Stable epinephrine suspension formulation with high inhalation delivery efficiency

• US 8,367,734 B1
• Filed: 05/07/2010
• Issued: 02/05/2013
• Est. Priority Date: 08/11/2005
• Status: Active Grant

• Current Assignee: Amphastar Pharmaceuticals Incorporated
• Original Assignee: Amphastar Pharmaceuticals Incorporated
• Inventors: Luo, Mary Ziping, Zhang, Jack Yongfeng, Gao, Jianxin, Luo, James, Zhou, Rong
• Primary Examiner(s): ALSTRUM ACEVEDO, JAMES HENRY
• Application Number:
  US12/776,338
• Time in Patent Office: 1,005 Days
• Field of Search: 514/653, 514/728, 424/45, 424/46, 424/489
• US Class Current: 514/653
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• 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 stable suspension aerosol formulation of epinephrine is suitable for administration through inhalation comprising a therapeutically effective amount of epinephrine, hydrofluorocarbon propellant, co-solvent, surfactant, and antioxidant. The suspension aerosol formulation further comprises [pre-] pre-micronized epinephrine suspended in an alcohol/surfactant solution with hydrofluoroalkane propellant. The suspension formulation provides a highly efficient delivery of drug microparticles into the respirable region of patients'"'"' lungs and has the following advantages: lower dosage requirement, minimum alcohol content, with less impurities generated during storage, improved efficacy and safety, and exhibits no ozone depleting potential compared to a formulation containing chlorofluorocarbon.

Claims

1. An aerosol formulation for use with a metered dose inhaler comprising:

a. a suspension dosage form of pre-micronized epinephrine free base,

b. a pressure liquefied propellant comprising a hydrofluoroalkane present in an amount in a range of 98% or more w/w based on the total weight of the formulation,

c. a co-solvent selected from the group consisting of ethyl alcohol, isopropyl alcohol, propylene glycol, ethylene glycol, propane, butane, isobutene, pentane, dimethyl ether, and diethyl ether, the co-solvent being present in the aerosol formulation and the amount of the co-solvent being less than 2% w/w based on the total weight of the formulation,

d. a surfactant selected from the group consisting of mono- or poly-sorbitan oleates, oleic acid, and lecithin, and

e. an antioxidant selected from the group consisting of thymol, tocopherol, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, citric acid, sodium metabisulfite and sodium sulfite, the antioxidant being present in the formulation.

2. The aerosol formulation as specified in claim 1, wherein said pre-micronized epinephrine free base is present in an amount in a range of 0.10% to 0.50% w/w based on the total weight of the formulation.

3. The aerosol formulation as specified in claim 1, wherein 99% in weight of said pre-micronized epinephrine free base has a particle size in a range of less than 5 micrometers in diameter.

4. The aerosol formulation as specified in claim 1, wherein said liquefied propellant comprises a hydrofluoroalkane selected from the group consisting of 1,1,1,2-tetrafluoroethane (HFA-134A), 1,1,1,2,3,3,3-heptafluoropropane (HFA-227), or a mixture thereof in an amount in a range of 98% or more w/w based on the total weight of the formulation.

5. The aerosol formulation as specified in claim 1, wherein said co-solvent is ethanol in an amount in a range of 0.5% to 1.5% w/w based on the total weight of the formulation.

6. The aerosol formulation as specified in claim 1, wherein said surfactant is present in an amount of no more than 0.05% w/w based on the total weight of the formulation.

7. The aerosol formulation as specified in claim 1, wherein said antioxidant is present in an amount of no more than 0.05% w/w based on the total weight of the formulation.

8. The aerosol formulation as specified in claim 1, wherein said formulation has a fine particle fraction which improves drug delivery efficiency and allows for a lower amount of total drug dosage to achieve therapeutic benefits as compared to a formulation containing less than 98% hydrofluoroalkane.

9. An aerosol formulation for use with a metered dose inhaler comprising:

a. pre-micronized epinephrine free base suspended in a surfactant-alcoholic solution in an amount in a range of 0.1% to 0.50% w/w based on the total weight of the formulation;

b. hydrofluoroalkane propellant in an amount in a range of 98% or more w/w of the total weight of the formulation;

c. an alcohol in an amount in a range of 0.5% to 1.5% w/w based on the total weight of the formulation;

d. polysorbate in an amount of no more than 0.05% w/w based on the total weight of the formulation; and

e. thymol in an amount of no more than 0.05% w/w based on the total weight of the formulation, the thymol being present in the formulation,

wherein 99% in weight of said pre-micronized epinephrine free base has a particle size of less than 5 micrometers in diameter.

10. An aerosol formulation for use with a metered dose inhaler comprising:

a suspension dosage form of pre-micronized epinephrine free base;

a pressure liquefied propellant comprising a hydrofluoroalkane present in an amount in a range of 98% or more w/w based on the total weight of the formulation;

a co-solvent selected from the group consisting of ethyl alcohol, isopropyl alcohol, propylene glycol, ethylene glycol, propane, butane, isobutane, pentane, dimethyl ether, diethyl ether and mixtures thereof, the co-solvent being present in the aerosol formulation and the amount of the co-solvent being less than 2% w/w based on the total weight of the formulation; and

a surfactant.

11. The aerosol formulation as specified in claim 10, wherein the co-solvent is present in an amount in a range of 1% to less than 2% w/w based on the total weight of the formulation.

12. The aerosol formulation as specified in claim 10, wherein the co-solvent is present in an amount less than or equal to 1% w/w based on the total weight of the formulation.

13. The aerosol formulation as specified in claim 10, wherein the hydrofluoroalkane is present in an amount of 98% to 99% w/w based on the total weight of the formulation.