EP3897570A1 - Pharmaceutical composition comprising glp-1 analogue - Google Patents

Pharmaceutical composition comprising glp-1 analogue

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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
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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.)
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Application number
EP19829134.6A
Other languages
German (de)
French (fr)
Inventor
Sasa ROZMAN
Tanja KOLESA DOBRAVC
Gordan Sladic
Iztok VIDIC
Haowen LIN
Guotao HE
Liangzheng QIN
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KRKA dd
Original Assignee
KRKA dd
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Application filed by KRKA dd filed Critical KRKA dd
Publication of EP3897570A1 publication Critical patent/EP3897570A1/en
Withdrawn legal-status Critical Current

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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

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

The present invention discloses new pharmaceutical compositions containing a Glucagon-like peptide-1 (GLP-1) analogue optionally in a combination with one or more other active substances. The present invention further provides methods for making the same.

Description

Pharmaceutical composition comprising GLP-1 analogue
1. Technical field of the invention
The present invention pertains to new pharmaceutical compositions containing a Glucagon like peptide- 1 (GLP-1) analogue. In particular, the present invention provides pharmaceutical compositions containing one or more 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.
2. Background of the invention
It is a well-known fact that 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 Arg34, Lys26(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. It is a derivative of a human incretin, glucagon-like peptide- 1 (GLP-1) that is used as a long-acting glucagon-like peptide- 1 receptor agonist, binding to the same receptors as does the endogenous metabolic hormone GLP-1 that stimulates insulin secretion. It is developed and marketed as 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.
Prior art documents already provided some compositions of GLP-1 analogues.
W02003002136 discloses 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.
Pharmaceutical 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.
Pharmaceutical 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.
However, for various reasons, there remains a need for alternative pharmaceutical compositions exhibiting a desired physical and chemical stability. The present invention has been completed based on these findings.
3. Summary of the invention
The present invention pertains to new pharmaceutical compositions containing a Glucagon like peptide- 1 (GLP-1) analogue. In particular, the present invention provides pharmaceutical compositions containing one or more 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.
Drawings
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.
4. Detailed description
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.
Temperature treatment of a peptide solution has been suggested in the literature, especially in EP 2 494 983 A as cited above, as a possible means for the improvement of the physico chemical stability of peptides, mainly with regards to the tendency for fibre formation. However, there is still a need for further improvement of the stabilization treatment. The present inventors have surprisingly found that suitably choosing the treatment conditions allows to further reduce the tendency for aggregate formation. Moreover, there is an unmet need for formulating GLP-1 analogue peptides with alternative excipients, e.g. to provide suitable treatment options for patients with allergies against specific excipients. The accomplishment of this objective is hampered by the need to maintain excellent performance characteristics with respect to stability and the like. The present inventors have found suitable materials that can be used without compromising performance of the GLP-1 analogue formulations. The present invention has been made on the basis of these findings.
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.
4.1. Definitions
According to the present invention and unless specified, all amount indications are provided on a weight basis.
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.
According to a preferred embodiment, the above tests are carried out as specified in the 9th Edition of Ph. Eur.
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). Experiment is performed on a 96-well plate enabling fluorescence measurements with a microplate reader. 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. Background is measured on the same plate with placebo solution (water for injection and excipients) treated in the same way as formulation solution. Comparison of fibrillation tendencies of the samples is performed by direct visual comparison of the curves of relative fluorescence units (RFU) as a function of time, or by comparison of the time needed for the signal to reach certain intensity of the fluorescence. Parameter t(15000) defines time from the start of the experiment to the signal reaching 15000 RFU. As more fibrils result in increased RFU, shorter times represent higher fibrillation tendencies.
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.
The term“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
In one embodiment, 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.
In one embodiment of the present invention 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.
In one embodiment 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.
In one embodiment the concentration of liraglutide present in the pharmaceutical composition according to the present invention is from 0.1 to 100 mg/ml.
In another embodiment the concentration of liraglutide present in the pharmaceutical composition according to the present invention is from 0.5 to 50 mg/ml.
In yet another embodiment 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,
CN103087181, W02015100876, CN103864918, CN103864918, CN104004083,
W02016005960, WO2016046753, W02016059609, WO2016067271, CN104650219,
CN104745597, W02017007324, CN105017381, CN106478805, CN105732798,
CN105294853, WO2017138855, WO2017162650, CN107286234, W02018020417, WO2018020417, WO2018032521, CN106397573, WO2018104922, CN106699871,
CN107056927, CN107022021.
In one embodiment of the present invention 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.
In one embodiment the concentration of semaglutide present in the pharmaceutical composition according to the present invention is from 0.1 to 100 mg/ml.
In another embodiment the concentration of semaglutide present in the pharmaceutical composition according to the present invention is from 0.5 to 50 mg/ml.
In yet another embodiment the concentration of semaglutide present in the pharmaceutical composition according to the present invention is from 1 to 10 mg/ml.
In one embodiment 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.
4.3. Buffering agent
The pharmaceutical composition of the present invention is designated by the use of at least one buffering agent. The term 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, 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, 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. 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 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.
In one embodiment the concentration of buffering agent used in the pharmaceutical composition of the present invention is in the range of 0.05 - 50 mg/ml.
In one embodiment the concentration of buffering agent used in the pharmaceutical composition of the present invention is in the range of 0.1 - 30 mg/ml.
In one embodiment the concentration of buffering agent used in the pharmaceutical composition of the present invention is in the range of 0.1 - 20 mg/ml.
4.4. Tonicity agent
The pharmaceutical composition of the present invention is designated by the use of at least one tonicity agent. The term 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, 22nd 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.
In one embodiment of the present invention the tonicity agent is a polyhydric alcohol selected from the group consisting of xylitol, mannitol, sorbitol and glycerol or any combinations thereof. Preferably 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.
In one embodiment of the present invention the tonicity agent is monosaccharide or disaccharide selected from the group consisting of glucose, maltose, fructose, galactose, lactose, sucrose, trehalose, or any combinations thereof. Preferably the disaccharide is selected from the group consisting of maltose, lactose, trehalose or any combinations thereof. Even more preferably disaccharide is trehalose.
In one embodiment of the present invention 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. Preferably the tonicity agent is selected from the group consisting of xylitol, sorbitol, glycerol, maltose, lactose and trehalose or any combinations thereof. More preferably 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.
In one embodiment the concentration of tonicity agent used in the pharmaceutical composition of the present invention is in the range of 0.5 - 100 mg/ml.
In one embodiment the concentration of tonicity agent used in the pharmaceutical composition of the present invention is in the range of 1 - 80 mg/ml.
4.5. Preservative
The pharmaceutical composition of the present invention is designated by the use of at least one preservative. The term 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, 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, 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. Each one of these specific preservatives and combinations thereof constitutes an alternative embodiment of the invention.
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.
In one embodiment the concentration of preservative used in the pharmaceutical composition of the present invention is in the range of 0.5 to 30 mg/ml.
In one embodiment the concentration of preservative used in the pharmaceutical composition of the present invention is in the range of 0.5 to 20 mg/ml.
In one embodiment the concentration of preservative used in the pharmaceutical composition of the present invention is in the range of 1 to 10 mg/ml.
4.6. Other pharmaceutically acceptable excipients
The pharmaceutical 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, 22nd Edition, 2013.
Particularly, 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.
4.7. Pharmaceutical composition
In one embodiment the pharmaceutical composition of the present invention is in the form of a solution.
In one embodiment the pharmaceutical composition of the present invention is in the form of a suspension.
In one embodiment 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. For this embodiment, 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.
In one embodiment the pH of the pharmaceutical composition according to the present invention is in the range of 7 to 12.
In one embodiment the pH of the pharmaceutical composition according to the present invention is in the range of 7 to 10.
In one embodiment the pH of the pharmaceutical composition according to the present invention is in the range of 7 to 9.
In one embodiment the pH of the pharmaceutical composition according to the present invention is in the range of 7 to 8.
In one embodiment the pH of the pharmaceutical composition according to the present invention is in the range of 7.9 to 8.4.
In one embodiment the pharmaceutical composition according to the present invention has the osmolality in the range of from 200 to 400 mOsmol/kg.
In one embodiment the pharmaceutical composition according to the present invention has the osmolality in the range of from 230 to 370 mOsmol/kg.
In one embodiment the pharmaceutical composition according to the present invention has the osmolality in the range of from 250 to 350 mOsmol/kg.
4.8. 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.
4.9. Manufacturing method
The pharmaceutical 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, 22nd Edition, 2013.
In particular, the processes of the present invention comprise the following steps:
Method A
a) dissolving the preservative, the buffering agent and the tonicity agent in water for injections (WFI),
b) adjusting the pH of solution a),
c) adding the GLP-1 analogue,
d) adjusting the pH of solution c),
e) adding WFI up to the final volume.
In addition, the processes of the present invention comprise the following steps:
Method B
a) dissolving the preservative, the buffering agent and the tonicity agent in water for injections (WFI),
b) adjusting the pH of solution a),
c) dissolving the GLP-1 analogue in WFI, d) adjusting the pH of solution c),
e) heating of the solution d),
f) cooling down of the solution e),
g) combining solutions b) and f),
h) adjusting the pH of solution g),
i) adding WFI up to the final volume.
In one embodiment, the process of the present invention comprises the following steps:
Method C
a) dissolving the preservative, the buffering agent and the tonicity agent in water for injections (WFI),
b) adjusting the pH of solution a),
c) dissolving the GLP-1 analogue in WFI by stirring,
d) adjusting the pH of solution c),
e) heating of the solution d),
f) cooling down of the solution e),
g) combining solutions b) and f) by stirring,
h) adjusting the pH of solution g),
i) adding WFI up to the final volume,
j) filtration of solution i) and filling into cartridges.
In one embodiment of Methods B and C the temperature of heating in step e) is between 26 and 49°C.
In another embodiment of Methods B and C the temperature of heating in step e) is between
27 and 48°C.
In another embodiment of Methods B and C the temperature of heating in step e) is between
28 and 45°C.
In another embodiment of Methods B and C the temperature of heating in step e) is between
29 and 44°C. In another embodiment of Methods B and C the temperature of heating in step e) is between 30 and 43°C.
The heating of step e) in some embodiments of Methods B and C is continued for at least 6 hours.
The heating of step e) in some embodiments of Methods B and C is continued for at least 4 hours.
In one embodiment of Methods B and C the heating of step e) is continued for at least 3 hours.
In another embodiment of Methods B and C the heating of step e) is continued for at least 2 hours.
In one embodiment of Methods B and C the heating of step e) lasts between 1-6 hours, preferably between 1.5-5 hours, more preferably between 2-4 hours.
In one embodiment of Methods A, B and C the pH of solution a) in step b) is adjusted to 7-8, preferably 7-7.7.
In one embodiment of Methods B and C the pH of solution c) in step d) is adjusted to 8-11, preferably 9-10.
In one embodiment of Method A pH of solution c) in step d) is adjusted to around 8-9, preferably 8-8.5, more preferably 8.15.
In one embodiment of Methods B and C the pH of solution g) in step h) is adjusted to around 8-9, preferably 8-8.5, more preferably 8.15.
In one embodiment of Methods B and C the temperature of the solution e) in step f) is 15- 30°C, preferably 20-25°C. In one embodiment of Method C filtration of solution i) is the sterile filtration.
For each of the methods of the invention, 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.
5. Examples
Preferred specific embodiments of the present invention are described in the following examples. It is, however, to be understood that the present invention is not limited to these examples.
5.1. Example 1
Table 1
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.
5.2. Example 2
Table 2:
The compositions F9 to F16 are prepared by the same process as disclosed in Example 1.
5.3.Example 3
Table 3:
The compositions F17 to F24 are prepared by the same process as disclosed in Example 1. 5.4. Example 4
Table 4:
The compositions F25 to F32 are prepared by the same process as disclosed in Example 1.
5.5. Example 5
Table 5:
The compositions F33 to F40 are prepared by the same process as disclosed in Example 1.
5.6. Example 6
Table 6:
The compositions F41 to F48 are prepared by the same process as disclosed in Example 1.
5.7. Example 7
Table 7:
The compositions F49 to F56 are prepared by the same process as disclosed in Example 1.
5.8.Example 8
Table 8:
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.
5.9. Example 9
Table 9:
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.
5.10. Example 10
Table 10:
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.
5.11.Example 11: Fibrillation tendency of formulations containing sorbitol as the tonicity agent, with the liraglutide active ingredient solution treated at temperature 25/35/40/70°C for lh, 4h and 6h
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.
Surprisingly, we have found that sorbitol-containing excipient solution exerts a stabilizing effect on the liraglutide structure and slows down the tendency for fibre formation even when the liraglutide active ingredient solution is treated at mild heating conditions (35°C or 40°C), before combining it with the excipient solution (Figure 1).
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.
5.12.Example 12: Fibrillation tendency of formulations containing sorbitol as the tonicity agent, with the liraglutide active ingredient solution treated at temperature 35/50°C for 2h
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. Surprisingly, we have found that 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. As is evident from Figure 2 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.
5.13.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.
Surprisingly, we have found that 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 (40°C), before combining it with the excipient solution (Figure 3).

Claims

Claims
1. A pharmaceutical composition comprising at least one GLP-1 peptide analogue and
a) a buffering agent
b) a tonicity agent
c) a preservative and
d) optionally other pharmaceutically acceptable excipients.
2. The pharmaceutical composition according to claim 1, wherein the buffering agent is selected from Hepes, asparagine, meglumine, maleic acid and methionine or any combinations thereof, and preferably maleic acid.
3. The pharmaceutical composition according to claim 1 or 2, wherein the tonicity agent is selected from the group consisting of sorbitol, glycerol, mannitol, trehalose and propylene glycol or any combinations thereof, and preferably sorbitol and trehalose, more preferably sorbitol.
4. The pharmaceutical composition according to claim 1, 2 or 3, comprising
a) liraglutide or semaglutide,
b) a buffering agent selected from the group consisting of Hepes, asparagine, meglumine, maleic acid and methionine or any combinations thereof,
c) a tonicity agent selected from the group consisting of sorbitol, glycerol, mannitol, trehalose and propylene glycol or any combinations thereof, and
d) a preservative selected from the group consisting of phenol and benzyl alcohol.
5. The pharmaceutical composition according to any one of claims 1 to 4, comprising
a) liraglutide,
e) a buffering agent selected from the group consisting of Hepes, asparagine, meglumine, maleic acid and methionine or any combinations thereof,
f) a tonicity agent which is sorbitol, and
g) a preservative selected from the group consisting of phenol and benzyl alcohol.
6. The pharmaceutical composition according to any one of claims 1 to 5, which shows a fibrillation tendency, expressed by parameter t(15000), which is a time from the beginning of experiment to the signal reaching relative fluorescence units (RFU) of 15000, of greater than 30 h, preferably greater than 33 h, such as 30 h to 50 h, and especially 33 h to 45 h, wherein the signal is a fluorescence signal, which is determined as a function of time under the conditions of measurement of fluorescence on BioTek Synergy Mx multi-mode reader of a solution obtained by transferring of the sample formulation to the 96-well plate in 190 pL portions followed by addition of 10 pL of 100 pM aqueous ThT and a stainless steel ball to each well, keeping the resulting solution at 37°C while shaking for 30 s every 15 min; while recording of fluorescence of ThT for a minimum of 48 hours at an excitation wavelength 440 nm and an emission wavelength of 480 nm, including a background measurement with placebo solution, i.e. water for injection and excipients, treated in the same way as formulation solution.
7. A method for the preparation of pharmaceutical composition according to any one of claims 1 to 6, which comprises the following steps:
a) dissolving the preservative, the buffering agent and the tonicity agent in water for injections (WFI),
b) adjusting the pH of solution a),
c) adding the GLP-1 analogue,
d) adjusting the pH of solution c),
e) adding WFI up to the final volume.
8. A method for the preparation of pharmaceutical composition according to any one of claims 1 to 6, which comprises the following steps:
a) dissolving the preservative, the buffering agent and the tonicity agent in water for injections (WFI),
b) adjusting the pH of solution a) to a pH of 7-8,
c) dissolving the GLP-1 analogue in WFI,
d) adjusting the pH of solution c) to a pH of 8- 11 ,
e) heating the solution d) to a temperature of 26-49°C,
f) cooling down solution e) to a temperature of 15-30°C, preferably 20-25°C, g) combining solutions b) and f),
h) adjusting the pH of solution g), i) adding WFI up to the final volume.
9. The method according to claim 8 wherein the temperature of heating in step e) is between 27-48°C, preferably between 28 to 45°C, more preferably 29-44°C and even more preferably between 30 to 43 °C.
10. The method according to claim 8 or 9 wherein the heating of step e) is continued for at least 4 hours and preferably at least 6 hours.
11. The method according to claim 8 or 9 wherein the heating of step e) is continued for 1- 6 hours, preferably between 1.5-5 hours, more preferably between 2-4 hours.
12. The method according to any one of claims 8 to 11, wherein step c) and/or step g) is carried out under stirring.
13. The method according to any one of claims 7 to 12, wherein the product obtained in the last step is subsequently sterile filtered and then filled into a container, preferably a cartridge.
14. The pharmaceutical composition according to claim 1 or 2, which is obtainable by a method according to any one of claims 7 to 13.
EP19829134.6A 2018-12-19 2019-12-18 Pharmaceutical composition comprising glp-1 analogue Withdrawn EP3897570A1 (en)

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