OIL IN WATER EMULSION COMPRISING NSAIDs AND QUATERNARY AMMONIUM HALIDES

• US 20110021443A1
• Filed: 07/29/2010
• Published: 01/27/2011
• Est. Priority Date: 07/09/2007
• Status: Active Grant

• Current Assignee: Santen SAS (Santen Pharmaceutical Company Limited)
• Original Assignee: Novagali Pharma S.A. (Santen Pharmaceutical Company Limited)
• Inventors: LALLEMAND, Frédéric, RABINOVICH-GUILATT, Laura, GARRIGUE, Jean-Sébastien, LAMBERT, Grégory, PHILIPS, Betty
• Granted Patent: US 8,512,687 B2
• Time in Patent Office: Days
• US Class Current: 514/20.5
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection

Abstract

Oil-in-water emulsion including a non-steroidal anti-inflammatory drug and a quaternary ammonium halide useful for the prevention and treatment of inflammation in the eye, and process for manufacturing thereof.

Claims

1. An oil-in-water emulsion comprising a non-steroidal anti-inflammatory drug and a quaternary ammonium halide in which the nitrogen atom is substituted by one or more alkyl group having at least 12 carbon atoms, wherein

said emulsion being prepared at pH lower than 7, and then buffered at physiological pH, and

said emulsion keeping a positive zeta potential overtime.

2. The oil-in-water emulsion according to claim 1, wherein said non-steroidal anti-inflammatory drug is selected from the group consisting of ketorolac, salicylate, indomethacin, ibuprofen, ketoprofen, flurbiprofen, suprofen, piroxicam, COX2 inhibitors, diclofenac, nimesulide, nepafenac, antineoplastics, cisplatin, mitomycin and fluorouracil.

3. The oil-in-water emulsion according to claim 1, wherein said non-steroidal anti-inflammatory drug is flurbiprofen, ketoprofen and/or ibuprofen.

4. The oil-in-water emulsion according to claim 1, comprising 0.001% to 10% by weight of a non-steroidal anti-inflammatory drug to the total weight of the emulsion.

5. The oil-in-water emulsion according to claim 1, wherein said quaternary ammonium halide is a C16-alkyl quaternary ammonium halide.

6. The oil-in-water emulsion according to claim 1, wherein said quaternary ammonium halide is benzyl dimethyl ammonium chloride or bromide, in which the nitrogen atom is substituted by an alkyl group having at least 12 carbon atoms.

7. The oil-in-water emulsion according to claim 6, wherein said quaternary ammonium halide is C16-alkyl benzyl dimethyl ammonium chloride.

8. The oil-in-water emulsion according to claim 1, wherein said quaternary ammonium halide is a trimethyl ammonium chloride or bromide, wherein the nitrogen atom is further substituted by an alkyl group having at least 12 carbon atoms.

9. The oil-in-water emulsion according to claim 1, said emulsion comprising:

an oil phase comprising an oil selected from the group consisting of medium chain triglycerides, castor oil, mineral oil, and combinations thereof;

at least one surfactant selected from the group consisting of tyloxapol, poloxamer, tocopherol polyethylene glycol succinate, sorbitan monolaurate and polysorbate; and

optionally antioxidants and/or at least one isotonicity agent selected from the group consisting of glycerol, glycerin and mannitol.

10. The oil-in-water emulsion according to claim 1, comprising 0.001 to 0.1% of ammonium halide.

11. The oil-in-water emulsion according to claim 1, said emulsion having a mean droplet size of 100 to 500 nm.

12. The oil-in-water emulsion according to claim 1, said emulsion being preserved.

13. The oil-in-water emulsion according to claim 1, said emulsion being unpreserved.

14. The oil-in-water emulsion according to claim 1, further comprising an immunosuppressive agent, preferably cyclosporin.

15. A medicament comprising the oil-in-water emulsion according to claim 1 and a pharmaceutically acceptable excipient.

16. The medicament according to claim 15, in a unitary dosage form.

17. The medicament according to claim 16, wherein the emulsion is sterile.

18. The medicament according to claim 15, wherein the emulsion is sterile.

19. A method for treating an eye disease caused by, associated with or accompanied by inflammatory processes, comprising the step of administering an effective amount of the oil-in-water emulsion according to claim 1 to a subject in need thereof.

20. A method of treating a subject at risk of developing inflammation or developing an inflammatory process from surgery or trauma, comprising the step of applying pre-surgically or immediately post-traumatically an effective amount of the oil-in-water emulsion according to claim 1 to a subject in need thereof.

21. A method of treating inflammation or limiting an inflammatory process comprising the step of administering an effective amount of the oil-in-water emulsion according to claim 1 to a subject in need thereof.

22. The method according to claim 19, wherein said medicament is administrated less than 4 times a day.

23. A process for manufacturing a pre-concentrate of an oil in water emulsion according to claim 1, said pre-concentrate having a content in oil of at least 3% v/v, the process comprising the steps of emulsifying/mixing the oil phase with an aqueous phase and with surfactant(s), the non-steroidal anti-inflammatory drug being dissolved in the oil phase.

24. A pre concentrate of a therapeutic oil-in-water emulsion, which is itself an oil-in-water emulsion obtainable by the process of claim 23.

25. A process for manufacturing an ophthalmic oil in water emulsion according to claim 1, comprising:

(1) manufacturing a pre-concentrate of an ophthalmic oil in water emulsion, said pre-concentrate having a content in oil of at least 3% v/v, comprising the steps of emulsifying/mixing an oil suitable for ophthalmic use selected from the group consisting of mineral oil, castor oil and medium chain triglycerides, with an aqueous phase and with surfactant(s) and

(2) diluting a volume of the resulting pre-concentrate with 2 to 50 volumes of water, optionally containing a quaternary ammonium chloride.