Claims for Patent: 10,993,914

Summary for Patent: 10,993,914

Title:	Stabilizing camptothecin pharmaceutical compositions
Abstract:	Irinotecan phospholipid liposomes with improved storage stability are provided, with related methods of treatment and manufacture. The irinotecan liposomes can have reduced formation of lyso-phosphatidylcholine (lyso-PC) during storage, and prior to administration to a patient.
Inventor(s):	Daryl C. Drummond, Dmitri B. Kirpotin, Mark Eamon Hayes, Charles Noble, Kevin Kesper, Antoine M. Awad, Douglas J. Moore, Andrew J. O'brien
Assignee:	Ipsen Biopharm Ltd
Application Number:	US16/567,902
Patent Claims:	1. A storage stabilized liposomal irinotecan composition comprising irinotecan sucrose octasulfate (SOS), cholesterol, and one or more phospholipids with a ratio corresponding to a total of 500 grams ±10% by weight irinotecan moiety per mol total phospholipids, the liposomal irinotecan composition stabilized to have less than 20 mol %, with respect to total phospholipids, of lyso-phosphatidylcholine (lyso-PC) after 180 days or 6 months of storage of the liposomal irinotecan composition at a storage temperature of from 2 to 8° C., the liposomal irinotecan composition obtained by a process comprising the steps of: (a) forming liposomes comprising 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and methoxy-terminated polyethylene glycol-distearoylphosphatidyl ethanolamine, encapsulating a substituted ammonium salt of SOS with a sulfate concentration of from 0.4 to 0.5 M; (b) incubating the liposomes with an aqueous solution comprising irinotecan, at conditions effective to load the irinotecan, thereby forming a preparation of liposomes encapsulating irinotecan sucrose octasulfate within the liposomes; and (c) obtaining the storage stabilized liposomal irinotecan composition by at least one additional step comprising adjusting the pH of the preparation of liposomes to a pH of from about 7.25 to about 7.50. 2. The storage stabilized liposomal irinotecan composition of claim 1, wherein the composition comprises unilamellar liposomes. 3. The storage stabilized liposomal irinotecan composition of claim 1, having a total irinotecan moiety content equivalent to about 4.3 mg/mL irinotecan free base. 4. The storage stabilized liposomal irinotecan composition of claim 1, having less than 20 mol %, with respect to total phospholipids, of lyso-PC after a storage time of from 9 months to 12 months, at a storage temperature of from 2 to 8° C. 5. The storage stabilized liposomal irinotecan composition of claim 1, comprising an isotonic HEPES aqueous buffer, wherein the HEPES aqueous buffer is present at a concentration of from 2 to 20 mM. 6. The storage stabilized liposomal irinotecan composition of claim 1, further comprising sodium chloride present at a concentration of from 130 to 160 mM. 7. The storage stabilized liposomal irinotecan composition of claim 1, wherein the irinotecan encapsulated within the liposomes is in a gelated or precipitated state as a sucrose octasulfate salt. 8. The storage stabilized liposomal irinotecan composition of claim 1, wherein the methoxy-terminated polyethylene glycol-distearoylphosphatidyl ethanolamine comprises MPEG-2000-DSPE. 9. The storage stabilized liposomal irinotecan composition of claim 1, comprising a total of 6.1 to 7.5 mg DSPC/mL, 2 to 2.4 mg cholesterol/mL, and 0.11 to 0.13 mg MPEG-2000-DSPE/mL. 10. The storage stabilized liposomal irinotecan composition of claim 9, comprising a total of 6.81 mg DSPC/mL, 2.22 mg cholesterol/mL, and 0.12 mg MPEG-2000-DSPE/mL. 11. The storage stabilized liposomal irinotecan composition of claim 1, wherein the storage temperature is about 4° C. 12. The storage stabilized liposomal irinotecan composition of claim 1, forming less than 1 mg/mL of lyso-PC after 180 days or 6 months, at a storage temperature of from 2 to 8° C. 13. The storage stabilized liposomal irinotecan composition of claim 9, forming less than 1 mg/mL of lyso-PC after 180 days or 6 months, at a storage temperature of from 2 to 8° C. 14. The storage stabilized liposomal irinotecan composition of claim 1, wherein the substituted ammonium salt of SOS is triethylammonium SOS or diethylammonium SOS. 15. The storage stabilized liposomal irinotecan composition of claim 14, comprising triethylammonium in a total amount of less than 100 ppm. 16. The storage stabilized liposomal irinotecan composition of claim 14, comprising diethylammonium in a total amount of less than 100 ppm. 17. The storage stabilized liposomal irinotecan composition of claim 15, comprising triethylammonium in a total amount of from 30 to 100 ppm. 18. The storage stabilized liposomal irinotecan composition of claim 16, comprising diethylammonium in a total amount of from 30 to 100 ppm. 19. The storage stabilized liposomal irinotecan composition of claim 1, wherein the sulfate concentration in step (a) ranges from 0.45 to 0.475 M. 20. The storage stabilized liposomal irinotecan composition of claim 1, wherein the total time the liposomes are incubated with the aqueous solution comprising irinotecan at conditions effective to load the irinotecan, in step (b) is from several minutes to several hours. 21. The storage stabilized liposomal irinotecan composition of claim 20, wherein the total time is from 30 to 60 minutes. 22. The storage stabilized liposomal irinotecan composition of claim 1, wherein for several minutes to several hours the conditions effective to load the irinotecan of step (b) comprises a temperature of 55° C. or greater. 23. The storage stabilized liposomal irinotecan composition of claim 1, wherein for several minutes to several hours the conditions effective to load the irinotecan of step (b) comprises a temperature of 60° C. or greater. 24. The storage stabilized liposomal irinotecan composition of claim 1, wherein for several minutes to several hours the conditions effective to load the irinotecan of step (b) comprises a temperature of 70° C. or greater. 25. The storage stabilized liposomal irinotecan composition of claim 1, wherein for several minutes to several hours the conditions effective to load the irinotecan of step (b) comprises a temperature of from 55° C. to 70° C. 26. The storage stabilized liposomal irinotecan composition of claim 1, wherein for several minutes to several hours the conditions effective to load the irinotecan of step (b) comprises a temperature of from 60° C. to 70° C. 27. The storage stabilized liposomal irinotecan composition of claim 22, wherein the total time the liposomes are incubated with the aqueous solution comprising irinotecan at 55° C. or greater in step (b) is from 30 to 60 minutes. 28. The storage stabilized liposomal irinotecan composition of claim 1, having less than 10 mol % of lyso-PC, with respect to total phospholipids, after 180 days or 6 months, at a storage temperature of from 2 to 8° C. 29. The storage stabilized liposomal irinotecan composition of claim 26, having less than 5 mol % of lyso-PC, with respect to total phospholipids, after 180 days or 6 months, at a storage temperature of from 2 to 8° C. 30. The storage stabilized liposomal irinotecan composition of claim 26, having less than 2 mol % of lyso-PC, with respect to total phospholipids, after 180 days or 6 months, at a storage temperature of from 2 to 8° C. 31. The storage stabilized liposomal irinotecan composition of claim 1, having from 3 mol % to less than 20 mol % of lyso-PC, with respect to total phospholipids, after 180 days or 6 months, at a storage temperature of from 2 to 8° C. 32. The storage stabilized liposomal irinotecan composition of claim 1, having less than 10 mol % of lyso-PC, with respect to total phospholipids, after 9 months, at a storage temperature of from 2 to 8° C. 33. The storage stabilized liposomal irinotecan composition of claim 32, having less than 5 mol % of lyso-PC, with respect to total phospholipids, after 9 months, at a storage temperature of from 2 to 8° C. 34. The storage stabilized liposomal irinotecan composition of claim 32, having less than 2 mol % of lyso-PC, with respect to total phospholipids, after 9 months, at a storage temperature of from 2 to 8° C. 35. The storage stabilized liposomal irinotecan composition of claim 1, where in step (b) the aqueous solution comprising irinotecan has a pH of 6.5. 36. A storage stabilized liposomal irinotecan composition comprising irinotecan sucrose octasulfate (SOS), cholesterol, and one or more phospholipids with a ratio corresponding to a total of 500 grams ±10% by weight irinotecan moiety per mol total phospholipids, the liposomal irinotecan composition stabilized to have less than 2 mg/mL with respect to total phospholipids, of lyso-phosphatidylcholine (lyso-PC) after 21 months of storage of the liposomal irinotecan composition at a storage temperature of from 2 to 8° C., the liposomal irinotecan composition obtained by a process comprising the steps of: (a) forming liposomes comprising 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and methoxy-terminated polyethylene glycol-distearoylphosphatidyl ethanolamine, encapsulating a substituted ammonium salt of SOS with a sulfate concentration of from 0.4 to 0.5 M; (b) incubating the liposomes with an aqueous solution comprising irinotecan, at conditions effective to load the irinotecan, thereby forming a preparation of liposomes encapsulating irinotecan sucrose octasulfate within the liposomes; and (c) obtaining the storage stabilized liposomal irinotecan composition by at least one additional step comprising adjusting the pH of the preparation of liposomes to a pH of from about 7.25 to about 7.50.