Sustained-release liposomal anesthetic compositions

• US 20060078606A1
• Filed: 04/01/2005
• Published: 04/13/2006
• Est. Priority Date: 09/18/1997
• Status: Active Grant

• Current Assignee: Pacira Pharmaceuticals, Inc. (Pacira Biosciences, Inc.)
• Original Assignee: SkyePharma PLC. (Vectura Group Ltd.)
• Inventors: Kim, Sinil, Kim, Taehee, Murdande, Sharad
• Granted Patent: US 8,182,835 B2
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 9/0002 Galenical forms characterised by the drug release technique; Application systems commanded by energy
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: A61P 23/02 Local anaesthetics

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.

Claims

1-22. -22. (canceled)

23. A pharmaceutical composition comprising:

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.

24. The pharmaceutical composition of claim 23, wherein the aqueous phase further comprises hydrochloric acid.

25. The pharmaceutical composition of claim 23, wherein the amphipathic lipid is provided in admixture with cholesterol, plant sterols, or combinations thereof.

26. The pharmaceutical composition of claim 23, wherein the mineral salt of the amide anesthetic is selected from the group consisting of sulfates, phosphates and combinations thereof.

27. The pharmaceutical composition of claim 23, wherein the polyhydroxy carboxylate salt of the amide anesthetic is selected from the group consisting of glucuronate, gluconate, tartarate and combinations thereof.

28. The pharmaceutical composition of claim 23, wherein the amphipathic lipid is selected form the group consisting of phosphatidylcholines, phosphatidylethanolamines, sphingomyelins, lysophosphatidylcholines, lysophosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols, phosphatidic acids, cardiolipins, diacyl dimethylammonium propanes, stearyl amines, and combinations thereof.

29. The pharmaceutical composition of claim 23, wherein the neutral lipid is selected from the group consisting of triglycerides, diglycerides, ethylene glycol, esters, squalene and combinations thereof.

30. The pharmaceutical composition of claim 23, wherein the amide anesthetic is xylidide.

31. The pharmaceutical composition of claim 30, wherein the xylidide is selected form the group consisting of bupivacaine, mepivacaine, ropivacaine, lidocaine, pyrrocaine, prilocaine, their stereoisomers and combinations thereof.

38. A method of locally anesthetizing a subject, the method comprising administering the pharmaceutical composition of claim 23.

39. The method of claim 38, wherein the pharmaceutical composition comprises a xylidide.

40. The method of claim 39, wherein the xylidide is selected form the group consisting of bupivacaine, mepivacaine, ropivacaine, lidocaine, pyrrocaine, prilocaine, their stereoisomers and combinations thereof.

35. A process for preparing a multivesicular liposome-encapsulated anesthetic composition, the process comprising:

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 comprises

a 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.

36. The process of claim 35, wherein the amide anesthetic is a xylidide.

37. The process of claim 36, wherein the xylidide is selected from the group consisting of bupivacaine, mepivacaine, ropivacaine, lidocaine, pyrrocaine, prilocaine, their stereoisomers and combinations thereof.

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.

42. The method of claim 41, wherein the polyhydroxy carboxylic acid is selected from the group consisting of sulfuric acid, phosphoric acid, and combinations thereof.

43. The method of claim 41, wherein the mineral acid is selected from the group consisting of glucuronic acid, gluconic acid, tartaric and combinations thereof.

44. The method of claim 41, wherein the amide anesthetic is a xylidide selected from the group consisting of bupivacaine, mepivacaine, ropivacaine, lidocaine, pyrrocaine, prilocaine, their stereoisomers and combinations thereof.