Liposomal compositions of glucocorticoid and glucocorticoid derivatives

Abstract

Provided are pharmaceutical compositions including a glucocorticoid or glucocorticoid derivative stably encapsulated in a liposome. The glucocorticoid or glucocorticoid derivative is selected from an amphipathic weak base glucocorticoid or glucocorticoid derivative having a pKa equal or below 11 and a logD at pH 7 in the range between −2.5 and 1.5; or an amphipathic weak acid GC or GC derivative having a pKa above 3.5 and a logD at pH 7 in the range between −2.5 and 1.5. The therapeutic effect of the pharmaceutical composition of the invention was exhibited in vivo with appropriate models of multiple sclerosis and cancer.

1 - 36 . (canceled) 
     
     
         37 . A method for delivery of a glucocorticoid (GC) to a target site within a body comprising: providing a glucocorticoid (GC) derivative that is an amphipathic weak base GC derivative having a pKa equal to or below 11 and a logD at pH 7 in a range of from −1.5 to 1.0 or an amphipathic weak acid GC derivative having a pKa above 3.5 and a logD at pH 7 in a range of from −1.5 to 1.0 and loading said GC into a liposome. 
     
     
         38 . The method of  claim 37 , wherein said GC is a water immiscible GC. 
     
     
         39 . The method of  claim 37 , wherein the GC is selected from the group consisting of prednisolone hemisuccinate, methylprednisolone hemisuccinate, hydrocortisone hemisuccinate, dexamethasone hemisuccinate, allopregnanolone hemisuccinate, beclomethasone 21-hemisuccinate, betamethasone 21-hemisuccinate, boldenone hemisuccinate, prednisolone 21-hemisuccinate, nandrolone hemisuccinate, 19-nortestosterone hemisuccinate, deoxycorticosterone 21-hemisuccinate, corticosterone hemisuccinate, and cortexolone hemisuccinate. 
     
     
         40 . The method of  claim 39 , wherein said GC is selected from the group consisting of methylprednisolone sodium hemisuccinate (MPS), hydrocortisone sodium hemisuccinate (HYD), dexamethasone hemisuccinate and prednisolone hemisuccinate. 
     
     
         41 . The method of  claim 37 , wherein said liposome comprises a counter ion to said GC. 
     
     
         42 . The method of  claim 37 , wherein said liposomes comprises a combination of a phospholipid, a lipopolymer and cholesterol. 
     
     
         43 . The method of  claim 42 , wherein said liposome comprises at least one of HSPC and DSPC, and a mole ratio between the GC derivative and HSPC or DSPC of between 0.01 and 2.0. 
     
     
         44 . The method of  claim 43 , wherein the mole ratio is between 0.04 and 0.25. 
     
     
         45 . A method for treatment of a disease or disorder comprising administration to a subject in need of said treatment a pharmaceutical composition comprising
 a liposome comprising   a glucocorticoid (GC) derivative that is an amphipathic weak base GC derivative having a pKa equal to or below 11 and a logD at pH 7 in a range of from −1.5 to 1.0 or an amphipathic weak acid GC derivative having a pKa above 3.5 and a logD at pH 7 in a range of from −1.5 to 1.0, the GC derivative being selected from the group consisting of prednisolone hemisuccinate, methylprednisolone hemisuccinate, hydrocortisone hemisuccinate, dexamethasone hemisuccinate, allopregnanolone hemisuccinate, beclomethasone 21-hemisuccinate, betamethasone 21-hemisuccinate, boldenone hemisuccinate, prednisolone 21-hemisuccinate, nandrolone hemisuccinate, 19-nortestosterone hemisuccinate, deoxycorticosterone 21-hemisuccinate, corticosterone hemisuccinate, and cortexolone hemisuccinate; and   a counter-ion to the GC derivative   
       wherein the GC derivative is retained in the liposome for at least six months. 
     
     
         46 . The pharmaceutical composition of  claim 45 , wherein the GC derivative is a pro-drug which is converted to an active GC upon release thereof from the liposome into a body fluid. 
     
     
         47 . The pharmaceutical composition of  claim 45 , wherein the GC corresponds to an acidic GC selected from the group consisting of methylprednisolone sodium hemisuccinate (MPS), hydrocortisone sodium hemisuccinate (HYD), dexamethasone hemisuccinate and prednisolone hemisuccinate. 
     
     
         48 . The method of  claim 45 , wherein said liposome comprises a combination of a phospholipid, a lipopolymer and cholesterol. 
     
     
         49 . The method of  claim 48 , wherein said liposome comprises a lipopolymer being PEG-DSPE. 
     
     
         50 . The method of  claim 48 , wherein said phospholipid comprises one or both of HSPC or DSPC, and the liposome comprises a mole ratio between the GC derivative and HSPC or DSPC of between 0.01 and 2.0. 
     
     
         51 . The method of  claim 50 , wherein the mole ratio is between 0.04 and 0.25. 
     
     
         52 . The method of  claim 45 , for the treatment of a neurodegenerative disorder. 
     
     
         53 . The method of  claim 52 , for the treatment of multiple sclerosis. 
     
     
         54 . The method of  claim 45 , for the treatment of cancer. 
     
     
         55 . A pharmaceutical composition, comprising:
 a liposome comprising   a glucocorticoid (GC) derivative that is an amphipathic weak base GC derivative having a pKa equal to or below 11 and a logD at pH 7 in a range of from −1.5 to 1.0 or an amphipathic weak acid GC derivative having a pKa above 3.5 and a logD at pH 7 in a range of from −1.5 to 1.0, the GC derivative being selected from the group consisting of prednisolone hemisuccinate, methylprednisolone hemisuccinate, hydrocortisone hemisuccinate, dexamethasone hemisuccinate, allopregnanolone hemisuccinate, beclomethasone 21-hemisuccinate, betamethasone 21-hemisuccinate, boldenone hemisuccinate, prednisolone 21-hemisuccinate, nandrolone hemisuccinate, 19-nortestosterone hemisuccinate, deoxycorticosterone 21-hemisuccinate, corticosterone hemisuccinate, and cortexolone hemisuccinate; and   a counter-ion to the GC derivative   
       wherein the GC derivative is retained in the liposome for at least six months.