Claims for Patent: 9,155,745

Summary for Patent: 9,155,745

Title:	Bevacizumab formulations with lower aggregation propensity, comprising corticosteroid anti-inflammatory drugs
Abstract:	The present invention is directed to combination formulations of monoclonal antibodies with anti-inflammatory agents, related methods and uses thereof.
Inventor(s):	Gurny; Robert (Geneva, CH), Stella; Cinzia (Geneva, CH), Tabatabay; Cyrus (Bernex, CH), Veurink; Marieke (Geneva, CH), Pournaras; Constantin (Conches, CH)
Assignee:	UNIVERSITE DE GENEVE (Geneva, CH)
Application Number:	12/797,166
Patent Claims:	1. A stable antibody formulation said formulation comprising an aqueous carrier, bevacizumab and a corticosteroid anti-inflammatory drug selected from dexamethasone, dexamethasone sodium phosphate, a dexamethasone derivative, betamethasone, betamethasone sodium phosphate, or a pharmaceutically acceptable salt thereof, wherein corticosteroid anti-inflammatory drug to bevacizumab-molar ratio ranges from is 1.53:1 to 153:1 and the dexamethasone derivative is of Formula (I): ##STR00002## wherein R.sup.1 is selected from H, halogen, --OH, --O.sub.4PHNa.sub.2, --O--C(O)--R.sup.9; R.sup.2 is selected from H, OH, --O--C(O)--R.sup.10; R.sup.3 is selected from H or --CH.sub.3; R.sup.4 is selected from H, and halogen; R.sup.5 is selected from H, OH and carbonyl; R.sup.6 and R.sup.7 are H or form together a double bond; R.sup.8 is selected from optionally substituted C.sub.1-C.sub.6 alkyl and optionally substituted acetyl; R.sup.9 and R.sup.10 are independently selected from optionally substituted C.sub.1-C.sub.6 alkyl and optionally substituted C.sub.3-C.sub.8-cycloalkyl; R.sup.11 is selected from H or optionally substituted C.sub.1-C.sub.6 alkyl. 2. The formulation according to claim 1, wherein the formulation is a pharmaceutical formulation. 3. The formulation according to claim 1 wherein said corticosteroid anti-inflammatory drug is: a) dexamethasone or a derivative thereof; or b) betamethasone, wherein the dexamethasone derivative is of Formula (I): ##STR00003## wherein R.sup.1 is selected from H, halogen, --OH, --O.sub.4PHNa.sub.2, --O--C(O)--R.sup.9; R.sup.2 is selected from H, OH, --O--C(O)--R.sup.10; R.sup.3 is selected from H or --CH.sub.3; R.sup.4 is selected from H, and halogen; R.sup.5 is selected from H, OH and carbonyl; R.sup.6 and R.sup.7 are H or form together a double bond; R.sup.8 is selected from optionally substituted C.sub.1-C.sub.6 alkyl and optionally substituted acetyl; R.sup.9 and R.sup.10 are independently selected from optionally substituted C.sub.1-C.sub.6 alkyl and optionally substituted C.sub.3-C.sub.8-cycloalkyl; R.sup.11 is selected from H or optionally substituted C.sub.1-C.sub.6 alkyl. 4. The formulation according to claim 3 wherein said corticosteroid anti-inflammatory drug is dexamethasone. 5. The formulation according to claim 3 wherein said corticosteroid anti-inflammatory drug is betamethasone. 6. The formulation according to claim 1 wherein the formulation has a pH in the range between pH 4.5 and pH 7.5. 7. The formulation according to claim 1, further comprising an excipient. 8. A pharmaceutical unit dosage form suitable for ocular administration to a mammal comprising an antibody formulation according to claim 1 in a suitable container. 9. A method of stabilizing bevacizumab in aqueous solution comprising combining bevacizumab with a corticosteroid anti-inflammatory drug, wherein said corticosteroid anti-inflammatory drug is selected from dexamethasone, dexamethasone sodium phosphate, a dexamethasone derivative, betamethasone, betamethasone sodium phosphate or pharmaceutically acceptable salts thereof, wherein the dexamethasone derivative is of Formula (I): ##STR00004## wherein R.sup.1 is selected from H, halogen, --OH, --O.sub.4PHNa.sub.2, --O--C(O)--R.sup.9; R.sup.2 is selected from H, OH, --O--C(O)--R.sup.10; R.sup.3 is selected from H or --CH.sub.3; R.sup.4 is selected from H, and halogen; R.sup.5 is selected from H, OH and carbonyl; R.sup.6 and R.sup.7 are H or form together a double bond; R.sup.8 is selected from optionally substituted C.sub.1-C.sub.6 alkyl and optionally substituted acetyl; R.sup.9 and R.sup.10 are independently selected from optionally substituted C.sub.1-C.sub.6 alkyl and optionally substituted C.sub.3-C.sub.8-cycloalkyl; R.sup.11 is selected from H or optionally substituted C.sub.1-C.sub.6 alkyl and the corticosteroid anti-inflammatory drug to bevacizumab molar ratio ranges from 1.53:1 to 153:1. 10. The method according to claim 9 wherein said corticosteroid anti-inflammatory drug is dexamethasone or a derivative thereof. 11. The method according to claim 10 wherein the corticosteroid anti-inflammatory drug is betamethasone. 12. A process for the preparation of a bevacizumab formulation comprising the steps of: (i) combining bevacizumab with a corticosteroid anti-inflammatory drug into a liquid mixture or forming a formulation comprising bevacizumab and a liquid medium containing a corticosteroid anti-inflammatory drug, said corticosteroid anti-inflammatory drug selected from dexamethasone, dexamethasone sodium phosphate, a dexamethasone derivative, betamethasone, betamethasone sodium phosphate or pharmaceutically acceptable salts of and wherein the dexamethasone derivative is of Formula (I): ##STR00005## wherein R.sup.1 is selected from H, halogen, --OH, --O.sub.4PHNa.sub.2, --O--C(O)--R.sup.9; R.sup.2 is selected from H, OH, --O--C(O)--R.sup.10; R.sup.3 is selected from H or --CH.sub.3; R.sup.4 is selected from H, and halogen; R.sup.5 is selected from H, OH and carbonyl; R.sup.6 and R.sup.7 are H or form together a double bond; R.sup.8 is selected from optionally substituted C.sub.1-C.sub.6 alkyl and optionally substituted acetyl; R.sup.9 and R.sup.10 are independently selected from optionally substituted C.sub.1-C.sub.6 alkyl and optionally substituted C.sub.3-C.sub.8-cycloalkyl; R.sup.11 is selected from H or optionally substituted C.sub.1-C.sub.6 alkyl and the corticosteroid anti-inflammatory drug to bevacizumab molar ratio ranges from 1.53:1 to 153:1; and formulation obtained under step (i. 13. The process according to claim 12 wherein said corticosteroid anti-inflammatory drug is dexamethasone or a derivative thereof. 14. The process according to claim 13 wherein said corticosteroid anti-inflammatory drug is betamethasone. 15. A method of inhibiting the biological activity of vascular endothelial growth factor (VEGF) in a subject comprising administering to a subject having a disease or a disorder selected from a cancer, a neovascular age-related macular degeneration disease (AMD) and a disorder associated with AMD a therapeutically effective amount of a stable antibody formulation according to claim 1. 16. The stable antibody formulation according to claim 1, wherein less than 10% of antibody in said formulation forms an aggregate during storage at 40.degree. C. for 35 days, as determined by multi-angle light scattering (MALS) coupled to asymmetrical flow field-flow fractionation (AFFF). 17. The stable antibody formulation according to claim 16, wherein said formulation comprises bevacizumab and dexamethasone. 18. The stable antibody formulation according to claim 1, wherein the corticosteroid anti-inflammatory drug is at a concentration in the range of about 0.1 mg/ml to about 13 mg/ml. 19. The stable antibody formulation according to claim 1, wherein bevacizumab is at a concentration in the range of about 5 mg/ml to about 100 mg/ml.

Details for Patent 9,155,745

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2029-06-16