Liposomal camptothecins and uses thereof

Abstract

This invention relates to improved liposomal camptothecin compositions and methods of manufacturing and using such compositions for treating neoplasia and for inhibiting angiogenesis.

1 . A liposomal topotecan unit dosage form, said unit dosage form comprising: a lipid; and a topotecan dosage of from about 0.01 mg/M 2 /dose to about 7.5 mg/M 2 /dose, wherein said liposomal topotecan unit dosage form has a drug:lipid ratio (by weight) of about 0.05 to about 0.2. 
     
     
         2 . The liposomal topotecan unit dosage form of  claim 1 , wherein said drug:lipid ratio (by weight) is about 0.05 to about 0.15. 
     
     
         3 . The liposomal topotecan unit dosage form of  claim 1 , wherein said lipid comprises a mixture of sphingomyelin and cholesterol. 
     
     
         4 . The liposomal topotecan unit dosage form of  claim 1 , wherein said lipid comprises sphingomyelin and cholesterol in a ratio by weight of about 30:70 to about 60:40. 
     
     
         5 . The liposomal topotecan unit dosage form of  claim 1 , comprising from about 1 mg/M 2 /dose to about 4 mg/M 2 /dose of topotecan. 
     
     
         6 . A liposomal topotecan formulation, wherein said liposomal topotecan formulation retains greater than 50% active lactone species after 12 hours in blood circulation. 
     
     
         7 . The liposomal topotecan formulation of  claim 6 , wherein said liposomal topotecan formulation retains greater than 80% active lactone species after 12 hours in blood circulation. 
     
     
         8 . A liposomal topotecan formulation comprising topotecan, sphingomyelin, cholesterol and a divalent cation ionophore. 
     
     
         9 . The liposomal topotecan formulation of  claim 8 , wherein said divalent ionophore is present in trace amounts. 
     
     
         10 . The liposomal topotecan formulation of  claim 8 , comprising a drug:lipid ratio (by weight) of about 0.05 to about 0.2. 
     
     
         11 . The liposomal topotecan formulation of  claim 10 , wherein said drug:lipid ratio (by weight) is about 0.05 to about 0.15 
     
     
         12 . The liposomal topotecan formulation of  claim 11 , comprising trace amounts or greater of a divalent ionophore. 
     
     
         13 . A method of treating a solid tumor in a human afflicted therewith, said method comprising administering to said human an effective amount of a topotecan dosage of  claim 1  in a pharmaceutically acceptable carrier. 
     
     
         14 . The method of  claim 13 , wherein said solid tumor is selected from the group consisting of solid tumors of the lung, mammary, colon and prostate. 
     
     
         15 . The method of  claim 13 , further comprising co-administration of a treatment for neutropenia or platelet deficiency. 
     
     
         16 . A method of treating solid tumors in a mammal, said method comprising: administering to said mammal having a solid tumor of the lung, mammary and/or colon a liposomal topotecan formulation having a drug:lipid ratio (by weight) of about 0.05 to about 0.2. 
     
     
         17 . A method of treating solid tumors in a mammal, said method comprising: administering to said mammal having a solid tumor of the lung, mammary and/or colon a liposomal topotecan formulation comprising from about 0.01 mg/M 2 /dose to about 7.5 mg/M 2 /dose of topotecan for an interval regime, wherein said interval regime is once a day for at least two consecutive days. 
     
     
         18 . The method of treating solid tumors of  claim 17 , wherein said interval regime is at least once a week. 
     
     
         19 . The method of treating solid tumors of  claim 17 , wherein said interval regime is at least once every two weeks. 
     
     
         20 . The method of treating solid tumors of  claim 17 , wherein said interval regime is at least once every three weeks. 
     
     
         21 . The method of treating solid tumors of  claim 17 , wherein said liposomal topotecan formulation has a drug:lipid ratio (by weight) of about 0.05 to about 0.2. 
     
     
         22 . A method of treating solid tumors in a mammal comprising administering to an animal having a solid tumor of the lung, mammary and/or colon a liposomal topotecan formulation comprising from about 0.01 to about 7.5 mg/M 2 /dose of topotecan every three days. 
     
     
         23 . A liposomal camptothecin unit dosage form, said unit dosage form comprising a lipid, a camptothecin dosage of from about 0.015 mg/M 2 /dose to about 1 mg/M 2 /dose and having a drug:lipid ratio (by weight) of about 0.05 to about 0.2. 
     
     
         24 . The use of topotecan in the manufacture of a medicament comprising a liposome having a sphingomyelin to cholesterol ratio (by weight) of from about 30:70 to about 60:40 for use in treating solid tumors in a mammal. 
     
     
         25 . The use of  claim 24 , for treating solid tumors of the lung, mammary and colon.