Method of stabilizing aerosol formulations

• US 5,376,359 A
• Filed: 07/07/1992
• Issued: 12/27/1994
• Est. Priority Date: 07/07/1992
• Status: Expired due to Term

• Current Assignee: Glaxo, Inc. (Glaxo Holdings Plc)
• Original Assignee: Glaxo, Inc. (Glaxo Holdings Plc)
• Inventors: Johnson, Keith A.
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US07/909,596
• Time in Patent Office: 903 Days
• Field of Search: 424/45, 424/46, 424/78.37, 424/489, 514/957, 514/958, 514/970, 514/772.3, 514/826, 514/856-859, 514/869, 514/929
• US Class Current: 424/46
• 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: C09K 3/30 for aerosols aerosol containers B65D83/14

Abstract

A method of making a stabilized aerosol drug formulation is disclosed, along with the formulations so produced and metered drug inhalers containing the same. The method comprises combining a solid particulate drug composition with a fluoropolymer in a liquid fluorocarbon aerosol propellant to form a stable suspension. Further stabilization can be achieved by cooling the suspension for a time and to a temperature sufficient to adsorb the fluoropolymer to the solid particulate drug composition in the liquid fluorocarbon aerosol propellant. Preferred propellants for carrying out the invention are 1,1,1,2-tetrafluoroethane, heptafluoropropane, and mixtures thereof, and preferred fluoropolymers for carrying out the invention are fluoropolyethers.

Claims

1. A method of adsorbing a solid particulate drug to a fluoropolymer useful for making a stabilized aerosol drug formulation, comprising:

combining a solid particulate drug with a fluoropolymer in an organic liquid fluorocarbon aerosol propellant to form a liquid suspension, wherein said fluoropolymer is soluble in said liquid fluorocarbon aerosol propellant, wherein said fluoropolymer is included in said suspension in an amount of from 0.001% to 20% by weight, and wherein said drug is included in said suspension in an amount of from 0.001% to 5% by weight; and

cooling said suspension for a time and to a temperature sufficient to adsorb said fluoropolymer to said solid particulate drug in said liquid fluorocarbon aerosol propellant, wherein said fluoropolymer is adsorbed to said drug so that said formulation is stabilized.

2. The method of claim 1, wherein said fluoropolymer is a fluoropolyether.

3. The method of claim 1, wherein said fluoropolymer has a molecular weight of from 500 to 25,000 grams per gram mole.

4. The method of claim 1, wherein said fluoropolymer is included in said suspension in an amount of from 0.1% to 10% by weight.

5. The method of claim 1, wherein said drug is included in said suspension in an amount of from 0.005% to 0.5% by weight.

6. The method of claim 1, wherein said propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane and heptafluoropropane.

7. The method of claim 1, wherein said solid particulate drug is a micronized drug.

8. The method of claim 1 wherein said drug is selected from the group consisting of albuterol, salmeterol, amiloride, fluticasone esters, beclomethasone esters and (-)-4-amino-3,5-dichloro-α

-[[[6-(2-pyridinyl)ethoxy]hexyl]amino]methyl benzenemethanol.

9. The method of claim 1 wherein said drug is albuterol.

10. A method of adsorbing a solid particulate drug to a fluoropolymer useful for making a metered-dose inhaler containing a stabilized aerosol drug formulation, comprising:

combining a solid particulate drug with a fluoropolymer in an organic liquid fluorocarbon aerosol propellant to form a suspension, wherein said fluoropolymer is soluble in said liquid fluorocarbon aerosol propellant, wherein said fluoropolymer is included in said suspension in an amount of from 0.001% to 20% by weight, and wherein said drug is included in said suspension in an amount of from 0.001% to 5% by weight;

cooling said suspension for a time and to a temperature sufficient to adsorb said fluoropolymer to said solid particulate drug in said liquid fluorocarbon; and

packaging said suspension in a metered dose inhaler;

wherein said cooling step is carried out before, after, or concurrently with said packaging step, wherein said fluoropolymer is adsorbed to said drug so that said formulation is stabilized.

11. A method according to claim 10, wherein said cooling step is carried out before said packaging step.

12. A method according to claim 10, wherein said cooling step is carried out after said packaging step.

13. A method according to claim 10, wherein said cooling step is carried out concurrently with said packaging step.

14. The method of claim 11, wherein said fluoropolymer is a fluoropolyether.

15. The method of claim 10, wherein said fluoropolymer has a molecular weight of from 500 to 25,000 grams per gram mole.

16. The method of claim 10, wherein said fluoropolymer is included in said suspension in an amount of from 0.1% to 10% by weight.

17. The method of claim 10, wherein said drug is included in said suspension in an amount of from 0.005% to 0.5% by weight.

18. The method of claim 10, wherein said propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane, heptafluoropropane, and mixtures thereof.

19. The method of claim 10, wherein said solid particulate drug is a micronized drug.

20. The method of claim 11 wherein said drug is selected from the group consisting of albuterol, salmeterol, amiloride, fluticasone esters, beclomethasone esters and (-)-4-amino-3,5-dichloro-α

-[[[6-(2-pyridinyl)ethoxy]hexyl]amino]methyl benzenemethanol.

21. The method of claim 10 wherein said drug is albuterol.