Lyophilization process and a teverelix-tfa lyophilizate obtained thereby

Abstract

The present invention relates to a lyophilization process for preparing a teverelix-TFA lyophilizate, said process comprises the following steps: a) providing a lyophilization suspension by mixing teverelix and trifluoroacetate at a molar ratio sufficient for providing a microcrystalline teverelix-TFA suspension without formation of a gel, and b) lyophilizating the lyophilization suspension, thereby providing a teverelix-TFA lyophilizate. The process provides the possibility of obtaining a “pure” teverelix-TFA lyophilizate i.e. without any undesirable residues in the composition.

1 . A lyophilization process for preparing a teverelix-TFA lyophilizate, said process comprises the following steps: a) providing a lyophilization suspension by mixing teverelix and trifluoroacetate at a molar ratio sufficient for providing a microcrystalline teverelix-TFA suspension without formation of a gel, b) lyophilizating the lyophilization suspension from step a) thereby providing a teverelix-TFA lyophilizate, characterized in, that step a) further comprises the following steps:
 a′) centrifuging or filtering the microcrystalline teverelix-TFA suspension thereby respectively providing a teverelix-TFA pellet or a teverelix-TFA filter cake, and   a″) suspending said teverelix-TFA pellet or said teverelix-TFA filter cake in an aqueous suspension solution.   
     
     
         2 . The lyophilization process according to  claim 1 , wherein the teverelix and trifluoroacetate in step a) are mixed at a molar ratio of at least 1:2.1, preferably at least 1:2.2. 
     
     
         3 . The lyophilization process according to  claim 1 , wherein the pellet after centrifuging or filter cake after filtering has a molar ratio of teverelix to trifluoroacetate which is lower than the molar ratio in the microcrystalline teverelix-TFA suspension. 
     
     
         4 . The lyophilization process according to  claim 1 , wherein the aqueous suspension solution is water or a mannitol solution. 
     
     
         5 . The lyophilization process according to  claim 1 , wherein the microcrystalline teverelix-TFA suspension is made in water if the molar ratio of teverelix to trifluoroacetate is at least 1:2.2. 
     
     
         6 . The lyophilization process according to  claim 1 , wherein the microcrystalline teverelix-TFA suspension is made in a trifluoroacetic acid solution if the molar ratio of teverelix to trifluoroacetate is below 1:2.2. 
     
     
         7 . The lyophilization process according to  claim 1 , wherein the teverelix-TFA lyophilizate from step b) is sterilized by gamma-sterilization. 
     
     
         8 . The lyophilization process according to  claim 1 , wherein the concentration of teverelix-TFA in the microcrystalline teverelix-TFA suspension is at least 100 mg/ml. 
     
     
         9 . The lyophilization process according to  claim 1 , wherein the resuspended pellet or resuspended filter cake is lyophilized or spray-dried to an extent such that the obtained teverelix-TFA lyophilizate comprises water in an amount of between 0.3% to 5% by weight based on the total weight of the teverelix-TFA lyophilizate . 
     
     
         10 . The lyophilization process according to  claim 1 , wherein the lyophilization is performed on a unit dosage of the teverelix-TFA lyophilizate and/or directly in the packaging for storage. 
     
     
         11 . A teverelix-TFA lyophilizate obtainable by the lyophilization process according to  claim 1 . 
     
     
         12 . A method of reconstituting the teverelix-TFA lyophilizate according to  claim 11 , and wherein said method comprises adding an aqueous reconstitution solution to the teverelix-TFA lyophilizate. 
     
     
         13 . The method according to  claim 12 , wherein the molar ratio of teverelix to trifluoroacetate is below 1:2.1 in the teverelix-TFA lyophilizate, and said method comprises adjusting the molar ratio to at least 1:2.1 by adding trifluoroacetate. 
     
     
         14 . The method according to  claim 13 , wherein the molar ratio of teverelix to trifluoroacetate is adjusted to at least 1:2.2 and preferably at least 1:2.4. 
     
     
         15 . The method according to  claim 12 , wherein the molar ratio of teverelix to trifluoroacetate is adjusted to be at or less than 1:2.8. 
     
     
         16 . A fluid, milky microcrystalline aqueous teverelix-TFA suspension obtainable by the method according to  claim 12 . 
     
     
         17 . The fluid, milky microcrystalline aqueous suspension according to  claim 16 , wherein the molar ratio of teverelix to trifluoroacetate is at least 1:2.2. 
     
     
         18 . The fluid, milky microcrystalline aqueous suspension according to  claim 16 , wherein the molar ratio of teverelix to trifluoroacetate is at or below 1:2.8. 
     
     
         19 . A pharmaceutical formulation comprising the fluid, milky microcrystalline aqueous suspension according to  claim 16 .