WO2023110833A1 - Formulations pharmaceutiques comprenant une cyclodextrine - Google Patents

Formulations pharmaceutiques comprenant une cyclodextrine Download PDF

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Publication number
WO2023110833A1
WO2023110833A1 PCT/EP2022/085558 EP2022085558W WO2023110833A1 WO 2023110833 A1 WO2023110833 A1 WO 2023110833A1 EP 2022085558 W EP2022085558 W EP 2022085558W WO 2023110833 A1 WO2023110833 A1 WO 2023110833A1
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Prior art keywords
semaglutide
cagrilintide
pharmaceutical formulation
formulation
cyclodextrin
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PCT/EP2022/085558
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English (en)
Inventor
Benjamin Troest KJELDSEN
Stig CHRISTOFFERSEN
Rosa Rebecca Erritzøe HANSEN
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Novo Nordisk A/S
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Priority to CA3239290A priority Critical patent/CA3239290A1/fr
Priority to JP2023566893A priority patent/JP2024515392A/ja
Priority to AU2022413347A priority patent/AU2022413347A1/en
Priority to KR1020237035479A priority patent/KR20230158563A/ko
Priority to PCT/EP2023/058317 priority patent/WO2023187067A1/fr
Publication of WO2023110833A1 publication Critical patent/WO2023110833A1/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
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • the current invention relates to a pharmaceutical formulation which is a coformulation of a GLP-1 receptor agonist and an amylin receptor agonist.
  • Said 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
  • Ozempic® and Wegovy® are liquid pharmaceutical formulations comprising 8 mM phosphate and having a pH of about 7.4.
  • a fixed-dose combination of an amylin receptor agonist, cagrilintide, and the GLP-1 receptor agonist, semaglutide, has been investigated for the treatment of overweight and obesity (Lancet 2021 ; 397: 1736-48).
  • the drug products investigated were in the form of separate liquid pharmaceutical formulations for subcutaneous use, comprising either cagrilintide or semaglutide.
  • 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.
  • cagrilintide and semaglutide preclude a simple mixture of these two peptides.
  • GLP-1 receptor agonist and amylin receptor agonist combinations when the two have incompatible optimal pH ranges.
  • GLP-1 receptor agonist such as semaglutide
  • amylin receptor agonist such as cagrilintide
  • Disclosed herein is a means of co-formulating an amylin receptor agonist and a GLP-1 receptor agonist.
  • a liquid pharmaceutical formulation comprising an amylin receptor agonist, a GLP-1 receptor agonist and a cyclodextrin comprising hydrophilic chemical substitutions such as hydroxypropyl substitutions.
  • the cyclodextrin may be of the hydroxypropyl-substituted alpha type, comprising six ring-arranged glucose units.
  • the cyclodextrin may be of the hydroxypropyl-substituted beta type, comprising seven ring- arranged glucose units.
  • the pharmaceutical formulation may further comprise a buffer such as histidine, a tonicity agent such as sorbitol and/or a surfactant such as polysorbate 20 and/or 80; and have a pH of about 5.5-6.5, such as a pH of 5.6-6.0.
  • a buffer such as histidine
  • a tonicity agent such as sorbitol and/or a surfactant
  • polysorbate 20 and/or 80 may be administered by parenteral injection, preferably subcutaneous injection.
  • the pharmaceutical formulation disclosed herein may be used for the medical treatment of subjects with: overweight or obesity, with or without one or more associated comorbidities; diabetes, with or without one or more associated co-morbidities; one or more cardiovascular diseases; non-alcoholic steatohepatitis (NASH); and/or cognitive impairment, such as that caused by Alzheimer’s disease.
  • the pharmaceutical formulation disclosed herein may improve convenience, treatment compliance and ultimately improved clinical outcome in such patients.
  • the current invention is a liquid pharmaceutical formulation comprising an amylin receptor agonist, a GLP-1 receptor agonist and a cyclodextrin comprising hydroxypropyl substitutions.
  • the pharmaceutical formulation disclosed herein may comprise two active pharmaceutical ingredients, namely a GLP-1 receptor agonist and an amylin receptor agonist.
  • 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 optimal pH of the amylin receptor agonist is the pH at which it is, chemically and physically, most stable.
  • the person skilled in the art can easily find the amylin receptor agonist’s optimal pH by testing its chemical and physical stability, in an aqueous solution essentially consisting of the amylin receptor agonist, a buffer and water for injection, across the pH range.
  • the optimal pH of the GLP-1 receptor agonist is the pH at which it is, chemically and physically, most stable.
  • the person skilled in the art can easily find the GLP-1 receptor agonist’s optimal pH by testing its chemical and physical stability, in an aqueous solution essentially consisting of the GLP-1 receptor agonist, a buffer and water for injection, across the pH range.
  • the physical stability of the GLP-1 receptor agonist may be a reflection of its isoelectric point, which may coincide with the pH where poorest physical stability might be expected.
  • any GLP-1 receptor agonist and/or any amylin receptor agonist in any liquid formulation can be quantified by means of, e.g., reversed phase (ultra) high performance liquid chromatography (RP-UHPLC or RP-HPLC) and/or by measuring the percentage of high molecular weight protein (%HMWP) by means of, e.g., size exclusion chromatography (SEC).
  • RP-UHPLC reversed phase high performance liquid chromatography
  • %HMWP percentage of high molecular weight protein
  • SEC size exclusion chromatography
  • 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.
  • the GLP-1 receptor agonist may be semaglutide.
  • the amylin receptor agonist may be cagrilintide or a biologically active metabolite or degradation product of cagrilintide.
  • composition of the formulation disclosed herein preserves/improves the chemical and physical stability of the active pharmaceutical ingredients, even when co-formulated at pH 5.5-6.5, such as pH 5.6-6.0; preserves the pharmacokinetic profiles of the active pharmaceutical ingredients in terms of their bioavailability and exposure; and exhibits an acceptable local tolerance upon subcutaneous injection.
  • pharmaceutical formulation may herein be used interchangeably to refer to a liquid pharmaceutical formulation comprising a GLP-1 receptor agonist and an amylin receptor agonist.
  • the pharmaceutical formulation disclosed herein is suitable for parenteral injection, preferably subcutaneous injection.
  • amylin herein refers to a polypeptide having the same amino acid sequence as an endogenous amylin, such as human amylin.
  • An amylin receptor agonist may bind to and activate the calcitonin receptor (CTR) and/or the amylin receptors (AMYRs).
  • CTR calcitonin receptor
  • AYRs amylin receptors
  • the latter consist of heterodimers of two components: the calcitonin receptor (CTR) and one of three receptor activity-modifying proteins (RAMP1- 3) resulting in three possible complexes, AMYR1-3.
  • amylin receptor agonist may be defined as a chemical entity which is capable of binding to an amylin receptor and is capable of activating or “agonising” it.
  • the amylin receptor agonist is capable of binding to and activating at least the amylin receptor 3 (AMYR3).
  • the amylin receptor agonist may also be capable of agonising the calcitonin receptor, the amylin receptor 1 (AMYR1) and/or the amylin receptor 2 (AMYR2).
  • 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®).
  • the amylin receptor agonist is capable of activating the amylin receptor; in other words, it is “potent” on the amylin receptor.
  • the in vitro potency of the amylin receptor agonist on amylin receptor 3 may be measured as described in WO/2022129526, Assay 2.
  • the potency of the compound may be described by means of its EC 5 o value, wherein EC 5 o represents the concentration of compound upon which 50% of its maximal effect is observed. The lower the EC 5 o value, the more potent the compound.
  • the amylin receptor agonist as disclosed herein may have an EC 5 o value of less than 300 pM, such as less than 200 pM, such as less than 150 pM, preferably less than 100 pM, such as less than 75 pM, preferably less than 50 pM, such as less than 40 pM, such as less than 30 pM, such as less than 20 pM, such as less than 10 pM.
  • amylin receptor agonist in the pharmaceutical formulation disclosed herein may be cagrilintide or a biologically active metabolite or degradation product of cagrilintide.
  • Cagrilintide also known as AM833 is the compound of Example 53 in
  • WO2012/168432 N-alpha-[(S)-4-Carboxy-4-(19-carboxynonadecanoylamino)butyryl]- [Glu14,Arg17,Pro37]-pramlintide.
  • Cagrilintide may be prepared as described in WO2012/168432, pages 153-155.
  • Cagrilintide may be in the form of a salt, preferably a pharmaceutically acceptable salt.
  • 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.
  • cagrilintide had an EC 5 o value of about 11 pM (WO/2022/129526, Tables 4b and 4c).
  • the concentration of cagrilintide in the pharmaceutical formulation disclosed herein may be from about 0.25 mg/ml to about 22 mg/ml.
  • 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 cagrilintide.
  • the pharmaceutical formulation disclosed herein may comprise no more than 12 mg/ml cagrilintide.
  • GLP-1 or “native GLP-1” herein refers to human Glucagon-Like Peptide-1 (GLP-1 (7-37)).
  • GLP-1 receptor agonist may be defined as a ligand which is capable of binding to the GLP-1 receptor and producing a biological response similar to that of the endogenous ligand, glucagon-like peptide 1 (GLP-1 (7-37)).
  • GLP-1 (7-37) glucagon-like peptide 1
  • a "full" GLP-1 receptor agonist may be defined as a GLP-1 receptor agonist which is capable of eliciting a biological response of the same magnitude as GLP-1 (7-37).
  • exogenous GLP-1 receptor agonists examples include semaglutide (the active pharmaceutical ingredient in Ozempic®, Rybelsus® and Wegovy®), liraglutide (the active pharmaceutical ingredient in Victoza® and Saxenda®), tirzepatide (the active pharmaceutical ingredient in Mounjaro®) and dulaglutide (the active pharmaceutical ingredient in Trulicity®).
  • the GLP-1 receptor agonist is capable of binding to and activating, or “agonising” the GLP-1 receptor; in other words, it is “potent” on the GLP-1 receptor.
  • the in vitro potency of the GLP-1 receptor agonist on the GLP-1 receptor may be measured as described in WO/2022/129526, Assay 1 .
  • the potency of the compound may be described by means of its EC 5 o values, wherein EC50 represents the concentration of compound upon which 50% of its maximal effect is observed. The lower the EC50 value, the more potent the compound.
  • the GLP-1 receptor agonist disclosed herein may have an EC50 value of less than 300 pM, such as less than 200 pM, such as less than 150 pM, preferably less than 100 pM, such as less than 75 pM, even more preferably less than 50 pM, such as less than 40 pM, such as less than 30 pM, such as less than 20 pM, such as less than 10 pM.
  • Semaglutide is a GLP-1 receptor agonist also known as N 626 - ⁇ 18-[N-(17- carboxyheptadecanoyl)-l_-Y-glutamyl]-10-oxo-3,6, 12, 15-tetraoxa-9, 18-diazaoctadecanoyl ⁇ -[8- (2-amino-2-propanoic acid),34-L-arginine]human glucagon-like peptide 1 (7-37). Semaglutide was described in W02006/097537 and in J. Med. Chem. 2015, 58, 18, 7370-7380 and may be manufactured using methods well known to the person skilled in the art, such as that briefly described in W02006/097537, Example 4.
  • Semaglutide may be present in the current pharmaceutical formulation in its fully or partly ionised form; for example one or more carboxylic acid groups (-COOH) may be deprotonated into the carboxylate group (-COO j and/or one or more amino groups (-NH 2 ) may be protonated into the -NH 3 + group.
  • carboxylic acid groups -COOH
  • -COO j carboxylate group
  • amino groups -NH 2
  • Semaglutide may be in the form of a salt, preferably a pharmaceutically acceptable salt.
  • semaglutide had an EC 5 o value of about 5.5 pM (see WO/2022/129526, Tables 4b and 4c).
  • the concentration of semaglutide in the pharmaceutical formulation disclosed herein may be from about 0.25 mg/ml to about 22 mg/ml.
  • the pharmaceutical formulation may comprise semaglutide 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 about 2.2 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 about 4.8 mg/ml; such as 5.0-6.0 mg/ml; such as 6.0- 7.0 mg/ml, such as about 6.4 mg/ml; such as 7.0-8.0 mg/ml, such as about 8.0 mg/ml; such as 8.0-9.0 mg/
  • 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, 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 isoelectric point (pl) of a molecule is the pH at which the molecule carries no net charge.
  • the pl of a peptide may be theoretically calculated from the pK values of its amino acids and of the terminal amine and carboxyl groups and can be used to predict the solubility of the peptide at a given pH.
  • 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 theoretically calculated isoelectric point of the amylin receptor agonist may have an isoelectric point (pl) in the range of 8-12, such as 8-9.
  • Cagrilintide has a theoretically calculated isoelectric point of about 8.56.
  • the pharmaceutical formulation disclosed herein comprises a cyclodextrin comprising hydroxypropyl substitutions.
  • the pharmaceutical formulation may comprise about 10-25% w/v of a cyclodextrin comprising hydroxypropyl substitutions.
  • the pharmaceutical formulation may comprise more than 10% w/v of a cyclodextrin comprising hydroxypropyl substitutions.
  • the pharmaceutical formulation may comprise less than 22% w/v of a cyclodextrin comprising hydroxypropyl substitutions.
  • the pharmaceutical formulation may comprise about 10-20% w/v, about 15- 25% w/v, about 12-18% w/v, about 10-17.5% w/v , about 11.25-15%, such as about 15% w/v of a cyclodextrin comprising hydroxypropyl substitutions.
  • Cyclodextrins are oligosaccharide starch derivatives consisting of 6, 7 or 8 a-(1 ,4)- linked glucopyranose (glucose) units arranged cyclically and denoted the alpha, beta or gamma type, respectively.
  • the cyclodextrins have a wide range of applications, amongst others as pharmaceutical excipients [P. Breen & S. S.
  • 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 cyclodextrins comprising hydrophilic substitutions adopt what may be described as cone-liked shapes having a hydrophobic inner cavity and a hydrophilic outer surface formed by the many hydrophilic substitutions capable of forming hydrogen bonds with neighbouring water molecules, thereby improving water solubility [T. Loftsson, Cyclodextrins in Parenteral Formulations, Journal of Pharmaceutical Sciences, 2020, 1-11],
  • 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. Further excipients
  • the pharmaceutical formulation may comprise a buffer.
  • 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. 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 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 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 is preferably 5.6-6.0.
  • the pH 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.
  • the pharmaceutical formulation 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 mg/ml.
  • the pharmaceutical formulation may comprise a surfactant.
  • the 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 surfactant 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 pharmaceutical formulation comprises 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 pharmaceutical formulation disclosed herein may comprise no preservative.
  • compositions disclosed herein may be 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, non-insulin 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.
  • the subject suffering from obesity is human, such as an adult human or a paediatric human (including infants, children, and adolescents).
  • a human subject suffering from obesity may have a BMI of 30 kg/m 2 or more; this subject may also be referred to as being obese.
  • the human subject suffering from obesity may have a BMI of >35 or a BMI in the range of >30 to ⁇ 40.
  • the obesity is severe obesity or morbid obesity, wherein the human subject may have a BMI of >40.
  • Disclosed herein is a method for the treatment or prevention of overweight, optionally in the presence of at least one weight-related comorbidity. Disclosed herein is use of the formulations disclosed herein for the treatment or prevention of overweight, optionally in the presence of at least one weight-related comorbidity.
  • the subject suffering from overweight is human, such as an adult human or a paediatric human (including infants, children, and adolescents).
  • a human subject suffering from overweight may have a BMI of 25 kg/m 2 or more, such as a BMI of 27 kg/m 2 or more.
  • a human subject suffering from overweight has a BMI in the range of 25 to ⁇ 30 or in the range of 27 to ⁇ 30.
  • a raised BMI increases the risk of an individual developing any one of a wide range of diseases or co-morbidities.
  • the weight-related comorbidity may be one, or a combination of, the diseases mentioned above.
  • the weight-related comorbidity is selected from the group consisting of hypertension, diabetes (such as type 2 diabetes), dyslipidaemia, high cholesterol and obstructive sleep apnoea.
  • a human to be subjected to reduction of body weight may have a BMI of 25 kg/m 2 or more, such as a BMI of 27 kg/m 2 or more (overweight) or a BMI of 30 kg/m 2 or more (obesity). In some embodiments the human to be subjected to reduction of body weight may have a BMI of 35 kg/m 2 or more or a BMI of 40 kg/m 2 or more.
  • the term “reduction of body weight” may include treatment or prevention of obesity and/or overweight.
  • administration of the semaglutide and cagrilintide pharmaceutical formulations disclosed herein may be used 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 30 kg/m 2 or more (obesity) or 27 kg/m 2 or more (overweight) in the presence of at least one weight-related comorbidity (e.g. hypertension, type 2 diabetes mellitus, or dyslipidaemia).
  • BMI body mass index
  • administration of the semaglutide and cagrilintide pharmaceutical formulations disclosed herein may result in >15% weight loss, such as >20% weight loss, such as >25% weight loss, such as >30% weight loss, such as about 15-40% weight loss, such as about 20-35% weight loss, such as about 25-30% weight loss, within 26 weeks of the start of treatment.
  • administration of the semaglutide and cagrilintide pharmaceutical formulations disclosed herein disclosed herein may result in >15% weight loss, such as >20% weight loss, such as >25% weight loss, such as >30% weight loss, such as about 15-40% weight loss, such as about 20-35% weight loss, such as about 25-30% weight loss, within 26 weeks of the start of treatment.
  • administration of the semaglutide and cagrilintide pharmaceutical formulations disclosed herein results in a higher HbAi c reduction, in Copoints, compared to that which results from treatment with either semaglutide as sole active ingredient or cagrilintide as sole active ingredient.
  • the pharmaceutical formulation of the invention comprises a specific concentration of amylin receptor agonist and a specific concentration of GLP-1 receptor agonist.
  • the pharmaceutical formulation may comprise from 0.25 to 22 mg/ml cagrilintide and from 0.25 to 22 mg/ml semaglutide.
  • the doses of GLP receptor agonist and amylin receptor agonist administered in a single injection depend on the concentrations of these active ingredients within the pharmaceutical formulation and the volume of pharmaceutical formulation administered.
  • the pharmaceutical formulation of the invention may be administered as a single dose at predefined intervals.
  • a single dose of the pharmaceutical formulation disclosed herein may contain any one of the following doses of an amylin receptor agonist, such as cagrilintide, and a GLP-1 receptor agonist, such as semaglutide.
  • an amylin receptor agonist such as cagrilintide
  • a GLP-1 receptor agonist such as semaglutide
  • An effective amount of an amylin receptor agonist, such as cagrilintide, and a GLP-1 receptor agonist, such as semaglutide, may be administered to a subject in need thereof.
  • the dose is administered approximately once weekly.
  • the interval between two fixed doses may be about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days or about 10 days.
  • a fixed maintenance dose is administered approximately once every 7 days (once weekly).
  • the dose is administered to an individual having any one or a combination of the diseases or co-morbidities listed above.
  • the dose is administered a subject with obesity (body mass index [BMI] >30 kg/m 2 ).
  • the dose is administered to individuals that are overweight (BMI >27 kg/m 2 - ⁇ 30 kg/m 2 ) and that have at least one weight-related co-morbidity (e.g. hypertension, type 2 diabetes mellitus, or dyslipidaemia).
  • once weekly treatment results in a statistically significant, dose-dependent, reduction in body weight.
  • the dose is administered as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
  • an amylin receptor agonist such as cagrilintide
  • a GLP-1 receptor agonist such as semaglutide
  • treatment is once weekly and the dose-escalation period is 16 weeks.
  • treatment is once weekly and dose escalation occurs approximately once weekly.
  • treatment is once weekly and dose escalation occurs approximately once every other week.
  • treatment is once weekly and dose escalation occurs approximately once every three weeks.
  • treatment is once weekly and dose escalation occurs approximately once every four weeks.
  • the dose of amylin receptor agonist administered may be about 0.25-16 mg, such as about 0.25-9.0 mg, such as about 0.25-4.5 mg, such as about 0.25-2.4 mg.
  • the dose of cagrilintide administered may be about 0.25-16 mg, such as about 0.25- 9.0 mg, such as about 0.25-4.5 mg, such as about 0.25-2.4 mg.
  • the dose of cagrilintide administered is about 0.25 mg.
  • the dose of cagrilintide administered is about 0.5 mg.
  • the dose of cagrilintide administered is about 1.0 mg.
  • the dose of cagrilintide administered is about 1.5 mg.
  • the dose of cagrilintide administered is about 1.7 mg.
  • the dose of cagrilintide administered is about 2.4 mg.
  • the dose of cagrilintide administered is about 3.4 mg.
  • the dose of cagrilintide administered is about 3.6 mg.
  • the dose of cagrilintide administered is about 4.5 mg. In some embodiments, the dose of cagrilintide administered is about 7.2 mg.
  • the dose of cagrilintide administered is about 8.0 mg.
  • the dose of cagrilintide administered is about 9.0 mg.
  • the dose of cagrilintide administered is about 16.0 mg.
  • the dose of GLP-1 receptor agonist administered may be about 0.25-16 mg, such as about 0.25-9.0 mg, such as about 0.25-4.5 mg, such as about 0.25-2.4 mg.
  • the dose of semaglutide administered may be about 0.25-16 mg, such as about 0.25-9.0 mg, such as about 0.25-4.5 mg, such as about 0.25-2.4 mg.
  • the dose of semaglutide administered is about 0.25 mg.
  • the dose of semaglutide administered is about 0.5 mg.
  • the dose of semaglutide administered is about 1.0 mg.
  • the dose of semaglutide administered is about 1.5 mg.
  • the dose of semaglutide administered is about 1.7 mg.
  • the dose of semaglutide administered is about 2.4 mg.
  • the dose of semaglutide administered is about 3.6 mg.
  • the dose of semaglutide administered is about 4.5 mg.
  • the dose of semaglutide administered is about 4.8 mg.
  • the dose of semaglutide administered is about 6.0 mg.
  • the dose of semaglutide administered is about 6.9 mg.
  • the dose of semaglutide administered is about 7.2 mg.
  • the dose of semaglutide administered is about 8.0 mg.
  • the dose of semaglutide administered is about 9.0 mg.
  • the dose of semaglutide administered is about 12 mg.
  • the dose of semaglutide administered is about 16.0 mg. In some embodiments, the dose of semaglutide administered is about 16.0 mg.
  • the ratio of amylin receptor agonist to GLP-1 receptor agonist is about 1 :2. In some embodiments, the ratio of cagrilintide to semaglutide is about 1 :2.
  • the dose of cagrilintide is about 0.125 mg and the dose of semaglutide is about 0.25 mg.
  • the dose of cagrilintide is about 0.25 mg and the dose of semaglutide is about 0.5 mg.
  • the dose of cagrilintide is about 0.5 mg and the dose of semaglutide is about 1.0 mg. In some embodiments, the dose of cagrilintide is about 0.75 mg and the dose of semaglutide is about 1.5 mg.
  • the dose of cagrilintide is about 0.85 mg and the dose of semaglutide is about 1.7 mg.
  • the dose of cagrilintide is about 1 .2 mg and the dose of semaglutide is about 2.4 mg.
  • the dose of cagrilintide is about 2.25 mg and the dose of semaglutide is about 4.5 mg.
  • the dose of cagrilintide administered is about 3.6 mg and the dose of semaglutide is about 7.2 mg.
  • the dose of cagrilintide is about 4.0 mg and the dose of semaglutide is about 8.0 mg.
  • the dose of cagrilintide is about 7.2 mg and the dose of semaglutide is about 14.4 mg.
  • the dose of cagrilintide is about 8.0 mg and the dose of semaglutide is about 16.0 mg.
  • the maintenance dose of cagrilintide is about 1.2 mg and the maintenance dose of semaglutide is about 2.4 mg.
  • the maintenance dose of cagrilintide is about 2.25 mg and the dose of semaglutide is about 4.5 mg.
  • the maintenance dose of cagrilintide is about 4.0 mg and the maintenance dose of semaglutide is about 8.0 mg.
  • the maintenance dose of cagrilintide is about 8.0 mg and the maintenance dose of semaglutide is about 16.0 mg.
  • the ratio of amylin receptor agonist to GLP-1 receptor agonist is about 1 :1. In some embodiments, the ratio of cagrilintide to semaglutide is about 1 :1.
  • the dose of cagrilintide is about 0.25 mg and the dose of semaglutide is about 0.25 mg.
  • the dose of cagrilintide is about 0.5 mg and the dose of semaglutide is about 0.5 mg.
  • the dose of cagrilintide is about 1 .0 mg and the dose of semaglutide is about 1.0 mg.
  • the dose of cagrilintide is about 1 .7 mg and the dose of semaglutide is about 1.7 mg. In some embodiments, the dose of cagrilintide is about 2.4 mg and the dose of semaglutide is about 2.4 mg.
  • the maintenance dose of cagrilintide is about 2.4 mg and the maintenance dose of semaglutide is about 2.4 mg.
  • the dose of cagrilintide is about 4.5 mg and the dose of semaglutide is about 4.5 mg.
  • the dose of cagrilintide is about 8.0 mg and the dose of semaglutide is about 8.0 mg.
  • the dose of cagrilintide is about 16.0 mg and the dose of semaglutide is about 16.0 mg.
  • the ratio of amylin receptor agonist to GLP-1 receptor agonist is between 1 :1 and 1 :7.
  • the dose of cagrilintide is about 2.4 mg and the dose of semaglutide is about 2.4 mg to 16.0 mg.
  • the dose of cagrilintide is about 2.4 mg and the dose of semaglutide is about 3.6 mg to 16.0 mg.
  • the dose of cagrilintide is about 2.4 mg and the dose of semaglutide is about 2.4 mg to 13.5 mg.
  • the dose of cagrilintide is about 2.4 mg and the dose of semaglutide is about 3.6 mg to 13.5 mg.
  • the dose of cagrilintide is about 2.4 mg and the dose of semaglutide is about 3.6 mg.
  • the dose of cagrilintide is about 2.4 mg and the dose of semaglutide is about 4.8 mg.
  • the dose of cagrilintide is about 2.4 mg and the dose of semaglutide is about 6.0 mg.
  • the dose of cagrilintide is about 2.4 mg and the dose of semaglutide is about 6.9 mg.
  • the dose of cagrilintide is about 2.4 mg and the dose of semaglutide is about 7.2 mg.
  • the dose of cagrilintide is about 2.4 mg and the dose of semaglutide is about 8.0 mg.
  • the dose of cagrilintide is about 2.4 mg and the dose of semaglutide is about 12 mg. In some embodiments, the dose of cagrilintide is about 3.4 mg and the dose of semaglutide is about 13.5 mg.
  • cagrilintide and semaglutide are administered once-weekly at an initial dose of 0.25 mg and then escalated to the subsequent dosing levels of 0.5 mg, 1.0 mg and 1.7 mg until reaching the target/maintenance dose of 2.4 mg once-weekly.
  • 0.25 mg cagrilintide and semaglutide are administered once- weekly and escalated every four weeks to the subsequent dosing levels of 0.5 mg, 1 .0 mg and 1.7 mg, until reaching the target/maintenance dose of 2.4 mg once-weekly.
  • 0.25 mg cagrilintide and semaglutide are administered once- weekly and escalated every four weeks to the subsequent dosing levels of 0.5 mg, 1 .0 mg and 1.7 mg, until reaching the target/maintenance dose of 2.4 mg once-weekly.
  • 0.25 mg cagrilintide and 0.25 mg semaglutide are administered once a week for four weeks (weeks 0-3) and escalated every four weeks to the subsequent dosing levels of 0.5 mg cagrilintide and 0.5 semaglutide (weeks 4-7), 1 .0 mg cagrilintide and 1 .0 semaglutide (weeks 8-11) and 1 .7 mg cagrilintide and 1 .7 mg semaglutide (weeks 12-15), until reaching the target/maintenance dose of 2.4 mg cagrilintide and 2.4 mg semaglutide mg once-weekly (weeks 16 and thereafter).
  • cagrilintide and semaglutide are administered once-weekly at initial doses of 0.25 mg and then escalated to the subsequent dosing levels of 0.5 mg, 1 .0 mg, 1.7 mg and 2.4 mg, until reaching the target/maintenance dose of 4.5 mg once-weekly.
  • cagrilintide and semaglutide are administered once-weekly at initial doses of 0.25 mg and then escalated to the subsequent dosing levels of 0.5 mg, 1 .0 mg, 1 .7 mg, 2.4 mg, 3.6 mg and 4.5 mg, until reaching the target/maintenance dose of 7.2 mg once-weekly.
  • cagrilintide and semaglutide are administered once-weekly at initial doses of 0.25 mg and then escalated to the subsequent dosing levels of 0.5 mg, 1 .0 mg, 1 .7 mg, 2.4 mg, 3.6 mg, 4.5 mg and 7.2 mg, until reaching the target/maintenance dose of 8.0 mg once-weekly.
  • cagrilintide and semaglutide are administered once-weekly at initial doses of 0.25 mg and then escalated to the subsequent dosing levels of 0.5 mg, 1 .0 mg, 1 .7 mg, 2.4 mg, 3.6 mg, 4.5 mg, 7.2 mg and 8.0, until reaching the target/maintenance dose of 16.0 mg once-weekly.
  • a liquid pharmaceutical formulation comprising an amylin receptor agonist, a GLP-1 receptor agonist and a cyclodextrin comprising hydroxypropyl substitutions.
  • liquid pharmaceutical formulation according to embodiment 1 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 of the preceding embodiments, wherein the optimal pH of the amylin receptor agonist is 3.5-4.5, such as about 4.0.
  • liquid pharmaceutical formulation according to any of the preceding embodiments, wherein said GLP-1 receptor agonist has an isoelectric point of less than 6.5, such as less than 6.0, such as 3.5-6.0, such as 3.0-5.0, such as 3.8-4.9.
  • composition according to any one of the preceding embodiments comprising at least about 1 mg/ml of said GLP-1 receptor agonist.
  • the pharmaceutical formulation according to any one of the preceding embodiments further comprising a tonicity agent; with the proviso that the tonicity agent is not sodium chloride.
  • the pharmaceutical formulation according to the preceding embodiment comprising mannitol in a concentration of about 16.5-37.5 mg/ml, such as about 20 mg/ml.
  • the pharmaceutical formulation according to the preceding embodiment 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.
  • composition according to any one of the preceding embodiments further comprising a buffer selected from the group consisting of histidine, citrate and/or phosphate.
  • the pharmaceutical formulation according to any one of the preceding embodiments 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 the preceding embodiment comprising a maximum of about 2.0 mg/ml polysorbate 20 and/or polysorbate 80.
  • the pharmaceutical formulation according to any one of the preceding embodiments 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 the preceding embodiments 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 the preceding embodiments 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 the preceding embodiments 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 the preceding embodiments 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 the preceding embodiments 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 the preceding embodiments 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 the preceding embodiments 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 hydroxypropyls 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 the preceding embodiments 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 the preceding embodiments 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
  • the pharmaceutical formulation according to any one of the preceding embodiments 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
  • 0.25-22 mg/ml 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 6 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.
  • the pharmaceutical formulation according to any one of embodiments 1-72 for use as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult subjects with an initial body mass index (BMI) of 30 kg/m 2 or greater (obesity) or 27 kg/m 2 or greater (overweight) in the presence of at least one weight-related co-morbidity.
  • BMI body mass index
  • 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 .
  • Table 1 Composition of cagrilintide formulations 1, 2 and 3
  • 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.
  • Table 3 Composition of semaglutide formulations 1, 2 and 3
  • ThT Thioflavin T
  • 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).
  • the presence of amyloid peptide fibrils was analysed with a Thioflavin-T (ThT) fluorescence assay.
  • the experiment was performed at 25°C.
  • the liquid from each syringe was taken out by first removing the plunger and then pipetting the liquid into the sample container.
  • 500 pl of the sample was mixed with approximately 9pl of ThT stock solution in a separate sample container, to give a final ThT concentration of 20 pM.
  • the sample was left to incubate in the dark for 25 min at ambient temperature. 200 pl sample was transferred to a well in a 96-well microtiter plate. Samples were measured on a BMG CLARIOstar fluorescence plate reader equipped with monochromators for both excitation and emission using 440 nm and 470-550 nm, respectively.
  • Results for number of sub-visible particles are the mean of 3 replicates and has been rounded to nearest integer value
  • EXAMPLE 5 EFFECT OF HYDROXYPROPYL-B-CYCLODEXTRIN CONCENTRATION ON SEMAGLUTIDE CHEMICAL STABILITY
  • This example shows the concentration-dependent effect of HP-B-CD on the chemical stability of semaglutide.
  • Samples were stored at 37°C for 28 days at which samples were analysed to determine the chemical purity of semaglutide after 14, 21 , and 28 days.
  • the purity of semaglutide was determined using reversed phase ultra-high performance liquid chromatography (RP-UHPLC), where the samples were analysed using a Waters Acquity phenyl-hexyl 1.7pm column (2.1 x 150mm) with a gradient elution of eluent A consisting of 0.09% TFA in MQ water, and eluent B consisting of 0.09% TFA in MQ water 0.09% TFA in 80% acetonitrile in MQ water. Chromatography was conducted with UV detection (215nm) at 62°C using 2-14pl injection volume and a flow rate of 0.25ml/min. Purity was evaluated as the area of the main peak of semaglutide divided by the area of all related peaks x 100%.
  • RP-UHPLC reversed phase ultra-high performance liquid chromatography
  • 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
  • EXAMPLE 7 EFFECT OF DIFFERENT SURFACTANTS ON CO-FORMULATION PHYSICAL STABILITY
  • compositions of co-formulation 13, co-formulation 14, and co-formulation 15 are shown in table 12.
  • Table 12 Composition of co-formulation 13, co-formulation 14, and co-formulation 15
  • 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.
  • composition of co-formulation 1 and co-formulation 16 are shown in table 14.
  • Table 14 Composition of co-formulation 1 and co-formulation 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 buffer concentration on the chemical stability of otherwise identical co-formulations.
  • 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 concentration dependent effect of HP-B-CD on the subcutaneous tissue upon subcutaneous injection.
  • compositions of the tested co-formulation vehicles prepared with varying HP-B- CD concentrations are shown in table 19.
  • Sorbitol concentration varies with varying HP-B-CD concentration to maintain isotonic conditions.
  • Formulations were prepared as described in example 1 except that addition of active pharmaceutical ingredients was abstained from.
  • the local (subcutaneous) tolerance upon subcutaneous administration of formulations containing HP-B-CD was studied in 5 live LandracexYorkshirexDuroc (LYD) pigs by evaluation of the resulting skin lesions 6 days (necropsy) after subcutaneous administration of 600pl using syringes equipped with 25 G sized needles and 5mm stoppers. Skin samples sized 2x2cm were collected at necropsy, fixed in neutral buffered formalin, trimmed using multi-knife, embedded in paraffin, cut in 4 pm thin sections, mounted on glass slides and subsequently hematoxylin-eosin (HE) stained.
  • HE hematoxylin-eosin
  • Isotonic co-formulation vehicle preparations containing 10% w/v to 20% w/v HP-B-CD were evaluated for the level of subcutaneous necrosis that they elicited upon subcutaneous injection. The results are presented in table 20.
  • EXAMPLE 12 EFFECT OF DIFFERENT TONICITY AGENTS ON SUBCUTANEOUS TOLERANCE UPON SUBCUTANEOUS INJECTION
  • This example shows the effect on local tolerance of any one of three different tonicity agents (sorbitol, mannitol and trehalose) in otherwise identical isotonic co-formulation vehicles.
  • compositions of the tested co-formulation vehicles are shown in table 21.
  • Table 21 Composition of isotonic co-formulation vehicles prepared with difference tonicity agents
  • Formulations were prepared as described in example 1 except that addition of active pharmaceutical ingredients was abstained from.
  • EXAMPLE 13 CONFIRMATION ON THE EFFECT OF TONICITY AGENT TYPE IN THE HISTIDINE-BUFFERED FORMULATION AND THE EFFECT OF THE CITRATE- BUFFERED FORMULATION ON THE SUBCUTANEOUS TOLERANCE UPON SUBCUTANEOUS INJECTION
  • compositions of the evaluated co-formulations are described in table 23a and
  • Co-formulations 19 and 21 were prepared as described in example 1.
  • Coformulation vehicle 21 was prepared as described in example 1 except that addition of active pharmaceutical ingredients was abstained from.
  • EXAMPLE 14 EFFECT OF HYDROXYPROPYL-SUBSTITUTED CYCLODEXTRINS OF VARYING TYPE ON CAGRILINTIDE AND SEMAGLUTIDE CO-FORMULATION PHYSICAL AND CHEMICAL STABILITY
  • 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 25.
  • the number of sub-visible particles was determined as described in example 4.
  • Results for number of sub-visible particles are the mean of 3 rep icates 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 15 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 28
  • Table 28 Compositions of citrate-buffered cagrilintide and semaglutide co- formulations containing HP-B-CD excipients of varying hydroxypropyl molar substitution degree
  • 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 16 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 32.
  • Table 32 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.
  • Table 33 Number of sub-visible particles in histidine-buffered cagrilintide and semaglutide co-formulations containing HP-B-CD of varying hydroxypropyl molar substitution degree
  • 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 36.
  • Table 36 Composition of co-formulation containing either HP-B-CD or SBE-B- CD
  • 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.
  • This example shows the effect of pH on the physical and chemical stability of cagrilintide in otherwise identical cagrilintide and semaglutide co-formulations.
  • compositions of co-formulation 41 to 45 are shown in table 38.
  • 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 40 Chemical purity (%) of cagrilintide in the cagrilintide and semaglutide co-formulations with varying pH within the pH-range 5.5 to 6.0
  • EXAMPLE 19 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 41
  • composition of histidine-buffered co-formulations 51 to 61 are shown in table 42.
  • Table 41 Composition of histidine-buffered co-formulations with varying cagrilintide and semaglutide concentration ratios
  • Table 42 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 44.
  • results presented in table 45 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 21 LOCAL TOLERANCE, IN PIGS, OF SUBCUTANEOUSLY INJECTED VEHICLE FORMULATIONS VARYING IN HP-B-CD CONTENT AND MOLAR SUBSTITUTION DEGREE, AS WELL AS IN OVERALL BUFFER COMPOSITION
  • compositions of the tested co-formulation vehicles are shown in table 46.
  • Table 46 Composition of co-formulation vehicles varying in HP-B-CD content and molar substitution degree as well as in overall buffer composition
  • Formulations were prepared as described in example 1 except that active pharmaceutical ingredients were not added.
  • the local (subcutaneous) tolerance, upon subcutaneous administration, of formulations containing HP-B-CD was studied in 4 live LandracexYorkshirexDuroc (LYD) pigs by evaluation of the resulting skin lesions 5 days (necropsy) after subcutaneous administration of 200 pl using NovoPen 4 with NovoFine Plus needles (32 G/4 mm). Skin samples sized 2x2 cm were collected at necropsy, fixed in neutral buffered formalin, trimmed using multi-knife, embedded in paraffin, cut in 4 pm thin sections, mounted on glass slides and subsequently hematoxylin-eosin (HE) stained.
  • HE hematoxylin-eosin
  • the co-formulation vehicles were evaluated for the level of subcutaneous tissue necrosis and inflammatory cell infiltration that they elicited upon subcutaneous injection. The results are presented in table 47.
  • Co-formulation vehicles comprising 20% w/v HP-B-CD or less resulted mainly in no or minimal necrosis or inflammatory cell infiltration (scores of 1 or 2) and a single observation of mild inflammatory cell infiltration (a score of 3).
  • Co-formulation vehicles comprising 22% w/v HP-B-CD or more all resulted in minimal to moderate necrosis and inflammatory cell infiltration (scores of up to 4). Based on these results, co-formulations containing less than 22% HP-B-CD appear suitable for subcutaneous use.
  • co-formulation vehicles containing 20% w/v and 22% w/v HP-B-CD and citrate resulted in marked necrosis and inflammatory cell infiltration (scores of up to 5).
  • co-formulation vehicles containing 20% w/v and 22% w/v HP-B-CD, histidine and sorbitol were more well tolerated, resulting in moderate necrosis and inflammatory cell infiltration (scores of up to 4).

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Abstract

L'invention concerne une formulation pharmaceutique liquide comprenant un agoniste du récepteur de l'amyline, un agoniste du récepteur du GLP-1 et une cyclodextrine comprenant des substitutions d'hydroxypropyle. Ladite coformulation peut être utilisée pour le traitement médical de sujets atteints de surpoids ou d'obésité, avec ou sans comorbidités associées ; de diabète, avec ou sans comorbidités associées ; de maladies cardiovasculaires, de la stéatohépatite non alcoolique (NASH) et d'une déficience cognitive, telle que celle causée par la maladie d'Alzheimer.
PCT/EP2022/085558 2021-12-13 2022-12-13 Formulations pharmaceutiques comprenant une cyclodextrine WO2023110833A1 (fr)

Priority Applications (5)

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CA3239290A CA3239290A1 (fr) 2021-12-13 2022-12-13 Formulations pharmaceutiques comprenant une cyclodextrine
JP2023566893A JP2024515392A (ja) 2021-12-13 2022-12-13 シクロデキストリンを含む医薬製剤
AU2022413347A AU2022413347A1 (en) 2021-12-13 2022-12-13 Pharmaceutical formulations comprising a cyclodextrin
KR1020237035479A KR20230158563A (ko) 2021-12-13 2022-12-13 시클로덱스트린을 포함하는 약학적 제형
PCT/EP2023/058317 WO2023187067A1 (fr) 2022-03-30 2023-03-30 Procédé de formulation

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WO2007022518A2 (fr) * 2005-08-19 2007-02-22 Amylin Pharmaceuticals, Inc. Nouvelles utilisations de proteines glucoregulatoires
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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
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