Process for the preparation of pharmaceutical compositions for the sustained release of somatostatin analogs

Abstract

Process for the preparation of an injectable pharmaceutical composition for the sustained release of somatostatin analogues. Composition prepared according to such a process.

1 . A process for preparing an injectable sustained release pharmaceutical composition, the process comprising the steps of:
 lyophilizing a mixture comprising a somatostatin analog salt and an aqueous acid solution; and   hydrating the resulting lyophilizate;   
       wherein:
 the lyophilization is performed only once; and 
 the final pH of the composition is from 5 to 7. 
 
     
     
         2 . The process of  claim 1 , wherein the somatostatin analog is lanreotide. 
     
     
         3 . The process of  claim 1 , wherein the acid is acetic acid. 
     
     
         4 . The process of  claim 1 , wherein the final pH of the composition is from 5.8 to 6.4. 
     
     
         5 . The process of  claim 1 , wherein the aqueous acid solution contains acetic acid at a concentration suitable for providing the requisite final pH. 
     
     
         6 . The process of  claim 1 , wherein the lyophilizate is hydrated with a solution containing acetic acid at a concentration suitable to provide a composition having an anhydrous acetate content of 9.1 to 10.5% by weight. 
     
     
         7 . The process of  claim 1 , wherein a 23 to 27 g/l lanreotide composition and a 13 to 17% by weight acetic acid composition are combined to form the mixture. 
     
     
         8 . (canceled) 
     
     
         9 . The process of  claim 7 , wherein the lyophilization occurs over a period of at least 40 hours. 
     
     
         10 . The process of  claim 7 , wherein the temperature of the mixture is:
 reduced over a period of up to 30 minutes and then retained constant for 2 to 4 hours;   further reduced over a period of up to 15 minutes and then retained constant for 2.5 to 4.5 hours;   increased over a period of 15 to 25 hours and then retained constant for at least 40 hours; and   further increased over a period of 0.5 to 1.5 hours and then retained constant for at least 16 hours.   
     
     
         11 . The process of  claim 10 , wherein, after the temperature of the mixture is reduced, the atmospheric pressure is reduced to 15 to 25 μbar and remains constant as the temperature of the mixture increases. 
     
     
         12 . The process of  claim 1 , wherein the lyophilizate is hydrated by dissolving it in an amount of water that is less than 50% of the amount needed to completely dissolve the lanreotide salt. 
     
     
         13 . A sustained release pharmaceutical composition prepared according to the process of  claim 1 . 
     
     
         14 . The composition of  claim 13 , the composition being capable of releasing the lanreotide in vivo over a period of at least 15 days. 
     
     
         15 . The composition of  claim 13 , wherein the composition comprises from 15 to 35% by weight lanreotide base. 
     
     
         16 . The composition of  claim 13 , wherein the composition is suitable for use after storage for more than 12 months at a temperature of between 2 and 8° C.