Phosphatidyl oligoglycerols

Abstract

In order to form liposomes with a longer half-life in blood, use is made of defined compounds with the general formula (A)

1 . A compound with the general formula (A)  
       
         
           
           
               
               
           
         
       
       where R 1  and R 2,  independent of each other, stand for hydrogen or a saturated or unsaturated alkyl or acyl residue, which may be branched and/or substituted, R 3  stands for hydrogen or an alkyl residue, 
 n=0 or 1,  
 x is a whole number from 1 to 4 and  
 m is a whole number from 2 to 10 if n=0, or a whole number from 1 to 10 if n=1, or 1 if x is greater than 1,  
 and where, in the case that n=0, the compound is more than 90% uniform with respect to the value of m.  
 
     
     
         2 . The compound of  claim 1 , 
 wherein,    in the case that n=0, the compound is more than 95% uniform with respect to the value of m.    
     
     
         3 . The compound of  claim 1  or  2 , 
 wherein,  
 in the case that n=0, the compound is more than 99% uniform with respect to the value of m.  
 
     
     
         4 . A compound according to one of  claims 1  to  3 , 
 wherein  
 x=1 and m is a whole number from 2 to 5.  
 
     
     
         5 . A compound according to one of  claims 1  to  4 , 
 wherein  
 x=1 and m is a whole number from 2 to 4.  
 
     
     
         6 . A compound according to one of the preceding claims, 
 wherein,    in formula (A), R 1  and R 2 , independent of each other, stand for hydrogen, a saturated or unsaturated C 1 -C 24  alkyl or C 1 -C 24  acyl residue.    
     
     
         7 . A compound according to one of the preceding claims, 
 wherein    said compound contains a phospho-rac-(1 or 3)-oligoglycerol linkage.    
     
     
         8 . A compound according to one of  claims 1  to  6 , 
 wherein  
 said compound contains a phospho-sn-1-oligoglycerol linkage.  
 
     
     
         9 . A compound according to one of  claims 1  to  6 , 
 wherein  
 said compound contains a phospho-sn-3-oligoglycerol linkage.  
 
     
     
         10 . A compound according to one of  claims 1  to  9 , 
 wherein  
 at least one of the residues R 1  and R 2  is an acyl residue.  
 
     
     
         11 . Liposomes, 
 wherein    said liposomes contain phospholipids and/or alkyl phospholipids, maybe cholesterol, and 1 to 50 mol % of a compound with the general formula (A),                          or salts thereof, where the cholesterol, the phospholipids, the alkyl phospholipids and the compound of formula (A) together make up 100 mol %, and R 1  and R 2 , independent of each other, stand for hydrogen, a saturated or unsaturated alky or acyl residue which may be branched and/or substituted,    R 3  stands for hydrogen or an alkyl residue,    n=0 or 1,    x is a whole number from 1 to 4 and    m is a whole number from 2 to 10 if n=0, or a whole number from 1 to 10 if n=1, or 1 if x is greater than 1, and where, in the case that n=0, the compound (A) is more than 90% uniform with respect to the value of m.    
     
     
         12 . The liposomes of  claim 11 , 
 wherein,    in the case that n=0, the compound (A) is more than 95% uniform with respect to the value of m.    
     
     
         13 . The liposomes of  claim 11  or  12 , 
 wherein,  
 in the case that n=0, the compound (A) is more than 99% uniform with respect to the value of m.  
 
     
     
         14 . Liposomes according to one of  claims 11  to  13 , 
 wherein  
 said liposomes contain 5 to 15 mol % of the compound of formula (A), with the cholesterol, the phospholipids, the alkyl phospholipids and the compound of formula (A) together making up 100 mol %.  
 
     
     
         15 . Liposomes according to one of  claims 11  to  14 , 
 wherein,  
 in formula (A), x=1 and m is a whole number from 2 to 5.  
 
     
     
         16 . Liposomes according to one of  claims 11  to  15 , 
 wherein,  
 in formula (A), x=1 and m is a whole number from 2 to 4.  
 
     
     
         17 . Liposomes according to one of  claims 11  to  16 , 
 wherein,  
 in formula (A), R 1  and R 2 , independent of each other, stand for hydrogen, or a saturated or unsaturated C 1 -C 24  alkyl or C 1 -C 24  acyl residue.  
 
     
     
         18 . Liposomes according to one of  claims 11  to  17 , 
 wherein  
 the compound of formula (A) has a phospho-rac-(1 or 3)-oligoglycerol linkage.  
 
     
     
         19 . Liposomes according to one  claims 11  to  17 , 
 wherein  
 the compound of formula (A) has a phospho-sn-1 -oligoglycerol linkage.  
 
     
     
         20 . Liposomes according to one of  claims 11  to  17 , 
 wherein  
 the compound of formula (A) has a phospho-sn-3-oligoglycerol linkage.  
 
     
     
         21 . Liposomes according to one of  claims 11  to  20 , 
 wherein,  
 in formula (A), at least one of the residues R 1  and R 2  is an acyl group.  
 
     
     
         22 . Liposomes according to one of  claims 11  to  21 , 
 wherein,  
 in formula (A), n=0.  
 
     
     
         23 . Liposomes according to one of  claims 11  to  22 , 
 wherein  
 said liposomes have an excess negative charge.  
 
     
     
         24 . Liposomes according to one of  claims 11  to  21 , 
 wherein,  
 in formula (A), n=1.  
 
     
     
         25 . The liposomes of  claim 24 , 
 wherein    said liposomes have no excess charge.    
     
     
         26 . The liposomes of  claim 24 , 
 wherein    said liposmes have an excess positive charge.    
     
     
         27 . Liposomes according to one of  claims 11  to  26 , 
 wherein  
 said liposomes contain 0 to 70 mol % cholesterol, 1 to 50 mol % of a compound of general formula (A), in which n=1, and phospholipids and/or alkyl phospholipids, and these components together make up 100-mol %.  
 
     
     
         28 . Liposomes according to one of  claims 11  to  26 , 
 wherein  
 said liposomes contain 0 to 70 mol % cholesterol, 1 to 15 mol % of a compound of general formula (A), in which n=0, and phospholipids and/or alkyl phospholipids, and these components together make up 100 mol %.  
 
     
     
         29 . Liposomes according to one of  claims 11  to  28 , 
 wherein  
 said liposomes contain 25 to 43 mol % cholesterol, 5 to 15 mol % of a compound of general formula (A), and phospholipids and/or alkyl phospholipids.  
 
     
     
         30 . Liposomes according to one of the preceding claims, 
 wherein    said liposomes contain 38 to 42 mol % cholesterol.    
     
     
         31 . Liposomes according to one of  claims 11  to  30 , 
 wherein  
 the residue —CH 2 (—CHOH) x —CH 2 —OH derives from sugar alcohols which have four hydroxyl groups for x 2, five hydroxyl groups for x 3 and six hydroxyl groups for x =4.  
 
     
     
         32 . Liposomes according to one of  claims 11  to  31 , 
 wherein  
 after 6 hours, more than 50% of the liposomes added are present in the blood.  
 
     
     
         33 . Liposomes according to one of  claims 11  to  32 , 
 wherein  
 after 6 hours, more than 60% of the liposomes added are present in the blood.  
 
     
     
         34 . Liposomes according to one of  claims 11  to  33 , 
 wherein  
 their half-life in blood is at least 10 h.  
 
     
     
         35 . Liposomes according to one of  claims 11  to  34 , 
 wherein  
 said liposomes contain, in addition, one or more pharmaceutical drugs.  
 
     
     
         36 . A pharmaceutical composition, 
 wherein    said composition contains liposomes according to one of  claims 11  to  35  and, entrapped in the liposomes, one or more pharmaceutical drugs, combined if necessary with standard pharmaceutical diluents, adjuvants, carrier media and fillers.    
     
     
         37 . A method of preparing liposomes according to one of  claims 11  to  35 , 
 wherein  
 1 to 50 mol % of a compound of general formula (A), together with the other components of the liposomes in a quantity which, together with the compound of formula (A) makes up 100 mol %, are transformed into a lipid suspension and the lipid suspension, in turn, is transformed into liposomes by means of suitable measures and in a manner known per se.  
 
     
     
         38 . The method of  claim 37 , 
 wherein    5 to 15 mol % of a compound of general formula (A), together with 35 to 43 mol % cholesterol and 42 to 60 mol % phospholipids and/or alkyl phospholipids are transformed into a lipid suspension and the lipid suspension, in turn, is transformed into liposomes by means of suitable measures and in a manner known per se.    
     
     
         39 . A method of preparing a pharmaceutical formulation as claimed in  claim 36 , 
 wherein    one proceeds according to the method of  claim 37  or  38 , water-insoluble drugs being entrapped by dissolving the drug together with the lipid constituents, and water-soluble drugs being entrapped by adding an aqeous solution which contains the water-soluble drug to the lipid film.    
     
     
         40 . A method of preparing a compound as claimed in one of  claims 1  to  10 , in which n equals 1, 
 wherein  
 a defined oligoglycerol is linked by way of the amino group with a phosphatidyl ethanolamine.  
 
     
     
         41 . A method of preparing a compound as claimed in one of  claims 1  to  10 , in which n equals 0, 
 wherein  
 a defined oligoglycerol is linked with a phosphatidylglycerol.  
 
     
     
         42 . A method of preparing a compound as claimed in one of  claims 1  to  10 , 
 wherein  
 a defined oligoglycerol or a C 4 -C 6  sugar alcohol is linked with an alcohol of the formula CH 2 OR 1 —CHOR 2 —CHOH through use of a phosphorylation agent, R 1  and R 2  having the meanings given in  claim 1 .  
 
     
     
         43 . The method of  claim 42 , 
 wherein    POCl 3  is used as phosphorylation agent.    
     
     
         44 . A method according to one of  claims 40  to  43 , 
 wherein  
 a phospho-rac-(1 or 3)-oligoglycerol linkage is formed.  
 
     
     
         45 . A method according to one of  claims 40  to  43 , 
 wherein  
 a stereospecific compound is formed.  
 
     
     
         46 . A method according to one of  claims 40  to  43  and  45 , 
 wherein  
 a phospho-sn-1-oligoglycerol linkage is formed.  
 
     
     
         47 . A method according to one of  claims 40  to  43  and  45 , 
 wherein  
 a phospho-sn-3-oligoglycerol linkage is formed.  
 
     
     
         48 . A method according to one of  claims 40  to  47 , 
 wherein  
 a linear oligoglycerol of defined chain length is used.  
 
     
     
         49 . A protected oligoglycerol with the formula (B),  
       
         
           
           
               
               
           
         
       
       in which Y is a whole number from 1 to 9 and X is a benzyl, alkyl or tetrahydropropanyl group.  
     
     
         50 . The protected oligoglycerol of  claim 49 , 
 wherein    Y is a whole number from 1 to 3.    
     
     
         51 . A protected oligoglycerol according to  claim 49  or 50, 
 wherein  
 the compound is a uniform one of defined structure.  
 
     
     
         52 . Use of a protected oligoglycerol as claimed in  claims 49  to  51  for preparing a compound of formula (A).  
     
     
         53 . An alkyl oligoglycerol with the formula (C)  
       
         
           
           
               
               
           
         
       
       in which Y is a whole number from 0 to 8 and one of the residues X or Z is a saturated or unsaturated alkyl residue, while the other residue is hydrogen.  
     
     
         54 . The alkyl oligoglycerol of  claim 53 , 
 wherein    Y is a whole number from 1 to 3.    
     
     
         55 . The alkyl oligoglycerol of  claim 53  or  54 , 
 wherein  
 the compound is a uniform one of defined structure.