# US 11,306,094 B2 · Stable formulations of 5,10-methylene-(6R)-tetrahydrofolic acid > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,306,094 B2 - Document ID: US11306094B2 - Status: Granted - Kind: B2 - Application number: 16/796,164 - Filed: 2020-02-20 - Published: 2020-09-10 - Granted: 2022-04-19 - Earliest claimed: 2016-02-17 - Assignees: Merck & Cie - Applicants: Merck & Cie - Inventors: Rudolf Moser; Viola Groehn; Thomas Egger; Thomas Ammann - Web page: https://patentgrep.com/patent/US11306094B2 ## CPC - C07D 475/12: containing pteridine ring systems condensed with carbocyclic rings or ring systems - 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 9/0095: {Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006)} - A61K 9/08: Solutions {(composition of solutions A61K47/00)} - A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} - A61K 31/282: Platinum compounds - A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) - A61K 31/519: ortho- or peri-condensed with heterocyclic rings - A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines} - C07D 475/04: with a nitrogen atom directly attached in position 2 - C07B 2200/13: Crystalline forms, e.g. polymorphs - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - 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) - C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F) ## Abstract The invention is directed towards stable formulations of 5,10-methylene-(6R)-tetrahydrofolic acid and its hemisulfate salt as well as pharmaceutical compositions and uses thereof in therapy, preferably chemotherapy. ## Claims ### Claim 1 A lyophilisate obtained by i) dissolving a hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid in a pharmaceutically acceptable vehicle to form a solution; ii) freezing the solution; and iii) thereafter removing the frozen pharmaceutically acceptable vehicle from the solution under vacuum. ### Claim 2 (depends on 1) A lyophilisate according to claim 1, wherein at least one buffering agent is added to the water in step i). ### Claim 3 (depends on 1) A lyophilisate according to claim 1, wherein at least one adjuvant is added to the water in step i). ### Claim 4 (depends on 1) A lyophilisate according to claim 1, wherein at least one further therapeutic agent is added to the water in step i). ### Claim 5 (depends on 1) A lyophilisate according to claim 1, wherein at least one surfactant is added to the water in step i). ### Claim 6 (depends on 1) A lyophilisate according to claim 1, wherein at least one wetting agent is added to the water in step i). ### Claim 7 (depends on 1) A lyophilisate according to claim 1, wherein a step of sterile filtration is performed between step i) and ii). ### Claim 8 (depends on 1) A lyophilisate according to claim 1, wherein the molar ratio of 5,10-methylene-(6R)-tetrahydrofolic acid to sulfate is 2 to 1. ### Claim 9 (depends on 1) A lyophilisate according to claim 1, wherein NaOH is added in step i). ### Claim 10 (depends on 1) A lyophilisate according to claim 1, wherein sodium citrate is added in step i). ### Claim 11 (depends on 1) A lyophilisate according to claim 1, which has such stability that the composition maintains greater than or equal to 99% of purity of the 5,10-methylene-(6R)-tetrahydrofolic acid for at least 12 months at +25° C. ### Claim 12 (depends on 1) A method for treating cancer, comprising administering an effective amount of the reconstituted product obtained by dissolving the lyophilisate of claim 1 in water to a patient in need thereof. ### Claim 13 (depends on 12) The method according to claim 12, wherein the cancer is breast cancer, esophageal cancer, gastric cancer, gall bladder cancer, bile duct cancer, colon cancer, rectal cancer, colorectal cancer, osteosarcoma, liver cancer, pancreatic cancer, ovarian cancer, head and neck cancer or mesotheolioma cancer. ### Claim 14 (depends on 12) The method according to claim 12, which further comprises administering an effective amount of at least one further chemotherapeutic agent suitable for the treatment of cancer to said patient. ### Claim 15 (depends on 14) The method according to claim 14, wherein the at least one further chemotherapeutic agent suitable for the treatment of cancer is one or more of oxaliplatin, irinotecan or bevacizumab. ### Claim 16 (depends on 1) A kit containing the lyophilisate according to claim 1 and a pharmaceutically acceptable liquid vehicle suitable for reconstitution of the lyophilisate to form a reconstituted solution. ### Claim 17 (depends on 16) The kit according to claim 16, in which the lyophilisate is in a syringe. ### Claim 18 (depends on 1) A kit containing the lyophilisate according to claim 1 and at least one further chemotherapeutic agent suitable for the treatment of cancer, which are present apart from each other in said kit, and wherein the kit optionally further contains a pharmaceutically acceptable liquid vehicle suitable for the reconstitution of the lyophilisate to form a reconstituted solution. ### Claim 19 (depends on 12) The method according to claim 12, wherein the cancer is colon cancer, rectal cancer or colorectal cancer.