Claims for Patent: 5,972,885

Summary for Patent: 5,972,885

Title:	Method for treatment of hemophilia by extravascular administration of factor VIII deletion derivatives
Abstract:	A pharmaceutical formulation for subcutaneous, intramuscular or intradermal administration comprising recombinant coagulation factor VIII and use thereof for manufacture of a medicament for treating haemophilia is provided. The formulation comprises a highly purified recombinant coagulation factor VIII in a concentration of at least 1000 IU/ml, which gives surprisingly high levels of active factor VIII in the blood stream after subcutaneous, intramuscular or intradermal administration. The formulation is intended for treatment of haemophilia by subcutaneous, intramuscular or intradermal administration. The recombinant factor VIII is preferably a deletion derivative thereof, which can be used for the manufacture of a medicament for subcutaneous administration.
Inventor(s):	Spira; Jack (Stockholm, SE), Widlund; Lars (Sp.ang.nga, SE), Osterberg; Thomas (Stockholm, SE)
Assignee:	Pharmacia & Upjohn Aktiebolag (Stockholm, SE)
Application Number:	08/564,161
Patent Claims:	1. Method for treatment of haemophilia by subcutaneous, intramuscular or intradermal administration of pharmaceutical formulation with a volume of 0.1 to 2 ml comprising a highly purified recombinant coagulation factor VIII with an activity of at least 1,000 IU/ml and a non-ionic surfactant, wherein said recombinant coagulation factor VIII is selected from the group consisting of deletion derivatives of factor VIII where the whole or part of the B-domain is missing and factor VIII which has been chemically modified by pegylation or covalently linked carbohydrates or polypeptides, which formulation is stabilized without albumin and is capable of increasing the factor VIII activity in the blood to a therapeutic level after subcutaneous, intramuscular or intradermal administration. 2. A method according to claim 1 in which the factor VIII activity is from 5000 to 100000 IU/ml. 3. A method according to claim 1 wherein the formulation has a volume of 0.5 to 1 ml. 4. A method according to claim 1 wherein said deletion derivative of recombinant coagulation factor VIII has a molecular weight of 170 kDa to 300 kDa. 5. A method according to claim 1 wherein said recombinant coagulation factor VIII is a deletion derivative of factor VIII where the whole or part of the B-domain is missing. 6. A method according to claim 1 wherein said recombinant coagulation factor VIII is factor VIII which has been chemically modified by pegylation or covalently linked carbohydrates or polypeptides. 7. A method according to claim 1 which comprises subcutaneous administration. 8. A method according to claim 7 wherein the formulation has a volume of 0.1 to 2 ml. 9. A method according to claim 7 in which the factor VIII activity is from 5000 to 100000 IU/ml. 10. A method according to claim 1 in which the factor VIII activity is more than 1500 IU/ml. 11. A method according to claim 10 wherein the formulation has a volume of 0.1 to 2 ml. 12. A method according to claim 1 in which the deletion derivative factor VIII is deletion derivative recombinant factor VIII SQ(r-VIII SQ). 13. A method according to claim 1 wherein the formulation is a stable aqueous solution ready for administration. 14. A method according to claim 1 wherein the formulation is freeze-dried and reconstituted with sterile water or a pharmaceutically acceptable buffer solution before administration. 15. A method according to claim 1 wherein the formulation is mixed or reconstituted with an aqueous solution containing absorption enhancers or protease inhibitors before administration. 16. Method for treatment of haemophilia by subcutaneous, intramuscular or intradermal administration of pharmaceutical formulation with a volume of 0.1 to 2 ml, comprising a highly purified recombinant coagulation factor VIII with an activity of at least 1500 IU/ml and a non-ionic surfactant, wherein said recombinant coagulation factor VIII comprises a deletion derivative of factor VIII where the whole or part of the B-domain is missing; said non-ionic surfactant comprises at least 0.01 mg/ml of a polyoxyethylene sorbitan fatty acid ester; and the formulation further comprises sodium chloride, calcium salt and an amino acid in an amount of more than 1 mM; which formulation is stabilized without albumin and is capable of increasing the factor VIII activity in the blood to a therapeutic level after subcutaneous, intramuscular or intradermal administration. 17. The method according to claim 16 wherein said sodium chloride is present in an amount of more than 0.1 M, said calcium salt is calcium chloride or calcium gluconate and is present in an amount of more than 0.5 mM, and wherein said amino acid is L-histidine. 18. A method according to claim 16 in which the deletion derivative factor VIII is deletion derivative recombinant factor VIII SQ (r-VIII SQ).

Details for Patent 5,972,885

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	ZOSTAVAX	zoster vaccine live	For Injection	125123	05/25/2006		2013-07-05