# US 11,925,608 B2 · Stabilization of epinephrine formulations > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,925,608 B2 - Document ID: US11925608B2 - Status: Granted - Kind: B2 - Application number: 16/650,979 - Filed: 2018-09-26 - Published: 2020-08-27 - Granted: 2024-03-12 - Earliest claimed: 2017-09-26 - Assignees: Ys Pharmtech - Applicants: Ys Pharmtech - Inventors: Yosyong Surakitbanharn - Web page: https://patentgrep.com/patent/US11925608B2 ## CPC - A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone} - A61J 1/10: Bag-type containers - A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame} - A61K 47/20: containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids - A61K 47/6951: {using cyclodextrin (cyclodextrins used as simple excipients A61K47/40)} - A61M 5/24: Ampoule syringes, i.e. syringes with needle for use in combination with replaceable ampoules or cartridges, e.g. automatic - A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure - A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)} - 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) - A61J: CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE - A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)} - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The disclosure herein relates to the innovative epinephrine formulations in aqueous solution of medicinal products that enhance the physicochemical stabilities of epinephrine and extend the product shelf life. In some instances, the formulations comprise epinephrine or a salt thereof, a complexing agent, and a “non-sulfite” antioxidant. The epinephrine formulations substantially demonstrated the superior physicochemical stabilities to conventional sulfite formulation of commercial medications currently available. In some instances, sulfite-free formulations further provide further benefit (e.g., safety benefits) to sulfite-sensitive patients. The compositions, methods for preparing the formulations, and methods of using the same (e.g., in the treatment of anaphylaxis) are also provided. ## Claims ### Claim 1 A pharmaceutical composition comprising: epinephrine; cysteine being present in the composition in an amount of about 0.05 wt. % to about 0.005 wt. % on a free base basis; and an aqueous medium; wherein the pharmaceutical composition has a pH of at least 3.5. ### Claim 2 (depends on 1) The pharmaceutical composition of claim 1, wherein cysteine is present in a concentration of about 0.005 wt. % to about 0.035 wt. %. ### Claim 3 (depends on 2) The pharmaceutical composition of claim 2, wherein cysteine present in a concentration of about 0.005 wt. % to about 0.03 wt. %. ### Claim 4 (depends on 1) The pharmaceutical composition of claim 1, wherein cysteine is present in a concentration of about 0.01 wt. % to about 0.05 wt. %. ### Claim 5 (depends on 4) The pharmaceutical composition of claim 4, wherein cysteine is present in a concentration of about 0.01 wt. % to about 0.035 wt. %. ### Claim 6 (depends on 5) The pharmaceutical composition of claim 5, wherein cysteine is present in a concentration of about 0.01 wt. % to about 0.03 wt. %. ### Claim 7 The pharmaceutical composition of any one of the preceding claims, wherein after 12 months of storage at 25±2° C. and 60±5% relative humidity (RH), (i) the composition comprises at least 90 wt. % of the epinephrine in the composition prior to storage; and (ii) the composition is substantially colorless. ### Claim 8 The pharmaceutical composition of any one of the preceding claims, wherein after at least 1 year of storage at 25° C./60%RH, less than 10% of the epinephrine is d-epinephrine. ### Claim 9 The pharmaceutical composition of any one of the preceding claims, wherein after at least 1.5 years of storage at 25° C./60%RH, less than 10% of the epinephrine is d-epinephrine. ### Claim 10 The pharmaceutical composition of any one of the preceding claims, wherein after at least 2 years of storage at 25° C./60%RH, less than 10% of the epinephrine is d-epinephrine. ### Claim 11 The pharmaceutical composition of any one of the preceding claims, wherein the epinephrine is present in the composition in an amount of about 0.0005 wt. % to about 1 wt. % on a free base basis. ### Claim 12 The pharmaceutical composition of any one of the preceding claims, wherein cysteine is present in the composition in a weight ratio of cysteine to epinephrine of about 7:10 down to a ratio of about 1:20. ### Claim 13 The pharmaceutical composition of any one of the preceding claims, wherein a weight ratio of cysteine-to-epinephrine is 1:10 to about 7:10. ### Claim 14 The pharmaceutical composition of any one of the preceding claims, wherein a weight ratio of cysteine-to-epinephrine is about 2:10 to about 4:10. ### Claim 15 The pharmaceutical composition of any one of the preceding claims, wherein the cysteine is present in the composition in an amount of greater than 0.001 wt. % or more. ### Claim 16 The pharmaceutical composition of any one of the preceding claims, further comprising as a pH buffering agent citric acid and/or citrate. ### Claim 17 The pharmaceutical composition of any one of the preceding claims, wherein the combined weight of pH buffering agent(s) citric acid and citrate constitute about 0.01 wt. % or less of the composition. ### Claim 18 The pharmaceutical composition of any one of the preceding claims, further comprising a chelating agent edetate. ### Claim 19 The pharmaceutical composition of any one of the preceding claims, wherein a chelating agent (edetate) is present in the composition in an amount of about 0.01 wt. % or less. ### Claim 20 The pharmaceutical composition of any one of the preceding claims, wherein a tonicity modifier is present in the composition in an amount suitable to provide a solution osmolality in the range of about 200 mOsm/kg to about 400 mOsm/kg. ### Claim 21 The pharmaceutical composition of any one of the preceding claims, wherein the composition is an aqueous solution having a pH of about 3.5 to about 6.5. ### Claim 22 The pharmaceutical composition of any one of the preceding claims, wherein the aqueous medium is water suitable for injection. ### Claim 23 The pharmaceutical composition of any one of the preceding claims, wherein the composition is loaded into an administrative device, the administrative device being a syringe or a cartridge suitable for use in a manual and/or auto injector.