Liposomes useful for drug delivery
The present invention provides liposome compositions containing substituted ammonium and/or polyanion, and optionally with a desired therapeutic or imaging entity. The present invention also provides methods of making the liposome compositions provided by the present invention.
1. A method of preparing a liposomal irinotecan composition, the method comprising contacting, in an aqueous medium,
a liposome comprising sucrose octasulfate and a substituted ammonium compound encapsulated within an aqueous interior space separated from the aqueous medium by a membrane comprised of one or more lipids;
with an irinotecan cationic antineoplastic agent;
wherein the substituted ammonium is a compound of formula: R 1 —(R 2 —)N + (—R 3 )—R 4 ,
wherein N is a an ammonium nitrogen atom, each of R 1 , R 2 , R 3 , R 4 is independently a hydrogen atom or an organic group having each independently not more than 8 carbon atoms, and in totality not more than 18 carbon atoms inclusive, wherein at least one of R 1 , R 2 , R 3 , R 4 is an organic group; wherein the organic group is independently alkyl, alkylidene, heterocyclic alkyl, cycloalkyl, aryl, alkenyl, cycloalkenyl, or a hydroxy-substituted derivative thereof, optionally including S, O, or N atoms forming an ether, ester, thioether, amine, or amide bond; and wherein at least three of R 1 , R 2 , R 3 , R 4 are the organic groups; or at least one of the organic groups has a secondary or tertiary carbon atom directly linked to the ammonium nitrogen atom; and
wherein the contacting is carried out for a time sufficient for the irinotecan antineoplastic agent to become encapsulated within the liposome as irinotecan sucrose octasulfate.
2. The method of claim 1 wherein said substituted ammonium compound is selected from the group consisting of isopropylethylammonium, isopropylmethylammonium, diisopropylammonium, tert-butylethylammonium, dicyclo-hexylammonium, morpholinium, pyridinium, piperidinium, pyrrolidinium, piperazinium, tert-butylammonium, 2-ammonio-2-methyl-propano-1,2-ammonio-2-methyl-propandiol-1,3, tris-(hydroxyethyl)-ammoniomethane, N,N′-diethyl-ethanolammonium, N,N′,N″-tris-(2-hydroxyethyl)ammonium, N,N′-bis-(2-hydroxyethyl)ethylammonium, trimethyl-ammonium, triethylammonium, diethylmethyl-ammonium, diisopropylethylammonium, triisopropylammonium, N-methyl-morpholinium, 1-(2-hydroxyethyl)piperidinium, 1-methylpyrrolidinium, 1,4-dimethyl-piperazinium, tetramethylammonium, tetraethyl-ammonium, and tetrabutylammonium.
3. The method of claim 1 wherein said substituted ammonium compound is diethylammonium or triethylammonium.
4. The method of claim 3 wherein the lipids comprise a neutral PEG-lipid derivative or an anionic PEG-lipid derivative.
5. The method of claim 4 wherein the composition is a fluid pharmaceutical formulation for parenteral administration.
6. The method of claim 1 wherein the composition is a fluid pharmaceutical formulation for parenteral administration.
7. A method of preparing a liposomal irinotecan composition, the method comprising
contacting liposomes comprising sucrose octasulfate, a substituted ammonium compound and one or more phospholipids, with irinotecan for a time and under conditions sufficient to load a total of 150-550 mg irinotecan per mmol total liposome phospholipids into the liposomes, while removing at least a portion of the substituted ammonium compound from the liposomes,
to form irinotecan liposomes comprising irinotecan sucrose octasulfate and having a volume-averaged mean of the liposome size distribution of approximately 110-120 nm determined by quasi-elastic light scattering (QELS) using Gaussian model,
wherein the substituted ammonium compound comprises an alkyl, alkylidene, heterocyclic alkyl, cycloalkyl, aryl, alkenyl, cycloalkenyl, or a hydroxy-substituted derivative thereof, optionally including S, O, or N atoms forming an ether, ester, thioether, amine, or amide bond.
8. The method of claim 7 , further comprising heating the liposomes above the transition temperature of the liposome lipids while loading the irinotecan into the liposomes.
9. The method of claim 8 , further comprising reducing the temperature of the liposomes below the phase transition temperature of the liposome lipids after loading the irinotecan into the liposomes.
10. The method of claim 9 , wherein the substituted ammonium is a compound of formula: R 1 —(R 2 —)N + (—R 3 )—R 4 , wherein N is a an ammonium nitrogen atom, each of R 1 , R 2 , R 3 , R 4 is independently a hydrogen atom or an organic group having each independently not more than 8 carbon atoms, and in totality not more than 18 carbon atoms inclusive, wherein at least one of R 1 , R 2 , R 3 , R 4 is an organic group; wherein the organic group is independently alkyl, alkylidene, heterocyclic alkyl, cycloalkyl, aryl, alkenyl, cycloalkenyl, or a hydroxy-substituted derivative thereof, optionally including S, O, or N atoms forming an ether, ester, thioether, amine, or amide bond; and wherein at least three of R 1 , R 2 , R 3 , R 4 are the organic groups; or at least one of the organic groups has a secondary or tertiary carbon atom directly linked to the ammonium nitrogen atom.
11. The method of claim 7 , wherein the irinotecan is loaded into the liposomes with an entrapment efficiency of at least 85%.
12. The method of claim 11 , wherein the liposomes comprise a neutral PEG-lipid derivative or an anionic PEG-lipid derivative.
13. The method of claim 12 , wherein said substituted ammonium compound is diethylammonium or triethylammonium.
14. A method of preparing a liposomal irinotecan composition comprising irinotecan liposomes comprising one or more phospholipids and a total of 150-550 mg irinotecan per mmol total liposome phospholipids and a volume-averaged mean of the liposome size distribution of approximately 110-120 nm determined by quasi-elastic light scattering (QELS) using Gaussian model, the method comprising: contacting, in an aqueous medium, liposomes comprising sucrose octasulfate, a substituted ammonium compound and one or more phospholipids with irinotecan above the transition temperature of the liposome phospholipids for a time and under conditions sufficient to load the irinotecan into the liposomes with an entrapment efficiency of at least 85% while removing at least a portion of the substituted ammonium compound from the liposomes, to form irinotecan liposomes comprising irinotecan sucrose octasulfate.
15. The method of claim 14 , wherein the substituted ammonium is a compound of formula: R 1 —(R 2 —)N + (—R 3 )—R 4 ,
wherein N is a an ammonium nitrogen atom, each of R 1 , R 2 , R 3 , R 4 is independently a hydrogen atom or an organic group having each independently not more than 8 carbon atoms, and in totality not more than 18 carbon atoms inclusive, wherein at least one of R 1 , R 2 , R 3 , R 4 is an organic group; wherein the organic group is independently alkyl, alkylidene, heterocyclic alkyl, cycloalkyl, aryl, alkenyl, cycloalkenyl, or a hydroxy-substituted derivative thereof, optionally including S, O, or N atoms forming an ether, ester, thioether, amine, or amide bond; and wherein at least three of R 1 , R 2 , R 3 , R 4 are the organic groups; or at least one of the organic groups has a secondary or tertiary carbon atom directly linked to the ammonium nitrogen atom.
16. The method of claim 14 , wherein the irinotecan liposomes comprise cholesterol and a lecithin.
17. The method of claim 14 , wherein the irinotecan liposomes comprise cholesterol, a lecithin and a PEGylatated lipid.
18. The method of claim 14 , wherein the irinotecan liposomes comprise DSPC and cholesterol and methoxy-PEG(2000)-DSPE in a 3:2:0.015 mole ratio.
19. The method of claim 14 , wherein the irinotecan liposomes comprise DSPC, and cholesterol in a 3:2 mole ratio.