Liquid neurotoxin formulation stabilized with tryptophan or tyrosine

Abstract

The invention relates to stable liquid neurotoxin formulations which are free of animal proteins, comprising a surfactant, an amino acid selected from tryptophan and tyrosine, a buffer comprising sodium, chloride and phosphate ions, which have a pH between 5.5 and 8, and which are stable for 2 months. These compositions are suitable for use in therapy and in particular for administration to a patient to achieve a desired therapeutic or aesthetic effect. The invention also relates to the use of an amino acid selected from tryptophan and tyrosine to protect a proteinaceous neurotoxin from degradation in a liquid composition which is free of animal derived proteins.

1 . A liquid composition comprising a proteinaceous neurotoxin, a surfactant, an amino acid selected from tryptophan and tyrosine, a buffer comprising sodium, chloride and phosphate ions,
 wherein said liquid composition has a pH between 5.5 and 8,   wherein said composition is free of animal derived proteins, and   wherein said liquid composition is stable over time.   
     
     
         2 . A liquid composition according to  claim 1 , wherein said surfactant is a non-ionic surfactant. 
     
     
         3 . A liquid composition according to  claim 2 , wherein said non-ionic surfactant is a polysorbate, preferably Polysorbate 20, Polysorbate 60 or Polysorbate 80. 
     
     
         4 . A liquid composition according to any one of  claims 1  to  3 , wherein said amino acid is tryptophan, preferably L-tryptophan. 
     
     
         5 . A liquid composition according to any one of  claims 1  to  4 , wherein said buffer further comprises potassium ions. 
     
     
         6 . A liquid composition according to any one of  claims 1  to  5 , wherein said composition has a pH between 6.0 and 7.5. 
     
     
         7 . A liquid composition according to any one of  claims 1  to  6 , wherein no more than 30% loss in extracellular proteolytic activity occurs over 2, 3, 6, 12, 18, 24 or 36 months at 5° C. 
     
     
         8 . A liquid composition according to any one of  claims 1  to  7 , wherein said proteinaceous neurotoxin is a botulinum neurotoxin, selected from a natural botulinum neurotoxin in complex form, a high purity natural botulinum neurotoxin and a recombinant botulinum neurotoxin. 
     
     
         9 . A liquid composition according to  claim 8 , wherein said botulinum neurotoxin is a recombinant botulinum neurotoxin selected from a botulinum neurotoxin A, B, C, D, E, For G, a modified botulinum neurotoxin and a chimeric botulinum neurotoxin. 
     
     
         10 . A liquid composition according to any one of  claims 1  to  9 , wherein said liquid composition comprises:
 4 to 10000 LD50 units of botulinum neurotoxin per mL, 
 0.001 to 15% v/v polysorbate, 
 0.1 to 5 mg/mL tryptophan, 
 10 to 500 mM NaCl, 
 1 to 50 mM KCl, 
 1 to 100 mM Sodium phosphate, 
 has a pH between 5.5 and 8, and is stable for 6 months at 5° C. 
 
     
     
         11 . A liquid composition according to  claim 10 , wherein said liquid composition comprises:
 10 to 2000 LD50 units of botulinum neurotoxin per mL,   0.05 to 0.2% v/v polysorbate 80,   0.1 to 5 mg/mL tryptophan,   25 to 300 mM NaCl,   1 to 10 mM KCl,   2 to 50 mM Sodium phosphate,   has a pH between 6.0 and 7.5, and is stable for 12 months at 5° C.   
     
     
         12 . A liquid composition according to any one of  claims 1  to  11  for use in therapy. 
     
     
         13 . A liquid composition according to  claim 12  for use in treating or preventing muscular disorders, neuromuscular disorders, neurological disorders, ophthalmological disorders, pain disorders, psychological disorders, articular disorders, inflammatory disorders, endocrine disorders or urological disorders. 
     
     
         14 . Use of liquid composition according to any one of  claims 1  to  11  in aesthetic medicine, for example for treating or preventing skin wrinkles, in particular facial wrinkles such as facial frown lines, wrinkles of the contour of the eye, glabellar frown lines, downturned mouth, wrinkles of the neck (platysmal bands), wrinkles of the chin (mentalis, peau d'orange, dimpled chin), forehead lines, “scratched skin” wrinkles, nasal lift treatment or sleep lines. 
     
     
         15 . Use of an amino acid selected from tryptophan and tyrosine to protect a proteinaceous neurotoxin from degradation in a liquid composition which is free of animal derived proteins. 
     
     
         16 . Use according to  claim 15 , wherein said amino acid is tryptophan. 
     
     
         17 . Use according to  claim 15  or  16 , wherein said proteinaceous neurotoxin is a botulinum neurotoxin. 
     
     
         18 . Use according to  claim 15 , wherein said amino acid is used in combination with a surfactant and a buffer comprising sodium, chloride and phosphate ions, and said liquid composition has a pH between 5.5 and 8.