Liquid Protein Formulations Containing Viscosity-Lowering Agents

Abstract

Concentrated, low-viscosity, low-volume liquid pharmaceutical formulations of proteins have been developed. Such formulations can be rapidly and conveniently administered by subcutaneous or intramuscular injection, rather than by lengthy intravenous infusion. These formulations include low-molecular-weight and/or high-molecular-weight proteins, such as mAbs, and viscosity-lowering agents that are typically bulky polar organic compounds, such as many of the GRAS (US Food and Drug Administration List of compounds generally regarded as safe) and inactive injectable ingredients and FDA approved therapeutics.

What is claimed: 
     
         1 . A liquid pharmaceutical formulation for injection comprising:
 (i) an antibody;   (ii) one or more viscosity-lowering agents; and   (iii) a pharmaceutically acceptable solvent;   wherein the liquid pharmaceutical formulation, when in a volume suitable for injection, has an absolute viscosity from about 1 cP to about 100 cP at 25° C. as measured using a cone and plate viscometer or a microfluidic viscometer; and the absolute viscosity of the liquid pharmaceutical formulation is less than the absolute viscosity of a control formulation comprising the antibody and the pharmaceutically acceptable solvent, but without the one or more viscosity-lowering agents;   wherein the absolute viscosity is an extrapolated zero-shear viscosity.   
     
     
         2 . The liquid pharmaceutical formulation of  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         3 . The liquid pharmaceutical formulation of  claim 1 , wherein the one or more viscosity-lowering agents comprises:
 1-(3-aminopropyl)-2-methyl-1H-imidazole (APMI),   camphorsulfonic acid-APMI (CSA-APMI),   lidocaine,   mepivacaine,   CSA-piperazine,   4-aminopyridine,   CSA-4-aminopyridine,   metoclopramide,   scopolamine,   levetiracetam,   chloroquine,   phenylephrine,   thiamine pyrophosphate (TPP),   TPP-APMI,   biotin,   4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid-tris(hydroxymethyl)aminomethane (HEPES-Tris), or   a pharmaceutically acceptable salt of any of the above viscosity-lowering agents.   
     
     
         4 . The liquid pharmaceutical formulation of  claim 1 , wherein the antibody has a molecular weight of from about 120 kDa to about 250 kDa. 
     
     
         5 . The liquid pharmaceutical formulation of  claim 1 , comprising from about 100 mg/ml to about 300 mg/ml of the antibody. 
     
     
         6 . The liquid pharmaceutical formulation of  claim 5 , comprising from about 174 mg/ml to about 230 mg/ml of the antibody. 
     
     
         7 . The liquid pharmaceutical formulation of  claim 1 , wherein the pharmaceutically acceptable solvent is aqueous. 
     
     
         8 . The liquid pharmaceutical formulation of  claim 1 , wherein the one or more viscosity-lowering agents are present at a concentration of from about 0.01 M to about 1.0 M. 
     
     
         9 . The liquid pharmaceutical formulation of  claim 8 , wherein the one or more viscosity-lowering agents are present at a concentration of from about 0.15 M to about 0.25 M. 
     
     
         10 . The liquid pharmaceutical formulation of  claim 1 , further comprising one or more pharmaceutically acceptable excipients comprising a sugar, sugar alcohol, buffering agent, preservative, carrier, antioxidant, chelating agent, natural polymer, synthetic polymer, cryoprotectant, lyoprotectant, surfactant, bulking agent, stabilizing agent, or any combination thereof. 
     
     
         11 . The liquid pharmaceutical formulation of  claim 10 , wherein the sugar alcohol is sorbitol or mannitol. 
     
     
         12 . The liquid pharmaceutical formulation of  claim 10 , wherein the one or more pharmaceutically acceptable excipients comprise a polysorbate, poloxamer 188, sodium lauryl sulfate, a polyol, a poly(ethylene glycol), glycerol, a propylene glycol, or a poly(vinyl alcohol). 
     
     
         13 . The liquid pharmaceutical formulation of  claim 1  in a unit-dose vial, multidose vial, cartridge, or pre-filled syringe. 
     
     
         14 . The liquid pharmaceutical formulation of  claim 1 , wherein the liquid pharmaceutical formulation is reconstituted from a lyophilized composition. 
     
     
         15 . The liquid pharmaceutical formulation of  claim 1 , wherein the liquid pharmaceutical formulation is isotonic to human blood serum. 
     
     
         16 . The liquid pharmaceutical formulation of  claim 1 , wherein the absolute viscosity is measured at a shear rate of at least about 0.5 s −1  when measured using a cone and plate viscometer, or a shear rate of at least about 1.0 s −1  when measured using a microfluidic viscometer. 
     
     
         17 . A method of administering to a subject a therapeutically effective amount of an antibody, the method comprising subcutaneously or intramuscularly injecting the liquid pharmaceutical formulation of  claim 1  into the subject. 
     
     
         18 . The method of  claim 17 , wherein the injecting is performed with a syringe. 
     
     
         19 . The method of  claim 18 , wherein the syringe is a heated syringe, a self-mixing syringe, an auto-injector, a pre-filled syringe, or combinations thereof. 
     
     
         20 . The method of  claim 19 , wherein the syringe is a heated syringe and the liquid pharmaceutical formulation has a temperature between 25° C. and 40° C. 
     
     
         21 . The method of  claim 17 , wherein the liquid pharmaceutical formulation produces a primary irritation index of less than 3 when evaluated using a Draize scoring system. 
     
     
         22 . The method of  claim 17 , wherein the injecting has an injection force that is at least 10% less than an injection force for a control composition comprising the antibody and the pharmaceutically acceptable solvent, but without the one or more viscosity-lowering agents, when administered in the same way. 
     
     
         23 . The method of  claim 17 , wherein the injecting has an injection force that is at least 20% less than an injection force for a control composition comprising the antibody and the pharmaceutically acceptable solvent, but without the one or more viscosity-lowering agents, when administered in the same way. 
     
     
         24 . The method of  claim 17 , wherein the injecting is performed with a needle between 27 and 31 gauge in diameter and the injection force is less than 30 N with the 27 gauge needle. 
     
     
         25 . A method of preparing the liquid pharmaceutical formulation  claim 1 , comprising the step of combining the antibody, the pharmaceutically acceptable solvent, and the one or more viscosity-lowering agents. 
     
     
         26 . A lyophilized composition comprising:
 (i) an antibody;   (ii) one or more viscosity-lowering agents; and   (iii) a pharmaceutically acceptable excipient.   
     
     
         27 . The lyophilized composition of  claim 26 , wherein the one or more viscosity-lowering agents comprise:
 1-(3-aminopropyl)-2-methyl-1H-imidazole (APMI),   camphorsulfonic acid-APMI (CSA-APMI),   lidocaine,   mepivacaine,   CSA-piperazine,   4-aminopyridine,   CSA-4-aminopyridine,   metoclopramide,   scopolamine,   levetiracetam,   chloroquine,   phenylephrine,   thiamine pyrophosphate (TPP),   TPP-APMI,   biotin,   4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid-tris(hydroxymethyl)aminomethane (HEPES-Tris), or   a pharmaceutically acceptable salt of any of the above viscosity-lowering agents.   
     
     
         28 . The lyophilized composition of  claim 26 , wherein, once reconstituted, the antibody has a concentration of at least 100 mg/ml.