Vancomycin Liposome Compositions and Methods
The inventive subject matter is directed to compositions and methods for liposomal vancomycin that have improved pharmacokinetics and enhanced drug loading and solution stability.
1 . A vancomycin liposome composition, comprising:
a plurality of liposomes encapsulating vancomycin, wherein the liposomes are disposed in an aqueous solution, and wherein the composition is formulated for injection;
wherein the liposomes comprise a first lipid component, an optional second lipid component, a cholesterol, and a PEGylated diglyceride;
wherein the first lipid component comprises a C14:0 fatty acid portion and wherein the second lipid component comprises a C16:0 fatty acid portion, and
wherein the liposomes have a drug loading of at least 0.55 mg vancomycin per mg of total lipid and exhibit no apparent loss of vancomycin from the liposomes in PBS at 37° C. over a period 24 hours.
2 . The liposome composition of claim 1 , wherein the liposomes have a particle size of 240 nm+/−15 nm at D 50 and/or wherein the aqueous solution has a pH of equal or less than pH 5.5.
3 . (canceled)
4 . The liposome composition of claim 1 , wherein the aqueous solution includes an osmolarity adjusting agent.
5 . (canceled) .
6 . The liposome composition of claim 1 , wherein the first and/or the second lipid component comprises a phosphatidyl choline portion.
7 . The liposome composition of claim 1 , wherein the first lipid component is 1,2-dimyristoyl-sn-glycero-3-phosphocholine.
8 . The liposome composition of claim 1 , wherein the second lipid component is 1,2-dipalmitoyl-sn-glycero-3-phosphocholine.
9 . The liposome composition of claim 1 , wherein the PEGylated diglyceride comprises a PEG chain with a molecular weight of 2,000+/−200.
10 . (canceled)
11 . The liposome composition of claim 1 , wherein the PEGylated diglyceride is 1,2-dimyristoyl-rac-glycero-3-methylpolyoxyethylene.
12 . (canceled)
13 . The liposome composition of claim 1 , wherein the ratio of the first and second lipid component to cholesterol is between 3.0:1 and 3.4:1, and/or wherein the ratio of the first and second lipid component to the PEGylated diglyceride is between 10:1 and 20:1.
14 . (canceled)
15 . The liposome composition of claim 1 , wherein the vancomycin is present in the composition at a concentration of between 1-10 mg/ml.
16 . (canceled)
17 . The liposome composition of claim 1 , wherein the liposomes have a drug loading of at least 0.80 mg vancomycin per mg of total lipid.
18 . (canceled)
19 . The liposome composition of claim 1 , wherein the composition has an ethanol concentration of equal or less than 0.05% (v/v).
20 - 29 . (canceled)
30 . A method of producing a vancomycin liposome composition, comprising:
preparing an alcoholic lipid solution that comprises a first lipid component, an optional second lipid component, a cholesterol, and a PEGylated diglyceride;
preparing an aqueous vancomycin solution;
mixing in a microfluidics channel having a static mixer the alcoholic lipid solution with the aqueous vancomycin solution at a flow rate that forms a product that comprises a plurality of liposomes encapsulating vancomycin;
subjecting the product to tangential flow filtration or dialysis to remove the alcohol and non-encapsulated vancomycin; and
wherein the liposomes have a drug loading of at least 0.55 mg vancomycin per mg of total lipid and exhibit no apparent loss of vancomycin from the liposomes in PBS at 37° C. over a period 24 hours.
31 . The method of claim 30 wherein the step of tangential flow filtration or dialysis is performed with an aqueous solution comprising an osmolarity adjusting agent.
32 . The method of claim 31 wherein osmolarity adjusting agent is sucrose,. and/or wherein the aqueous solution has a pH of equal or less than pH 5.5.
33 . (canceled)
34 . The method of claim 30 wherein the liposomes have a particle size of 240 nm+/−15 nm at D 50 .
35 . The method of claim 30 wherein the first and/or the second lipid component comprises a phosphatidyl choline portion.
36 . The method of claim 30 wherein the first lipid component is 1,2-dimyristoyl-sn-glycero-3-phosphocholine and/or wherein the second lipid component is 1,2-dipalmitoyl-sn-glycero-3-phosphocholine.
37 - 39 . (canceled)
40 . The method of claim 30 wherein the PEGylated diglyceride is 1,2-dimyristoyl-rac-glycero-3-methylpolyoxyethylene.
41 . (canceled)
42 . The method of claim 30 wherein the ratio of the first and second lipid component to cholesterol is between 3.0:1 and 3.4:1, and/or wherein the ratio of the first and second lipid component to the PEGylated diglyceride is between 10:1 and 20:1.
43 - 65 . (canceled)