A stable parenteral dosage form of cetrorelix acetate

Abstract

The present invention relates to a stable parenteral dosage form with a ready-to-inject sterile stable aqueous solution of cetrorelix acetate. The invention also relates to an injection device prefilled with the ready-to-inject sterile stable aqueous solution of cetrorelix acetate. The present invention relates a method of inhibiting premature luteinizing hormone surges in women undergoing controlled ovarian stimulation comprising a stable parenteral dosage form with a ready-to-inject sterile stable aqueous solution of cetrorelix acetate.

1 . A parenteral dosage form comprising a stable aqueous solution comprising:
 (i) cetrorelix or a pharmaceutically acceptable salt thereof; and   (ii) an impurity of Formula I in an amount less than 1% w/v of cetrorelix base,   
       
         
           
           
               
               
           
         
       
     
     
         2 . The parenteral dosage form as claimed in  claim 1 , wherein the dosage form is a sterile, stable, aqueous solution. 
     
     
         3 . The parenteral dosage form as claimed in  claim 1 , wherein the dosage form is a sterile, ready-to-infuse dosage form. 
     
     
         4 . The parenteral dosage form as claimed in  claim 1 , wherein the stable, aqueous solution further comprises an organic acid to adjust the pH in the range of 3 to 5. 
     
     
         5 . The parenteral dosage form as claimed in  claim 4 , wherein the stable, aqueous solution further comprises an osmotic agent. 
     
     
         6 . A parenteral dosage form according to  claim 1 , wherein the amount of cetrorelix or a pharmaceutically acceptable salt thereof is 0.25 mg/ml. 
     
     
         7 . A parenteral dosage form according to  claim 5 , wherein the osmotic agent is present in an amount sufficient for osmolality of the solution in the range of 250 to 375 mOsm/Kg. 
     
     
         8 . The parenteral dosage form according to  claim 1 , wherein the parenteral dosage form is a ready-to-inject, sterile, stable aqueous solution present in the reservoir of an injection device. 
     
     
         9 . The parenteral dosage form according to  claim 8 , wherein the injection device is a prefilled syringe. 
     
     
         10 . The parenteral dosage form according to  claim 8 , wherein the injection device is an auto-injector. 
     
     
         11 . The parenteral dosage form according to  claim 8 , wherein the injection device is a pen auto-injector. 
     
     
         12 . The parenteral dosage form according to  claim 1 , wherein the stable, aqueous solution is stable for at least 1 month at 25° C. temperature and 60% relative humidity. 
     
     
         13 . The parenteral dosage form according to  claim 1 , wherein the stable, aqueous solution is stable for at least 3 months at 25° C. temperature and 60% relative humidity. 
     
     
         14 . The parenteral dosage form according to  claim 1 , wherein the stable, aqueous solution is stable for at least 6 months at 25° C. temperature and 60% relative humidity. 
     
     
         15 . The parenteral dosage form according to  claim 1 , wherein the parenteral dosage form is suitable for subcutaneous use. 
     
     
         16 . The parenteral dosage form according to  claim 1 , wherein the parenteral dosage form is suitable for intramuscular use. 
     
     
         17 . A pharmaceutical composition of cetrorelix or a pharmaceutically acceptable salt thereof, comprising a decapeptide of formula I: 
       
         
           
           
               
               
           
         
       
     
     
         18 . A method of inhibiting premature luteinizing hormone surges in women undergoing controlled ovarian stimulation comprising:
 a parenteral dosage form comprising: a ready-to-inject, sterile, stable, aqueous solution comprising:   (i) cetrorelix or a pharmaceutically acceptable salt thereof,   (ii) Impurity A, a decapeptide of formula I, in an amount less than 1% w/v of cetrorelix base,   
       
         
           
           
               
               
           
         
       
     
     
         19 . A decapeptide of formula I 
       
         
           
           
               
               
           
         
       
     
     
         20 . The decapeptide of  claim 19 , wherein the decapeptide is identified by HPLC analysis, the process comprising:
 a) injecting a diluent comprising water, acetonitrile and formic acid into the chromatographic system,   b) injecting a system suitability solution comprising cetrorelix acetate, diluent and impurity stock solution and recording the chromatogram,   c) injecting a standard solution comprising cetrorelix acetate and diluent into the chromatographic system,   d) injecting a sample comprising aqueous solution of cetrorelix acetate and placebo preparation into the chromatographic system, and   e) determining the relative retention time and relative response factor of impurities and cetrorelix acetate with respect to cetrorelix acetate.   
     
     
         21 . A process to identify the decapeptide of  claim 19  by HPLC analysis, the process comprising:
 a) injecting a diluent comprising water, acetonitrile and formic acid into the chromatographic system, 
 b) injecting a system suitability solution comprising cetrorelix acetate, diluent and impurity stock solution and recording the chromatogram, 
 c) injecting a standard solution comprising cetrorelix acetate and diluent into the chromatographic system, 
 d) injecting a sample comprising aqueous solution of cetrorelix 
 acetate and placebo preparation into the chromatographic system, and e) determining the relative retention time and relative response factor of impurities and cetrorelix acetate with respect to cetrorelix acetate. 
 
     
     
         22 . The process of  claim 21 , wherein the mobile phase A and B in the HPLC analysis comprises a buffer, acetonitrile and tetrahydrofuran, and
 wherein the relative retention time and relative response factor for the decapeptide is determined to be 0.57 and 1.0, respectively.