Preservative free insulin formulations

• US 10,076,613 B2
• Filed: 10/08/2015
• Issued: 09/18/2018
• 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): Sippel, Rachel T
• Application Number:
  US14/878,951
• Publication Number:
  US 20160129088A1
• Time in Patent Office: 1,076 Days
• 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. An insulin formulation specifically adapted for aerosolization, the formulation comprising:

a major amount of water;

a minor amount of insulin;

a minor amount of HCl;

a minor amount of NaOH; and

2 to 4 Zn² per insulin hexamer;

wherein the formulation is preservative free thereby facilitating aerosolization of the formulation as an aerosolized spray using a vibrating aperture plate having a plurality of apertures, and wherein the spray is produced without substantial foaming of the formulation when the formulation is held on a rear face of the aperture plate by gravity and the aerosolized spray exits a front face of the aperture plate solely by vibration of the aperture plate that is vibrated using an annular vibratable element that circumscribes the apertures.

2. An insulin formulation as in claim 1, wherein the insulin has a concentration of about 100 IU/ml to about 1200 IU/ml of human insulin.

3. An insulin formulation as in claim 1, wherein the water comprises in volume about 99.8% to about 97.0%, and the human insulin comprises in volume about 0.2% to about 3.0%.

4. An insulin formulation as in claim 1, wherein the formulation does not include meta-cresol, cresol or phenol.

5. An insulin formulation as in claim 1

wherein the formulation is aerosolized as a spray without substantial foaming when the vibrating aperture plate vibrates at a frequency in the range from about 50 kHz to about 150 kHz, and wherein the amount of the insulin formulation has a volume of up to about 200 μ

L, and wherein the time to aerosolize at least 97% of the formulation is less than about 22 seconds.

6. An insulin formulation as in claim 1, wherein the insulin formulation does not contain a preservative and thereby is aerosolized without substantial foaming of the formulation.

7. An insulin formulation as in claim 1, wherein the amount of the insulin formulation has a volume of about 40 μ

L, to about 200 μ

L.

8. An insulin formulation as in claim 1, wherein the amount of the insulin formulation has a volume of up to about 100 μ

L, and wherein the time to aerosolize at least 97% of the formulation is less than about 11 seconds.

9. An insulin formulation as in claim 1, wherein the aperture plate is vibrated using the annular vibratable element with an amplitude that is less than about 2 μ

m.

10. An insulin formulation 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.

11. An insulin formulation as in claim 1, wherein less than 3% of the formulation is converted to foam during aerosolization.