Pharmaceutical liquid composition of botulinum toxin with improved stability

Abstract

Disclosed herein is a liquid pharmaceutical composition of botulinum toxin which is improved in stability. It comprises botulinum toxin, polysorbate 20, and methionine and optionally isoleucine. Employing, instead of the animal-derived protein albumin or gelatin, a combination of polysorbate 20 and methionine and optionally isoleucine as botulinum toxin stabilizers, the liquid pharmaceutical composition eliminates the risk of contaminating the body with serum-derived pathogens or microorganisms and can be administered safely to the body. Also, the composition is convenient for use as a direct injection for patients. Superior to conventional compositions employing either detergents or amino acids in terms of the storage stability of botulinum toxin at 25˜37° C. as well as at refrigerated temperatures, the liquid pharmaceutical composition of the present invention is very useful for storing botulinum toxin under an emergency condition such as an environment without maintaining low temperature. The liquid pharmaceutical composition can be readily prepared because it employs a detergent and an amino acid(s) without lyophilization process.

1 - 12 . (canceled) 
     
     
         13 . A method of treating a disorder in a patient comprising directly injecting an effective amount of a liquid pharmaceutical composition to the patient, wherein the composition comprises botulinum toxin, polysorbate 20 and methionine, and wherein the composition is free of gelatin or human serum albumin. 
     
     
         14 . The method of  claim 13 , wherein the disorder is selected from the group consisting of dystonia, stiff muscle spasm, a neurological disorder, and a combination thereof. 
     
     
         15 . The method of  claim 14 , wherein the neurological disorder is selected from the group consisting of migraine, lumbago, cervical spinal disorder, and any combination thereof. 
     
     
         16 . The method of  claim 13 , wherein the methionine is present in an amount of 0.5 to 100 μmol per 100 units of botulinum toxin. 
     
     
         17 . The method of  claim 13 , wherein the methionine ranges in concentration from 0.5 to 100 mM. 
     
     
         18 . The method of  claim 13 , wherein the polysorbate 20 is present in an amount of 0.01 to 50 mg per 100 units of botulinum toxin. 
     
     
         19 . The method of  claim 13 , wherein the polysorbate 20 ranges in concentration from 0.01 to 50 mg/mL. 
     
     
         20 . The method of  claim 13 , wherein the botulinum toxin is selected from a group consisting of botulinum toxin serotypes A, B, C, D, E, F, and G. 
     
     
         21 . The method of  claim 13 , wherein the botulinum toxin is in a noncomplex form or in a complex form with a protein. 
     
     
         22 . The method of  claim 13 , wherein the liquid pharmaceutical composition ranges in pH from 5.5 to 7.0. 
     
     
         23 . The method of  claim 13 , wherein the liquid pharmaceutical further comprises isoleucine. 
     
     
         24 . The method of  claim 13 , wherein the botulinum toxin ranges in concentration from 50 to 5,000 units/mL.