Liquid aerosol formulations containing insulin and aerosol generating devices and methods for generating aerosolized insulin

• US 20040223917A1
• Filed: 04/23/2004
• Published: 11/11/2004
• Est. Priority Date: 05/07/2003
• Status: Active Grant

• Current Assignee: Philip Morris USA Incorporated (Altria Group, Inc.)
• Original Assignee: Chrysalis Technologies Incorporated (Altria Group, Inc.)
• Inventors: Hindle, Michael, Cox, Kenneth A.
• Granted Patent: US 7,683,029 B2
• Time in Patent Office: Days
• US Class Current: 424/45
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/007 Pulmonary tract; Aromatherapy
• CPC Class Codes: A61M 11/007 Syringe-type or piston-type sprayers or atomisers
• CPC Class Codes: A61M 11/041 using heaters
• CPC Class Codes: A61M 11/042 electrical
• 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 15/008 Electronic counters
• CPC Class Codes: A61M 15/02 with activated or ionised fluids, e.g. electrohydrodynamic [EHD] or electrostatic devices; Ozone-inhalators with radioactive tagged particles
• CPC Class Codes: A61M 15/025 Bubble jet droplet ejection devices
• CPC Class Codes: A61M 2016/0039 in the inspiratory circuit
• CPC Class Codes: A61M 2205/8206 battery-operated
• CPC Class Codes: A61M 2205/8237 Charging means
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

Liquid aerosol formulations for generating aerosolized insulin include insulin and at least one high volatility carrier which protects the insulin from thermal degradation during vaporization of the carrier. The carrier can be a mixture of ethanol and water and the liquid aerosol formulation can be propellant free. An aerosol generating device generates the aerosolized insulin by passing the liquid aerosol formulation through a flow passage heated to convert the liquid into a vapor which entrains insulin particles which mix with air to form an aerosol. The insulin particles can be dry insulin particles produced by a hand held inhaler. By controlling the concentration of the insulin in the formulation, the size of the flow passage and/or the amount of heat which heats the flow passage, the aerosol can be provided with a selected mass median aerodynamic diameter of 1 to 3 μm or less than 1 μm so as to be delivered to a targeted portion of the lung using the inhaler.

Claims

1. A liquid aerosol formulation adapted to form a vaporization aerosol comprised of aerosolized insulin, comprising insulin and at least one high volatility carrier which protects the insulin from thermal degradation upon vaporization of the carrier, the liquid aerosol formulation being propellant free.

2. The liquid aerosol formulation of claim 1, wherein the carrier is ethanol and the liquid formulation is at a temperature of at least 50°

C.

3. The liquid aerosol formulation of claim 1, wherein the second component is human insulin.

4. The liquid aerosol formulation of claim 3, comprising up to 5 weight % human insulin.

5. The liquid aerosol formulation of claim 1, wherein the carrier comprises 10 to 90 volume % ethanol and 90 to 10 volume % water.

6. The liquid aerosol formulation of claim 1, wherein the insulin is dissolved in the carrier.

7. The liquid aerosol formulation of claim 1, wherein the carrier is ethanol and the insulin is human insulin.

8. The liquid aerosol formulation of claim 1, which is formulated to form a vapor when heated and to produce an aerosol comprised of aerosol particles that consist essentially of the insulin when the vapor is admixed with ambient air.

9. The liquid aerosol formulation of claim 8, wherein the aerosol particles are substantially dry solid particles.

10. The liquid aerosol formulation of claim 1, which consists essentially of the carrier and the insulin.

11. A propellant-free aerosol containing aerosol particles entrained in a vapor, wherein substantially all of the aerosol particles consist essentially of insulin and the vapor consists essentially of a vaporized liquid carrier.

12. The aerosol of claim 11, wherein the aerosol has a mass median aerodynamic diameter of 0.01 to 1 μ

m or 1 to 3 μ

m.

13. The aerosol of claim 11, wherein the carrier is a mixture of ethanol and water.

14. An aerosol containing aerosol particles of insulin entrained in a vapor, wherein the aerosol particles consist essentially of insulin and the vapor is propellant free and the aerosol has a mass median aerodynamic diameter of 0.01 to 1 μ

m or 1 to 3 μ

m.

15. An aerosol generating device, comprising:

a liquid source of a liquid aerosol formulation comprising a high volatility carrier and insulin;

a flow passage in fluid communication with the liquid source; and

a heater disposed to heat the liquid aerosol formulation in a heated portion of the flow passage to produce a vapor which admixes with air to produce an aerosol.

16. The aerosol generating device of claim 15, wherein the carrier is ethanol.

17. The aerosol generating device of claim 15, wherein the insulin is human insulin.

18. The aerosol generating device of claim 17, wherein the carrier is an ethanol and water mixture.

19. The aerosol generating device of claim 17, wherein the water comprises at least 20 volume %.

20. The aerosol generating device of claim 15, wherein the insulin is dissolved in the carrier.

21. The aerosol generating device of claim 15, wherein the liquid aerosol formulation is propellant free.

22. The aerosol generating device of claim 15, wherein the aerosol comprises aerosol particles that consist essentially of the insulin.

23. The aerosol generating device of claim 15, wherein the heater is operable to heat the liquid aerosol formulation to about 100 to 150°

C.

24. The aerosol generating device of claim 15, wherein the aerosol particles consist essentially of substantially dry solid particles.

25. The aerosol generating device of claim 15, further comprising:

a power supply; and

a controller operable to deliver power from the power supply to the heater so as to maintain the heater at a temperature range effective to vaporize the liquid aerosol formulation in the flow passage.

26. The aerosol generating device of claim 25, further comprising at least one valve disposed between the liquid source and the flow passage, the controller is operable to actuate the valve to open and close the flow passage to control flow of the liquid aerosol formulation from the liquid source to the flow passage.

27. The aerosol generating device of claim 25, further comprising:

a mouthpiece through which the aerosol is inhaled by a user of the aerosol generating device;

a pressure sensor;

an air passage through which air is supplied into the mouthpiece; and

a valve which opens and closes the air passage;

wherein the controller is operable to actuate the valve within a predetermined time period after the pressure sensor detects a pressure drop in the mouthpiece as the user inhales on the mouthpiece to allow air to be supplied into the mouthpiece.

28. The aerosol generating device of claim 15, wherein the flow passage comprises a metering chamber having a predetermined volume, and the aerosol generating device comprises a discharge member operable to deliver an amount of the liquid aerosol formulation equal to the predetermined volume into the heated portion of the flow passage.

29. The aerosol generating device of claim 15, which is a hand held inhaler.

30. The aerosol generating device of claim 15, wherein the liquid source is removably attached to the aerosol generating device.

31. An aerosol generating device, comprising:

a liquid source of a liquid aerosol formulation comprising a carrier and insulin;

a flow passage in fluid communication with the liquid source; and

a heater disposed to heat liquid aerosol formulation in a heated portion of the flow passage to produce a vapor which admixes with air to produce an aerosol.

32. A method of generating an aerosol, comprising:

(a) supplying a liquid aerosol formulation comprising a high volatility carrier and insulin to a flow passage;

(b) heating liquid aerosol formulation in a heated portion of the flow passage to produce a vapor; and

(c) admixing the vapor with air to produce aerosolized insulin particles.

33. The method of claim 32, wherein the carrier comprises ethanol.

34. The method of claim 32, wherein the carrier further comprises water.

35. The method of claim 34, wherein the insulin is human insulin

36. The method of claim 32, wherein the carrier comprises ethanol and at least 10 volume % water.

37. The method of claim 32, wherein the insulin is dissolved in the carrier.

38. The method of claim 32, wherein the liquid aerosol formulation is propellant free.

39. The method of claim 32, wherein the aerosol comprises aerosol particles that consist essentially of insulin.

40. The method of claim 32, wherein the aerosol particles have a mass median aerodynamic diameter of less than 1 μ

m.

41. The method of claim 32, wherein the aerosol particles consist essentially of substantially dry solid particles.

42. The method of claim 32, wherein aerosol particles of the aerosol have a mass median aerodynamic diameter of less than 3 microns.

43. The method of claim 32, wherein the flow passage is a capillary sized circular flow passage and the aerosol particles have a mass median aerodynamic diameter of at least 4 times smaller than in internal diameter of the capillary passage.

44. The method of claim 32, further comprising:

supplying a predetermined volume of the liquid aerosol formulation into the heated portion of the flow passage; and

heating the predetermined volume of the liquid aerosol formulation to produce the vapor.

45. The method of claim 32, wherein (a)-(c) are performed using an aerosol generating device comprising a mouthpiece, the method further comprising:

detecting a pressure drop in the mouthpiece of the aerosol generating device caused by a user inhaling on the mouthpiece;

supplying a predetermined volume of the liquid aerosol formulation into the heated portion of the flow passage after detecting the pressure drop; and

delivering the aerosol to the user through the mouthpiece.

46. The method of claim 32, comprising producing the aerosol continuously.

47. The method of claim 32, further comprising:

performing (a)-(c) using a first fluid delivery assembly attached to an aerosol generating device;

removing the first fluid delivery assembly from the aerosol generating device;

attaching a second fluid delivery-assembly to the aerosol generating device; and

repeating (a)-(c) using the second fluid delivery assembly.

48. The method of claim 47, wherein the first fluid delivery assembly supplies a first liquid aerosol formulation, and the second fluid delivery assembly supplies a second liquid aerosol formulation different from the first liquid aerosol formulation.

49. The method of claim 47, comprising producing a first aerosol containing aerosol particles having a first mass median aerodynamic diameter with the first fluid delivery assembly, and producing a second aerosol containing aerosol particles having a second mass median aerodynamic diameter different from the first mass median aerodynamic diameter with the second fluid delivery assembly.

50. A method of generating an aerosol, comprising:

(a) supplying a liquid aerosol formulation comprising insulin to a flow passage;

(b) heating the liquid aerosol formulation in a heated portion of the flow passage to produce a vapor; and

(c) admixing the vapor with air to produce aerosolized insulin particles.