Lipid-based drug delivery systems against parasitic infections

Abstract

The present invention is directed to a lipid-based delivery system for administration of an active drug substance selected from lysolipid derivatives which are particularly useful in the treatment or detection of parasitic infections, especially parasitic infections which causes an elevated PLA 2 level in the infected mammal. Preferred parasitic infection are infections wherein the life cycle of the parasite involves the liver and/or spleen of the infected organism.

1 - 35 . (canceled)  
   
   
       36 . A method for the treatment of parasitic infections of a mammal, preferably a human, said parasitic infection being characterised by increasing the PLA 2  level in said mammal by administering to the mammal an efficient amount of a lipid-based drug delivery system comprising an active drug substance selected from lysolipid derivatives, wherein the active drug substance is present in the lipid-based system in the form of a prodrug, said prodrug being a lipid derivative having (a) an aliphatic group of a length of at least 7 carbon atoms and an organic radical having at least 7 carbon atoms, and (b) a hydrophilic moiety, said prodrug furthermore being a substrate for extracellular phospholipase A2 to the extent that the organic radical can be hydrolytically cleaved off, whereas the aliphatic group remains substantially unaffected, whereby the active drug substance is liberated in the form of a lysolipid derivative which is not a substrate for lysophospholipase.  
   
   
       37 . A method according to  claim 36 , wherein the increased level of PLA 2  is localized to a specific tissue and/or organ of the mammal, said tissue and/or organ being infected by the parasite.  
   
   
       38 . A method according to  claim 36 , wherein the parasitic infection involves the liver and/or the spleen of the mammal.  
   
   
       39 . A method according to  claim 36 , wherein the organic radical which can be hydrolytically cleaved off, is an auxiliary drug substance or an efficiency modifier for the active drug substance.  
   
   
       40 . A method according to  claim 36 , wherein the prodrug is a lipid derivative of the following formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 X and Z independently are selected from O, CH 2 , NH, NMe, S, S(O), and S(O) 2 ;  
 Y is —OC(O)—, Y then being connected to R 2  via either the oxygen or carbonyl carbon atom;  
 R 1  is an aliphatic group of the formula Y 1 Y 2 ;  
 R 2  is an organic radical having at least 7 carbon atoms;  
 where Y 1  is —(CH 2 ) n1 —(CH═CH) n2 —(CH 2 ) n3 —(CH═CH) n4 —(CH 2 ) n5 —(CH═CH) n6 —(CH 2 ) n7 —(CH═CH) n8r —(CH 2 ) n9 , and the sum of n1+2n2+n3+2n4+n5+2n6+n7+2n8+n9 is an integer of from 9 to 29; n1 is zero or an integer of from 1 to 29, n3 is zero or an integer of from 1 to 20, n5 is zero or an integer of from 1 to 17, n7 is zero or an integer of from 1 to 14, and n9 is zero or an integer of from 1 to 11; and each of n2, n4, n6 and n8 is independently zero or 1; and Y 2  is CH 3  or CO 2 H; where each Y 1 —Y 2  independently may be substituted with halogen or C 1-4 -alkyl,  
 R 3  is selected from phosphatidic acid (P0 2 —OH), derivatives of phosphatidic acid and bioisosters to phosphatic acid and derivatives thereof.  
 
   
   
       41 . A method according to  claim 40 , wherein R 2  is an aliphatic group of a length of at least 7 carbon atoms.  
   
   
       42 . A method according to  claim 41 , wherein R 2  is a group of the formula Y 1 Y 2 .  
   
   
       43 . A method according to  claim 36 , wherein at least a fraction of the prodrug is of the formula defined in  claim 40 , wherein R 3  is a derivative of phosphatidic acid to which a polymer selected from polyethylene glycol, poly(lactic acid), poly(glycolic acid), poly(lactic acid)-poly(glycolic acid) copolymers, polyvinyl alcohol, polyvinylpyrrolidone, polymethoxazoline, polyethyloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide, polydimethylacrylamide, and derivatised celluloses, is covalently attached.  
   
   
       44 . A method according to  claim 36 , wherein the prodrug constitutes 15-100 mol % of the total dehydrated lipid-based system.  
   
   
       45 . A method according to  claim 36 , wherein the lipopolymer, if present, constitutes 0.110 mol % of the total dehydrated system.  
   
   
       46 . A method according to  claim 36 , wherein the lipid-based system is in the form of liposomes.  
   
   
       47 . A method according to  claim 36  which is in the form of liposomes wherein a second drug substance is incorporated.  
   
   
       48 . A method according to  claim 47 , wherein the second drug substance is a therapeutically and/or prophylactically active substance selected from (i) anti-parasitic agents, (ii) antibiotics and antifungals, and (iii) antiinflammatory agents.  
   
   
       49 . A method according to  claim 36 , wherein the parasitic infection is caused by a parasitic organism selected from the group consisting of  Leishmania, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Entamoeba histolytica  and  Chlornorchis sinensis.    
   
   
       50 . A method according to  claim 36  for systemic treatment.  
   
   
       51 . A method according to  claim 50  for intravenous administration.  
   
   
       52 - 66 . (canceled)  
   
   
       67 . A method for detecting or quantifying parasitic infections of a mammal, preferably a human, said parasitic infection being characterised by increasing the PLA 2  level in said mammal, by administering to the mammal an efficient amount of a lipid based drug delivery system comprising a second substance which is a label, said system including lipid derivatives which has (a) an aliphatic group of a length of at least 7 carbon atoms and an organic radical having at least 7 carbon atoms, and (b) a hydrophilic moiety, where the lipid derivative furthermore is a substrate for extracellular phospholipase A2 to the extent that the organic radical can be hydrolytically cleaved off, whereas the aliphatic group remains substantially unaffected, so as to result in an organic acid fragment or an organic alcohol fragment and a lysolipid fragment, said lysolipid fragment not being a substrate for lysophospholipase and said second substance being a label.  
   
   
       68 . A method according to  claim 67 , wherein the increased level of PLA 2  is localized to a specific tissue and/or organ of the mammal, said tissue and/or organ being infected by the parasite.  
   
   
       69 . A method according to  claim 67 , wherein the parasitic infection involves the liver and/or the spleen of the mammal.  
   
   
       70 . A method according to  claim 67 , wherein the lipid derivative is a lipid derivative of the following formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 X and Z independently are selected from O, CH 2 , NH, NMe, S, S(O), and S(O) 2 ;  
 Y is —OC(O)—, Y then being connected to R 2  via either the oxygen or carbonyl carbon atom;  
 R 1  is an aliphatic group of the formula Y 1 Y 2 ;  
 R 2  is an organic radical having at least 7 carbon atoms;  
 where Y 1  is —(CH 2 ) n1 —(CH═CH) n2 —(CH 2 ) n3 (CH═CH) n4 —(CH 2 ) n5 —(CH═CH) n6 —(CH 2 ) n7 —(CH═CH) n8r —(CH 2 ) n9 , and the sum of n1+2n2+n3+2n4+n5+2n6+n7+2n8+n9 is an integer of from 9 to 29; n1 is zero or an integer of from 1 to 29, n3 is zero or an integer of from 1 to 20, n5 is zero or an integer of from 1 to 17, n7 is zero or an integer of from 1 to 14, and n9 is zero or an integer of from 1 to 11; and each of n2, n4, n6 and n8 is independently zero or 1; and y 2  is CH 3  or CO 2 H; where each Y 1 —Y 2  independently may be substituted with halogen or C 1-4 -alkyl,  
 R 3  is selected from phosphatidic acid (P0 2 —OH), derivatives of phosphatidic acid and bioisosters to phosphatic acid and derivatives thereof.  
 
   
   
       71 . A method according to  claim 70 , wherein R 2  is an aliphatic group of a length of at least 7 carbon atoms.  
   
   
       72 . A method according to  claim 70 , wherein R 2  is a group of the formula Y 1 Y 2 .  
   
   
       73 . A method according to  claim 67 , wherein at least a fraction of the prodrug is of the formula defined in  claim 70 , wherein R 3  is a derivative of phosphatidic acid to which a polymer selected from polyethylene glycol, poly(lactic acid), poly(glycolic acid), poly(lactic acid)-poly(glycolic acid) copolymers, polyvinyl alcohol, polyvinylpyrrolidone, polymethoxaoline, polyethyloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide, polydimethylacrylamide, and derivatised celluloses, is covalently attached.  
   
   
       74 . A method according to  claim 67 , wherein the lipid derivative constitutes 15-100 mol % of the total dehydrated system.  
   
   
       75 . A method according to  claim 67 , wherein the lipopolymer, if present, constitutes 0.110 mol % of the total dehydrated system.  
   
   
       76 . A method according to  claim 67 , wherein the system is in the form of liposomes.  
   
   
       77 . A method according to  claim 67 , wherein the parasitic infection is caused by a parasitic organism selected from the group consisting of  Leishmania major  Friedlin,  Leishmania  ( viannia ) gr.,  Leishmania mexicana, Leishmania tropica, Leishmania donovani  ( infantum ),  Leishmania aethiopica, Leishmania amazonensis, Leishmania enriettii, Leishmania chagasi Leishmania pifanoi, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, Trypanosoma cruzi  (causing Chargas' disease),  Trypanosoma brucei, Trypanosoma equiperdum, Trypanosoma evansi Entamoeba histolytica  and  Chlomorchis sinensis.    
   
   
       78 . A method according to  claim 67  for systemic treatment.  
   
   
       79 . A method according to  claim 78  for intravenous administration.  
   
   
       80 . A method according to  claim 67 , wherein the label is selected from the group consisting of  111 In,  99m Tc,  67 Ga,  11 C; Gd, Mn, iron oxide, argon, nitrogen, Iodine, bromine and barium.