Sustained release formulations comprising GNRH analogues
The present invention relates to pharmaceutical compositions for the controlled and sustained release of active substance comprising a biodegradable polymer or copolymer. Furthermore, the invention relates to pharmaceutical compositions for the controlled and sustained release of at least one active substance such as peptides or hormones and analogs thereof and the manufacturing process of such pharmaceutical compositions.
1. An implant comprising:
an elongated biodegradable polymeric core comprising at least one GnRH analogue, wherein said GnRH analogue is triptorelin acetate;
an elongated biodegradable polymeric sleeve outside of the core;
the core being exposed through an opening in the sleeve proximate at least one end of the implant,
wherein the implant is capable of controlled and sustained release of the GnRH analogue, and
said implant is prepared by a method comprising the steps of:
(a) preparing a polymeric sleeve,
(b) preparing a 40% to 80% (w/w) solution of triptorelin acetate in water,
(c) placing the solution in the sleeve,
(d) incubating the solution at 20 to 30° C. for 2 to 48 hours and
(e) drying under vacuum for 6 to 24 hours.
2. The implant of claim 1 , wherein the controlled and sustained release occurs at least in part via release of triptorelin acetate through the opening in the sleeve.
3. The implant of claim 1 , wherein the controlled and sustained release occurs at least in part via release of triptorelin acetate through the sleeve, as the sleeve and core degrades.
4. The implant of claim 1 , wherein the polymeric core is 30 to 90% by weight triptorelin acetate relative to the total weight of the polymeric core.
5. The implant of claim 4 , wherein the polymeric core is 35 to 65% by weight triptorelin acetate relative to the total weight of the polymeric core.
6. The implant of claim 1 , wherein the polymeric core and the polymeric sleeve comprise the same polymer.
7. The implant of claim 6 , wherein the polymer is poly(lactide-co-glycolide) acid (PLGA).
8. The implant of claim 7 , wherein the ratio of lactic acid to glycolic acid in the PLGA is within the range of 70:30 to 90:10.
9. The implant of claim 8 , wherein the ratio of lactic acid to glycolic acid in the PLGA is 85:15.
10. The implant of claim 1 , wherein the implant is capable of sustained release for at least 3 months.
11. The implant of claim 10 , wherein the implant is capable of sustained release for at least 6 months.
12. The implant of claim 1 , wherein the implant comprises 0.5 to 50 mg of triptorelin acetate.
13. The implant of claim 12 , wherein the implant comprises 2 to 20 mg of triptorelin acetate.
14. The implant of claim 13 , wherein the implant comprises 5 mg of triptorelin acetate.
15. The implant of claim 13 , wherein the implant comprises 6 mg of triptorelin acetate.
16. The implant of claim 13 , wherein the implant comprises 7 mg of triptorelin acetate.
17. The implant of claim 13 , wherein the implant comprises 8 mg of triptorelin acetate.
18. The implant of claim 13 , wherein the implant comprises 9 mg of triptorelin acetate.
19. The implant of claim 13 , wherein the implant comprises 10 mg of triptorelin acetate.
20. The implant of claim 1 , wherein the implant has an axial length of between 2 and 3 cm.
21. The implant of claim 20 , wherein the implant has an axial length of 2.6 cm.
22. The implant of claim 1 , wherein the implant has a ratio of the diameter to axial length of between 1:20 and 1:40.
23. The implant of claim 22 , wherein the implant has a ratio of the diameter to axial length of 1:30.
24. The implant of claim 7 , wherein the PLGA has a molecular mass of at least 60 kDa.
25. The implant of claim 7 , wherein the PLGA has a molecular mass of at least 100 kDa.
26. An implant comprising:
(a) a polymeric sleeve having at least one open end, and
(b) a core within the sleeve comprising triptorelin acetate,
wherein the implant comprises a void between the sleeve and the core,
wherein the implant is obtained by manual insertion of the core into the polymeric sleeve.
27. The implant of claim 26 , wherein the polymeric sleeve is a polymer of poly(lactide-co-glycolide) acid (PLGA).
28. A method for preparing an implant, comprising the steps of:
(a) preparing a polymeric sleeve,
(b) preparing a 40% to 80% (w/w) solution of triptorelin acetate in water,
(c) placing the solution in the sleeve,
(d) incubating the solution at 20 to 30° C. for 2 to 48 hours and
(e) drying under vacuum for 6 to 24 hours.
29. The implant of claim 1 , wherein the implant comprises a void between the sleeve and the core.
30. An implant comprising:
an elongated biodegradable polymeric core comprising at least one GnRH analogue,
wherein said GnRH analogue is triptorelin acetate;
an elongated biodegradable polymeric sleeve outside of the core,
wherein said the polymeric sleeve is a polymer of poly(lactide-co-glycolide) acid (PGLA);
the core being exposed through an opening in the sleeve proximate at least one end of the implant,
wherein said implant has an external diameter of 0.70 mm to 1.2 mm;
wherein said implant has an axial length of 2.6 cm to 4 cm;
wherein the implant is capable of controlled and sustained release of the GnRH analogue.
31. The implant of claim 30 , wherein said implant has an external diameter of 0.70 mm, 0.80 mm, 0.85 mm, 0.87 mm, 0.90 mm, 0.95 mm, 1.0 mm, 1.08 mm, 1.1 mm, or 1.2 mm.
32. The implant of claim 30 , wherein said implant has an axial length of 2.5, 2.6, 2.7, or 2.8 cm.
33. The implant of claim 30 , wherein said biodegradable polymeric sleeve has a thickness of 280 μm to 400 μm.