Sustained release formulation of a non-steroidal anti-inflammatory drug

Patent metadata

Field	Value
Publication number	US-10675245-B2
Application number	US-201313787382-A
Country	US
Kind code	B2
Filing date	Mar 6, 2013
Priority date	Oct 28, 2010
Publication date	Jun 9, 2020
Grant date	Jun 9, 2020

Abstract

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.

First claim

What is claimed is:

1. A process for preparing multivesicular liposomal formulations, the process comprising:
providing a first emulsion comprising at least one non-steroidal anti-inflammatory drug selected from the group consisting of piroxicam, and meloxicam by mixing a first aqueous phase comprising the at least one non-steroidal anti-inflammatory drug and one or more pH modifiers and a volatile water-immiscible solvent phase, wherein said solvent phase comprises at least one amphipathic lipid and at least one neutral lipid;
mixing and emulsifying said first emulsion and a second aqueous phase to provide a second emulsion, said second emulsion comprising a continuous 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 liposomes are characterized by an internal pH of about 7 or higher.

2. The process of claim 1 , wherein the multivesicular liposomes further comprise a pH modifier in the second aqueous phase.

3. The process of claim 1 , wherein the pH modifier of the first aqueous phase comprises lysine or glutamic acid, or a combination thereof.

4. The process of claim 1 , wherein the pH modifier of the first aqueous phase comprises an inorganic acid.

5. The process of claim 1 , wherein the pH modifier of the first aqueous phase comprises an organic base.

6. The process of claim 1 , wherein the pH modifier of the first aqueous phase comprises an inorganic base.

7. The process of claim 1 , wherein the non-steroidal anti-inflammatory drug is piroxicam.

8. The process of claim 1 , wherein the non-steroidal anti-inflammatory drug is meloxicam.

9. The process of claim 1 , wherein the pH modifier of the first aqueous phase comprises an organic acid.

10. The process 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 process of claim 1 , wherein at least one amphipathic lipid is selected from phosphatidylcholines, phosphatidylethanolamines, sphingomyelins, lysophosphatidylcholines, lysophosphatidylethanolamines, or combinations thereof.

12. The process of claim 1 , wherein at least one amphipathic lipid is selected from phosphatidylglycerols, phosphatidylserines, phosphatidylinositols, phosphatidic acids, cardiolipins, or combinations thereof.

13. The process of claim 1 , wherein at least one amphipathic lipid is selected from acyl trimethylammonium propanes, diacyl dimethylammonium propanes, stearylamine, or combinations thereof.

14. The process 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 process 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 process of claim 1 , wherein at least one neutral lipid is selected from tricaprylin, or triolein or combination of the two.

17. The process of claim 1 , wherein the multivesicular liposomes are characterized by an internal pH of about 8 to about 9.

18. The process of claim 7 , wherein the multivesicular liposomes are characterized by an internal pH of about 8 to about 9.

19. The process of claim 8 , wherein the multivesicular liposomes are characterized by an internal pH of about 8 to about 9.

Assignees

• Pacira Pharmaceuticals Inc

Inventors

• Garcia Louie Daniel
• Zhu Liangjin
• Lambert William Joseph
• Patou Gary

Classifications

• A61K31/5415

  ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam · CPC title

• A61K9/1278

  Post-loading, e.g. by ion or pH gradient · CPC title

• A61K9/127

  Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant · CPC title

• A61K31/196

  the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil · CPC title

• A61K9/1272 Primary

  comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543}) · CPC title