Lipase Degradation Resistant Surfactants for Use in Large Molecule Therapeutic Formulations

Abstract

The present invention is directed to pharmaceutical formulations of therapeutic proteins that comprise one or more polyethoxylated fatty alcohol (PFA) surfactants that are resistant to lipase mediated degradation. The present invention is also directed to methods of reducing aggregate and/or particulate formation in pharmaceutical formulations of therapeutic proteins and methods of maintaining a stable surfactant level in pharmaceutical formulations of therapeutic proteins.

What is claimed is: 
     
         1 . A pharmaceutical formulation comprising:
 about 20 mg/mL to about 200 mg/mL of a therapeutic protein;   
       a pharmaceutically acceptable carrier; and
 one or more polyethoxylated fatty alcohol (PFA) surfactants, wherein said one or more PFA surfactants is resistant to lipase degradation. 
 
     
     
         2 . The pharmaceutical formulation of  claim 1 , wherein the therapeutic protein is a non-recombinant, serum isolated protein, a recombinant protein, an antibody or an antigen binding portion thereof, or an antibody-drug conjugate. 
     
     
         3 . The method of  claim 1 , wherein the concentration of the therapeutic protein in the formulation is about 50 mg/mL to about 150 mg/mL 
     
     
         4 . The pharmaceutical formulation of  claim 1 , wherein the one or more PFA surfactants comprise a PFA having between 5 to 40 ethylene glycol units. 
     
     
         5 . The pharmaceutical formulation of  claim 4 , wherein the one or more PFA surfactants is polyoxyethylene (23) lauryl ether and/or polyoxyethylene (20) oleyl ether. 
     
     
         6 . The pharmaceutical formulation of  claim 1 , wherein the PFA surfactant concentration in the formulation is about 0.005% to about 0.2% (w/v). 
     
     
         7 . The pharmaceutical formulation of  claim 1 , wherein the formulation comprises lipase/esterase activity that is ≥1 unit/mL of purified porcine esterase or equivalent thereof. 
     
     
         8 . The pharmaceutical formulation of  claim 1 , wherein >90% the PFA surfactant remains intact in the formulation over the formulation's shelf life. 
     
     
         9 . The pharmaceutical formulation of  claim 1 , wherein the therapeutic protein was produced in a cell line selected from the group consisting of Chinese hamster ovary (CHO) cell line, PER.C6 cell line, and Sp2/0 cell line. 
     
     
         10 . The pharmaceutical formulation of  claim 1  further comprising:
 a saccharide, said saccharide comprising about 0.5% to 15% w/v of the formulation; and, 
 buffering salts in a concentration of about 5 mM to 50 mM. 
 
     
     
         11 . The pharmaceutical formulation of  claim 1 , wherein said formulation has a pH of between 5-8. 
     
     
         12 . The pharmaceutical formulation of  claim 1 , wherein the formulation is resistant to particulate formation. 
     
     
         13 . The pharmaceutical formulation of  claim 12 , wherein the formulation contains ≤80 particle/mL of particles having an equivalent circular diameter of ≥70 μm over formulation's shelf life. 
     
     
         14 . The pharmaceutical formulation of  claim 12 , wherein the formulation contains ≤6000 particles (≥10 μm in size) per container and ≤600 particles (≥25 μm in size) per container over the formulation's shelf life. 
     
     
         15 . The pharmaceutical formulation of  claim 1 , wherein the formulation is resistant to protein aggregation. 
     
     
         16 . The pharmaceutical formulation of  claim 15 , wherein >90% of the protein in the formulation is in a non-aggregated state over the formulation's shelf life. 
     
     
         17 . A method of reducing aggregate and/or particulate formation in a pharmaceutical formulation comprising a biological composition, said method comprising:
 providing a biological composition, said composition comprising about 20 mg/mL to about 200 mg/mL of therapeutic protein and   incorporating one or more lipase resistant polyethoxylated fatty alcohol (PFA) surfactants in the biological composition as a replacement for a polysorbate surfactant.   
     
     
         18 . The method of  claim 17 , wherein the therapeutic protein of the biological composition is a non-recombinant, serum isolated protein, a recombinant protein, an antibody or an antigen binding portion thereof, or an antibody-drug conjugate. 
     
     
         19 . The method of  claim 17 , wherein the concentration of the therapeutic protein in the biological composition is about 50 mg/mL to about 150 mg/mL 
     
     
         20 . The method of  claim 17 , wherein the one or more PFA surfactants comprise a PFA having between 5 to 40 ethylene glycol units. 
     
     
         21 . The method of  claim 17 , wherein the one or more PFA surfactants is polyoxyethylene (23) lauryl ether and/or polyoxyethylene (20) oleyl ether. 
     
     
         22 . The method of  claim 17 , wherein the PFA surfactant is incorporated into the pharmaceutical formulation in an amount of about 0.005% to about 0.2% (w/v). 
     
     
         23 . The method of  claim 17 , wherein the therapeutic protein was produced in a cell line selected from the group consisting of CHO cell line, PER.C6 cell line, and Sp2/0 cell line. 
     
     
         24 . The method of  claim 17  further comprising:
 measuring lipase activity of the biological composition, wherein said incorporating is based on said measuring. 
 
     
     
         25 . The method of any of  claims 17 - 24 , wherein said biological composition comprises a lipase/esterase activity that is ≥1 unit/mL of purified porcine esterase or equivalent thereof. 
     
     
         26 . The method of any of  claims 17 - 24 , wherein said biological composition comprises a lipase/esterase activity that is ≥0.1 unit/mL of purified porcine esterase or equivalent thereof.