Sustained-release liposomal anesthetic compositions
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Abstract
The invention provides a method for obtaining local anesthetics encapsulated in liposomes, such as multivesicular liposomes, with high encapsulation efficiency and slow release in vivo. When the encapsulated anesthetic is administered as a single intracutaneous dose, the duration of anesthesia and half-life of the drug at the local injection site is increased as compared to injection of unencapsulated anesthetic. The maximum tolerated dose of the encapsulated anesthetic is also markedly increased in the liposomal formulation over injection of unencapsulated anesthetic. These results show that the liposomal formulation of local anesthetic is useful for sustained local infiltration and nerve block anesthesia.
114 Citations
44 Claims
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1-22. -22. (canceled)
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23. A pharmaceutical composition comprising:
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a) a multivesicular liposome comprising at least one amphipathic lipid, and at least one neutral lipid; and
b) an aqueous phase comprising a salt of an amide anesthetic selected from the group consisting of polyhydroxy carboxylate, diprotic mineral, triprotic mineral, and combinations thereof;
wherein the aqueous phase is encapsulated within the multivesicular liposome. - View Dependent Claims (24, 25, 26, 27, 28, 29, 30, 31, 38, 39, 40)
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35. A process for preparing a multivesicular liposome-encapsulated anesthetic composition, the process comprising:
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a) forming a “
water-in-oil”
emulsion from a first aqueous phase and a volatile organic phase, wherein the first aqueous phase comprises a salt of an amide anesthetic selected from the group consisting of polyhydroxy carboxylate, diprotic mineral, triprotic mineral, and combinations thereof, and wherein the volatile organic phase comprisesa volatile organic solvent, at least one amphipathic lipid, and at least one neutral lipid;
b) dispersing the “
water-in-oil”
emulsion into a second aqueous phase to form solvent spherules; and
c) removing the volatile organic solvent from the solvent spherules to form a multivesicular liposome-encapsulated amide anesthetic suspended in the aqueous phase. - View Dependent Claims (36, 37)
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- 41. A method of increasing drug loading in a multivesicular liposome by converting an amide anesthetic into a binary salt mixture wherein two counterions are derived from an acid selected from the group consisting of polyhydroxy carboxylic, diprotic mineral, triprotic mineral, and combinations thereof.
Specification