Sustained-release liposomal anesthetic compositions
First Claim
1. A multivesicular liposome formulation comprising bupivacaine phosphate made by a process comprising:
- a) preparing a first aqueous component comprising at least one acid in sufficient quantity to solubilize bupivacaine or a salt thereof, said acid being phosphoric acid;
b) preparing a lipid component comprising at least one organic solvent, at least one amphipathic lipid, and at least one neutral lipid lacking a hydrophilic head group;
c) mixing said first aqueous component and said lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof;
d) mixing said water-in-oil emulsion with a second aqueous component to form solvent spherules; and
e) removing the organic solvent from the solvent spherules to form multivesicular liposomes.
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Accused Products
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.
183 Citations
21 Claims
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1. A multivesicular liposome formulation comprising bupivacaine phosphate made by a process comprising:
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a) preparing a first aqueous component comprising at least one acid in sufficient quantity to solubilize bupivacaine or a salt thereof, said acid being phosphoric acid; b) preparing a lipid component comprising at least one organic solvent, at least one amphipathic lipid, and at least one neutral lipid lacking a hydrophilic head group; c) mixing said first aqueous component and said lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof; d) mixing said water-in-oil emulsion with a second aqueous component to form solvent spherules; and e) removing the organic solvent from the solvent spherules to form multivesicular liposomes. - View Dependent Claims (2, 3, 4)
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5. A pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposome comprising
bupivacaine or a salt thereof; -
phosphoric acid; a lipid component comprising at least one amphipathic lipid and at least one neutral lipid lacking a hydrophilic head group; and
,optionally, a cholesterol and/or a plant sterol wherein said multivesicular liposome encapsulating bupivacaine is made by a process comprising; a) preparing a first aqueous component comprising phosphoric acid; b) preparing a lipid component comprising at least one organic solvent, at least one amphipathic lipid, and at least one neutral lipid lacking a hydrophilic head group; c) mixing said first aqueous component and said lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof; d) mixing said water-in-oil emulsion with a second aqueous component to form solvent spherules; and e) removing the organic solvent from the solvent spherules to provide multivesicular liposomes encapsulating bupivacaine phosphate. - View Dependent Claims (6, 7, 8, 9, 10, 11, 12, 13)
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14. A method providing regional anesthesia to a subject in need thereof by administering in a single dose a multivesicular liposome comprising a therapeutically effective amount of bupivacaine phosphate, wherein the multivesicular liposome comprises bupivacaine phosphate;
- a lipid component comprising at least one amphipathic lipid and at least one neutral lipid lacking a hydrophilic head group; and
, optionally, a cholesterol and/or a plant sterol. - View Dependent Claims (15, 16, 17)
- a lipid component comprising at least one amphipathic lipid and at least one neutral lipid lacking a hydrophilic head group; and
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18. A method of treating post-operative or post-trauma pain in a subject in need thereof comprising administering in a single dose a multivesicular liposome comprising a therapeutically effective amount of bupivacaine phosphate, wherein the multivesicular liposome comprises bupivacaine phosphate;
- a lipid component comprising at least one amphipathic lipid and at least one neutral lipid lacking a hydrophilic head group; and
, optionally, a cholesterol and/or a plant sterol. - View Dependent Claims (19, 20, 21)
- a lipid component comprising at least one amphipathic lipid and at least one neutral lipid lacking a hydrophilic head group; and
Specification