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.