Process for the preparation of pharmaceutical compositions for the sustained release of somatostatin analogs
A process for the preparation of injectable pharmaceutical compositions for the sustained release of somatostatin analogs and compositions prepared according to the process. The process may comprise lyophilizing a mixture of lanreotide acetate and acetic acid to form a lyophilizate and hydrating the lyophilizate, wherein the lyophilization is performed only once.
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 in a stepwise temperature pattern, wherein the temperature is:
initially reduced from room temperature to 1 to 3° C.;
then reduced from to −45 to −35° C.;
then increased to 20 to 30° C. and
then increased to 30 to 40° C.; 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 2 , 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. The process of claim 1 , wherein the lyophilization occurs over a period of at least 40 hours.
9. The process of claim 1 , wherein: the temperature of the mixture is:
reduced from room temperature to 1 to 3° C. over a period of up to 30 minutes and then retained constant for 2 to 4 hours;
further reduced to −45 to −35° C. over a period of up to 15 minutes and then retained constant for 2.5 to 4.5 hours;
increased to 20 to 30° C. over a period of 15 to 25 hours and then retained constant for at least 40 hours; and
further increased to 30 to 40° C. over a period of 0.5 to 1.5 hours and then retained constant for at least 16 hours.
10. The process of claim 1 , wherein, after the temperature of the mixture is reduced to −45 to −35° C., the atmospheric pressure is reduced to 15 to 25 μbar and remains constant as the temperature of the mixture increases.
11. The process of claim 2 , wherein the lyophilizate is hydrated by dissolving it in water that is less than 50% of the amount needed to completely dissolve the lanreotide salt.
12. A sustained-release pharmaceutical composition prepared according to claim 1 .
13. The composition of claim 12 , the composition being capable of releasing the lanreotide in vivo over a period of at least 15 days.
14. The composition of claim 12 , wherein the composition comprises from 15 to 35% by weight lanreotide base.
15. The composition of claim 12 , wherein the composition is suitable for use after storage for more than 12 months at a temperature of between 2 and 8° C.
16. The process of claim 2 , wherein water is used to hydrate the lyophilizate.
17. The process of claim 2 , 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 7 to 11% by weight.