Source: http://www.google.com/patents/US8182835?dq=5987118
Timestamp: 2016-05-25 11:17:15
Document Index: 60033639

Matched Legal Cases: ['Application No. 2', 'Application No. 98', 'Application No. 98', 'Application No. 2000', 'Application No. 2000', 'Application No. 98']

Patent US8182835 - Sustained-release liposomal anesthetic compositions - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsThe 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...http://www.google.com/patents/US8182835?utm_source=gb-gplus-sharePatent US8182835 - Sustained-release liposomal anesthetic compositionsAdvanced Patent SearchPublication numberUS8182835 B2Publication typeGrantApplication numberUS 11/097,756Publication dateMay 22, 2012Priority dateSep 18, 1997Fee statusPaidAlso published asCA2304096A1, CA2304096C, DE69841598D1, EP1014946A1, EP1014946A4, EP1014946B1, EP2198854A2, EP2198854A3, EP2198854B1, EP2308470A1, US6045824, US8834921, US9192575, US9205052, US20060078606, US20120231070, US20130189349, US20130344132, WO1999013865A1Publication number097756, 11097756, US 8182835 B2, US 8182835B2, US-B2-8182835, US8182835 B2, US8182835B2InventorsSinil Kim, Taehee Kim, Sharad MurdandeOriginal AssigneePacira Pharmaceuticals, Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (136), Non-Patent Citations (80), Referenced by (7), Classifications (24), Legal Events (6) External Links: USPTO, USPTO Assignment, EspacenetSustained-release liposomal anesthetic compositions
US 8182835 B2Abstract
1. A multivesicular liposome formulation comprising bupivacaine phosphate made by a process comprising:
2. The multivesicular liposome formulation made by a process of claim 1, wherein said amphipathic lipid is dierucoylphosphatidyl choline.
3. The multivesicular liposome formulation made by a process of claim 1, wherein said amphipathic lipid is dipalmitoylphosphatidyl glycerol.
4. The multivesicular liposome formulation made by a process of claim 1, wherein said neutral lipid is tricaprylin.
5. A pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposome comprising
bupivacaine or a salt thereof;
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;
e) removing the organic solvent from the solvent spherules to provide multivesicular liposomes encapsulating bupivacaine phosphate.
6. The pharmaceutical composition made by a process of claim 5, wherein said at least one amphipathic lipid is selected from the group consisting of dierucoylphosphatidylcholine and dipalmitoylphosphatidylglyceral.
7. The pharmaceutical composition made by a process of claim 5, wherein said at least one amphipathic lipid comprises dierucoylphosphatidylcholine.
8. The pharmaceutical composition made by a process of claim 5, wherein said at least one amphipathic lipid comprises dipalmitoylphosphatidylglycerol.
9. The pharmaceutical composition made by a process of claim 5, wherein said at least one neutral lipid comprises tricaprylin.
10. The pharmaceutical composition made by a process of claim 5, wherein said at least one amphipathic lipid comprises dierucoylphosphatidylcholine and/or dipalmitoylphosphatidyl glycerol, and said at least one neutral lipid comprises tricaprylin.
11. The pharmaceutical composition made by a process of claim 5, wherein the amphipathic lipid is dierucoylphosphatidylcholine and dipalmitoylphosphatidyl glycerol; and each neutral lipid is selected from the group consisting of triolein, tripalmitolein, trimyristolein, trilinolein, tributyrin, tricaproin, tricaprylin, and tricaprin.
12. The pharmaceutical composition made by a process of claim 11, wherein the neutral lipid is tricaprylin.
13. The pharmaceutical composition made by a process of claim 12, including cholesterol.
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.
15. The method of claim 14, wherein the single dose administration is intracutaneously, subcutaneously, or via nerve block.
16. The method of claim 15, wherein the nerve block is local or regional nerve block.
17. The method of claim 14, wherein the regional anesthesia has a duration of 12 hours or more.
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.
19. The method of claim 18, wherein the single dose administration of a multivesicular liposome comprising a therapeutically effective amount of bupivacaine phosphate provides pain relief of 12 hours or more.
20. The method of claim 18, wherein the single dose contains from at least 20 mg of bupivacaine present in the phosphate salt form.
21. The method of claim 18, wherein the single dose contains from about 20 mg to about 300 mg of bupivacaine present in the phosphate salt form.
This is a continuation of International Application Serial Number PCT/US98/19583, with an international filing date of Sep. 18, 1998, published in English under PCT Article 21(2) (now abandoned), which claims priority to U.S. Provisional Application Serial Number 60/059,233, filed on Sep. 18, 1997 is (now expired), both of which are incorporated by reference herein in their entirety.
Recovery of Bupivicaine from Different MVL Formulations
(clumped)
no MVL formed
150 mM glucuronic
Anesthetic efficacy curves were plotted as the number of non-responses as a function of time. Areas under the curve (AUC) were calculated by the trapezoidal rule to the last data point. With regard to FIG. 1A, the MVL-encapsulated bupivacaine concentrations by weight per volume percent (w/v %) were 2.1% ( ). 1.0% ( ), and 0.5% (▴). With regard to FIG. 1B, unencapsulated bupivacaine concentrations by weight per volume percent were 0.25% (∇), 0.5% (Δ), 0.75% ( ), and 1.0% (□). Each data point represents the average for 5 to 6 animals. The error bars represent the standard error of mean (SEM).
The in vivo pharmacokinetics of the MVL formulations of bupivacaine and free bupivacaine hydrochloride were compared following a single 1 mL intracutaneous dose of the MVL formulation containing 1.0 percent (w/v) of bupivacaine, or a dose of 0.5 percent (w/v) of unencapsulated bupivacaine hydrochloride to a group of guinea pigs. The lower concentration was selected for bupivacaine hydrochloride because the 400-600 gram animals were unable to tolerate a 1.0% concentration dose of the unencapsulated drug. For the animals that received free bupivacaine hydrochloride, samples were collected at 0 and 30 minutes, and 1, 3, 6, and 9 hours following injection, while the animals that received the MVL formulations of bupivacaine were sampled 0, 6, 12, 18, 24, 48, and 72 hours following injection. At each time point, 3 or more animals were first anesthetized with halothane and then exanguinated by cardiac puncture. Serum samples were obtained by centrifugation of clotted whole blood. Skin was collected around the injection site with 3 cm margins, together with a 2-3 mm layer of underlying subcutaneous tissue. The skin and serum samples were kept frozen at −20� C. until analysis.
MVL-encapsulated
Drug Concentration Administered
Peak Amount (mg), Skin
t1/2 (hr), Skin
AUC (mg * hr), Skin
Cmax (μg/mL), Serum
t1/2 (hr), Serum
AUC (μg * hr * mL−1), Serum
r2, Skin
r2, Serum
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