Liposomes useful for drug delivery

Patent metadata

Field	Value
Publication number	US-9717723-B2
Application number	US-201514632422-A
Country	US
Kind code	B2
Filing date	Feb 26, 2015
Priority date	May 3, 2004
Publication date	Aug 1, 2017
Grant date	Aug 1, 2017

Abstract

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.

First claim

What is claimed is:

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 r

Assignees

• Ipsen Biopharm Ltd

Inventors

• Hong Keelung
• Drummond Daryl C
• Kirpotin Dmitri

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61K9/127 Primary

  Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant · CPC title