Stable liquid interferon formulations

Abstract

Liquid interferon compositions having a pH between 4.0 and 7.2 are described. The compositions comprise interferon-beta and a stabilizing agent at between about 0.3% and 5% by weight which is an amino acid selected from the group consisting of acidic amino acids, arginine and glycine. If needed, salt is added to provide sufficient ionic strength. The liquid composition has not been previously lyophilized or previously cavitated. The liquid is preferably contained within a vessel having at least one surface in contact with the liquid that is coated with a material inert to adsorption of interferon-beta. A kit for parenteral administration of a liquid interferon formulation and a method for stabilizing liquid interferon compositions are also described.

1 . A liquid composition comprising an interferon and a stabilizing agent at between about 0.3% and 5% by weight which is an amino acid selected from the group consisting of acidic amino acids, arginine and glycine, wherein the liquid composition has not been previously lyophilized.  
     
     
         2 . The liquid composition of  claim 1 , further comprising a vessel containing said liquid composition, the vessel having at least one surface coated with a material inert to interferon.  
     
     
         3 . The liquid composition of  claim 1 , wherein the interferon is a interferon-beta, or a recombinantly produced interferon.  
     
     
         4 . The liquid composition of  claim 1  having a pH between about 4.0 and about 7.2.  
     
     
         5 . The liquid composition of  claim 4 , having a pH of 4.8 to 5.2.  
     
     
         6 . The liquid composition of  claim 5 , having a pH of 5.0.  
     
     
         7 . The liquid composition of  claim 5  wherein the acidic amino acid is glutamic acid.  
     
     
         8 . The liquid composition of  claim 1 , wherein the arginine is arginine-HCl.  
     
     
         9 . The liquid composition of  claim 1  having an interferon concentration between about 6 IMU/ml and 50 IMU/ml.  
     
     
         10 . The liquid composition of  claim 2 , wherein said at least one surface of the vessel is coated with a material selected from the group consisting of silicone and polytetrafluoroethylene.  
     
     
         11 . The liquid composition of  claim 10 , wherein the vessel is a syringe.  
     
     
         12 . A 20 mM acetate buffer at pH 5.0 that includes interferon-beta plus a stabilizing agent selected from the group consisting of: (a) 150 mM arginine; (b) 100 mM sodium chloride and 70 mM glycine; (c) 150 mM arginine and 15 mg/ml human serum albumin; (d) 150 mM arginine and a surfactant; (d) 140 mM sodium chloride; (e) 140 mM sodium chloride and 15 mg/ml human serum albumin; and (f) 140 mM sodium chloride and a surfactant, wherein the buffer has not been previously lyophilized.  
     
     
         13 . The buffer of  claim 12 , wherein the surfactant is 0.1% (w/v) Pluronic F-68.  
     
     
         14 . The buffer of  claim 12 , wherein the arginine is arginine-HCl.  
     
     
         15 . The buffer of  claim 12 , further comprising a vessel containing said buffer, wherein at least one surface of the vessel in contact with the buffer is coated with a material selected from the group consisting of silicone and polytetrafluoroethylene.  
     
     
         16 . The buffer of  claim 15 , wherein the vessel is a syringe.  
     
     
         17 . A liquid composition at pH 5.0 that comprises interferon-beta and 170 mM L-glutamic acid, the liquid not previously lyophilized.  
     
     
         18 . The liquid composition of  claim 1 , comprising the amino acid glycine and further comprising a salt.  
     
     
         19 . The liquid composition of  claim 17 , further including ingredients selected from the group consisting of 15 mg/ml human serum albumin and 0.1% (whv) Pluronic F-68.  
     
     
         20 . A 20 mM phosphate buffer at pH 7.2 including interferon-beta plus a stabilizing agent selected from the group consisting of: (a) 140 mM arginine; and (b) 100 mM sodium chloride combined with 70 mM glycine, wherein the buffer has not been previously lyophilized.  
     
     
         21 . The liquid composition of  claim 20 , further comprising a vessel containing said liquid, wherein at least one surface of the vessel in contact with the liquid is coated with a material selected from the group consisting of silicone and polytetrafluoroethylene.  
     
     
         22 . The liquid composition of  claim 20 , wherein the vessel is a syringe.  
     
     
         23 . A liquid pharmaceutical composition contained within a storage vessel, the liquid suitable for parenteral administration to mammals and comprising an effective amount of interferon-beta, a buffer maintaining the pH within the range of 4.0 to 6.0, and an amino acid stabilizing agent, wherein the interferon-beta has not been subjected to prior lyophilization and wherein the storage vessel has at least one surface thereof in contact with the liquid composition that is coated with a material selected from the group consisting of silicone and polytetrafluoroethylene.  
     
     
         24 . The liquid composition of  claim 23 , wherein the storage vessel lacks an oxygen-containing/liquid interface.  
     
     
         25 . The liquid composition of  claim 23 , wherein the interferon-beta essentially retains its anti-viral activity during storage at a temperature of between about 2 degrees C. and about 25 degrees C. for a period of at least 2 months.  
     
     
         26 . The liquid composition of  claim 23 , wherein the interferon-beta has not been subjected to prior cavitation.  
     
     
         27 . The liquid composition of  claim 23  wherein the buffer is an organic acid buffer selected from the group consisting of citrate, succinate, tartrate, fumarate, gluconate, oxalate, lactate and acetate buffer.  
     
     
         28 . The liquid composition of  claim 23 , wherein the amino acid stabilizing agent is an amino acid selected from the group consisting of acid amino acids, glycine and arginine.  
     
     
         29 . The liquid composition of  claim 28 , wherein the amino acid is added in an amount of about 0.3% to about 5.0% by weight based on the composition.  
     
     
         30 . The liquid composition of  claim 23 , wherein the pH of the liquid composition is in the range of 4.5 to 5.5.  
     
     
         31 . The liquid composition of  claim 30 , wherein the pH of the liquid composition is 5.0.  
     
     
         32 . The liquid composition of  claim 23 , which is sterile.  
     
     
         33 . The liquid composition of  claim 23 , which is isotonic to blood.  
     
     
         34 . The liquid composition of  claim 23 , wherein the interferon-beta is human recombinant interferon-beta.  
     
     
         35 . The liquid composition of  claim 34  wherein the activity of the human recombinant interferon-beta is in the range of 6 to 50 IMU/ml protein.  
     
     
         36 . A frozen liquid composition comprising an interferon and a stabilizing agent at between about 0.3% and 3.13%.by weight which is an amino acid selected from the group consisting of acidic amino acids, arginine and glycine, wherein the composition has not been previously lyophilized.  
     
     
         37 . A kit for parenteral administration of a liquid interferon formulation, wherein the kit comprises: a) a vessel containing a liquid formulation at a pH of between 4 and 6, the liquid comprising a pharmaceutically effective amount of interferon-beta that has not been previously lyophilized and a amino acid stabilizing agent at less than about 3.1% by weight; and b) instructions for use thereof.  
     
     
         38 . The kit of  claim 37 , further comprising: c) an alcohol swab; d) a needle; and at least one adhesive bandage.  
     
     
         39 . The kit of  claim 37 , wherein the vessel is a syringe having at least one surface in contact with the liquid formulation, the surface coated with a material selected from the group consisting of silicone and polytetrafluoroethylene.  
     
     
         40 . The kit of  claim 39 , wherein the vessel is a syringe and the liquid formulation contained with the syringe lacks an oxygen-containing/liquid interface.  
     
     
         41 . A process for stabilizing interferon-beta in liquid pharmaceutical compositions so that it essentially retains its anti-viral activity during storage at a temperature of between about 2 and about 25 degrees C. for a period of at least 3 months, comprising admixing: a) interferon-beta; b) a buffer maintaining the pH within the range of 4.0 to 7.2; and c) an amino acid stabilizing agent, wherein the liquid has previously not been lyophilized and has not been cavitated.  
     
     
         42 . The process of  claim 42 , further comprising admixing i salt to provide an appropriate ionic strength.  
     
     
         43 . The process of  claim 42 , wherein the salt is sodium chloride.