FIELD: medicine; pharmaceutics.
SUBSTANCE: group of inventions relates to pharmaceutics, specifically to a composition of double GLP-1/GLP-2 agonists, a method for improving chemical stability of an isotonic parenteral pharmaceutical composition containing 1 to 15 mg/ml of one or more double GLP-1/GLP-2 agonists certain structure, use of mannitol or a salt selected from NaCl and KCl, in amount of 1 to 500 mM, to improve the chemical stability of composition containing 1 to 15 mg/ml of one or more double GLP-1/GLP-2 agonists of said structure, as well as to the use of said composition for: increasing intestinal weight, improving intestinal function, increasing intestinal blood flow or eliminating intestinal damage or dysfunction in a subject in need thereof, or prevention or treatment of malabsorption, ulcers, short bowel syndrome, blind sac syndrome, inflammatory bowel disease, irritable bowel syndrome, pouchitis, celiac disease-sprue, tropic sprue, hypogammaglobulinemic sprue, inflammation of the mucous membrane induced by chemotherapy or radiation therapy, diarrhea induced by chemotherapy or radiation therapy, nonspecific inflammation, metabolic endotoxicosis, necrotizing enterocolitis, primary biliary cirrhosis, hepatitis, fatty liver disease or gastrointestinal side effects of inflammatory conditions, in a subject in need thereof, or reducing or inhibiting weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite or promoting weight loss in a subject in need thereof, or preventing or treating obesity, morbid obesity, obesity-related gallbladder disease caused by obesity sleep apnea, inadequate glucose control, glucose tolerance, dyslipidemia, diabetes, pre-diabetes, metabolic syndrome or hypertension in a subject in need thereof. Composition of double agonists GLP-1/GLP-2, where composition contains: from 1 to 15 mg/ml of one or more double GLP-1/GLP-2 agonists containing general formula A: H[Aib]EG-X5-F-X7-SELATILD-[Ψ]-QAARDFIAWLI-X28-X29-KITD (A), where X5 is T or S; X7 is T or S; X28 is Q, E, A, H, Y, L, K, R or S; X29 is H and at least one of X5 and X7 is T, and where [Ψ] indicates L or D is a lysine residue in which an albumin-binding group is conjugated with a double agonist GLP-1/GLP-2, and where said albumin-binding group is [K([17-carboxyheptadecanoyl]-isoGlu)]; and b. from 1 to 200 mM of a buffer component selected from the group consisting of a phosphate buffer, a citrate buffer, a tris buffer or bis tris, or a combination thereof; and p. from 1 to 500 mM of one or more tonicity regulating agents, wherein said one or more tonicity regulating agents comprises mannitol or a salt selected from NaCl and KCl, wherein said composition further comprises a solvent, and wherein said composition has a pH from pH 6.0 to pH 8.2. Method of improving chemical stability of isotonic parenteral pharmaceutical composition containing from 1 to 15 mg/ml of one or more double agonists GLP-1/GLP-2 containing general formula A: H[Aib]EG-X5-F-X7-SELATILD-[Ψ]-QAARDFIAWLI-X28-X29-KITD (A), where X5 is T or S; X7 is T or S; X28 is Q, E, A, H, Y, L, K, R or S; X29 is H and at least one of X5 and X7 is T, and where [Ψ] indicates an L or D lysine residue in which an albumin-binding group is conjugated to a double agonist GLP-1/GLP-2, and wherein said albumin-binding group is [K([17-carboxyheptadecanoyl]-isoGlu)]; where said method involves adding from 1 to 500 mM mannitol or a salt selected from NaCl and KCl, into said composition. Use of mannitol or a salt selected from NaCl and KCl in amount of 1 to 500 mM, to improve chemical stability of composition containing 1 to 15 mg/ml of one or more double GLP-1/GLP-2 agonists containing general formula A: H[Aib]EG-X5-F-X7-SELATILD-[Ψ]-QAARDFIAWLI-X28-X29-KITD (A), where X5 is T or S; X7 is T or S; X28 is Q, E, A, H, Y, L, K, R or S; X29 is H and at least one of X5 and X7 is T, and where [Ψ] indicates an L or D lysine residue in which an albumin-binding group is conjugated with a double agonist GLP-1/GLP-2, and wherein said albumin-binding group is [K([17-carboxyheptadecanoyl]-isoGlu)]. Use of said composition for: (i) increasing intestinal weight, improving intestinal function, increasing intestinal blood flow or eliminating intestinal damage or dysfunction in a subject, in need thereof; or (ii) prevention or treatment of malabsorption, ulcers, short bowel syndrome, blind sac syndrome, inflammatory bowel disease, irritable bowel syndrome, sprue, celiac sprue, hypogammaglobulinemic sprue, chemotherapy-induced mucosal inflammation or radiation therapy, chemotherapy or radiation therapy-induced diarrhea, non-specific inflammation, metabolic endotoxicosis, necrotizing enterocolitis, primary biliary cirrhosis, hepatitis, fatty liver disease or gastrointestinal side effects of inflammatory conditions, in a subject in need thereof; or (iii) reducing or inhibiting weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite or facilitating weight loss in a subject in need thereof; or (iv) preventing or treating obesity, morbid obesity, obesity-related gallbladder disease caused by obesity sleep apnea, inadequate glucose control, glucose tolerance, dyslipidemia, diabetes, pre-diabetes, metabolic syndrome or hypertension in a subject in need thereof.
EFFECT: said group of inventions provides high stability of the parenteral pharmaceutical composition containing the double agonist GLP-1/GLP-2 and mannitol or sodium chloride.
47 cl, 40 tbl, 11 ex
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Authors
Dates
2024-10-08—Published
2020-06-12—Filed