Aqueous ophthalmic compositions containing anionic therapeutic agents
View Patent ↗The present invention is directed to the provision of multi-dose, ophthalmic compositions. The compositions possess sufficient antimicrobial activity to satisfy USP preservative efficacy requirements, as well as similar preservative standards (e.g., EP and JP). The compositions include a balance of ingredients that allow for the formation of ophthalmic compositions that include an anionic drug and exhibit desired characteristics such as stability, preservation efficacy, desired pH, desired osmolality, combinations thereof or the like.
1. An aqueous ophthalmic composition, comprising:
an anionic therapeutic agent;
mannitol at a concentration that is at least 0.05 w/v % but is no greater than 1.5 w/v %;
borate at a concentration that is at least 0.1 w/v % but is no greater than 0.5 w/v %;
sodium chloride a concentration that is at least 85 mmol wherein the sodium chloride enhances the physical stability or clarity of the composition;
a positively charged antimicrobial agent that is a polymeric quaternary ammonium compound; and
water, wherein the osmolality of the ophthalmic composition is in the range of 240 to 360 mOsm/kg and wherein the composition is an aqueous solution having a turbidity of less than 2 NTU.
2. An aqueous ophthalmic composition as in claim 1 wherein the anionic therapeutic agent includes a negatively charged carboxylic acid group at a pH that is from about 5 to about 9.
3. An aqueous ophthalmic composition as in claim 1 wherein the therapeutic agent is a PDE-4 inhibitor.
4. An aqueous ophthalmic composition as in claim 1 wherein the therapeutic agent is cilomilast.
5. An aqueous ophthalmic composition as in claim 1 wherein the mannitol is at a concentration that is at least 0.08 w/v % but is no greater than 0.12 w/v %.
6. An aqueous ophthalmic composition as in claim 1 wherein the positively charged antimicrobial agent is present in the composition at a concentration that is at least 0.0001 w/v % but is no greater than 0.0012 w/v %.
7. An aqueous ophthalmic composition as in claim 1 wherein the antimicrobial agent is polyquaternium-1.
8. An aqueous ophthalmic composition as in claim 7 wherein the antimicrobial agent is present in the composition in a concentration that is at least 0.0001 w/v % but is no greater than 0.0012 w/v %.
9. An aqueous ophthalmic composition as in claim 1 wherein the composition satisfies Ph. Eur. A, Ph. Eur. B or both.
10. An aqueous ophthalmic composition as in claim 1 wherein the composition is substantially free of any benzalkonium chloride.
11. An aqueous ophthalmic composition as in claim 1 wherein the therapeutic agent includes an acidic group that exhibits a negative charge at a pH in the range of 5 to 9.
12. An aqueous ophthalmic composition as in claim 1 wherein the concentration of borate is no greater than 0.4 w/v % and the concentration of mannitol is no greater than 0.2 w/v %.
13. An aqueous ophthalmic composition as in claim 1 wherein the composition is substantially free of any surfactant.
14. An aqueous ophthalmic composition as in claim 1 wherein the composition is entirely free of any surfactant.
15. An aqueous ophthalmic composition as in claim 1 wherein the pH of the ophthalmic composition is about 6 to about 8.
16. An aqueous ophthalmic composition as in claim 1 wherein the concentration of the therapeutic agent is at least 0.01 w/v % and no greater than 0.5 w/v %.
17. An aqueous ophthalmic composition as in claim 1 wherein the therapeutic agent is cilomilast and the concentration of the therapeutic agent is at least 0.01 w/v % and no greater than 0.3 w/v %.
18. An aqueous ophthalmic composition as in claim 1 wherein the sodium chloride is present in the composition at a concentration that is at least 100 mmol.
19. An aqueous ophthalmic composition, comprising:
an anionic therapeutic agent wherein the concentration of the therapeutic agent is at least 0.01 w/v % and no greater than 0.5 w/v %;
mannitol at a concentration that is at least 0.05 w/v % but is no greater than 1.5 w/v %;
borate at a concentration that is at least 0.1 w/v % but is no greater than 0.5 w/v %;
a positively charged antimicrobial agent that is a polymeric quaternary compound wherein the positively charged antimicrobial agent is present in the composition in a concentration that is at least 0.0001 w/v % but is no greater than 0.0012 w/v %;
osmolality enhancing agent wherein the osmolality enhancing agent raises the osmolality of the ophthalmic composition at least 160 mOsm/Kg relative to a control composition that includes the exact same ingredients as the ophthalmic composition with the exception that the osmolality enhancing agent is replaced with water and pH is brought to the same value as that of the ophthalmic composition by using sodium hydroxide or hydrogen chloride if necessary and wherein the osmolality enhancing agent is present in the composition at a concentration that is at least 110 mmol but no greater than no greater than 200 mmol and wherein the osmolality enhancing agent also enhances the physical stability or clarity of the composition; and
water;
wherein the osmolality of the ophthalmic composition is in the range of 240 to 360 mOsm/kg and wherein the composition is substantially free of any benzalkonium chloride and wherein the osmolality enhancing agent is sodium chloride and wherein the composition is an aqueous solution having a turbidity of less than 2 NTU.
20. An aqueous ophthalmic composition as in claim 1 wherein the borate is boric acid.
21. An aqueous ophthalmic composition as in claim 19 wherein the borate is boric acid and wherein the anionic therapeutic agent includes a negatively charged carboxylic acid group at a pH that is from about 5 to about 9.
22. An aqueous ophthalmic composition, comprising:
an anionic therapeutic agent wherein the concentration of the therapeutic agent is at least 0.01 w/v % and no greater than 0.5 w/v %;
mannitol at a concentration that is at least 0.05 w/v % but is no greater than 1.5 w/v %;
borate at a concentration that is at least 0.1 w/v % but is no greater than 0.5 w/v %;
a positively charged antimicrobial agent that is a polymeric quaternary ammonium compound wherein the positively charged antimicrobial agent is present in the composition in a concentration that is at least 0.0001 w/v % but is no greater than 0.0012 w/v %;
osmolality enhancing agent that is entirely or substantially entirely sodium chloride wherein the osmolality enhancing agent is present in the composition at a concentration that is at least 110 mmol but no greater than no greater than 200 mmol and wherein the osmolality enhancing agent also enhances the physical stability or clarity of the composition; and
water;
wherein the osmolality of the ophthalmic composition is in the range of 240 to 360 mOsm/kg and wherein the composition is substantially free of any benzalkonium chloride and wherein the osmolality enhancing agent is sodium chloride and wherein the composition is an aqueous solution having a turbidity of less than 2 NTU.
23. An aqueous ophthalmic composition as in claim 22 wherein the therapeutic agent includes an acidic group that exhibits a negative charge at a pH in the range of 5 to 9.
24. An aqueous ophthalmic composition as in claim 19 wherein the osmolality enhancing agent is entirely sodium chloride.