Treatment of pain by administration of sustained-release liposomal anesthetic compositions

Abstract

In some embodiments provided herein is a method of treating pain, the method comprising administering into the subject a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes 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.

1 . A method of treating pain in a subject, the method comprising administering into the subject in proximity to a wound in the subject
 a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes 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 liposomes are 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 form multivesicular liposomes encapsulating bupivacaine phosphate,   wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject does not result in cardiac side effects or CNS side effects in the subject.   
     
     
         2 . A method of treating pain in a subject, the method comprising administering into the subject in proximity to a wound in the subject a pharmaceutical composition comprising a multivesicular liposome comprising 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,
 wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject does not result in cardiac side effects or CNS side effects in the subject.   
     
     
         3 . The method of  claim 1  or  2 , wherein the aqueous phase further comprises hydrochloric acid. 
     
     
         4 . The method of  claim 1 , wherein the at least one polyhydroxy carboxylic acid is selected from the group consisting of glucuronic acid, gluconic acid and tartaric acid. 
     
     
         5 . The method of any one of  claims 1  to  4 , wherein the amphipathic lipid is selected from the group consisting of phosphatidylcholines, phosphatidylethanolamines, sphingomyelins, lysophosphatidylcholines, lysophosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols, phosphatidic acids, cardiolipins, diacyl dimethylammonium propanes, and stearylamines. 
     
     
         6 . The method of any one of  claims 1  to  5 , wherein the neutral lipid is at least one triglyceride. 
     
     
         7 . The method of any one of the preceding claims, wherein the pharmaceutical composition comprises a therapeutically effective amount of bupivacaine phosphate. 
     
     
         8 . The method of  claim 7 , wherein the pharmaceutical composition is present in an amount equivalent to from about 10 mg to about 70 mg of bupivacaine. 
     
     
         9 . The method of  claim 7 , wherein the pharmaceutical composition is present in an amount equivalent to from about 10 mg to about 60 mg of bupivacaine. 
     
     
         10 . The method of  claim 7 , wherein the pharmaceutical composition is present in an amount equivalent to from about 20 mg to about 60 mg of bupivacaine. 
     
     
         11 . The method of  claim 7 , wherein the pharmaceutical composition is present in an amount equivalent to from about 20 mg to about 50 mg of bupivacaine. 
     
     
         12 . The method of  claim 7 , wherein the pharmaceutical composition is present in an amount equivalent to from about 20 mg to about 40 mg of bupivacaine. 
     
     
         13 . The method of any one of the preceding claims, wherein the method does not comprise administering an opioid to the subject following the administration of the pharmaceutical composition into the subject. 
     
     
         14 . The method of any one of the preceding claims, wherein the method comprises administering an opioid to the subject following the administration of the pharmaceutical composition into the subject. 
     
     
         15 . The method of  claim 14 , wherein the opioid is oxycodone and the method comprises administering oxycodone in a total amount less than or equal to 10 mg or administering morphine in a total amount less than or equal to 15 mg in the first about 72 hours following the administration of the pharmaceutical composition. 
     
     
         16 . The method of any one of  claims 1  to  15 , wherein the method comprises administering a non-opioid analgesic to the subject following the administration of the pharmaceutical composition into the subject. 
     
     
         17 . The method of any one of the preceding claims, comprising administering into the subject the pharmaceutical composition at a distance of less than about 20 cm, such as less than about 10 cm, from the wound. 
     
     
         18 . The method of any one of the preceding claims, comprising administering into the subject the pharmaceutical composition at a distance of less than about 5 cm, such as less than about 2 cm, such as less than about 1 cm, such as less than about 0.5 cm, such as less than about 0.1 cm, from the wound. 
     
     
         19 . The method of any one of  claims 1  to  18 , wherein the subject has an AUC for VAS pain intensity scores over the first 72 hours following the administration of the pharmaceutical composition into the subject of from about 100 to about 200. 
     
     
         20 . The method of any one of  claims 1  to  19 , wherein the subject has a distress from itchiness score as determined by the OBAS scale of less than 4, such as 0, 1, 2 or 3, following the administration of the pharmaceutical composition into the subject. 
     
     
         21 . A method of anesthetizing a subject in need thereof, the method comprising administering into the subject in proximity to a wound in the subject
 a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes 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 liposomes are 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 form multivesicular liposomes encapsulating bupivacaine phosphate,   wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject does not result in cardiac side effects or CNS side effects in the subject.   
     
     
         22 . A method of anesthetizing a subject in need thereof, the method comprising administering into the subject in proximity to a wound in the subject a pharmaceutical composition comprising a multivesicular liposome comprising 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,
 wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject does not result in cardiac side effects or CNS side effects in the subject.   
     
     
         23 . A method of reducing pain in a subject, the method comprising administering into the subject in proximity to a wound in the subject
 a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes 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 liposomes are 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 form multivesicular liposomes encapsulating bupivacaine phosphate,   wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject does not result in cardiac side effects or CNS side effects in the subject.   
     
     
         24 . A method of reducing pain in a subject, the method comprising administering into the subject in proximity to a wound in the subject a pharmaceutical composition comprising a multivesicular liposome comprising 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,
 wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject does not result in cardiac side effects or CNS side effects in the subject.   
     
     
         25 . A method of reducing an amount of an analgesic, such as an opioid, or such as a non-opioid analgesic, administered to a subject in need thereof, the method comprising administering into the subject in proximity to a wound in the subject
 a multivesicular liposome pharmaceutical composition comprising bupivacaine phosphate made by a process comprising:   a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes 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 liposomes are 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 form multivesicular liposomes encapsulating bupivacaine phosphate,   wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject does not result in cardiac side effects or CNS side effects in the subject.   
     
     
         26 . A method of reducing an amount of an analgesic, such as an opioid, or such as a non-opioid analgesic, administered to a subject in need thereof, the method comprising administering into the subject in proximity to a wound in the subject a pharmaceutical composition comprising a multivesicular liposome comprising 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,
 wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject does not result in cardiac side effects or CNS side effects in the subject.   
     
     
         27 . A method of reducing a duration of time during which an analgesic, such as an opioid, or such as a non-opioid analgesic, is administered to a subject in need thereof, the method comprising administering into the subject in proximity to a wound in the subject
 a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes 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 liposomes are 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 form multivesicular liposomes encapsulating bupivacaine phosphate,   wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject does not result in cardiac side effects or CNS side effects in the subject.   
     
     
         28 . A method of reducing a duration of time during which an analgesic, such as an opioid, or such as a non-opioid analgesic, is administered to a subject in need thereof, the method comprising administering into the subject in proximity to a wound in the subject a pharmaceutical composition comprising a multivesicular liposome comprising 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,
 wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject does not result in cardiac side effects or CNS side effects in the subject.   
     
     
         29 . The method of  claim 25 ,  26 ,  27  or  28 , wherein the analgesic is administered following a surgical procedure in the subject. 
     
     
         30 . The method of  claim 29 , wherein the analgesic reduces pain in the subject following the surgical procedure. 
     
     
         31 . A method of treating pain in a subject, the method comprising administering into the subject in proximity to a wound in the subject
 a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes 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 liposomes are 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 form multivesicular liposomes encapsulating bupivacaine phosphate,   wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         32 . A method of treating pain in a subject, the method comprising administering into the subject in proximity to a wound in the subject a pharmaceutical composition comprising a multivesicular liposome comprising 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,
 wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         33 . A method of anesthetizing a subject in need thereof, the method comprising administering into the subject in proximity to a wound in the subject
 a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes 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 liposomes are 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 form multivesicular liposomes encapsulating bupivacaine phosphate,   wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         34 . A method of anesthetizing a subject in need thereof, the method comprising administering into the subject in proximity to a wound in the subject a pharmaceutical composition comprising a multivesicular liposome comprising 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,
 wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         35 . A method of reducing pain in a subject, the method comprising administering into the subject in proximity to a wound in the subject
 a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes 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 liposomes are 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 form multivesicular liposomes encapsulating bupivacaine phosphate,   wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         36 . A method of reducing pain in a subject, the method comprising administering into the subject in proximity to a wound in the subject a pharmaceutical composition comprising a multivesicular liposome comprising 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,
 wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         37 . A method of reducing an amount of an analgesic, such as an opioid, or such as a non-opioid analgesic, administered to a subject in need thereof, the method comprising administering into the subject in proximity to a wound in the subject
 a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes 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 liposomes are 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 form multivesicular liposomes encapsulating bupivacaine phosphate,   wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         38 . A method of reducing an amount of an analgesic, such as an opioid, or such as a non-opioid analgesic, administered to a subject in need thereof, the method comprising administering into the subject in proximity to a wound in the subject a pharmaceutical composition comprising a multivesicular liposome comprising 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,
 wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         39 . A method of reducing a duration of time during which an analgesic, such as an opioid, or such as a non-opioid analgesic, is administered to a subject in need thereof, the method comprising administering into the subject in proximity to a wound in the subject
 a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes 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 liposomes are 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 form multivesicular liposomes encapsulating bupivacaine phosphate,   wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         40 . A method of reducing a duration of time during which an analgesic, such as an opioid, or such as a non-opioid analgesic, is administered to a subject in need thereof, the method comprising administering into the subject in proximity to a wound in the subject a pharmaceutical composition comprising a multivesicular liposome comprising 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,
 wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         41 . A method of treating pain in a subject, the method comprising:
 A) cautiously administering into the subject in a first time period in proximity to a wound in the subject an amount of   a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes 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 liposomes are 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 form multivesicular liposomes encapsulating bupivacaine phosphate,   and   B) monitoring the plasma level of bupivacaine in the subject.   
     
     
         42 . A method of treating pain in a subject, the method comprising:
 A) cautiously administering into the subject in a first time period in proximity to a wound in the subject an amount of a pharmaceutical composition comprising a multivesicular liposome comprising 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,   and   B) monitoring the plasma level of bupivacaine in the subject.   
     
     
         43 . The method of  claim 41  or  42 , wherein the pharmaceutical composition is administered in an amount equivalent to up to 266 mg of bupivacaine. 
     
     
         44 . The method of  claim 41 ,  42  or  43 , further comprising:
 C) determining that the plasma level of bupivacaine in the subject at a time point following the administering of the pharmaceutical composition is less than 2,000 ng/mL, such as less than 1,500 ng/mL, such as less than 1,000 ng/mL, such as less than 500 ng/mL; and 
 D) cautiously administering into the subject in an additional time period, which is the same or different as the first time period, in proximity to the wound an additional amount of the pharmaceutical composition to the subject, wherein the additional amount is the same as or greater than the amount in step A). 
 
     
     
         45 . A method of treating pain in a subject, the method comprising administering into the subject by infiltration
 a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes 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 liposomes are 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 form multivesicular liposomes encapsulating bupivacaine phosphate,   wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         46 . A method of treating pain in a subject, the method comprising administering into the subject by infiltration a pharmaceutical composition comprising a multivesicular liposome comprising 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,
 wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         47 . A method of treating pain in a subject, the method comprising administering into the subject by interscalene brachial plexus nerve block
 a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes 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 liposomes are 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 form multivesicular liposomes encapsulating bupivacaine phosphate,   wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         48 . A method of treating pain in a subject, the method comprising administering into the subject by interscalene brachial plexus nerve block a pharmaceutical composition comprising a multivesicular liposome comprising 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,
 wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         49 . A method of treating pain in a subject, the method comprising administering into the subject by transversus abdominis plane (TAP) block
 a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes 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 liposomes are 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 form multivesicular liposomes encapsulating bupivacaine phosphate,   wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         50 . A method of treating pain in a subject, the method comprising administering into the subject by transversus abdominis plane (TAP) block a pharmaceutical composition comprising a multivesicular liposome comprising 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,
 wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         51 . A method of treating pain in a subject, the method comprising administering into the subject by subarachnoid injection
 a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes 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 liposomes are 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 form multivesicular liposomes encapsulating bupivacaine phosphate,   wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         52 . A method of treating pain in a subject, the method comprising administering into the subject by subarachnoid injection a pharmaceutical composition comprising a multivesicular liposome comprising 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,
 wherein inadvertent administration of the pharmaceutical composition into the vasculature of the subject provides a plasma Cmax of bupivacaine that is lower than the plasma Cmax of bupivacaine in the subject that would result from administration of an amount of non-liposomal bupivacaine equivalent to the same amount of bupivacaine as the amount of the pharmaceutical composition into the vasculature of the subject.   
     
     
         53 . The method of any one of the preceding claims, wherein the method does not comprise administering the pharmaceutical composition by intravenous injection. 
     
     
         54 . The method of any one of the preceding claims, wherein the pharmaceutical composition is administered to the subject in proximity to a wound in the subject 
     
     
         55 . The method of any one of the preceding claims, wherein the subject is a human. 
     
     
         56 . The method of any one of the preceding claims, wherein the subject is a non-human animal. 
     
     
         57 . The method of any one of the preceding claims, wherein the subject is a dog. 
     
     
         58 . The method of any one of the preceding claims, wherein the plasma level of bupivacaine in the subject at a time point following the administering of the pharmaceutical composition is from about 2 times to about 4 times less than the plasma level of bupivacaine in the subject at the same time point that would result from administration to the subject of the non-liposomal bupivacaine. 
     
     
         59 . The method of any one of the preceding claims, wherein the plasma level of bupivacaine in the subject at a time point following the administering of the pharmaceutical composition is at least 2 times less than the plasma level of bupivacaine in the subject at the same time point that would result from administration to the subject of the non-liposomal bupivacaine. 
     
     
         60 . The method of any one of the preceding claims, wherein the plasma level of bupivacaine in the subject at a time point following the administering of the pharmaceutical composition is at least 3 times less than the plasma level of bupivacaine in the subject at the same time point that would result from administration to the subject of the non-liposomal bupivacaine. 
     
     
         61 . The method of any one of the preceding claims, wherein the plasma level of bupivacaine in the subject at a time point following the administering of the pharmaceutical composition is about 4 times less than the plasma level of bupivacaine in the subject at the same time point that would result from administration to the subject of the non-liposomal bupivacaine.