Details for Patent: 9,782,349
✉ Email this page to a colleague
Title: | Liposomes useful for drug delivery |
Abstract: | The present invention provides liposome compositions containing substituted ammonium and/or polyanion, and optionally with a desired therapeutic or imaging entity. The present invention also provide methods of making the liposome compositions provided by the present invention. |
Inventor(s): | Hong; Keelung (San Francisco, CA), Drummond; Daryl C. (Lincoln, MA), Kirpotin; Dmitri (Revere, MA) |
Assignee: | Ipsen Biopharma Ltd. (Wrexham, GB) |
Filing Date: | Dec 11, 2015 |
Application Number: | 14/966,458 |
Claims: | 1. An irinotecan liposome composition comprising irinotecan and a sulfated sugar encapsulated in a lipid vesicle, wherein the composition is obtainable by a process comprising the steps of: (a) forming the lipid vesicle encapsulating the sulfated sugar and one or more substituted ammonium compounds selected from the group consisting of diethylammonium and triethylammonium in a lipid composition comprising one or more lipid components forming the lipid vesicle; (b) contacting the lipid vesicle with irinotecan at a temperature above the phase transition temperature of the lipid vesicle, to load at least 85% of the irinotecan into the lipid vesicle; wherein at least about 70% of the irinotecan remains encapsulated in the lipid vesicle after 8 hours in the blood of a CD-1 mouse. 2. The irinotecan liposome composition of claim 1, wherein the sulfated sugar has a pKa of 3 or less. 3. The irinotecan liposome composition of claim 1, wherein the lipid vesicle comprises DSPC and cholesterol in a 3:2 molar ratio. 4. The irinotecan liposome composition of claim 1, wherein the sulfated sugar is selected from the group consisting of sucrose hexasulfate, sucrose heptasulfate, and sucrose octasulfate. 5. The irinotecan liposome composition of claim 4, wherein the sulfated sugar is sucrose octasulfate. 6. An irinotecan liposome composition comprising irinotecan and a sulfated sugar selected from the group consisting of sucrose hexasulfate, sucrose heptasulfate, and sucrose octasulfate encapsulated in a lipid vesicle, wherein the composition is obtained by a process comprising the steps of: (a) forming the lipid vesicle encapsulating the sulfated sugar and one or more substituted ammonium compounds selected from the group consisting of: diethylammonium and triethylammonium in a lipid composition comprising one or more lipid components forming the lipid vesicle; (b) contacting the lipid vesicle with irinotecan at a temperature above the phase transition temperature of the lipid vesicle, to load at least 85% of the irinotecan into the lipid vesicle. 7. The irinotecan liposome composition of claim 6, wherein the sulfated sugar has a pKa of 3 or less. 8. The irinotecan liposome composition of claim 6, wherein the lipid vesicle comprises DSPC and cholesterol in a 3:2 molar ratio. 9. The irinotecan liposome composition of claim 8, wherein at least about 70% of the irinotecan remains encapsulated in the lipid vesicle after 8 hours in the blood of a CD-1 mouse. 10. The irinotecan liposome composition of claim 9, wherein the lipid vesicle comprises DSPC and cholesterol in a 3:2 molar ratio and the sulfated sugar has a pKa of 3 or less. 11. An irinotecan liposome composition comprising liposomes encapsulating irinotecan and a sulfated sugar, wherein at least about 70% of the irinotecan remains encapsulated in the lipid vesicles after 8 hours in the blood of a CD-1 mouse. 12. The irinotecan liposome composition of claim 11, wherein the amount of encapsulated irinotecan in the lipid vesicles is determined by a method comprising the steps of: a) administering a radioactive labeled version of the irinotecan liposome composition to six-week-old female CD-1 mice by tail vein injection at a dose of 10 mg/kg (0.2 mg CPT-11/mouse); b) anesthetizing and exsanguinating the mice eight hours later; c) collecting the blood from the mice in step (b) into heparinized syringes (10-20 .mu.l of 1000 U/mL heparin USP) and transferring into weighed tubes containing 0.4 mL of the phosphate-buffered physiological saline solution (PBS) containing 0.04% EDTA (Gibco BRL) and keeping on ice; d) weighing the tubes to determine weights of the blood samples; e) separating the blood cells by centrifugation at 9,000 g for 5 minutes, and saving supernatants containing PBS-diluted plasma for drug and liposome lipid assays; f) quantifying irinotecan in the samples by the fluorometric assay, whereby liposome lipid is quantified by quenching-corrected radioactivity scintillation counting, using liposome and phospholipid-radioactivity standards counted in parallel with the plasma samples; and g) calculating the percent of the drug remaining encapsulated by dividing the drug/radioactivity ratio in the plasma samples by the drug/radioactivity ratio of the injected liposomes, wherein the percent of injected lipid dose (% I.D.) remaining in the circulation was calculated assuming 100% of the injected bolus entered the circulation. 13. The irinotecan liposome composition of claim 11, wherein the sulfated sugar has a pKa of 3 or less. 14. The irinotecan liposome composition of claim 13, wherein the liposomes comprise DSPC and cholesterol in a 3:2 molar ratio. 15. A pharmaceutical composition comprising liposomes encapsulating irinotecan and sucrose hexasulfate. 16. The pharmaceutical composition of claim 15, wherein the amount of encapsulated irinotecan in the lipid vesicles is determined by a method comprising the steps of: a) administering a radioactive labeled version of the irinotecan liposome composition to six-week-old female CD-1 mice by tail vein injection at a dose of 10 mg/kg (0.2 mg CPT-11/mouse); b) anesthetizing and exsanguinating the mice eight hours later; c) collecting the blood from the mice in step (b) into heparinized syringes (10-20 .mu.l of 1000 U/mL heparin USP) and transferring into weighed tubes containing 0.4 mL of the phosphate-buffered physiological saline solution (PBS) containing 0.04% EDTA (Gibco BRL) and keeping on ice; d) weighing the tubes to determine weights of the blood samples; e) separating the blood cells by centrifugation at 9,000 g for 5 minutes, and saving supernatants containing PBS-diluted plasma for drug and liposome lipid assays; f) quantifying irinotecan in the samples by the fluorometric assay, whereby liposome lipid is quantified by quenching-corrected radioactivity scintillation counting, using liposome and phospholipid-radioactivity standards counted in parallel with the plasma samples; and g) calculating the percent of the drug remaining encapsulated by dividing the drug/radioactivity ratio in the plasma samples by the drug/radioactivity ratio of the injected liposomes, wherein the percent of injected lipid dose (% I.D.) remaining in the circulation was calculated assuming 100% of the injected bolus entered the circulation. 17. A pharmaceutical composition comprising liposomes comprising DSPC and cholesterol in a 3:2 molar ratio, encapsulating irinotecan and a sulfated sugar having a pKa of 3 or less, wherein at least about 70% of the irinotecan remains encapsulated in the lipid vesicles after 8 hours in the blood of a CD-1 mouse. |