Highly concentrated pharmaceutical formulations

Patent metadata

Field	Value
Publication number	US-10752696-B2
Application number	US-201916450906-A
Country	US
Kind code	B2
Filing date	Jun 24, 2019
Priority date	Sep 11, 2009
Publication date	Aug 25, 2020
Grant date	Aug 25, 2020

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. α,α-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.

First claim

The invention claimed is:

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.

Assignees

• Genentech Inc

Inventors

• Adler Michael
• Mahler Hanns-Christian
• Stauch Oliver Boris

Classifications

• A61K47/12

  Carboxylic acids; Salts or anhydrides thereof · CPC title

• A61K9/0021

  Intradermal administration, e.g. through microneedle arrays or needleless injectors · CPC title

• A61K39/39591 Primary

  Stabilisation, fragmentation · CPC title

• A61K2039/54

  characterised by the route of administration · CPC title

• A61K2039/505

  comprising antibodies · CPC title