WO2023187067A1 - Procédé de formulation - Google Patents

Procédé de formulation Download PDF

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Publication number
WO2023187067A1
WO2023187067A1 PCT/EP2023/058317 EP2023058317W WO2023187067A1 WO 2023187067 A1 WO2023187067 A1 WO 2023187067A1 EP 2023058317 W EP2023058317 W EP 2023058317W WO 2023187067 A1 WO2023187067 A1 WO 2023187067A1
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WO
WIPO (PCT)
Prior art keywords
formulation
semaglutide
receptor agonist
cagrilintide
glp
Prior art date
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PCT/EP2023/058317
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English (en)
Inventor
Rosa Rebecca Erritzøe HANSEN
Benjamin Troest KJELDSEN
Original Assignee
Novo Nordisk A/S
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Publication date
Priority claimed from PCT/EP2022/085558 external-priority patent/WO2023110833A1/fr
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Publication of WO2023187067A1 publication Critical patent/WO2023187067A1/fr

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    • 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
    • A61K38/225—Calcitonin gene related peptide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof

Definitions

  • the current invention relates to a method of formulating a pharmaceutical formulation which is a co-formulation of a GLP-1 receptor agonist and an amylin receptor agonist.
  • the pharmaceutical formulation may be used for the medical treatment of subjects with overweight or obesity, with or without one or more associated co-morbidities; diabetes, with or without one or more associated comorbidities; one or more cardiovascular diseases; non-alcoholic steatohepatitis (NASH); and/or cognitive impairment, such as that caused by Alzheimer’s disease.
  • NASH non-alcoholic steatohepatitis
  • Semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist and is the active pharmaceutical ingredient in Ozempic®.
  • Ozempic® is indicated (i) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus and (ii) to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease.
  • Semaglutide is also the active pharmaceutical ingredient in Wegovy®.
  • Wegovy® is indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of greater or equal to 30 kg/m 2 or greater than 27 kg/m 2 , in the presence of at least one weight-related comorbidity.
  • BMI body mass index
  • Semaglutide a GLP-1 receptor agonist
  • Semaglutide is optimally stable at pH 7.4 and has previously needed to be formulated in a neutral to slightly basic solution of pH 7-8, to ensure its solubility in aqueous solution.
  • Cagrilintide is optimally stable at pH 4.0 and has needed to be formulated in acidic solution, increasing pH accelerating the rate of its chemical degradation.
  • the formulation method by which a protein drug product formulation is manufactured must aim to decrease the total stress the protein is subject to, in order to ensure sufficient physical stability of the product.
  • Figures 1-12 depict formulation methods 1-12, wherein formulation methods 5, 9, and 11 are embodiments of the current invention.
  • Figure 1 is a flow diagram depicting formulation method 1.
  • pH was adjusted to pH 5.8 using 0.05N hydrochloride acid and/or 0.05N sodium hydroxide.
  • Figure 3 is a flow diagram depicting formulation method 3.
  • Figure 4 is a flow diagram depicting formulation method 4.
  • pH was adjusted to pH 6.0 using 0.05N hydrochloride acid and/or 0.05N sodium hydroxide.
  • pH was adjusted to pH 6.0 using 0.05N hydrochloride acid and/or 0.05N sodium hydroxide.
  • Figure 6 is a flow diagram depicting formulation method 6.
  • HP-B-CD, sorbitol and histidine was dissolved in water for injection (60% of the final volume).
  • Semaglutide drug substance was dissolved in the solution.
  • pH was adjusted to pH 5.8 using 0.05N hydrochloride acid and/or 0.05N sodium hydroxide.
  • Figure 7 is a flow diagram depicting formulation method 7.
  • pH was adjusted to pH 6.0 using 0.05N hydrochloride acid and/or 0.05N sodium hydroxide.
  • pH was adjusted to pH 5.8 using 0.05N hydrochloride acid and/or 0.05N sodium hydroxide.
  • Figure 8 is a flow diagram depicting formulation method 8.
  • HP-B-CD, histidine and polysorbate 80 was dissolved in water for injection (60% of the final volume).
  • Semaglutide drug substance was dissolved in the solution.
  • pH was adjusted to pH 6.0 using 0.05N hydrochloride acid and/or 0.05N sodium hydroxide.
  • pH was adjusted to pH 5.8 using 0.05N hydrochloride acid and/or 0.05N sodium hydroxide.
  • Figure 9 is a flow diagram depicting formulation method 9.
  • HP-B-CD was dissolved in water for injection (60% of the final volume).
  • Semaglutide drug substance was dissolved in the solution. 3. pH was adjusted to pH 6.0 using 0.05N hydrochloride acid and/or 0.05N sodium hydroxide.
  • pH was adjusted to pH 5.8 using 0.05N hydrochloride acid and/or 0.05N sodium hydroxide.
  • Figure 10 is a flow diagram depicting formulation method 10.
  • HP-B-CD and sorbitol was dissolved in water for injection (60% of the final volume).
  • Semaglutide drug substance was dissolved in the solution.
  • pH was adjusted to pH 6.0 using 0.05N hydrochloride acid and/or 0.05N sodium hydroxide.
  • pH was adjusted to pH 5.8 using 0.05N hydrochloride acid and/or 0.05N sodium hydroxide.
  • Figure 11 is a flow diagram depicting formulation method 11 .
  • HP-B-CD and histidine was dissolved in water for injection (60% of the final volume).
  • Semaglutide drug substance was dissolved in the solution.
  • pH was adjusted to pH 6.0 using 0.05N hydrochloride acid and/or 0.05N sodium hydroxide.
  • Sorbitol and polysorbate 80 was added and dissolved.
  • pH was adjusted to pH 5.8 using 0.05N hydrochloride acid and/or 0.05N sodium hydroxide.
  • Water for injection was added to reach 100% of the final volume the formulation before being sterile filtered and filled into pre-fillable syringes.
  • Figure 12 is a flow diagram depicting formulation method 12.
  • HP-B-CD and polysorbate 80 was dissolved in water for injection (60% of the final volume).
  • Semaglutide drug substance was dissolved in the solution.
  • pH was adjusted to pH 6.0 using 0.05N hydrochloride acid and/or 0.05N sodium hydroxide.
  • pH was adjusted to pH 5.8 using 0.05N hydrochloride acid and/or 0.05N sodium hydroxide.
  • the current invention is a method of formulating a liquid pharmaceutical formulation comprising an amylin receptor agonist, a GLP-1 receptor agonist and a cyclodextrin comprising hydroxypropyl substitutions.
  • a method of preparing a pharmaceutical formulation comprising an amylin receptor agonist and a GLP-1 receptor agonist comprising:
  • the GLP-1 receptor agonist may be semaglutide.
  • the amylin receptor agonist may be cagrilintide.
  • the cyclodextrin may be of the hydroxypropyl-substituted alpha type, comprising six ring-arranged glucose units, and/or the hydroxypropyl-substituted beta type, comprising seven ring-arranged glucose units.
  • the aqueous, surfactant-free excipient solution comprising cyclodextrin may comprise one or more further excipients, with the proviso that said one or more further excipients is not a surfactant.
  • One or more further excipients may be added to the mixture of the aqueous, surfactant-free excipient solution and the GLP-1 receptor agonist, with the proviso that said further excipient is not a surfactant.
  • One or more further excipients may be added to the mixture of the excipient solution, the GLP-1 receptor agonist and the amylin receptor agonist.
  • concentrations of cyclodextrin, GLP-1 receptor agonist, amylin receptor agonist, surfactant and any further excipient will be such as to arrive at the composition of the pharmaceutical formulation (drug product) also disclosed herein.
  • Also disclosed herein is a means of co-formulating an amylin receptor agonist and a GLP-1 receptor agonist, wherein the GLP-1 receptor agonist has an isoelectric point that precludes its co-formulation in the pH range enabling chemical stability of the amylin receptor agonist.
  • a means of co-formulating a GLP-1 receptor agonist having an isoelectric point (pl) of less than 6.5, preferably less than 6.0, such as 3.5-6.0, such as 3.0- 5.0, such as 4.0-6.0, and an amylin receptor agonist.
  • the physical stability of a GLP-1 receptor agonist and/or any amylin receptor agonist in any liquid formulation can be quantified by measuring particle formation and/or fibrillation by means of micro-flow imaging (MFI) or a Thioflavin T (ThT) fluorescence stress assay, respectively.
  • MFI micro-flow imaging
  • ThT Thioflavin T fluorescence stress assay
  • an amylin receptor agonist and a GLP-1 receptor agonist whose optimal pHs differ by at least about two pH units, such as 2-5 pH units, such as 2-4 pH units, such as 3-5 pH units.
  • Production of the drug substances precedes implementation of the formulation method disclosed herein, whose aim is to create the final drug product, a pharmaceutical formulation.
  • Application of the method disclosed herein ensures that the pharmaceutical formulation or “drug product” has an improved shelf-life.
  • a solid or “dried” form of the purified active pharmaceutical ingredient (or drug substance) may be obtained as described in WO2012/168432.
  • the drug substance may be dried by freeze drying (i.e., lyophilization; see, for example, Williams and Rolli (1984) J. Parenteral Sci. Technol. 38:48-59), spray drying (see Masters (1991) in Spray-Drying Handbook (5th ed; Longman Scientific and Technical, Essez, U.K.), pp. 491-676; Broadhead et al. (1992) Drug Devel. Ind. Pharm. 18:1169-1206; and Mumenthaler et al. (1994) Pharm. Res. 11 :12-20), or air drying (Carpenter and Crowe (1988) Cryobiology 25:459-470; and Roser (1991) Biopharm. 4:47-53).
  • amylin herein refers to a polypeptide having the same amino acid sequence as an endogenous amylin, such as human amylin.
  • Examples of endogenous amylin receptor agonists are human amylin and human calcitonin.
  • exogenous amylin receptor agonists are cagrilintide and pramlintide (the active pharmaceutical ingredient in Symlin®).
  • amylin receptor agonist in the pharmaceutical formulation disclosed herein may be cagrilintide or a biologically active metabolite or degradation product of cagrilintide.
  • a biologically active metabolite or degradation product of cagrilintide may have an aspartate (Asp) in position 21 or 22.
  • a biologically active metabolite or degradation product of cagrilintide may have an iso-aspartate (iso-Asp) in position 21 or 22.
  • the pharmaceutical formulation disclosed herein may comprise cagrilintide in a concentration of about 0.33-18 mg/ml; such as 0.25-0.5 mg/ml, such as about 0.33 mg/ml; such as 0.5-1 .0 mg/ml, such as about 0.67 mg/ml; such as 1 .0-1 .5 mg/ml, such as about 1.33 mg/ml; such as 1.5-2.0 mg/ml, such as about 1.5 mg/ml; such as 2.0-2.5 mg/ml; such as 2.5-3.0 mg/ml; such as 3.0-3.5 mg/ml; such as about 3.2 mg/ml; such as 3.5-4.0 mg/ml; such as 4.0-5.0 mg/ml; such as 5.0-6.0 mg/ml; such as 6.0-7.0 mg/ml, such as 7.0-8.0 mg/ml, such as 8.0-9.0 mg/ml, such as 9.0-10.0 mg/ml, such as about 9.6 mg/ml; such as 10-11 mg/ml,
  • the pharmaceutical formulation disclosed herein may comprise no more than 22 mg/ml semaglutide.
  • the pharmaceutical formulation disclosed herein may comprise no more than 12 mg/ml semaglutide.
  • the GLP-1 receptor agonist and/or amylin receptor agonist in the pharmaceutical formulation disclosed herein may also, for instance, be produced by classical peptide synthesis, e.g. solid phase peptide synthesis using t-Boc or Fmoc chemistry, or other well established techniques, see e.g. Greene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley & Sons, 1999; Florencio Zaragoza Dbrwald, “Organic Synthesis on Solid Phase”, Wiley-VCH Verlag GmbH, 2000; and “Fmoc Solid Phase Peptide Synthesis”, Edited by W.C. Chan and P.D. White, Oxford University Press, 2000.
  • the compounds may be produced by recombinant methods, e.g. by culturing a host cell containing a DNA sequence encoding the peptide sequence and capable of expressing the peptide, in a suitable nutrient medium under conditions permitting the expression of the peptide.
  • host cells suitable for expression of these peptides are Escherichia coli, Saccharomyces cerevisiae and mammalian BHK or CHO cell lines.
  • the theoretically calculated isoelectric point of the GLP-1 receptor agonist may be in the range of 3.5-6.5, such as 3.5-6.0, such as 4.0-6.0, such as 3.8-4.9, such as 4.0-4.5.
  • Semaglutide has a theoretically calculated isoelectric point of about 4.37.
  • the excipient solution is an aqueous solution, comprising water for injection (WFI).
  • WFI water for injection
  • the pharmaceutical formulation may comprise more than 75% w/w water, such as 80% w/w water, such as about 85% w/w water, such as up to 90% w/w water.
  • the excipient solution may further comprise one or more further excipients, with the proviso that such further excipient is not a surfactant.
  • a buffer may be such a further excipient.
  • a tonicity agent may be such a further excipient.
  • the aqueous, surfactant-free excipient solution utilised in the formulation method described herein comprises a cyclodextrin comprising hydroxypropyl substitutions.
  • the pharmaceutical formulation disclosed herein necessarily comprises a cyclodextrin comprising hydroxypropyl substitutions.
  • the hydroxyl groups of the glucose units of the cyclodextrins may be substituted by a varying number of hydrophilic chemical substitutions, e.g., by hydroxypropyl groups, leading to differences in degree of substitution which can be described as either the average number of hydroxypropyl per cyclodextrin molecule (abbreviated DS) or the molar substitution degree corresponding to the average number of hydroxypropyl per glucose units present in the cyclodextrin in question (abbreviated MS).
  • DS average number of hydroxypropyl per cyclodextrin molecule
  • MS molar substitution degree corresponding to the average number of hydroxypropyl per glucose units present in the cyclodextrin in question
  • hydroxypropyl per cyclodextrin can be achieved by multiplication of the molar substitution degree by the number of glucose units comprised in the cyclodextrin in question. Difference in degree of substitution can result in alterations in physicochemical properties such as surface activity and complexing abilities.
  • the hydroxyl groups may also be chemically substituted by groups of sulfobutylether. These mostly hydrophilic modifications have yielded cyclodextrin derivates highly suitable for parenteral administration [Cyclodextrins used as excipients, 2017, EMA/CHMP/333892/2013, Committee for Human Medicinal Products (CHMP)]. Cyclodextrins comprising hydroxypropyl substitutions are commonly abbreviated HP-CDs whereas cyclodextrins comprising sulfobutylether substitutions are abbreviated SBE-CDs.
  • the pharmaceutical formulation disclosed herein preferably comprises a cyclodextrin of the hydroxypropyl-substituted alpha type and/or a cyclodextrin of the hydroxypropyl-substituted beta type.
  • the pharmaceutical formulation disclosed herein may comprise a cyclodextrin of the hydroxypropyl-substituted alpha type, comprising six ring-arranged glucose units.
  • the hydroxypropyl substituted cyclodextrin of the alpha type is abbreviated HP-A-CD.
  • Hydroxypropyl-alpha-cyclodextrins (CAS: 128446-33-3/99241-24-4) are commercially available, with an average molar substitution (MS) of 0.8 and a molar substitution range of 0.5-0.9.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl- alpha-cyclodextrin having a minimum of about 0.4 hydroxypropyls per glucose unit.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-alpha-cyclodextrin having a maximum of about 1.0 hydroxypropyls per glucose unit.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl- alpha-cyclodextrin having a molar substitution range of 0.5-0.9 hydroxy propyls per glucose unit.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-alpha- cyclodextrin having an average molar substitution (MS) of about 0.8 hydroxypropyls per glucose unit.
  • the pharmaceutical formulation disclosed herein may comprise a cyclodextrin of the hydroxypropyl-substituted beta type, comprising seven ring-arranged glucose units.
  • the hydroxypropyl substituted cyclodextrin of the beta type is abbreviated HP-B-CD.
  • Hydroxypropyl-beta-cyclodextrins are well known pharmaceutical excipients, typically used in small molecule pharmaceutical formulations, primarily to increase solubility and bioavailability [T. Loftsson, Cyclodextrins in Parenteral Formulations, Journal of Pharmaceutical Sciences, 2020, 1-11], Thus far, the use of cyclodextrins and cyclodextrin substituted derivatives in protein and peptide-based pharmaceutical formulations is limited.
  • hydroxypropyl substitution degrees for hydroxypropyl-beta-cyclodextrins as pharmaceutical excipients ranges between 2.8 and 10.5 according to the European and US pharmacopoeia [USP 38 NF 33, Pharm Eur 8, as estimated by methods described in USP ⁇ 761 > /Pharm. Eur. 2.2.33], corresponding to 0.4- 1.5 hydroxypropyl per glucose unit (MS).
  • cyclodextrins such as hydroxypropyl-beta-cyclodextrins are usually described by means of the average molar substitutions (MS) of their molar substitution ranges.
  • Hydroxypropyl-beta-cyclodextrins are commercially available for use as excipients, with average molar substitutions (MS) including: MS 0.62, with a molar substitution range of 0.58-0.68; MS 0.67, with a molar substitution range from (0.6-0.9); MS 0.68, with a molar substitution range from (0.58-0.72); MS 0.84, with a molar substitution range from (0.8-1.0); MS 0.92, with a molar substitution range from (0.81-0.99); MS 1 .08, with a molar substitution range from (0.86-1 .14); each value describing the number of hydroxypropyls per glucose unit.
  • MS average molar substitutions
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta- cyclodextrin having a minimum of about 0.4 hydroxy propyls per glucose unit.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta-cyclodextrin having a maximum of about 1.0 hydroxypropyls per glucose unit.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta- cyclodextrin having a molar substitution range of 0.58-1.0 hydroxy propyls per glucose unit.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta- cyclodextrin having an average molar substitution (MS) range of about 0.62-0.92 hydroxypropyls per glucose unit.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta- cyclodextrin having an average molar substitution (MS) of about 0.62-0.84 hydroxypropyls per glucose unit.
  • MS average molar substitution
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta- cyclodextrin having about 0.4-0.75 hydroxy propyls per glucose unit.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta- cyclodextrin having about 0.75 hydroxypropyls per glucose unit.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta- cyclodextrin having an average molar substitution (MS) of about 0.62.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta-cyclodextrin having about 0.58-0.68 hydroxypropyls per glucose unit.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta- cyclodextrin having an average molar substitution (MS) of about 0.68.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta-cyclodextrin having about 0.58-0.72 hydroxypropyls per glucose unit.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta- cyclodextrin having an average molar substitution (MS) of about 0.67.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta-cyclodextrin having about 0.6-0.9 hydroxypropyls per glucose unit.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta- cyclodextrin having an average molar substitution (MS) of about 0.84.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta-cyclodextrin having about 0.8-1.0 hydroxypropyls per glucose unit.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta- cyclodextrin having an average molar substitution (MS) of about 0.92.
  • the pharmaceutical formulation disclosed herein may comprise hydroxypropyl-beta-cyclodextrin having about 0.81-0.99 hydroxypropyls per glucose unit.
  • the pharmaceutical formulation disclosed herein may comprise 10-25% w/v, such as more than 10% w/v and less than 22% w/v, such as about 10-20% w/v, such as about 12- 18% w/v, such as about 10-17.5% w/v, such as about 11.25-15%, such as about 15% w/v hydroxypropyl-beta-cyclodextrin having a minimum of about 0.4 hydroxypropyls per glucose unit and a maximum of about 1.0 hydroxypropyls per glucose unit; such as an average of 0.62-0.92 hydroxypropyls per glucose unit, such as about 0.75 hydroxypropyls per glucose unit; such as an average of 0.62-0.84 hydroxy propyls per glucose unit; such as about 0.4- 0.75 hydroxy propyls per glucose unit; such as an average of 0.62 hydroxypropyls per glucose unit, such as about 0.58-0.68 hydroxy propyls per glucose unit.
  • a surfactant may further increase the physical stability and robustness of a formulation during its manufacture, storage and use as a medicament; for example, preserve the stability of a formulation when it is exposed to air inside a container.
  • the use of surfactants in pharmaceutical formulations is well-known to the skilled person. For convenience, reference is made to Remington: The Science and Practice of Pharmacy, 20 th edition, 2000.
  • the method disclosed herein involves adding surfactant to a mixture of an aqueous, surfactant-free excipient solution, a GLP-1 receptor agonist and an amylin receptor agonist.
  • the pharmaceutical formulation disclosed herein necessarily comprises a surfactant.
  • the surfactant utilised in the method disclosed herein may be selected from the group consisting of polysorbate 20 and/or polysorbate 80.
  • the surfactant may be polysorbate 20.
  • the surfactant may be polysorbate 80.
  • the pharmaceutical formulation may comprise 0.01 mg/ml or more polysorbate 20 and up to 2.0, such as up to 1 .5 mg/ml polysorbate 20, such as about 0.01-1 .0 mg/ml polysorbate 20, such as about 0.05 mg/ml polysorbate 20.
  • the pharmaceutical formulation may comprise 0.01 mg/ml or more polysorbate 80 and up to 2.0, such as up to 1 .5 mg/ml polysorbate 80, such as about 0.01-1.0 mg/ml polysorbate 80, such as about 0.05 mg/ml polysorbate 80.
  • the aqueous, surfactant-free excipient solution may comprise one or more further excipients, with the proviso that such further excipient is not a surfactant.
  • the method disclosed herein may comprise adding one or more further excipients to the mixture of the excipient solution and the GLP-1 receptor agonist, with the proviso that said further excipient is not a surfactant.
  • the method disclosed herein may comprise adding one or more further excipients to the mixture of the excipient solution, the GLP-1 receptor agonist and the amylin receptor agonist.
  • Further excipients may include a buffer and a tonicity agent.
  • the pharmaceutical formulation disclosed herein necessarily comprises any further excipient employed during the method disclosed herein.
  • the pharmaceutical formulation may comprise a buffer.
  • the use of a buffer in pharmaceutical formulations is well-known to the skilled person. For convenience, reference is made to Remington: The Science and Practice of Pharmacy, 20 th edition, 2000.
  • the pharmaceutical formulation disclosed herein may comprise a buffer having a pKa close to the desired pH of the solution.
  • the pharmaceutical formulation may comprise a buffer having at least one pKa value of about 5.0-7.0.
  • the pharmaceutical formulation may comprise a buffer having a pKa of about 5.0-7.0.
  • the pharmaceutical formulation may comprise a buffer selected from the group consisting of histidine, citrate and/or phosphate.
  • the buffer may be histidine, citrate and/or phosphate in a total concentration of 3-30 mM.
  • the buffer may be citrate, in a concentration of 3-30 mM.
  • the buffer may be histidine, in a concentration of 3-30 mM.
  • the buffer may be phosphate, in a concentration of 3-30 mM
  • the pharmaceutical formulation may further comprise one or more agents for adjusting pH, such as NaOH and/or HCI.
  • the desired pH of the pharmaceutical formulation may be about 5.5-6.5.
  • the pH of the pharmaceutical formulation is preferably 5.6-6.0.
  • the pH of the pharmaceutical formulation may be about 5.6, such as about 5.7, such as about pH 5.8, such as about 5.9, such as about 6.0.
  • pH may be measured at “room temperature”, typically defined as 15-25°C or 15- 20°C. pH is preferably measured at about 20°C.
  • the pharmaceutical formulation disclosed herein may comprise a tonicity agent.
  • a tonicity agent in pharmaceutical formulations is well-known to the skilled person. For convenience, reference is made to Remington: The Science and Practice of Pharmacy, 20 th edition, 2000.
  • the purpose of the tonicity agent is to protect living tissue when the formulation is injected into the body.
  • the tonicity agent may be selected from the group consisting of mannitol, sorbitol or trehalose, or a combination thereof.
  • the tonicity agent is mannitol.
  • the tonicity agent is sorbitol.
  • the tonicity agent is trehalose.
  • the concentration of the tonicity agent is such as to render the formulation isotonic.
  • the tonicity agent is mannitol, it may be present in a concentration of 16.5-37.5 mg/ml, such as about 20 mg/ml.
  • the tonicity agent is sorbitol, it may be present in a concentration of about 10-40 mg/ml; such as about 16.5-37.5 mg/ml; such as about 10-30 mg/ml; such as about 16-28 mg/ml, such as about 16.5-25 mg/ml, such as about 16-26 mg/ml; such as about 16-24 mg/ml; such as about 26 mg/ml, such as about 24 mg/ml, such as about 22 mg/ml, such as about 20 mg/ml, such as about 18 mg/ml, such as about 16 mg/ml, such as about 12 mg/ml.
  • the tonicity agent is trehalose, it may be present in a concentration of 33-75 mg/ml, such as about 38
  • compositions disclosed herein are for medical use.
  • the pharmaceutical formulation disclosed herein may be administered by parenteral injection.
  • the pharmaceutical formulation disclosed herein may be administered by subcutaneous injection.
  • treatment refers to the medical therapy of any human or other vertebrate subject in need thereof.
  • Said subject is expected to have undergone physical examination by a medical practitioner, or a veterinary medical practitioner, who has given a tentative or definitive diagnosis which would indicate that the use of said specific treatment is beneficial to the health of said human or other vertebrate.
  • the timing and purpose of said treatment may vary from one individual to another, according to the status quo of the subject’s health.
  • said treatment may be prophylactic (preventative), palliative, symptomatic and/or curative.
  • the pharmaceutical formulation disclosed herein may be administered to a human subject.
  • the pharmaceutical formulation disclosed herein may be used in:
  • diabetes and associated symptoms such as hyperglycaemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, noninsulin dependent diabetes, maturity onset diabetes of the young (MODY), gestational diabetes and/or for the reduction of HbA1c;
  • diabetes the delaying or prevention of diabetic disease progression, such as progression in type 2 diabetes, delaying the progression of impaired glucose tolerance (IGT) to insulinrequiring type 2 diabetes and/or delaying the progression of non-insulin requiring type 2 diabetes to insulin-requiring type 2 diabetes;
  • ITT impaired glucose tolerance
  • eating disorders such as obesity, e.g. by decreasing food intake, suppressing appetite, inducing satiety, reducing body weight; treating or preventing binge eating disorder, food cravings, bulimia nervosa and/or obesity induced by the administration of an antipsychotic or a steroid; reducing gastric motility; and/or delaying gastric emptying;
  • cardiovascular disease such as the delaying or reduction of the development of a major adverse cardiovascular event (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularisation, hospitalisation for unstable angina pectoris, and hospitalisation for heart failure;
  • MACE major adverse cardiovascular event
  • NASH non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • the indication is (i). In some embodiments the indication is (ii). In a still further particular aspect the indication is (iii). In a still further particular aspect, the indication is (iv). In a still further particular aspect, the indication is (v). In a still further particular aspect, the indication is (vi). In some embodiments, the indication is type 2 diabetes and/or obesity.
  • a method of preparing a pharmaceutical formulation comprising an amylin receptor agonist and a GLP-1 receptor agonist comprising:
  • a drug substance such as a solid DS, comprising an amylin receptor agonist as the active pharmaceutical ingredient
  • a drug substance such as a solid DS, comprising a GLP-1 receptor agonist as the active pharmaceutical ingredient
  • a method of preparing a pharmaceutical formulation comprising an amylin receptor agonist and a GLP-1 receptor agonist comprising:
  • a drug substance such as a solid DS, comprising an amylin receptor agonist as the active pharmaceutical ingredient
  • a drug substance such as a solid DS comprising a GLP-1 receptor agonist as the active pharmaceutical ingredient
  • a method of preparing a pharmaceutical formulation comprising an amylin receptor agonist and a GLP-1 receptor agonist comprising:
  • a drug substance such as a solid DS, comprising an amylin receptor agonist as the active pharmaceutical ingredient
  • a drug substance such as a solid DS, comprising a GLP-1 receptor agonist as the active pharmaceutical ingredient; • preparing an aqueous, surfactant-free excipient solution comprising a cyclodextrin comprising hydroxypropyl substitutions; a tonicity agent, such as sorbitol; a buffer, such as histidine; and water for injection (WFI) to about 50-80%, such as about 65%, of the final, pre-defined volume; and having a pH of 6.5-8.5, such as a pH of about 7.0-8.0, preferably a pH of about 7.5;
  • a drug substance such as a solid DS, comprising a GLP-1 receptor agonist as the active pharmaceutical ingredient
  • preparing an aqueous, surfactant-free excipient solution comprising a cyclodextrin comprising hydroxypropyl substitutions
  • a tonicity agent such as sorbitol
  • a buffer such as histidine
  • WFI water for injection
  • amylin receptor agonist is cagrilintide or a biologically active metabolite or degradation product of cagrilintide.
  • a method of preparing a pharmaceutical formulation comprising cagrilintide and a semaglutide comprising:
  • a drug substance such as a solid DS, comprising semaglutide as the active pharmaceutical ingredient
  • preparing an aqueous, surfactant-free excipient solution comprising a cyclodextrin comprising hydroxypropyl substitutions and water for injection (WFI) to about 50- 80%, such as about 65%, of the final, pre-defined volume; optionally, one or more further excipients, with the proviso that one or more further excipient is not a surfactant; and having a pH of 6.5-8.5, such as a pH of about 7.0-8.0, preferably a pH of about 7.5; • dissolving the semaglutide DS in the excipient solution;
  • a method of preparing a pharmaceutical formulation comprising cagrilintide and a semaglutide comprising:
  • a drug substance such as a solid DS, comprising semaglutide as the active pharmaceutical ingredient
  • preparing an aqueous, surfactant-free excipient solution comprising a cyclodextrin comprising hydroxypropyl substitutions, sorbitol, histidine and water for injection (WFI) to about 50-80%, such as about 65%, of the final, pre-defined volume; and having a pH of 6.5-8.5, such as a pH of about 7.0-8.0, preferably a pH of about 7.5;
  • cyclodextrin is of the hydroxypropyl-substituted alpha type comprising six ring-arranged glucose units and/or the hydroxypropyl-substituted beta type comprising seven ring-arranged glucose units.
  • aqueous, surfactant-free excipient solution comprising cyclodextrin comprises one or more further excipients, with the proviso that said further excipient is not a surfactant.
  • aqueous, surfactant-free excipient solution comprising cyclodextrin further comprises a buffer. 17. The method according to any one of the preceding embodiments, further comprising adding a buffer to the mixture of the excipient solution and the GLP-1 receptor agonist.
  • aqueous, surfactant-free excipient solution further comprises a tonicity agent, with the proviso that the tonicity agent is not sodium chloride.
  • liquid pharmaceutical formulation according to embodiment 31 wherein the GLP-1 receptor agonist has an isoelectric point that is incompatible with the optimal pH of the amylin receptor agonist.
  • liquid pharmaceutical formulation according to any one embodiments 30-32, wherein the optimal pH of the amylin receptor agonist is 3.5-4.5, such as about 4.0.
  • composition according to any one of embodiments 30-59 comprising at least about 1 mg/ml of said GLP-1 receptor agonist.
  • composition according to any one of embodiments 30-69 comprising an effective amount of cagrilintide and semaglutide.
  • the pharmaceutical formulation according to embodiment 73 comprising mannitol in a concentration of about 16.5-37.5 mg/ml, such as about 20 mg/ml.
  • the pharmaceutical formulation according to embodiment 75 comprising sorbitol in a concentration of about 10-40 mg/ml, such as about 10-30 mg/ml, such as about 16-28 mg/ml, such as about 16.5-37.5 mg/ml, such as about 16.5-25 mg/ml, such as about 16-24 mg/ml, such as about 24 mg/ml, such as about 20 mg/ml, such as about 16 mg/ml, such as about 12 mg/ml.
  • said tonicity agent is trehalose.
  • the pharmaceutical formulation according to embodiment 77 comprising trehalose in a concentration of about 33-75 mg/ml, such as about 33-45 mg/ml, such as about 38 mg/ml.
  • the pharmaceutical formulation according to embodiment 79 comprising a buffer selected from the group consisting of histidine, citrate and/or phosphate.
  • the pharmaceutical formulation according to any one of embodiments 80-81 comprising about 3-30 mM histidine, such as 3-15 mM histidine, such as 3-10 mM histidine, such as about 6 mM histidine.
  • the pharmaceutical formulation according to embodiment 86 comprising a maximum of about 2.0 mg/ml polysorbate 20 and/or polysorbate 80.
  • the pharmaceutical formulation according to embodiment 87 comprising a maximum of about 1 .5 mg/ml polysorbate 20 and/or polysorbate 80.
  • the pharmaceutical formulation according to any one of embodiments 30-90 comprising at least 75% w/w water, such as about 80% w/w water, such as about 85% w/w water, such as up to about 90% w/w water.
  • the pharmaceutical formulation according to any one of embodiments 30-91 essentially consisting of: an effective amount of cagrilintide and semaglutide, a cyclodextrin of the hydroxypropyl-substituted alpha and/or beta type comprising a minimum of about 0.4 hydroxypropyls per glucose unit and a maximum of about 1.0 hydroxypropyls per glucose unit, histidine, sorbitol, polysorbate 20 and/or 80 and about 75-90% w/w water; and having a pH of 5.6-6.0.
  • the pharmaceutical formulation according to any one of embodiments 30-91 essentially consisting of: an effective amount of cagrilintide and semaglutide; a cyclodextrin of the hydroxypropyl-substituted alpha and/or beta type, comprising 0.58-1.0 hydroxypropyls per glucose unit, histidine, sorbitol, polysorbate 20 and/or 80 and about 75-90% w/w water; and having a pH of 5.6-6.0.
  • the pharmaceutical formulation according to any one of embodiments 30-91 essentially consisting of: an effective amount of cagrilintide and semaglutide; a cyclodextrin of the hydroxypropyl-substituted alpha and/or beta type, comprising an average of 0.62-0.92 hydroxypropyls per glucose unit; histidine, sorbitol, polysorbate 20 and/or 80 and about 75- 90% w/w water; and having a pH of 5.6-6.0.
  • the pharmaceutical formulation according to any one of embodiments 30-91 essentially consisting of: an effective amount of cagrilintide and semaglutide; a cyclodextrin of the hydroxypropyl-substituted alpha and/or beta type, comprising an average of 0.62-0.84 hydroxypropyls per glucose unit; histidine and/or citrate, sorbitol, polysorbate 20 and/or 80 and about 75-90% w/w water; and having a pH of 5.6-6.0.
  • the pharmaceutical formulation according to any one of embodiments 30-91 essentially consisting of: an effective amount of cagrilintide and semaglutide; a cyclodextrin of the hydroxypropyl-substituted alpha and/or beta type, comprising an average of 0.62-0.68 hydroxypropyls per glucose unit; histidine and/or citrate, sorbitol, polysorbate 20 and/or 80 and about 75-90% w/w water; and having a pH of 5.6-6.0.
  • the pharmaceutical formulation according to any one of embodiments 30-91 essentially consisting of: an effective amount of cagrilintide and semaglutide; a cyclodextrin of the hydroxypropyl-substituted alpha and/or beta type, comprising an average of 0.62 hydroxypropyls per glucose unit; histidine and/or citrate, sorbitol, polysorbate 20 and/or 80 and about 75-90% w/w water; and having a pH of 5.6-6.0.
  • the pharmaceutical formulation according to any one of embodiments 30-91 essentially consisting of: an effective amount of cagrilintide and semaglutide, a hydroxypropyl beta cyclodextrin comprising a maximum of about 0.75 hydroxypropyls per glucose unit, such as about 0.4-0.75 hydroxy propyls per glucose unit, histidine, sorbitol, polysorbate 80 and about 75-90% w/w water; and having a pH of 5.5-6.5.
  • the pharmaceutical formulation according to any one of embodiments 30-91 essentially consisting of: an effective amount of cagrilintide and semaglutide, a hydroxypropyl beta cyclodextrin comprising a maximum of about 0.75 hydroxypropyls per glucose unit, such as about 0.4-0.75 hydroxy propyls per glucose unit, histidine and/or citrate, sorbitol, polysorbate 20 and/or 80 and about 75-90% w/w water; and having a pH of 5.6-6.0.
  • the pharmaceutical formulation according to any one of embodiments 30-91 which essentially consists of: an effective amount of cagrilintide and semaglutide, more than 10% w/v and less than 22% w/v, such as 10-20% w/v cyclodextrin of the hydroxypropyl-substituted alpha and/or beta type (0.58-1.0 hydroxypropyls per glucose unit), about 3-30 mM histidine, about 10-40 mg/ml sorbitol, up to 2.0 mg/ml polysorbate 20 and/or 80, pH 5.6-6.0, preferably pH 5.8, water for injection.
  • an effective amount of cagrilintide and semaglutide more than 10% w/v and less than 22% w/v, such as 10-20% w/v cyclodextrin of the hydroxypropyl-substituted alpha and/or beta type (0.58-1.0 hydroxypropyls per glucose unit)
  • about 3-30 mM histidine about
  • the pharmaceutical formulation according to any one of embodiments 30-91 which essentially consists of: an effective amount of cagrilintide and semaglutide, more than 10% w/v and less than 22% w/v, such as 10-20% w/v cyclodextrin of the hydroxypropyl-substituted alpha and/or beta type, comprising an average of 0.62- 0.84 hydroxypropyls per glucose unit, about 3-30 mM histidine and/or citrate, about 10-40 mg/ml sorbitol, up to 2.0 mg/ml polysorbate 20 and/or polysorbate 80, pH 5.6-6.0, preferably pH 5.8, water for injection.
  • an effective amount of cagrilintide and semaglutide more than 10% w/v and less than 22% w/v, such as 10-20% w/v cyclodextrin of the hydroxypropyl-substituted alpha and/or beta type, comprising an average of 0.62- 0.84 hydroxy
  • EXAMPLE 1 EFFECT OF HYDROXYPROPYL-BETA-CYCLODEXTRIN (HP-B-CD) ON THE CHEMICAL STABILITY OF CAGRILINTIDE
  • HP-B-CD chemically stabilise cagrilintide
  • chemical stability being measured in terms of cagrilintide purity and cagrilintide-related high molecular weight protein (HMWP).
  • HMWP high molecular weight protein
  • Cagrilintide is optimally stable at pH 4.0, the rate of its chemical degradation typically accelerating with an increase in pH. Surprisingly, a stable cagrilintide formulation was obtained at pH 6 when it was formulated with HP-B-CD.
  • compositions of cagrilintide formulations 1 , 2 and 3 are shown in table 1 .
  • Each cagrilintide formulation was prepared by first dissolving the excipients in water and then dissolving cagrilintide drug substance in the excipient solution.
  • the solution was pH adjusted and water was added to reach the final desired volume before being sterilised by filtration through a 0.22 pm sterile filter. After filtration, the formulation was filled in a 1 ml prefilled syringe.
  • Samples were stored at 37°C for up to 21 days. After 14 days and 21 days, samples were analysed to determine the HMWP and cagrilintide purity levels.
  • HMWP size exclusion chromatography
  • T able 2 shows that when cagrilintide was stored at 37°C and at a pH of 4.0, very little HMWP was formed and only a minor decrease in cagrilintide purity was seen. In contrast, when the pH was 6.0 the rate of HMWP formation and decrease in cagrilintide purity accelerated. Surprisingly, this rapid chemical degradation was counteracted by the addition of HP-B-CD to the formulation, making it possible to formulate cagrilintide at pH 6.
  • compositions of semaglutide formulations 1 , 2 and 3 are shown in table 3.
  • ThT Thioflavin T
  • ThT fluorescence assay Two samples were pooled and 1400 pl sample was added to 28 pl 1 mM ThT stock solution, of which 200 pl was then transferred to 6 different wells on a 96 well microtiter plate with a glass bead in.
  • the assay was run with double orbital shaking and a speed of 300 rpm at 40°C for 169 hours on a BMG CLARIOstar fluorescence plate reader equipped with monochromators for both excitation and emission using 450 nm and 480 nm, respectively.
  • the lag time was measured from the start of the experiment until fibrillation occurs, shown as an increase in ThT fluorescence.
  • HP-B-CD chemically stabilise semaglutide, chemical stability being measured in terms of semaglutide purity and semaglutide-related high molecular weight protein (HMWP).
  • HMWP high molecular weight protein
  • HMWP and semaglutide purity were determined after 0 days, 14 days, and 21 days’ storage at 37°C.
  • Semaglutide purity was determined using reversed phase high performance liquid chromatography (RP-HPLC) where the samples were analysed using a Kinetex C18, 2.6 pm column (4.6 x 150 mm) with a gradient elution of eluent A consisting of 90% v/v 0.09 M phosphate solution, pH 3.6 and 10% v/v acetonitrile, and eluent B consisting of 60% v/v acetonitrile and 20% v/v isopropanol. Chromatography was conducted with UV detection (210 nm) at 30°C using a 10-100 pl injection volume and a flow rate of 0.7 ml/min. Purity was quantified as being the area of the main peak divided by the area of all peaks x 100%.
  • RP-HPLC reversed phase high performance liquid chromatography
  • HMWP size exclusion chromatography
  • Samples were analysed using a Waters SEC 1 .7 pm column (4.6 x 150 mm) with an isocratic elution consisting of 300 mM sodium chloride, 10 mM sodium dihydrogen phosphate, 5 mM ortho-phosphate and 50% v/v 2-propanol.
  • Chromatography was conducted with UV detection (280 nm) at 50°C using a 1-10 pl injection volume and a flow rate of 0.3 ml/min.
  • HMWP was quantified as being the area of all components eluting before the main peak divided by the area of the main peak x 100%.
  • EXAMPLE 4 EFFECT OF THE MOLAR SUBSTUTION OF HP-B-CD ON CAGRILINTIDE AND SEMAGLUTIDE CO-FORMULATION PHYSICAL STABILITY
  • This example shows the effect of HP-B-CD molar substitution on the physical stability of cagrilintide and semaglutide.
  • compositions of co-formulation 1 and co-formulation 2 are shown in table 6.
  • the number of sub-visible particles present quantifies the physical stability of cagrilintide and semaglutide combined and were obtained by means of micro-flow imaging (MFI, see e.g. Sharma, D.K. et al. AAPS J. (2010), 12: 455-464 for principles of the MFI technique).
  • MFI micro-flow imaging
  • the sample was analysed by standard MFI system settings implying that the liquid was pipetted into a reservoir connected to a flow cell, the liquid was illuminated by a 10 LED light source (470 nm), and a digital camera (via magnification optics) recorded the contents of the flow cell as bright field images throughout the experiment. Data acquisition was accomplished using Protein Simple MVSS software. The recorded image stream from the entire run was processed by validated Novo Nordisk proprietary software MFI Data Validator whereby the number (normalised to counts per ml analysed liquid) of individual particles was obtained and presented by size; >5 pm, >10 pm, and >25 pm which are standard size ranges for sub-visible particles.
  • the number of particles >5 pm includes all particles greater than 5 pm in diameter (>5 pm, >10 pm and >25 pm) and the number of particles > 10 pm includes all particles greater than 10 pm in diameter (>10 pm and >25 pm).
  • the particle size is defined as the equivalent circular diameter (ECD).
  • Results for number of sub-visible particles are the mean of 3 replicates and has been rounded to nearest integer value
  • EXAMPLE 6 EFFECT OF DIFFERENT TONICITY AGENTS ON CO-FORMULATION PHYSICAL STABILITY
  • This example shows the stabilising effect of different tonicity agents on the physical stability of otherwise identical cagrilintide and semaglutide co-formulations.
  • compositions of co-formulation 6 to co-formulation 12 are shown in in table 10.
  • Results are the mean of 2 replicates and has been rounded to nearest integer value (-) Sampling not performed
  • EXAMPLE 7 EFFECT OF DIFFERENT SURFACTANTS ON CO-FORMULATION PHYSICAL STABILITY
  • This example shows the effect of different surfactants on the physical stability of otherwise identical cagrilintide and semaglutide co-formulations.
  • compositions of co-formulation 13, co-formulation 14, and co-formulation 15 are shown in table 12.
  • Results are the mean of 2 replicates and has been rounded to nearest integer value
  • Co-formulation 14 contained the lowest number of sub-visible particles when stored for 17 days under stressed conditions. In co-formulation 13, containing polysorbate 20, an increase in sub-visible particles was observed after 14 days, while in co-formulation 15 containing poloxamer 188 sub-visible particles are formed after 7 days at stressed conditions. It is evident that the co-formulation containing polysorbate 80 was the most stable and that the co-formulation containing polysorbate 20 was also acceptably stable.
  • EXAMPLE 8 EFFECT OF DIFFERENT BUFFER SUBSTANCES ON CO-FORMULATION PHYSICAL STABILITY
  • This example shows that the buffer substance has an effect on the physical stability of an otherwise identical cagrilintide and semaglutide co-formulation.
  • the number of sub-visible particles was quantified as described in example 4.
  • Results are the mean of 2 replicates and has been rounded to nearest integer value
  • compositions of co-formulation 17 and co-formulation 18 are shown in table 16.
  • EXAMPLE 10 EFFECT OF DIFFERENT BUFFERS CONCENTRATION ON COFORMULATION PHYSICAL STABILITY
  • This example shows the effect of histidine buffer concentration on co-formulation physical stability.
  • compositions of the tested co-formulations are as shown in table 16
  • the number of sub-visible particles was quantified as described in example 4.
  • Results are the mean of 2 replicates and has been rounded to nearest integer value.
  • This example shows the effect of hydroxypropyl-alpha-cyclodextrin (HP-A-CD), hydroxypropyl-beta-cyclodextrin (HP-B-CD) and hydroxypropyl-gamma-cyclodextrin (HP-G- CD) on the formation of sub-visible particles and chemical degradation of cagrilintide in an otherwise identical cagrilintide and semaglutide co-formulation.
  • HP-A-CD hydroxypropyl-alpha-cyclodextrin
  • HP-B-CD hydroxypropyl-beta-cyclodextrin
  • HP-G- CD hydroxypropyl-gamma-cyclodextrin
  • compositions of co-formulation 22, 23 and 24 are shown in table 19.
  • the number of sub-visible particles was determined as described in example 4. Samples used to determine the purity of cagrilintide were stored at 37°C for up to 42 days. Purity of cagrilintide was determined using the following reversed phase high performance liquid chromatography (RP-HPLC) where the samples were analysed using a Kinetex C18, 2.6 pm column (4.6 x 150 mm) with a gradient elution of eluent A consisting of 90% v/v 0.09 M phosphate solution, pH 3.6 and 10% v/v acetonitrile, and eluent B consisting of 60% v/v acetonitrile and 20% v/v isopropanol.
  • RP-HPLC reversed phase high performance liquid chromatography
  • Results for number of sub-visible particles are the mean of 3 replicates and has been rounded to nearest integer value
  • HP-A-CD or HP-B-CD is acceptable for coformulations of cagrilintide and semaglutide.
  • HP-B- CD is preferred compared to HP-A-CD for a cagrilintide and semaglutide co-formulation, due to the superior purity of cagrilintide when formulated with HP-B-CD.
  • EXAMPLE 12 EFFECT OF THE MOLAR SUBSTITUTION DEGREE OF HP-B-CD ON THE PHYSICAL AND CHEMICAL STABILITY OF CAGRILINTIDE AND SEMAGLUTIDE COFORMULATIONS
  • This example shows the effect of the molar substitution of HP-B-CD on the formation of sub-visible particles, HMWP level and chemical purity of semaglutide in otherwise identical, citrate-buffered cagrilintide and semaglutide co-formulations.
  • compositions of co-formulations 25 to 32 are shown in table 22.
  • Table 22 Compositions of citrate-buffered cagrilintide and semaglutide co- formulations containing HP-B-CD excipients of varying hydroxypropyl molar substitution degree
  • the number of sub-visibles was quantified as described in example 4.
  • HMWP size exclusion chromatography
  • Samples were analysed using a Waters SEC 1 .7 pm column (4.6 x 150 mm) with an isocratic elution consisting of 185 mM sodium chloride, 5 mM sodium dihydrogen phosphate monohydrate, 3mM ortho-phosphate and 47% (v/v) isopropanol.
  • Chromatography was conducted with UV detection (215 nm) at 50°C using a 1-8 pl injection volume and a flow rate of 0.3 ml/min.
  • HMWP was quantified as being the area of all components eluting before the main peak divided by the area of the main peak x 100%.
  • the histidine-buffered cagrilintide and semaglutide co-formulations 33 to 37, containing 15% w/v HP-B-CD, are preferred due to their superior physical stability.
  • Histidine as buffer and sorbitol as tonicity agent the preferred HP-B-CD molar substitution range was widened to an average of 0.62-0.92 (or a total of 0.58-1 .0).
  • EXAMPLE 13 EFFECT OF MOLAR SUBSTITUTION DEGREE OF HP-B-CD ON PHYSICAL STABILITY OF CAGRILINTIDE AND SEMAGLUTIDE CO-FORMULATIONS
  • This example shows the effect of the molar substitution degree of HP-B-CD on the levels of sub-visible particles in otherwise identical, histidine-buffered cagrilintide and semaglutide co-formulations.
  • compositions of co-formulation 33 to 38 are shown in table 26.
  • Table 26 Compositions of histidine-buffered cagrilintide and semaglutide coformulation 33 to 38 containing HP-B-CD excipients of varying hydroxypropyl molar substitution degree
  • the number of sub-visible particles was quantified as described in example 4.
  • Results for number of sub-visible particles are the mean of 3 replicates and have been rounded to nearest integer value
  • compositions of co-formulations 39 and 40 are shown in table 28.
  • Table 28 Composition of co-formulation containing either HP-B-CD or SBE-B-
  • Samples used to determine the number of sub-visible particles were stored at stressed conditions, defined as: - Duration: 35 days
  • the number of sub-visible particles was quantified as described in example 4.
  • Results for number of sub-visible particles are the mean of 3 replicates and has been rounded to nearest integer value
  • compositions of co-formulation 41 to 45 are shown in table 30.
  • the number of sub-visible particles was quantified as described in example 4. Samples used to determine the purity of cagrilintide was stored at 37°C for up to 28 days. The purity of cagrilintide was determined as described in example 14.
  • Table 31 Physical stability of the cagrilintide and semaglutide co-formulations with varying pH within the pH-range 5.5 to 6.0 Results for number of sub-visible particles are the mean of 3 replicates and has been rounded to nearest integer value (-) sampling not performed.
  • Table 32 Chemical purity (%) of cagrilintide in the cagrilintide and semaglutide co-formulations with varying pH within the pH-range 5.5 to 6.0
  • EXAMPLE 16 EFFECT OF CAGRILINTIDE AND SEMAGLUTIDE CONCENTRATION RATIOS ON THE PHYSICAL STABILITY OF THE CO-FORMULATION
  • This example shows the effect of different concentration ratios of cagrilintide and semaglutide on the levels of sub-visible particles observed in the co-formulation.
  • composition of histidine-buffered co-formulations 46 to 50 are shown in table 33, and the composition of histidine-buffered co-formulations 51 to 61 are shown in table 34.
  • Table 33 Composition of histidine-buffered co-formulations with varying cagrilintide and semaglutide concentration ratios
  • Table 34 Composition of histidine-buffered co-formulations with modified composition with varying cagrilintide and semaglutide concentration ratios
  • the number of sub-visible particles was quantified as described in example 4.
  • Results for number of sub-visible particles are the mean of 3 replicates and has been rounded to nearest integer value
  • This example shows the effect of HP-B-CD concentration on the physical stability of the cagrilintide and semaglutide co-formulation, when the co-formulation is exposed to physical stress.
  • composition of co-formulation 62 to 65 with the histidine-buffered composition is shown in table 36.
  • results presented in table 37 show that the physical stability of the cagrilintide and semaglutide co-formulation is dependent upon the concentration of HP-B-CD, with lower concentrations resulting in shorter lag time until fibrillation occurs.
  • the co-formulation comprising 7.5% w/v HP-B-CD was the least stable.
  • the co-formulation comprising 15% w/v HP-B-CD was the most stable.
  • EXAMPLE 18 EFFECT OF THE SEQUENCE OF DRUG SUBSTANCE ADDITION ON THE PHYSICAL STABILITY OF THE CAGRILINTIDE AND SEMAGLUTIDE CO- FORMULATION
  • This example shows how the sequence of adding semaglutide and cagrilintide drug substances during co-formulation manufacture affects the co-formulation physical stability in form of subvisible particle counts.
  • the co-formulation was manufactured using formulation either method 1 or formulation method 3 shown in Table 39 and depicted in figures 1 and 3.
  • the number of sub-visible particles was quantified as described in example 4.
  • Results for content of sub-visible particles are the mean of 3 replicates and has been rounded to nearest integer value
  • This example shows the effect, on drug substance dissolution time, of the presence or absence of polysorbate 80.
  • composition of the cagrilintide and semaglutide co-formulation is as shown in Example 18.
  • the co-formulation was manufactured using either formulation method 1 or formulation method 5, shown in Table 41 and depicted in figures 1 and 5.
  • the dissolution time of semaglutide drug substance is affected by the presence of polysorbate 80 in process step 1.
  • the dissolution time of semaglutide drug substance can be significantly reduced by omitting polysorbate 80 from process step 1 and adding it in process step 5 instead (i.e. formulation method 5).
  • This example shows how the sequence of adding semaglutide or cagrilintide drug substance first during the co-formulation manufacture affects the drug substance dissolution time.
  • composition of the cagrilintide and semaglutide co-formulation 67 was as shown in table 43.
  • Table 44 Dissolution time of semaglutide drug substance and cagrilintide drug substance in co-formulation 67 comprising HP-B-CD (Average MS: 0.62) manufactured using different formulation methods
  • the dissolution time of semaglutide and cagrilintide drug substance was affected by the sequence of adding the drug substances.
  • the total dissolution time of cagrilintide and semaglutide drug substance can be significantly reduced by adding semaglutide before cagrilintide during manufacture of the cagrilintide and semaglutide co-formulation.
  • EXAMPLE 21 EFFECT OF THE SEQUENCE OF DRUG SUBSTANCE ADDITION ON THE DRUG SUBSTANCE DISSOLUTION TIME IN CAGRILINTIDE AND SEMAGLUTIDE COFORMUALTION COMPRISING HP-B-CD (AVERAGE MS: 0.92)
  • composition shows how the sequence of adding semaglutide or cagrilintide drug substance first during the co-formulation manufacture affects the drug substance dissolution time.
  • composition of the cagrilintide and semaglutide co-formulation 68 was as shown in table 45.
  • Table 46 Dissolution time of semaglutide drug substance and cagrilintide drug substance in co-formulation 68 comprising HP-B-CD (Average MS: 0.92) manufactured using different formulation methods
  • the dissolution time of semaglutide and cagrilintide drug substance was affected by the sequence of adding the drug substances when polysorbate 80 is present in the excipient solution.
  • the total dissolution time of cagrilintide and semaglutide drug substance can be significantly reduced by adding semaglutide before adding cagrilintide in formulation method 2. No effect of the sequence of adding drug substances were observed when comparing formulation method 5 and 6 where polysorbate 80 is not present in excipient solution.
  • EXAMPLE 22 EFFECT OF THE SEQUENCE OF ADDING THE EXCIPIENTS ON THE DRUG SUBSTANCE DISSOLUTION TIME IN CAGRILINTIDE AND SEMAGLUTIDE COFORMUALTION COMPRISING HP-B-CD (AVERAGE MS: 0.62)
  • This example shows how the sequence of adding the excipients during the coformulation manufacture affects the drug substance dissolution time. The effect of each excipient being present in the initial excipient solution contra being added after the addition of drug substances are shown.
  • EXAMPLE 23 EFFECT OF THE SEQUENCE OF ADDING THE EXCIPIENTS ON THE DRUG SUBSTANCE DISSOLUTION TIME IN CAGRILINTIDE AND SEMAGLUTIDE COFORMUALTION COMPRISING HP-B-CD (AVERAGE MS: 0.92)
  • This example shows how the sequence of adding the excipients during the coformulation manufacture affects the drug substance dissolution time. The effect of each excipient being present in the initial excipient solution contra being added after the addition of drug substances are shown.
  • composition of the cagrilintide and semaglutide co-formulation 68 was as presented in example 21.
  • Table 48 Dissolution time for semaglutide drug substance and cagrilintide drug substance in co-formulation 68 comprising HP-B-CD (Average MS: 0.92) manufactured using different formulation methods
  • This example shows how the sequence of adding semaglutide and cagrilintide drug substances during co-formulation manufacture affects the co-formulation physical stability measured as lag time until fibrillation occurs.
  • composition of the cagrilintide and semaglutide co-formulation was shown in example 20.
  • the physical stability of the final cagrilintide and semaglutide co-formulation is affected by the sequence of added the two drug substances. Increased physical stability measured as longer lag time from initiation of the ThT fibrillation assay until fibrillation occurred was achieved by adding semaglutide drug substance before adding the cagrilintide drug substance. This observation was seen regardless of polysorbate 80 being added in the initial excipient solution or after the dissolution of both drug substances.
  • This example shows the effect of in-process pH adjustment before or after the addition of cagrilintide on co-formulation physical stability, measured as lag time until fibrillation occurs

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Abstract

L'invention concerne un procédé de co-formulation d'un agoniste du récepteur de l'amyline et d'un agoniste du récepteur GLP-1. L'invention concerne une formulation pharmaceutique liquide comprenant un agoniste du récepteur de l'amyline, un agoniste du récepteur GLP-1 et une cyclodextrine comprenant des substitutions hydroxypropyle. Ladite co-formulation peut être utilisée pour le traitement médical de sujets présentant les maladies ou troubles suivants : surpoids ou obésité, avec ou sans comorbidités associées; diabète, avec ou sans comorbidités associées; maladies cardiovasculaires, stéatohépatite non alcoolique (NASH) et troubles cognitifs, tels que ceux provoqués par la maladie d'Alzheimer.
PCT/EP2023/058317 2022-03-30 2023-03-30 Procédé de formulation WO2023187067A1 (fr)

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
EP22165607.7 2022-03-30
EP22165607 2022-03-30
EP22191564 2022-08-22
EP22191564.8 2022-08-22
PCT/EP2022/085558 WO2023110833A1 (fr) 2021-12-13 2022-12-13 Formulations pharmaceutiques comprenant une cyclodextrine
ARP220103410A AR127945A1 (es) 2021-12-13 2022-12-13 Formulaciones farmacéuticas que comprenden un agonista del receptor de amilina, un agonista del receptor de glp-1 y una ciclodextrina
PK8362022 2022-12-13
PK836/2022 2022-12-13
ARP20220103410 2022-12-13
TW111147761A TW202339788A (zh) 2021-12-13 2022-12-13 包括環糊精的醫藥調配物
TW111147761 2022-12-13
EPPCT/EP2022/085558 2022-12-13

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006097537A2 (fr) 2005-03-18 2006-09-21 Novo Nordisk A/S Composes de glp-1 acyles
WO2007022518A2 (fr) * 2005-08-19 2007-02-22 Amylin Pharmaceuticals, Inc. Nouvelles utilisations de proteines glucoregulatoires
WO2008073448A2 (fr) * 2006-12-12 2008-06-19 Amylin Pharmaceuticals, Inc. Formulations pharmaceutiques et leurs procédés de production
WO2012168432A1 (fr) 2011-06-10 2012-12-13 Novo Nordisk A/S Polypeptides
WO2021152184A1 (fr) * 2020-01-31 2021-08-05 Adocia Compositions comprenant au moins un agoniste du récepteur de l'amyline et un agoniste du récepteur de glp-1
WO2022129526A1 (fr) 2020-12-18 2022-06-23 Novo Nordisk A/S Co-agonistes des récepteurs du glp 1 et de l'amyline

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Publication number Priority date Publication date Assignee Title
WO2006097537A2 (fr) 2005-03-18 2006-09-21 Novo Nordisk A/S Composes de glp-1 acyles
WO2007022518A2 (fr) * 2005-08-19 2007-02-22 Amylin Pharmaceuticals, Inc. Nouvelles utilisations de proteines glucoregulatoires
WO2008073448A2 (fr) * 2006-12-12 2008-06-19 Amylin Pharmaceuticals, Inc. Formulations pharmaceutiques et leurs procédés de production
WO2012168432A1 (fr) 2011-06-10 2012-12-13 Novo Nordisk A/S Polypeptides
WO2021152184A1 (fr) * 2020-01-31 2021-08-05 Adocia Compositions comprenant au moins un agoniste du récepteur de l'amyline et un agoniste du récepteur de glp-1
WO2022129526A1 (fr) 2020-12-18 2022-06-23 Novo Nordisk A/S Co-agonistes des récepteurs du glp 1 et de l'amyline

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