Stabilizing Camptothecin Pharmaceutical Compositions
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.
1 - 23 . (canceled)
24 . A storage stabilized liposomal irinotecan composition comprising irinotecan sucrose octasulfate (SOS) encapsulated in liposomes comprising cholesterol and one or more phospholipids, said composition having:
(i) an irinotecan moiety amount equivalent to that provided by 500 g (±10%) irinotecan free anhydrous base per mol phospholipid;
(ii) an irinotecan/sulfate compound gram-equivalent ratio of from 0.85 to 1.1, calculated for each irinotecan liposome preparation by determining molar amounts of liposomally co-encapsulated irinotecan (I) and sulfate compound(S) per unit of the liposome composition, and using the formula: ER=I/(SN), where N=8;
(iii) a pH after manufacture and before storage between 7.1 and 7.5 at room temperature; and
wherein, after the first 6 months storage of said composition at a storage temperature of from 2-8° C., there is less than 20 mol % lyso-phosphatidylcholine (“lyso-PC”), relative to the total phospholipids.
25 . The composition of claim 24 , wherein the one or more phospholipids comprises phosphatidylcholine and PEG-phosphatidylethanolamine.
26 . The composition of claim 25 , wherein the phosphatidylcholine is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and the PEG-phosphatidylethanolamine is N-(methoxy-poly(ethylene glycol)-oxycarbonyl)-distearoylphosphatidylethanolamine.
27 . The composition of claim 26 , wherein the N-(methoxy-poly(ethylene glycol)-oxycarbonyl)-distearoylphosphatidylethanolamine comprises N-methoxy-terminated polyethylene glycol (MW 2000)-distearoylphosphatidyl ethanolamine.
28 . The composition of claim 27 , wherein, before storage, the ratio of moles of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) to cholesterol is about 3:2:0.015.
29 . The composition of claim 27 , wherein before storage, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) is present at a concentration of 6.4 to 7.2 mg/mL and cholesterol is present at a concentration of from 2.09 to 2.354 mg/mL and N-methoxy-terminated polyethylene glycol (MW 2000)-distearoylphosphatidyl ethanolamine is present at 0.113 to 0.127 mg/ml.
30 . The composition of claim 29 , wherein after the first 6 months of said composition at a storage temperature of from 2-8° C., the composition contains less than 20 mol % lyso-PC, relative to the total phospholipids, as quantified by an HPLC method.
31 . The composition of claim 30 , wherein the composition further comprises triethylammonium or diethylammonium in a total amount of less than about 100 ppm.
32 . The composition of claim 31 , wherein the lyso-PC accumulation rate at a storage temperature of 4° C. is less than about 0.015 mg per mL per month.
33 . The composition of claim 31 , wherein the lyso-PC accumulation rate at a storage temperature of 4° C. is less than about 0.03 mg per mL per month.
34 . The composition of claim 31 , wherein the lyso-PC accumulation rate at a storage temperature of 4° C. is less than about 0.06 mg per mL per month.
35 . The composition of claim 31 , wherein the lyso-PC accumulation rate at a storage temperature of from 2-8° C. is less than 0.033 mg per mL per month.
36 . The composition of claim 31 , wherein the lyso-PC accumulation rate at a storage temperature of from 2-8° C. is less than 0.062 mg per mL per month.
37 . The composition of claim 31 , wherein the composition comprises less than 100 ppm TEA and the lyso-PC accumulation rate at a storage temperature of 4° C. is less than about 0.06 mg per mL per month.
38 . The composition of claim 31 , wherein the composition comprises less than about 100 ppm TEA and the lyso-PC accumulation rate at a storage temperature of from 2-8° C. is less than 0.062 mg per mL per month.
39 . The composition of claim 31 , wherein the composition comprises less than 80 ppm TEA and the lyso-PC accumulation rate at a storage temperature of 4° C. is less than about 0.03 mg per mL per month.
40 . The composition of claim 31 , wherein the composition comprises less than about 70 ppm TEA and the lyso-PC accumulation rate at a storage temperature of from 2-8° C. is less than 0.033 mg per mL per month.
41 . The composition of claim 31 , wherein the composition comprises less than 20 ppm TEA and the lyso-PC accumulation rate at a storage temperature of 4° C. is less than about 0.015 mg per mL per month.