PHARMACEUTICAL COMPOSITION COMPRISING A CAMPOTHECIN DERIVATIVE

• US 20100166843A1
• Filed: 01/30/2008
• Published: 07/01/2010
• Est. Priority Date: 02/01/2007
• Status: Abandoned Application

• Current Assignee: Sigma-Tau Industrie Farmaceutiche Riunite SPA (Alfasigma S.p.A.)
• Original Assignee: Sigma-Tau Industrie Farmaceutiche Riunite SPA (Alfasigma S.p.A.)
• Inventors: Zhang, Jia-ai, Francese, Giancarlo, Ogorka, Jörg
• Application Number:
  US12/525,012
• Publication Number:
  US 20100166843A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 31/4741 condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• 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 to pharmaceutical compositions comprising a topoisomerase I inhibitor including, but not limited to, a camptothecin derivative.

Claims

1. A method of treating a cellular proliferative disease comprising administering to a mammalian host a pharmaceutical composition comprising:

a) a therapeutically effective amount of 7-t-butoxyiminomethylcamptothecin entrapped in liposomes; and

b) a pharmaceutically acceptable excipient.

2. The method of claim 1, wherein said mammalian host is a human.

3. The method of claim 1, wherein the liposomes are made from synthetic or natural phospholipids that are selected from the group consisting of phosphatidyicholine, distearoylphosphatidylcholine, sphingomyelin, diacyl glycerol, phosphatidyl ethanolamine, phosphatidylglycerol, distearylphosphatidylcholine and distearyl phosphatidylethanolamine.

4. The method of claim 1, wherein the liposomes have a negative charge.

5. The method of claim 1, wherein the liposomes are neutral.

6. The method of claim 1, wherein the liposomes have a positive charge.

7. The method of claim 1, wherein the liposome surfaces are grafted with a hydrophilic polymer.

8. The method of claim 7, wherein said hydrophilic polymer is composed of hydrophilic polymers selected from the group consisting of polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, polyhydroxypropylmethacrylate, polyhydroxyethylacrylate, hydroxymethylcellulose, hydroxyethyl cellulose, polyethyleneglycol and polyaspartamide.

9. The method of claim 8, wherein said hydrophilic polymer coating is composed of polyethylene glycol chains having a molecular weight of between about 500 Daltons and about 10,000 Daltons.

10. The method of claim 1, wherein the liposomes are about 0.05 to about 1 microns.

11. The method of claim 1, wherein said liposomes further contain a ligand attached to the distal end of at least a portion of said hydrophilic polymer chains.

12. The method of claim 1, wherein the liposomes further include a ligand attached the polar head group of at least a portion of the vesicle-forming lipids of the liposome.

13. The method of claim 11, wherein the ligand is selected from the group consisting of folic acid, pyridoxal phosphate, sialyl Lewis, transferrin, epidermal growth factor, basic fibroblast growth factor, vascular endothelial growth factor, VCAM-1, ICAM-1, PECAN-1 and RGD peptides.

14. The method of claim 11, wherein the ligand is selected from the group consisting of water soluble vitamins, apolipoproteins, insulin, galactose, Mac-1, PECAM-1/CD31, fibronectin, osteopontin, RGD sequences of matrix proteins, HIV GP 120/41 domain peptomers, GP120C4 domain peptomers, T cell tropic isolates, SDF-1 chemokines, Macrophage tropic isolates, anti-cell surface receptor antibodies or fragments thereof, pyridoxyl ligands, RGD peptide mimetics, and anti-E-selectin Fab.

15. The method of claim 10, wherein the ligand binds a receptor selected from the group consisting of folate receptor, E-selectin receptor, L-selectin receptor, P-selectin receptor, CD4 receptor, α

β

integrin receptors and chemokine receptors.

16. A pharmaceutical composition comprising:

a) a therapeutically effective amount of 7-t-butoxyiminomethylcamptothecin entrapped in liposomes; and

b) a pharmaceutically acceptable excipient.

17. The pharmaceutical composition according to claim 16 wherein the liposomes are made from synthetic or natural phospholipids that are selected from the group consisting of phosphatidylcholine, distearoylphosphatidylcholine, sphingomyelin, diacyl glycerol, phosphatidyl ethanolamine, phosphatidylglycerol, distearylphosphatidylcholine and distearyl phosphatidylethanolamine.

18. The pharmaceutical composition according to claim 16. wherein the liposomes are surface grafted with a hydrophilic polymer.

19. The pharmaceutical composition according to claim 18 wherein the hydrophilic polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, polyhydroxypropylmethacrylate, polyhydroxyethylacrylate, hydroxymethylcellulose, hydroxyethylcellulose, polyethyleneglycol and polyaspartamide.

22. A method for the treatment of disease symptoms that are caused by the activation of the topoisomerase I receptor, comprising administering an effective amount of a pharmaceutical composition according to claim 16 to a patient in need thereof.

20-21. -21. (canceled)