Sustained release formulation of a non-steroidal anti-inflammatory drug
Disclosed are formulations comprising multivesicular liposomes and one or more non-steroidal anti-inflammatory drugs which minimize the side effects of unencapsulated non-steroidal anti-inflammatory drugs while maintaining or improving efficacy. Methods of making and administering the formulations comprising multivesicular liposomes and one or more non-steroidal anti-inflammatory drugs and their use as medicaments are also provided.
1. A formulation comprising one or more non-steroidal anti-inflammatory drugs encapsulated in multivesicular liposomes prepared by a process comprising:
providing a volume of first emulsion comprising at least one non-steroidal anti-inflammatory drug selected from the group consisting of diclofenac, piroxicam, meloxicam and ketorolac by mixing a first aqueous phase and a volatile water-immiscible solvent phase, wherein said solvent phase comprises at least one amphipathic lipid and at least one neutral lipid, and wherein said first aqueous phase comprises one or more pH modifiers;
providing a volume of second emulsion comprising a continuous aqueous phase by mixing and emulsifying said first emulsion and a second aqueous phase; and
removing the volatile water-immiscible solvent from the second emulsion to form a composition of multivesicular liposomal particles encapsulating at least one non-steroidal anti-inflammatory drug in the first aqueous phase, wherein the multivesicular liposomal particles are characterized by an internal pH of about 7 or higher.
2. The formulation of claim 1 , wherein the multivesicular liposomes further comprise a pH modifier in the second aqueous phase.
3. The formulation of claim 1 , wherein the pH modifier of the first aqueous phase comprises lysine or glutamic acid, or a combination thereof.
4. The formulation of claim 1 , wherein the pH modifier of the first aqueous phase comprises an inorganic acid.
5. The formulation of claim 1 , wherein the pH modifier of the first aqueous phase comprises an organic base.
6. The formulation of claim 1 , wherein the pH modifier of the first aqueous phase comprises an inorganic base.
7. The formulation of claim 1 , wherein the non-steroidal anti-inflammatory drug is piroxicam.
8. The formulation of claim 1 , wherein the non-steroidal anti-inflammatory drug is meloxicam.
9. The formulation of claim 1 , wherein the pH modifier of the first aqueous phase comprises an organic acid.
10. The formulation of claim 1 , wherein at least one amphipathic lipid is selected from zwitterionic phospholipids, anionic amphipathic phospholipids, cationic amphipathic lipids, or combinations thereof.
11. The formulation of claim 1 , wherein at least one amphipathic lipid is selected from phosphatidylcholines, phosphatidylethanolamines, sphingomyelins, lysophosphatidylcholines, lysophosphatidylethanolamines, or combinations thereof.
12. The formulation of claim 1 , wherein at least one amphipathic lipid is selected from phosphatidylglycerols, phosphatidylserines, phosphatidylinositols, phosphatidic acids, cardiolipins, or combinations thereof.
13. The formulation of claim 1 , wherein at least one amphipathic lipid is selected from acyl trimethylammonium propanes, diacyl dimethylammonium propanes, stearylamine, or combinations thereof.
14. The formulation of claim 1 , wherein at least one amphipathic lipid is selected from dioleyl phosphatidyl choline (DOPC), dierucoyl phosphatidylcholine or 1,2-dierucoyl-sn-glycero-3-phosphocholine (DEPC), dipalmitoylphosphatidylglycerol or 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG), or combinations thereof.
15. The formulation of claim 1 , wherein at least one neutral lipid is selected from triglycerides, propylene glycol esters, ethylene glycol esters, squalene, or combinations thereof.
16. The formulation of claim 1 , wherein at least one neutral lipid is selected from tricaprylin, or triolein or combination of the two.
17. The formulation of claim 1 , wherein the multivesicular liposomes are characterized by an internal pH of about 8 to about 9.
18. The formulation of claim 7 , wherein the multivesicular liposomes are characterized by an internal pH of about 8 to about 9.
19. The formulation of claim 8 , wherein the multivesicular liposomes are characterized by an internal pH of about 8 to about 9.
20. The formulation of claim 1 , wherein the first aqueous phase comprises at least one non-steroidal anti-inflammatory drug and one or more pH modifiers.