Method for treating a metabolite toxicopathy
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. A method for treating a metabolite toxicopathy in a patient in need thereof, 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, wherein the pH within the liposomes results in liposomes-encapsulated charged metabolite, wherein the metabolite toxicopathy is selected from the group consisting of hyperammonemia, argininosuccinic acidemia, hyperuricemia, isovaleric acidemia and propionic acidemia, and wherein the liposome composition comprises liposomes having a diameter size larger than 600 nm; and
the step of extracting the liposomes-encapsulated charged metabolite from the peritoneal cavity.
2. The method according to claim 1 , wherein said metabolite toxicopathy is hyperammonemia, isovaleric acidemia or propionic acidemia.
3. The method according to claim 2 , wherein said metabolite toxicopathy is hyperammonemia.
4. The method according to claim 1 , wherein the liposome composition comprises liposomes having a diameter size of larger than 600 nm and up to 10 μm, of 700 nm to 10 μm, or of 800 nm to 5 μm.
5. The method according to claim 1 , wherein the pH within the liposomes is 1 to 6.5.
6. The method according to claim 5 , wherein the pH within the liposomes is 1.5 to 5.
7. The method according to claim 6 , wherein the pH within the liposomes is 1.5 to 4.
8. The method according to claim 1 , wherein the pH within the liposomes is 8.5 to 12.
9. The method according to claim 8 , wherein the pH within the liposomes is 9 to 11.
10. The method according to claim 9 , wherein the pH within the liposomes is 9 to 10.
11. The method according to claim 1 , 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.
12. The method according to claim 11 , 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.
13. The method according to claim 11 , wherein the sphingolipids comprise sphingomyelin.
14. The method according to claim 11 , wherein the surfactants are selected from the group consisting of hydrophobic alkyl ethers, alkyl esters, polysorbates, sorbitan esters, and alkyl amides.
15. The method according to claim 11 , 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.
16. The method according to claim 15 , wherein the at least one block of a hydrophilic polymer or copolymer comprises polyethylene glycol (PEG).
17. The method according to claim 11 , wherein the toxin retention-enhancing compounds are selected from the group consisting of cholesterol and sterol derivatives.
18. The method according to claim 11 , wherein the steric stabilizers are selected from the group consisting of PEGylated compounds, PEGylated lipids, and DSPE-PEG.
19. The method according to claim 11 , wherein the liposome composition comprises liposomes having a diameter of 800 nm or larger.
20. The method according to claim 19 , wherein the liposome composition comprises liposomes having a diameter size of 900 nm or larger.
21. The method according to claim 19 , wherein the liposome composition comprises liposomes having a diameter size of 1000 nm or larger.
22. The method according to claim 1 , 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 liposome composition comprises liposomes having a diameter of 800 nm or larger.
23. The method according to claim 22 , wherein the aqueous solution within the liposomes comprises a citrate solution buffered at pH 1.5 to 3.
24. The method according to claim 22 , wherein the bilayer of the liposomes comprises 0.5 to 2 mol % of DSPE-PEG.
25. The method according to claim 24 , wherein the liposome composition comprises liposomes having a diameter size of 900 nm or larger.
26. The method according to claim 25 , wherein the liposome composition comprises liposomes having a diameter size of 1000 nm or larger.
27. The method according to claim 11 , wherein the physiologically acceptable phospholipid is DPPC, the toxin retention-enhancing compound is cholesterol, and the steric stabilizer is DSPE-PEG.
28. The method according to claim 1 , wherein the bilayer of the liposomes comprises: (i) 1 to 100 mol % of DPPC; (ii) 0 to 60 mol % of cholesterol; and (iii) 0 to 30 mol % of DSPE-PEG.
29. The method according to claim 28 , wherein the bilayer of the liposomes comprises: (i) 10 to 100 mol % of DPPC; (ii) 0 to 60 mol % of cholesterol; and (iii) 0.5 to 2% mol % of DSPE-PEG.
30. The method according to claim 1 , wherein the patient in need thereof is a human.
31. The method according to claim 1 , wherein the patient in need thereof is a mammal or a bird.
32. The method according to claim 31 , wherein the mammal is selected from the group consisting of swine, cattle, dog, cat, sheep, goat and horse.