[go: up one dir, main page]

WO2024180511A1 - Processus de préparation de peptides glp-1 ayant une taille de particule contrôlée - Google Patents

Processus de préparation de peptides glp-1 ayant une taille de particule contrôlée Download PDF

Info

Publication number
WO2024180511A1
WO2024180511A1 PCT/IB2024/051965 IB2024051965W WO2024180511A1 WO 2024180511 A1 WO2024180511 A1 WO 2024180511A1 IB 2024051965 W IB2024051965 W IB 2024051965W WO 2024180511 A1 WO2024180511 A1 WO 2024180511A1
Authority
WO
WIPO (PCT)
Prior art keywords
semaglutide
peptide
sec
salt
liraglutide
Prior art date
Application number
PCT/IB2024/051965
Other languages
English (en)
Inventor
Offir BAREL
Abed Masarwa
Polina Lapido
Original Assignee
Novetide Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novetide Ltd. filed Critical Novetide Ltd.
Publication of WO2024180511A1 publication Critical patent/WO2024180511A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
    • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
    • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
    • F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing

Definitions

  • the present disclosure relates to processes for preparation of a peptide powder, and the preparation of peptide particles, for example a GLP-1 peptide such as Liraglutide, Dulaglutide, Exanetide, Lixisenatide and/or Semaglutide, and/or a salt thereof; particularly Liraglutide and Semaglutide and salts thereof; preferably Semaglutide and salts thereof, and more preferably Semaglutide. More specifically, the disclosure relates to a process comprising lyophilizing a solution comprising the peptide; and particle size reduction of the obtained lyophilizate.
  • a GLP-1 peptide such as Liraglutide, Dulaglutide, Exanetide, Lixisenatide and/or Semaglutide, and/or a salt thereof; particularly Liraglutide and Semaglutide and salts thereof; preferably Semaglutide and salts thereof, and more preferably Semaglutide.
  • the disclosure further relates to GLP-1 peptides, particularly wherein the GLP-1 peptide is selected from Liraglutide, Dulaglutide, Exanetide, Lixisenatide and/or Semaglutide, and/or a salt thereof; preferably selected from Liraglutide and Semaglutide, and a salt thereof; and more preferably Semaglutide and a salt thereof, and most preferably Semaglutide, obtainable by said process and its use in medicine and cosmetic treatment.
  • the GLP-1 peptide is selected from Liraglutide, Dulaglutide, Exanetide, Lixisenatide and/or Semaglutide, and/or a salt thereof; preferably selected from Liraglutide and Semaglutide, and a salt thereof; and more preferably Semaglutide and a salt thereof, and most preferably Semaglutide, obtainable by said process and its use in medicine and cosmetic treatment.
  • Glucagon-like peptide 1 encompasses peptides such as Liraglutide, Dulaglutide, Exanetide, Lixisenatide and/or Semaglutide, represent a class of drugs that can be used to treat type 2 diabetes. These GLP-1 agonists improve blood sugar control and may also be used for the treatment of overweight or obesity since they can assist with weight loss through appetite suppression. GLP-1 agonists can also be used in cosmetic weight loss in non-overweight non- obese subjects.
  • Synthetic peptide drugs such as GLP-1 peptides are typically manufactured using multistep solid phase synthesis.
  • the resulting peptides are typically purified by HPLC, and the products isolated primarily by lyophilization or by spray drying in order to remove the chromatography solvents and buffers.
  • Lyophilization and spray drying are well-known processes used for the solidification of unstable or biopharmaceutical formulations.
  • the products (lyophilizates) produced by lyophilization are generally characterized by low bulk density.
  • Lyophilized particles of an active pharmaceutical ingredient (“API”) having low bulk density may display poor or limited flowability, which may ultimately result in difficulties in milling processes, as well as difficulties in blending during the manufacture of a pharmaceutical composition.
  • API active pharmaceutical ingredient
  • content uniformity in a solid dosage form is of particular importance. Content uniformity is particularly difficult to control in the case of poorly flowable substances and/or substances having unsuitable particle size distribution.
  • preparation of a solid dosage form particularly of peptides such as GLP-1 peptides generally require an API having a specific particle size distribution (“PSD”) and other characteristics that cannot be controlled by lyophilization.
  • PSD particle size distribution
  • prior art lyophilization processes which are typically used in the preparation of peptides such as GLP-1 peptides result in the production of fluffy and non-flowable materials.
  • the lyophilized products typically do not have the required small particle sizes for the final dosage form in the case of low dose drugs, such as the GLP-1 peptides and are not good candidates for particle size reduction steps such as milling or sieving.
  • spray drying technology requires preparation of a feed solution comprising the API and exposure of the API- containing feed solution to heat, which can be especially detrimental for the API purity over time (for example due to decomposition), especially in large scale during spray drying of drug substances.
  • This problem can be particularly acute in the case of peptides, which are often heat sensitive.
  • Another drawback of the spray drying process is the low yield obtained because of material loss, which is particularly undesirable in the cases of high cost APIs such as peptides. For at least these reasons, there is still a need for additional processes for preparation of APIs such as peptides and particular GLP-1 peptides having controlled PSDs that will be suitable in large scale production.
  • the present disclosure relates to a process for the preparation of a peptide powder, preferably wherein the peptide is a GLP-1 peptide, wherein the process comprises: a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from Liraglutide, Dulaglutide, Exanetide, Lixisenatide or Semaglutide, or a salt thereof; preferably selected from Liraglutide and Semaglutide, and a salt thereof; more preferably Semaglutide, or a salt thereof; and most preferably Semaglutide; wherein the concentration (w/w) of the peptide in the solution is not less than about 2.5% [particularly the concentration of the peptide may range from: about 2.5% (w/w) to about 40% w/w), about 2.5% (w/w) to about 35% (w/w), about 2.5% to about 30% (w/w), about 2.5% (w/w)
  • the peptides produced by the lyophilization process described herein are advantageously in the form of a powder, particularly a flowable or free-flowing powder.
  • the powder may be subjected to particle size reduction, optionally by milling or by sieving.
  • the present disclosure provides a peptide powder, preferably wherein the peptide is a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide or Semaglutide, or a salt thereof; preferably selected from Liraglutide and Semaglutide, and a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide, produced by any of the processes disclosed herein.
  • the present disclosure also provides the use of a peptide powder produced by any of the processes of the disclosure in the preparation of pharmaceutical compositions and/or formulations or dietary compositions, preferably in the preparation of oral dosage forms, more preferably in the preparations of tablets.
  • the present disclosure also provides a peptide powder produced by the processes of the disclosure for use in the preparation of pharmaceutical compositions and/or formulations, or dietary compositions, preferably in the preparation of oral dosage forms, more preferably in the preparations of tablets.
  • the present disclosure further includes processes for the preparation of the above mentioned pharmaceutical compositions, pharmaceutical formulations, or dietary compositions, comprising a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide or Semaglutide, or a salt thereof; preferably wherein the peptide is selected from Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof, and most preferably Semaglutide; wherein the process comprises combining the peptide powder obtained by any one of the processes of the present disclosure with at least one pharmaceutically acceptable, or dietary acceptable excipient.
  • the peptide powder produced according to the processes described herein and the pharmaceutical compositions or formulations thereof may be used as medicaments, such as for the treatment of type 2 diabetes, overweight or obesity, and preferably type 2 diabetes.
  • the peptide powder produced according to the processes described herein and the pharmaceutical compositions or formulations thereof may be used for the treatment of Systemic Scleroderma, obesity and polycystic ovarian syndrome, Atherosclerosis or Cardiovascular Diseases in people with type 2 diabetes and/or obesity, Chronic Kidney Disease or dialysis-dependent end-stage kidney disease in T2DM and overweight/obesity, Cystic Fibrosis or Cystic Fibrosis-related Diabetes, Advanced Lung Disease, NASH - Nonalcoholic Steatohepatitis or NAFLD or Liver Transplant Recipients with poorly-controlled Diabetes Mellitus, Addiction Alcohol Use Disorder, Tobacco Use Disorder Nicotine Addiction, obesity in patients with schizophrenia-spectrum disorder who did not demonstrate adequate weight loss on metformin.
  • the peptide powder produced according to the processes described herein and the dietary compositions thereof may be used for cosmetic weight loss in non-overweight non-obese subjects.
  • the present disclosure also provides methods for the treatment of patients suffering from type 2 diabetes, overweight or obesity, and preferably type 2 diabetes, by administering a therapeutically effective amount of a peptide powder produced according to the processes described herein, or a pharmaceutical composition thereof, to a subject suffering from type 2 diabetes, overweight or obesity, and preferably type 2 diabetes, or otherwise in need of the treatment.
  • the present disclosure also provides methods for the treatment of patients suffering from Systemic Scleroderma, obesity and polycystic ovarian syndrome, Atherosclerosis or Cardiovascular Diseases in people with type 2 diabetes and/or obesity, Chronic Kidney Disease or dialysis-dependent end-stage kidney disease in T2DM and overweight/obesity, Cystic Fibrosis or Cystic Fibrosis-related Diabetes, Advanced Lung Disease, NASH - Nonalcoholic Steatohepatitis or NAFLD or Liver Transplant Recipients with poorly-controlled Diabetes Mellitus, Addiction Alcohol Use Disorder, Tobacco Use Disorder Nicotine Addiction, obesity in patients with schizophrenia-spectrum disorder who did not demonstrate adequate weight loss on metformin.
  • the present disclosure further provides methods for cosmetic weight loss in nonoverweight non-obese subjects by administering an effective amount of a peptide powder produced according to the processes described herein, or a dietary composition thereof.
  • the present disclosure also provides uses of a peptide powder obtainable by the methods of the present disclosure or at least one of the above pharmaceutical compositions thereof, for the manufacture of medicaments for treating type 2 diabetes, overweight or obesity and preferably type 2 diabetes.
  • the present disclosure also provides uses of a peptide powder obtainable by the methods of the present disclosure or at least one of the above pharmaceutical compositions thereof, for the manufacture of medicaments for treating Systemic Scleroderma, obesity and polycystic ovarian syndrome, Atherosclerosis or Cardiovascular Diseases in people with type 2 diabetes and/or obesity, Chronic Kidney Disease or dialysis-dependent end-stage kidney disease in T2DM and overweight/obesity, Cystic Fibrosis or Cystic Fibrosis-related Diabetes, Advanced Lung Disease, NASH - Nonalcoholic Steatohepatitis or NAFLD or Liver Transplant Recipients with poorly- controlled Diabetes Mellitus, Addiction Alcohol Use Disorder, Tobacco Use Disorder Nicotine Addiction, obesity in patients with schizophrenia-spectrum disorder who did not demonstrate adequate weight loss on metformin.
  • the present disclosure also provides uses of a peptide powder obtainable by the methods of the present disclosure or at least one dietary composition thereof, for cosmetic weight loss in non-overweight non-obese subjects
  • the present disclosure further relates to processes for the preparation of a peptide particles, preferably wherein the peptide is a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide, or a salt thereof; particularly wherein the peptide is selected from: Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof, and most preferably Semaglutide; wherein the process comprises: a) providing a solution comprising one or more solvents and a peptide, wherein the concentration of the peptide in the solution is not less than about 2.5% w/w; and wherein the solution has a pH of: about 5 to about 10, preferably about 6 to about 9, and more preferably about 7 to about 8, about 7.1 to about 7.5, or about 7.3; b) lyophilizing the solution; and c) particle size reduction of the product of step b).
  • the peptide is a GLP- 1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide, or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide.
  • the maximum concentration (w/w) of the peptide may be just below the saturation concentration of the peptide in the solvent.
  • the concentration of the peptide may particularly range from: about 2.5% (w/w) to about 40% w/w), about 2.5% (w/w) to about 35% (w/w), about 2.5% to about 30% (w/w), about 2.5% (w/w) to about 25% (w/w), or about 2.5% (w/w) to about 20% (w/w).
  • the concentration of the peptide in the solution is: about 2.5% (w/w) to about 20% (w/w) or about 2.5% (w/w) to about 13.5% (w/w).
  • the particle size reduction in step (c) is carried out to produce particles having a particle size suitable for including in a pharmaceutical formulation, preferably in an oral formulation.
  • step (c) may be carried out to produce particles having a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%, or a PSD characterized by a D(90) value of D(90) of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm, wherein the concentration (w/w) of the peptide in step a) is not less than about 2.5% and as high as saturation of the peptide in the solvent or mixture of solvents.
  • the concentration (w/w) of the peptide is: about 2.5% (w/w) to about 40% w/w), about 2.5% (w/w) to about 35% (w/w), about 2.5% to about 30% (w/w), about 2.5% (w/w) to about 25% (w/w), or about 2.5% (w/w) to about 20% (w/w). More preferably, the concentration of the peptide is from about 2.5% (w/w) to about 20% (w/w) and especially 2.5% (w/w) to about 13.5% (w/w).
  • the particles obtained in step (c) preferably have a PSD characterized by a D(90) of: not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%; or a D(90) of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm.
  • the disclosure further relates to processes for preparation of a peptide particles, preferably wherein the peptide is a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide, or a salt thereof, preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises: providing a lyophilized peptide powder, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide, wherein the peptide is obtained by steps (a)-(b
  • the disclosure further relates to processes for preparation of Liraglutide or Semaglutide, or a salt thereof, preferably Liraglutide and Semaglutide, and most preferably Semaglutide; wherein the particles have a PSD characterized by a D(90) value of: not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%; or a D(90) of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 m., wherein the process comprises: preparing a peptide powder by a process according to any of steps (a)-(b) as described herein; and subjecting the lyophilized peptide powder to particle size reduction.
  • the present disclosure provides peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; having a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%; or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%; or a D(90) value of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60
  • the present disclosure also provides the use of peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; having a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%; or a D(90) value of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm., obtainable by the processes of the disclosure in the preparation of pharmaceutical compositions and/or formulations or dietary compositions
  • the present disclosure also provides peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; having a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%; or a D(90) value of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 m to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm., obtainable by any of the processes of the disclosure for use in the preparation of pharmaceutical compositions and/or formulations or dietary
  • the present disclosure further includes processes for the preparation of the above mentioned pharmaceutical composition or pharmaceutical formulation, or dietary composition, preferably for oral administration and more preferably wherein the pharmaceutical formulation is a tablet a GLP-1 peptide, particularly wherein the peptide is selected from Liraglutide, Dulaglutide, Exanetide, Lixisenatide and/or Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises combining the GLP-1 peptide particles, particularly wherein the peptide is selected from Liraglutide, Dulaglutide, Exanetide, Lixisenatide and/or Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; having a PSD characterized by a D(90) value of not
  • the present disclosure provides GLP-1 peptide particles, particularly wherein the peptide is selected from Liraglutide, Dulaglutide, Exanetide, Lixisenatide and/or Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; having a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%; ; or a D(90) value of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm., obtainable according to any of the processes described herein and the pharmaceutical compositions or formulations, may be used as medicaments, such as for the treatment of
  • the present disclosure provides GLP-1 peptide particles, particularly wherein the peptide is selected from Liraglutide, Dulaglutide, Exanetide, Lixisenatide and/or Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; having a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%; or a D(90) value of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm., obtainable according to any of the processes described herein and the compositions or formulations comprising the GLP-1 peptide particles having a PSD characterized by
  • the present disclosure also provides methods for the treatment of type 2 diabetes, overweight or obesity, and preferably type 2 diabetes, or for the treatment of Systemic Scleroderma, obesity and polycystic ovarian syndrome, Atherosclerosis or Cardiovascular Diseases in people with type 2 diabetes and/or obesity, Chronic Kidney Disease or dialysis-dependent end-stage kidney disease in T2DM and overweight/obesity, Cystic Fibrosis or Cystic Fibrosis-related Diabetes, Advanced Lung Disease, NASH - Nonalcoholic Steatohepatitis or NAFLD or Liver Transplant Recipients with poorly-controlled Diabetes Mellitus, Addiction Alcohol Use Disorder, Tobacco Use Disorder Nicotine Addiction, obesity in patients with schizophrenia-spectrum disorder who did not demonstrate adequate weight loss on metformin by administering a therapeutically effective amount of GLP-1 peptide particles, particularly wherein the peptide is selected from Liraglutide, Dulaglutide, Exanetide, Lixisenatide and/or Semaglutide or a salt
  • the present disclosure further provides methods for cosmetic weight loss in nonoverweight non-obese subjects comprising administering an effective amount of GLP-1 peptide particles, particularly wherein the peptide is selected from Liraglutide, Dulaglutide, Exanetide, Lixisenatide and/or Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; having a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20% or a D(90) value of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm., obtainable according to any of the processes described herein
  • the present disclosure also provides uses of GLP-1 peptide particles, particularly wherein the peptide is selected from Liraglutide, Dulaglutide, Exanetide, Lixisenatide and/or Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; having a PSD characterized by a D(90) value of not more than 80 m ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20% or a D(90) value of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm, obtainable by the processes of the present disclosure or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating type 2 diabetes, overweight
  • the present disclosure also provides uses of GLP-1 peptide particles, particularly wherein the peptide is selected from Liraglutide, Dulaglutide, Exanetide, Lixisenatide and/or Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; having a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20% or a D(90) value of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm, obtainable by any of the processes of present disclosure or at least one of the above pharmaceutical compositions, for the manufacture of compositions of formulations for cosmetic weight loss
  • Figure 1 shows scanning electron microscopy (SEM) images of the powders prepared using different initial solution concentrations according to Example 1 by: (A) 0.5% (w/w); (B) 1% (w/w); (C) 2% (w/w); (D) 4% (w/w); (E) 6.2% (w/w).
  • Figure 2 shows powders prepared according to Example 1 by using different initial solution concentrations: (A) 0.5% (w/w); (C) 2% (w/w); (E) 6.2% (w/w).
  • Figure 3 shows scanning electron microscopy (x750) images of the lyophilized powder prepared according to Example 2 (A) and after micronization according to Example 3 (B).
  • Figure 4 shows scanning electron microscopy images of the micronized particles prepared according to example 4 (40g scale): x750 (A); xl500 (B).
  • Figure 5 shows scanning electron microscopy images of the sieved particles prepared according to example 5: x750 (A); xl500 (B).
  • room temperature refers to a temperature of about 20°C to about 30°C, about 22°C to about 27°C, or about 25°C.
  • GLP-1 peptide refers to a compound which fully or partially activates the human GLP-1 receptor.
  • the GLP-1 peptide is a GLP-1 analogue optionally comprising one substituent.
  • analogue refers to a GLP-1 peptide wherein at least one amino acid residue of the peptide has been substituted with another amino acid residue and/or wherein at least one amino acid residue has been deleted from the peptide and/or at least one amino acid residue has been added to the peptide and/or wherein at least one amino acid has been modified.
  • the GLP-1 peptide comprises one substituent which is covalently attached to the peptide.
  • GLP-1 peptides are: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide.
  • particle size distribution is determined by means of laser diffractometry. More specifically, unless otherwise indicated, the particle size was determined using a Mastersizer 3000 from Malvern Instruments. Preferably, particle size and particle size distribution are determined by laser light diffraction, using Mie theory, and Isopar-G dispersant (isoparaffinic fluid (CAS No) 64742-48-9)) refractive index 1.42.
  • D(90) refers to a particle size distribution where 90% of the volume of particles have a diameter lower than the D(90) value.
  • reference to a (w/w) concentration is to be understood as a reference to concentration based on the weight of the solution of peptide and solvent(s).
  • obesity encompasses obese and severely obese classes of subjects. Obesity is defined in adult humans as a BMI of 30 to 39.9. Severely obese is defined in adult humans as a BMI of 40 or above.
  • overweight is defined in adult humans as a BMI of 25 to 29.9.
  • cosmetic weight loss is understood to mean weight loss in nonoverweight, non-obese subjects.
  • cosmetic weight loss optionally refers weight loss in subjects having a body mass index (BMI) of: 18.5 to 24.9, 19 to 24, 20 to 23.5, or 21.0 to 23.
  • BMI body mass index
  • the flowable particles obtained by the lyophilization process of the present disclosure is easier to handle, suitable for large scale production processes, and may more readily undergo further particle size reduction processes, such as micronizing by a jet mill or sieving to obtain particles having controlled PSD while maintaining the purity of the API.
  • Reduction of particle size by agitative sieving is particularly advantageous for large scale processes.
  • the process of Particle size reduction by Sieving has a very short cycle time in production, it does not involve additional solvents, has low energy consumption and high yield. Therefore the processes of the present disclosure allow preparation of material having any desired particle size distribution by preparation of the flowable powder and further processing the powder to the required PSD.
  • the present disclosure relates to processes for preparation of peptide powder, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises: a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the concentration (w/w) of the peptide is not less than about 2.5%,
  • the concentration of the peptide in the solution of step a) is from about 2.5% (w/w) to about 10% (w/w), more preferably from about 2.5% (w/w) to about 8% (w/w), most preferably from about 2.5% (w/w) to about 7% (w/w).
  • the solvents in step a) may be any solvent or a combination of solvents having a freezing point above -70 °C and that are suitable for lyophilization, i.e. a solvent that sublimes below the triple point at a given minimal pressure, for example 10 pbar.
  • the solvents in step a) may be one or more solvents selected from the list consisting of acetic acid, acetone, dimethyl sulfoxide (DMSO), ethanol, water, isopropanol (IP A), methanol, menthol, TFA (Trifluoroacetic acid), and acetonitrile.
  • the solvent in step a) may be one or more selected from the group consisting of acetonitrile, IP A, ethanol and water, more preferably the solvent in step a) comprises water.
  • the solvent in step a) may comprise water and up to about 60% (w/w), preferably up to about 40% (w/w) of any one or a mixture of acetonitrile, IPA and ethanol.
  • the solvent comprises water and about 15% (w/w) to about 25% (w/w) of acetonitrile, more preferably the solvent in step a) comprises water and about 20% (w/w) of acetonitrile.
  • the one or more solvents in step (a) consists essentially of, and preferably consists of, acetonitrile and water, more preferably wherein acetonitrile is present at a concentration of: about 0.5% (w/w) to about 50% (w/w), about 1.0% (w/w) to about 50% (w/w), about 2.0% (w/w) to about 40% (w/w), about 3.0% (w/w) to about 40% (w/w), about 4.0% (w/w) to about 40% (w/w), about 5.0% (w/w) to about 40% (w/w), about 8% (w/w) to about 35% (w/w), about 10% (w/w) to about 30% (w/w), about 12% (w/w) to about 28% (w/w); about 15% (w/w) to about 25% (w/w), about 18% (w/w) to about 22% (w/w), or about 20% (w/w).
  • the one or more solvents in step a) consists essentially of (and preferably consists of) acetonitrile and water, preferably wherein acetonitrile is present at about 15% (w/w) to about 25% (w/w), more preferably about 18% (w/w) to about 22% (w/w), and most preferably about 20% (w/w).
  • the pH of the solution in step (a) is: about 6 to about 9, or about 6 to about 8.5, preferably to about 7 to about 8, or about 7 to about 7.5, or more preferably to about 7.3.
  • the solution may have a pH of: about 6 to about 9, more preferably about 7 to about 8, about 7.1 to about 7.5, and even more preferably about 7.3.
  • the pH of the solution may be adjusted by the use of an acidic or basic, typically a basic, agent.
  • the pH may be adjusted to the specified range by any suitable basic agent such as but not limited to sodium bicarbonate, ammonium acetate, phosphate buffer, ammonium hydroxide or NaOH.
  • the pH is adjusted by ammonium hydroxide, preferably 25% (w/w) solution of ammonium hydroxide or NaOH, to provide the solution in step (a) having a pH within the specified range.
  • step (a) may be performed at a temperature of about 15 °C to about 40 °C, or about 15 °C to about 30 °C, and preferably at room temperature; or wherein step (a) is performed at a temperature of: about 15 °C to about 35 °C, about 18 °C to about 25 °C, or about 18 °C to about 22 °C, or about 20 °C.
  • step (a) may be performed at any suitable temperature, typically at a temperature of about 15 °C to about 40 °C and preferably at room temperature.
  • the solution in step (a) may filtered prior to step (b), preferably wherein the filtration is carried out using a 0.2 micron filter.
  • the freeze drying step (b) may be carried at a temperature of: about -50 °C to about 30 °C, about -45 °C to about 25 °C or about -45 °C to about 20 °C.
  • the solution in step (a) optionally after a filtration step as discussed above, is cooled to a suitable freeze-drying temperature (preferably: about -15 °C to about -55 °C, about -20 °C to about -55 °C, about -25 °C to about -50 °C, about -35 °C to about -50 °C, or about -45 °C.
  • the mixture may then be warmed, preferably to a temperature of about 20 °C to about 30 °C, about 20 °C to about 25 °C, or about 20 °C to about 22 °C, or about 20 °C, whereupon the solvent(s) is removed by sublimation.
  • the product may be subjected to a further drying step.
  • the further drying step may be carried out at a temperature of: 15 °C to about 55 °C, about 18 °C to about 45 °C, about 18 °C to about 40 °C, or about 20 °C to about 40 °C.
  • the further drying step may be carried out at reduced pressure, preferably at a pressure of: about 100 pbar to about 600 pbar, about 120 pbar to about 550 pbar, about 140 to about 450 pbar, about 160 to about 350 pbar, about 170 to about 300 pbar, about 180 to about 250 pbar, or about 200 to about 250 pbar, or about 200 pbar.
  • the disclosure relates to processes for preparation of peptide powder, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the concentration of the peptide is from about 2.5% (w/w) to about
  • the disclosure relates to processes for preparation of peptide powder, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the concentration of the peptide is from about 2.5% (w/w) to about
  • the disclosure relates to processes for preparation of peptide powder, preferably GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; and wherein the concentration of the peptide is from about 2.5% (w/w) to about
  • the disclosure relates to processes for preparation of a peptide powder, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the concentration of the peptide is from about 2.5% (w/w)
  • the disclosure relates to processes for preparation of peptide powder, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the concentration of the peptide is from about 2.5% (w/w) to about
  • the solvent in the process consists essentially of, or more particularly or consists of, water and acetonitrile.
  • the present disclosure provides peptide powder, preferably GLP-1 peptide powder, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; produced by any one of the processes described herein.
  • the present disclosure also provides the use of peptide powder produced by the processes described herein in the preparation of pharmaceutical compositions and/or formulations.
  • the present disclosure also provides peptide powder produced by the processes described herein for use in the preparation of pharmaceutical compositions and/or formulations.
  • the present disclosure further includes processes for the preparation of the above mentioned pharmaceutical composition comprising a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises combining the peptide powder obtained by any one of the processes described herein with at least one pharmaceutically acceptable excipient.
  • the peptide powder produced according to the processes described herein and the pharmaceutical compositions or formulations may be used as medicaments, such as for the treatment of type 2 diabetes, overweight or obesity and preferably type 2 diabetes or for the treatment of Systemic Scleroderma, obesity and polycystic ovarian syndrome, Atherosclerosis or Cardiovascular Diseases in people with type 2 diabetes and/or obesity, Chronic Kidney Disease or dialysis-dependent end-stage kidney disease in T2DM and overweight/obesity, Cystic Fibrosis or Cystic Fibrosis-related Diabetes, Advanced Lung Disease, NASH - Nonalcoholic Steatohepatitis or NAFLD or Liver Transplant Recipients with poorly-controlled Diabetes Mellitus, Addiction Alcohol Use Disorder, Tobacco Use Disorder Nicotine Addiction, obesity in patients with schizophrenia-spectrum disorder who did not demonstrate adequate weight loss on metformin.
  • the peptide powder produced according to the processes described herein and the pharmaceutical compositions or formulations may be used as an appetite suppressant, or for cosmetic weight loss in non-overweight non-obese subjects.
  • the present disclosure also provides methods for the treatment of type 2 diabetes, overweight or obesity, and preferably type 2 diabetes, or for the treatment of Systemic Scleroderma, obesity and polycystic ovarian syndrome, Atherosclerosis or Cardiovascular Diseases in people with type 2 diabetes and/or obesity, Chronic Kidney Disease or dialysis-dependent end-stage kidney disease in T2DM and overweight/obesity, Cystic Fibrosis or Cystic Fibrosis-related Diabetes, Advanced Lung Disease, NASH - Nonalcoholic Steatohepatitis or NAFLD or Liver Transplant Recipients with poorly-controlled Diabetes Mellitus, Addiction Alcohol Use Disorder, Tobacco Use Disorder Nicotine Addiction, obesity in patients with schizophrenia-spectrum disorder who did not demonstrate adequate weight loss on metformin.
  • the present disclosure further provides methods for cosmetic weight loss in nonoverweight non-obese subjects by administrating an effective amount of peptide powder produced according to the processes described herein, or pharmaceutical compositions containing the peptide particles produced according to the processes described herein.
  • the present disclosure also provides uses of peptide powder obtained by the methods of the present disclosure or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating type 2 diabetes, overweight or obesity and preferably type 2 diabetes or for Systemic Scleroderma, obesity and polycystic ovarian syndrome, Atherosclerosis or Cardiovascular Diseases in people with type 2 diabetes and/or obesity, Chronic Kidney Disease or dialysis-dependent end-stage kidney disease in T2DM and overweight/obesity, Cystic Fibrosis or Cystic Fibrosis-related Diabetes, Advanced Lung Disease, NASH - Nonalcoholic Steatohepatitis or NAFLD or Liver Transplant Recipients with poorly- controlled Diabetes Mellitus, Addiction Alcohol Use Disorder, Tobacco Use Disorder Nicotine Addiction, obesity in patients with schizophrenia-spectrum disorder who did not demonstrate adequate weight loss on metformin.
  • the present disclosure also provides uses of the peptide powder obtained by the methods of the present disclosure or at least one of the above pharmaceutical compositions, for the manufacturing of medicaments for cosmetic weight loss in non-overweight non-obese subjects.
  • the present disclosure further relates to processes for preparation of peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises: a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Li
  • the solvents in step a) may be any solvent or a combination of solvents having a freezing point above -70 °C and is suitable for Lyophilization, i.e. sublimes below the triple point in a given minimal pressure, for example 10 pbar.
  • the solvents in step a) may be one or more selected from the list consisting of acetic acid, acetone, dimethyl sulfoxide (DMSO), ethanol, water, isopropanol (IP A), methanol, menthol, TFA, and acetonitrile.
  • the solvent in step a) may be one or more selected from the group consisting of acetonitrile, IP A, ethanol and water, more preferably the solvent in step a) comprises water.
  • the solvent in step a) may comprise water and up to about 60% (w/w), preferably up to about 40% (w/w) of any one or a mixture of acetonitrile, IPA and ethanol.
  • the solvent comprises water and about 15% (w/w) to about 25% (w/w) of acetonitrile, more preferably the solvent in step a) comprises water and about 20% (w/w) of acetonitrile.
  • the one or more solvents in step a) essentially consists of (and preferably consists of) acetonitrile and water, optionally wherein acetonitrile is present at a concentration of: about 0.5% (w/w) to about 50% (w/w), about 1.0% (w/w) to about 50% (w/w), about 2.0% (w/w) to about 40% (w/w), about 3.0% (w/w) to about 40% (w/w), about 4.0% (w/w) to about 40% (w/w), about 5.0% (w/w) to about 40% (w/w), about 8% (w/w) to about 35% (w/w), about 10% (w/w) to about 30% (w/w), about 12% (w/w) to about 28% (w/w); about 15% (w/w) to about 25% (w/w), about 18% (w/w) to about 22% (w/w), or about 20% (w/w); or preferably wherein acetonitrile is present at a concentration of
  • the pH of the solution may be: about 6 to about 9, more preferably about 7 to about 8, about 7.1 to about 7.5, even more preferably the pH may be about 7.3.
  • the pH may be adjusted to within the specified ranges by any suitable basic agent such as but not limited to sodium bicarbonate, ammonium acetate, phosphate buffer, ammonium hydroxide or NaOH.
  • the pH is adjusted by ammonium hydroxide, 1 preferably 25% (w/w) solution of ammonium hydroxide or NaOH, to provide the solution in step (a).
  • step (a) may be performed at any suitable temperature, typically at a temperature of about 15 °C to about 40 °C and preferably at room temperature.
  • step c) the particle size reduction in step c) may be performed for example by any milling technology known in the art or by vibration sieve technology.
  • a jet mill micronizer may be used for milling.
  • the compressed grinding air (or gas) pressure may be in the range of about 0.1 bar to about 6.0 bar, preferably about 0.1 bar to about 3.0 bar, more preferably about 0.1 bar to about 1.5 bar, most preferably about 0.3 bar to about 1.0 bar.
  • the compressed feed air (or gas) pressure may be in the about 0. Ibar to about 6.0 bar, preferably about 0.1 bar to about 5.0 bar, more preferably about 1.0 bar to about 4.0 bar, even more preferably about 2.0 bar to about 4.0 bar, and particularly about 3.0 bar.
  • the feeding rate of the starting particles may range from about 0.5 g/min to about 50 g/min, preferably from about 0.5 g/min to about 10 g/min, more preferably from about 0.5 g/min to about 1.5 g/min and most preferably from about 0.5 g/min to about 1.0 g/min.
  • a mesh sieve with balls aid may be used for particle size reduction. Vacuum may be applied to improve particle flow through the mesh.
  • the balls may be for example ceramic balls, silicate balls or stainless steel balls, preferably ceramic.
  • the balls are made of zirconium-based ceramics, preferably zirconia.
  • the size of the balls may vary and may have a diameter of about 0.1 mm to about 10 mm, about 1 to 5 mm, preferably the ball has a diameter of 2 mm.
  • the mesh size may vary from about 10pm to about 500pm depending on the desired PSD.
  • the mesh size is from about 10 to about 300 pm, from about 10 to about 200 pm, from about 10 to about 100 pm, from about 10 to about 80 pm, from about 20 to about 60 pm, more preferably from about 25 pm to about 50 pm, most preferably from about 30 pm to about 50 pm, particularly about 40 pm.
  • the disclosure relates to processes for preparation of peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises: a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the concentration (w/w) of the peptide is not less than about 2.5%, preferably wherein the concentration of the peptide is not less
  • the disclosure relates to processes for preparation of peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide particles; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the concentration of the peptide is from about 2.5% (w/w) to
  • the disclosure relates to processes for preparation of peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide particles; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the concentration of the peptide is from about 2.5% (w/w) to
  • the disclosure relates to processes for preparation of peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide particles; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the concentration of the peptide is from about 2.5% (w/w) to
  • the solvent in step a) comprises water and up to about 60% (w/w), preferably up to about 40% (w/w) of any one or a mixture of acetonitrile, IPA and ethanol; wherein the pH of the solution is about 5 to about 10, about 6 to about 9, about 7 to about 8, about 7.1 to about 7.5, or about 7.3; b) lyophilizing the solution and c) reducing the PSD of the particles obtained in step b) by milling or by sieving using a mesh sieve with ball aids, preferably wherein the resulting particles have a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%, or a PSD characterized by a D(90) value of: about 8 pm to about 80 pm,
  • the disclosure relates to processes for preparation of peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide particles; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the concentration of the peptide is from about 2.5% (w/w) to
  • the disclosure relates to processes for preparation of peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; the concentration of the peptide is from about 2.5% (w/w) to about 13.5%
  • step b) lyophilizing the solution; and c) reducing the PSD of the particles obtained in step b) by milling or by sieving using a mesh sieve with ball aids, preferably wherein the resulting particles have a PSD characterized by a D(90) value of not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%, preferably wherein the resulting particles have a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%, or a PSD characterized by a D(90) value of: about
  • 8 pm to about 80 pm about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm.
  • the disclosure relates to processes for preparation of peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the concentration of the peptide is from about 2.5% (w/w) to about
  • the compressed gas or air for grinding) pressure is in the range of about 0. Ibar to about 6.0bar, preferably about 0.1 bar to about 3.0 bar, more preferably about 0.1 bar to about 1.5 bar, and most preferably about 0.3 bar to about 1.0 bar; ii)
  • the compressed feed air (or gas) is in the range of about 0.
  • the feeding rate of the starting particles ranges from about 0.5g/min to about 50 g/min, preferably from about 0.5 g/min to about lOg/min, more preferably from about 0.5 g/min to about 1.5 g/min and most preferably from about 0.5 g/min to about 1.0 g/min; and preferably wherein the resulting particles have a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20% or a PSD characterized by a D(90) value of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about
  • the disclosure relates to processes for preparation of peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the concentration of the peptide is from about 2.5% (w/w) to about
  • the disclosure relates to processes for preparation of peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the concentration of the peptide is from about 2.5% (w/w) to about
  • the balls are made of zirconium-based ceramic or zirconia.
  • the balls have a diameter of about 0.1mm to about 1cm, preferably the ball has a diameter of 2 mm iii)
  • the mesh size is from about 10pm to about 500pm, preferably the mesh size is 40 pm; and preferably wherein the resulting particles have a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20% or a PSD characterized by a D(90) value of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm.
  • the disclosure relates to processes for preparation of peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; the concentration of the peptide is from about 2.5% (w/w) to about 13.5%
  • the disclosure relates to processes for preparation of peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the concentration of the peptide is from about 2.5% (w/w) to about
  • the compressed gas or air for grinding) pressure is in the range of about 0.1 bar to about 6.0 bar, preferably about 0.1 bar to about 3.0 bar, more preferably about 0.1 bar to about 1.5 bar, and most preferably about 0.3 bar to about 1.0 bar;
  • the compressed feed air (or gas) is in the range of about 0.1 bar to about 6.0 bar, preferably about 0.1 bar to about 5.0 bar, more preferably about 1.0 bar to about 4.0 bar, even more preferably about 2.0 bar to about 4.0 bar, and particularly about 3.0 bar; and iii)
  • the feeding rate of the starting particles ranges from about 0.5 g/min to about 50 g/min, preferably from about 0.5 g/min to about 10 g/min, more preferably from about 0.5 g/min to about 1.5 g/min and most preferably from about 0.5 g/min to about 1.0 g/min; and preferably wherein the resulting particles have a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%
  • the disclosure relates to processes for preparation of peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the concentration of the peptide is from about 2.5% (w/w) to about
  • the disclosure relates to processes for preparation of peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises a) providing a solution comprising one or more solvents and a peptide, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the concentration of the peptide is from about 2.5% (w/w) to about
  • the balls are made of zirconium-based ceramic or zirconia.
  • the balls have a diameter of about 0.1mm to about 1cm, preferably the ball has a diameter of 2 mm iii)_The mesh size is from about 10pm to about 500pm, preferably the mesh size is 40 pm; and preferably wherein the resulting particles have a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20% or a PSD characterized by a D(90) value of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm.
  • the disclosure further relates to processes for preparation of peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises: providing peptide powder, preferably a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the peptide is obtainable by the process of any aspect or embodiment the present disclosure; and reducing the particle size, preferably wherein the peptide is selected from:
  • the particle size reduction in step c) may be performed by any milling technology known in the art.
  • a jet mill micronizer may be used.
  • the pressure grinding air (or gas) may be in the range of about 0. Ibar to about 6.0bar, preferably about 0.1 bar to about 3.0 bar, more preferably about 0.1 bar to about 1.5 bar, most preferably about 0.3 bar to about 1.0 bar.
  • the compressed feed air (or gas) pressure may be in the about 0.1 bar to about 6.0 bar, preferably about 0.1 bar to about 5.0 bar, more preferably about 1.0 bar to about 4.0 bar, even more preferably about 2.0 bar to about 4.0 bar, and particularly about 3.0 bar.
  • the feeding rate of the starting particles may range from about 0.5 g/min to about 50 g/min, preferably from about 0.5 g/min to about 10 g/min, about 0.5 g/min to about 1.5 g/min and most preferably from about 0.5 g/min to about 1.0 g/min.
  • a mesh sieve with balls aid may be used for particle size reduction. Vacuum may be applied to improve flow of the particles through the mesh.
  • the balls may be for example ceramic balls, silicate balls or stainless steel balls, preferably ceramic.
  • the balls are made of zirconium-based ceramics, preferably zirconia.
  • the size of the balls may vary and may have a diameter of about 1 mm to about 10 mm, about 1 to about 5 mm, and preferably wherein the ball has a diameter of 2 mm.
  • the mesh size may vary from about 10pm to about 500pm depending on the desired PSD.
  • the mesh size from about 10 to about 500 microns, about 10 to about 300 microns, about 0 to about 200 microns, about 10 to about 100 microns, about 10 to about 80 microns, about 20 to about 60 pm, more preferably from about 25 pm to about 50 pm, most preferably from about 30 pm to about 50 pm, particularly about is 40 pm.
  • the present disclosure provides peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; having a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%, or a PSD characterized by a D(90) value of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm, obtainable by any of the processes disclosed herein.
  • the present disclosure also provides the use of peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; having a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%, or a PSD characterized by a D(90) value of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm, obtainable by the processes of the disclosure in the preparation of pharmaceutical compositions and/or formulations
  • the present disclosure also provides the peptide particles, preferably GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; having a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%, or a PSD characterized by a D(90) value of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm, obtainable by the processes of the disclosure for use in the preparation of pharmaceutical compositions and/or formulations
  • the present disclosure further includes processes for the preparation of the above mentioned pharmaceutical composition, or pharmaceutical formulation preferably for oral administration and more preferably wherein the pharmaceutical formulation is a tablet a GLP-1 peptide, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; wherein the process comprises combining the GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; having a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%
  • the present disclosure provides GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; having a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%, , or a PSD characterized by a D(90) value of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm, obtainable by any of the processes described herein and the pharmaceutical compositions or formulations may be used as medicaments, such as for the
  • the present disclosure provides GLP-1 peptide particles, particularly Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide particles, and more preferably Semaglutide particles having a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%, a PSD characterized by a D(90) value of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm, obtainable by any of the processes described herein, and dietary compositions thereof for cosmetic weight loss in non-overweight non-obese subjects.
  • the process of the invention can provide lyophilized, peptide powder [i.e.
  • the flowability is: at least about 0.2 g/sec, at least about 0.3 g/sec, at least about 0.4 g/sec; or wherein the flowability is: about 0.2 g/sec to about 80 g/sec, about 0.2 g/sec to about 60 g/sec, about 0.2 g/sec to about 40 g/sec, about 0.2 g/sec to about 30 g/sec, about 0.2 g/sec to about 25 g/sec, about 0.2 g/sec to about 20 g/sec, about 0.2 g/sec to about 10 g/sec, about 0.2 g/sec to about 5.0 g/sec, about 0.2 g/sec to about 4.0 g/sec, about 0.2 g/sec to about 3.0 g/sec, or about 0.2 g/sec to about 2.0 g/sec.
  • This product may be obtainable by any of the lyophilization processes disclosed herein.
  • the surprisingly advantageous flowability of lyophilized product enables a greater ease of further processing of the peptide powder, for example, in subsequent particle size reduction.
  • the present disclosure also provides methods for the treatment of patients with type 2 diabetes, overweight or obesity, preferably type 2 diabetes, or for the treatment of Systemic Scleroderma, obesity and polycystic ovarian syndrome, Atherosclerosis or Cardiovascular Diseases in people with type 2 diabetes and/or obesity, Chronic Kidney Disease or dialysis-dependent end-stage kidney disease in T2DM and overweight/obesity, Cystic Fibrosis or Cystic Fibrosis-related Diabetes, Advanced Lung Disease, NASH - Nonalcoholic Steatohepatitis or NAFLD or Liver Transplant Recipients with poorly-controlled Diabetes Mellitus, Addiction Alcohol Use Disorder, Tobacco Use Disorder Nicotine Addiction, obesity in patients with schizophrenia-spectrum disorder who did not demonstrate adequate weight loss on metformin.
  • GLP-1 peptide particles by administering a therapeutically effective amount of GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; having a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%, or a PSD characterized by a D(90) value of: about 8 pm to about 80 pm, about 10 m to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm, obtainable by the processes described herein, or at least one of the above pharmaceutical compositions,
  • the present disclosure further provides methods for cosmetic weight loss in nonoverweight non-obese subjects by administering an effective amount of peptide particles produced according to the processes described herein, or a dietary composition containing the peptide particles produced according to the processes described herein.
  • the present disclosure also provides uses of GLP-1 peptide particles, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide; having a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20% obtained by the methods of the present disclosure or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g., patients with type 2 diabetes, overweight or obesity, and preferably type 2 diabetes or for the treatment of Systemic Scleroderma, obesity and polycystic ovarian syndrome, Atherosclerosis or Cardiovascular Diseases in people with
  • the present disclosure also provides uses of the peptide particles obtained by the methods of the present disclosure or at least one of the above described dietary compositions for cosmetic weight loss in non-overweight non-obese subjects.
  • Instrument BEP2 Flowability Tester from Copley Scientific, with Funnel Attachment and Manually Operated Stirrer with a nozzle corresponding to aperture size of 25 mm.
  • test sample was introduced into the funnel and the time required for the entire sample to flow out of the funnel was measure using a suitable stopwatch.
  • Semaglutide may be prepared for example according to any method known in the art.
  • the pH of the solutions was adjusted to 7.3 by the addition of a few drops of 0. IN NaOH or 25% ammonium hydroxide in a magnetically stirred vessel at 20°C.
  • the solutions were filtered using a 0.2 micron filter and the samples were lyophilized in parallel in a Pilot Edwards Lyophilizer mini according to the process described below.
  • the solution was charged to a Minifast 10 freeze dryer and then cooled down from 20°C to -45°C.
  • the frozen material was warmed slowly to -20°C with reduce pressure of 500 pbar to obtain a primary drying step. After most of the solvent was sublimated, a secondary drying was carried out at 20°C under a reduced pressure of 200 pbar until complete dryness.
  • the lyophilized material was discharged at room temperature.
  • a 23 kg solution containing 800 grams (3.5% w/w) Semaglutide in a 20% (w/w) Acetonitrile and 80% w/w H2O was prepared, and the pH was adjusted by addition of 0. IN NaOH to 7.3.
  • the solution was filtered using a 0.2 micron stainless steel filter at room temperature, and lyophilized according to the freeze process as described below.
  • the solution was charged to a Lyofast 10 industrial freeze dryer and then cooled down from 20°C to -45°C.
  • the frozen material was warmed slowly to -40°C under reduced pressure of 900 pbar in a primary drying step. After most of the solvent was sublimated a secondary drying was carried out at 40°C under a reduced pressure of 200 pbar till complete dryness.
  • the lyophilized material was discharged at room temperature to obtain a flowable powder, having a bulk density >0.04 g/ml.
  • Example 2A Preparation of flowable Semaglutide powder by lyophilization
  • a 10 gram solution containing 2 grams (20% w/w) Semaglutide in a 20% (w/w) Acetonitrile and 80%w/w H2O is prepared, and the pH is adjusted by addition of 0. IN NaOH or 25%NH4OH to 7.0-7.5.
  • the solution is filtered using a 0.2 micron Nylon filter at room temperature, and lyophilized according to the freeze process as described below.
  • Semaglutide powder prepared according to example 2, was fed into a 50mm jet mill using vibration feeder with a feeding rate of 0.58g/min, compressed grinding air pressure of 0.8-1.0 bar and compressed feed air pressure of 3.0 bar.
  • a process for preparation of a peptide powder comprising: a) providing a solution comprising one or more solvents and a peptide, wherein the concentration (w/w) of the peptide is not less than about 2.5%, preferably wherein the concentration of the peptide is from about 2.5% (w/w) to about 20% (w/w) and more preferably wherein the concentration of the peptide is from about 2.5% (w/w) to about 13.5% (w/w); and wherein the pH of the solution is: about 5 to about 10, about 6 to about 9 or about 7 to about 8; and b) lyophilizing the solution.
  • concentration of the peptide in the solution of step a) is from: about 2.5% (w/w) to about 40% w/w), about 2.5% (w/w) to about 35% (w/w), about 2.5% to about 30% (w/w), about 2.5% (w/w) to about 25% (w/w), or about 2.5% (w/w) to about 20% (w/w), about 2.5% (w/w) to about 13.5% (w/w), about 2.5% (w/w) to about 10% (w/w), more preferably from about 2.5% (w/w) to about 8% (w/w), most preferably from about 2.5% (w/w) to about 7% (w/w).
  • the one or more solvents are selected from the group consisting of acetic acid, acetone, dimethyl sulfoxide (DMSO), ethanol, water, isopropanol (IP A), methanol, menthol, TFA, and acetonitrile, preferably from the group consisting of acetonitrile, IP A, ethanol and water.
  • the one or more solvents consists essentially of, and preferably consists of, acetonitrile and water, more preferably wherein acetonitrile is present at a concentration of: about 0.5% (w/w) to about 50% (w/w), about 1.0% (w/w) to about 50% (w/w), about 2.0% (w/w) to about 40% (w/w), about 3.0% (w/w) to about 40% (w/w), about 4.0% (w/w) to about 40% (w/w), about 5.0% (w/w) to about 40% (w/w), about 8% (w/w) to about 35% (w/w), about 10% (w/w) to about 30% (w/w), about 12% (w/w) to about 28% (w/w); about 15% (w/w) to about 25% (w/w), about 18% (w/w) to about 22% (w/w), or about 20% (w/w).
  • the one or more solvents consists essentially of, and preferably consists of, acetonitrile and water, optionally wherein acetonitrile is present at a concentration of: about 0.5% (w/w) to about 50% (w/w), about 1.0% (w/w) to about 50% (w/w), about 2.0% (w/w) to about 40% (w/w), about 3.0% (w/w) to about 40% (w/w), about 4.0% (w/w) to about 40% (w/w), about 5.0% (w/w) to about 40% (w/w), about 8% (w/w) to about 35% (w/w), about 10% (w/w) to about 30% (w/w), about 12% (w/w) to about 28% (w/w); about 15% (w/w) to about 25% (w/w), about 18% (w/w) to about 22% (w/w), or about 20% (w/w); or more preferably wherein
  • step a) essentially consists of (and preferably consists of) acetonitrile and water, and wherein acetonitrile is present at a concentration of: about 15% (w/w) to about 25% (w/w), more preferably about 18% (w/w) to about 22% (w/w), and particularly about 20% (w/w).
  • a base preferably selected from the group consisting of: sodium bicarbonate, ammonium acetate, phosphate buffer, ammonium hydroxide or NaOH, preferably wherein the pH is adjusted by addition of ammonium hydroxide or NaOH, more preferably by addition of a 25% (w/w) solution of ammonium hydroxide or NaOH.
  • step (a) is performed at a temperature of about 15 °C to about 40 °C, or about 15 °C to about 30 °C, and preferably at room temperature; or wherein step (a) is performed at a temperature of: about 15 °C to about 35 °C , about 18 °C to about 25 °C, or about 18 °C to about 22 °C, or about 20 °C.
  • step (a) is performed at a temperature of about 15 °C to about 40 °C and preferably at room temperature.
  • step (a) A process according to any of clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the solution in step (a) is filtered prior to step (b).
  • step (b) is carried at a temperature of: about -50 °C to about 30 °C, about -45 °C to about 25 °C or about -45 °C to about 20 °C.
  • step c) has a PSD characterized by a D(90) value of not more than 80 pm ⁇ 20%, not more than 60 pm ⁇ 20%, or a PSD characterized by a D(90) value of: not more than 40 pm ⁇ 20%, preferably not more than 30 pm ⁇ 20%, or a PSD characterized by a D(90) value of D(90) of: about 8 pm to about 80 pm, about 10 pm to about 70 pm, about 15 pm to about 65 pm, about 20 pm to about 60 pm, or about 20 to about 40 pm.
  • step (c) comprises milling and/or sieving.
  • the compressed grinding air (or gas) pressure in the jet mill may be in the range of about 0.1 bar to about 6.0 bar, preferably about 0.1 bar to about 3.0 bar, more preferably about 0.1 bar to about 1.5 bar, most preferably about 0.3 bar to about 1.0 bar.
  • the feeding air (or gas) pressure may be in the about 0.1 bar to about 6.0 bar, preferably about 0.1 bar to about 5.0 bar, more preferably about 1.0 bar to about 4.0 bar, even more preferably about 2.0 bar to about 4.0 bar, and particularly about 3.0 bar.
  • step (b) A process according to any of clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, wherein the flowability of the lyophilized product obtained in step (b) is:, at least about 0.2 g/sec, at least about 0.3 g/sec, at least about 0.4 g/sec; or wherein the flowability is: about 0.2 g/sec to about 80 g/sec, about 0.2 g/sec to about 60 g/sec, about 0.2 g/sec to about 40 g/sec, about 0.2 g/sec to about 30 g/sec, about 0.2 g/sec to about 25 g/sec, about 0.2 g/sec to about 20 g/sec, about 0.2 g/sec to about 10 g/sec, about 0.2 g/sec to about 5.0 g/sec, about 0.2 g/sec to about 4.0 g/sec, about 0.2 g/sec to about 3.0 g/sec
  • a peptide powder, or peptide particles obtainable by any of the processes of clauses 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32, preferably wherein the peptide is a dual GLP-1 peptide, preferably Semaglutide or a salt thereof; and most preferably Semaglutide.
  • Lyophilized peptide powder produced by any of the processes of clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein the flowability is: at least about 0.1 g/sec, at least about 0.2 g/sec, at least about 0.3 g/sec, at least about 0.4 g/sec; about 0.2 g/sec to about 80 g/sec, about 0.2 g/sec to about 60 g/sec, about 0.2 g/sec to about 40 g/sec, about 0.2 g/sec to about 30 g/sec, about 0.2 g/sec to about 25 g/sec, about 0.2 g/sec to about 20 g/sec, about 0.2 g/sec to about 10 g/sec, about 0.2 g/sec to about 5.0 g/sec, about 0.2 g/sec to about 4.0 g/sec, about 0.2 g/sec to about 3.0 g/sec, or about 0.2 g/sec to about 2.0 g/sec, as measured
  • GLP-1 peptide particles according to any of clauses 33, 34 or 35, a pharmaceutical composition or pharmaceutical formulation thereof according to clause 36, for use in the treatment of type 2 diabetes, overweight or obesity, and preferably type 2 diabetes, or in the treatment of Systemic Scleroderma, obesity and polycystic ovarian syndrome, Atherosclerosis or Cardiovascular Diseases in people with type 2 diabetes and/or obesity, Chronic Kidney Disease or dialysis-dependent end-stage kidney disease in T2DM and overweight/obesity, Cystic Fibrosis or Cystic Fibrosis-related Diabetes, Advanced Lung Disease, NASH - Nonalcoholic Steatohepatitis or NAFLD or Liver Transplant Recipients with poorly-controlled Diabetes Mellitus, Addiction Alcohol Use Disorder, Tobacco Use Disorder Nicotine Addiction, obesity in patients with schizophrenia-spectrum disorder who did not demonstrate adequate weight loss on metformin, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and
  • GLP-1 peptide particles according to clause 33, 34 or 35, or dietary composition according to clause 36 for cosmetic weight loss in non-overweight non-obese subjects, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide.
  • a method for cosmetic weight loss in non-overweight non-obese subjects comprising by administering an effective amount of GLP-1 peptide particles according to clause 33, 34 or 35, or dietary composition according to clause 36, particularly wherein the peptide is selected from: Liraglutide, Dulaglutide, Exanetide, Lixisenatide and Semaglutide or a salt thereof; preferably Liraglutide and Semaglutide, or a salt thereof; more preferably Semaglutide or a salt thereof; and most preferably Semaglutide.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Mechanical Engineering (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Zoology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Toxicology (AREA)
  • Immunology (AREA)
  • Analytical Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente divulgation concerne des processus de préparation d'une poudre peptidique, et la préparation de particules peptidiques, par exemple un peptide GLP-1 tel que le Liraglutide, le Dulaglutide, l'Exanetide, le Lixisenatide et/ou le Sémaglutide, et/ou leurs sels ; en particulier le Liraglutide et le Sémaglutide et leurs sels ; de préférence le Sémaglutide et ses sels, et de manière davantage préférée le Sémaglutide. Plus spécifiquement, la divulgation concerne un processus comprenant la lyophilisation d'une solution comprenant le peptide ; et la réduction de la taille des particules du lyophilisat obtenu. La divulgation concerne en outre des peptides GLP-1, le peptide GLP-1 étant en particulier choisi parmi le Liraglutide, le Dulaglutide, l'Exanetide, le Lixisenatide et/ou le Sémaglutide, et/ou leurs sels ; de préférence choisi parmi le Liraglutide et le Sémaglutide, et leurs sels ; et de manière davantage préférée le Sémaglutide et un sel de celui-ci, et de manière préférée entre toutes le Sémaglutide, pouvant être obtenu par ledit processus et son utilisation en médecine et dans un traitement cosmétique.
PCT/IB2024/051965 2023-03-02 2024-02-29 Processus de préparation de peptides glp-1 ayant une taille de particule contrôlée WO2024180511A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363449375P 2023-03-02 2023-03-02
US63/449,375 2023-03-02

Publications (1)

Publication Number Publication Date
WO2024180511A1 true WO2024180511A1 (fr) 2024-09-06

Family

ID=90362037

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2024/051965 WO2024180511A1 (fr) 2023-03-02 2024-02-29 Processus de préparation de peptides glp-1 ayant une taille de particule contrôlée

Country Status (1)

Country Link
WO (1) WO2024180511A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060029599A1 (en) * 2001-07-25 2006-02-09 Kaisheva Elizabet A Stable lyophilized pharmaceutical formulation of IgG antibodies
US20100137213A1 (en) * 2008-10-29 2010-06-03 Wyeth Formulations of single domain antigen binding molecules
US20120114646A1 (en) * 2009-06-18 2012-05-10 Wyeth Llc Lyophilized formulations for small modular immunopharmaceuticals
US20190105268A1 (en) * 2016-03-31 2019-04-11 Sun Pharma Advanced Research Company Limited Viscoelastic Gel of Liraglutide Adapted for Once-Weekly or Once Bi-Weekly Administration
US20190322742A1 (en) * 2016-06-27 2019-10-24 Morphosys Ag Anti-cd19 antibody formulations
US20220133633A1 (en) * 2019-12-10 2022-05-05 Remegen Co., Ltd. Pharmaceutical taci-fc fusion protein formulation
CN114507703A (zh) * 2022-03-10 2022-05-17 青岛浩然海洋科技有限公司 一种海参肽的制作工艺

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060029599A1 (en) * 2001-07-25 2006-02-09 Kaisheva Elizabet A Stable lyophilized pharmaceutical formulation of IgG antibodies
US20100137213A1 (en) * 2008-10-29 2010-06-03 Wyeth Formulations of single domain antigen binding molecules
US20120114646A1 (en) * 2009-06-18 2012-05-10 Wyeth Llc Lyophilized formulations for small modular immunopharmaceuticals
US20190105268A1 (en) * 2016-03-31 2019-04-11 Sun Pharma Advanced Research Company Limited Viscoelastic Gel of Liraglutide Adapted for Once-Weekly or Once Bi-Weekly Administration
US20190322742A1 (en) * 2016-06-27 2019-10-24 Morphosys Ag Anti-cd19 antibody formulations
US20220133633A1 (en) * 2019-12-10 2022-05-05 Remegen Co., Ltd. Pharmaceutical taci-fc fusion protein formulation
CN114507703A (zh) * 2022-03-10 2022-05-17 青岛浩然海洋科技有限公司 一种海参肽的制作工艺

Similar Documents

Publication Publication Date Title
DE69631881T2 (de) Pulmonale verabreichung von medikamenten in aerosolform
JP5317960B2 (ja) 微粉砕化有機化合物粒子の製造方法
JP3874789B2 (ja) 吸入用治療製剤
EP2314298B1 (fr) Microparticules comprenant des sels de diketopiperazine permettant l'administration de médicaments
JPH09500621A (ja) 吸入用組成物
Klingler et al. Insulin-micro-and nanoparticles for pulmonary delivery
HU217975B (hu) Polipeptidet higítóként melezitózt tartalmazó inhalációs porkészítmények és eljárás előállításukra
US20100092453A1 (en) Method of producing porous microparticles
CA2430318C (fr) Formulation pulverulente et son procede de production
US20050139144A1 (en) Method for the production and the use of microparticles and nanoparticles by constructive micronisation
SK279576B6 (sk) Ciclosporinu
MX2008012794A (es) Microparticulas de farmacos.
JPH07503154A (ja) 微細化ポリペプチド薬剤の改良調製方法
DK153920B (da) Toert, pulverformigt allergenmateriale og fremgangsmaade til fremstilling deraf
JPH10511090A (ja) 副甲状腺ホルモン，ｐｔｈ含有吸入用治療製剤
AU1054399A (en) Soft-pellet drug and process for the preparation thereof
WO2010011813A1 (fr) Complexe de trospium et ses compostions pharmaceutiques
CZ255599A3 (cs) Inhalační prostředek, způsob jeho přípravy a jeho použití pro přípravu léčiva
TW581681B (en) Liquid crystal forms of cyclosporin
Kadota et al. An effective approach to modify the inhalable betamethasone powders based on morphology and surface control using a biosurfactant
Miyazaki et al. Improved respirable fraction of budesonide powder for dry powder inhaler formulations produced by advanced supercritical CO2 processing and use of a novel additive
WO2024180511A1 (fr) Processus de préparation de peptides glp-1 ayant une taille de particule contrôlée
WO2024180512A1 (fr) Processus de préparation de peptides doubles gip/glp-1 ayant une taille de particule contrôlée
WO2022181750A1 (fr) Préparation inhalée et procédé de production d'une préparation inhalée
WO2024009079A1 (fr) Composition pharmaceutique pour inhalateur à poudre sèche de poudre sèche cristalline enrobée destinée a l'inhalation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24709859

Country of ref document: EP

Kind code of ref document: A1