Zinc meloxicam complex microparticle multivesicular liposome formulations and processes for making the same

1. A formulation of multivesicular liposomes (MVLs) having multiple nonconcentric internal compartments, comprising:

a zinc meloxicam complex having the formula Zn(MLX) 2 , and one or more pH adjusting agents encapsulated in a first aqueous phase of the multivesicular liposomes; and

lipid components comprising at least one amphipathic lipid selected from phosphatidyl choline or salts thereof, phosphatidyl glycerol or salts thereof, or combinations thereof, and at least one neutral lipid;

wherein at least a portion of the zinc meloxicam complex forms a suspension of microparticles in the first aqueous phase.

2. The formulation of claim 1 , wherein the zinc meloxicam complex has the formula Zn(MLX) 2 (OH 2 ) 2 .

3. The formulation of claim 1 , wherein at least a portion of the zinc meloxicam complex is in a microcrystalline form.

4. The formulation of claim 3 , wherein the microcrystalline zinc meloxicam complex is present as Zn(MLX) 2 .4(H 2 O).

5. The formulation of claim 1 , wherein the microparticles have a median particle diameter of less than 2 μm.

6. The formulation of claim 1 , wherein the pH adjusting agents comprise one or more organic acids, one or more organic bases, or combinations thereof.

7. The formulation of claim 6 , wherein said one or more organic acids comprise tartaric acid.

8. The formulation of claim 6 , wherein said one or more organic bases comprise lysine or histidine, or both.

9. The formulation of claim 1 , wherein the pH of the first aqueous phase of the multivesicular liposomes is from about 5.4 to about 6.6.

10. The formulation of claim 1 , wherein the first aqueous phase of the multivesicular liposomes further comprises one or more tonicity agents.

11. The formulation of claim 10 , wherein the tonicity agents comprise sucrose.

12. The formulation of claim 10 , wherein the osmolality of the first aqueous phase of the multivesicular liposomes is from about 250 mOsm/kg to about 350 mOsm/kg.

13. The formulation of claim 1 , having a packed particle volume of 40-60%.

14. The formulation of claim 1 , wherein the lipid components comprise at least one triglyceride.

15. The formulation of claim 1 , wherein the phosphatidyl glycerol is dipalmitoyl phosphatidyl glycerol (DPPG).

16. The formulation of claim 1 , wherein the phosphatidyl choline is dierucoyl phosphatidyl choline (DEPC).

17. The formulation of claim 14 , wherein the at least one triglyceride is tricaprylin.

18. The formulation of claim 1 , wherein the lipid components further comprise cholesterol.

19. The formulation of claim 1 , wherein the multivesicular liposomes have a median particle diameter ranging from about 10 μm to about 50 μm.

20. The formulation of claim 1 , wherein the concentration of the meloxicam in the multivesicular liposome formulation is from about 1 mg/mL to about 25 mg/mL.

21. The formulation of claim 20 , wherein the concentration of the meloxicam in the multivesicular liposome formulation is from about 2.0 mg/mL to about 7.0 mg/mL.

22. The formulation of claim 3 , wherein the microcrystalline form of the zinc meloxicam complex exhibits 20 characteristic peaks in an XRPD spectrum of about 6.3, about 10.3, about 12.5, about 13.7, about 16.9, about 23.1, about 23.3, about 25.3, about 26.3, about 31.3, about 39.9, and about 42.4 degrees.

23. The formulation of claim 1 , wherein the formulation further comprises unencapsulated meloxicam or zinc meloxicam complex.

24. A method of treating pain or inflammation, comprising administering a formulation of claim 1 to a subject in need thereof.

25. The method of claim 24 , wherein said subject is suffering from postoperative pain from a surgical site or pain from an acute or chronic condition.

26. The method of claim 24 , wherein said subject is suffering from arthritis.

27. The method of claim 24 , wherein the formulation is administered by intraarticular, intramuscular, subcutaneous, intraperitoneal, intraocular, or intrathecal injection, or administered topically, or by wound infiltration or instillation.

28. A multivesicular liposomes formulation prepared by a process comprising:

preparing a first aqueous suspension of zinc meloxicam complex microparticles by mixing a first solution comprising meloxicam, a second solution comprising a zinc salt, and one or more pH adjusting agents to form a zinc meloxicam complex microparticle suspension;

preparing a first emulsion by mixing the first aqueous suspension with a water-immiscible organic solvent phase comprising a volatile organic solvent, said organic solvent phase comprising at least one amphipathic lipid selected from phosphatidyl choline or salts thereof, phosphatidyl glycerol or salts thereof, or combinations thereof, and at least one neutral lipid;

combining said first emulsion and a second aqueous phase to provide a second emulsion; and

substantially removing the organic solvent from the second emulsion.

29. The multivesicular liposomes formulation of claim 28 , wherein the zinc meloxicam complex microparticles have a median particle diameter of less than about 2 μm.

30. The multivesicular liposomes formulation of claim 28 , the one or more pH adjusting agents of the first aqueous suspension comprise tartaric acid, lysine or histidine, or combinations thereof.

31. The multivesicular liposomes formulation of claim 28 , wherein the pH of the first aqueous suspension is from about 5.6 to about 6.6.

32. The multivesicular liposomes formulation of claim 28 , wherein the zinc meloxicam complex microparticle suspension has a pH of about 4.5 to about 8.0.

33. The multivesicular liposomes formulation of claim 28 , wherein the pH of the second aqueous phase is from about 5 to about 9.0.

34. The multivesicular liposomes formulation of claim 28 , further comprising exchanging the second aqueous phase with a suspending medium having a pH of 5.5 to 6.5.