Small particle aerosol liposome and liposome-drug combinations for medical use

• US 5,049,388 A
• Filed: 07/21/1989
• Issued: 09/17/1991
• Est. Priority Date: 11/06/1986
• Status: Expired due to Term

• Current Assignee: Research Development Foundation Carson City Nevada A Nevada Non-Profit Corporation
• Original Assignee: Research & Development Foundation
• Inventors: Knight, Jack V., Six, Howard R., Wilson, Samuel Z., Wyde, Philip R., Gilbert, Brian E.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): McPhail, Donald R.
• Application Number:
  US07/383,383
• Time in Patent Office: 788 Days
• Field of Search: 252/305, 264/413, 428/402.2, 424/43, 424/417, 424/450, 436/829, 436/826, 514/885, 514/958
• US Class Current: 424/450
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]

Abstract

Disclosed are aqueous aerosol droplets containing liposome or interacted liposome-drug or medication combination particles in a continuous phase of air or oxygen-enriched air advantageous for the treatment of a wide variety of diseases. The drug or medication is interacted with the liposome membrane so that on its rupture the drug or medication is not lost from the liposome. Different methods of preparation of the aerosol particles containing the liposome and interacted liposome-drug combination particles are described which can be used in small particle aerosol treatment. The majority of the aerosol droplets containing the liposome particles alone or with drugs has a diameter less than 5 microns and has an aerodynamic mass median diameter ranging from about 1 to 3 microns, and the liposome and interacted-liposome drug particles are substantially uniform in size and less than 1 micron in diameter.

Claims

1. Aqueous aerosol droplets containing one or more liposome particles, the majority of the mass of the aerosol droplets having a diameter from 1 to 5 microns, and having an aerodynamic mass median diameter ranging from about 1 to 3 microns, the liposome particles being substantially homogeneous in size and having a diameter of less than 1 micron thereby providing deposition of the droplets containing the one or more liposome particles throughout a respiratory tract of a patient when inhaled.

6. A method of treating a patient comprising, introducing into the respiratory tract of the patient the aqueous aerosol droplets of claim 1 by one of air and oxygen enriched air.

11. A method of generating the aqueous aerosol droplets of claim 1 comprising, nebulizing heterogeneous particles of liposomes in an aqueous medium with air or oxygen enriched air by a nebulizer effective to produce the aqueous aerosol droplets and homogenize the particles of liposomes.

16. An aerosol container having a reservoir containing the liposome particles of claim 1 in n aqueous medium, and having aerosol generating means including an air or an oxygen enriched air source in fluid communication with the reservoir effective to produce the aqueous aerosol droplets.

21. A method of producing the aerosol droplets of claim 1 comprising, placing heterogeneous particles of the liposomes in an aqueous medium in an aerosol reservoir, and aerosolizing the heterogeneous particles of liposomes with air or oxygen enriched air effective to produce the aqueous aerosol droplets and to homogenize the heterogeneous particles of liposomes.

2. Aqueous aerosol droplets containing one or more liposome particles and one or more lipophilic medications interacted with the liposome'"'"'s membrane, the majority of the mass of the aerosol droplets having a diameter from 1 to 5 microns, and having an aerodynamic mass median diameter ranging from about 1 to about 3 microns, the particles being substantially homogenous in size and having a diameter of less than 1 micron thereby providing deposition of the droplets containing the one or more liposome particles through out a respiratory tract of a patient when inhaled.

4. The aqueous aerosol droplets of claim 2 wherein, the medication is selected from a lipophilic or a compound made lipophilic by derivatization of the group consisting of antiasthma, antiarrhythmic, antifungals, antihypertensive, anticancer, antibiotics, antidiabetics, antihistamines, antiparasitics, antivirals, cardiac glycosides, hormones, immunotherapies, antihypotensives, steroids, sedatives and analgesics, tranquilizers, vaccines, and cell surface receptor blockers.

7. A method of treating a ptient comprising, introducing into the respiratory tract of the patient the aqueous aerosol droplets of claim 2 by one of air and oxygen enriched air.

9. A method of treating a patient comprising, introducing into the respiratory tract of the patient the aqueous aerosol droplets of claim 4 by one of air and oxygen enriched air.

12. A method of generating the aqueous aerosol droplets of claim 2 comprising, nebulizing the particles of liposomes and the one or more medications with the liposome'"'"'s membrane of heterogeneous size in an aqeuous medium with air or oxygen enriched air in a nebulizer effective to produce the aerosol droplets and to homogenize the particles without loss of the medications and their activity.

14. A method of generating the aqueous aerosol droplets of claim 4 comprising, nebulizing the particles of liposomes and the selected medication of heterogeneous size in an aqueous medium with air or oxygen enriched air in a nebulizer effective to produce the aerosol droplets and to homogenize the particles of liposomes without loss of the medication and its activity.

17. An aerosol container having a reservoir containing the liposomes and medications of claim 2 in an aqueous medium, and having aerosol generating means including an air or oxygen enriched air source in fluid communication with the reservoir effective to produce the aqueous aerosol droplets.

19. An aerosol container having a reservoir containing the liposomes and medications of claim 4 in an aqueous medium, and having aerosol generating means including an air or oxygen enriched air source in fluid communication with the reservoir effective to produce the aqueous aerosol droplets.

22. A method of producing the aerosol droplets of claim 2 comprising, placing heterogeneous particles of the liposomes and medication in an aqueous medium in an aerosol reservoir and aerosolizing the heterogeneous particles of liposomes and medication with air or oxygen enriched air effective to produce the aqueous aerosol droplets and to homogenize the heterogeneous particles of liposomes.

24. A method of producing the aerosol droplets of claim 4 comprising, placing the particles of medication interacted with membranes of liposomes of heterogeneous size in an aqueous medium in an aerosol reservoir, and aerosolizing them with air or oxygen enriched air effective to produce the aerosol droplets and to homogenize the heterogeneous particles.

3. Aqueous aerosol droplets containing one or more liposome particles having multiple aqueous compartments and one or more lipophilic medications interacted with membranes of the liposome particles, the majority of the mass of the aerosol droplets having a diameter of from 1 to 5 microns, and having an aerodynamic mass median diameter ranging from about 1 to about 3 microns, the particles being substantially homogeneous in size and having a diameter of less than 1 micron thereby providing deposition of the droplets containing the one or more liposome particles throughout a respiratory tract of a patient when inhaled.

5. The aqueous aerosol droplets of claim 3 where, the one or more medications are selected for man insoluble or a compound made lipophilic by derivatization of the group consisting of antiasthma, antiarrhythmic, antifungals, antihypertensives, anticancer, antibiotics, antidiabetics, antihistamines, antiparasitics, antivirals, cardiac glycosides, hormones, imunotherapies, antihypotensives, steroids, sedatives, and analgesics, tranquilizers, vaccines, and cell surface receptor blockers.

8. A method of treating a patient comprising, introducing into the respiratory tract of the patient the aqueous aerosol droplets of claim 3 by one of air and oxygen enriched air.

10. A method of treating a patient comprising, introducing into the respiratory tract of the patient the aqueous aerosol droplets of claim 5 by one of air and oxygen enriched air.

13. A method of generating the aqueous aerosol droplets of claim 3 comprising, nebulizing the particles of liposomes and the one or more lipophilic medications interacted with the membranes of the liposomes of heterogeneous size in an aqueous medium with air or oxygen enriched air in a nebulizer effective to produce the aerosol droplets and to homogenize the particles of liposomes without loss of medication and its activity.

15. A method of generating the aqueous aerosol droplets of claim 5 comprising, nebulizing the liposome particles and the selected medication of heterogeneous size in an aqueous medium with air or oxygen enriched air in an nebulizer effective to produce the aerosol droplets and to homogenize the liposome particles without loss of the medication and its activity.

18. An aerosol container having a reservoir containing the liposomes and medications of claim 3 in an aqueous medium, and having aerosol generating means including an air or oxygen enriched air source in fluid communication with the reservoir effective to produce the aqueous aerosol droplets.

20. An aerosol container having a reservoir containing the liposomes and medications of claim 5 in an aqueous medium, and having aerosol generating means including an air or oxygen enriched air source in fluid communication with the reservoir effective to produce the aqueous aerosol droplets.

23. A method of producing the aerosol droplets of claim 3 comprising, placing the particles of medications interacted with membranes of the liposomes of heterogeneous size in an aqueous medium in an aerosol reservoir, and aerosolizing them with air or oxygen enriched air effective to produce the aerosol droplets and to homogenize the heterogeneous particles.

25. A method of producing the aerosol droplets of claim 5 comprising, placing the particles of one or more medications interacted with membranes of the liposomes of heterogeneous size in an aqueous medium in an aerosol reservoir, and aerosolizing them with air or oxygen enriched air effective to produce the aerosol droplets and to homogenize the heterogeneous particles.