High-concentration monoclonal antibody formulations

Abstract

The present application discloses high-concentration monoclonal antibody formulations suitable for subcutaneous administration, e.g. via a pre-filled syringe. In particular, it discloses a formulation comprising a spray dried monoclonal antibody at a concentration of about 200 mg/mL or more suspended in a non-aqueous suspension vehicle where the viscocity of the suspension vehicle is less than about 20 centipoise. Also disclosed are: a subcutaneous administration device with the formulation therein, a method of making the formulation, a method of making an article of manufacture comprising the suspension formulation, use of the formulation in the preparation of a medicament, and a method of treating a patient with the formulation.

What is claimed is: 
     
         1 . A suspension formulation comprising a spray dried monoclonal antibody at a concentration of about 200 mg/mL or more suspended in a non-aqueous suspension vehicle, wherein the viscocity of the suspension vehicle is less than about 20 centipoise. 
     
     
         2 . The formulation of  claim 1  wherein the viscosity of the suspension vehicle is less than about 10 centipoise. 
     
     
         3 . The formulation of  claim 2  wherein the viscosity of the suspension vehicle is less than about 5 centipoise. 
     
     
         4 . The formulation of  claim 1  wherein the injection glide force of the formulation is about 20 newton or less. 
     
     
         5 . The formulation of  claim 4  wherein the injection glide force of the formulation is about 15 newton or less. 
     
     
         6 . The formulation of  claim 1  wherein the average particle size in the formulation is from about 2 microns to about 30 microns. 
     
     
         7 . The formulation of  claim 6  wherein the average particle size in the formulation is from about 2 microns to about 10 microns. 
     
     
         8 . The formulation of  claim 1  wherein the antibody concentration in the formulation is from about 200 mg/mL to about 500 mg/mL. 
     
     
         9 . The formulation of  claim 8  wherein the antibody concentration in the formulation is from about 200 mg/mL to about 350 mg/mL. 
     
     
         10 . The formulation of  claim 1  further comprising a saccharide. 
     
     
         11 . The formulation of  claim 10  wherein the saccharide is trehalose or sucrose. 
     
     
         12 . The formulation of  claim 10  wherein the molar ratio of saccharide: monoclonal antibody is from about 50 to about 400:1. 
     
     
         13 . The formulation of  claim 12  wherein the molar ratio of saccharide: monoclonal antibody is from about 100 to about 250:1. 
     
     
         14 . The formulation of  claim 1  further comprising a surfactant. 
     
     
         15 . The formulation of  claim 14  wherein the surfactant is polysorbate 20 or polysorbate 80. 
     
     
         16 . The formulation of  claim 1  which is suitable for subcutaneous administration. 
     
     
         17 . The formulation of  claim 1  wherein the monoclonal antibody is a full length monoclonal antibody. 
     
     
         18 . The formulation of  claim 17  wherein the monoclonal antibody is a human IgG1. 
     
     
         19 . The formulation of  claim 1  wherein the monoclonal antibody is a chimeric, humanized, or human antibody. 
     
     
         20 . The formulation of  claim 1  wherein the monoclonal antibody binds an antigen selected from the group consisting of: CD20, HER2, VEGF, IL6R, beta7, Abeta, HER3, EGFR, and M1′. 
     
     
         21 . The formulation of  claim 20  wherein the antibody is rituximab, trastuzumab, or bevacizumab. 
     
     
         22 . The formulation of  claim 1  wherein the non-aqueous suspension vehicle comprises propylene glycol dicarprylate/dicaprate, benzyl benzoate, ethyl lactate, or mixtures thereof. 
     
     
         23 . The formulation of  claim 22  wherein the non-aqueous suspension vehicle comprises ethyl lactate. 
     
     
         24 . The formulation of  claim 22  wherein the non-aqueous suspension vehicle comprises a mixture of propylene glycol dicarprylate/dicaprate and ethyl lactate. 
     
     
         25 . A subcutaneous administration device with the formulation of  claim 1  therein. 
     
     
         26 . The device of  claim 25  which comprises a pre-filled syringe. 
     
     
         27 . A method of making a suspension formulation comprising suspending a spray dried monoclonal antibody in a non-aqueous suspension vehicle with a viscosity less than about 20 centipoise, wherein the monoclonal antibody concentration in the suspension formulation is about 200 mg/mL or more. 
     
     
         28 . A method of making an article of manufacture comprising filling a subcutaneous administration device with the formulation of  claim 1 . 
     
     
         29 . A suspension formulation comprising a spray dried full length human IgG1 monoclonal antibody at a concentration from about 200 mg/mL to about 400 mg/mL suspended in a non-aqueous suspension vehicle with a viscocity less than about 20 centipoise, wherein the formulation has an average particle size from about 2 microns to about 10 microns, and injection glide force less than about 15 newton. 
     
     
         30 . The formulation of  claim 29  which further comprises saccharide wherein the molar ratio of saccharide: monoclonal antibody is from about 100 to about 250:1. 
     
     
         31 . The formulation of  claim 29  wherein the antibody is rituximab, trastuzumab, or bevacizumab. 
     
     
         32 . The formulation of  claim 1  for use in treating a disease or disorder in a patient. 
     
     
         33 . Use of the formulation of  claim 1  in the preparation of a medicament for treating a patient in need of treatment with the monoclonal antibody in the formulation. 
     
     
         34 . A method of treating a patient comprising administering the formulation of  claim 1  to a patient in need of treatment with the monoclonal antibody in the formulation. 
     
     
         35 . The method of  claim 34  wherein the formulation is administered subcutaneously to the patient. 
     
     
         36 . The method of  claim 34  wherein the formulation is administered by a pre-filled syringe containing the formulation therein.