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|Title:||Liposomes useful for drug delivery to the brain|
|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. The present invention also provides for the methods and kits for the delivery of liposomal compositions to the brain.|
|Inventor(s):||Drummond; Daryl C. (Pacifica, CA), Kirpotin; Dmitri (San Francisco, CA)|
|Assignee:||Merrimack Pharmaceuticals, Inc. (Cambridge, MA)|
|Filing Date:||Nov 17, 2006|
|Claims:||1. A method for treating a brain tumor in a mammal, the method comprising: (a) providing a liposomal formulation comprising liposomes in a medium, the liposomes having an interior aqueous space separated from the medium by a membrane, the membrane comprising lipids, the 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, or 3) irinotecan and inositol hexaphosphate, or 4) irinotecan and inositol hexaphosphate and a substituted ammonium compound, wherein the irinotecan entrapped inside the liposomes is at a concentration that exceeds the irinotecan concentration in the medium; and (b) administering the liposomal formulation to the mammal via a conduit placed into the brain tissue of the mammal. |
2. The method of claim 1, wherein the 1) irinotecan and sucrose octasulfate, or 2) irinotecan and sucrose octasulfate and a substituted ammonium compound, or 3) irinotecan and inositol hexaphosphate, or 4) irinotecan and inositol hexaphosphate and a substituted ammonium compound, is 1) irinotecan and sucrose octasulfate, or 2) irinotecan and sucrose octasulfate and a substituted ammonium compound.
3. The method of claim 1, wherein the irinotecan entrapped inside the liposomes of the liposomal formulation is at 500 g/mol phospholipid.
4. The method of claim 1, wherein molar ratio of irinotecan to the totality of the lipids is at least 1.0.
5. The method of claim 1, wherein the membrane further comprises a polymer-conjugated lipid.
6. The method of claim 1, wherein the liposomal formulation is a fluid pharmaceutical formulation for parenteral administration.
7. The method of claim 1, wherein the conduit comprises a catheter, a wick, a tubing, a capillary, a needle, or a cannula.
8. The method of claim 1, wherein the substituted ammonium compound has 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, cyclo- alkenyl, 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.
9. The method of claim 8, wherein the substituted ammonium compound is selected from the group consisting of isopropylethylammonium, isopropylmethyl-ammonium, diisopropylammonium, tert-butylethylammonium, dicyclo-hexylammonium, morpholinium, pyridinium, piperidinium, pyrrolidinium, piperazinium, tert-butylammonium, 2-ammonio-2-methylpropano1-1,2-ammonio-2-methyl-propandiol-1,3-tris-(hydr- oxyethyl)-arnmoniomethane, N,N'-diethyl-ethanolammonium, N,N',N''-tris-(2-hydroxyethy)ammonium, N,N'-bis-(2-hydroxyethyl)ethyl ammonium, trimethyl-ammonium, triethylammonium, diethylmethylammonium, diisopropylethylammonium, triisopropylammonium, N-methylmorpholinium, 1-(2-hydroxyethyl)piperidinium, 1methylpyrrolidinium, 1,4-dimethylpiperazinium, tetramethylammonium, tetraethyl-5ammonium, and tetrabutylammonium.
10. The method of claim 9, wherein the substituted ammonium compound is triethylammonium.
11. The method of claim 2, wherein at least 95% of irinotecan remains inside the liposomes after 6 months at 2-8.degree. C.
12. The method of claim 1, wherein when said irinotecan formulation is administered into the bloodstream of a mammal, said irinotecan has a half-release time from said liposomes of at least 24 hours.
13. The method of claim 2, wherein when said irinotecan formulation is administered into the bloodstream of a mammal, said irinotecan has a half-release time from said liposomes of at least 48 hours.
14. The method of claim 2 wherein the liposomes of said liposomal irinotecan formulation provide better drug retention following intravenous administration in mice than liposomes of a preparation of liposomes with a) entrapped irinotecan and entrapped inositol hexaphosphate, or b) entrapped irinotecan, entrapped inositol hexaphosphate and an entrapped substituted ammonium compound.
15. The method of claim 1, wherein the brain tumor is neoplastic and the liposomal formulation is administered in an amount effective to inhibit the growth of the brain tumor.
16. The method of claim 15, wherein the liposomal formulation is administered into, or near, the neoplastic brain tumor.
17. The method of claim 16, wherein the administration is by convection enhanced delivery.
18. The method of claim 17, wherein the convection enhanced delivery is image-guided convection enhanced delivery.
19. The method of claim 17, wherein the brain tumor is a glioma.
20. The method of claim 19, wherein the glioma is an astrocytoma.
21. The method of claim 17 wherein brain tumor is human brain cancer and the brain tissue is in the brain of a human patient.
22. The method of claim 17 wherein said administering of said liposomal formulation comprises administering of a detectable marker.
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