US2011226650A1PendingUtilityA1

Antibody formulation

Assignee: GENENTECH INCPriority: Dec 21, 2009Filed: Dec 20, 2010Published: Sep 22, 2011
Est. expiryDec 21, 2029(~3.4 yrs left)· nominal 20-yr term from priority
A61P 35/04A61P 35/02A61P 3/10A61P 35/00A61P 9/00A61P 9/10A61P 27/02A61P 29/00A61P 19/02A61P 11/06A61P 17/06A61P 1/04A61P 13/12A61K 47/183A61K 47/22A61K 39/39591A61K 9/0019C07K 2317/94C07K 16/22A61K 2039/505A61K 47/26A61K 9/08A61J 1/1412A61K 39/395A61K 39/3955C07K 2317/76A61J 1/2006A61K 2300/00
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Claims

Abstract

The invention provides a stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody, optionally, not subjected to prior lyophilization, a buffer maintaining the pH in the range from about 4.0 to about 6.0, and an optional surfactant, methods for making such a formulation, and methods of using such a formulation.

Claims

exact text as granted — not AI-modified
1 . A stable aqueous pharmaceutical formulation, the formulation comprising a therapeutically effective amount of an antibody in an arginine buffer, pH 4.0 to 6.0. 
     
     
         2 . The formulation of  claim 1 , wherein the buffer is an arginine acetate buffer, pH 4.5 to 5.5. 
     
     
         3 . The formulation of  claim 1 , wherein the buffer is an arginine acetate buffer, pH 4.8 to 5.4. 
     
     
         4 . The formulation of  claim 1 , wherein the buffer is an arginine acetate buffer, pH 5.2. 
     
     
         5 . The formulation of  claims 2 ,  3 , or  4  wherein the arginine actetate concentration in the buffer is from about 25 mM to about 250 mM. 
     
     
         6 . The formulation of  claims 2 ,  3 , or  4  wherein the arginine actetate concentration in the buffer is from about 50 mM to about 250 mM. 
     
     
         7 . The formulation of  claims 2 ,  3 , or  4  wherein the arginine actetate concentration in the buffer is from about 75 mM to about 250 mM. 
     
     
         8 . The formulation of  claims 2 ,  3 , or  4  wherein the arginine actetate concentration in the buffer is from about 100 mM to about 250 mM. 
     
     
         9 . The formulation of  claims 2 ,  3 , or  4 , wherein the arginine acetate concentration in the buffer is from about 120 mM to about 240 mM. 
     
     
         10 . The formulation of  claims 2 ,  3 , or  4 , wherein arginine acetate concentration in the buffer is from about 150 mM to about 225 mM. 
     
     
         11 . The formulation of  claims 2 ,  3 , or  4 , wherein the arginine acetate concentration in the buffer is about 200 mM. 
     
     
         12 . The formulation of  claim 1 , further comprising a surfactant. 
     
     
         13 . The formulation of  claim 12 , wherein the surfactant is polysorbate. 
     
     
         14 . The formulation of  claim 13 , wherein the polysorbate is polysorbate 20. 
     
     
         15 . The formulation of  claim 12 , wherein the surfactant concentration is from 0.0001% to about 1.0%. 
     
     
         16 . The formulation of  claim 12 , wherein the surfactant concentration is from about 0.01% to about 0.05%. 
     
     
         17 . The formulation of  claim 12 , wherein the surfactant concentration is 0.04%. 
     
     
         18 . The formulation of  claim 1 , wherein the antibody concentration is from about 10 mg/ml to about 250 mg/ml. 
     
     
         19 . The formulation of  claim 1 , wherein the antibody concentration is from about 25 mg/ml to 200 mg/ml. 
     
     
         20 . The formulation of  claim 1 , wherein the antibody concentration is from about 50 mg/ml to about 150 mg/ml. 
     
     
         21 . The formulation of  claim 1 , wherein the antibody concentration is from about 75 mg/ml to about 125 mg/ml. 
     
     
         22 . The formulation of  claim 1 , wherein the antibody is not subject to prior lyophilization. 
     
     
         23 . The formulation of  claim 1  wherein the antibody binds VEGF. 
     
     
         24 . The formulation of  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         25 . The formulation of  claim 24  wherein the monoclonal antibody is a full length antibody. 
     
     
         26 . The formulation of  claim 24  wherein the monoclonal antibody is an IgG1 antibody. 
     
     
         27 . The formulation of  claim 24  wherein the monoclonal antibody is a humanized antibody. 
     
     
         28 . The formulation of  claim 24  wherein the monoclonal antibody is an antibody fragment comprising an antigen-binding region. 
     
     
         29 . The formulation of  claim 28  wherein the antibody fragment is a Fab or F(ab′)2 fragment. 
     
     
         30 . The formulation of  claim 24  wherein the monoclonal antibody binds VEGF. 
     
     
         31 . The formulation of  claim 30  wherein the antibody is bevacizumab. 
     
     
         32 . The formulation of  claim 1  wherein the monoclonal antibody is susceptible to aggregation. 
     
     
         33 . The formulation of  claim 2  wherein the buffer is 200 mM arginine acetate pH 5.2, the surfactant is polysorbate in an amount of about 0.01-0.1% v/v, wherein the formulation is stable at a temperature of about 40° C. for at least 28 days 
     
     
         34 . An article of manufacture comprising a container holding a stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody, an arginine acetate buffer from about pH 4.5 to about 6.0, and a surfactant. 
     
     
         35 . The article of manufacture of  claim 34 , wherein the antibody binds VEGF. 
     
     
         36 . The article of manufacture of  claim 35 , wherein the antibody is bevacizumab. 
     
     
         37 . A method for stabilizing an antibody in an aqueous pharmaceutical formulation by combining a therapeutically effective amount of an antibody, an arginine acetate buffer from about pH 4.5 to about 6.0, and a surfactant. 
     
     
         38 . The method of  claim 37 , wherein the antibody binds VEGF. 
     
     
         39 . The method of  claim 38 , wherein the antibody is bevacizumab. 
     
     
         40 . A stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody, 200 mM arginine acetate buffer at pH 5.2, and a surfactant. 
     
     
         41 . The formulation of  claim 40  wherein the antibody binds VEGF. 
     
     
         42 . The formulation of  claim 41  wherein the antibody is bevacizumab 
     
     
         43 . An article of manufacture comprising a container holding the formulation of any one of  claims 40 - 42 . 
     
     
         44 . The formulation of  claim 1  which is sterile. 
     
     
         45 . The formulation of  claim 1  which is stable upon storage at about 40° C. for at least 28 days. 
     
     
         46 . The formulation of  claim 1  which is aqueous and is administered to a subject. 
     
     
         47 . The formulation of  claim 46  wherein the formulation is for intravenous (IV), subcutaneous (SQ) or intramuscular (IM) administration. 
     
     
         48 . The formulation of  claim 46 , which is for W administration and the antibody concentration is from about 10 mg/ml to about 250 mg/ml. 
     
     
         49 . The formulation of  claim 46 , which is for IV administration and the antibody concentration is from about 50 mg/ml to about 100 mg/ml. 
     
     
         50 . The formulation of  claim 46 , which is for SQ administration and the antibody concentration is from about 25 mg/ml to about 250 mg/ml. 
     
     
         51 . The formulation of  claim 46 , which is for SQ administration and the antibody concentration is from about 50 mg/ml to about 100 mg/ml. 
     
     
         52 . A vial with a stopper pierceable by a syringe comprising the formulation of  claim 1  inside the vial. 
     
     
         53 . The vial of  claim 52  which is stored at about 2-8° C. 
     
     
         54 . The vial of  claim 52  which is a 3 cc, 20 cc or 50 cc vial. 
     
     
         55 . A stainless steel tank comprising the formulation of  claim 1  inside the tank. 
     
     
         56 . The tank of  claim 55  wherein the formulation is frozen. 
     
     
         57 . A method of treating a disease or disorder in a subject comprising administering the formulation of  claim 1  to a subject in an amount effective to treat the disease or disorder. 
     
     
         58 . The method of  claim 57  wherein the antibody binds VEGF. 
     
     
         59 . The method of  claim 58  wherein the antibody is bevacizumab 
     
     
         60 . A pharmaceutical formulation comprising: (a) a full length IgG1 antibody susceptible to deamidation or aggregation in an amount from about 10 mg/mL to about 250 mg/mL; (b) arginine acetate buffer, pH 4.5 to 6.0; and (c) polysorbate 20 in an amount from about 0.01% to about 0.1%. 
     
     
         61 . The formulation of  claim 60  wherein the antibody binds VEGF. 
     
     
         62 . The formulation of  claim 61  wherein the antibody is bevacizumab 
     
     
         63 . A method for reducing aggregation of a therapeutic monoclonal antibody, comprising formulating the antibody in an arginine acetate buffer, pH 4.5 to 6.0. 
     
     
         64 . The method of  claim 63  wherein the antibody binds VEGF. 
     
     
         65 . The method of  claim 64  wherein the antibody is bevacizumab. 
     
     
         66 . A pharmaceutical formulation comprising an antibody that binds to VEGF in an arginine acetate buffer at a pH from about 4.5 to about 6.0, and a surfactant. 
     
     
         67 . The formulation of  claim 66  wherein the antibody is bevacizumab. 
     
     
         68 . A method of making a pharmaceutical formulation comprising:
 (a) preparing the formulation of  claim 1 ; and   (b) evaluating physical stability, chemical stability, or biological activity of the antibody in the formulation.   
     
     
         69 . The method of  claim 68 , wherein the antibody binds VEGF. 
     
     
         70 . The method of  claim 69 , wherein the antibody is bevacizumab

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