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

1. A method for preparing an injectable sustained release pharmaceutical composition, comprising the steps of:

lyophilizing a mixture of a lanreotide salt and an aqueous acid solution in a stepwise temperature pattern, wherein the stepwise temperature pattern is:

initially reduced from room temperature to 2° C.±1° C. and then held constant;

further reduced from 2±1° C. to −40±5° C. and then held constant;

increased from −40±5° C. to 25±5° C. and then held constant; and

further increased to 35±5° C. and then held constant; the resulting mixture to form a lyophilizate; and

hydrating the lyophilizate; wherein the composition has a final pH ranging between pH 5.8 to 6.4; and the method comprising only one lyophilization.

2. The method of claim 1 , wherein the acid is acetic acid.

3. The method of claim 1 , wherein the aqueous acid solution comprises acetic acid in a concentration sufficient to provide a pH that ranges between 5 to 7.

4. The method of claim 1 , wherein the aqueous acid solution used to hydrate the lyophilizate comprises a concentration of acetic acid to provide an anhydrous acetate content of 9.1 to 10.5% by weight.

5. The method of claim 1 , wherein the mixture of a lanreotide salt and an aqueous acid solution comprises 25 ±2 g/l of the lanreotide salt and 15±2% by weight acetic acid.

6. The method of claim 1 wherein the lyophilizing is for a duration of at least 40 hours.

7. The method of claim 1 wherein the mixture, during the lyophilization step, has a temporal pattern that is:

initially reduced up to 30 minutes and then held constant for 3±1 hours;

further reduced up to 15 minutes and then held constant for 3.5±1 hours;

increased over 20±5 hours and then held constant for at least 40 hours; and

further increased over 1±0.5 hours and then held constant for at least 16 hours.

8. The method of claim 1 wherein the mixture, after the temperature is reduced, has an atmospheric pressure that is reduced to 20±5 μbar and said atmospheric pressure remains constant as the temperature of the mixture increases.

9. The method of claim 1 , wherein the lyophilizate is dissolved in an amount of water that is less than 50% of the amount needed to completely dissolve the somatostatin analog salt and adapted to give the composition a semi-solid consistency.

10. A sustained release pharmaceutical composition prepared according to the process of claim 1 .

11. The composition of claim 10 , wherein the composition comprises lanreotide that is capable of in vivo release over a period of at least 15 days.

12. The composition of claim 11 comprising between 15% and 35% by weight lanreotide base.

13. The composition of claim 10 suitable for use after storage at between 2 and 8° C. for more than 12 months.

14. The method of claim 1 , wherein the lyophilization step is for a duration of at least 60 hours.

15. The method of claim 7 , wherein the mixture, during the lyophilization step, has a temperature that is:

initially reduced up to 10 minutes and then held constant for 3±1 hours;

further reduced up to 10 minutes and then held constant for 3.5±1 hours;

increased over 20±5 hours and then held constant for at least 40 hours; and

further increased over 1±0.5 hours and then held constant for at least 16 hours.

16. The process method of claim 9 , wherein the amount of water is less than 30%.

17. The method of claim 9 , wherein the amount of water is less than 10%.

18. The composition of claim 9 , wherein the in vivo release is over a period of 1 month.

19. The composition of claim 11 , wherein the in vivo release is over a period of 2 months.

20. The composition of claim 12 , comprising between 15% and 25±5% by weight lanreotide base.

21. The composition of claim 12 , comprising between 15% and approximately 24.6±2.5% by weight lanreotide base.

22. The composition of claim 10 suitable for use after storage at between 2 and 8° C. for more than 24 months.