Method and apparatus for administering dehydrated liposomes by inhalation

• US 4,895,719 A
• Filed: 03/06/1987
• Issued: 01/23/1990
• Est. Priority Date: 05/22/1985
• Status: Expired due to Term

• Current Assignee: Liposome Technology, Inc.
• Original Assignee: Liposome Technology, Inc.
• Inventors: Radhakrishnan, Ramachandran, Abra, Robert M., Mihalko, Paul J.
• Primary Examiner(s): Higel, Floyd D.
• Application Number:
  US07/022,937
• Time in Patent Office: 1,054 Days
• Field of Search: 424/45, 424/46, 514/956, 514/958, 514/964, 514/965
• US Class Current: 424/45
• 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 9/008 comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61M 15/0008 rotating by airflow
• 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

Abstract

A system and method for administering a drug, at a selected dose, via the respiratory tract. Spray-dried liposome particles containing the selected dose of the entrapped drug are released into the air in aerosolized form, either by entrainment in an air or propellant stream, or by release from a pressurized can containing a suspension of the liposomes in a fluorchlorocarbon solvent.

Claims

1. Apparatus for administering a water-soluble drug, at a selected dose, via the respiratory tract comprising

dehydrated liposome particles formed by the steps of (a) producing a liposome suspension having at least about 50% liposome-encapsulated drug, and (b) dehydrating the suspension, and

a device for producing an airborne suspension of the liposome particles containing such selected dose of the drug.

2. The apparatus of claim 1, wherein the liposomes are composed predominantly of saturated or partially saturated phospholipids.

3. The apparatus of claim 1, wherein the liposomes are suspended in a fluorocarbon propellant solvent, and said device includes a cannister containing the liposome/propellant suspension in pressurized form, and a valve connected to the cannister for delivering a selected volume of the suspension in aerosolized form.

4. The apparatus of claim 3, wherein the propellant is selected from the group consisting of CCl₂ F₂, CClF₂ CClF₂, and CClF₂ CF₃.

5. The apparatus of claim 3, wherein the liposome particles are formed by dehydrating the liposomes by spray drying, and the liposomes are composed predominantly of phospholipids whose phase transition provides protection to drying at temperatures above about 40°

C.

6. The system of claim 3, for use in delivering a lipid soluble drug selected from the group consisting of prostaglandins, amphotericin B, progesterone, isosorbide dinitrate, testosterone, nitroglycerin, estradiol, doxorubicin, beclomethasone and esters, vitamin E, cortisone, dexamethasone and esters, DPPC/DPPG phospholipids, and betamethasone valerete, wherein the drug is present predominantly in propellant-solubilized form, and becomes entrapped in liposomes upon aerosolization and evaporation of the propellant.

7. The apparatus of claim 1, wherein the liposomes are contained in dehydrated packets, each packet containing such selected amount of the drug in liposome-entrapped form, and said device includes means for expelling the liposomes from the packet in an air-borne form.

8. The apparatus of claim 7, wherein said device is a spray device containing a pressurized fluorocarbon propellant, a valve for releasing the pressurized propellant in an aerosolized stream, and means connecting the valve to a liposome packet, effective to bring the aerosolized propellant stream into contact with the liposomes in the packet, to entrain the liposomes in the propellant stream.

9. The apparatus of claim 8, wherein each packet includes a porous matrix on which the liposomes are supported and through which the stream is directed.

10. The apparatus of claim 7, wherein said device defines air passageway adapted to hold a packet, to allow a stream of air drawn into the passageway to entrain the liposomes.

11. The apparatus of claim 7, wherein the drug is selected from the group consisting of terbutaline, albuterol (salbutamol) sulfate, ephidrine sulfate, ephidrine bitartrate, isoetharine hydrochloride, isoetharine mesylate, isoproteranol hydrochloride, isoproteranol sulfate, metaproteranol sulfate, terbutaline sulfate, procaterol, bitolterol mesylate, atropine methyl nitrate, cromolyn sodium, propranalol, fluroisolide, ibuprofin, gentamycin, tobermycin, pentamidine, penicillin, theophylline, bleomycin, etoposide, captopril, n-acetyl cysteine, verapamil, calcitonin, atriopeptin, α

-1 antitrypsin (protease inhibitor), interferon, vasopressin, insulin, interleukin-2, superoxide dismutase, tissue plasminogen activator (TPA), plasma factor 8, epidermal growth factor, tumor necrosis factor, heparin, lung surfactant protein, and lipocortin.

12. A method for administering a water-soluble drug, at a selected dose, to the respiratory tract comprising

providing dehydrated liposome particles formed by the steps of (a) producing a liposome suspension having at least about 50% liposome-encapsulated drug, and (b) dehydrating the suspension, and

producing an airborne suspension of the liposome particles containing the selected dose of the drug.

13. The method of claim 12, wherein the liposome particles are formed by dehydrating the liposomes by spray drying, and the liposomes are composed predominantly of phospholipids which provide protection against liposome disruption on drying in a stream of gas at a temperature above about 37°

C.

14. The method of claim 12, wherein the liposomes are suspended in a fluorocarbon propellant, and, and said producing includes storing the suspension under pressure in a cannister, and releasing a selected amount of the suspension from the cannister in an aerosolized form.

15. The method of claim 14 for use in administering a water-soluble drug selected from the group consisting of terbutaline, albuterol (salbutamol) sulfate, ephidrine sulfate, ephidrine bitartrate, isoetharine hydrochloride, isoetharine mesylate, isoproteranol hydrochloride, isoproteranol sulfate, metaproteranol sulfate, terbutaline sulfate, procaterol, bitolterol mesylate, atropine methyl nitrate, cromolyn sodium, propranalol, fluroisolide, ibuprofin, gentamycin, tobermycin, pentamidine, penicillin, theophylline, bleomycin, etoposide, captopril, n-acetyl cysteine, and verapamil, wherein the drug is present in the suspension predominantly in liposome entrapped form.

16. The method of claim 12, wherein the liposomes are contained in dehydrated packets, each packet containing the selected amount of the drug in liposome-entrapped form, and said producing includes expelling the liposomes from the packet in an air-borne form.

17. The method of claim 16, wherein said producing includes spraying a stream of aerosolized fluorocarbon solvent through the packet, to entrain liposomes in the packet in the stream.

18. The system of claim 12, wherein the drug is selected from the group consisting of terbutaline, albuterol (salbutamol) sulfate, ephidrine sulfate, ephidrine bitartrate, isoetharine hydrochloride, isoetharine mesylate, isoproteranol hydrochloride, isoproteranol sulfate, metaproteranol sulfate, terbutaline sulfate, procaterol, bitolterol mesylate, atropine methyl nitrate, cromolyn sodium, propranalol, fluroisolide, ibuprofin, gentamycin, tobermycin, pentamidine, penicillin, theophylline, bleomycin, etoposide, captopril, n-acetyl cysteine, verapamil, calcitonin, atriopeptin, α

-1 antitrypsin (protease inhibitor), interferon, vasopressin, insulin, interleukin-2, superoxide dismutase, tissue plasminogen activator (TPA), plasma factor 8, epidermal growth factor, tumor necrosis factor, heparin, lung surfactant protein, and lipocortin.