Particles for inhalation having sustained release properties
View Patent ↗The invention generally relates to a method for pulmonary delivery of therapeutic, prophylactic and diagnostic agents to a patient wherein the agent is released in a sustained fashion, and to particles suitable for use in the method. In particular, the invention relates to a method for the pulmonary delivery of a therapeutic, prophylactic or diagnostic agent comprising administering to the respiratory tract of a patient in need of treatment, prophylaxis or diagnosis an effective amount of particles comprising a multivalent metal cation which is complexed with a therapeutic, prophylactic or diagnostic agent or any combination thereof having a charge capable of complexing with the cation upon association with the agent, a pharmaceutically acceptable carrier and optionally, a multivalent metal cation-containing component wherein the total amount of multivalent metal cation present in the particles is more than 1% weight/weight of the total weight of the agent (% w/w). Release of the agent from the administered particles occurs in a sustained fashion.
1. A method of delivery to the pulmonary system comprising:
administering to the respiratory tract of a patient in need of treatment, prophylaxis or diagnosis an effective amount of a dry powder comprising:
a) a multivalent metal cation which is complexed with a therapeutic, prophylactic or diagnostic agent;
b) a pharmaceutically acceptable carrier; and
c) a multivalent metal cation-containing component wherein the dry powder is spray-dried and has a total amount of multivalent metal cation which is about 10% w/w or more of the total weight of the agent, a tap density of about 0.4 g/cm 3 or less, a median geometric diameter of between about 5 micrometers and about 30 micrometers and an aerodynamic diameter of from about 1 to about 5 microns.
2. The method of claim 1 , wherein the biologically active agent is a protein.
3. The method of claim 2 , wherein the protein is insulin.
4. The method of claim 2 , wherein the multivalent metal cation is selected from Zn(II), Ca(II), Cu(II), Ni(II), Co(II), Fe(II), Ag(II), Mn(II), Mg(II) or Cd(II).
5. The method of claim 4 , wherein the multivalent metal cation is Zn(II).
6. The method of claim 2 , wherein the multivalent metal cation is present at about 3% w/w or more of the total weight of the agent.
7. The method of claim 2 , wherein the multivalent metal cation is present at about 50% w/w or more of the total weight of the agent.
8. The method of claim 2 , wherein complexation of the agent and multivalent metal cation comprises a metal coordination.
9. The method of claim 2 , wherein the dry powder has a tap density about 0.1 g/cm 3 or less.
10. The method of claim 2 , wherein the dry powder has an aerodynamic diameter of from about 1 to about 3 microns.
11. The method of claim 2 , wherein the dry powder has an aerodynamic diameter of from about 3 to about 5 microns.
12. The method of claim 2 , wherein delivery to the pulmonary system includes delivery to the deep lung.
13. The method of claim 2 , wherein delivery to the pulmonary system includes delivery to the central airways.
14. The method of claim 2 , wherein delivery to the pulmonary system includes delivery to the upper airways.
15. The method of claim 2 , wherein the dry powder further comprise a carboxylic acid.
16. The method of claim 15 , wherein the carboxylic acid includes at least two carboxyl groups.
17. The method of claim 16 , wherein the carboxylic acid is citric acid or a salt thereof.
18. The method of claim 2 , wherein the dry powder further comprise an amino acid.
19. The method of claim 18 , wherein the amino acid is hydrophobic.
20. The method of claim 19 , wherein the hydrophobic amino acid is leucine, isoleucine, alanine, valine, phenylalanine or any combination thereof.
21. The method of claim 2 wherein the pharmaceutically acceptable carrier is a phospholipid.
22. The method of claim 21 wherein the phospholipid is a phosphatidic acid, a phosphatidylcholine, a phosphatidylalkanolamine, a phosphatidylethanolamine, a phosphatidylglycerol, a phosphatidylserine, a phosphatidylinositol or combinations thereof.
23. A method of delivery to the pulmonary system comprising:
administering to the respiratory tract of a patient in need of treatment, prophylaxis or diagnosis an effective amount of a dry powder comprising:
a) a protein which is complexed with zinc;
b) a pharmaceutically acceptable carrier; and
c) a multivalent metal cation-containing component wherein the dry powder is spray-dried and has a total amount of multivalent metal cation which is about 10% w/w or more of the total weight of the agent, a tap density of about 0.4 g/cm 3 or less, a median geometric diameter of between about 5 micrometers and about 30 micrometers and an aerodynamic diameter of from about 1 to about 5 microns.
24. The method of claim 23 , wherein the dry powder has a tap density about 0.1 g/cm 3 or less.
25. The method of claim 23 , wherein the pharmaceutically acceptable carrier is a phospholipid.
26. The method of claim 23 wherein the dry powder further comprises a carboxylic acid.
27. A composition for delivery to the pulmonary system comprising:
administering to the respiratory tract of a patient in need of treatment, prophylaxis or diagnosis an effective amount of a dry powder comprising:
a) a protein which is complexed with zinc;
b) a pharmaceutically acceptable carrier; and
c) a multivalent metal cation-containing component wherein the dry powder is spray-dried and has a total amount of multivalent metal cation which is about 10% w/w or more of the total weight of the agent, a tap density of about 0.4 g/cm 3 or less, a median geometric diameter of between about 5 micrometers and about 30 micrometers and an aerodynamic diameter of from about 1 to about 5 microns.
28. The method of claim 27 , wherein the dry powder has a tap density about 0.1 g/cm 3 or less.
29. The method of claim 27 , wherein the pharmaceutically acceptable carrier is a phospholipid.
30. The method of claim 27 wherein the dry powder further comprises a carboxylic acid.