Claims for Patent: 10,752,696

Summary for Patent: 10,752,696

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:	16/450,906
Patent Claims:	1. A method of treating chronic lymphocytic leukemia (CLL) in a human patient comprising administering a formulation comprising Rituximab subcutaneously to the patient, wherein the Rituximab is administered at a fixed dose of 1600 mg thereof. 2. The method according to claim 1, further comprising administering chemotherapy to the patient. 3. The method according to claim 2, wherein the chemotherapy comprises FC (fludarabine and cyclophosphamide). 4. The method according to claim 1, comprising administering recombinant human PH20 (rHuPH20) to the subject to increase dispersion and absorption of the Rituximab. 5. The method according to claim 1, wherein the formulation comprises about 50 to 350 mg/ml Rituximab and at least one hyaluronidase enzyme. 6. The method according to claim 5, wherein the hyaluronidase enzyme comprises recombinant human PH20 (rHuPH20). 7. The method according to claim 6, wherein the formulation comprises about 1,000 to 16,000 U/ml rHuPH20. 8. The method according to claim 1, wherein the formulation comprises about 100 to 150 mg/ml Rituximab; histidine buffer providing a pH of about 5.3 to 6.5; about 15 to 250 mM saccharide, selected from the group consisting of trehalose and sucrose, as a first stabilizer; about 5 to 25 mM methionine as a second stabilizer; about 0.02 to 0.08% of a polysorbate; and about 1,000 to 16,000 U/ml of recombinant human PH20 (rHuPH20) hyaluronidase enzyme. 9. The method according to claim 8, wherein the formulation comprises about 120 mg/ml Rituximab; histidine buffer, pH of about 5.5; about 210 mM trehalose; about 10 mM methionine; about 0.06% polysorbate 80; and about 12,000 U/ml of recombinant human PH20 (rHuPH20) hyaluronidase enzyme. 10. The method according to claim 1, wherein the Rituximab concentration in the formulation is from 100 to 150 mg/ml. 11. The method according to claim 10, further comprising administering chemotherapy to the patient. 12. The method according to claim 11, wherein the chemotherapy comprises FC (fludarabine and cyclophosphamide). 13. The method according to claim 10, comprising administering recombinant human PH20 (rHuPH20) to the patient to increase dispersion and absorption of the Rituximab. 14. The method according to claim 10, wherein the formulation comprises at least one hyaluronidase enzyme. 15. The method according to claim 14, wherein the hyaluronidase enzyme comprises recombinant human PH20 (rHuPH20). 16. The method according to claim 15, wherein the formulation comprises about 1,000 to 16,000 U/ml rHuPH20. 17. The method according to claim 10, wherein the formulation comprises about 100 to 150 mg/ml Rituximab; histidine buffer providing a pH of about 5.3 to 6.5; about 15 to 250 mM saccharide, selected from the group consisting of trehalose and sucrose, as a first stabilizer; about 5 to 25 mM methionine as a second stabilizer; about 0.02 to 0.08% of a polysorbate; and about 1,000 to 16,000 U/ml of recombinant human PH20 (rHuPH20) hyaluronidase enzyme. 18. The method according to claim 10, wherein the formulation comprises about 120 mg/ml Rituximab; histidine buffer, pH of about 5.5; about 210 mM trehalose; about 10 mM methionine; about 0.06% polysorbate 80; and about 12,000 U/ml of recombinant human PH20 (rHuPH20) hyaluronidase enzyme. 19. A method of treating chronic lymphocytic leukemia (CLL) in a human patient comprising administering a formulation comprising Rituximab subcutaneously to the patient, wherein the Rituximab concentration in the formulation is from 100 to 150 mg/ml wherein the Rituximab is administered at a fixed dose of 1600 mg/ml thereof.

Details for Patent 10,752,696

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	May 05, 2004		2039-06-24
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	December 02, 2004		2039-06-24
Amphastar Pharmaceuticals, Inc.	AMPHADASE	hyaluronidase	Injection	021665	October 26, 2004		2039-06-24
Akorn, Inc.	HYDASE	hyaluronidase	Injection	021716	October 25, 2005		2039-06-24

International Patent Family for US Patent 10,752,696

Country	Patent Number	Estimated Expiration
South Africa	201201605
World Intellectual Property Organization (WIPO)	2011029892
United States of America	2025197520
United States of America	2021054092