Protein formulation

• US 6,685,940 B2
• Filed: 03/14/2001
• Issued: 02/03/2004
• Est. Priority Date: 07/27/1995
• Status: Expired due to Term

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Wu, Sylvia Sau-Yan, Overcashier, David E., Shire, Steven J., Hsu, Chung C., Lam, Xanthe M., Cleland, Jeffrey L., Yang, Janet Yu-Feng, Andya, James
• Primary Examiner(s): Chan, Christina
• Assistant Examiner(s): VANDERVEGT, FRANCOIS P
• Application Number:
  US09/809,511
• Publication Number:
  US 20010014326A1
• Time in Patent Office: 1,056 Days
• Field of Search: 424/130.1, 424/133.1, 435/810, 435/188, 435/963, 514/2, 514/23, 514/53, 422/40
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• 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 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: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Abstract

A stable lyophilized protein formulation is described which can be reconstituted with a suitable diluent to generate a high protein concentration reconstituted formulation which is suitable for subcutaneous administration. For example, anti-IgE and anti-HER2 antibody formulations have been prepared by lyophilizing these antibodies in the presence of a lyoprotectant. The lyophilized mixture thus formed is reconstituted to a high protein concentration without apparent loss of stability of the protein.

Claims

1. A formulation comprising a lyophilized mixture of a non-reducing sugar, a humanized antibody, and histidine, wherein the molar ratio of non-reducing sugar to humanized antibody is within the range from 100 to 600 mole non-reducing sugar:

1 mole humanized antibody.

2. The formulation of claim 1 wherein the nonreducing sugar is trehalose or mannitol.

3. The formulation of claim 2 wherein the nonreducing sugar is mannitol.

4. The formulation of claim 3 wherein the molar ratio of mannitol to humanized antibody is within the range from 200 to 600 mole mannitol:

1 mole humanized antibody.

5. The formulation of claim 3 further comprising glycine.

6. The formulation of claim 1 wherein less than about 10% of the humanized antibody is present as an aggregate in the formulation.

7. The formulation of claim 1 wherein increase in aggregated humanized antibody in the lyophilized formulation is less than about 5% when the lyophilized formulation is stored at 2-8°

C. for at least one year.

8. A reconstituted formulation comprising the formulation of claim 1 reconstituted in a diluent, wherein the humanized antibody concentration in the reconstituted formulation is within the range from 50 mg/mL to 400 mg/mL.

9. The reconstituted formulation of claim 8 wherein the humanized antibody concentration in the reconstituted formulation is within the range from 80 mg/mL to 300 mg/mL.

10. The reconstituted formulation of claim 8 wherein the diluent is sterile water, or bacteriostatic water for injection (BWFI).

11. The reconstituted formulation of claim 8 which is for subcutaneous or intramuscular administration.

12. The reconstituted formulation of claim 8 which is isotonic.

13. A sterile formulation comprising a lyophilized mixture of a non-reducing sugar and a humanized antibody, wherein the molar ratio of non-reducing sugar to humanized antibody is within the range from 200 to 600 mole non-reducing sugar:

1 mole humanized antibody.

14. An article of manufacture comprising:

(a) a container which holds the formulation of claim 13; and

(b) instructions for reconstituting the lyophilized formulation with a diluent to a humanized antibody concentration in the reconstituted formulation within the range from 80 mg/mL to 300 mg/mL.

15. The article of manufacture of claim 14 further comprising a second container which holds the diluent, wherein the diluent is sterile water, or bacteriostatic water for injection (BWFI).