Ophthalmic oil-in-water emulsions containing prostaglandins
The present invention refers to an oil-in-water emulsion for ophthalmic application comprising at least one prostaglandin as active agent and a surfactant component comprising a combination of at least two non-ionic surfactants. The emulsion is suitable for medical applications, particularly for the treatment of glaucoma, and has an increased chemical stability of the prostaglandin active agent so to allow long-term storage also at room temperature.
1. An oil-in-water emulsion comprising
(i) a dispersed oily phase in an amount between 3-20%,
(ii) at least one prostaglandin as active agent, which is dissolved in the oily phase component (i),
(iii) a surfactant comprising a combination of at least two non-ionic surfactants in amounts which result in a zeta-potential of −10 mV to +10 mV, and
(iv) a contiguous aqueous phase, optionally comprising formulation agents, wherein components (i)-(iv) are suitable for ophthalmic use, said emulsion is stable for at least six months at 25° C., and wherein the non-ionic surfactants of the surfactant component (iii) are selected from the group consisting of polyoxyethylene (20) sorbitan monooleate (Tween 80®), polyoxyethylene (20) sorbitan monolaurate (Tween 20®), polyoxyethylene (2) cetylether (Brij 52®), polyoxyethylene (10) cetylether (Brij 56®), polyoxyethylene (20) cetylether (Brij 58®), and combinations thereof.
2. The oil-in-water emulsion of claim 1 , wherein the oily phase component (i) is selected from pharmaceutically acceptable oils, such as animal or vegetable oils, synthetic oils and mixtures thereof.
3. The oil-in-water emulsion of claim 1 , wherein the oily phase component (i) is selected from the group consisting of ethyl oleate, a mixture of C 8 to C 10 fatty acid triglycerides, ricinus oil, corn oil or mixtures thereof.
4. The oil-in-water emulsion of claim 1 , wherein the oily phase (i) has a solubilization degree of at least 0.1 mg/ml for the prostaglandin component (ii).
5. The oil-in-water emulsion of claim 4 , wherein the oily phase (i) has a solubilization degree of at least 10 mg/ml for the prostaglandin component (ii).
6. The oil-in-water emulsion of claim 1 , wherein the oil/water partition coefficient of the prostaglandin component (ii) is at least log P=0.5 in favor of the oily phase (i).
7. The oil-in-water emulsion of claim 6 , wherein the oil/water partition coefficient of the prostaglandin component (ii) is at least log P=2 in favor of the oily phase (i).
8. The oil-in-water emulsion of claim 1 , wherein the prostaglandin component (ii) is a prostaglandin F2α analogue.
9. The oil-in-water emulsion of claim 8 , wherein the prostaglandin component (ii) is selected from the group consisting of latanoprost, travoprost, bimatoprost and unoprostone and mixtures of two or more thereof.
10. The oil-in-water emulsion of claim 9 , wherein the prostaglandin component (ii) is latanoprost.
11. The oil-in-water emulsion of claim 1 , wherein the non-ionic surfactants of the surfactant component (iii) have a combined total HLB value of at least 10, preferably of at least 13 and preferably up to 18.
12. The oil-in-water emulsion of claim 1 , wherein the at least two surfactants of the surfactant component (iii) are present in a self-emulgation promoting amount.
13. The oil-in-water emulsion of claim 1 , wherein the aqueous phase component (iv) is a pharmaceutically acceptable aqueous phase, preferably selected from the group consisting of sterilized water, purified water or of any other type of water suitable for ophthalmic application.
14. The oil-in-water emulsion of claim 1 , wherein the aqueous phase component (iv) optionally comprises further additives such as buffer agents, isotonic agents, viscosity-increasing compounds, antimicrobial preservatives, antioxidants, stabilizers.
15. The oil-in-water emulsion of claim 14 , wherein the antimicrobial preservative is chlorobutanol.
16. The oil-in-water emulsion of claim 1 , which has a zeta potential between −4 mV and +4 mV.
17. The oil-in-water emulsion of claim 1 , which is a microemulsion wherein the average size of the oil droplets is less than 1 μm.
18. The oil-in-water emulsion of claim 1 , wherein the average droplet size of the oily droplets of the emulsion is 700 nm or less.
19. The oil-in-water emulsion of claim 1 , which has a stability of at least 6 months, preferably at least 9 months, more preferably at least 12 months at 25° C.
20. The oil-in-water emulsion of claim 1 , wherein the components (i) to (iv) are present in the following amounts: (i) 3.0-20.0% (w/w) of the oily phase, (ii) 0.001-5.0% (w/w) of the prostaglandin active agent, (iii) 0.1-10.0% (w/w) of the first non-ionic surfactant and 0.1-10.0% (w/w) of the second non-ionic surfactant, and (iv) 50.0-95.0% (w/w) of the aqueous phase; based on the total weight of the emulsion.
21. The oil-in-water emulsion of claim 1 , wherein the emulsion is free from cosurfactant components, selected from short chain alcohols, mono carboxylic acids, cationic and/or anionic surfactants, lecithins and/or phospholipids.
22. The oil-in-water emulsion of claim 1 , wherein said components (i)-(iv) are present in amounts suitable for alleviation and/or treatment of glaucoma and/or ocular hypertension.
23. The oil-in-water emulsion of claim 1 , wherein the oily phase (i) is present in an amount of at least 5% (w/w) based on the total weight of the emulsion.
24. The emulsion according to claim 1 , wherein the combination of non-ionic surfactants of the surfactant component (iii) is selected from the group consisting of polyoxyethylene (20) sorbitan monooleate (Tween 80®)/polyoxyethylene (20) sorbitan monolaurate (Tween 20®), polyoxyethylene (20) sorbitan monooleate (Tween 80®)/polyoxyl (2) cetylether (Brij 52®), polyoxyl (2) cethylether (Brij 52®)/polyoxyl (20) cethylether (Brij 58®), and polyoxyl (20) cethylether (Brij 58®)/polyoxyl (10) cethylether (Brij 56®).
25. An oil-in-water emulsion comprising
(i) a dispersed oily phase in an amount between 3-20%,
(ii) at least one prostaglandin as active agent, which is dissolved in the oily phase component (i),
(iii) a surfactant comprising a combination of at least two non-ionic surfactants in amounts which result in a zeta-potential of −10 mV to +10 mV, and
(iv) a contiguous aqueous phase,
wherein components (i)-(iv) are suitable for ophthalmic use, said emulsion is stable for at least six months at 25° C., said non-ionic surfactants are each present in an amount of 0.1-10% (w/w) based on the total amount of the emulsion, and wherein the non-ionic surfactants of the surfactant component (iii) are selected from the group consisting of polyoxyethylene (20) sorbitan monooleate (Tween 80®), polyoxyethylene (20) sorbitan monolaurate (Tween 20®), polyoxyethylene (2) cetylether (Brij 52®), polyoxyethylene (10) cetylether (Brij 56®), polyoxyethylene (20) cetylether (Brij 58®).