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|Title:||Liposomes useful for drug delivery|
|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.|
|Inventor(s):||Hong; Keelung (San Francisco, CA), Drummond; Daryl C. (Pacifica, CA), Kirpotin; Dmitri (San Francisco, CA)|
|Assignee:||Merrimack Pharmaceuticals, Inc. (Cambridge, MA)|
1. A liposomal composition comprising liposomes in an aqueous medium, the liposomes having an interior aqueous space separated from the aqueous medium by a membrane
comprising 1,2-distearoyl-SN-phosphatidylcholine, cholesterol and N-(omega-methoxy-poly(ethylene glycol)-oxycarbonyl)-1,2-distearoylphosphatidyl ethanolamine, and entrapped inside the liposomes are either: 1) irinotecan and sucrose octasulfate, or 2)
irinotecan, sucrose octasulfate and a substituted ammonium compound; wherein, the irinotecan entrapped inside the liposomes is at a concentration that exceeds the concentration of the irinotecan in the aqueous medium.
2. The liposomal composition of claim 1, where irinotecan, sucrose octasulfate, and substituted ammonium compound are entrapped inside the liposomes and wherein the substituted ammonium compound has a formula: R.sub.1--(R.sub.2--)N.sup.+(--R.sub.3)--R.sub.4, wherein N is a an ammonium nitrogen atom, each of R.sub.1, R.sub.2, R.sub.3, and R.sub.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.sub.1, R.sub.2, R.sub.3, and R.sub.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.sub.1, R.sub.2, R.sub.3, and R.sub.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.
3. The liposomal composition of claim 2, wherein the 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-propanol-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.
4. The liposomal composition of claim 2, wherein the substituted ammonium compound is triethylammonium.
5. The liposomal composition of claim 2, wherein the substituted ammonium compound is diethylammonium.
6. The liposomal composition of claim 1, wherein the membrane comprises about 59.8 mol. % of the 1,2-distearoyl-SN-phosphatidylcholine; about 39.9 mol. % of the cholesterol and about 0.3 mol. % of the N-(omega-methoxy-poly(ethylene glycol)-oxycarbonyl)-1,2-distearoylphosphatidyl ethanolamine.
7. The liposomal composition of claim 6, wherein the poly(ethylene glycol) in the N-(omega-methoxy-poly(ethylene glycol)-oxycarbonyl)-1,2-distearoylphosphatidyl ethanolamine has a molecular weight of about 2,000.
8. The liposomal composition of claim 1, wherein the composition is a fluid pharmaceutical formulation for parenteral administration.
9. The liposomal composition of claim 1, wherein molar ratio of the irinotecan to the totality of the lipids is at least 1.0.
10. The liposomal composition of claim 1, wherein the relative amounts of the irinotecan and the sucrose octasulfate are near the point of stoichiometric equivalency.
11. The liposomal composition of claim 1, wherein the relative amounts of the irinotecan and the sucrose octasulfate are at the point of stoichiometric equivalency.
12. The liposomal composition of claim 1, wherein the irinotecan and the sucrose octasulfate are comprised in the form of a salt.
13. The liposomal composition of claim 1, wherein the aqueous medium comprises hydroxyethylpiperazine-ethylsulfonate (HEPES) and NaCl.
14. The liposomal composition of claim 1, wherein the irinotecan has been partially or substantially removed from the aqueous medium.
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