Use of monomeric insulin as a means for improving the bioavailability of inhaled insulin

• US 5,888,477 A
• Filed: 01/31/1997
• Issued: 03/30/1999
• Est. Priority Date: 01/29/1993
• Status: Expired due to Term

• Current Assignee: Aradigm Corporation
• Original Assignee: Aradigm Corporation
• Inventors: Farr, Stephen J., Gonda, Igor, Rubsamen, Reid M.
• Primary Examiner(s): Bawa, Raj
• Application Number:
  US08/792,616
• Time in Patent Office: 788 Days
• Field of Search: 424/45, 424/489, 514/3, 514/4, 514/866, 530/303
• US Class Current: 424/45
• CPC Class Codes: A61J 7/0418 with electronic history memory
• CPC Class Codes: A61J 7/0427 with direct interaction with a dispensing or delivery system
• CPC Class Codes: A61J 7/0445 for preventing drug dispensing during a predetermined time period
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/007 Pulmonary tract; Aromatherapy
• 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: A61M 11/001 Particle size control
• CPC Class Codes: A61M 15/00 Inhalators drug delivery in endotracheal tubes A61M16/04
• CPC Class Codes: A61M 15/0031 by bursting or breaking the package, i.e. without cutting or piercing
• CPC Class Codes: A61M 15/0043 Non-destructive separation of the package, e.g. peeling
• CPC Class Codes: A61M 15/0045 using multiple prepacked dosages on a same carrier, e.g. blisters
• CPC Class Codes: A61M 15/0051 the dosages being arranged on a tape, e.g. strips
• CPC Class Codes: A61M 15/0066 with means for varying the dose size
• CPC Class Codes: A61M 15/008 Electronic counters
• 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 16/142 with semi-permeable walls separating the liquid from the respiratory gas
• CPC Class Codes: A61M 2016/0021 with a proportional output signal, e.g. from a thermistor
• CPC Class Codes: A61M 2016/0036 in the breathing tube and used in both inspiratory and expiratory phase
• CPC Class Codes: A61M 2202/062 Desiccants
• CPC Class Codes: A61M 2202/064 : Powder
• CPC Class Codes: A61M 2205/50 : with microprocessors or computers
• CPC Class Codes: A61M 2205/8206 : battery-operated
• CPC Class Codes: B05B 17/0607 : generated by electrical means, e.g. piezoelectric transducers

Abstract

The need for the delivery of insulin by injection can be reduced or eliminated by a method whereby an aerosolized insulin formulation is delivered to a patient'"'"'s lungs and the rate at which the insulin is absorbed into the blood is increased by the use of monomeric insulin and/or an inhale-exhale breathing maneuver. Particles of insulin and in particular monomeric insulin delivered to the surface of lung tissue will be absorbed into the circulatory system. The rate of absorption is enhanced by the monomeric form of insulin and by instructing the patient to inhale maximally and thereafter exhale maximally. This maneuver causes a spike in the rate at which insulin enters the circulatory system thereby increasing the rate at which glucose is removed from the circulatory system. The insulin or insulin analog may be a dry powder but is preferably in a liquid formulation delivered to the patient from a hand-held, self-contained device which automatically releases an aerosolized burst of formulation. The device includes a sensor which is preferably electronic which measures inspiratory flow and volume which measurement can be used to control the point of drug release. The sensor can also assist the patient in the inhale-exhale maneuver.

Claims

1. A method of enhancing the rate at which an inhaled drug migrates into a patient'"'"'s circulatory system, comprising:

aerosolizing a formulation comprised of a monomeric insulin;

inhaling the aerosolized formulation into lungs of a patient and allowing particles of the monomeric insulin to deposit on lung tissue.

2. The method of claim 1, further comprising:

inhaling maximally followed by exhaling the forced vital capacity of the lungs;

wherein the inhaling maximally and exhaling the forced vital capacity are measured.

3. The method of claim 2, wherein the measuring is carried out electronically and a first signal is sent after the inhaling reaches a desired point and a second signal is sent after the exhaling reaches a desired point.

4. The method of claim 1, wherein the formulation is a liquid formulation comprised of a pharmaceutically acceptable carrier and insulin lispro.

12. The method of claim 1, wherein the insulin is insulin lispro.

13. The method of claim 1, further comprising:

inhaling maximally followed by exhaling the forced vital capacity of the lungs.

14. The method of claim 13, further comprising:

electronically measuring the inhaling and exhaling.

5. A method of improving the bioavailability of insulin delivered via the lung, comprising:

aerosolizing a formulation of an insulin analog which analog rapidly disassociates into monomeric form;

inhaling the aerosolized formulation of the insulin analog into the lungs in a manner which allows the particles of the insulin analog to deposit on the lung tissue.

6. The method of claim 5, wherein the inhaled insulin analog is insulin lispro which rapidly disassociates in a monomeric form producing a relative bioavailability greater than twice that seen after the inhalation of a similar amount of recombinant human insulin.

7. A method of reducing sequestration of drug on lung tissue, comprising:

aerosolizing a formulation comprised of a monomeric insulin;

inhaling the aerosolized formulation into lungs of a patient and allowing particles of the monomeric insulin to deposit on lung tissue.

8. The method of claim 7, wherein the monomeric insulin is insulin lispro.

9. The method of claim 7, further comprising:

inhaling maximally followed by exhaling the forced vital capacity of the lungs.

10. The method of claim 9, further comprising:

electronically measuring the inhaling and exhaling.

11. The method of claim 10, further comprising:

sending a first signal after the inhaling reaches a desired point; and

sending a second signal after the exhaling reaches a desired point.

15. A method of reproducibly effecting a serum glucose level, comprising:

aerosolizing a formulation comprising monomeric insulin;

administering the aerosolized formulation.

16. The method of claim 15, further comprising:

repeatedly administering the aerosolized formulation at substantially the same inspiratory flow rate and inspiratory volume at each administration.

17. The method of claim 15, wherein the monomeric insulin is insulin lispro.

18. The method of claim 15, further comprising:

monitoring inspiratory flow rate and inspiratory volume; and

automatically releasing aerosolized formulation based on a monitored rate and volume.

19. The method of claim 15, further comprising:

inhaling maximally followed by exhaling the forced vital capacity of the lungs.

20. The method of claim 19, further comprising:

measuring the inhaling maximally and exhaling the forced vital capacity.

21. The method of claim 20, wherein the measuring is carried out electronically and a first signal is sent after the inhaling reaches a desired point and a second signal is sent after the exhaling reaches a desired point.