Claims for Patent: 10,280,227

Summary for Patent: 10,280,227

Title:	Highly concentrated pharmaceutical formulations
Abstract:	The present invention relates to a highly concentrated, stable pharmaceutical formulation of a pharmaceutically active anti-CD20 antibody, such as e.g. Rituximab, Ocrelizumab, or HuMab<CD20>, 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-CD20 antibody, an effective amount of at least one hyaluronidase enzyme as a combined formulation or for use in form of a co-formulation. The said 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), Mahler; Hanns-Christian (Basel, CH), Stauch; Oliver Boris (Freiburg, DE)
Assignee:	Genentech, Inc. (South San Francisco, CA)
Application Number:	14/260,558
Patent Claims:	1. A highly concentrated, stable pharmaceutical formulation suitable for subcutaneous administration comprising: a. about 100-150 mg/ml Rituximab; b. a buffering agent providing a pH of 5.3- 6.5; c. about 15 to 250 mM saccharide as a first stabilizer; d. about 5 to 25 mM methionine as a second stabilizer; e. about 0.01 to 0.1% of a nonionic surfactant; and f. about 1,000 to 16,000 U/ml of recombinant human PH20 (rHuPH20) hyaluronidase enzyme. 2. A highly concentrated, stable pharmaceutical formulation according to claim 1, wherein the Rituximab concentration is 100 to 150 mg/ml. 3. A highly concentrated, stable pharmaceutical formulation according to claim 1, wherein the Rituximab concentration is 120.+-.20 mg/ml. 4. A highly concentrated, stable pharmaceutical formulation according to claim 1, comprising about 12,000 U/ml of rHuPH20. 5. A highly concentrated, stable pharmaceutical formulation according to claim 1, wherein the buffering agent provides a pH selected from the group consisting of 5.3, 5.5, 6.0, 6.1 and 6.5. 6. A highly concentrated, stable pharmaceutical formulation according to claim 1, wherein the buffering agent is a histidine buffer. 7. A highly concentrated, stable pharmaceutical formulation according to claim 1, wherein the nonionic surfactant comprises a polysorbate. 8. A highly concentrated, stable pharmaceutical formulation according to claim 7, wherein the concentration of the polysorbate is 0.02% (w/v) to 0.08% (w/v). 9. A highly concentrated, stable pharmaceutical formulation according to claim 7, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 80, and polyethylene-polypropylene copolymer. 10. A highly concentrated, stable pharmaceutical formulation according to claim 1, which is stable upon freezing and thawing. 11. A highly concentrated, stable pharmaceutical formulation according to claim 1 in liquid form. 12. A highly concentrated, stable pharmaceutical formulation according to claim 1, wherein the first stabilizer comprises trehalose. 13. A highly concentrated, stable pharmaceutical formulation according to claim 1, wherein the first stabilizer comprises sucrose. 14. A highly concentrated, stable pharmaceutical formulation suitable for subcutaneous administration comprising: a. about 100 to 150 mg/ml Rituximab; b. histidine buffer providing a pH of about 5.3 to 6.5; c. about 15 to 250 mM saccharide, selected from the group consisting of trehalose and sucrose, as a first stabilizer; d. about 5 to 25 mM methionine as a second stabilizer; e. about 0.02 to 0.08% of a polysorbate; and f. about 1,000 to 16,000 U/ml of recombinant human PH20 (rHuPH20) hyaluronidase enzyme. 15. A highly concentrated, stable, liquid pharmaceutical formulation suitable for subcutaneous administration comprising: a. about 120 mg/ml Rituximab; b. histidine buffer, pH of about 5.5; c. about 210 mM trehalose; d. about 10 mM methionine; e. about 0.06% polysorbate 80; and f. about 12,000 U/ml of recombinant human PH20 (rHuPH20) hyaluronidase enzyme.

Details for Patent 10,280,227

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	05/05/2004		2029-09-11
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	12/02/2004		2029-09-11
Amphastar Pharmaceuticals, Inc.	AMPHADASE	hyaluronidase	Injection	021665	10/26/2004		2029-09-11