# US 10,441,665 B2 · Liquid formulation of long acting insulinotropic peptide conjugate > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,441,665 B2 - Document ID: US10441665B2 - Status: Granted - Kind: B2 - Application number: 15/714,556 - Filed: 2017-09-25 - Published: 2018-01-18 - Granted: 2019-10-15 - Earliest claimed: 2012-07-25 - Assignees: Hanmi Pharm. Co., Ltd. - Applicants: Hanmi Pharm. Co., Ltd. - Inventors: Hyun Uk Kim; Hyung Kyu Lim; Sung Hee Hong; Dae Jin Kim; Sung Min Bae; Se Chang Kwon - Web page: https://patentgrep.com/patent/US10441665B2 ## CPC - A61K 47/68: the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment - A61K 9/08: Solutions {(composition of solutions A61K47/00)} - A61K 39/39591: {Stabilisation, fragmentation} - A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin - A61K 47/6811: {the drug being a protein or peptide, e.g. transferrin or bleomycin} - C07K 14/57563: {Vasoactive intestinal peptide [VIP]; Related peptides} - C07K 14/605: Glucagons - C07K 16/065: {Purification, fragmentation} - C07K 16/28: against receptors, cell surface antigens or cell surface determinants - C07K 16/4283: {against an allotypic or isotypic determinant on Ig} - C07K 19/00: Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes} - C07K 2317/50: characterized by immunoglobulin fragments - C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto - G01N 33/5047: {Cells of the immune system} - 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) - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) ## Abstract Provided are a liquid formulation of long-acting insulinotropic peptide conjugate, containing a pharmaceutically effective amount of long-acting insulinotropic peptide conjugate consisting of a physiologically active peptide, insulinotropic peptide, and an immunoglobulin Fc region; and an albumin-free stabilizer, wherein the stabilizer comprises a buffer, a sugar alcohol, and a non-ionic surfactant, and a method for preparing the formulation. For the purpose of preventing microbial contamination, a preservative may be added. The liquid formulation of the present invention is free of human serum albumin and other potentially hazardous factors to body, having no risk of viral contamination, and thus can provide excellent storage stability for insulinotropic peptide conjugates at high concentration. ## Claims ### Claim 1 A liquid formulation of a long-acting insulinotropic peptide conjugate, comprising: a pharmaceutically effective amount of the long-acting insulinotropic peptide conjugate wherein an insulinotropic peptide is linked to an immunoglobulin Fc region; and an albumin-free stabilizer, wherein the stabilizer comprises a buffer, a sugar alcohol, and a non-ionic surfactant, wherein the insulinotropic peptide is glucagon-like peptide-1, glucagon-like peptide-2, exendin-3, exendin-4, or imidazo-acetyl exendin-4; wherein the formulation has a pH of about 5.2 to about 7.0; and wherein the non-ionic surfactant has a concentration of about 0.001% (w/v) to about 0.05% (w/v). ### Claim 2 (depends on 1) The liquid formulation according to claim 1, wherein the immunoglobulin Fc region is an Fc region derived from IgG, IgA, IgD, IgE, or IgM. ### Claim 3 (depends on 2) The liquid formulation according to claim 2, wherein the immunoglobulin Fc region is a hybrid of domains of different origins derived from immunoglobulins selected from the group consisting of IgG, IgA, IgD, IgE, and IgM. ### Claim 4 (depends on 2) The liquid formulation according to claim 2, wherein the immunoglobulin Fc region is a dimer or multimer consisting of single-chain immunoglobulins composed of domains of the same origin. ### Claim 5 (depends on 2) The liquid formulation of according to claim 2, wherein the immunoglobulin Fc region is an IgG4 Fc region. ### Claim 6 (depends on 5) The liquid formulation according to claim 5, wherein the immunoglobulin Fc region is a human aglycosylated IgG4 Fc region. ### Claim 7 (depends on 1) The liquid formulation according to claim 1, wherein the insulinotropic peptide is linked to the immunoglobulin Fc region via a non-peptidyl polymer or a fusion protein. ### Claim 8 (depends on 7) The liquid formulation according to claim 7, wherein the non-peptidyl polymer is a polyethylene glycol. ### Claim 9 (depends on 7) The liquid formulation according to claim 7, wherein the non-peptidyl polymer is selected from the group consisting of a biodegradable polymer; a lipid polymer; chitins; hyaluronic acid; and a combination thereof, wherein said biodegradable polymer is selected from the group consisting of polypropylene glycol, a copolymer of ethylene glycol and propylene glycol, polyoxyethylated polyol, polyvinyl alcohol, polysaccharide, dextran, polyvinyl ethyl ether, polylactic acid, and polylactic-glycolic acid. ### Claim 10 (depends on 1) The liquid formulation according to claim 1, wherein the pharmaceutically effective amount of the long-acting insulinotropic peptide conjugate has a concentration of about 0.5 mg/mL to about 150 mg/mL. ### Claim 11 (depends on 1) The liquid formulation according to claim 1, wherein the pharmaceutically effective amount of the long-acting insulinotropic peptide conjugate has a concentration of about 4.0 mg/mL to about 50 mg/mL. ### Claim 12 (depends on 1) The liquid formulation according to claim 1, wherein the sugar alcohol is one or more selected from the group consisting of mannitol, sorbitol, and sucrose. ### Claim 13 (depends on 12) The liquid formulation according to claim 12, wherein a concentration of the sugar alcohol is about 3% (w/v) to about 15% (w/v) based on a total volume of the liquid formulation. ### Claim 14 (depends on 1) The liquid formulation according to claim 1, wherein the buffer is a citrate buffer, an acetate buffer, or a histidine buffer. ### Claim 15 (depends on 1) The liquid formulation according to claim 1, wherein the buffer is a citrate buffer. ### Claim 16 (depends on 15) The liquid formulation according to claim 15, wherein a concentration of the citrate is about 10 mM to about 100 mM based on a total volume of the liquid formulation. ### Claim 17 (depends on 15) The liquid formulation according to claim 15, wherein the citrate is present in a form of citric acid monohydrate. ### Claim 18 (depends on 1) The liquid formulation according to claim 1, wherein the pH range of the formulation is about 5.2 to about 6.0. ### Claim 19 (depends on 1) The liquid formulation according to claim 1, wherein the pH range of the formulation is about 5.4 to about 7.0. ### Claim 20 (depends on 1) The liquid formulation according to claim 1, wherein the pH of the formulation is adjusted by using HCl and/or NaOH. ### Claim 21 (depends on 1) The liquid formulation according to claim 1, wherein the non-ionic surfactant is polysorbate 80 or polysorbate 20. ### Claim 22 (depends on 1) The liquid formulation according to claim 1, wherein the stabilizer further comprises methionine. ### Claim 23 (depends on 22) The liquid formulation according to claim 22, wherein a concentration of the methionine is about 0.005% (w/v) to about 0.1% (w/v) based on a total volume of the liquid formulation. ### Claim 24 (depends on 1) The liquid formulation according to claim 1, wherein the stabilizer further comprises one or more substances selected from the group consisting of a sugar, a polyalcohol, and an amino acid. ### Claim 25 (depends on 1) The liquid formulation according to claim 1, further comprising one or more preservatives selected from the group consisting of m-cresol, phenol, and benzyl alcohol. ### Claim 26 (depends on 25) The liquid formulation according to claim 25, wherein a concentration of the one or more preservatives is about 0.001% (w/v) to about 1% (w/v) based on a total volume of the liquid formulation. ### Claim 27 (depends on 25) The liquid formulation according to claim 25, wherein the preservative is m-cresol. ### Claim 28 A liquid formulation of a long-acting insulinotropic peptide conjugate, the liquid formulation comprising: a pharmaceutically effective amount of the long-acting insulinotropic peptide conjugate wherein an insulinotropic peptide is linked to an immunoglobulin Fc region via polyethylene glycol; and an albumin-free stabilizer, wherein the stabilizer comprises citrate buffer, mannitol, and polysorbate 20, wherein, the insulinotropic peptide is glucagon-like peptide-1, glucagon-like peptide-2, exendin-3, exendin-4, or imidazo-acetyl exendin-4; the formulation has a pH of about 5.2 to about 7.0; and the non-ionic surfactant has a concentration of about 0.001% (w/v) to about 0.05% (w/v). ### Claim 29 (depends on 28) The liquid formulation according to claim 28, wherein the stabilizer further comprises methionine. ### Claim 30 A liquid formulation of a long-acting insulinotropic peptide conjugate, comprising: about 4 mg/mL, about 8.0 mg/mL, or about 12.0 mg/mL of the long-acting insulinotropic peptide conjugate wherein an insulinotropic peptide is linked to an immunoglobulin Fc region via polyethylene glycol; about 4.203 mg/mL citric acid monohydrate; about 0.1 mg/mL L-methionine; about 0.05 mg/mL polysorbate 20; and about 40 mg/mL D-mannitol; wherein the formulation has a pH of about 5.6, and the pH of the formulation is adjusted by using NaOH; and the insulinotropic peptide is imidazo-acetyl exendin-4. ### Claim 31 A multiple-use liquid formulation of a long-acting insulinotropic peptide conjugate, the multiple-use liquid formulation comprising: a pharmaceutically effective amount of the long-acting insulinotropic peptide conjugate wherein an insulinotropic peptide is linked to an immunoglobulin Fc region; an albumin-free stabilizer, wherein the stabilizer comprises a buffer, a sugar alcohol, and a non-ionic surfactant; and one or more preservatives selected from the group consisting of m-cresol, phenol, and benzyl alcohol, wherein the insulinotropic peptide is glucagon-like peptide-1, glucagon-like peptide-2, exendin-3, exendin-4, or imidazo-acetyl exendin-4; wherein the formulation has a pH of about 5.2 to about 7.0; and wherein the non-ionic surfactant has a concentration of about 0.001% (w/v) to about 0.05% (w/v). ### Claim 32 (depends on 1) A method for preparing the liquid formulation of claim 1, the method comprising: mixing a long-acting insulinotropic peptide conjugate wherein an insulinotropic peptide is linked to an immunoglobulin Fc region with a stabilizer comprising a buffer, a sugar alcohol, and a non-ionic surfactant; wherein the insulinotropic peptide is glucagon-like peptide-1, glucagon-like peptide-2, exendin-3, exendin-4, or imidazo-acetyl exendin-4; wherein the buffer has a pH of about 5.2 to about 7.0; and wherein the non-ionic surfactant has a concentration of about 0.001% (w/v) to about 0.05% (w/v). ### Claim 33 (depends on 32) The method according to claim 32, wherein the stabilizer further comprises methionine and/or a preservative.