Liposome composition for use in peritoneal dialysis

Abstract

The present invention is directed to a liposome composition for use in the peritoneal dialysis of patients suffering from endogenous or exogenous toxicopathies, wherein the pH within the liposomes differs from the pH in the intraperitoneal cavity and wherein the pH within the liposome results in a liposome-encapsulated charged toxin. The invention also relates to a pharmaceutical composition comprising said liposomes. A further aspect of the present invention relates to a method of treating patients suffering from endogenous or exogenous toxicopathies, preferably selected from drug, metabolite, pesticide, insecticide, toxin, and chemical warfare toxicopathies, more preferably hyperammonemia, comprising the step of administering liposomes of the invention in a therapeutically effective amount into the peritoneal space of a patient in need thereof. Next to human, the present invention is particularly suitable to veterinary aspects.

1 .- 12 . (canceled) 
     
     
         13 . A method for treating a metabolite toxicopathy in a patient in need thereof by peritoneal dialysis, comprising:
 the step of administering a therapeutically effective amount of a liposome composition into the peritoneal cavity of said patient, wherein the pH within the liposomes differs from the pH in the peritoneal cavity and wherein the pH within the liposomes results in a liposome-encapsulated charged metabolite, wherein the metabolite toxicopathy is selected from the group consisting of hyperammonemia, argininosuccinic acidemia, hyperuricemia, isovaleric acidemia and propionic acidemia.   
     
     
         14 . The method according to  claim 13 , wherein said metabolite toxicopathy is hyperammonemia, isovaleric acidemia or propionic acidemia. 
     
     
         15 . The method according to  claim 14 , wherein said metabolite toxicopathy is hyperammonemia. 
     
     
         16 . The method according to  claim 13 , wherein the diameter size of the liposomes in the liposome composition is larger than 600 nm. 
     
     
         17 . The method according to  claim 16 , wherein the diameter size of the liposomes in the liposome composition is 600 nm to 10 μm, 700 nm to 10 μm, or 800 nm to 5 μm. 
     
     
         18 . The method according to  claim 13 , wherein the pH within the liposome composition is 1 to 6.5. 
     
     
         19 . The method according to  claim 18 , wherein the pH within the liposome composition is 1.5 to 5. 
     
     
         20 . The method according to  claim 19 , wherein the pH within the liposome composition is 1.5 to 4. 
     
     
         21 . The method according to  claim 13 , wherein the pH within the liposome composition is 8.5 to 12. 
     
     
         22 . The method according to  claim 21 , wherein the pH within the liposome composition is 9 to 11. 
     
     
         23 . The method according to  claim 22 , wherein the pH within the liposome composition is 9 to 10. 
     
     
         24 . The method according to  claim 13 , wherein the liposomes in the liposome composition are uni- and/or multilamellar, and comprise at least one of:
 (i) 1 to 100 mol % physiologically acceptable phospholipids;   (ii) 1 to 100 mol % sphingolipids;   (iii) 1 to 100 mol % surfactants;   (iv) 5 to 100 mol % amphiphilic polymers and/or copolymers;   (v) 0 to 60 mol % toxin retention-enhancing compounds; or   (vi) 0 to 30 mol % steric stabilizers.   
     
     
         25 . The method according to  claim 24 , wherein the physiologically acceptable phospholipids are selected from the group consisting of DLPC, DMPC, DPPC, DSPC, DOPC, DMPE, DPPE, DSPE, DOPE, MPPC, PMPC, SPPC, PSPC, DMPG, DPPG, DSPG, DOPG, DMPA, DPPA, DPPS, EPC, and SPC. 
     
     
         26 . The method according to  claim 24 , wherein the sphingolipids comprise sphingomyelin. 
     
     
         27 . The method according to  claim 24 , wherein the surfactants are selected from the group consisting of hydrophobic alkyl ethers, alkyl esters, polysorbates, spans, and alkyl amides. 
     
     
         28 . The method according to  claim 24 , wherein the amphiphilic polymers and/or copolymers are selected from the group consisting of block copolymers comprising at least one block of a hydrophilic polymer or copolymer, and at least one block of a hydrophobic polymer or copolymer. 
     
     
         29 . The method according to  claim 28 , wherein the at least one block of a hydrophilic polymer or copolymer comprises polyethylene glycol (PEG). 
     
     
         30 . The method according to  claim 24 , wherein the toxin retention-enhancing compounds are selected from the group consisting of cholesterol and sterol derivatives. 
     
     
         31 . The method according to  claim 24 , wherein the steric stabilizers are selected from the group consisting of PEGylated compounds, PEGylated lipids, and DSPE-PEG. 
     
     
         32 . The method according to  claim 24 , wherein the liposome bilayer comprises:
 (i) 50 to 60 mol % 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC),   (ii) 40 to 50 mol % cholesterol (CHOL), and   (iii) 0.5 to 2 mol % 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG),   wherein the aqueous solution within the liposomes comprises 250 mM citrate solution buffered at pH 1.5 to 3,   and wherein the diameter of the liposomes is 800 nm or larger.   
     
     
         33 . The method according to  claim 32 , wherein the liposome bilayer comprises about 54 mol % DPPC. 
     
     
         34 . The method according to  claim 32 , wherein the liposome bilayer comprises about 45 mol % CHOL. 
     
     
         35 . The method according to  claim 32 , wherein the liposome bilayer comprises about 1 mol % DSPE-PEG. 
     
     
         36 . The method according to  claim 32 , wherein the aqueous solution within the liposomes comprises 250 mM citrate solution buffered at pH 2. 
     
     
         37 . The method according to  claim 32 , wherein the diameter of the liposomes is 900 nm or larger. 
     
     
         38 . The method according to  claim 32 , wherein the diameter of the liposomes is 1000 nm or larger. 
     
     
         39 . The method according to  claim 13 , wherein the bilayer of the liposomes comprises:
 (i) 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC),   (ii) cholesterol (CHOL), and   (iii) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG),   wherein the diameter of the liposomes is 800 nm or larger.   
     
     
         40 . The method according to  claim 39 , wherein the aqueous solution within the liposomes comprises a citrate solution buffered at pH 1.5 to 3. 
     
     
         41 . The method according to  claim 39 , wherein the bilayer of the liposome comprises 0.5 to 2 mol % of DSPE-PEG. 
     
     
         42 . The method according to  claim 39 , wherein the diameter of the liposomes is 900 nm or larger. 
     
     
         43 . The method according to  claim 42 , wherein the diameter of the liposomes is 1000 nm or larger. 
     
     
         44 . The method according to  claim 13 , wherein the patient in need thereof is a human. 
     
     
         45 . The method according to  claim 13 , wherein the patient in need thereof is a mammal or a bird. 
     
     
         46 . The method according to  claim 45 , wherein the mammal is selected from the group consisting of swine, cattle, dog, cat, sheep, goat and horse.