Claims for Patent: 10,377,831

Summary for Patent: 10,377,831

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:	14/944,508
Patent Claims:	1. A method of treating non-Hodgkin's lymphoma (NHL) in a human patient comprising administering a formulation comprising Rituximab subcutaneously to the patient, wherein the Rituximab is administered at a fixed dose of 1400 mg thereof. 2. The method according to claim 1, wherein the formulation comprising Rituximab is administered approximately every 2 months or approximately every 3 months. 3. The method according to claim 1, further comprising administering chemotherapy to the patient. 4. The method according to claim 3, wherein the chemotherapy is selected from the group consisting of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and CVP (cyclophosphamide, vincristine, and prednisone). 5. The method according to claim 1, comprising administering recombinant human PH20 (rHuPH20) to the subject to increase dispersion and absorption of the Rituximab. 6. The method according to claim 1, wherein the formulation comprises about 50 to 350 mg/ml Rituximab and at least one hyaluronidase enzyme. 7. The method according to claim 6, wherein the hyaluronidase enzyme comprises recombinant human PH20 (rHuPH20). 8. The method according to claim 7, wherein the formulation comprises about 1,000 to 16,000 U/ml rHuPH20. 9. 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. 10. The method according to claim 9, 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. 11. The method according to claim 1, wherein the Rituximab concentration in the formulation is from 100 to 150 mg/ml. 12. The method according to claim 11, wherein the formulation comprising Rituximab is administered approximately every 2 months or approximately every 3 months. 13. The method according to claim 11, further comprising administering chemotherapy to the patient. 14. The method according to claim 13, wherein the chemotherapy is selected from the group consisting of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and CVP (cyclophosphamide, vincristine, and prednisone). 15. The method according to claim 11, comprising administering recombinant human PH20 (rHuPH20) to the patient to increase dispersion and absorption of the Rituximab. 16. The method according to claim 11, wherein the formulation comprises at least one hyaluronidase enzyme. 17. The method according to claim 16, wherein the hyaluronidase enzyme comprises recombinant human PH20 (rHuPH20). 18. The method according to claim 17, wherein the formulation comprises about 1,000 to 16,000 U/ml rHuPH20. 19. The method according to claim 11, 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. 20. The method according to claim 11, 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. 21. A method of treating non-Hodgkin's lymphoma (NHL) in a human patient comprising administering a formulation comprising from 100 to 150 mg/ml Rituximab subcutaneously to the patient, wherein the Rituximab is administered at a fixed dose of 1400 mg thereof, and further comprising administering recombinant human PH20 (rHuPH20) to the patient to increase dispersion and absorption of the Rituximab. 22. The method according to claim 21, wherein the 1400 mg dose of Rituximab is subcutaneously administered approximately every 2 months or approximately every 3 months. 23. The method according to claim 21, wherein the formulation further comprises about 1,000 to 16,000 U/ml rHuPH20. 24. The method according to claim 21, further comprising administering chemotherapy to the patient. 25. The method according to claim 24, wherein the chemotherapy is selected from the group consisting of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and CVP (cyclophosphamide, vincristine, and prednisone).

Details for Patent 10,377,831

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
Akorn, Inc.	HYDASE	hyaluronidase	Injection	021716	10/25/2005		2029-09-11
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2029-09-11
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2029-09-11