Claims for Patent: 9,345,661

Summary for Patent: 9,345,661

Title:	Subcutaneous anti-HER2 antibody formulations and uses thereof
Abstract:	The present invention relates to a highly concentrated, stable pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody, such as e.g. Trastuzumab (HERCEPTIN.TM.), Pertuzumab or T-DM1, or a mixture of such antibody molecules for subcutaneous injection. In particular, the present invention relates to formulations comprising, in addition to a suitable amount of the anti-HER2 antibody, an effective amount of at least one hyaluronidase enzyme as a combined formulation or for use in form of a co-formulation. The formulations comprise additionally at least one buffering agent, such as e.g. a histidine buffer, a stabilizer or a mixture of two or more stabilizers (e.g. a saccharide, such as e.g. .alpha.,.alpha.-trehalose dihydrate or sucrose, and optionally methionine as a second stabilizer), a nonionic surfactant and an effective amount of at least one hyaluronidase enzyme. Methods for preparing such formulations and their uses thereof are also provided.
Inventor(s):	Adler; Michael (Riehen, CH), Grauschopf; Ulla (Riehen, CH), Mahler; Hanns-Christian (Basel, CH), Stauch; Oliver Boris (Freiburg, DE)
Assignee:	Genentech, Inc. (South San Francisco, CA)
Application Number:	12/804,703
Patent Claims:	1. A highly concentrated, stable liquid pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody for subcutaneous injection comprising: a. 120.+-.18 mg/ml anti-HER2 antibody, wherein said antibody is Trastuzumab; b. 1 to 50.+-.5% mM of a buffering agent providing a pH of 5.5.+-.2.0; c. 150 to 250.+-.5% mM of .alpha.,.alpha.-trehalose dihydrate or sucrose as a first stabilizer and 5 to 15.+-.5% mM methionine as a second stabilizer; d. 0.01 to 0.08%.+-.5% of a nonionic surfactant; and e. 1'000 to 16'000.+-.5% U/ml of at least one hyaluronidase enzyme. 2. A highly concentrated, stable liquid pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody for subcutaneous injection comprising: a. 100 to 150 mg/ml anti-HER2 antibody, wherein said antibody is Trastuzumab; b. 1 to 50 mM of a buffering agent providing a pH of 5.5.+-.2.0; c. 150 to 250 mM of .alpha.,.alpha.-trehalose dihydrate or sucrose as a first stabilizer and 5 to 15 mM methionine as a second stabilizer; d. 0.01 to 0.08% of a nonionic surfactant; and e. 1'000 to 16'000 U/ml of at least one hyaluronidase enzyme. 3. The formulation according to claim 1, wherein the anti-HER2 antibody concentration is 110, 120, or 130 mg/ml. 4. The formulation according to claim 1 or claim 2, comprising 2'000 U/ml to 12'000 U/ml of a hyaluronidase enzyme. 5. The formulation according to claim 1 or claim 2, wherein said buffering agent is a histidine buffer. 6. The formulation according to claim 1 or claim 2, wherein the first stabilizer is .alpha.,.alpha.-trehalose dihydrate. 7. The formulation according to claim 1 or claim 2, wherein the nonionic surfactant is a polysorbate selected from the group consisting of polysorbate 20, polysorbate 80, and polyethylene-polypropylene copolymer. 8. The formulation according to claim 7, wherein the concentration of the polysorbate is 0.02% (w/v), 0.04% (w/v) or 0.06% (w/v), respectively. 9. The formulation according to claim 1 or claim 2 which is stable upon freezing and thawing. 10. The formulation according to claim 1 or claim 2, wherein the hyaluronidase enzyme is rHuPH20. 11. The formulation according to claim 1 or claim 2, wherein the buffering agent provides a pH of 5.5.+-.0.5. 12. The formulation according to claim 1 or claim 2 for the treatment of a disease or disorder amenable to treatment with an anti-HER2 antibody. 13. An injection device comprising a highly concentrated, stable, liquid pharmaceutical anti-HER2 antibody formulation according to claim 1 or claim 2. 14. The injection device according to claim 13 wherein the formulation is co-administered concomitantly or sequentially with a chemotherapeutic agent. 15. A method of treating cancer cells expressing HER2 receptor in a subject comprising administering a formulation according to claim 1 or claim 2 to said subject in an amount effective to treat the said cancer cells. 16. A kit comprising one or more vials containing the formulation according to claim 1 or claim 2 and instructions for subcutaneous administration of the formulation to a patient. 17. The kit according to claim 16 further comprising an injection device for subcutaneous administration of the formulation to a patient. 18. A highly concentrated, stable liquid pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody for subcutaneous injection comprising: a. 120.+-.18 mg/ml anti-HER2 antibody, wherein said antibody is Trastuzumab; b. 1 to 50.+-.2% mM of a histidine buffer; c. 150 to 250 mM.+-.2% of .alpha.,.alpha.-trehalose dihydrate or sucrose as a first stabilizer and 5 to 15 mM methionine as a second stabilizer; d. 0.01 to 0.08%.+-.2% of a nonionic surfactant; and e. 1000 to 16'000.+-.2% U/ml of at least one hyaluronidase enzyme. 19. A highly concentrated, stable liquid pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody for subcutaneous injection comprising: a. 120.+-.2% mg/ml anti-HER2 antibody, wherein said antibody is Trastuzumab; b. 20 mM.+-.2% of a histidine buffer; c. 210 mM.+-.2% of .alpha.,.alpha.-trehalose dihydrate or sucrose as a first stabilizer and 5 to 15 mM methionine as a second stabilizer; d. 0.04 to 0.06%.+-.2% of polysorbate 20; and e. 12'000.+-.2% U/ml of at least one hyaluronidase enzyme. 20. The formulation according to claim 19, wherein said hyaluronidase enzyme is rHuPH20. 21. A highly concentrated, stable liquid pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody for subcutaneous injection comprising: a. 120.+-.2% mg/ml anti-HER2 antibody, wherein said antibody is Trastuzumab; b. 20 mM.+-.2% of a histidine buffer; c. 210 mM.+-.2% of .alpha.,.alpha.-trehalose dihydrate or sucrose as a first stabilizer and 5 to 25 mM methionine as a second stabilizer; d. 0.04 to 0.06%.+-.2% of polysorbate 20; and e. 2'000.+-.2% U/ml of at least one hyaluronidase enzyme. 22. The formulation according to claim 21, wherein said hyaluronidase enzyme is rHuPH20. 23. The formulation according to claim 18, wherein said hyaluronidase enzyme is rHuPH20. 24. A highly concentrated, stable pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody comprising 120 mg/ml Trastuzumab, 20 mM L-histidine/HCl pH 5.5, 210 mM .alpha.,.alpha.-trehalose dihydrate, 10 mM methionine, 0.04% polysorbate 20, and 2'000 U/ml rHuPH20.

Details for Patent 9,345,661

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	05/05/2004		2029-07-31
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	12/02/2004		2029-07-31
Amphastar Pharmaceuticals, Inc.	AMPHADASE	hyaluronidase	Injection	021665	10/26/2004		2029-07-31
Akorn, Inc.	HYDASE	hyaluronidase	Injection	021716	10/25/2005		2029-07-31