Medicinal aerosol formulations

• US 6,475,467 B1
• Filed: 04/20/2001
• Issued: 11/05/2002
• Est. Priority Date: 08/04/1998
• Status: Expired due to Term

• Current Assignee: Jagotec Ag (Vectura Group Ltd.)
• Original Assignee: Jago Research AG
• Inventors: Keller, Manfred, Müller-Walz, Rudi, Kraus, Holger, Herzog, Kurt
• Primary Examiner(s): Dees, Jose′ G.
• Assistant Examiner(s): HAGHIGHATIAN, MINA
• Application Number:
  US09/744,798
• Time in Patent Office: 564 Days
• Field of Search: 424/283, 424/45, 424/451, 424/47, 424/46, 424/489, 128/200.14, 128/200.24
• US Class Current: 424/45
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 9/008 comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• CPC Class Codes: A61K 9/124 characterised by the propellant
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The use of solid, pharmaceutically acceptable salts of cromoglycic acid and/or nedocromil as carriers in a therapeutically and prophylactically inefficacious amount in suspension aerosol formulations of pharmaceutical active compounds improves the dispersion properties, increases the chemical and physical stability of moisture-sensitive active compounds, makes possible a more accurate dosage, in particular even of low-dose active compounds, and as a rule permits the abandonment of surface-active agents.

Claims

1. A medicinal aerosol formulation, comprising a solid, pharmaceutically acceptable salt of at least one compound selected from the group consisting of cromoglycic acid and nedocromil, in a therapeutically and prophylactically inefficacious amount in the range from 5 to 250 μ

g per puff of spray, an efficacious amount of a finely divided pharmaceutically active compound which is different from said salt, having a mean particle diameter of less than 6 μ

m, and a non-toxic liquid propellant, in which said active compound is present in suspended form.

2. The aerosol formulation as claimed in claim 1, wherein said salt is selected from the group consisting of alkali metal salts and alkaline earth metal salts.

3. The aerosol formulation as claimed in claim 1, wherein said salt is selected from the group consisting of disodium cromoglycate and nedocromil sodium.

4. The aerosol formulation as claimed in claim 1, wherein said salt is present in suspended form having a particle size of less than 6 μ

m.

5. The aerosol formulation as claimed in claim 1, wherein said salt is present in an amount of from 10 to 100 μ

g, per puff of spray.

6. The aerosol formulation as claimed in claim 1, wherein said salt and said suspended pharmaceutically active compound are present in a weight ratio of said salt to the suspended pharmaceutically active compound of from 10:

1 to 1;

10.

7. The aerosol formulation as claimed in claim 1, wherein said pharmaceutically active compound is selected from the group consisting of beta-mimetics, anticholinergics, antiallergics and antiinflammatory active compounds.

8. The aerosol formulation as claimed in claim 1, wherein said pharmaceutically active compound is selected from the group consisting of formoterol, salmeterol, fenoterol, clenbuterol, levalbuterol, ipratropium, oxitropium, glycopyrronium, tiotropium, budesonide, ciclesonide, mometasone, fluticasone, beclomethasone, flunisolide, loteprednol, triamcinolone, amiloride, rofleponide and pharmaceutically acceptable salts and derivatives thereof.

9. The aerosol formulation as claimed in claim 1, wherein the suspended active compound is present in an amount of from 0.0001% to 0.2% by weight, based on the total weight of the formulation.

10. The aerosol formulation as claimed in claim 1, wherein said pharmaceutically active compound comprises at least one compound selected from the group consisting of fluticasone, ipratropium, oxitropium, glycopyrronium, tiotropium, budesonide, mometasone, ciclesonide, rofleponide and pharmaceutically acceptable salts and derivatives thereof, and the aerosol formulation further comprising an active compound selected from the group consisting of levalbuterol, formoterol, salmeterol and pharmaceutically acceptable derivatives thereof.

11. The aerosol formulation as claimed in claim 1, wherein the propellant comprises one or more hydrofluoroalkanes of formula

12. The aerosol formulation as claimed in claim 1, wherein said propellant comprises at least one compound selected from the group consisting of 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoropropane.

13. The aerosol formulation as claimed in claim 1, further comprising at least one compound selected from the group consisting of dinitrogen monoxide and carbon dioxide in an amount of from 0.0001% to 10% by weight, based on the total weight of the formulation.

14. The aerosol formulation as claimed in claim 1, having a pressure of 3 to 10 bar at 20°

C.

15. The aerosol formulation as claimed in claim 1, further comprising a cosolvent.

16. The aerosol formulation as claimed in claim 15, comprising at most 15% by weight of said cosolvent, based on the total weight of the formulation.

17. The aerosol formulation as claimed in claim 1, being essentially free of surface-active agents.

18. The aerosol formulation as claimed in claim 1, wherein said salt is selected from the group consisting of sodium salts and potassium salts.

19. The aerosol formulation as claimed in claim 1, wherein said salt and said suspended pharmaceutically active compound are present in a weight ratio of said salt to said suspended pharmaceutically active compound of from 5:

1 to 1;

5.

20. The aerosol formulation as claimed in claim 1, wherein said suspended pharmaceutically active compound is present in an amount of from 0.0001% to 0.1% by weight, based on the total weight of the formulation.

21. The aerosol formulation as claimed in claim 1, further comprising at least one compound selected from the group consisting of dinitrogen monoxide and carbon dioxide in an amount of from 0.01% to 3% by weight, based on the total weight of the formulation.

22. The aerosol formulation as claimed in claim 1, having a pressure of 3.5 to 6 bar at 20°

C.

23. The aerosol formulation as claimed in claim 15, wherein said cosolvent is at least one compound selected from the group consisting of ethanol, glycerol, propylene glycol and diethyl ether.

24. A method of improving dosage accuracy of a medicinal suspension aerosol formulation comprising a finely divided pharmaceutically active compound having a mean particle diameter of less than 6 μ

m, and a non-toxic liquid propellant, in which the active compound is present in suspended form, said method comprising adding to said formulation a solid, pharmaceutically acceptable salt of at least one compound selected from the group consisting of cromoglycic acid and nedocromil, in a therapeutically and prophylactically inefficacious amount.

25. A method of reducing moisture sensitivity of a suspended pharmaceutically active compound in a medicinal suspension aerosol formulation comprising said pharmaceutically active compound in finely divided form having a mean particle diameter of less than 6 μ

m, and a non-toxic liquid propellant, in which said active compound is present in suspended form, said method comprising adding to said formulation a solid, pharmaceutically acceptable salt of at least one compound selected from the group consisting of cromoglycic acid and nedocromil, in a therapeutically and prophylactically inefficacious amount.