Non-protein clostridial toxin compositions

Abstract

Pharmaceutical compositions that stabilize a Clostridial toxin active ingredient are described. The compositions can be liquid or solid compositions, and comprise a surfactant and an antioxidant. In some embodiments, the compositions comprise a surfactant selected from a poloxamer and a polysorbate; an antioxidant selected from methionine, N-acetyl cysteine, ethylenediaminetetraacetic acid and combinations thereof, and, optionally, a tonicity agent and/or a lyoprotector selected from, for example, trehalose, sucrose.

1 . A stable liquid pharmaceutical composition, the composition comprising:
 (i) a Clostridial botulinum serotype A toxin active ingredient in an amount of about 1.0 U/ml to about 1,000 U/ml;   (ii) a tonicity agent selected from trehalose, sucrose, sodium chloride, mannitol, sorbitol, glucose, and combinations thereof;   (iii) a poloxamer surfactant;   (iv) methionine in an amount between about 0.01 to 5 wt %; and   (v) a buffering agent,   wherein the composition has a pH of between about 5 and 8; wherein the composition is suitable for subcutaneous or intramuscular injection; and wherein the composition is stable for at least one month at 5° C.   
     
     
         2 . (canceled) 
     
     
         3 . The stable liquid pharmaceutical composition of  claim 1 , wherein the composition further comprises trehalose. 
     
     
         4 . The stable liquid pharmaceutical composition of  claim 3 , wherein trehalose is present in an amount between about 1 to 15 wt %. 
     
     
         5 . The stable liquid pharmaceutical composition of  claim 1 , wherein the poloxamer surfactant is poloxamer 188 (P188). 
     
     
         6 . The stable liquid pharmaceutical composition of  claim 5 , wherein the poloxamer surfactant is present in an amount between about 0.5 to 8 wt %. 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . The stable liquid pharmaceutical composition of  claim 1 , wherein the composition comprises trehalose and poloxamer 188 (P188). 
     
     
         10 . (canceled) 
     
     
         11 . A stable liquid pharmaceutical composition, the composition comprising:
 (i) a Clostridial botulinum serotype A toxin active ingredient in an amount of about 1.0 U/ml to about 1,000 U/ml;   (ii) an aqueous carrier;   (iii) at least one tonicity agent;   (iv) poloxamer 188 (P188) in an amount between about 0.5-8 wt %;   (v) methionine in an amount between about 0.05-5 wt %; and   (vi) a buffer,   wherein the composition is isotonic and has a pH of between about 5-8, wherein the composition is suitable for subcutaneous or intramuscular injection, and wherein the composition is stable for at least one month at 5° C.   
     
     
         12 . (canceled) 
     
     
         13 . The stable liquid pharmaceutical composition of  claim 11 , wherein methionine is present in an amount between about 0.05-2 wt %. 
     
     
         14 . The stable liquid pharmaceutical composition of  claim 11 , wherein the P188 is present in an amount between about 2-6 wt %. 
     
     
         15 . The stable liquid pharmaceutical composition of  claim 11 , wherein the at least one tonicity agent comprises NaCl and/or trehalose in an amount between about 1-15 wt %. 
     
     
         16 - 19 . (canceled) 
     
     
         20 . A stable liquid pharmaceutical composition, the composition comprising:
 (i) a Clostridial botulinum serotype A toxin active ingredient in an amount of between about 1.0 U/ml to about 1,000 U/ml;   (ii) an aqueous carrier;   (iii) at least one tonicity agent;   (iii) P188 in an amount between about 0.6-4 wt %;   (iv) trehalose in an amount between about 2-8 wt %;   (v) methionine in an amount between about 0.05-5 wt %; and   (vi) histidine buffer,   wherein the composition has a pH of between about 5-8; wherein the composition is suitable for subcutaneous or intramuscular injection; and wherein the composition is stable for at least one month at 5° C.   
     
     
         21 . The stable liquid pharmaceutical composition of  claim 20 , wherein the composition comprises:
 a Clostridial botulinum serotype A toxin active ingredient in an amount of about 40 U/ml,   trehalose in an amount of about 8 wt %,   P188 in an amount of about 4 wt %,   methionine in an amount of about 0.2 wt %, and   about 20 mM histidine buffer,   wherein the composition has a pH of about 6.0.   
     
     
         22 . The stable liquid pharmaceutical composition of  claim 20 , wherein the composition comprises:
 a Clostridial botulinum serotype A toxin active ingredient in an amount of about 40 U/ml,   trehalose in an amount of about 2 wt %,   P188 in an amount of about 4 wt %,   sodium chloride in an amount of about 0.6 wt %,   methionine in an amount of about 0.2 wt %, and   about 20 mM histidine buffer,   wherein the composition has a pH of about 6.0.   
     
     
         23 . The stable liquid pharmaceutical composition of  claim 20 , wherein the composition comprises
 a Clostridial botulinum serotype A toxin active ingredient in an amount of about 40 U/ml,   trehalose in an amount of about 8 wt %,   poloxamer P188 in an amount of about 4 wt %,   methionine in an amount of about 0.2 wt %,   EDTA in an amount of about 0.03 wt %, and   a 20 mM histidine buffer at a pH of about 6.0.   
     
     
         24 . The stable liquid pharmaceutical composition of  claim 1 , wherein the composition retains at least 50% potency after one month of storage at 5° C. 
     
     
         25 . The stable liquid pharmaceutical composition of  claim 11 , wherein the composition retains at least 50% potency after one month of storage at 5° C. 
     
     
         26 . The stable liquid pharmaceutical composition of  claim 20 , wherein the composition retains at least 50% potency after one month of storage at 5° C.