Formulation of insoluble small molecule therapeutics in lipid-based carriers
View Patent ↗The present invention provides formulations containing at least one unsaturated amphiphilic lipid and an amphipathic or hydrophobic drug and methods of making these formulations. In particular, the present invention provides formulations of at least one unsaturated phospholipid and an amphipathic or hydrophobic pyrimidine drug, methods of making these formulations and the use of such formulations in a variety of contexts, including, for example, the treatment of proliferative disorders, such as tumors and cancers.
1. A liposomal formulation comprising at least one unsaturated amphiphilic lipid and a 2,4-pyrimidinediamine drug selected from
or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein the drug and the lipid are present in a ratio ranging from between about 0.015 and about 0.15 on a mole/mole basis.
2. The formulation of claim 1 further comprising a pharmaceutically acceptable vehicle.
3. The formulation of claim 1 in which the 2,4-pyrimidinediamine is
4. The formulation of claim 1 in which the lipid has a transition temperature below about 30° C.
5. The formulation of claim 1 in which the lipid includes one or more unsaturated acyl moieties.
6. The formulation of claim 1 in which the lipid is a phospholipid.
7. The formulation of claim 6 in which the phospholipid includes one or more unsaturated acyl moieties.
8. The formulation of claim 5 in which the unsaturated acyl moiety is C 12 -C 24 alkenyl.
9. The formulation of claim 5 in which the unsaturated acyl moiety is C 16 -C 20 alkenyl.
10. The formulation of claim 8 in which the unsaturated acyl moiety is cis n-alkenyl.
11. The formulation of claim 9 in which the unsaturated acyl moiety is cis n-alkenyl.
12. The formulation of claim 7 in which the unsaturated acyl moiety is selected from the group consisting of oleoyl, elaidoyl, myristoleoyl, palmitoleoyl, arachidonyl, linoleoyl, linolenyl, petroselinyl and erucyl.
13. The formulation of claim 7 in which the phospholipid is a phosphatidylglycerol, a phosphatidylserine, a phosphatidylethanolamine or a phosphatidic acid.
14. The formulation of claim 7 in which the phospholipid is a phosphatidylcholine.
15. The formulation claim 13 in which the unsaturated acyl moiety is selected from the group consisting of petroselinyl, erucyl, oleoyl, elaidoyl, palmitoleoyl, myristoleoyl, arachidonyl, linoleoyl, linoleny, and combinations thereof.
16. The formulation of claim 14 in which the phosphatidylcholine is dioleoylphosphatidylcholine, dielaidoylphosphatidylcholine, dipetroselinylphosphatidylcholine, dierucylphosphatidylcholine, dipalmitoleoylphosphatidylcholine, dimyristoleoylphosphatidylcholine, diarchidonylphosphatidylcholine, dilinoleoylphosphatidylcholine, dilinolenylphosphatidylcholine, or combinations thereof.
17. The formulation of claim 14 in which the phosphatidylcholine is dioleoylphosphatidylcholine.
18. The formulation of claim 1 in which the drug and the lipid are present in a ratio ranging from between about 0.05 and about 0.12 on a mole/mole basis.
19. The formulation of claim 1 in which the ratio of the drug and the lipid is about 0.10 on a mole to mole basis.
20. The formulation of claim 1 in which the bilayer is a liposome, and the liposome is a small unilamellar liposome, a large unilamellar liposome, a multilamellar liposome, or combinations thereof.
21. The formulation of claim 1 in which the lipid is dioleoylphosphatidylcholine and the 2,4-pyrimidinediamine is
22. The formulation of claim 1 in which the lipid has a loading capacity of drug in a range between about 2 mg/mL and about 8 mg/mL.
23. A method of making a liposomal formulation, comprising:
mixing at least one unsaturated amphiphilic lipid, and a 2,4-pyrimidinediamine drug selected from
or pharmaceutically acceptable salts, hydrates, or solvates thereof, and a solvent;
removing the solvent to form a residue comprising drug and lipid; and
mixing the residue with water or an aqueous solution;
wherein the drug and the lipid are present in a ratio ranging from between about 0.015 and about 0.15 on a mole/mole basis.
24. The method of claim 23 in which the mixing steps include stirring, blending, heating, shaking, agitating, sonicating, vortexing, centrifugating or combinations thereof.
25. The method of claim 23 in which the solvent is an organic solvent, a surfactant, or combinations thereof.
26. The method of claim 25 in which the organic solvent is selected from the group consisting of dichloromethane, chloroform, haloalkanes, ethers, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethyl formamide, alcohols, polyols, water and mixtures thereof.
27. The method of claim 25 in which the surfactant is a detergent selected from TPGS, PS 80, sodium cholate, sodium dodecylsulfate, sodium salt of N-lauroylsarcosine, lauryldimethylamine-oxide, cetyltrimethylammoniumbromide, the sodium salt of bis(2-ethylhexyl)sulfosuccinate, or combinations thereof.
28. The method of claim 23 in which the residue is a film.
29. The method of claim 23 in which the removing step includes lyophilization, vacuum evaporation, reverse phase evaporation, vacuum distillation, air drying, inert gas transfer or combinations thereof.
30. The method of claim 23 in which the aqueous solution is a buffer.
31. A liposomal formulation made by a process, comprising:
mixing at least one unsaturated amphiphilic lipid and a 2,4-pyrimidinediamine drug selected from
or pharmaceutically acceptable salts, hydrates, or solvates, thereof, and a solvent;
removing the solvent to form a residue comprising drug and lipid; and
mixing the residue with water or an aqueous solution;
wherein the drug and the lipid are present in a ratio ranging from between about 0.015 and about 0.15 on a mole/mole basis.