Production of multivesicular liposomes
First Claim
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1. A process for preparing a multivesicular liposomal particle composition of pre-determined, uniform size distribution, the process comprising:
- a) providing a first emulsion by mixing a first aqueous phase and a volatile water-immiscible solvent phase, said solvent phase comprising at least one amphipathic lipid and at least one neutral lipid;
b) mixing and emulsifying said first emulsion and a second aqueous phase in a mixer to provide a second emulsion, said second emulsion comprising a continuous aqueous phase;
c) sparging the volatile water-immiscible solvent from the second emulsion to form an aqueous suspension of multivesicular liposomal particles by bubbling an inert gas through the second emulsion using at least one sparge ring, at least one sparge tube or at least one fit;
d) primary filtration of the aqueous suspension of multivesicular liposomal particles by cross-flow filtration using a filter to exchange the second aqueous phase with an aqueous component to provide an initial volume of aqueous media, wherein the filter has a membrane pore size from 0.07 to 0.45 μ
m;
e) secondary filtration by cross-flow filtration to reduce the initial volume to provide a subsequent volume of aqueous media that is 10% to 90% of the initial volume, further wherein the cross-flow filtration is carried out with a process-scale tangential flow filter with a filtration area of 23 square feet or more, wherein all steps are carried out under aseptic conditions,f) the composition is prepared in quantities or batches greater than a liter;
wherein the first emulsion is mixed in a first emulsification vessel of at least 10 liters in volume; and
g) wherein the uniform size distribution has a number weighted mean particle size of at least 10 microns.
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Abstract
Multivesicular liposomes are prepared at commercial scales by combining a first w/o emulsion with a second aqueous solution to form a w/o/w emulsion using a static mixer. Solvent is removed from the resulting emulsion to form multivesicular liposome-containing compositions. Further optional process steps include primary filtration and secondary cross-flow filtration. The products produced according to the processes of the invention can be produced through a series of aseptic steps.
182 Citations
43 Claims
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1. A process for preparing a multivesicular liposomal particle composition of pre-determined, uniform size distribution, the process comprising:
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a) providing a first emulsion by mixing a first aqueous phase and a volatile water-immiscible solvent phase, said solvent phase comprising at least one amphipathic lipid and at least one neutral lipid; b) mixing and emulsifying said first emulsion and a second aqueous phase in a mixer to provide a second emulsion, said second emulsion comprising a continuous aqueous phase; c) sparging the volatile water-immiscible solvent from the second emulsion to form an aqueous suspension of multivesicular liposomal particles by bubbling an inert gas through the second emulsion using at least one sparge ring, at least one sparge tube or at least one fit; d) primary filtration of the aqueous suspension of multivesicular liposomal particles by cross-flow filtration using a filter to exchange the second aqueous phase with an aqueous component to provide an initial volume of aqueous media, wherein the filter has a membrane pore size from 0.07 to 0.45 μ
m;e) secondary filtration by cross-flow filtration to reduce the initial volume to provide a subsequent volume of aqueous media that is 10% to 90% of the initial volume, further wherein the cross-flow filtration is carried out with a process-scale tangential flow filter with a filtration area of 23 square feet or more, wherein all steps are carried out under aseptic conditions, f) the composition is prepared in quantities or batches greater than a liter;
wherein the first emulsion is mixed in a first emulsification vessel of at least 10 liters in volume; andg) wherein the uniform size distribution has a number weighted mean particle size of at least 10 microns. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
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16. A process for preparing a multivesicular liposomal particle composition of pre-determined, uniform size distribution, the process comprising:
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a) primary filtration by cross-flow filtration of an aqueous suspension of multivesicular liposomal particles by cross-flow filtration; and b) secondary filtration by cross-flow filtration of the aqueous suspension to reduce the initial volume to provide a subsequent volume of aqueous media that is 10% to 90% of the initial volume, wherein all steps are carried out under aseptic conditions. - View Dependent Claims (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27)
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28. A process for preparing a multivesicular liposomal particle composition, the process comprising:
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a) providing a volume of first emulsion by mixing a volume of a first aqueous phase and a volume of a volatile water-immiscible solvent phase, said solvent phase comprising at least one amphipathic lipid and at least one neutral lipid; b) mixing and emulsifying said first emulsion and a volume of a second aqueous phase in a high shear mixer to provide a volume of a second emulsion, said second emulsion comprising a continuous aqueous phase; and c) removing the volatile water-immiscible solvent from the second emulsion to form a volume of multivesicular liposomal particle composition, wherein said solvent removal comprises contacting the second emulsion with an inert gas flow; and wherein said process further comprises primary filtration of the multivesicular liposomal particle composition by cross-flow filtration using a filter having a membrane where the multivesicular liposomal particle composition does not pass through the membrane; wherein all steps are carried out under aseptic conditions, and wherein all solutions are sterile filtered, and wherein the multivesicular liposomal particle composition is immediately suitable for administration into humans; and wherein the primary filtration comprises; a first concentration of the multivesicular liposomal particle composition; and a buffer exchange, resulting in a pH of the multivesicular liposomal particle composition of between about 5 and about 8, and the primary filtration is conducted at a transmembrane pressure of from about 0.1 psi to about 7 psi. - View Dependent Claims (29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42, 43)
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40. A process for preparing a multivesicular liposomal particle composition, the process comprising:
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a) providing a volume of first emulsion by mixing a volume of a first aqueous phase and a volume of a volatile water-immiscible solvent phase, said solvent phase comprising at least one amphipathic lipid and at least one neutral lipid; b) mixing and emulsifying said first emulsion and a volume of a second aqueous phase in a mixer to provide a volume of a second emulsion, said second emulsion comprising a continuous aqueous phase; and c) removing the volatile water-immiscible solvent from the second emulsion to form a volume of multivesicular liposomal particle composition, wherein said solvent removal comprises contacting the second emulsion with an inert gas flow; and wherein said process further comprises primary filtration of the multivesicular liposomal particle composition by cross-flow filtration using a filter having a membrane where the multivesicular liposomal particle composition does not pass through the membrane; wherein the multivesicular liposomal particle composition is sterilized before filling, and wherein the multivesicular liposomal particle composition is immediately suitable for administration into humans; and wherein the primary filtration comprises; a first concentration of the multivesicular liposomal particle composition; and a buffer exchange, resulting in a pH of the multivesicular liposomal particle composition of between about 5 and about 8, and the primary filtration is conducted at a transmembrane pressure of from about 0.1 psi to about 7 psi.
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Specification