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Claims for Patent: 8,147,867

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Claims for Patent: 8,147,867

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 provide 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: Hermes Biosciences, Inc. (South San Francisco, CA)
Application Number:11/121,294
Patent Claims: 1. A liposomal irinotecan composition comprising liposomes in a an aqueous medium, the liposomes having an interior aqueous space separated from the aqueous medium by a membrane, said membrane comprising lipids, said lipids comprising an uncharged lipid component and a neutral phospholipid, with, entrapped inside the liposomes: 1) irinotecan and sucrose octasulfate, or 2) irinotecan and sucrose octasulfate and a substituted ammonium compound, wherein, when administered into the bloodstream of a mammal, said irinotecan has a half-release time from said liposomes of at least 24 hours and the irinotecan entrapped inside the liposomes is at a concentration that exceeds the irinotecan concentration in the aqueous medium.

2. The liposomal irinotecan composition of claim 1, wherein when administered into the bloodstream of a rat, said irinotecan has a half-release time from said liposomes in excess of 48 hours.

3. The liposomal irinotecan composition of claim 1, wherein said composition is at least 4-fold more active at reducing human colon carcinoma xenograft tumor doubling time in nude mice than free irinotecan given at the same dose and schedule.

4. The liposomal irinotecan composition of claim 3, wherein activity is determined by measuring xenograft tumor size for 56 days.

5. The liposomal irinotecan composition of claim 1, wherein said composition is at least 10-fold more active at reducing human colon carcinoma xenograft tumor doubling time in nude mice than free irinotecan given at the same dose and schedule.

6. The liposomal irinotecan composition of claim 5, wherein activity is determined by measuring xenograft tumor size for 56 days.

7. The liposomal irinotecan composition of claim 1, wherein at least 90% of said irinotecan remains encapsulated in the liposomes after 6 months at 2-8.degree. C.

8. The liposomal irinotecan composition of claim 1 wherein, 48 hours after intravenous bolus administration into a rat there is no detectable conversion of the entrapped irinotecan from lactone form of irinotecan to carboxylate form of irinotecan, when assayed by HPLC in which the eluted products are detected by fluorescence with an excitation at 375 nm and emission at 500 nm.

9. The liposomal irinotecan composition of claim 1, wherein said 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 of a first ammonium group, each of R.sub.1, R.sub.2, R.sub.3, 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, 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, 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.

10. The liposomal irinotecan composition 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-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.

11. The liposomal irinotecan composition of claim 10, wherein said substituted ammonium compound is triethylammonium.

12. The liposomal irinotecan composition of claim 1, wherein said membrane further comprises a polymer-conjugated lipid.

13. The liposomal irinotecan composition of claim 1, wherein said composition is a fluid pharmaceutical formulation for parenteral administration.

14. The liposomal irinotecan composition of claim 1, wherein molar ratio of irinotecan to the totality of said lipids is at least 1.0.

15. The liposomal irinotecan composition of claim 1, wherein said irinotecan is present at a ratio of about 1.76 mol irinotecan per mol of said neutral phospholipid.

16. The liposomal irinotecan composition of claim 1, wherein said irinotecan is present at a ratio of about 1.67-1.70 mol irinotecan/g of lipids comprised by the membrane.

17. The liposomal irinotecan composition of claim 1, wherein the relative amounts of said irinotecan and said sucrose octasulfate are at the point of stoichiometric equivalency.

18. The liposomal irinotecan composition of claim 1, wherein said mammal is a mouse.

19. The liposomal irinotecan composition of claim 1, wherein said irinotecan and said sucrose octasulfate are comprised in the form of an acid or a salt.

20. The liposomal irinotecan composition of claim 1, wherein said neutral phospholipid comprises a diacylphosphatidylcholine.

21. The liposomal irinotecan composition of claim 20, wherein said diacylphosphatidylcholine is 1,2-distearoyl-sn-phosphatidylcholine (DSPC).

22. The liposomal irinotecan composition of claim 1, wherein said aqueous medium comprises HEPES and NaCl.

23. The liposomal irinotecan composition of claim 1, wherein said substituted ammonium compound is diethylammonium.

24. The liposomal irinotecan composition of claim 1, wherein said irinotecan is present at a ratio of about 550 mg irinotecan hydrochloride per mmol of said neutral phospholipid.

25. The liposomal irinotecan composition of claim 12, wherein said polymer is a polyethylene glycol-lipid derivative.

26. The liposomal irinotecan composition of claim 25, wherein said polymer-conjugated lipid is N-(methoxy-poly(ethylene glycol)-oxycarbonyl)-distearoylphosphatidylethanolamine (PEG-DSPE).

27. The liposomal irinotecan composition of claim 1, wherein said uncharged lipid component comprises cholesterol.

28. The liposomal irinotecan composition of claim 27, wherein said neutral phospholipid is a lecithin.

29. The liposomal irinotecan composition of claim 28 wherein said lecithin and said cholesterol are at a ratio of about 3:2 by mole.

30. The liposomal irinotecan composition of claim 29 wherein said lecithin is 1,2-distearoyl-sn-phosphatidylcholine (DSPC).

31. The liposomal irinotecan composition of claim 30, comprising 1,2-distearoyl-sn-phosphatidylcholine (DSPC) 200 mol. parts, Cholesterol 133 mol. parts, and N-(methoxy-poly(ethylene glycol)-oxycarbonyl)-distearoylphosphatidylethanolamine (PEG-DSPE) 1 mol. part.

32. The liposomal irinotecan composition of claim 1, wherein leakage of irinotecan from said liposomes during storage is less than 5% over 6 months at 4-8.degree. C.

33. The liposomal irinotecan composition of claim 1, wherein 48 hours after intravenous bolus administration into a rat there is no detectable conversion of entrapped irinotecan to SN-38, when assayed by HPLC in which the eluted products are detected by fluorescence with an excitation at 375 nm and emission at 500 nm.

34. The liposomal irinotecan composition of claim 1, wherein said irinotecan comprises irinotecan hydrochloride.

35. The liposomal irinotecan composition of claim 1, wherein the interior space of the liposomes with entrapped irinotecan and sucrose octasulfate, or the interior space of the liposomes with entrapped irinotecan and sucrose octasulfate and a substituted ammonium compound, has an intraliposomal volume of approximately 1.7 l/mol phospholipid.
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