Liquid pharmaceutical composition comprising nitisinone

Abstract

The invention concerns a liquid pharmaceutical formulation suitable for oral administration, comprising a suspension of an effective amount of micronized 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (nitisinone); and citric acid buffer having a pH in the range of 2.5 to 3.5. The formulation is useful in the treatment of disorders and diseases in which inhibition of 4-hydroxyphenylpyruvate dioxygenase (HPPD) is desirable, e.g. in hereditary tyrosinaemia type I.

1 . A liquid pharmaceutical formulation suitable for oral administration, comprising
 (a) a suspension of an effective amount of micronized 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (nitisinone); and   (b) citric acid buffer having a pH in the range of 2.5 to 3.5, or having a pH of 3.0.   
     
     
         2 . The formulation according to  claim 1  wherein the amount of nitisinone is 1 to 10 mg/ml, or is 4 mg/ml. 
     
     
         3 . The formulation according to  claim 1 , in addition comprising one or more pharmaceutically acceptable constituents selected from the group consisting of suspending agents, sweeteners, preservatives, surfactants, and flavoring agents. 
     
     
         4 . The formulation according to  claim 3  wherein the suspending agent is hydroxypropyl methylcellulose. 
     
     
         5 . The formulation according to  claim 4  wherein the suspending agent is hydroxypropyl methylcellulose in an amount of 1 to 20 mg/ml, or in an amount of 5 mg/ml. 
     
     
         6 . The formulation according to  claim 3  wherein the sweetener is glycerol. 
     
     
         7 . The formulation according to  claim 6  wherein the sweetener is glycerol in an amount of 100 to 500 mg/ml, or in an amount of 500 mg/ml. 
     
     
         8 . The formulation according to  claim 3  wherein the preservative is methyl paraben and/or propyl paraben. 
     
     
         9 . The formulation according to  claim 8  wherein the preservatives are methyl paraben in an amount of 1 to 2 mg/ml, or in an amount of 1.4 mg/ml, and propyl paraben in an amount of 0.1 to 0.2 mg/ml, or in an amount of 0.14 mg/ml. 
     
     
         10 . The formulation according to  claim 3  wherein the preservative is sodium benzoate in an amount of 0.2 to 5 mg/ml, or in an amount of 1 mg/ml. 
     
     
         11 . The formulation according to  claim 3  wherein the surfactant is polysorbate 80. 
     
     
         12 . The formulation according to  claim 11  wherein the surfactant is polysorbate 80 in an amount of 0.1 to 20 mg/ml, or in an amount of from 0.10 to 0.15 mg/ml. 
     
     
         13 . The formulation according to  claim 1 , comprising:
 (a) nitisinone (4 mg/ml);   (b) citric acid monohydrate (9 mg/ml);   (c) trisodium citrate dehydrate (2.1 mg/ml)   (d) hydroxypropyl methylcellulose (5 mg/ml);   (e) glycerol (500 mg/ml);   (f) methyl paraben (1.4 mg/ml);   (g) propyl paraben (0.14 mg/ml); and   (h) polysorbate 80 (0.14 mg/ml).   
     
     
         14 . The formulation according to  claim 1 , comprising:
 (a) nitisinone (4 mg/ml);   (b) citric acid monohydrate (9 mg/ml);   (c) trisodium citrate dehydrate (2.1 mg/ml)   (d) hydroxypropyl methylcellulose (5 mg/ml);   (e) glycerol (500 mg/ml);   (f) sodium benzoate (1.0 mg/ml); and   (g) polysorbate 80 (0.14 mg/ml).   
     
     
         15 . The formulation according to  claim 13 , in addition comprising a flavoring agent. 
     
     
         16 . A method of treating a medical condition in a subject, comprising administering to a subject in need of such treatment an effective amount of the formulation according to  claim 1 , wherein the medical condition is selected from the group consisting of tyrosinaemia, Parkinson's disease, depression, restless leg syndrome, and alkaptonuria. 
     
     
         17 . The method according to  claim 16 , wherein the medical condition is hereditary tyrosinaemia type 1 (HT-1). 
     
     
         18 . The method according to  claim 17 , wherein the medical condition is hereditary tyrosinaemia type 1 (HT-1) in a paediatric patient. 
     
     
         19 . The formulation according to  claim 14 , in addition comprising a flavoring agent.