Conjugates of a phospholipid and a drug for the treatment of inflammatory bowel disease

Abstract

Conjugates of drugs suitable for use in the treatment of inflammatory bowel disease and phospholipids, and their use in the treatment of inflammatory bowel disease, are disclosed. The disclosed conjugates serve as targeted prodrugs which are suitable for oral administration, and which are capable of releasing the drug selectively at the diseased tissue upon activation by PLA 2 .

What is claimed is: 
     
         1 . A method of treating an inflammatory bowel disease in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of a conjugate which comprises a drug useful in the treatment of the inflammatory bowel disease covalently linked to a phospholipid. 
     
     
         2 . The method of  claim 1 , wherein the conjugate is administered as a liquid oral formulation. 
     
     
         3 . The method of  claim 1 , wherein said drug useful in the treatment of inflammatory bowel disease is selected from the group consisting of a drug that comprises 5-ASA, tacrolimus and methotrexate. 
     
     
         4 . The method of  claim 1 , wherein said phospholipid is a phosphoglycerol. 
     
     
         5 . The method of  claim 4 , wherein said drug is linked to position sn-2 of said phosphoglycerol. 
     
     
         6 . The method of  claim 1 , wherein said drug is linked to said phospholipid via a bridging unit. 
     
     
         7 . The method of  claim 6 , wherein said bridging unit is an alkylene being from 3 to 6 carbon atoms in length. 
     
     
         8 . The method of  claim 1 , wherein said conjugate has a general Formula: 
       
         
           
           
               
               
           
         
         wherein:
 A is an alkylene chain being 3-30 carbon atoms in length; 
 X is a bridging unit; 
 D is said drug suitable for use in the treatment of said inflammatory bowel disease; and 
 R is selected from the group consisting of —P(═O)(ORa)(ORb), phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N-[methoxy(propylene glycol)], phosphoinositol-4-phosphate, phosphoinositol-4,5-biposphonate, pyrophosphate, phosphoethanolamine-diethylenetriamine-pentaacetate, dinitrophenyl-phosphoethanolamine and phsophoglycerol, wherein Ra and Rb are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl. 
 
       
     
     
         9 . The method of  claim 8 , wherein said drug comprises 5-ASA. 
     
     
         10 . The method of  claim 9 , wherein X is an alkylene chain being 3-6 carbon atoms in length. 
     
     
         11 . The method of  claim 9 , wherein R is phosphoryl choline. 
     
     
         12 . A pharmaceutical composition comprising, as an active ingredient, a conjugate which comprises a drug useful in the treatment of the inflammatory bowel disease covalently linked to a phospholipid, and a pharmaceutically acceptable carrier, the composition being formulated for oral administration and is being packaged in a packaging material and identified in print, in or on said packaging material, for use in the treatment of said inflammatory bowel disease. 
     
     
         13 . The composition of  claim 12 , being formulated as a liquid oral formulation. 
     
     
         14 . The composition of  claim 13 , wherein said drug useful in the treatment of inflammatory bowel disease is selected from the group consisting of a drug that comprises 5-ASA, tacrolimus and methotrexate. 
     
     
         15 . The composition of  claim 13 , wherein said phospholipid is a phosphoglycerol. 
     
     
         16 . The composition of  claim 15 , wherein said drug is linked to position sn-2 of said phosphoglycerol. 
     
     
         17 . The composition of  claim 13 , wherein said drug is linked to said phospholipid via a bridging unit. 
     
     
         18 . The composition of  claim 17 , wherein said bridging unit is an alkylene being from 3 to 6 carbon atoms in length. 
     
     
         19 . The composition of  claim 13 , wherein said conjugate has a general Formula: 
       
         
           
           
               
               
           
         
         wherein:
 A is an alkylene chain being 3-30 carbon atoms in length; 
 X is a bridging unit; 
 D is said drug suitable for use in the treatment of said inflammatory bowel disease; and 
 R is selected from the group consisting of —P(═O)(ORa)(ORb), phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N-[methoxy(propylene glycol)], phosphoinositol-4-phosphate, phosphoinositol-4,5-biposphonate, pyrophosphate, phosphoethanolamine-diethylenetriamine-pentaacetate, dinitrophenyl-phosphoethanolamine and phsophoglycerol, wherein Ra and Rb are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl. 
 
       
     
     
         20 . The composition of  claim 19 , wherein said drug comprises 5-ASA. 
     
     
         21 . The composition of  claim 20 , wherein X is an alkylene chain being 3-6 carbon atoms in length. 
     
     
         22 . The composition of  claim 20 , wherein R is phosphoryl choline. 
     
     
         23 . An oral liquid dosage form comprising a conjugate which comprises a drug useful in the treatment of the inflammatory bowel disease covalently linked to a phospholipid, and a pharmaceutically acceptable carrier. 
     
     
         24 . The dosage form of  claim 23 , wherein said drug useful in the treatment of inflammatory bowel disease is selected from the group consisting of a drug that comprises 5-ASA, tacrolimus and methotrexate. 
     
     
         25 . The dosage form of  claim 23 , wherein said phospholipid is a phosphoglycerol. 
     
     
         26 . The dosage form of  claim 25 , wherein said drug is linked to position sn-2 of said phosphoglycerol. 
     
     
         27 . The dosage form of  claim 23 , wherein said conjugate has a general Formula: 
       
         
           
           
               
               
           
         
         wherein:
 A is an alkylene chain being 3-30 carbon atoms in length; 
 X is a bridging unit; 
 D is said drug suitable for use in the treatment of said inflammatory bowel disease; and 
 R is selected from the group consisting of —P(═O)(ORa)(ORb), phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N-[methoxy(propylene glycol)], phosphoinositol-4-phosphate, phosphoinositol-4,5-biposphonate, pyrophosphate, phosphoethanolamine-diethylenetriamine-pentaacetate, dinitrophenyl-phosphoethanolamine and phsophoglycerol, wherein Ra and Rb are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl. 
 
       
     
     
         28 . The dosage form of  claim 27 , wherein said drug comprises 5-ASA. 
     
     
         29 . The dosage form of  claim 28 , wherein X is an alkylene chain being 3-6 carbon atoms in length. 
     
     
         30 . The dosage form of  claim 28 , wherein R is phosphoryl choline. 
     
     
         31 . A conjugate comprising a phospholipid having attached thereto 5-aminosalicylic acid (5-ASA). 
     
     
         32 . The conjugate of  claim 31 , wherein said conjugate has a general Formula: 
       
         
           
           
               
               
           
         
         wherein:
 A is an alkylene chain being 3-30 carbon atoms in length; 
 X is a bridging unit or absent; 
 D is 5-ASA; and 
 R is selected from the group consisting of —P(═O)(ORa)(ORb), phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N-[methoxy(propylene glycol)], phosphoinositol-4-phosphate, phosphoinositol-4,5-biposphonate, pyrophosphate, phosphoethanolamine-diethylenetriamine-pentaacetate, dinitrophenyl-phosphoethanolamine and phsophoglycerol, wherein Ra and Rb are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl. 
 
       
     
     
         33 . An oral liquid dosage form comprising the conjugate of  claim 31 .