Pharmaceutical composition comprising Factor VIII and neutral liposomes

• US 6,593,294 B1
• Filed: 11/22/2000
• Issued: 07/15/2003
• Est. Priority Date: 04/27/1998
• Status: Expired due to Term

• Current Assignee: Cantab Biopharmaceuticals Patents Limited
• Original Assignee: Opperbas Holding B.V.
• Inventors: Nur, Israel, Bar, Liliana, Baru, Moshe
• Primary Examiner(s): Low, Christopher S. F.
• Assistant Examiner(s): SCHNIZER, HOLLY G
• Application Number:
  US09/673,412
• Time in Patent Office: 965 Days
• Field of Search: 424/450, 514/2, 514/802, 514/834, 530/350, 530/380, 530/383
• US Class Current: 514/13.7
• CPC Class Codes: A61K 38/37 Factors VIII
• 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 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Abstract

A pharmaceutical composition for parenteral administration comprising a therapeutically effective amount of a protein or polypeptide and substantially neutral colloidal particles. The particles comprise approximately 1-20 mole percent of an amphipathic lipid derivatized with a biocompatible hydrophilic polymer which carriers substantially no net charge. The protein or polypeptide is capable of externally binding the colloidal particles, or is capable of binding polyethylene glycol, and is not encapsulated in the colloidal particles. A preferred protein is factor VIII, whose half-life is extended and which is protected from serum inhibitor antibodies by injecting it as a component of the composition.

Claims

1. A pharmaceutical composition for parenteral administration comprising a therapeutically effective amount of coagulation factor VIII (FVIII) and substantially neutral colloidal particles, said particles comprising approximately 1-20 mole percent of an amphipathic lipid derivatized with a biocompatible hydrophilic polymer, said polymer carrying substantially no net charge,

wherein said FVIII is not encapsulated in said colloidal particles.

2. The pharmaceutical composition of claim 1 wherein the colloidal particle has a mean particle diameter of about 0.05 to about 0.4 microns.

3. The pharmaceutical composition of claim 2 wherein the colloidal particle has a mean particle diameter of approximately 0.1 microns.

4. The pharmaceutical composition of claim 1 wherein said amphipathic lipid is a phospholipid from natural or synthetic sources.

5. The pharmaceutical composition of claim 4 wherein said amphipathic lipid is phosphatidylethanolamine (PE).

6. The pharmaceutical composition of claim 1 wherein said biocompatible hydrophilic polymer is selected from the group consisting of polyalkylether, polylactic and polyglycolic acid families.

7. The pharmaceutical composition of claim 6 wherein said biocompatible hydrophilic polymer is polyethylene glycol.

8. The pharmaceutical composition of claim 7 wherein the polyethylene glycol has a molecular weight of about 1000 to about 5000 daltons.

9. The pharmaceutical composition of claim 8 wherein the polyethylene glycol has a molecular weight of approximately 2000 daltons.

10. The pharmaceutical composition of claim 1 wherein the FVIII is from a natural source.

11. The pharmaceutical composition of claim 1 wherein the FVIII is recombinantly prepared.

12. The pharmaceutical composition of claim 1 wherein the particle to FVIII ratio (w/unit FVIII) is about 0.1 mg/unit to about 10 mg/unit.

13. The pharmaceutical composition of claim 12 wherein the particle to FVIII ratio (w/unit FVIII) is approximately 1 mg/unit.

14. The pharmaceutical composition of claim 1 wherein said colloidal particles further comprise a second amphipathic lipid obtained from either natural or synthetic sources.

15. The pharmaceutical composition of claim 14 wherein said second amphipathic lipid is phosphatidylcholine.

16. Method of treatment of a patient suffering from hemophilia comprising administrating to said patient a pharmaceutical composition for parenteral administration comprising a therapeutically effective amount of coagulation factor VIII (FVIII) and substantially neutral colloidal particles, said particles comprising approximately 1-20 mole percent of an amphipathic lipid derivatized with a biocompatible hydrophilic polymer, said polymer carrying substantially no net charge,

wherein said FVIII is not encapsulated in said colloidal particles.

17. A method according to claim 16 wherein said patient has developed FVIII inhibitor antibodies.