Highly concentrated pharmaceutical formulations

Patent metadata

Field	Value
Publication number	US-10280227-B2
Application number	US-201414260558-A
Country	US
Kind code	B2
Filing date	Apr 24, 2014
Priority date	Sep 11, 2009
Publication date	May 7, 2019
Grant date	May 7, 2019

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 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.

Assignees

• Genentech Inc

Inventors

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

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/20

  containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids · CPC title

• C07K2317/734

  Complement-dependent cytotoxicity [CDC] · CPC title