Subcutaneous anti-HER2 antibody formulations and uses thereof

• US 9,968,676 B2
• Filed: 02/25/2016
• Issued: 05/15/2018
• Est. Priority Date: 07/31/2009
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Adler, Michael, Grauschopf, Ulla, Mahler, Hanns-Christian, Stauch, Oliver Boris
• Primary Examiner(s): Aeder, Sean E
• Application Number:
  US15/053,217
• Publication Number:
  US 20160166689A1
• Time in Patent Office: 810 Days
• Field of Search: None
• CPC Class Codes: A61K 38/47 acting on glycosyl compounds (3.2), e.g. cellulases, lactases
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C12Y 302/01035 Hyaluronoglucosaminidase (3.2.1.35), i.e. hyaluronidase

Abstract

The present invention relates to a highly concentrated, stable pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody, such as e.g. Trastuzumab (HERCEPTIN™), Pertuzumab or T-DM1, 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-HER2 antibody, an effective amount of at least one hyaluronidase enzyme as a combined formulation or for use in form of a co-formulation. The 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.

Claims

1. A highly concentrated, stable liquid pharmaceutical composition of pharmaceutically active anti-HER2 antibody for subcutaneous injection comprising:

a. 100 to 150 mg/ml anti-HER2 antibody, wherein the anti-HER2 antibody is a combination of Trastuzumab and Pertuzumab;

b. 1 to 50±

5% mM of a buffering agent providing a pH of 5.5±

2.0;

c. 150 to 250±

5% mM of a mixture of trehalose and sucrose as a first stabilizer and 5 to 15 mM methionine as a secondary stabilizer;

d. 0.01 to 0.08±

5% (w/v) of a nonionic surfactant; and

e. 1,000 to 16,000 U/ml of at least one hyaluronidase enzyme.

2. The pharmaceutical composition of claim 1 comprising 120 mg/ml of the combination of Trastuzumab and Pertuzumab.

3. The pharmaceutical composition of claim 1, comprising 1′

500 U/ml to 12,000 U/ml of the hyaluronidase enzyme.

4. The pharmaceutical composition of claim 3, comprising 2,000 U/ml of the hyaluronidase enzyme.

5. The pharmaceutical composition of claim 4, wherein the hyaluronidase enzyme is recombinant human hyaluronidase, rHuPH20.

6. The pharmaceutical composition of claim 1, wherein the buffering agent is a histidine buffer.

7. The pharmaceutical composition of claim 5, wherein the histidine buffer is a histidine chloride buffer at a pH of 5.5±

0.6.

8. The pharmaceutical composition of claim 6, wherein the histidine chloride buffer has a pH of 5.5.

9. The pharmaceutical composition of claim 1, wherein the nonionic surfactant is a polysorbate selected from the group consisting of polysorbate 20, polysorbate 80, and polyethylene-polypropylene copolymer.

10. The pharmaceutical composition of claim 9, wherein the nonionic surfactant is polysorbate 20.

11. An injection device comprising the highly concentrated stable ready for use pharmaceutical composition of claim 1.

12. A method of treating a disease or disorder which is amenable to treatment with an anti-HER2 antibody in a subject comprising administering to said subject a pharmaceutical composition according to claim 1 in an amount effective to treat said disease or disorder.

13. The method of claim 12, wherein the disease is cancer.

14. The method of claim 13, wherein the cancer is breast cancer.

15. The method of claim 14, wherein the cancer is HER2 overexpressing breast cancer.

16. A kit comprising a vial containing the highly concentrated stable ready for use pharmaceutical composition of claim 1 and instructions for subcutaneous administration of the composition to a patient.

17. The kit of claim 16 further comprising an injection device for subcutaneous administration of the pharmaceutical composition to the patient.