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 .

1 - 33 . (canceled) 
     
     
         34 . 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. 
     
     
         35 . The method of  claim 34 , wherein the conjugate is formulated as a liquid oral formulation. 
     
     
         36 . The method of  claim 34 , 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. 
     
     
         37 . The method of  claim 34 , wherein said phospholipid is a phosphoglycerol. 
     
     
         38 . The method of  claim 37 , wherein said drug is linked to position sn-2 of said phosphoglycerol. 
     
     
         39 . The method of  claim 34 , wherein said drug is linked to said phospholipid directly. 
     
     
         40 . The method of  claim 34 , wherein said drug is linked to said phospholipid via a bridging unit. 
     
     
         41 . The method of  claim 40 , wherein said bridging unit comprises an alkylene being from 1 to 20 carbon atoms in length. 
     
     
         42 . The method of  claim 40 , wherein said alkylene is being from 3 to 6 carbon atoms in length. 
     
     
         43 . The method of  claim 34 , wherein said conjugate has a general Formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is an alkylene chain being 3-30 carbon atoms in length; 
 X is said bridging unit or absent; 
 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. 
 
     
     
         44 . The method of  claim 43 , wherein said drug comprises 5-ASA. 
     
     
         45 . The method of  claim 44 , wherein X is an alkylene chain being 3-6 carbon atoms in length. 
     
     
         46 . The method of  claim 44 , wherein R is phosphoryl choline. 
     
     
         47 . The method of  claim 44 , wherein A is an alkylene chain being 15 or 17 carbon atoms in length. 
     
     
         48 . 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. 
     
     
         49 . The composition of  claim 48 , being formulated as a liquid oral formulation. 
     
     
         50 . The composition of  claim 49 , 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. 
     
     
         51 . The composition of  claim 49 , wherein said phospholipid is a phosphoglycerol. 
     
     
         52 . The composition of  claim 51 , wherein said drug is linked to position sn-2 of said phosphoglycerol. 
     
     
         53 . The composition of  claim 49 , wherein said drug is linked to said phospholipid directly. 
     
     
         54 . The composition of  claim 49 , wherein said drug is linked to said phospholipid via a bridging unit. 
     
     
         55 . The composition of  claim 54 , wherein said bridging unit comprises an alkylene being from 1 to 20 carbon atoms in length. 
     
     
         56 . The composition of  claim 54 , wherein said alkylene is being from 3 to 6 carbon atoms in length. 
     
     
         57 . The composition of  claim 49 , wherein said conjugate has a general Formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is an alkylene chain being 3-30 carbon atoms in length; 
 X is said bridging unit or absent; 
 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. 
 
     
     
         58 . The composition of  claim 57 , wherein said drug comprises 5-ASA. 
     
     
         59 . The composition of  claim 58 , wherein X is an alkylene chain being 3-6 carbon atoms in length. 
     
     
         60 . The composition of  claim 58 , wherein R is phosphoryl choline. 
     
     
         61 . The composition of  claim 58 , wherein A is an alkylene chain being 15 or 17 carbon atoms in length. 
     
     
         62 . 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. 
     
     
         63 . The dosage form of  claim 62 , 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. 
     
     
         64 . The dosage form of  claim 62 , wherein said phospholipid is a phosphoglycerol. 
     
     
         65 . The dosage form of  claim 64 , wherein said drug is linked to position sn-2 of said phosphoglycerol. 
     
     
         66 . The dosage form of  claim 62 , wherein said conjugate has a general Formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is an alkylene chain being 3-30 carbon atoms in length; 
 X is said bridging unit or absent; 
 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. 
 
     
     
         67 . The dosage form of  claim 66 , wherein said drug comprises 5-ASA. 
     
     
         68 . The dosage form of  claim 67 , wherein X is an alkylene chain being 3-6 carbon atoms in length. 
     
     
         69 . The dosage form of  claim 67 , wherein R is phosphoryl choline. 
     
     
         70 . The dosage form of  claim 67 , wherein A is an alkylene chain being 15 or 17 carbon atoms in length. 
     
     
         71 . A process of preparing a conjugate which comprises a phospholipid having attached thereto a drug suitable for the treatment of an inflammatory bowel disease, the process comprising covalently coupling said drug to a lysophospholipid. 
     
     
         72 . A conjugate comprising a phospholipid having attached thereto 5-amino salicylic acid (5-ASA). 
     
     
         73 . The conjugate of  claim 72 , 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. 
 
     
     
         74 . An oral liquid dosage form comprising the conjugate of  claim 72 .