EP3897570A1 - Composition pharmaceutique comprenant un analogue de glp -1 - Google Patents

Composition pharmaceutique comprenant un analogue de glp -1

Info

Publication number
EP3897570A1
EP3897570A1 EP19829134.6A EP19829134A EP3897570A1 EP 3897570 A1 EP3897570 A1 EP 3897570A1 EP 19829134 A EP19829134 A EP 19829134A EP 3897570 A1 EP3897570 A1 EP 3897570A1
Authority
EP
European Patent Office
Prior art keywords
solution
pharmaceutical composition
present
glp
composition according
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.)
Withdrawn
Application number
EP19829134.6A
Other languages
German (de)
English (en)
Inventor
Sasa ROZMAN
Tanja KOLESA DOBRAVC
Gordan Sladic
Iztok VIDIC
Haowen LIN
Guotao HE
Liangzheng QIN
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 EP3897570A1 publication Critical patent/EP3897570A1/fr
Withdrawn legal-status Critical Current

Links

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

Definitions

  • composition comprising GLP-1 analogue
  • the present invention pertains to new pharmaceutical compositions containing a Glucagon like peptide- 1 (GLP-1) analogue.
  • GLP-1 analogues such as liraglutide and semaglutide, optionally in a combination with one or more other active substances.
  • the pharmaceutical compositions according to the present invention are physically and chemically stable, are easy to manufacture and suitable for parenteral administration.
  • the present invention further provides methods for making the same.
  • GLP-1 analogues are useful in many different fields. They are widely used in medicine to control insulin levels and digestion, to improve glucose control in adults with type 2 diabetes mellitus, as well as to treat obesity, sleep apnoea and diabetic complications, such as angiopathy, neuropathy and retinopathy. Additionally, growing evidence suggest that GLP-1 analogues can be used to prevent or treat cardiovascular complications and neurodegenerative diseases.
  • Glucagon-like peptide- 1 (GLP-1) is a 30 amino acid long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon gene. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption.
  • the initial product GLP-l(l-37) is susceptible to amidation and proteolytic cleavage which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7-36) amide and GLP-1 (7-37).
  • Active GLP-1 composes two a-helices from amino acid position 13-20 and 24-35 separated by a linker region.
  • Liraglutide Arg 34 , Lys 26 (N-s(y-Glu(N-ahexadecanoyl)))-GLP- l (7-37) is a long acting analogue of the naturally occurring human glucagon-like peptide-1 (GLP-l(7-37)).
  • Liraglutide has a substitution of the naturally occurring amino acid residue in position 34 (Lys) by Arg and addition of a Glu-spaced hexadecanoic acid (palmitic acid) to the e-amino group of Lys in position 26.
  • GLP-1 glucagon-like peptide- 1
  • Victoza by Novo Nordisk for the treatment of type 2 diabetes and under the brand name Saxenda, again by Novo Nordisk, for obese or overweight adults.
  • Liraglutide is marketed under brand name VICTOZA ® and SAXENDA ® in the United States. Both products contain propylene glycol as the tonicity agent.
  • Semaglutide N-epsilon26-[2-(2- ⁇ 2-[2-(2- ⁇ 2-[(S)-4-carboxy-4-(17-carboxyheptadecanoyl amino)butyrylamino]ethoxy ⁇ ethoxy)acetylamino]ethoxy ⁇ ethoxy)acetyl][Aib8,Arg34]-GLP-l (7-37) is a long-acting once-weekly human GLP-1 analogue, marketed as Ozempic by Novo Nordisk for the treatment of Type 2 diabetes.
  • the main protraction mechanism of semaglutide is albumin binding, facilitated by modification of position 26 lysine with a hydrophilic spacer and a Cl 8 fatty di-acid.
  • Semaglutide is modified in position 8 to provide stabilization against degradation by the enzyme dipeptidyl-peptidase 4. A minor modification was made in position 34 to ensure the attachment of only one fatty di-acid. Semaglutide is marketed under brand name OZEMPIC ® in the United States which contains propylene glycol as the tonicity agent as well.
  • W02003002136 discloses isotonic composition
  • isotonic composition comprising GLP-l(7-37) analogue in a concentration from 0.1 mg/ml to 100 mg/ml, a buffer, an isotonic agent and a preservative wherein the composition has a pH of 7.0 to 10.
  • W02004105781 discloses composition comprising specific buffers and specific preservatives wherein GLP-1 analogue is prepared by freeze-drying and the pH of composition is lower than the pH of bulk peptide.
  • a method for increasing the shelf-life of a pharmaceutical composition which comprises a glucagon-like peptide, a pharmaceutically acceptable buffer and a pharmaceutically acceptable preservative, characterized in that said pharmaceutical composition is prepared from a bulk peptide product which has been produced by drying a solution or suspension of said glucagon-like peptide having a pH above 8.0 is disclosed in W02004105790.
  • W02005049061 discloses propylene glycol containing peptide compositions for use in injection devices. The document teaches that by using propylene glycol at concentrations of 1-100 mg/ml the reduction of deposits in production equipment and in the final product and reducing clogging of injection devices is observed.
  • EP2494983B1 describes the method for preparation of a stable solution of a GLP-l(7-37) (SEQ ID NO. 1), insulinotropic analogue thereof and insulinotropic derivatives thereof, which method comprises heating a solution of said GLP-l(7-37), wherein the temperature is between 50° C and 85 °C, the pH is between 8.0 to 10.5 and the heating is continued for a period of time which is between 3 minutes and 180 minutes.
  • WO2007146448 describes intranasal compositions ofGLP-1 compounds.
  • CN102429876 and CN110368376 describe sustained release microsphere liraglutide preparation.
  • CN110339166 discloses polycystic liposome comprising liraglutide, membrane material, osmotic pressure regulator and stabilizer.
  • a pharmaceutical composition comprising liraglutide, a buffer selected from the group consisting of dipotassium phosphate, sodium bicarbonate, and disodium phosphate anhydrous; propylene glycol and a preservative is disclosed in WO2016038521.
  • composition comprising liraglutide wherein manufacturing process comprising mixing liraglutide and adjuvant in a solvent, stirring at 500-1 lOOrpm until homogeneous mixture is obtained and pH is adjusted to 7.5-9.5 is disclosed in WO2017147783.
  • WO2018096460 discloses liraglutide composition comprising specific buffers, specific isotonic agents and specific preservatives.
  • compositions for the transmucosal delivery of therapeutic peptides and proteins comprising an excipient with pKa value of 12 or higher, such as arginine free base, EDTA tetrasodium salt, trisodium phosphate, tris(hydroxymethyl)aminomethane, lysine, and calcium hydroxide, are disclosed in WO2019193204.
  • WO2019110837 discloses a composition in the form of an injectable aqueous solution including human glucagon and a co-polyaminoacid.
  • the present invention pertains to new pharmaceutical compositions containing a Glucagon like peptide- 1 (GLP-1) analogue.
  • GLP-1 analogues such as liraglutide and semaglutide, optionally in a combination with one or more other active substances and methods for making the same as specified in the appended claims.
  • Figure 1 Fibrillation tendency of sorbitol formulations, with the liraglutide active ingredient solution treated at temperature 25°C, 35°C, 40°C, 70°C fori hour, 4 hours, 6 hours
  • Figure 2 Fibrillation tendency of sorbitol formulations, with the liraglutide active ingredient solution treated at temperature 35°C, 50°C for 2 hours
  • Figure 3 Fibrillation tendency of sorbitol formulation, with the liraglutide active ingredient solution treated at temperature 25°C for 1 hour and 40°C for 1 hour, 4 hours, 6 hours.
  • the pharmaceutical composition of the present invention comprises a GLP-1 analogue, a buffering agent, a tonicity agent, a preservative and optionally other pharmaceutically acceptable excipients selected from the group consisting of but not limited to one or more solvents, one or more chelating agents, one or more stabilisers, pH adjusting agents, antioxidants and surfactants.
  • the pharmaceutical composition of the present invention may comprise in addition to at least one GLP-1 analogue at least one other active substance.
  • the pharmaceutical composition of the present invention is in the form of a solution, more particularly in the form of an injectable solution.
  • the pharmaceutical formulations of the present invention surprisingly show less tendency for fibre formation after treating the active ingredient solution at mild heating conditions i.e. lower temperature in comparison to the already known and previously described compositions and conditions for the preparation of GLP-1 analogue formulations.
  • 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.
  • Measurement of fibrillation tendency of liraglutide in formulations after inducing heat and mechanical stress is performed with BioTek Synergy Mx multi-mode reader by monitoring flurescence of the amyloid dye thioflavin T (ThT).
  • ThT amyloid dye thioflavin T
  • Sample formulations are transferred to the plate in 190 pL portions followed by addition of 10 pL of 100 pM aqueous ThT and a stainless steel ball to each well. Plate is then kept at 37°C and shaken for 30 s every 15 min. Fluorescence of ThT is recorded for minimum 48 hours with excitation wavelength 440 nm and emission wavelength 480 nm.
  • 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 GLP-1 peptide analogue, such as, in embodiments of the present invention, the concentrations specified in Section 4.2 below. 4.2. Active pharmaceutical ingredient
  • the GLP-1 peptide analogue is any peptide that binds to Glucagon-like peptide- 1 receptor, commonly found on beta cells of the pancreas and on neurons of the brain, and acts as an agonist for the receptor.
  • the GLP-1 analogue is liraglutide.
  • Liraglutide was first described in WO99/43705.
  • the term liraglutide as used in the present invention denotes liraglutide and all pharmaceutically acceptable salts, hydrates, solvates, prodrugs, chelates and complexes thereof.
  • liraglutide prior to freeze drying according to the present invention has a pH ofbetween 7 to 12, preferably between 7.2 to 11.8, more preferably between 7.5 to 11.5.
  • the concentration of liraglutide present in the pharmaceutical composition according to the present invention is from 0.1 to 100 mg/ml.
  • the concentration of liraglutide present in the pharmaceutical composition according to the present invention is from 0.5 to 50 mg/ml.
  • the concentration of liraglutide present in the pharmaceutical composition according to the present invention is from 1 to 10 mg/ml.
  • GLP-1 peptide analogue used in the pharmaceutical composition according to the present invention may be prepared according to any manufacturing process known from the state art such as for example US6268343, US7273921, US6451974, W02000055119, W02005019261, W02005019262, W02005058954, W02007090496, WO2010029159, WO2013037266, WO2013117135, CN104045705, CN104045706, CN103275208, CN103275208, WO2014199397, CN103288951, CN103304659, CN103304660,
  • the GLP-1 analogue is semaglutide.
  • Semaglutide was first described in WO 2006/097537.
  • the term semaglutide as used in the present invention denotes semaglutide and all pharmaceutically acceptable salts, hydrates, solvates, prodrugs, chelates and complexes thereof.
  • the concentration of semaglutide present in the pharmaceutical composition according to the present invention is from 0.1 to 100 mg/ml.
  • the concentration of semaglutide present in the pharmaceutical composition according to the present invention is from 0.5 to 50 mg/ml.
  • the concentration of semaglutide present in the pharmaceutical composition according to the present invention is from 1 to 10 mg/ml.
  • the pharmaceutical composition according to the present invention may further comprise any other active ingredients suitable to be incorporated into the same composition, for example active ingredients for treatment of cardiovascular diseases or active ingredients for treatment of diabetes, such as for example insulin, insulin analogues or any other antidiabetic drugs.
  • the pharmaceutical composition of the present invention is designated by the use of at least one buffering agent.
  • buffering agent as used in the present 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, 22 nd 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, citrate, meglumine, glycine, histidine, lysine, arginine, asparagine, glutamic acid, sodium glutamate, tris (hydroxymethyl)-aminomethan, methionine, Hepes, maleic acid, malic acid, lactate or any combinations thereof.
  • sodium dihydrogen phosphate disodium hydrogen phosphate, sodium phosphate, sodium acetate, sodium carbonate, citrate, meglumine, glycine, histidine, lysine, arginine, asparagine, glutamic acid, sodium glutamate, tris (hydroxymethyl)-aminomethan, methionine, Hepes, maleic acid, malic acid, lactate or any combinations thereof.
  • sodium dihydrogen phosphate disodium hydrogen phosphate
  • sodium phosphate sodium a
  • the buffering agent to be used according to one embodiment of the present invention is selected from the group consisting of sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, meglumine, glycine, histidine, lysine, arginine, asparagine, methionine, Hepes, maleic acid or any combinations thereof.
  • the buffering agent to be used according to one embodiment of the present invention is selected from the group consisting of asparagine, methionine, Hepes, maleic acid or any combinations thereof.
  • the concentration of buffering agent used in the pharmaceutical composition of the present invention is in the range of 0.05 - 50 mg/ml.
  • the concentration of buffering agent used in the pharmaceutical composition of the present invention is in the range of 0.1 - 30 mg/ml.
  • the concentration of buffering agent used in the pharmaceutical composition of the present invention is in the range of 0.1 - 20 mg/ml.
  • the pharmaceutical composition of the present invention is designated by the use of at least one tonicity agent.
  • tonicity agent as used in the present 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, 22 nd Edition, 2013, to provide the effective osmolality i.e. to adjust the osmolality of the solution to that which is almost isotonic to blood plasma, for instance the osmolality ranges indicated in the pharmaceutical composition section below.
  • the tonicity agent can include, but it is not limited to xylitol, sorbitol, PEG 400, sucrose, glucose, lactose, maltose, sodium chloride, glycerol, mannitoltrehalose and propylene glycol or any combinations thereof. Each one of these specific tonicity agents and combinations thereof constitutes an alternative embodiment of the invention.
  • the tonicity agent to be used according to one embodiment of the present invention is selected from the group consisting of xylitol, sucrose, maltose, sorbitol, glycerol, mannitol, trehalose and propylene glycol or any combinations thereof.
  • the tonicity agent to be used according to one embodiment of the present invention is selected from the group consisting of sorbitol, glycerol, mannitol, trehalose and propylene glycol or any combinations thereof.
  • the tonicity agent is a polyhydric alcohol selected from the group consisting of xylitol, mannitol, sorbitol and glycerol or any combinations thereof.
  • polyhydric alcohol is selected from the group consisting of xylitol, sorbitol and glycerol or any combinations thereof. More preferably polyhydric alcohol is selected from the group consisting of sorbitol and glycerol or any combinations thereof. Even more preferably polyhydric alcohol is sorbitol.
  • the tonicity agent is monosaccharide or disaccharide selected from the group consisting of glucose, maltose, fructose, galactose, lactose, sucrose, trehalose, or any combinations thereof.
  • the disaccharide is selected from the group consisting of maltose, lactose, trehalose or any combinations thereof. Even more preferably disaccharide is trehalose.
  • the tonicity agent comprises a combination of polyhydric alcohol and monosaccharide or disaccharide wherein polyhydric alcohol is selected from the group consisting of xylitol, mannitol, sorbitol and glycerol or any combinations thereof and monosaccharide or disaccharide is selected from the group consisting of glucose, maltose, fructose, galactose, lactose, sucrose and trehalose or any combinations thereof.
  • the tonicity agent is selected from the group consisting of xylitol, sorbitol, glycerol, maltose, lactose and trehalose or any combinations thereof.
  • the tonicity agent is selected from the group consisting of sorbitol, glycerol and trehalose or any combinations thereof. Even more preferably the tonicity agent is sorbitol and trehalose. In one embodiment the concentration of tonicity agent used in the pharmaceutical composition of the present invention is in the range of 0.5 - 120 mg/ml.
  • the concentration of tonicity agent used in the pharmaceutical composition of the present invention is in the range of 0.5 - 100 mg/ml.
  • the concentration of tonicity agent used in the pharmaceutical composition of the present invention is in the range of 1 - 80 mg/ml.
  • the pharmaceutical composition of the present invention is designated by the use of at least one preservative.
  • preservative as used in the present 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, 22 nd 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, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzoic acid, benzyl alcohol, benzyl benzoate, 2-phenoxyethanol, butyl p-hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol, acetone sodium bisulfite, benzalkonium chloride, benzethonium chloride and thiomerosal, or any combinations thereof.
  • phenol m-cresol
  • methyl p-hydroxybenzoate propyl p-hydroxybenzoate
  • benzoic acid benzyl alcohol
  • benzyl benzoate 2-phenoxyethanol
  • butyl p-hydroxybenzoate 2-phenylethanol
  • benzyl alcohol chlorobutanol
  • acetone sodium bisulfite benzalkonium chloride
  • benzethonium chloride and thiomerosal or any combinations
  • the preservative to be used according to one embodiment of the present invention is selected from the group consisting of phenol, m-cresol, methyl p-hydroxybenzoate, propyl p- hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol or any combinations thereof.
  • the preservative to be used according to one embodiment of the present invention is selected from the group consisting of phenol and benzyl alcohol.
  • the preservative to be used according to one embodiment of the present invention is phenol.
  • the concentration of preservative used in the pharmaceutical composition of the present invention is in the range of 0.5 to 30 mg/ml.
  • the concentration of preservative used in the pharmaceutical composition of the present invention is in the range of 0.5 to 20 mg/ml.
  • the concentration of preservative used in the pharmaceutical composition of the present invention is in the range of 1 to 10 mg/ml.
  • composition according to the present 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, 22 nd Edition, 2013.
  • other pharmaceutically acceptable excipients present in the pharmaceutical composition according to the present 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 stabilisers, one or more pH adjusting agents, one or more antioxidants, one or more surfactants or any combinations thereof.
  • the pharmaceutical composition of the present invention is in the form of a solution.
  • the pharmaceutical composition of the present invention is in the form of a suspension.
  • the pharmaceutical composition of the present 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 this application 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 according to the present invention is a clear solution with no visible particles.
  • pH of the pharmaceutical composition according to the present invention is in the range of 7 to 12.
  • pH of the pharmaceutical composition according to the present invention is in the range of 7 to 10.
  • pH of the pharmaceutical composition according to the present invention is in the range of 7 to 9.
  • pH of the pharmaceutical composition according to the present invention is in the range of 7 to 8.
  • pH of the pharmaceutical composition according to the present invention is in the range of 7.9 to 8.4.
  • the pharmaceutical composition according to the present invention has the osmolality in the range of from 200 to 400 mOsmol/kg.
  • the pharmaceutical composition according to the present invention has the osmolality in the range of from 230 to 370 mOsmol/kg.
  • the pharmaceutical composition according to the present invention has the osmolality in the range of from 250 to 350 mOsmol/kg.
  • Amount of components The above-mentioned components may be present in amounts as shown in the following table. Amount indications may be understood as indications of absolute weight, the unit being mass concentration.
  • compositions of the present invention can be manufactured by means of any processes known from the state of the art, as for example disclosed in e.g. in Remington: The Science and Practice of Pharmacy, 22 nd Edition, 2013.
  • the processes of the present invention comprise the following steps:
  • the process of the present invention comprises the following steps:
  • the temperature of heating in step e) is between 26 and 49°C.
  • the temperature of heating in step e) is between
  • the temperature of heating in step e) is between
  • the temperature of heating in step e) is between
  • the temperature of heating in step e) is between 30 and 43°C.
  • step e) in some embodiments of Methods B and C is continued for at least 6 hours.
  • step e) in some embodiments of Methods B and C is continued for at least 4 hours.
  • step e) the heating of step e) is continued for at least 3 hours.
  • step e) is continued for at least 2 hours.
  • the heating of step e) lasts between 1-6 hours, preferably between 1.5-5 hours, more preferably between 2-4 hours.
  • the pH of solution a) in step b) is adjusted to 7-8, preferably 7-7.7.
  • the pH of solution c) in step d) is adjusted to 8-11, preferably 9-10.
  • pH of solution c) in step d) is adjusted to around 8-9, preferably 8-8.5, more preferably 8.15.
  • the pH of solution g) in step h) is adjusted to around 8-9, preferably 8-8.5, more preferably 8.15.
  • the temperature of the solution e) in step f) is 15- 30°C, preferably 20-25°C.
  • Method C filtration of solution i) is the sterile filtration.
  • the above process conditions can be combined as desired. Such combinations of process conditions are preferred. Especially preferred are the combination of heating temperatures of 30 to 45°C with heating times of 1-6 hours, 1.5-5 hours or 2-4 hours, the combination of heating temperatures of 32 to 44°C with heating times of 1-6 hours, 1.5-5 hours or 2-4 hours and the combination of heating temperatures of 33 to 43°C with heating times of 1-6 hours, 1.5-5 hours or 2-4 hours. Most preferably are these listed combinations of heating temperatures and heating times when they are applied in the context of making pharmaceutical compositions containing sorbitol as tonicity agent.
  • the present 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 present invention. These process-derived characteristics may also be present in combination with any one of the further features described elsewhere in the present application.
  • Preservative, buffering agent and tonicity agent were dissolved in water for injections.
  • the pH of solution was adjusted to around 7-9.
  • Liraglutide was added to this solution and the pH of said solution was adjusted to around 7-9.
  • Water for injection was added up to the final volume.
  • compositions F9 to F16 are prepared by the same process as disclosed in Example 1.
  • compositions F17 to F24 are prepared by the same process as disclosed in Example 1. 5.4.
  • Example 4
  • compositions F25 to F32 are prepared by the same process as disclosed in Example 1.
  • compositions F33 to F40 are prepared by the same process as disclosed in Example 1.
  • compositions F41 to F48 are prepared by the same process as disclosed in Example 1.
  • compositions F49 to F56 are prepared by the same process as disclosed in Example 1.
  • Solution 1 was prepared by dissolving the preservative, buffering agent and tonicity agent in water for injections. The pH of solution 1 was adjusted to around 7-9.
  • Solution 2 was prepared by dissolving liraglutide in water for injection, adjusting the pH to 8-10 and heating the solution. Solution 1 and solution 2 were combined and the pH was adjusted to 7-9. Water for injection was added up to the final volume.
  • Solution 1 was prepared by dissolving the preservative, buffering agent and tonicity agent in water for injections. The pH of solution 1 was adjusted to around 7-9.
  • Solution 2 was prepared by dissolving liraglutide in water for injection, adjusting the pH to 8-10 and heating the solution. Solution 1 and solution 2 were combined and the pH was adjusted to 7-9. Water for injection was added up to the final volume.
  • Solution 1 was prepared by dissolving the preservative, buffering agent and tonicity agent in water for injections. The pH of solution 1 was adjusted to around 7-9.
  • Solution 2 was prepared by dissolving liraglutide in water for injection, adjusting the pH to 8-10 and heating the solution. Solution 1 and solution 2 were combined and the pH was adjusted to 7-9. Water for injection was added up to the final volume.
  • Solution 1 (excipient solution) was prepared by dissolving maleic acid as the buffering agent, phenol as the preservative and sorbitol as the tonicity agent in water for injections (WFI) and adjusting the pH to about 7-7.7.
  • Solution 2 was prepared by dissolving liraglutide in WFI by stirring slowly, adjusting the pH to about 9-10, then heating the liraglutide active ingredient solution at 25°C, 35°C, 40°C or 70°C for 1, 4 or 6 hours. After cooling down the liraglutide active ingredient solution to around 20-25°C, it was combined with the excipient solution by stirring slowly and the pH was adjusted to around 8.15. The obtained solution was then filtered through a sterilizing-grade filter and filled into 3 ml cartridges.
  • Fibrillation tendency is expressed by parameter t(l 5000), which is a time from the beginning of experiment to the signal reaching (Relative Fluorescence Units) RFU of 15000.
  • the temperature treatment of the liraglutide active ingredient solution at milder heating conditions is preferable to the treatment at higher temperatures, since stability of peptides in solutions is highly affected by elevated temperatures.
  • Solution 1 (excipient solution) was prepared by dissolving maleic acid as the buffering agent, phenol as the preservative and sorbitol as the tonicity agent in water for injections (WFI) and adjusting the pH to about 7-7.7.
  • Solution 2 was prepared by dissolving liraglutide in WFI by stirring slowly, adjusting the pH to about 9-10, then heating the liraglutide active ingredient solution at 35°C or 50°C for 2 hours. After cooling down the liraglutide active ingredient solution to around 20-25°C, it was combined with the excipient solution by stirring slowly and the pH was adjusted to around 8.15. The solution was then filtered through a sterilizing- grade filter and filled into 3 ml cartridges.
  • the sorbitol-containing excipient solution exerts a stabilizing effect on the liraglutide structure and slows down the tendency for fibre formation, when the liraglutide active ingredient solution is treated at mild heating conditions (35°C), before combining it with the excipient solution.
  • mild heating conditions 35°C
  • treating the liraglutide active ingredient solution at 35°C for 2h has a similar effect on the tendency for fibre formation as treating the same solution at 50°C for the same period of time. This is contrary to the knowledge from the state of the art disclosing the benefits of liraglutide solution treatment at higher temperatures.
  • Lower temperature treatment of the liraglutide active ingredient solution is preferable to the treatment at higher temperatures, since stability of peptides in solutions is highly affected by elevated temperatures.
  • Example 13 Fibrillation tendency of formulations containing sorbitol as the tonicity agent with the liraglutide active ingredient solution treated at temperature 25/40°C for lh, 4h, 6h
  • Solution 1 (excipient solution) was prepared by dissolving the buffering agent (maleic acid), phenol as the preservative and the tonicity agent (sorbitol) in water for injections (WFI) and adjusting the pH to about 7-7.7.
  • Solution 2 was prepared by dissolving liraglutide in WFI by stirring slowly, adjusting the pH to about 9-10, then heating the liraglutide active ingredient solution at a heating condition (25°C or 40°C) for 1, 4, 6 hours. After cooling down the liraglutide active ingredient solution to around 20-25°C, it was combined with the excipient solution by stirring slowly and the pH was adjusted to around 8.15. The solution was then filtered through a sterilizing-grade filter and filled into 3 ml cartridges.

Abstract

La présente invention concerne de nouvelles compositions pharmaceutiques contenant un analogue de peptide-1 de type Glucagon (GLP -1) facultativement en combinaison avec une ou plusieurs autres substances actives. La présente invention porte également sur des procédés pour les préparer.
EP19829134.6A 2018-12-19 2019-12-18 Composition pharmaceutique comprenant un analogue de glp -1 Withdrawn EP3897570A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SI201800275 2018-12-19
SI201900172 2019-09-12
PCT/EP2019/085942 WO2020127476A1 (fr) 2018-12-19 2019-12-18 Composition pharmaceutique comprenant un analogue de glp -1

Publications (1)

Publication Number Publication Date
EP3897570A1 true EP3897570A1 (fr) 2021-10-27

Family

ID=69061351

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19829134.6A Withdrawn EP3897570A1 (fr) 2018-12-19 2019-12-18 Composition pharmaceutique comprenant un analogue de glp -1

Country Status (2)

Country Link
EP (1) EP3897570A1 (fr)
WO (1) WO2020127476A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022178737A1 (fr) * 2021-02-25 2022-09-01 杭州九源基因工程有限公司 Procédé de traitement pour préparation pharmaceutique stable de liraglutide

Family Cites Families (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6268343B1 (en) 1996-08-30 2001-07-31 Novo Nordisk A/S Derivatives of GLP-1 analogs
EP1056774A1 (fr) 1998-02-27 2000-12-06 Novo Nordisk A/S Derives de glp-1 tronques a l'extremite n-terminale
US6451974B1 (en) 1999-03-17 2002-09-17 Novo Nordisk A/S Method of acylating peptides and novel acylating agents
EP1956000B1 (fr) 1999-03-17 2016-10-05 Novo Nordisk A/S Agents d'acylation utilisés dans l'acylation de peptides
WO2003002136A2 (fr) 2001-06-28 2003-01-09 Novo Nordisk A/S Formulation stable de glp-1 modifie
US7273921B2 (en) 2002-09-25 2007-09-25 Novo Nordisk A/S Method for producing acylated peptides
PL1633390T3 (pl) 2003-06-03 2012-06-29 Novo Nordisk As Stabilizowane kompozycje farmaceutyczne peptydu glp-1
WO2004105790A1 (fr) 2003-06-03 2004-12-09 Novo Nordisk A/S Compositions peptidiques pharmaceutiques stabilisees
JP5622998B2 (ja) 2003-08-21 2014-11-12 ノヴォ ノルディスク アー／エス ラセミ化されたアミノ酸を含むポリペプチドの分離
EP1664109B1 (fr) 2003-08-21 2009-07-22 Novo Nordisk A/S Purification de peptides apparentes au glucagon
MXPA06005581A (es) 2003-11-20 2006-08-11 Novo Nordisk As Formulaciones de peptidos que contienen propilenglicol que son optimas para la produccion y uso en dispositivos de inyeccion.
RU2006120079A (ru) 2003-12-18 2008-01-27 Ново Нордиск А/С (DK) Производные глюкагоноподобного пептида-1 (glp-1)
WO2006051110A2 (fr) * 2004-11-12 2006-05-18 Novo Nordisk A/S Formulations stables de peptides
TWI362392B (en) 2005-03-18 2012-04-21 Novo Nordisk As Acylated glp-1 compounds
ES2364982T3 (es) 2006-02-08 2011-09-20 Lonza Ag Síntesis de péptidos similares a glucagón.
WO2007146448A1 (fr) 2006-06-07 2007-12-21 Nastech Pharmaceutical Company Inc. Formulations pharmaceutiques de dérivés glp-1
CN102149411A (zh) 2008-09-12 2011-08-10 诺沃—诺迪斯克有限公司 酰化肽或蛋白的方法
CN102286092B (zh) 2011-09-14 2014-01-01 深圳翰宇药业股份有限公司 利拉鲁肽的固相合成方法
CN102429876B (zh) 2011-12-14 2014-12-24 深圳翰宇药业股份有限公司 利拉鲁肽缓释微球制剂及其制备方法
CN102584982B (zh) 2012-02-10 2014-02-05 深圳翰宇药业股份有限公司 一种纯化固相合成利拉鲁肽粗肽的方法
CN103087181A (zh) 2013-01-17 2013-05-08 刘卫 一种利拉鲁肽的固相合成方法
CN104045705B (zh) 2013-03-12 2016-12-28 深圳翰宇药业股份有限公司 一种利拉鲁肽的合成方法
CN104045706B (zh) 2013-03-12 2017-09-05 深圳翰宇药业股份有限公司 一种利拉鲁肽的合成方法
CN103275208B (zh) 2013-05-27 2015-04-01 成都圣诺生物制药有限公司 利拉鲁肽的制备方法
WO2014199397A2 (fr) 2013-06-11 2014-12-18 Mylan Laboratories Ltd Procédé pour la préparation de liraglutide
CN103288951A (zh) 2013-06-19 2013-09-11 深圳翰宇药业股份有限公司 一种利拉鲁肽的制备方法
CN103304659B (zh) 2013-06-19 2015-12-02 深圳翰宇药业股份有限公司 利拉鲁肽的固相制备方法
CN103304660B (zh) 2013-07-12 2016-08-10 上海昂博生物技术有限公司 一种利拉鲁肽的合成方法
CN103980358B (zh) 2014-01-03 2016-08-31 杭州阿诺生物医药科技股份有限公司 一种制备利拉鲁肽的方法
CN103864918B (zh) 2014-03-31 2016-08-17 哈尔滨吉象隆生物技术有限公司 一种利拉鲁肽的固相合成方法
CN104004083B (zh) 2014-06-13 2016-10-05 成都圣诺生物科技股份有限公司 一种合成利拉鲁肽的方法
US20170283478A1 (en) 2014-07-11 2017-10-05 Dr. Reddy's Laboratories Limited Process for preparation of liraglutide
WO2016038521A1 (fr) 2014-09-08 2016-03-17 Sun Pharmaceutical Industries Limited Compositions pharmaceutiques de liraglutide
GR20140100479A (el) 2014-09-23 2016-05-05 Novetide, Ltd., Συνθεση λιραγλουτιδης
WO2016059609A1 (fr) 2014-10-17 2016-04-21 Dr. Reddy' S Laboratories Limited Procédé d'acylation pour la préparation de liraglutide
WO2016067271A1 (fr) 2014-10-31 2016-05-06 Auro Peptides Ltd Procédé de préparation de liraglutide
CN104650219B (zh) 2015-02-15 2017-11-14 兰州大学 片段缩合制备利拉鲁肽的方法
CN104745597A (zh) 2015-03-27 2015-07-01 杭州北斗生物技术有限公司 一种高效表达重组利拉鲁肽的方法
WO2017007324A1 (fr) 2015-07-09 2017-01-12 Enzypep B.V. Conception d'une stratégie de condensation enzymatique de fragments peptidiques
CN105017381A (zh) 2015-07-20 2015-11-04 吉尔生化（上海）有限公司 一种纯化利拉鲁肽的方法
CN106478805B (zh) 2015-08-28 2021-05-04 甘李药业股份有限公司 一种glp-1衍生物的制备方法
CN105732798B (zh) 2015-11-03 2018-10-02 江苏诺泰澳赛诺生物制药股份有限公司 一种利拉鲁肽的合成方法
CN105294853A (zh) 2015-11-13 2016-02-03 中肽生化有限公司 一种制备利拉鲁肽的方法
EP3205664A1 (fr) 2016-02-11 2017-08-16 Polypeptide Laboratories Holding (PPL) AB Procédé de préparation de liraglutide utilisant un lieur bal
EP3424521A4 (fr) 2016-03-01 2019-12-18 Hybio Pharmaceutical Co., Ltd Composition pharmaceutique et son procédé de fabrication
CA3018618A1 (fr) 2016-03-23 2017-09-28 Bachem Holding Ag Procede de preparation de peptides de type glucagon
CN107286234B (zh) 2016-03-31 2021-06-08 深圳翰宇药业股份有限公司 一种减少和/或去除多肽固相合成中缺省肽的方法
WO2018020417A1 (fr) 2016-07-27 2018-02-01 Dr. Reddy's Laboratories Limited Procédé de préparation de protéines ou de peptides
WO2018032521A1 (fr) 2016-08-19 2018-02-22 深圳市健元医药科技有限公司 Procédé de synthèse de liraglutide
CN106397573A (zh) 2016-10-24 2017-02-15 合肥国肽生物科技有限公司 一种利拉鲁肽的固相合成方法
US20190374613A1 (en) 2016-11-22 2019-12-12 Biocon Research Limited Pharmaceutical compositions of glp-1 analogues
CA3046425A1 (fr) 2016-12-10 2018-06-14 Biocon Limited Synthese de liraglutide
CN106699871B (zh) 2016-12-27 2020-06-12 哈药集团技术中心 一种利拉鲁肽的制备方法
CN107056927B (zh) 2017-01-16 2021-03-02 四川吉晟生物医药有限公司 一种利拉鲁肽的制备方法
CN107022021A (zh) 2017-03-24 2017-08-08 吉尔生化（上海）有限公司 一种利拉鲁肽的固相合成法
TWI783890B (zh) * 2017-08-24 2022-11-11 丹麥商諾佛 儂迪克股份有限公司 Glp-1組成物及其用途
WO2019110837A1 (fr) 2017-12-07 2019-06-13 Adocia Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide
CN110339166B (zh) 2018-04-04 2022-04-22 沈阳药科大学 一种利拉鲁肽多囊脂质体及其制备方法和应用
US20210087250A1 (en) 2018-04-06 2021-03-25 Cyprumed Gmbh Pharmaceutical compositions for the transmucosal delivery of therapeutic peptides and proteins
CN110368376A (zh) 2019-08-08 2019-10-25 浙江美华鼎昌医药科技有限公司 一种利拉鲁肽缓释微球组合物及其制备方法

Also Published As

Publication number Publication date
WO2020127476A1 (fr) 2020-06-25

Similar Documents

Publication Publication Date Title
EP2877158B1 (fr) Formulation liquide d'un conjugué de peptide insulinotrope à longue action
JP5973918B2 (ja) Ｇｌｐ−１アゴニスト及びメチオニンを含む薬学的組成物
JP5241849B2 (ja) インスリン及びインスリン分泌性ペプチドを含む薬学的組成物
RU2440097C2 (ru) Способ лечения диабета ii типа и ожирения, осмотическое устройство для доставки и способ его изготовления
JP5248113B2 (ja) ペプチドの安定な処方
JP5312054B2 (ja) アミリンとインスリンの混合物
US8614181B2 (en) Stabilized pharmaceutical peptide compositions
JP5675799B2 (ja) 遅効性インスリン製剤
US20080318865A1 (en) Stabilized Pharmaceutical Peptide Compositions
US20060183682A1 (en) Stabilized pharmaceutical peptide compositions
US20100234299A1 (en) Stable formulation of modified glp-1
CN107308442A (zh) 包含glp‑1激动剂、胰岛素和甲硫氨酸的药物组合物
KR20050010939A (ko) 안정성이 개선된 산성 인슐린 제제
EP2200583A1 (fr) Formulations stables d'amyline et analogues associés
EP3295952A1 (fr) Formulation pharmaceutique comprenant un analogue du glp-1 et son procédé de préparation
WO2021123228A1 (fr) Composition pharmaceutique comprenant un analogue de glp-1
EP3897570A1 (fr) Composition pharmaceutique comprenant un analogue de glp -1
FR3069437A1 (fr) Compositions sous forme d'une solution aqueuse injectable comprenant au moins de l'insuline humaine a21g et un suppresseur de glucagon a action prandiale
JP2014505042A (ja) 改良された放出特性を備えたｇｌｐ−１医薬組成物
ZA200101541B (en) Method for administering insulinotropic peptides.

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20210719

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20220428