# US 8,785,497 B2 · Aqueous ophthalmic compositions containing anionic therapeutic agents > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,785,497 B2 - Document ID: US8785497B2 - Status: Granted - Kind: B2 - Application number: 12/759,803 - Filed: 2010-04-14 - Published: 2010-10-21 - Granted: 2014-07-22 - Earliest claimed: 2009-04-17 - Assignees: Alcon Research, Ltd. - Applicants: Bhagwati P. Kabra - Inventors: Bhagwati P. Kabra - Web page: https://patentgrep.com/patent/US8785497B2 ## CPC - A61K 31/195: having an amino group - A61K 9/0048: {Eye, e.g. artificial tears} - A61K 9/08: Solutions {(composition of solutions A61K47/00)} - A61K 31/277: having a ring, e.g. verapamil - A61P 27/02: Ophthalmic agents - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract 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. ## Claims ### Claim 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. ### Claim 2 (depends on 1) 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. ### Claim 3 (depends on 1) An aqueous ophthalmic composition as in claim 1 wherein the therapeutic agent is a PDE-4 inhibitor. ### Claim 4 (depends on 1) An aqueous ophthalmic composition as in claim 1 wherein the therapeutic agent is cilomilast. ### Claim 5 (depends on 1) 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 %. ### Claim 6 (depends on 1) 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 %. ### Claim 7 (depends on 1) An aqueous ophthalmic composition as in claim 1 wherein the antimicrobial agent is polyquaternium-1. ### Claim 8 (depends on 7) 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 %. ### Claim 9 (depends on 1) An aqueous ophthalmic composition as in claim 1 wherein the composition satisfies Ph. Eur. A, Ph. Eur. B or both. ### Claim 10 (depends on 1) An aqueous ophthalmic composition as in claim 1 wherein the composition is substantially free of any benzalkonium chloride. ### Claim 11 (depends on 1) 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. ### Claim 12 (depends on 1) 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 %. ### Claim 13 (depends on 1) An aqueous ophthalmic composition as in claim 1 wherein the composition is substantially free of any surfactant. ### Claim 14 (depends on 1) An aqueous ophthalmic composition as in claim 1 wherein the composition is entirely free of any surfactant. ### Claim 15 (depends on 1) An aqueous ophthalmic composition as in claim 1 wherein the pH of the ophthalmic composition is about 6 to about 8. ### Claim 16 (depends on 1) 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 %. ### Claim 17 (depends on 1) 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 %. ### Claim 18 (depends on 1) 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. ### Claim 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. ### Claim 20 (depends on 1) An aqueous ophthalmic composition as in claim 1 wherein the borate is boric acid. ### Claim 21 (depends on 19) 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. ### Claim 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. ### Claim 23 (depends on 22) 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. ### Claim 24 (depends on 19) An aqueous ophthalmic composition as in claim 19 wherein the osmolality enhancing agent is entirely sodium chloride.