Methods for preparing oil-in-water emulsions comprising cetalkonium chloride
Compositions containing quaternary compounds in which the nitrogen atom is substituted by at least one alkyl group having at least 12 carbon atoms, and the composition includes at least 20% in weight by weight of the total composition, of ammonium halides in which the nitrogen atom is substituted by at least one alkyl group having at least 14 carbon atoms and more than 5%, preferably more than 7% in weight by weight of the total composition, of ammonium halides in which the nitrogen atom is substituted by at least one alkyl group having at least 16 carbon atoms. Also, ophthalmic oil-in-water emulsions containing such compositions, the ophthalmic emulsions being useful for eye care or for the treatment of eye conditions.
1. A method for preparing an oil-in-water emulsion;
said oil-in-water emulsion comprising:
an oil phase comprising mineral oil, castor oil or medium chain triglycerides,
0.0005% to 0.1% w/w of ammonium halide, cetalkonium chloride being the sole ammonium halide of the emulsion, and
0.1% to 1% w/w of a surfactant selected from tyloxapol, poloxamer 188, tocopherol polyethylene glycol succinate and a mixture thereof; and
said method comprising the following steps:
(i) providing said oil phase and an aqueous phase;
(ii) optionally, heating said oil phase and said aqueous phase at the same temperature;
(iii) dissolving said ammonium halide and said surfactant in said oil phase and/or in said aqueous phase;
(iv) mixing said oil phase and said aqueous phase by magnetic stirring, so as to obtain a first coarse emulsion;
(v) adjusting the droplet size of said first coarse emulsion by high shear mixing and/or high-pressure homogenization, so as to obtain said oil-in-water emulsion; and
(vi) optionally, sterilizing said oil-in-water emulsion by heating.
2. The method according to claim 1 , wherein said mineral oil phase is a mixture of heavy and light mineral oil.
3. The method according to claim 1 , wherein said oil-in-water emulsion further comprises buffering agents and/or at least one tonicity agent.
4. The method according to claim 1 , wherein said oil-in-water emulsion has a positive zeta potential.
5. The method according to claim 1 , wherein said oil-in-water emulsion has a droplet size of 100 to 500 nm.
6. The method according to claim 1 , wherein said oil-in-water emulsion comprises light and heavy mineral oil, tyloxapol, poloxamer 188, mannitol and cetalkonium chloride.
7. The method according to claim 1 , wherein said oil-in-water emulsion comprises light and heavy mineral oil, tyloxapol, poloxamer 188, glycerol and cetalkonium chloride.
8. The method according to claim 1 , wherein said oil-in-water emulsion comprises medium chain triglycerides, tyloxapol, poloxamer 188, glycerol and cetalkonium chloride.
9. The method according to claim 1 , wherein said oil-in-water emulsion further comprises an active principle.
10. The method according to claim 9 , wherein said active principle is cyclosporine.
11. A method for preparing an oil-in-water emulsion;
said oil-in-water emulsion comprising:
an oil phase comprising mineral oil, castor oil or medium chain triglycerides,
0.0005% to 0.1% w/w of ammonium halide, cetalkonium chloride being the sole ammonium halide of the emulsion, and
0.1% to 1% w/w of a surfactant selected from tyloxapol, poloxamer 188, tocopherol polyethylene glycol succinate and s rbitan m n lauratc and a mixture thereof; and
said method comprising the following steps:
(1) manufacturing a pre-concentrate of said oil-in-water emulsion, said pre-concentrate having a content in oil of at least 4% v/v,
by emulsifying and/or mixing said oil phase and said surfactant with an aqueous phase, so as to obtain said pre-concentrate; and then
(2) diluting one volume of said pre-concentrate with 2 to 50 volumes of water, so as to obtain said oil-in-water emulsion.
12. The method according to claim 11 , wherein said pre-concentrate has a content in oil of at least 10% v/v.
13. The method according to claim 12 , wherein said pre-concentrate has a content in oil of at least 20% v/v.
14. The method according to claim 13 , wherein said pre-concentrate has a content in oil of at least 30% v/v.
15. The method according to claim 11 , wherein said oil phase and/or said diluting water comprise(s) said cetalkonium chloride.
16. The method according to claim 11 , wherein the droplet size or the distribution of the droplet size in said pre-concentrate is the same as the droplet size or the distribution of the droplet size in said oil-in-water emulsion.
17. The method according to claim 11 , wherein said diluting water comprises additives selected from tonicity agents, viscosifying agents, buffering agents, preservatives, antioxidants, and colorants.
18. The method according to claim 11 , wherein said mineral oil phase is a mixture of heavy and light mineral oil.
19. The method according to claim 11 , wherein said oil-in-water emulsion further comprises buffering agents and/or at least one tonicity agent.
20. The method according to claim 11 , wherein said oil-in-water emulsion has a positive zeta potential.
21. The method according to claim 11 , wherein said oil-in-water emulsion has a droplet size of 100 to 500 nm.
22. The method according to claim 11 , wherein said oil-in-water emulsion comprises light and heavy mineral oil, tyloxapol, poloxamer 188, mannitol and cetalkonium chloride.
23. The method according to claim 11 , wherein said oil-in-water emulsion comprises light and heavy mineral oil, tyloxapol, poloxamer 188, glycerol and cetalkonium chloride.
24. The method according to claim 11 , wherein said oil-in-water emulsion comprises medium chain triglycerides, tyloxapol, poloxamer 188, glycerol and cetalkonium chloride.
25. The method according to claim 11 , wherein said oil phase further comprises an active principle.
26. The method according to claim 25 , wherein said active principle is cyclosporine.