherein the propellant gas is a hydrocarbon or halohydrocarbon.

23. The pharmaceutical composition according to claim 22, wherein the propellant gas is selected from n-propane;

n-butane;

isobutane;

or the chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane, or cyclobutane.

24. The pharmaceutical composition according to claim 22, wherein the propellant gas is selected from TG11, TG12, TG134a, TG227, or a mixture thereof.

25. The pharmaceutical composition according to claim 21, wherein the pharmaceutical composition comprises 5% by weight or less of active substance 1′

and 2′

.

26. The pharmaceutical composition according to claim 16, wherein the pharmaceutical composition is a propellant-free inhalable solution or suspension further comprising a solvent selected from water, ethanol, or a mixture thereof.

27. The pharmaceutical composition according to claim 26, further comprising a cosolvent or excipient.

28. The pharmaceutical composition according to claim 27, wherein the cosolvent is selected from an alcohol, a glycol, glycerol, a polyoxyethylene alcohol, and a polyoxyethylene fatty acid ester.

29. The pharmaceutical composition according to claim 28, wherein the cosolvent is selected from isopropyl alcohol, propyleneglycol, polyethyleneglycol, polypropyleneglycol, or glycol ether.

30. The pharmaceutical composition according to claim 27, wherein the excipient is selected from a surfactant, a stabilizer, a complexing agent, an antioxidant, a preservative, a flavoring, and a vitamin.

31. The pharmaceutical composition according to claim 30, wherein the excipient is edetic acid or a salt of edetic acid.

20. A pharmaceutical composition consisting essentially of:

(a) a salt of formula 1

wherein;

X⁻

is an anion with a single negative charge; and

(b) a betamimetic 2.