Method for treating respiratory disorders associated with pulmonary elastic fiber injury

• US 20020086852A1
• Filed: 05/23/2001
• Published: 07/04/2002
• Est. Priority Date: 05/14/1998
• Status: Abandoned Application

• Current Assignee: Trustees Of Columbia University In The City Of New York (Columbia University), CoTherix, Inc. (Johnson & Johnson), St Luke's-Roosevelt Hospital Center (Sinai Health System)
• Original Assignee: Trustees Of Columbia University In The City Of New York (Columbia University), CoTherix, Inc. (Johnson & Johnson), St Luke's-Roosevelt Hospital Center (Sinai Health System)
• Inventors: Turino, Gerard, Mihalko, Paul J., Sachs, Dan, Cantor, Jerome O., Kuo, Jing-wen
• Application Number:
  US09/863,849
• Publication Number:
  US 20020086852A1
• Time in Patent Office: Days
• US Class Current: 514/54
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/721 Dextrans
• CPC Class Codes: A61K 31/726 Glycosaminoglycans, i.e. mucopolysaccharides chondroitin sulfate, dermatan sulfate A61K31/737
• 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: A61M 15/00 Inhalators drug delivery in endotracheal tubes A61M16/04
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention relates generally to the field of respiratory therapeutics, and in particular to the treatment of disorders of the lung matrix caused by damage to the elastic fibers of the lung matrix. More specifically, methods and materials are disclosed for the delivery to the lungs of polysaccharides, derivatives thereof and/or drug conjugates, used in the treatment and/or prevention of pulmonary disorders.

Claims

1. A method of treating respiratory disorders which comprises administering to a mammal a therapeutically effective amount of a polysaccharide that binds to elastic fibers, thereby preventing enzymes, oxidants, or other injurious agent from contacting and damaging said elastic fibers.

2. The method of claim 1, wherein the polysaccharide is a glycosaminoglycan.

3. The method of claim 2, wherein the glycosaminoglycan is selected from the group consisting of hyaluronic acid, chondroitin sulfate A, chondroitin sulfate B, chondroitin sulfate C, heparan sulfate and heparin.

4. The method of claim 1, wherein the polysaccharide is dextran.

5. The method of claim 1, wherein said administering comprises delivery via a route selected from the group consisting of aerosol inhalation, dry powder inhalation, liquid inhalation and liquid instillation.

6. The method of claim 5, wherein said administering via aerosol inhalation comprises:

preparing a liquid formulation comprising the polysaccharide, wherein the concentration of the polysaccharide is less than about 5 mg/ml and the molecular weight of the polysaccharide is less than about 1.5×

10⁶ Daltons;

aerosolizing said liquid formulation to form a breathable mist such that the particle size of the polysaccharide is less than about 10 microns; and

delivering said therapeutically effective amount of the polysaccharide by inhalation of said breathable mist by said mammal.

7. The method of claim 6, wherein the molecular weight of the polysaccharide is less than about 587,000 Daltons.

8. The method of claim 6, wherein the molecular weight of the polysaccharide is less than about 220,000 Daltons.

9. The method of claim 6, wherein the molecular weight of the polysaccharide is less than about 150,000 Daltons.

10. The method of claim 6, wherein said breathable mist is formed by a nebulizer.

11. The method of claim 10, wherein said nebulizer operates at a pressure of at least about 15 psi.

12. The method of claim 10, wherein said nebulizer operates at a pressure of at least about 30 psi.

13. The method of claim 1, wherein the polysaccharide is chemically modified.

14. The method of claim 13, wherein the modification comprises cross-linking.

15. The method of claim 13, wherein the modification comprises addition of sulfate groups.

16. The method of claim 13, wherein the modification comprises addition of carboxyl groups.

17. The method of claim 13, wherein the modification comprises attachment of lipophilic side chains.

18. The method of claim 13, wherein the modification comprises introduction of acetyl groups.

19. The method of claim 13, wherein the modification comprises formation of an ester.

20. The method of claim 13, wherein the modification comprises reaction with a carbodiimide.

21. A method of administering to a mammal a therapeutic formulation comprising a polysaccharide at a selected dose via a respiratory tract, comprising:

formulating a solution comprising the polysaccharide to achieve a controlled polysaccharide size of between about 50,000 and 1.5×

10⁶ Daltons at a concentration of less than about 5 mg/ml (w/v) of the polysaccharide;

producing an aerosol of the solution such that a droplet of the aerosol has a median mass distribution size of between about 0.5 to about 10 microns; and

delivering said aerosol into said respiratory tract by inhalation.

22. The method of claim 21, wherein the selected dose of polysaccharide is in a range of about 10 μ

tg/kg body weight/day to about 1 mg/kg body weight/day.

23. The method of claim 21, wherein the selected dose of polysaccharide is in a range of about 50 μ

g/kg body weight/day to about 500 μ

g/kg body weight/day.

24. The method of claim 21, wherein the selected dose of polysaccharide is in a range of about 100 μ

g/kg body weight/day to about 300 μ

g/kg body weight/day.

25. The method of claim 21 wherein the solution further comprises a drug.

26. The method of claim 25, wherein the drug is selected from the group consisting of terbutaline, albuterol (salbutamol) sulfate, ephedrine sulfate, ephedrine 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, verapainil, calcitonin, atriopeptin, alpha.-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.

27. The method of claim 21, wherein the polysaccharide is chemically modified.

28. The method of claim 27, wherein the solution further comprises a drug.

29. The method of claim 28, wherein the drug is selected from the group consisting of prostaglandins, amphotericin B, progesterone, isosorbide dinitrate, testosterone, nitroglycerin, estradiol, doxorubicin, beclomethasone and esters thereof, vitamin E, cortisone, dexamethasone and esters thereof, DPPC/DPPG phospholipids, and betamethasone valerete.

30. The method of claim 21, wherein a drug is conjugated to the polysaccharide.

31. A system for delivering a polysaccharide formulation to a respiratory tract of a mammal, comprising:

a mixture comprising a polysaccharide having a molecular weight of between about 50,000 and 1.5×

10⁶ Daltons at a concentration of less than about 5.0 mg/ml (w/v) of polysaccharide, and a breathable fluorocarbon propellant;

a cannister adapted to contain said mixture under pressure;

a valve connected to said cannister for regulating delivery of said mixture; and

a nozzle interconnected with said valve for transforming said mixture under pressure into an inhalable aerosol mist when said valve is actuated.

32. The system of claim 31, wherein the polysaccaride in said aerosol mist has a median mass distribution size of between about 0.5 to about 10 microns.

33. The system of claim 31 wherein said mixture further comprises a drug.