Preservative free insulin formulations and systems and methods for aerosolizing

• US 9,180,261 B2
• Filed: 01/11/2011
• Issued: 11/10/2015
• Est. Priority Date: 01/12/2010
• Status: Active Grant

• Current Assignee: Aerami Therapeutics, Inc. (Dance Biopharm Holdings, Inc.)
• Original Assignee: Dance BioPharm Incorporated (Dance Biopharm Holdings, Inc.)
• Inventors: Patton, John S., Patton, Ryan S., Kuo, Mei-chang, Ivri, Yehuda
• Primary Examiner(s): YOUNG, RACHEL T
• Application Number:
  US13/004,645
• Publication Number:
  US 20110168170A1
• Time in Patent Office: 1,764 Days
• Field of Search: 12820014-20018
• US Class Current: 1/1
• CPC Class Codes: A61K 33/30 Zinc; Compounds thereof
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/122 Foams; Dry foams edible foams A61K9/0056
• CPC Class Codes: A61M 11/00 Sprayers or atomisers specially adapted for therapeutic purposes in general B05B; aerosol containers B65D83/14
• CPC Class Codes: A61M 11/001 Particle size control
• CPC Class Codes: A61M 11/005 using ultrasonics spraying or atomising liquids using ultrasonic vibrations in general B05B17/06
• CPC Class Codes: A61M 15/0021 Mouthpieces therefor
• CPC Class Codes: A61M 15/0028 using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
• CPC Class Codes: A61M 15/0065 Inhalators with dosage or measuring devices A61M15/0028 takes precedence; dosage devices incorporated in aerosol cans B65D83/52
• CPC Class Codes: A61M 15/0085 using ultrasonics spraying or atomising liquids using ultrasonic vibrations in general B05B17/06
• CPC Class Codes: A61M 15/009 using medicine packages with incorporated spraying means, e.g. aerosol cans pocket atomiser of the injector type A61M11/08
• CPC Class Codes: A61M 15/0091 mechanically breath-triggered
• CPC Class Codes: A61M 2016/0021 with a proportional output signal, e.g. from a thermistor
• CPC Class Codes: A61M 2016/0039 in the inspiratory circuit
• CPC Class Codes: A61M 2202/0468 non-physiological
• CPC Class Codes: A61M 2205/3334 Measuring or controlling the flow rate
• CPC Class Codes: A61M 2205/583 by visual feedback
• CPC Class Codes: A61M 2205/587 Lighting arrangements
• CPC Class Codes: A61M 2209/045 for filling, e.g. for filling reservoirs
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics

Abstract

One embodiment describes an insulin formulation that is specifically adapted for aerosolization. The formulation includes a major amount of water and a minor amount of insulin. Further, the formulation is preservative free, without meta-cresol, cresol or phenol, to permit the formulation to be aerosolized using a vibrating aperture plate without substantial foaming of the insulin formulation.

Claims

1. A method for aerosolizing an insulin formulation, the method comprising:

providing a preservative free insulin formulation comprising a major amount of water, and minor amounts of insulin, HCl and NaOH;

supplying an amount of the insulin formulation in the range from about 40 μ

L to about 200 μ

L to a rear side of an aperture plate having a plurality of apertures where the amount is stored while resting on the rear side by force of gravity, wherein the aperture plate is dome shaped in geometry, and wherein the aperture plate is vibrated by an annular piezoelectric element that circumscribes the apertures;

vibrating the aperture plate with the annular piezoelectric element while the amount of the insulin formulation is at the rear side, wherein vibration causes the supplied insulin to be ejected from a front side of the aperture plate that is beneath the rear side as an aerosolized spray without substantial foaming of the insulin formulation.

2. A method as in claim 1, wherein at least about 97% of the formulation is ejected.

3. A method as in claim 2, wherein the amount of the insulin formulation has a volume of up to about 100 microliters, and wherein the time to aerosolize to at least about 97% is less than about 11 seconds.

4. A method as in claim 1, further comprising vibrating the aperture plate with an amplitude that is less than about 2 μ

m.

5. A method as in claim 1, wherein the aerosolized spray comprises aerosolized droplets having a mean size in the range from about 3 μ

m to about 8 μ

m.

6. A method as in claim 1, wherein the formulation has less than about 3% converted to foam when vibrating the aperture plate.

7. A method as in claim 1, wherein the insulin has a concentration of about 100 IU/ml to about 1200 IU/ml of human insulin.

8. A method as in claim 1, wherein the aperture plate has apertures having a size in the range from about 3 μ

m to 8 μ

m, and is vibrated at a frequency in the range from about 50 kHz to about 150 kHz.

9. A method as in claim 1, wherein the insulin formulation further comprises 2 to 4 Zn²⁺ per insulin hexamer.

10. An aerosolization system, comprising:

an inhaler comprising a housing defining a mouthpiece, an aerosol generator disposed in the housing, wherein the aerosol generator comprises a vibratable membrane having a front face, a rear face and a plurality of apertures, wherein the rear face is vertically above the front face and is exposed to the atmosphere and a vibratable element used to vibrate the membrane, wherein the membrane is dome shaped in geometry, and wherein the vibratable element is annular in geometry and circumscribes the apertures;

a container containing a volume of an insulin formulation comprising a major amount of water, a minor amount of insulin, a minor amount of HCl, and a minor amount of NaOH, wherein the formulation is preservative free such that the formulation may be aerosolized using a vibrating aperture plate without substantial foaming of the formulation, and wherein the container is positioned vertically above the rear face such that the volume of insulin is gravity fed to the rear face where it is held by gravity until it is aerosolized solely by vibration of the aperture plate, wherein the container is configured to dispense a metered amount of insulin formulation, and wherein the metered amount of insulin formulation is in the range from about 40 μ

L to about 200 μ

L, wherein the diameter of the membrane is about 5 mm to about 8 mm such that the metered amount may be held on the rear face until aerosolized.

11. A system as in claim 10, wherein the insulin has a concentration of about 100 IU/ml to about 1200 IU/ml of human insulin.

12. A system as in claim 11, wherein the aperture plate has apertures having a size in the range from about 3 μ

m to 8 μ

m.

13. A system as in claim 11, wherein the vibratable membrane is configured to vibrate with an amplitude that is less than about 2 μ

m.

14. A system as in claim 10, wherein the insulin formulation further comprises 2 to 4 Zn²⁺ per insulin hexamer.