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 and sucrose.

1 . A pharmaceutical composition comprising:
 (i) a botulinum toxin;   (ii) poloxamer 188; and   (iii) methionine.   
     
     
         2 . The composition according to  claim 1 , further comprising trehalose or sucrose, and optionally NaCl, and optionally EDTA. 
     
     
         3 . The composition according to  claim 2 , wherein the relative weight amounts (%, w/w) of trehalose or sucrose, poloxamer 188, methionine, and optionally NaCl, and optionally EDTA are within the following ranges: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   trehalose or sucrose 
                    1 to 10 
                 
                     
                   poloxamer 188 
                   0.5 to 5   
                 
                     
                   methionine 
                   0.1 to 0.3 and optionally 
                 
                     
                   NaCl 
                   0.1 to 10 and optionally 
                 
                     
                   EDTA 
                   0.01 to 0.1.  
                 
                     
                     
                 
             
                
               
               
                
                
                
                
                
                
               
            
           
         
       
     
     
         4 . The composition according to  claim 3 , wherein the relative weight amounts (%, w/w) of trehalose, poloxamer 188, methionine, and optionally NaCl, and optionally EDTA are: 
       
         
           
                 
                 
                 
               
                     
                 
                   a) 
                   trehalose or sucrose 
                   7 to 9 
                 
                     
                   pol oxamer 188 
                   3.5 to 4.5 
                 
                     
                   methionine 
                   0.15 to 0.25; and are preferably 
                 
                     
                   trehalose or sucrose 
                   8 
                 
                     
                   pol oxamer 188 
                   4 
                 
                     
                   methionine 
                   0.2; or 
                 
                   b) 
                   trehalose or sucrose 
                   7 to 9 
                 
                     
                   pol oxamer 188 
                   0.5 to 0.7 
                 
                     
                   methionine 
                   0.15 to 0.25; and are preferably 
                 
                     
                   trehalose or sucrose 
                   8 
                 
                     
                   pol oxamer 188 
                     0.6 
                 
                     
                   methionine 
                   0.2; or 
                 
                   c) 
                   trehalose or sucrose 
                   1 to 3 
                 
                     
                   pol oxamer 188 
                   3.5 to 4.5 
                 
                     
                   methionine 
                   0.15 to 0.25 
                 
                     
                   NaCl 
                   0.4 to 0.8; and are preferably 
                 
                     
                   trehalose or sucrose 
                   2 
                 
                     
                   pol oxamer 188 
                   4 
                 
                     
                   methionine 
                     0.2 
                 
                     
                   NaCl 
                   0.6; or 
                 
                   d) 
                   trehalose or sucrose 
                   7 to 9 
                 
                     
                   pol oxamer 188 
                   3.5 to 4.5 
                 
                     
                   methionine 
                   0.15 to 0.25 
                 
                     
                   EDTA 
                   0.01 to 0.05; and are preferably 
                 
                     
                   trehalose or sucrose 
                   8 
                 
                     
                   pol oxamer 188 
                   4 
                 
                     
                   methionine 
                     0.2 
                 
                     
                   EDTA 
                      0.03. 
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         5 . The composition according to  claim 1 , comprising trehalose. 
     
     
         6 . The composition according to  claim 1 , wherein
 the composition does not comprise a sugar or polyalcohol.   
     
     
         7 . The composition according to  claim 6 , wherein the relative weight amounts (%, w/w) of poloxamer 188, and methionine are within the following ranges: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   poloxamer 188 
                   0.5 to 5   
                 
                     
                   methionine 
                    0.1 to 0.3. 
                 
                     
                     
                 
             
                
               
               
                
                
                
               
            
           
         
       
     
     
         8 . The composition according to  claim 7 , wherein the relative weight amounts (%, w/w) of poloxamer 188, and methionine are: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   pol oxamer 188 
                   3.5 to 4.5 
                 
                     
                   methionine 
                   0.15 to 0.25; and are preferably 
                 
                     
                   pol oxamer 188 
                   4 
                 
                     
                   methionine 
                      0.2. 
                 
                     
                     
                 
             
                
               
               
                
                
                
                
                
               
            
           
         
       
     
     
         9 . The composition according to  claim 1 , wherein the composition is a liquid composition, wherein the composition preferably comprises a buffer. 
     
     
         10 . The composition according to  claim 9 , wherein the buffer is histidine, wherein the concentration of histidine is preferably 20 mM, wherein the pH is preferably in the range 5-7, and wherein the pH is most preferably in the range 5.5-6. 
     
     
         11 . The composition according to  claim 1 , wherein the composition is a solid composition, wherein the composition is preferably lyophilised. 
     
     
         12 . The composition according to  claim 11 , further comprising a buffer, wherein the buffer is preferably histidine, wherein the histidine is preferably comprised in a relative weight amount of 0.1 to 0.5 (% w/w), more preferably in a relative weight amount of 0.3-0.4% (w/w). 
     
     
         13 . The composition according to  claim 1 , wherein the composition is a liquid composition consisting of one or more botulinum toxins, trehalose or sucrose, poloxamer 188, methionine, a buffer, and optionally NaCl, and optionally EDTA. 
     
     
         14 . The composition according to  claim 1 , wherein the composition is a solid composition consisting of one or more botulinum toxins, trehalose, poloxamer 188, methionine, a buffer, and optionally NaCl, and optionally EDTA. 
     
     
         15 . The composition according to  claim 1 , wherein the composition is a liquid composition and consists of one or more botulinum toxins, poloxamer 188, methionine, and a buffer. 
     
     
         16 . The composition according to  claim 1 , comprising no animal-derived protein. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . A method of treating, reducing the symptoms, and/or prevention of diseases, disorders, and conditions, wherein the method comprises the step of administering the pharmaceutical composition of  claim 1  to a subject in need thereof. 
     
     
         20 . The method of  claim 19 , wherein the diseases, disorders, and conditions are selected from neuromuscular diseases, pain, psychological disorders, urological disorders, inflammation, and skin disorders. 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . A method of cosmetic treatment comprising the step of administering the pharmaceutical composition of  claim 1  to a subject in need thereof.