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

1. A method of treating pain in a subject, the method comprising:

(A) administering, at a rate of at least 12.5 mg/min and less than 2 cm from 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;

(B) determining that inadvertent administration of the pharmaceutical composition into the vasculature of the subject has occurred;

(C) monitoring the subject for cardiac side effects and CNS side effects; and

(D) if cardiac side effects and CNS side effects are absent in the subject, administering into the subject in an additional time period, which is the same or different as the first time period, less than 2 cm from a 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).

2. A method of treating pain in a subject, the method comprising (A) administering, at a rate of at least 12.5 mg/min and less than 2 cm from 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,

(B) determining that inadvertent administration of the pharmaceutical composition into the vasculature of the subject has occurred;

(C) monitoring the subject for cardiac side effects and CNS side effects; and

(D) if cardiac side effects and CNS side effects are absent in the subject, administering into the subject an additional amount of the pharmaceutical composition the same as or greater than the amount administered less than 2 cm from a wound in the subject.

3. The method of claim 1 , wherein the aqueous phase further comprises hydrochloric acid.

4. The method of claim 1 , 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.

5. The method of claim 1 , wherein the neutral lipid is at least one triglyceride.

6. The method of claim 1 , wherein the pharmaceutical composition comprises a therapeutically effective amount of bupivacaine phosphate.

7. The method of claim 6 , wherein the pharmaceutical composition is present in an amount equivalent to from about 10 mg to about 70 mg of bupivacaine.

8. The method of claim 1 , wherein the method comprises administering an opioid to the subject following the administration of the pharmaceutical composition into the subject.

9. The method of claim 8 , 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.

10. The method of claim 1 , wherein the method comprises administering a non-opioid analgesic to the subject following the administration of the pharmaceutical composition into the subject.

11. The method of claim 1 , 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.

12. The method of claim 1 , wherein the subject has a distress from itchiness score as determined by the OBAS scale of less than 4 following the administration of the pharmaceutical composition into the subject.

13. A method of treating pain in a subject, the method comprising:

(A) administering, at a rate of at least 12.5 mg/min and less than 2 cm from 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;

(B) determining that inadvertent administration of the pharmaceutical composition into the vasculature of the subject has occurred;

(C) monitoring the subject for cardiac side effects and CNS side effects; and

(D) if cardiac side effects and CNS side effects are absent in the subject, administering an additional amount of the pharmaceutical composition, wherein the additional amount is the same as or greater than the amount administered in step (A).

14. A method of treating pain in a subject, the method comprising:

A) administering in a first time period at a rate of at least 12.5 mg/min and less than 2 cm from 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;

B) monitoring the plasma level of bupivacaine in the subject; and

C) if cardiac side effects and CNS side effects are absent in the subject, administering an additional amount of the pharmaceutical composition, wherein the additional amount is the same as or greater than the amount administered in step (A).

15. The method of claim 14 , wherein the pharmaceutical composition is administered in an amount equivalent to up to 266 mg of bupivacaine.

16. The method of claim 14 , further comprising:

determining that the plasma level of bupivacaine in the subject at a time point following the first administration of the pharmaceutical composition is less than 2,000 ng/mL.

17. The method of claim 1 , wherein the subject is a human.

18. The method of claim 1 , 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.

19. The method of claim 1 , 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.

20. The method of claim 12 , wherein the subject has a distress from itchiness score as determined by the OBAS scale of 2 following the administration of the pharmaceutical composition into the subject.

21. The method of claim 12 , wherein the subject has a distress from itchiness score as determined by the OBAS scale of 1 following the administration of the pharmaceutical composition into the subject.

22. The method of claim 12 , wherein the subject has a distress from itchiness score as determined by the OBAS scale of 0 following the administration of the pharmaceutical composition into the subject.

23. The method of claim 1 , wherein the rate of at least 12.5 mg/min is between 12.5 mg/min and 100 mg/min.

24. The method of claim 2 , wherein the rate of at least 12.5 mg/min is between 12.5 mg/min and 100 mg/min.

25. The method of claim 13 , wherein the rate of at least 12.5 mg/min is between 12.5 mg/min and 100 mg/min.

26. The method of claim 1 , wherein the pharmaceutical composition is administered at a rate selected from the group consisting of: 15 mg/minute, 20 mg/minute, 30 mg/minute, 40 mg/minute, 50 mg/minute, 60 mg/minute, 70 mg/minute, 80 mg/minute, 90 mg/minute, and 100 mg/minute.

27. The method of claim 2 , wherein the pharmaceutical composition is administered at a rate selected from the group consisting of: 15 mg/minute, 20 mg/minute, 30 mg/minute, 40 mg/minute, 50 mg/minute, 60 mg/minute, 70 mg/minute, 80 mg/minute, 90 mg/minute, and 100 mg/minute.

28. The method of claim 13 , wherein the pharmaceutical composition is administered at a rate selected from the group consisting of: 15 mg/minute, 20 mg/minute, 30 mg/minute, 40 mg/minute, 50 mg/minute, 60 mg/minute, 70 mg/minute, 80 mg/minute, 90 mg/minute, and 100 mg/minute.

29. The method of claim 14 , wherein the pharmaceutical composition is administered at a rate selected from the group consisting of: 15 mg/minute, 20 mg/minute, 30 mg/minute, 40 mg/minute, 50 mg/minute, 60 mg/minute, 70 mg/minute, 80 mg/minute, 90 mg/minute, and 100 mg/minute.

30. The method of claim 14 , wherein the rate of at least 12.5 mg/min is between 12.5 mg/min and 100 mg/min.