WO2025237925A1

WO2025237925A1 - A dry powder composition comprising glp-1 antagonist

Info

Publication number: WO2025237925A1
Application number: PCT/EP2025/062942
Authority: WO
Inventors: Orest Lastow; Johan WÄBORG; Roger LASSING; Gary PITCAIRN
Original assignee: Iconovo AB
Current assignee: Iconovo AB
Priority date: 2024-05-15
Filing date: 2025-05-13
Publication date: 2025-11-20
Anticipated expiration: 2026-11-15

Abstract

The invention pertains to an inhalable dry powder formulation comprising a therapeutically effective amount of Glucagon-like peptide-1 (GLP-1) receptor agonist. Further, use of the inhalable dry powder formulation treatment of chronic weight management for people who are overweight or obese, with or without a weight-related comorbid condition. Further, a process for forming particles comprising a Glucagon- like peptide-1 (GLP-1) receptor agonist suitable for airborne inhalation.

Description

A DRY POWDER COMPOSITION COMPRISING GLP-1 ANTAGONIST

Field of the Invention

This invention pertains in general to the field of a method for managing the weight of people with overweight or obesity with/without diabetes and hyperglycemia with an inhaled glucagon-like peptide 1 (GLP-1) molecule therapy. In particular, the method comprises the administration of a GLP-1 molecule into the systemic circulation by inhalation using a dry powder drug delivery system. Further, the invention pertains to a process for forming particles comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist suitable for delivery to the respiratory tract.

Background of the Invention

Semaglutide, tirzepatide, and liraglutide are glucagon-like peptide-1 (GLP-1) receptor agonists used in the treatment of obesity and type 2 diabetes. They belong to the same class of medications and share similar mechanisms of action. Some other GLP-1 receptor agonists that are similar to semaglutide, tirzepatide, and liraglutide include exenatide, dulaglutide, albiglutide and/or lixisenatide.

These medications work by mimicking the action of the natural hormone GLP- 1, which helps to lower blood sugar levels by stimulating insulin secretion, reducing glucagon secretion, slowing gastric emptying and suppress appetite. GLP-1 also have favorable effects on the cardiovascular system. They are often prescribed as adjunct therapy to improve glycemic control in patients with type 2 diabetes or as an adjunct therapy to exercise and dietary counselling for weight loss.

Current technology includes sub-cutaneous injection of aqueous solution using an injection pen and disposable single-use needles. These techniques have several limitations, including a requirement to be stored at 2-8°C and when in use, kept below 30°C and used within 6 weeks. There is also a risk of infection at the injection site along with risk of clogging of needles, leakage of drug solution and contamination of drug solution. The ‘used’ injection equipment also results in hazardous waste with requirement for safe management and disposal of used and contaminated needles. The most common side effects of semaglutide are related to the gastrointestinal system. These can include nausea, vomiting, diarrhea, constipation, abdominal pain, and indigestion.

An oral dosage form is available (REF) to address some of these shortcomings, but the oral route of administration results in very poor bioavailability (approxinately 1%). Thus, while administration of GLP-1 via injection or a tablet is clinically viable and may deliver sufficient medication for the treatment, there are numerous challenges associated with these drug delivery approaches.

Thus, there is a need for alternative technologies for treatment using glucagon- like peptide- 1 (GLP-1) receptor agonists. However, there are several challenges when changing drug delivery system, such as making a robust delivery formulation that is stable under ambient conditions while ensuring that the correct amount of active agent in the correct form can reach the target site in the respiratory tract following inhalation.

Summary of the Invention

Accordingly, the present invention preferably seeks to mitigate, alleviate or eliminate one or more of the above-identified deficiencies in the art and disadvantages singly or in any combination and solves at least the above mentioned problems by providing an inhalable dry powder formulation comprising a therapeutically effective amount of Glucagon-like peptide-1 (GLP-1) receptor agonist.

In one variant, the Glucagon-like peptide-1 (GLP-1) receptor agonist is one or several selected from the list containing semaglutide, tirzepatide, liraglutide, exenatide, dulaglutide, albiglutide and/or lixisenatide, or pharmaceutically acceptable salts thereof.

In one variant, the Glucagon-like peptide-1 (GLP-1) receptor agonist is semaglutide, tirzepatide, and/or liraglutide.

In one variant, the inhalable dry powder formulation is a carrier-based formulation, a spray dried formulation, a lyophilised formulation, and/or a coprecipitated formulation.

In one variant, the inhalable dry powder formulation further comprises a carrier material and the Glucagon-like peptide-1 (GLP-1) receptor agonist is dispersed within the carrier to form an ordered mixture

In one variant, the formulation further comprises excipients suitable for inhalation, selected from the group consisting of lactose, mannitol, L-leucine, trileucine, trehalose, cyclodextrin, microcrystalline cellulose, synthetic and semisynthetic polymers, lipids, surfactants, amino acids, ammonium salts and chlorides of calcium and sodium and/or combinations thereof.

In one variant, the formulation further comprises excipients such as a contact force reducing agent like magnesium stearate. In one variant, the formulation further comprises a clinically enhancing excipient, like an adjuvant, a peptide stabilizing agent, a penetration enhancer or a immunogenicity reduction agent.

In one variant, the inhalable dry powder formulation is for either nasal or pulmonary administration, or a combination of nasal and pulmonary adminstration.

In one variant, the inhalable dry powder formulation has a particle size of active pharmaceutical ingredient in the range of 0.1 pm to 50 pm.

In one variant, the inhalable dry powder formulation is suitable for nasal delivery and has a particle size of active pharmaceutical ingredient in the range of 10 pm to 50 pm.

In one variant, the inhalable dry powder formulation is for pulmonary delivery and has a particle size of active pharmaceutical ingredient in the range of 0.1 pm to 5 pm.

According to one aspect, the formulation is for use in the treatment of chronic weight management for people who are overweight or obese, with or without a weight- related comorbid condition, such as high blood pressure, type 2 diabetes, dyslipidemia and hypothalamic injury induced obesity.

According to one aspect, the formulation is for use in the treatment of obesitas or type 2 diabetes mellitus in a patient.

In one variant, the patient is a mammal suffering with Type 2 diabetes mellitus.

In one variant, the inhalable dry powder formulation is for prandial use.

In one variant, the inhalable dry powder formulation is for use in combination with administration of insulin.

In one variant, the inhalable dry powder formulation comprising the GLP-1 further comprises a therapeutically effective amount of insulin.

Also provided is a process for forming particles comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist and a pharmaceutically acceptable excipient, comprising the steps of: providing the Glucagon-like peptide-1 (GLP-1) receptor agonist and a carrier material, reducing the particle size of the components to a suitable size, sizing of particles comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist suitable for airborne inhalation, blending of the components to mix the GLP-1 and carrier material uniformly,

According to another aspect, the components are dry powder components which are blended using tumbling blenders, fluidized bed blenders and high shear blenders, or other mechanical mixing to achieve uniform mixing of powders to create a homogenous formulation.

In one variant, the components are blended in a homogeneous solution or suspension comprising the of the components and particle comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist is formed by removing said solvent.

In one variant, the solvent is removed using using Spray drying.

In one variant, the particle further comprises an excipient, or excipients, selected from a group of excipients suitable for inhalation consisting of sugars, synthetic polymers, lipids, surfactants, amino acids, ammonium salts and chlorides of calcium and sodium.

In one variant, the sizing of the particles uses cascade impactors, optical methods, electrical zone sensing (using the Coulter principle) or Scanning Electron Microscopy (SEM).

In one variant, the particle further comprises a carrier material selected from a group of excipients suitable for inhalation consisting of lactose, mannitol, microcrystalline cellulose, and/or combinations thereof, and/or excipients suitable for spray drying, consisting of L-leucine, trileucine, trehalose, cyclodextrin.

In one variant, the particle further comprises an excipient, such as a contact force reducing agent, such as MgSt.

In one variant, the particle further comprises a clinically enhancing excipients, like an adjuvant.

In one variant, the particles comprises a Glucagon-like peptide-1 (GLP-1) receptor agonist is for nasal and pulmonary adminstration.

Description of embodiments

The present invention relates to a dry powder Glucagon-like peptide-1 (GLP-1) receptor agonist formulation for inhalation comprising GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof. The GLP-1 receptor agonist may be comprised in, or in the form of, nano- and/or micron sized particles. The GLP-1 receptor agonist may be present in the formulation in a therapeutically effective amount.

The Glucagon-like peptide-1 (GLP-1) receptor agonist is semaglutide, tirzepatide, and/or liraglutide, but may also be exenatide, dulaglutide, albiglutide and/or lixisenatide, or pharmaceutically acceptable salts thereof. The primary indication for the inhaled dry powder formulation is Chronic weight management for people who are overweight or obese with or without a weight- related comorbid condition, such as high blood pressure, type 2 diabetes and dyslipidemia, and hypothalamic injury induced obesity).

Secondary indications include Prevention of CV events in obesity and diabetes, MASH (Metabolically associated steatohepatitis), Parkinson’s Disease, Alzheimer’s Disease and Sleep apnea.

Using an inhaled dry powder solves several problems in the art, since it requires no cold storage and is stable at room temperature. Also, there is no hazardous waste, nor risk of infections or of contamination.

Types of suitable dry powder formulations for inhalation include, but are not limited to, carrier-based formulations, spray dried formulations, lyophilised formulations and/or co-precipitated formulations.

A carrier-based formulation for inhalation comprises a carrier material and one or more active pharmaceutical ingredients (APIs) dispersed across the the carrier particles. It can also comprise other excipients like a contact force reducing agent like magnesium stearate or clinically enhancing excipients like an adjuvant.

The carrier material facilitates the delivery of APIs to the respiratory system upon inhalation as the ordered mixture formed by combining drug particles and carrier particles can be accurately metered into individual doses. The carrier serves as a vehicle for the dispersion or dissolution of APIs, facilitating their delivery to the respiratory system upon inhalation. The formulation can be tailored to accommodate various APIs and optimize their therapeutic effects. The carrier-based formulation can also enhance the stability of APIs, reducing degradation and extending shelf life.

The formulation may comprises excipients suitable for inhalation selected from the group consisting of hydroxyproyl methylcellulose (HPMC), lactose, mannitol, L- leucine, trileucine, trehalose, cyclodextrin, microcrystalline cellulose, synthetic and semisynthetic polymers, lipids, surfactants, amino acids, ammonium salts and chlorides of calcium and sodium and/or combinations thereof.

The carrier material may be in the form of particles, powders, or granules, with particle sizes ranging from nanometers to hundreds of micrometers. The API particles are uniformly distributed within the carrier matrix to ensure consistent dosing and efficacy. The carrier-based formulation demonstrates improved stability compared to existing liquid formulations which results in a shelf life of 2 years when the DPI product is stored under ambient conditions. The combination of excipients such as lactose, cyclodextrin, trehalose, leucine, trileucine, microcrystalline cellulose, ammonium salts, and chlorides of calcium and sodium with GLP-1 receptor agonists like semaglutide, tirzepatide, liraglutide, exenatide, dulaglutide, albiglutide, and lixisenatide brings about synergistic effects. These formulations leverages the unique properties of these excipients to enhance the stability, bioavailability, and therapeutic efficacy of the APIs in inhalable formats.

One of the key aspects of this inventive combination is the stabilization effect these excipients have on peptide-based drugs. Cyclodextrins, for instance, can form inclusion complexes with the APIs, effectively shielding them from degradation and preserving their bioactivity. This stabilization is important for maintaining the efficacy of GLP-1 receptor agonists, which are inherently sensitive to enzymatic degradation. Furthermore, the combination of these excipients can significantly improve the bioavailability of the APIs. Cyclodextrins, known for enhancing the solubility of poorly soluble compounds, contribute to better absorption and increased bioavailability when these drugs are delivered via inhalation. Trehalose is another excipient used for stabilization of biomolecules. It is a matrix former that protects the biomolecule from denaturation, i.e. loss of bioactivity, when being exposed to heat during the spray drying process. Compared to other sugars, it absorbs less moisture, which helps in maintaining powder stability and shelf life. Its compatibility with other excipients is also an advantage. Leucine and/or trileucine amino acids are used for improved aerosolization. During spray drying they migrate to the surface of drying droplets, being shell formers, forming a hydrophobic outer shell that protect the GLP-1 receptor agonist. This results in reduced cohesive forces between particles and thereby improved deaggregation. ater- permeable shell results in as reduced hygroscopicity. Hydroxyproyl methylcellulose (HPMC) is another excipient that is specifically suitable when administering GLP-1 receptor agonists. HPMC is a versatile excipient used in pharmaceutical formulations. A key technical effect of using HPMC in formulations with GLP-1 receptor agonsits is its ability to act as a film-forming agent and stabilizer. HPMC can enhance the stability of GLP-1 receptor agonists by forming a protective matrix around the active ingredient, thus shielding it from environmental factors such as moisture and temperature that could lead to degradation. Additionally, HPMC can improve the controlled release properties of the formulation, allowing for a more sustained and consistent delivery of the active ingredient, which is particularly beneficial for maintaining therapeutic levels of GLP-1 receptor agonists over time. Inhalable formulations of GLP-1 receptor agonists face specific challenges due to the nature of the peptides and the delivery route. The use of HPMC as an excipient is particularly important for these formulations for several reasons. Inhaled therapies benefit from controlled release mechanisms to maintain therapeutic drug levels within the respiratory tract and potentially in systemic circulation. HPMC can help modulate the release profile of the GLP-1 receptor agonist, ensuring that the drug is delivered at a consistent rate, which is important for maintaining efficacy and reducing dosing frequency. Moreover, the physical properties of HPMC can enhance the dispersibility and flow characteristics of the dry powder. This is critical for inhalable formulations, as it ensures that the powder forms an aerosol with particles of the appropriate size to reach the lower respiratory tract, specifically the alveoli, where systemic absorption can occur. Still further, the film-forming properties of HPMC can contribute to a smoother deposition of the formulation on the respiratory epithelium, minimizing irritation that can be caused by coarser particles or less stable formulations. This is particularly important for enhancing patient compliance and comfort with inhaled therapies. Overall, the inclusion of HPMC in inhalable GLP-1 receptor agonist formulations addresses key challenges related to stability, release kinetics, and aerosol performance, which are critical for the efficacy and safety of peptide-based inhalation therapies. For these reasons, in one embodiment the content interval for HPMC is from 1% to 20% by weight of the total composition, such as from 5% to 15% by weight of the total composition. This concentration ensures adequate film-forming and stabilizing effects while maintaining the overall efficacy and performance of the inhalable dry powder formulation.

In one embodiment the formulation comprises trehalose in an amount ranging from 20% to 90% by weight of the total composition, such as from 30% to 70% by weight of the total composition, wherein trehalose functions as a stabilizing agent to enhance the stability and shelf-life of the GLP-1 receptor agonist. In one embodiment the formulation comprises trileucine in an amount ranging from 0.1% to 2% by weight of the total composition, wherein trileucine acts as a dispersibility enhancer, improving the aerosolization efficiency and delivery of the GLP-1 receptor agonist to the respiratory tract. In one embodiment the trehalose of 20% to 90% by weight of the total composition is combined with trileucine in an amount ranging from 0.1% to 2% by weight of the total composition. In one embodiment the formulation comprises leucine in an amount ranging from 5% to 50% by weight of the total composition, such as from 10% to 30% by weight of the total composition, wherein leucine acts as a dispersibility enhancer, improving the aerosolization efficiency and delivery of the GLP-1 receptor agonist to the respiratory tract. The formulation properties are further optimized through the use of lactose and microcrystalline cellulose, which act as carriers in dry powder formulations. This ensures not only uniform distribution of the API but also consistent dosing with each administration. The flow properties and aerosolization performance are enhanced, leading to a more efficient and reliable delivery system, being of special relevance when the APIs are delivered via inhalation. Additionally, the inclusion of ammonium salts and calcium or sodium chlorides allows for modulation of the ionic strength and pH of the formulation. This can be tailored to enhance the stability of the peptide drugs, such as the APIs, and modify their release profiles, leading to controlled release, which is particularly beneficial for the management of chronic conditions like diabetes, and also obesity.

Moreover, the combination of these excipients allows for tailored particle engineering, providing precise control over particle size and morphology. This is crucial for targeting specific regions of the respiratory tract, such as the alveoli for systemic delivery, thereby ensuring a more targeted and efficient drug delivery system. The multifunctionality of these excipients plays a significant role as they can act simultaneously as stabilizers, carriers, and solubilizers. This leads to a more streamlined formulation process and potentially reduces the need for additional components, minimizing the overall excipient load, which is advantageous for inhalation therapies.

The combination addresses specific challenges associated with GLP-1 receptor agonists, such as their propensity for enzymatic degradation. The excipients create a protective microenvironment that limits exposure to degrading enzymes, significantly enhancing the stability and effectiveness of the formulation. In addition, this strategic combination provides a controlled release profile, which ensures sustained therapeutic levels of the API, thereby enhancing therapeutic outcomes and patient compliance.

The unique approach presented herein offers enhanced therapeutic profiles compared to existing formulations. This includes improved patient compliance due to reduced dosing frequency and minimized side effects due to better targeting and release profiles.

In conclusion, the combination of these excipients with GLP-1 receptor agonists represents a strategic and synergistic formulation approach that addresses the inherent challenges of inhalable peptide-based therapies. It offers significant advantages in terms of stability, bioavailability, and therapeutic efficacy, making it a compelling advancement over existing solutions. The formulation of the invention can make use of a unit dose disposable passive inhalation devices, such as ICOone version developed for nasal and pulmonary administration, both delivered by Iconovo AB.

The dry powder may be a carrier based formulation formed by mixing particle size controlled active pharmaceutical ingredient with the carrier particles.

The formulations according to the present invention are adapted for both nasal, and pulmonary delivery. The adaptation of the formulations according to the present invention comprises optimization of particle sizes, to ensure that the drug is deposited where it can be rapidly absorbed into the bloodstream. This optimization comprises particle size of active pharmaceutical ingredient in the range of 0.1 pm to 50 pm. In this range of particle sizes, delivery of the APIs to the pulmonary region is maximised. For nasal delivery, the optimal particle size for the formulations according to the present invention is in the range of 10 pm to 50 pm, such as 15 pm to 35 pm. For pulmonary delivery the optimal particle size for the formulations according to the present invention is in the range of 0.1 pm to 5 pm.

The preparation of a carrier-based formulation includes dry blending of the dry powder components. Various blending techniques can be used to mix the APIs and carrier material uniformly. The blending techniques may include tumbling blenders, fluidized bed blenders and high shear blenders, or other mechanical mixing to achieve uniform mixing of API and carrier/excipient particles to create homogenous powder formulations. The choice of blending method depends on factors such as the physicochemical properties of the APIs and carrier material, desired particle size distribution, and stability requirements. Optimization of the formulation process is crucial to ensure consistent product quality, efficacy, and safety for inhalation therapy.

Tumbling blenders, such as V-blenders and double cone blenders, operate by rotating a container that contains the powder ingredients. The rotation causes the powders to tumble and mix thoroughly. These blenders are suitable for blending powders with similar particle sizes and densities and are often used for small to medium-scale blending operations. These blenders can often be referred to as low-shear blenders.

Fluidized bed mixers utilize air or gas to fluidize and suspend powder particles within a chamber. As the particles become airborne, they collide and mix, resulting in rapid and efficient blending. Fluidized bed mixers are suitable for blending cohesive powders and for applications requiring gentle mixing to prevent powder degradation. High shear mixers, such as planetary mixers and high-speed mixers, employ intense mechanical forces to disperse and blend powder ingredients. These mixers are particularly effective for blending powders with disparate particle sizes or densities and for achieving fine particle dispersion. High shear mixers are commonly used in pharmaceutical manufacturing for blending processes.

Paddle mixers feature a rotating shaft with paddles that move the powder ingredients in a radial and axial direction within a mixing vessel. Paddle mixers are suitable for blending cohesive powders and for applications requiring gentle mixing to avoid powder degradation. They are commonly used in pharmaceutical manufacturing for blending cohesive powders.

When mixing dry powders, a number of process parameters should be monitored, controlled and optimized. The relevant parameters include, but are not limited by, mixing time, mixing speed, temperature in mixing vessel, ambient temperature, ambient relative humidity, water content in powder, charging order, intermediate sieving etc.

Spray drying is a method that involves atomizing a solution or suspension of the APIs and various excipients into fine droplets, which are then dried to form powder particles. The droplets are typically dried using hot air or inert gases, resulting in the formation of dry powder particles containing the APIs uniformly dispersed within the particle. Spray drying is suitable for API like proteins, peptides and other types of biomolecules. A number of different excipients have been used to form spray dried particles containing API. Examples include, but are not limited, to sugars, synthetic polymers, lipids, surfactants, amino acids, ammonium salts and chlorides of calcium and sodium (Alhajj et al, 2021). Spray drying is preferred since the relevant APIs are shorter peptides, whereby more complex drying methods not are necessary.

Lyophilization is a method where a solution or suspension of APIs and excipients is frozen and then subjected to sublimation under vacuum conditions to remove the frozen solvent. This process results in the formation of dry powder particles with a porous structure with a very low density. Lyophilization is suitable for API like proteins, peptides and other types of biomolecules.

Co-precipitation involves precipitating the APIs and possibly an excipient from a solution or suspension by adding a precipitating agent. This method allows for the simultaneous formation of particles containing both the APIs and possibly an excipient, ensuring uniform distribution and intimate mixing. Co-precipitation can be performed under controlled conditions to optimize particle size and morphology.

Sizing of airborne inhalable solid particles is crucial for assessing their pharmaceutical and clinical properties and effects. Several methods are employed for particle sizing, each with its advantages and limitations. Two referred sizing methods are cascade impactors and optical methods.

Cascade impactors operate on the principle of inertial impaction, where particles of different sizes are separated based on their aerodynamic diameters. A cascade impactor consists of multiple stages, each with a successively smaller cut-off diameter. As air containing particles passes through the impactor, particles impact onto collection surfaces at different stages based on their aerodynamic sizes. The collected particles are then analyzed gravimetrically, chemically or using other analytical techniques such as microscopy or spectroscopy to determine their size distribution.

The Next Generation Impactor (NGI) is a widely used type of cascade impactor instrument for determining the aerodynamic particle size distribution of inhalable pharmaceutical aerosols used in metered dose inhalers (MDIs) and dry powder inhalers (DPIs). The NGI offers several advantages for aerosol characterization, including high precision, reproducibility, and sensitivity to a wide range of particle sizes relevant to inhalation therapy. It is commonly used in pharmaceutical development and quality control to determine the fine particle fraction (FPF), emitted dose (ED), and aerodynamic particle size distribution (APSD) of aerosol formulations. The NGI is a tool for optimizing inhalation drug delivery systems and ensuring their efficacy and safety.

Optical methods utilize light scattering, light diffraction or light-blocking techniques to measure the number concentration and size distribution of airborne particles in real-time. These instruments typically employ laser-based or LED-based light sources to illuminate particles passing through a measurement zone. The scattered, diffracted or blocked light is then detected by photodetectors, and the signal is analyzed to determine the particle size distribution. Examples of suitable light scattering instruments is the Malvern Panalytical Mastersizer series including a range of instruments based on laser diffraction technology. These instruments utilize a laser beam to illuminate particles in a dispersion, and the scattered light is measured at different angles to determine the particle size distribution. The Mastersizer series offers high-resolution particle sizing from nanometers to millimeters and is widely used in pharmaceutical formulation, powder characterization, and quality control. Another well used particle sizing method is the Coulter principle that detects particles via electrical zone sensing. This is regardless of the particle’s shape or optical properties.

Scanning Electron Microscopy (SEM) is a microscopy technique that provides high-resolution imaging of particles on a micron to nanometer scale. SEM is commonly used for characterizing the morphology and size of airborne particles collected on filters or impactor substrates. Samples are prepared by mounting collected particles onto a substrate and coating them with a conductive material to enhance imaging quality. SEM images can provide valuable information about particle shape, size, and surface features, complementing other particle sizing techniques. Image analysis techniques can be used for high analysis through-put.

Although the present invention has been described above with reference to specific embodiments, it is not intended to be limited to the specific form set forth herein. Rather, the invention is limited only by the accompanying claims and, other embodiments than the specific above are equally possible within the scope of these appended claims, e.g. different than those described above.

In the claims, the term “comprises/comprising” does not exclude the presence of other elements or steps. Furthermore, although individually listed, a plurality of means, elements or method steps may be implemented by e.g. a single unit or processor. Additionally, although individual features may be included in different claims, these may possibly advantageously be combined, and the inclusion in different claims does not imply that a combination of features is not feasible and/or advantageous. In addition, singular references do not exclude a plurality. The terms “a”, “an”, “first”, “second” etc. do not preclude a plurality. Reference signs in the claims are provided merely as a clarifying example and shall not be construed as limiting the scope of the claims in any way.

Claims

1. An inhalable dry powder formulation comprising a therapeutically effective amount of Glucagon-like peptide-1 (GLP-1) receptor agonist.

2. The formulation of claim 1, wherein the Glucagon-like peptide-1 (GLP-1) receptor agonist is one or several selected from the list containing semaglutide, tirzepatide, liraglutide, exenatide, dulaglutide, albiglutide and/or lixisenatide, or pharmaceutically acceptable salts thereof.

3. The formulation according to any one of claims 1 to 2, wherein the Glucagon-like peptide-1 (GLP-1) receptor agonist is semaglutide, tirzepatide, and/or liraglutide.

4. The formulation according to any one of claims 1 to 3, wherein the inhalable dry powder formulation is a carrier-based formulation, a spray dried formulation and/or a co-precipitated formulation.

5. The formulation according to any one of claims 1 to 4, wherein the inhalable dry powder formulation further comprises a carrier material and the Glucagon-like peptide-1 (GLP-1) receptor agonist is dispersed within the carrier to form an ordered mixture

6. The formulation according to any one of claims 1 to 5, further comprising excipients suitable for inhalation, selected from the group consisting of hydroxyproyl methylcellulose (HPMC), lactose, mannitol, L-leucine, trileucine, trehalose, cyclodextrin, microcrystalline cellulose, synthetic and semisynthetic polymers, lipids, surfactants, amino acids, ammonium salts and chlorides of calcium and sodium and/or combinations thereof.

7. The formulation according to claim 6, comprising HPMC with a content from 1% to 20% by weight of the total composition.

8. The formulation according to claim 6 or 7, wherein the formulation comprises trehalose in an amount ranging from 20% to 90% by weight of the total composition, wherein trehalose functions as a stabilizing agent to enhance the stability and shelf-life of the GLP-1 receptor agonist.

9. The formulation according to any one of claims 6 to 8, wherein the formulation comprises trileucine in an amount ranging from 0.1% to 2% by weight of the total composition, wherein trileucine acts as a dispersibility enhancer, improving the aerosolization efficiency and delivery of the GLP-1 receptor agonist to the respiratory tract.

10. The formulation according to any one of claims 6 to 9, wherein the formulation comprises leucine in an amount ranging from 5% to 50% by weight of the total composition, wherein trileucine acts as a dispersibility enhancer, improving the aerosolization efficiency and delivery of the GLP-1 receptor agonist to the respiratory tract.

11. The formulation according to any one of claims 1 to 10, further comprising excipients such as a contact force reducing agent like magnesium stearate.

12. The formulation according to any one of claims 1 to 11, further comprising a clinically enhancing excipient, like an adjuvant, a peptide stabilizing agent, a penetration enhancer or a immunogenicity reduction agent.

13. The formulation according to any one of claims 1 to 12, wherein the inhalable dry powder formulation is for nasal and/or pulmonary adminstration.

14. The formulation according to any one of claims 1 to 13, wherein the inhalable dry powder formulation has a particle size of active pharmaceutical ingredient in the range of 0.1 pm to 50 pm.

15. The formulation according to any one of claims 1 to 14, wherein the inhalable dry powder formulation is suitable for nasal delivery and has a particle size of active pharmaceutical ingredient in the range of 10 pm to 50 pm.

16. The formulation according to claim 15, wherein the inhalable dry powder formulation is suitable for nasal delivery and has a particle size of active pharmaceutical ingredient in the range of 15 pm to 35 pm.

17. The formulation according to any one of claims 1 to 16, wherein the inhalable dry powder formulation is for pulmonary delivery and has a particle size of active pharmaceutical ingredient in the range of 0.1 pm to 5 pm.

18. The formulation according to claim 17, wherein the inhalable dry powder formulation is for pulmonary delivery and has a particle size of active pharmaceutical ingredient in the range of 0.5 pm to 3 pm.

19. The formulation according to any one of claims 1 to 18, for use in the treatment of chronic weight management for people who are overweight or obese, with or without a weight-related comorbid condition, such as high blood pressure, type 2 diabetes, dyslipidemia and hypothalamic injury induced obesity.

20. The formulation according to any one of claims 1 to 19, for use in the treatment of obesitas or type 2 diabetes mellitus in a patient.

21. The formulation for use according to claims 19 or 20, wherein the patient is a mammal suffering with Type 2 diabetes mellitus.

22. The formulation for use according to any one of claims claim 19 to 21, wherein the inhalable dry powder formulation is for prandial use.

23. The formulation for use according to any one of claims claim 19 to 22, wherein the inhalable dry powder formulation is for use in combination with administration of insulin.

24. The formulation for use according to any one of claims claim 21 to 23, wherein the inhalable dry powder formulation comprising the GLP-1 further comprises a therapeutically effective amount of insulin.

25. A process for forming particles comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist and a pharmaceutically acceptable excipient, comprising the steps of: providing the Glucagon-like peptide-1 (GLP-1) receptor agonist and a carrier material, reducing the particle size of the components to a suitable size, sizing of particles comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist suitable for airborne inhalation, blending of the components to mix the GLP-1 and carrier material uniformly,

26. The process according to claim 25, wherein the components are dry powder components which are blended using tumbling blenders, fluidized bed blenders and high shear blenders, or other mechanical mixing to achieve uniform mixing of powders to create a homogenous formulation.

27. The process according to claim 25, wherein the components are blended in a homogeneous solution or suspension comprising the of the components and particle comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist is formed by removing said solvent.

28. The process according to claim 27, wherein the solvent is removed using using Spray drying.

29. The process according to any one of claims 25 to 28, wherein the particle further comprises an excipient, or excipients, selected from a group of excipients suitable for inhalation consisting of sugars, synthetic polymers, lipids, surfactants, amino acids, ammonium salts and chlorides of calcium and sodium.

30. The process according to any one of claims 25 to 29, wherein the sizing of the particles uses cascade impactors, optical methods, electrical zone sensing (using the Coulter principle) or Scanning Electron Microscopy (SEM).

31. The process according to any one of claims 24 to 30, wherein the particle further comprises a carrier material selected from a group of excipients suitable for inhalation consisting of HPMC, lactose, mannitol, microcrystalline cellulose, and/or combinations thereof, and/or excipients suitable for spray drying, consisting of L- leucine, trileucine, trehalose, cyclodextrin.

32. The process according to any one of claims 25 to 31, wherein the particle further comprises an excipient, such as a contact force reducing agent, such as MgSt.

33. The process according to any one of claims 25 to 32, wherein the particle further comprises a clinically enhancing excipients, like an adjuvant.

34. The process according to any one of claims 25 to 33, wherein the particles comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist is for nasal and pulmonary adminstration.