Unit doses, aerosols, kits, and methods for treating heart conditions by pulmonary administration

• US 10,441,537 B2
• Filed: 05/10/2018
• Issued: 10/15/2019
• Est. Priority Date: 05/10/2017
• Status: Active Grant

• Current Assignee: Incarda Therapeutics, Inc.
• Original Assignee: Incarda Therapeutics, Inc.
• Inventors: Schuler, Carlos, Narasimhan, Rangachari, Belardinelli, Luiz, Madhavapeddi, Prashanti
• Primary Examiner(s): Pak, John
• Assistant Examiner(s): Branson, Daniel L
• Application Number:
  US15/976,516
• Publication Number:
  US 20180325818A1
• Time in Patent Office: 523 Days
• Field of Search: None
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• 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: A61M 15/00 Inhalators drug delivery in endotracheal tubes A61M16/04
• CPC Class Codes: A61P 9/06 Antiarrhythmics

Abstract

Methods of treating a heart condition include administering by inhalation an effective amount of at least one antiarrhythmic pharmaceutical agent to a patient in need thereof. Nebulized drug product and kits are also contemplated.

Claims

1. An inhalation pharmaceutical composition comprising a unit dose of an antiarrhythmic agent in a liquid solution that is therapeutically effective for treating atrial arrhythmia in a human subject in need thereof, wherein said antiarrhythmic agent is selected from the group consisting of:

flecainide, a salt thereof, and a solvate thereof, wherein said unit dose of said antiarrhythmic agent is about 50 mg to about 350 mg, wherein a concentration of said antiarrhythmic agent in said unit dose is about 35 to about 60 mg/mL, and wherein said pharmaceutical composition is formulated for administration via inhalation.

2. The inhalation pharmaceutical composition of claim 1, wherein said unit dose of said antiarrhythmic agent, when administered to a healthy subject via inhalation, has a maximum Δ

QRS of from about 1 to about 100 msec as measured by electrocardiography in a human pharmacokinetics/pharmacodynamics study.

3. The inhalation pharmaceutical composition of claim 2, wherein said maximum Δ

QRS is from about 3 to about 20 msec.

4. The inhalation pharmaceutical composition of claim 1, wherein said unit dose of said antiarrhythmic agent, when administered to a healthy subject via inhalation, has a maximum Δ

QRS same as or greater than a maximum Δ

QRS achieved by a second amount of said antiarrhythmic agent when administered intravenously to said subject as measured by electrocardiography in a human pharmacokinetics/pharmacodynamics study, wherein said unit dose is less than half of said second amount.

5. The inhalation pharmaceutical composition of claim 1, wherein said concentration of said antiarrhythmic agent is about 35 to about 50 mg/mL.

6. The inhalation pharmaceutical composition of claim 1, wherein said concentration of said antiarrhythmic agent is about 45 mg/mL.

7. The inhalation pharmaceutical composition of claim 1, wherein said concentration of said antiarrhythmic agent is 45 mg/mL.

8. The inhalation pharmaceutical composition of claim 1, comprising about 60 to about 130 mg of said antiarrhythmic agent.

9. The inhalation pharmaceutical composition of claim 1, comprising about 50 to about 90 mg of said antiarrhythmic agent.

10. The inhalation pharmaceutical composition of claim 1, wherein a volume of said liquid solution in said unit dose is about 1 mL to about 6 mL.

11. The inhalation pharmaceutical composition of claim 1, wherein said antiarrhythmic agent comprises flecainide acetate.

12. The inhalation pharmaceutical composition of claim 1, further comprising a pH buffer prepared from acetic acid.

13. The inhalation pharmaceutical composition of claim 1, wherein a pH of said inhalation pharmaceutical composition is from 5.0 to 6.5.

14. The inhalation pharmaceutical composition of claim 1, wherein said inhalation pharmaceutical composition has physiological isotonicity.

15. The inhalation pharmaceutical composition of claim 1, wherein said unit dose of said antiarrhythmic agent, when administered to a healthy subject via inhalation, has a T_max of from about 0.2 to about 5 minutes as measured in a human pharmacokinetics/pharmacodynamics study.

16. The inhalation pharmaceutical composition of claim 1, wherein said unit dose of said antiarrhythmic agent, when administered to a healthy subject via inhalation, has a C_max of from about 100 to about 250 ng/mL as measured in a human pharmacokinetics/pharmacodynamics study.

17. The inhalation pharmaceutical composition of claim 1, wherein said unit dose of said antiarrhythmic agent, when administered to a healthy subject via inhalation, has a AUC_Last of from about 100 to about 10000 hr*ng/mL as measured in a human pharmacokinetics/pharmacodynamics study.

18. The inhalation pharmaceutical composition of claim 17, wherein said AUC_Last is from about 200 to about 2000 hr*ng/mL.

19. The inhalation pharmaceutical composition of claim 1, wherein said unit dose of said antiarrhythmic agent, when administered to a healthy subject via inhalation, has a distribution t_1/2 of from about 0.1 to about 15 minutes as measured in a human pharmacokinetics/pharmacodynamics study.

20. The inhalation pharmaceutical composition of claim 19, wherein said distribution t_1/2 is from about 3 to about 5 minutes.

21. The inhalation pharmaceutical composition of claim 1, wherein said unit dose of said antiarrhythmic agent, when administered to a healthy subject via inhalation, has an elimination t_in, of from about 1 to about 25 hours as measured in a human pharmacokinetics/pharmacodynamics study.

22. The inhalation pharmaceutical composition of claim 21, wherein said elimination t_1/2 is from about 8.5 to about 10.5 hours.

23. A kit comprising the inhalation pharmaceutical composition of claim 1 and an aerosolization device.