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WO2025191149A1 - Composition pharmaceutique comprenant un agoniste du récepteur glp-1 et gip double - Google Patents

Composition pharmaceutique comprenant un agoniste du récepteur glp-1 et gip double

Info

Publication number
WO2025191149A1
WO2025191149A1 PCT/EP2025/057057 EP2025057057W WO2025191149A1 WO 2025191149 A1 WO2025191149 A1 WO 2025191149A1 EP 2025057057 W EP2025057057 W EP 2025057057W WO 2025191149 A1 WO2025191149 A1 WO 2025191149A1
Authority
WO
WIPO (PCT)
Prior art keywords
concentration
phenol
metacresol
optionally
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/057057
Other languages
English (en)
Inventor
Sasa ROZMAN
Gordan Sladic
Ales Gasparic
Tanja KOLESA
Anja PUCER JANEZ
Timotej ZALETEL
Borut Kovacic
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KRKA dd
Original Assignee
KRKA dd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by KRKA dd filed Critical KRKA dd
Publication of WO2025191149A1 publication Critical patent/WO2025191149A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—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

Definitions

  • the invention pertains to new pharmaceutical compositions containing a GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (Glucagon-like peptide- 1) receptor agonist.
  • GIP glycose-dependent insulinotropic polypeptide
  • GLP-1 Glucagon-like peptide- 1 receptor agonist
  • the invention provides pharmaceutical compositions containing tirzepatide.
  • the pharmaceutical compositions according to the invention are physically and chemically stable, are easy to manufacture and suitable for parenteral administration.
  • the invention further provides methods for making the same.
  • GLP-1 and GIP are hormones involved in blood-sugar control. After a meal, these hormones are secreted by cells of the intestines, and they cause the secretion of insulin from the pancreas.
  • Tirzepatide is a long-acting GIP/GLP analogue that activates both the GLP-1 and GIP receptors, leading to improved blood-sugar control. It has a greater affinity to GIP receptors than to GLP-1 receptors, and this dual agonist behavior has been shown to produce greater reductions of hyperglycemia compared to a selective GLP-1 receptor agonist. Tirzepatide mimics the actions of natural GIP at the GIP receptor. At the GLP-1 receptor tirzepatide shows bias towards cAMP (a messenger associated with regulation of glycogen, sugar, and lipid metabolism) generation, rather than [3-arrestin recruitment. This combination of preference towards GIP receptor and distinct signaling properties at GLP-1 suggest this biased agonism increases insulin secretion. Tirzepatide has also been reported to increase levels of adi- ponectin, an adipokine involved in the regulation of both glucose and lipid metabolism.
  • cAMP a messenger associated with regulation of glycogen, sugar, and lipid metabolism
  • Tirzepatide (CAS 2023788-19-2, ATC A10BX16) is a linear polypeptide of 39 amino acids that has been chemically modified by lipidation (fatty-diacid section (eicosanedioic acid) is linked via a glutamic acid and two (2-(2-aminoethoxy)ethoxy)acetic acid units to the side chain of the lysine residue.), which improves its uptake into cells and also enables a much longer half-life (because of its high affinity to albumin), thereby extending the time between doses.
  • lipidation fatty-diacid section (eicosanedioic acid) is linked via a glutamic acid and two (2-(2-aminoethoxy)ethoxy)acetic acid units to the side chain of the lysine residue.
  • Tirzepatide sold under the brand name Mounjaro® among others, is an antidiabetic medication used for the treatment of type 2 diabetes and for weight loss. It is administered once a week through subcutaneous injections.
  • Tirzepatide was first described in WO 2016/111971 Al. The same document also describes a method of synthesis of tirzepatide.
  • WO 2019/245893 A2 describes formulations of tirzepatide.
  • One composition comprises tirzepatide, NaCl, and dibasic sodium phosphate.
  • An alternative composition comprises tirzepatide, propylene glycol, and dibasic sodium phosphate.
  • Compositions which further comprise a preservative (metacresol or phenol) are described as well.
  • a preservative metalacresol or phenol
  • Measurement of pH is performed according to the Ph. Eur. test 2.2.3. Potentiometric determination of pH, where determination of pH is made by measuring the potential difference between the reference electrode and the electrode, sensitive to hydrogen ions.
  • Measurement of osmolality is performed according to the Ph. Eur. test 2.2.35. Osmolality, where osmolality is determined by measurement of depression of freezing point.
  • Clarity of solution is measured according to the Ph. Eur. test 2.2.1. Clarity and degree of opalescence of liquids, where clarity can be determined by a visual or an instrumental method.
  • the above tests are carried out as specified in the 9th Edition of Ph. Eur. [0029] If no temperature is specified, the temperature for carrying out the described methods is not particularly restricted. Unless the context dictates otherwise, the described operations may for instance be carried out at any temperature within the normal room temperature range, i.e. 15-30°C, such as 20- 25 °C and more specifically 21-23 °C.
  • final volume is meant to characterize the volume that is obtained when adding sufficient water for injections to reach the intended concentration of the GIP/GLP analogue, such as, in embodiments of the invention, the concentrations specified in Section 5.
  • the GIP/GLP analogue is tirzepatide.
  • Tirzepatide was first described in WO 2016/111971 Al.
  • the term tirzepatide as used in the invention denotes tirzepatide and all pharmaceutically acceptable salts, hydrates, solvates, prodrugs, chelates and complexes thereof.
  • the concentration of tirzepatide present in the pharmaceutical composition according to the invention is from 4-30 mg/ml.
  • Tirzepatide used in the pharmaceutical composition according to the invention may be prepared according to any manufacturing process known from the state art such as for example WO 2016/111971 Al.
  • the pharmaceutical composition of the invention is designated by the use of at least one buffering agent.
  • buffering agent as used in the invention denotes a compound used to maintain the pH near a desired value.
  • a suitable buffering agent can be any compound known to the person skilled in the art as described e.g. in Remington: The Science and Practice of Pharmacy, 22nd Edition, 2013, to maintain the pH in basic environment, e.g. in one of the pH ranges specified in the pharmaceutical composition section below, and which is suitable for using in pharmaceutical compositions.
  • the buffering agent can include, but it is not limited to, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, sodium acetate, sodium carbonate, sodium citrate, meglumine, glycine, histidine, lysine, arginine, asparagine, glutamic acid, sodium glutamate, TRIS (hydroxymethyl)-amino- methane, methionine, Hepes, maleic acid, malic acid, lactate or any combinations thereof.
  • Each one of these specific buffering agents and combinations thereof constitutes an alternative embodiment of the invention.
  • the buffering agent to be used according to a preferred embodiment of the invention is selected from the group consisting of TRIS, sodium citrate, histidine and disodium hydrogen phosphate or any combination thereof.
  • the buffering agent to be used according to a preferred embodiment of the invention is selected from the group consisting of TRIS, sodium citrate and histidine or any combination thereof.
  • the concentration of buffering agent used in the pharmaceutical composition of the invention is in the range of 0.30-1.70 mg/ml.
  • concentration of buffering agent used in the pharmaceutical composition of the invention is in the range of 0.55-1.20 mg/ml.
  • the buffering agent used in the pharmaceutical composition of the invention is TRIS.
  • the concentration of TRIS used in the pharmaceutical composition of the invention is in the range of 0.30-0.90 mg/ml.
  • the concentration of TRIS used in the pharmaceutical composition of the invention is in the range of 0.45-0.75 mg/ml.
  • the concentration of TRIS used in the pharmaceutical composition of the invention is in the range of 0.50-0.70 mg/ml.
  • the concentration of Na-citrate used in the pharmaceutical composition of the invention is in the range of 0.75-1.45 mg/ml.
  • the concentration of Na-citrate used in the pharmaceutical composition of the invention is in the range of 0.90-1.30 mg/ml.
  • the concentration of lactose monohydrate used in the pharmaceutical composition of the invention is in the range of 49-69 mg/ml.
  • the tonicity agent used in the pharmaceutical composition of the invention is maltose or a hydrate thereof, preferably maltose or maltose monohydrate, more preferably maltose.
  • the concentration of glycine used in the pharmaceutical composition of the invention is in the range of 15-30 mg/ml.
  • concentration of glycine used in the pharmaceutical composition of the invention is in the range of 19-24 mg/ml.
  • the concentration of PEG 400 used in the pharmaceutical composition of the invention is in the range of 116-128 mg/ml.
  • the concentration of myo-inositol used in the pharmaceutical composition of the invention is in the range of 20-90 mg/ml.
  • the concentration of myo-inositol used in the pharmaceutical composition of the invention is in the range of 30-65 mg/ml.
  • the concentration of myo-inositol used in the pharmaceutical composition of the invention is in the range of 39-58 mg/ml.
  • the concentration of myo-inositol used in the pharmaceutical composition of the invention is in the range of 39-48 mg/ml.
  • the concentration of myo-inositol used in the pharmaceutical composition of the invention is in the range of 49-58 mg/ml.
  • the concentration of myo-inositol used in the pharmaceutical composition of the invention is in the range of 45-55 mg/ml.
  • the tonicity agent used in the pharmaceutical composition of the invention is L-arginine.
  • concentration of L-arginine used in the pharmaceutical composition of the invention is in the range of 23-70 mg/ml.
  • the concentration of L-arginine used in the pharmaceutical composition of the invention is in the range of 38-66 mg/ml.
  • the concentration of L-arginine used in the pharmaceutical composition of the invention is in the range of 45-56 mg/ml.
  • the tonicity agent used in the pharmaceutical composition of the invention is dimethylsulfone.
  • the concentration of dimethylsulfone used in the pharmaceutical composition of the invention is in the range of 10-45 mg/ml.
  • the concentration of dimethylsulfone used in the pharmaceutical composition of the invention is in the range of 15-35 mg/ml.
  • the concentration of dimethylsulfone used in the pharmaceutical composition of the invention is in the range of 20-30 mg/ml.
  • the tonicity agent used in the pharmaceutical composition of the invention is sorbitol.
  • the concentration of sorbitol used in the pharmaceutical composition of the invention is in the range of 20-90 mg/ml.
  • the concentration of sorbitol used in the pharmaceutical composition of the invention is in the range of 30-65 mg/ml.
  • the concentration of sorbitol used in the pharmaceutical composition of the invention is in the range of 39-58 mg/ml.
  • the concentration of sorbitol used in the pharmaceutical composition of the invention is in the range of 49-58 mg/ml.
  • the tonicity agent used in the pharmaceutical composition of the invention is xylitol.
  • the concentration of xylitol used in the pharmaceutical composition of the invention is in the range of 20-75 mg/ml. [0138] In a preferred embodiment the concentration of xylitol used in the pharmaceutical composition of the invention is in the range of 30-60 mg/ml.
  • the concentration of xylitol used in the pharmaceutical composition of the invention is in the range of 39-49 mg/ml.
  • the concentration of xylitol used in the pharmaceutical composition of the invention is in the range of 39-48 mg/ml.
  • the concentration of xylitol used in the pharmaceutical composition of the invention is in the range of 49-58 mg/ml.
  • the concentration of KC1 used in the pharmaceutical composition of the invention is in the range of 9-12 mg/ml.
  • the tonicity agent used in the pharmaceutical composition of the invention is sodium chloride.
  • the concentration of sodium chloride used in the pharmaceutical composition of the invention is in the range of 1-12 mg/ml.
  • the concentration of sodium chloride used in the pharmaceutical composition of the invention is in the range of 4-12 mg/ml.
  • the concentration of sodium chloride used in the pharmaceutical composition of the invention is in the range of 5-11 mg/ml.
  • the concentration of sodium chloride used in the pharmaceutical composition of the invention is in the range of 6-10 mg/ml.
  • the pharmaceutical composition of the invention is designated by the use of at least one preservative.
  • preservative as used in the invention denotes any pharmaceutically acceptable excipient known to the person skilled in the art as described e.g. in Remington: The Science and Practice of Pharmacy, 22nd Edition, 2013, used to prevent microbial growth.
  • Multidose aqueous preparations provide excellent growth media for microorganisms, such as molds, yeast and bacteria and therefore require the presence of an antimicrobial preservative to maintain aseptic conditions throughout their shelf life.
  • the preservative can include, but it is not limited to phenol, m-cresol (metacresol), methyl p- hydroxybenzoate, propyl p-hydroxybenzoate, benzoic acid, benzyl alcohol, benzyl benzoate, 2-phenox- yethanol, butyl p-hydroxybenzoate, 2-phenylethanol, chlorobutanol, acetone sodium bisulfite, benzalkonium chloride, benzethonium chloride and thiomerosal, or any combinations thereof.
  • Preferred preservatives are phenol, metacresol, benzyl alcohol, and any combinations thereof, preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol. Each one of these specific preservatives and combinations thereof constitutes an alternative embodiment of the invention.
  • the preservative to be used according to a preferred embodiment of the invention is selected from the group consisting of phenol and metacresol.
  • the concentration of preservative used in the pharmaceutical composition of the invention is in the range of 0.5-20 mg/ml.
  • the concentration of preservative used in the pharmaceutical composition of the invention is in the range of 1-10 mg/ml.
  • the preservative used in the pharmaceutical composition of the invention is phenol.
  • the concentration of phenol used in the pharmaceutical composition of the invention is in the range of 1-10 mg/ml.
  • the concentration of phenol used in the pharmaceutical composition of the invention is in the range of 2.5-10 mg/ml.
  • the concentration of phenol used in the pharmaceutical composition of the invention is in the range of 3.5-8.5 mg/ml.
  • the concentration of phenol used in the pharmaceutical composition of the invention is in the range of 4-7 mg/ml.
  • the preservative used in the pharmaceutical composition of the invention is metacresol.
  • the concentration of metacresol used in the pharmaceutical composition of the invention is in the range of 1.75-7 mg/ml.
  • the concentration of metacresol used in the pharmaceutical composition of the invention is in the range of 2.5-5.5 mg/ml.
  • the concentration of metacresol used in the pharmaceutical composition of the invention is in the range of 3-4.5 mg/ml.
  • the preservative used in the pharmaceutical composition of the invention is benzyl alcohol.
  • the concentration of benzyl alcohol used in the pharmaceutical composition of the invention is in the range of 5-13 mg/ml.
  • composition according to the invention optionally further comprises other pharmaceutically acceptable excipients selected among any known state of the art for pharmaceutical ingredients used in liquid dosage forms, as described e.g. in Remington: The Science and Practice of Pharmacy, 22nd Edition, 2013.
  • other pharmaceutically acceptable excipients present in the pharmaceutical composition according to the invention can be selected from the group consisting of, but not limited to, one or more solvents, one or more chelating agents, one or more stabilizers, one or more pH adjusting agents, one or more antioxidants, one or more surfactants or any combinations thereof.
  • the pharmaceutical composition of the invention is in the form of a solution.
  • the pharmaceutical composition of the invention is in the form of a suspension.
  • the pharmaceutical composition of the invention is a solid to which a reconstitution solvent is added prior to use.
  • the reconstitution solvent may be any suitable solvent, particularly water for injection.
  • the amount indications provided elsewhere in the specification apply only indirectly to the solid composition insofar as it must allow fulfilment of the amount indications after reconstitution. Similar considerations apply also with respect to other characteristics like the pH of the composition.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.30 mg/ml; c) lactose, wherein the concentration is 44-165 mg/ml, preferably 60-125 mg/ml, most preferably 88- 110 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.30 mg/ml; c) L-arginine, wherein the concentration is 23-70 mg/ml, preferably 38-60 mg/ml, most preferably 45-56 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.30 mg/ml; c) sorbitol, wherein the concentration is 20-90 mg/ml, preferably 30-65 mg/ml, most preferably 39- 58 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.30 mg/ml; c) xylitol, wherein the concentration is 20-75 mg/ml, preferably 30-60 mg/ml, most preferably 39-49 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.30 mg/ml; c) glycerol, wherein the concentration is 8-45 mg/ml, preferably 18-40 mg/ml, most preferably 24-29 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.30 mg/ml; c) dextrose, wherein the concentration is 20-90 mg/ml, preferably 30-65 mg/ml, most preferably 39- 58 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.30 mg/ml; c) KC1, wherein the concentration is 4.5-18 mg/ml, preferably 6-14 mg/ml, most preferably 9-12 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.30 mg/ml; c) sodium chloride, wherein the concentration is 1-12 mg/ml, preferably 4-12 mg/ml, most preferably 5-11 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) glucose, wherein the concentration is 20-90 mg/ml, preferably 30-65 mg/ml, most preferably 39- 58 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) lactose, wherein the concentration is 44-165 mg/ml, preferably 60-125 mg/ml, most preferably 88- 110 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) maltose, wherein the concentration is 44-165 mg/ml, preferably 60-125 mg/ml, most preferably 88- 110 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) glycine, wherein the concentration is 10-36 mg/ml, preferably 15-30 mg/ml, most preferably 19-24 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) PEG 400, wherein the concentration is 50-192 mg/ml, preferably 75-165 mg/ml, most preferably 104-128 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) myo-inositol, wherein the concentration is 20-90 mg/ml, preferably 30-65 mg/ml, most preferably 39-58 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) L-arginine, wherein the concentration is 23-70 mg/ml, preferably 38-60 mg/ml, most preferably 45-56 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) dimethylsulfone, wherein the concentration is 10-45 mg/ml, preferably 15-35 mg/ml, most preferably 20-30 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) sorbitol, wherein the concentration is 20-90 mg/ml, preferably 30-65 mg/ml, most preferably 39- 58 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) xylitol, wherein the concentration is 20-75 mg/ml, preferably 30-60 mg/ml, most preferably 39-49 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) mannitol, wherein the concentration is 20-90 mg/ml, preferably 30-65 mg/ml, most preferably 39- 58 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) glycerol, wherein the concentration is 8-45 mg/ml, preferably 18-40 mg/ml, most preferably 24-29 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) dextrose, wherein the concentration is 20-90 mg/ml, preferably 30-65 mg/ml, most preferably 39- 58 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) KC1, wherein the concentration is 4.5-18 mg/ml, preferably 6-14 mg/ml, most preferably 9-12 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) sodium chloride, wherein the concentration is 1-12 mg/ml, preferably 4-12 mg/ml, most preferably 5-11 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) disodium hydrogen phosphate, wherein the concentration is 0.67-1.65 mg/ml, preferably 1-1.55 mg/ml, most preferably 1.20-1.50 mg/ml; c) glucose, wherein the concentration is 20-90 mg/ml, preferably 30-65 mg/ml, most preferably 39- 58 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) disodium hydrogen phosphate, wherein the concentration is 0.67-1.65 mg/ml, preferably 1-1.55 mg/ml, most preferably 1.20-1.50 mg/ml; c) lactose, wherein the concentration is 44-165 mg/ml, preferably 60-125 mg/ml, most preferably 88- 110 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) disodium hydrogen phosphate, wherein the concentration is 0.67-1.65 mg/ml, preferably 1-1.55 mg/ml, most preferably 1.20-1.50 mg/ml; c) L-arginine, wherein the concentration is 23-70 mg/ml, preferably 38-60 mg/ml, most preferably 45-56 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) disodium hydrogen phosphate, wherein the concentration is 0.67-1.65 mg/ml, preferably 1-1.55 mg/ml, most preferably 1.20-1.50 mg/ml; c) dimethylsulfone, wherein the concentration is 10-45 mg/ml, preferably 15-35 mg/ml, most preferably 20-30 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) disodium hydrogen phosphate, wherein the concentration is 0.67-1.65 mg/ml, preferably 1-1.55 mg/ml, most preferably 1.20-1.50 mg/ml; c) sorbitol, wherein the concentration is 20-90 mg/ml, preferably 30-65 mg/ml, most preferably 39- 58 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) disodium hydrogen phosphate, wherein the concentration is 0.67-1.65 mg/ml, preferably 1-1.55 mg/ml, most preferably 1.20-1.50 mg/ml; c) xylitol, wherein the concentration is 20-75 mg/ml, preferably 30-60 mg/ml, most preferably 39-49 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) disodium hydrogen phosphate, wherein the concentration is 0.67-1.65 mg/ml, preferably 1-1.55 mg/ml, most preferably 1.20-1.50 mg/ml; c) sucrose, wherein the concentration is 44-165 mg/ml, preferably 60-125 mg/ml, most preferably 88- 110 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) disodium hydrogen phosphate, wherein the concentration is 0.67-1.65 mg/ml, preferably 1-1.55 mg/ml, most preferably 1.20-1.50 mg/ml; c) mannitol, wherein the concentration is 20-90 mg/ml, preferably 30-65 mg/ml, most preferably 39- 58 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) disodium hydrogen phosphate, wherein the concentration is 0.67-1.65 mg/ml, preferably 1-1.55 mg/ml, most preferably 1.20-1.50 mg/ml; c) glycerol, wherein the concentration is 8-45 mg/ml, preferably 18-40 mg/ml, most preferably 24-29 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) disodium hydrogen phosphate, wherein the concentration is 0.67-1.65 mg/ml, preferably 1-1.55 mg/ml, most preferably 1.20-1.50 mg/ml; c) dextrose, wherein the concentration is 20-90 mg/ml, preferably 30-65 mg/ml, most preferably 39- 58 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) disodium hydrogen phosphate, wherein the concentration is 0.67-1.65 mg/ml, preferably 1-1.55 mg/ml, most preferably 1.20-1.50 mg/ml; c) KC1, wherein the concentration is 4.5-18 mg/ml, preferably 6-14 mg/ml, most preferably 9-12 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) TRIS, wherein the concentration is 0.30-0.90 mg/ml, preferably 0.45-0.75 mg/ml, most preferably 0.50-0.70 mg/ml; c) glucose monohydrate, wherein the concentration is 20-39 mg/ml, preferably 20-31 mg/ml, most preferably 25-36 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) TRIS, wherein the concentration is 0.30-0.90 mg/ml, preferably 0.45-0.75 mg/ml, most preferably 0.50-0.70 mg/ml; c) lactose monohydrate, wherein the concentration is 50-70 mg/ml, preferably 49-69 mg/ml, most preferably 45-65 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) TRIS, wherein the concentration is 0.30-0.90 mg/ml, preferably 0.45-0.75 mg/ml, most preferably 0.50-0.70 mg/ml; c) maltose monohydrate, wherein the concentration is 50-100 mg/ml, preferably 45-65 mg/ml, most preferably 37-57 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) TRIS, wherein the concentration is 0.30-0.90 mg/ml, preferably 0.45-0.75 mg/ml, most preferably 0.50-0.70 mg/ml; c) glycine, wherein the concentration is 10-15 mg/ml, preferably 8-13 mg/ml, most preferably 7-12 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) TRIS, wherein the concentration is 0.30-0.90 mg/ml, preferably 0.45-0.75 mg/ml, most preferably 0.50-0.70 mg/ml; c) PEG 400, wherein the concentration is 41-64 mg/ml, preferably 54-78 mg/ml, most preferably 47- 71 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) TRIS, wherein the concentration is 0.30-0.90 mg/ml, preferably 0.45-0.75 mg/ml, most preferably 0.50-0.70 mg/ml; c) myo-inositol, wherein the concentration is 20-39 mg/ml, preferably 18-37 mg/ml, most preferably 18-29 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) TRIS, wherein the concentration is 0.30-0.90 mg/ml, preferably 0.45-0.75 mg/ml, most preferably 0.50-0.70 mg/ml; c) L-arginine, wherein the concentration is 20-31 mg/ml, preferably 23-34 mg/ml, most preferably 17-27 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) TRIS, wherein the concentration is 0.30-0.90 mg/ml, preferably 0.45-0.75 mg/ml, most preferably 0.50-0.70 mg/ml; c) sorbitol, wherein the concentration is 25-44 mg/ml, preferably 20-39 mg/ml, most preferably 19- 29 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) TRIS, wherein the concentration is 0.30-0.90 mg/ml, preferably 0.45-0.75 mg/ml, most preferably 0.50-0.70 mg/ml; c) xylitol, wherein the concentration is 20-30 mg/ml, preferably 17-27 mg/ml, most preferably 15-24 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) TRIS, wherein the concentration is 0.30-0.90 mg/ml, preferably 0.45-0.75 mg/ml, most preferably 0.50-0.70 mg/ml; c) sucrose, wherein the concentration is 40-60 mg/ml, preferably 35-55 mg/ml, most preferably 46- 66 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) TRIS, wherein the concentration is 0.30-0.90 mg/ml, preferably 0.45-0.75 mg/ml, most preferably 0.50-0.70 mg/ml; c) mannitol, wherein the concentration is 19-38 mg/ml, preferably 20-39 mg/ml, most preferably 19- 29 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) TRIS, wherein the concentration is 0.30-0.90 mg/ml, preferably 0.45-0.75 mg/ml, most preferably 0.50-0.70 mg/ml; c) glycerol, wherein the concentration is 8-29 mg/ml, preferably 18-23 mg/ml, most preferably 19-24 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) TRIS, wherein the concentration is 0.30-0.90 mg/ml, preferably 0.45-0.75 mg/ml, most preferably 0.50-0.70 mg/ml; c) dextrose monohydrate, wherein the concentration is 25-36 mg/ml, preferably 20-31 mg/ml, most preferably 23-42 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.40 mg/ml; c) glucose monohydrate, wherein the concentration is 25-36 mg/ml, preferably 20-31 mg/ml, most preferably 23-42 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.40 mg/ml; c) lactose monohydrate, wherein the concentration is 45-65 mg/ml, preferably 37-57 mg/ml, most preferably 49-69 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.40 mg/ml; c) maltose monohydrate, wherein the concentration is 45-65 mg/ml, preferably 37-57 mg/ml, most preferably 49-69 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.40 mg/ml; c) glycine, wherein the concentration is 8-13 mg/ml, preferably 7-12 mg/ml, most preferably 9-14 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.40 mg/ml; c) PEG 400, wherein the concentration is 50-74 mg/ml, preferably 41-64 mg/ml, most preferably 54- 78 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.40 mg/ml; c) myo-inositol, wherein the concentration is 20-39 mg/ml, preferably 18-29 mg/ml, most preferably 18-37 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.40 mg/ml; c) sorbitol, wherein the concentration is 20-39 mg/ml, preferably 19-29 mg/ml, most preferably 21- 40 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.40 mg/ml; c) xylitol, wherein the concentration is 17-27 mg/ml, preferably 15-24 mg/ml, most preferably 20-30 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.40 mg/ml; c) sucrose, wherein the concentration is 40-60 mg/ml, preferably 35-55 mg/ml, most preferably 46- 66 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.40 mg/ml; c) mannitol, wherein the concentration is 20-39 mg/ml, preferably 19-29 mg/ml, most preferably 21- 40 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.40 mg/ml; c) glycerol, wherein the concentration is 8-39 mg/ml, preferably 18-23 mg/ml, most preferably 19-24 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) Na-citrate, wherein the concentration is 0.55-1.65 mg/ml, preferably 0.75-1.45 mg/ml, most preferably 0.90-1.40 mg/ml; c) dextrose monohydrate, wherein the concentration is 25-36 mg/ml, preferably 20-31 mg/ml, most preferably 20-39 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) glucose monohydrate, wherein the concentration is 23-42 mg/ml, preferably 20-39 mg/ml, most preferably 25-36 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) lactose monohydrate, wherein the concentration is 49-69 mg/ml, preferably 43-63 mg/ml, most preferably 50-70 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) maltose monohydrate, wherein the concentration is 49-69 mg/ml, preferably 43-63 mg/ml, most preferably 45-65 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) glycine, wherein the concentration is 9-14 mg/ml, preferably 8-13 mg/ml, most preferably 10-15 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) PEG 400, wherein the concentration is 54-78 mg/ml, preferably 47-71 mg/ml, most preferably SO- 74 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) myo-inositol, wherein the concentration is 20-39 mg/ml, preferably 18-37 mg/ml, most preferably 18-29 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) L-arginine, wherein the concentration is 23-34 mg/ml, preferably 25-31 mg/ml, most preferably 20-31 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) sorbitol, wherein the concentration is 21-40 mg/ml, preferably 20-39 mg/ml, most preferably 25- 44 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) xylitol, wherein the concentration is 20-30 mg/ml, preferably 18-28 mg/ml, most preferably 17-27 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) mannitol, wherein the concentration is 21-40 mg/ml, preferably 20-39 mg/ml, most preferably 19- 29 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the pharmaceutical composition of the invention comprises: a) tirzepatide or a pharmaceutically acceptable salt thereof, wherein the concentration is 2.5-60 mg/ml, preferably 5-45 mg/ml, most preferably 4-30 mg/ml; b) histidine, wherein the concentration is 0.40-1.20 mg/ml, preferably 0.55-1.05 mg/ml, most preferably 0.70-0.90 mg/ml; c) dextrose monohydrate, wherein the concentration is 23-42 mg/ml, preferably 20-39 mg/ml, most preferably 25-36 mg/ml; d) optionally, a preservative, preferably phenol, metacresol, benzyl alcohol, or any combinations thereof; more preferably phenol, or metacresol, or a combination of phenol with benzyl alcohol; e) optionally, other pharmaceutically acceptable excipients; preferably glycerol.
  • the processes of the invention comprises the following steps: a) dissolving the buffering agent and the tonicity agent in water for injections (WFI), b) adjusting the pH of the solution, c) adding the GIP/GLP analogue, d) adjusting the pH of solution, e) adding WFI up to the final volume.
  • Amount indications may be understood as indications of absolute weight, the unit being mass concentration.
  • Method B a) dissolving the buffering agent and the tonicity agent in water for injections (WFI), b) adjusting the pH of the solution, c) adding the GIP/GLP analogue, d) adjusting the pH of solution, e) adding WFI up to the final volume.
  • WFI water for injections
  • the invention also pertains to the pharmaceutical compositions obtainable by any one of the methods specified herein. Any specific product characteristic obtainable by the specified methods is to be understood as a characteristic of pharmaceutical compositions of certain embodiments of the invention. These process-derived characteristics may also be present in combination with any one of the further features described elsewhere in the specification.
  • Buffering agent, isotonicity agent and preservative were dissolved in water for injections.
  • the pH of the solution was adjusted to around 6-8. Tirzepatide was added to the solution while stirring slowly. The pH was then adjusted to 6.5-7.5. Water for injection was added up to the final volume. The solution was stirred.
  • compositions F16-F30 are prepared by the same process as disclosed in Table 1
  • compositions F31-F45 are prepared by the same process as disclosed in Table 1.
  • compositions F46-F60 are prepared by the same process as disclosed in Table 1.
  • compositions F61-F75 are prepared by the same process as disclosed in Table 1.
  • compositions F76-F90 are prepared by the same process as disclosed in Table 1.
  • Buffering agent, isotonicity agent and preservative were dissolved in water for injections.
  • the pH of the solution was adjusted to around 6-8.
  • Tirzepatide was added to the solution while stirring slowly.
  • the pH was then adjusted to 6.5-7.5.
  • Water for injection was added up to the final volume.
  • the solution was stirred and filtered through a 0.2pm filter.
  • compositions F13P-F25P are prepared by the same process as disclosed in Table 8.
  • compositions F26P-F37P are prepared by the same process as disclosed in Table 8.
  • compositions F38P-F50P are prepared by the same process as disclosed in Table 8.
  • compositions F51P-F62P are prepared by the same process as disclosed in Table 8.
  • compositions F63P-F75P are prepared by the same process as disclosed in Table 8.
  • Accelerated stability testing Subject the peptide formulation to elevated temperatures, thermal cycling, light exposure and extreme pH conditions to observe degradation, aggregation, and loss of activity. Techniques like HPLC, mass spectrometry, and size-exclusion chromatography (SEC) are used to monitor aggregation, oxidation, and other degradation pathways.
  • Techniques like HPLC, mass spectrometry, and size-exclusion chromatography (SEC) are used to monitor aggregation, oxidation, and other degradation pathways.
  • DSC Differential scanning calorimetry
  • thermal shift assays provide insight into the thermal stability of peptides in formulations and help predict how they will behave under prolonged storage at different temperatures.
  • Mass spectrometry are used to monitor for oxidation, deamidation, fragmentation, that may occur over time, and help identify weak points in the peptide structure that may lead to degradation.
  • Formulations F7P, F19P, F32P, F44P, F57P and F69P contain L-arginine as the isotonicity agent, which causes aggregation in the proposed compositions.
  • L-arginine the isotonicity agent
  • the formulations with L-arginine are disadvantageous. Because of high aggregate content, the A2 second virial coefficient could not be measured in formulations with L-arginine.
  • formulations F72P and F73P demonstrate negative A2, which also points to low longterm stability.

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Abstract

L'invention concerne des compositions pharmaceutiques contenant un agoniste du récepteur GIP (polypeptide insulino-tropique dépendant du glucose) et GLP-1 (peptide-1 de type glucagon). En particulier, l'invention concerne des compositions pharmaceutiques contenant du tirzépatide. Les compositions pharmaceutiques selon l'invention sont stables physiquement et chimiquement, sont faciles à fabriquer et appropriées pour une administration parentérale. L'invention concerne en outre des procédés de fabrication de ceux-ci tels que spécifiés dans les revendications.
PCT/EP2025/057057 2024-03-15 2025-03-14 Composition pharmaceutique comprenant un agoniste du récepteur glp-1 et gip double Pending WO2025191149A1 (fr)

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