Combination therapies using cyclosporine and aromatic cationic peptides

Patent metadata

Field	Value
Publication number	US-9561258-B2
Application number	US-201414185471-A
Country	US
Kind code	B2
Filing date	Feb 20, 2014
Priority date	Mar 15, 2010
Publication date	Feb 7, 2017
Grant date	Feb 7, 2017

Abstract

The invention provides compositions and methods for preventing or treating an ischemia-reperfusion injury, such as occurs during acute myocardial infarction and organ transplant in a mammalian subject. The methods comprise administering to the subject an effective amount of an aromatic-cationic peptide or a pharmaceutically acceptable salt thereof, and one or more additional active agents such as cyclosporine.

First claim

What is claimed is:

1. A method for treating ischemia and/or reperfusion injury in a subject in need thereof, the method comprising administering simultaneously, separately or sequentially an effective amount of (i) an aromatic-cationic peptide or a pharmaceutically acceptable salt thereof, wherein the aromatic-cationic peptide is selected from the group consisting of: 2′,6′-Dmt-D-Arg-Phe-Lys-NH 2 ; Phe-D-Arg-Phe-Lys-NH 2 ; 2′,6′-Dmp-D-Arg-Phe-Lys-NH 2 ; and D-Arg-2′,6′-Dmt-Lys-Phe-NH 2 and (ii) the cyclosporine derivative NIM811, wherein the aromatic-cationic peptide is linked to the cyclosporine derivative by a pH-sensitive linker or an enzyme-cleavable linker.

2. The method of claim 1 , wherein the pharmaceutically acceptable salt comprises acetate salt or trifluoroacetate salt.

3. The method of claim 1 , wherein the aromatic-cationic peptide comprises D-Arg-2′6′-Dmt-Lys-Phe-NH 2 or a pharmaceutically acceptable salt thereof selected from acetate salt or trifluoroacetate salt.

4. A pharmaceutical composition comprising (i) an aromatic-cationic peptide or a pharmaceutically acceptable salt thereof, wherein the aromatic-cationic peptide is selected from the group consisting of: 2′,6′-Dmt-D-Arg-Phe-Lys-NH 2 ; Phe-D-Arg-Phe-Lys-NH 2 ; 2′,6′-Dmp-D-Arg-Phe-Lys-NH 2 ; and D-Arg-2′,6′-Dmt-Lys-Phe-NH 2 , and (ii) the cyclosporine derivative NIM811, wherein the aromatic-cationic peptide is linked to the cyclosporine derivative by a pH-sensitive linker or an enzyme-cleavable linker.

5. The pharmaceutical composition of claim 4 , wherein the pharmaceutically acceptable salt comprises acetate salt or trifluoroacetate salt.

6. The pharmaceutical composition of claim 4 , wherein the aromatic-cationic peptide comprises D-Arg-2′6′-Dmt-Lys-Phe-NH 2 or a pharmaceutically acceptable salt thereof selected from acetate salt or trifluoroacetate salt.

7. A composition comprising: an (i) an aromatic-cationic peptide or a pharmaceutically acceptable salt thereof, wherein the aromatic-cationic peptide is selected from the group consisting of: 2′,6′-Dmt-D-Arg-Phe-Lys-NH 2 ; Phe-D-Arg-Phe-Lys-NH 2 ; 2′,6′-Dmp-D-Arg-Phe-Lys-NH 2 ; and D-Arg-2′,6′-Dmt-Lys-Phe-NH 2 , and (ii) the cyclosporine derivative NIM811; wherein the aromatic-cationic peptide is linked to the active agent by a pH-sensitive linker or an enzyme-cleavable linker.

8. The composition of claim 7 , wherein the pharmaceutically acceptable salt comprises acetate salt or trifluoroacetate salt.

9. The composition of claim 7 , wherein the aromatic-cationic peptide comprises D-Arg-2′,6′-Dmt-Lys-Phe-NH 2 or a pharmaceutically acceptable salt thereof selected from acetate salt or trifluoroacetate salt.

10. The method of claim 1 , wherein the aromatic-cationic peptide is administered intravenously, intradermally, intraperitoneally, subcutaneously, orally, transdermally, topically, intraocularly, iontophoretically, transmucosally, or by inhalation.

11. The method of claim 1 , wherein the ischemia and/or reperfusion injury comprises vessel occlusion injury or cardiac ischemia-reperfusion injury.

12. The pharmaceutical composition of claim 4 , wherein the aromatic-cationic peptide is administered intravenously, intradermally, intraperitoneally, subcutaneously, orally, transdermally, topically, intraocularly, iontophoretically, transmucosally, or by inhalation.

13. The composition of claim 7 , wherein the aromatic-cationic peptide is administered intravenously, intradermally, intraperitoneally, subcutaneously, orally, transdermally, topically, intraocularly, iontophoretically, transmucosally, or by inhalation.

14. The composition of claim 7 , wherein the aromatic-cationic peptide comprises D-Arg-2′,6′-Dmt-Lys-Phe-NH 2 or a pharmaceutically acceptable salt thereof selected from acetate salt or trifluororacetate salt.

Assignees

• Stealth Peptides Int Inc
• Stealth Biotherapeutics Corp

Inventors

• Wilson D Travis

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61K38/08

  Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61K38/07

  Tetrapeptides · CPC title