Liposomes useful for drug delivery to the brain

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 1 -( R 2 -) N + (- R 3 )- R 4 ,

wherein N is a an ammonium nitrogen atom of a first ammonium group, 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, 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 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.

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-methylpropano 1 -1,2-ammonio-2-methyl-propandiol-1,3-tris-(hydroxyethyl)-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° 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.