Dry powder inhaler of GLP-1 receptor agonist as well as preparation method and application of dry powder inhaler

Abstract

The invention discloses a dry powder inhaler of a GLP-1 receptor stimulant and a preparation method and application of the dry powder inhaler, and belongs to the technical field of biological medicine, the dry powder inhaler comprises the following raw materials in percentage by mass: 0.01%-10% of GLP-1 drugs, 10%-99% of carriers and 0-80% of auxiliary materials, the carrier is at least two of first lactose, second lactose, mannitol, xylitol, cyclodextrin, a cyclodextrin derivative, trehalose, trehalose hydrate, dipalmitoyl lecithin, distearoyl phosphatidylcholine, glucose, amino acid and an amino acid derivative, and the prepared dry powder inhalant of the GLP-1 receptor agonist is used for pulmonary administration, has the advantages of high bioavailability and high bioavailability, and can be used for preparing the dry powder inhalant of the GLP-1 receptor agonist. The medicine can be directly inhaled into the end bronchus or alveolus of the respiratory tract in the form of particles and absorbed by the lung, and the medicine can be rapidly absorbed into blood by utilizing the characteristics of short pulmonary circulation path, thin pulmonary artery wall, multiple pulmonary vessel branches and the like, so that the medicine takes effect more rapidly.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a dry powder inhaler of a GLP-1 receptor agonist, its preparation method, and its application. Background Technology

[0002] GLP-1 receptor agonists, also known as glucagon-like peptide-1 receptor agonists, are a new type of hypoglycemic drug that works by activating GLP-1 receptors to enhance insulin secretion in a glucose concentration-dependent manner, inhibit glucagon secretion, and delay gastric emptying. They reduce food intake through central appetite suppression, thereby lowering blood sugar and aiding in weight loss.

[0003] Exenatide was the first GLP-1 receptor agonist-based drug successfully developed for treatment, and it was launched in the United States in 2005. It requires twice-daily subcutaneous injections and is a short-acting formulation. Subsequently, intermediate-acting formulations such as liraglutide and lixisenatide, and long-acting formulations such as smegglutide, dulaglutide, and telpoxetine were launched.

[0004] Currently, most GLP-1 drugs, due to their protein-peptide nature, can only be administered via subcutaneous injection. This invasive method of administration not only causes pain and inconvenience for patients but also carries the risk of local infection, leading to psychological resistance and treatment inertia among many patients, especially those with chronic diseases requiring long-term treatment. Furthermore, the drugs need to enter the bloodstream through blood vessels in the subcutaneous tissue, which is predominantly composed of capillaries, resulting in a slow onset of action. In recent years, the successful launch of oral semaglutide has provided patients with a non-invasive option. However, oral medications require absorption, distribution, and conversion through the digestive system, necessitating not only larger doses but also longer times to reach peak blood concentration. Achieving effective blood concentrations requires the use of extremely high doses of the active pharmaceutical ingredient (API) supplemented with expensive absorption enhancers, significantly increasing production costs and potentially leading to additional gastrointestinal adverse reactions.

[0005] To overcome the drawbacks of injection and oral administration, pulmonary inhalation has been extensively studied as a potential non-invasive alternative to systemic drug delivery. The lungs possess a vast alveolar surface area, abundant capillaries, and an extremely thin gas exchange barrier, resulting in rapid drug absorption and avoiding the first-pass effect of the liver. Theoretically, this could achieve bioavailability comparable to injection, while offering a superior user experience. Therefore, providing dry powder inhalers of GLP-1 receptor agonists is a key technical challenge that needs to be addressed. Summary of the Invention

[0006] One of the objectives of this invention is to provide a dry powder inhaler of GLP-1 receptor agonists to fill the gap in the pulmonary inhalation administration of GLP-1 receptor agonists.

[0007] A second objective of this invention is to provide a method for preparing a dry powder inhaler of the aforementioned GLP-1 receptor agonist.

[0008] A third objective of this invention is to provide the application of the above-mentioned GLP-1 receptor agonist dry powder inhaler.

[0009] The objective of this invention can be achieved through the following technical solutions: In a first aspect, the present invention provides a dry powder inhaler of a GLP-1 receptor agonist, comprising the following raw materials in weight percentages: 0.01% to 10% of a GLP-1 drug, 10% to 99% of a carrier, and 0% to 80% of excipients.

[0010] Furthermore, the dry powder inhaler of the GLP-1 receptor agonist comprises the following raw materials in weight percentages: 0.05% to 10% GLP-1 drug, 10% to 99% carrier, and 0% to 80% excipients.

[0011] The GLP-1 class drugs are at least one of the following: GLP-1R single-target drugs, GLP-1R / GIPR dual-target drugs, and GLP-1R / GIPR / GCGR triple-target drugs.

[0012] Further, the GLP-1 class drug is at least one of semaglutide, liraglutide, oxaliplatin, telpoglycinide, texipatide, retaglutide, loxenatide, mastodextrin, abiglutide, sevidotide, loxenatide, esupagglutide α, glutazine monoclonal antibody, vepenaenatide, liximab, ibennatide, exenatide, and dulaglutide.

[0013] The carrier is at least two of the following: lactose, dactose, mannitol, xylitol, cyclodextrin, cyclodextrin derivatives, trehalose, trehalose hydrate, dipalmitoyl lecithin (DPPC), distearate phosphatidylcholine (DSPC), glucose, amino acids, and amino acid derivatives.

[0014] Furthermore, the carrier is composed of hydroxypropyl-β-cyclodextrin, trehalose, and distearate phosphatidylcholine.

[0015] Furthermore, the carrier is composed of a combination of first lactose and second lactose.

[0016] Furthermore, the D90 value of the first lactose is 65-250 μm.

[0017] Furthermore, the D90 value of the second lactose is less than 30 μm.

[0018] Furthermore, the amino acid is at least one selected from leucine, alanine, and glycine.

[0019] Further, the cyclodextrin derivative is at least one selected from hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, methyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, glucosyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and 2,6-dimethoxy-β-cyclodextrin.

[0020] Furthermore, the trehalose hydrate is a trehalose dihydrate.

[0021] Furthermore, the amino acid derivative is at least one selected from dileucine, trileucine, N-acetyl-L-leucine, alanine methyl ester, guanidinoacetic acid, and N-acetylglycine.

[0022] Furthermore, the excipient is at least one of a dispersant, a flavoring agent, and a flow aid.

[0023] Furthermore, the dispersant is at least one selected from lactose, poloxamer, polyethylene glycol, calcium chloride, and chitosan.

[0024] Furthermore, the third lactose is lactose that has passed through a 60-120 mesh sieve.

[0025] Furthermore, the molecular weight of the polyethylene glycol is between 1000 and 40000.

[0026] Furthermore, the flavoring agent is at least one of aspartame, sucrose, and peppermint extract.

[0027] Furthermore, the flow aid is at least one of magnesium stearate, micronized silica gel, and talc.

[0028] Secondly, the present invention provides a method for preparing a dry powder inhaler of a GLP-1 receptor agonist, including an air jet milling method and a spray drying method.

[0029] The preparation of a dry powder inhaler of a GLP-1 receptor agonist using an air jet milling method includes the following steps: The GLP-1 drug, after being pulverized by airflow, is first mixed with a carrier to obtain a mixture; the mixture is then second mixed with excipients to obtain a dry powder inhaler of the GLP-1 receptor agonist.

[0030] Furthermore, the inlet pressure for GLP-1 class drugs in air jet milling is 9.0-15.5 bar, the milling pressure is 8.5-15 bar, and the feed rate is 2-5 rpm.

[0031] Furthermore, the first mixing speed is 24 rpm, and the mixing time is 30-45 min.

[0032] Furthermore, the second mixing speed is 24 rpm, and the mixing time is 25-30 min.

[0033] The preparation of a dry powder inhaler of a GLP-1 receptor agonist using a spray drying method includes the following steps: GLP-1 drugs, carriers, and excipients are added to a solvent and stirred until homogeneous to prepare a stock solution with a solid content of 5% to 50%. The stock solution is then spray-dried to obtain a dry powder inhaler of GLP-1 receptor agonists.

[0034] Furthermore, the solvent is at least one selected from deionized water, anhydrous ethanol, dimethyl sulfoxide, and methanol.

[0035] Furthermore, the spray drying conditions are as follows: inlet air temperature 100℃~150℃, feed rate 4mL / min~7mL / min, outlet air temperature 40℃~70℃, and atomization pressure 1.20bar~1.70bar.

[0036] Thirdly, the present invention provides the application of a dry powder inhaler of a GLP-1 receptor agonist in lowering blood sugar, reducing weight, and comprehensive metabolic management.

[0037] The beneficial effects of this invention are: 1. The dry powder inhaler of GLP-1 receptor agonist prepared by this invention is used for pulmonary drug delivery. It delivers GLP-1 drugs in the form of powder inhaler, allowing the drug to be directly inhaled into the terminal bronchioles or alveoli of the respiratory tract in particulate form and absorbed by the lungs. Taking advantage of the short pulmonary circulation route, thin pulmonary artery walls, and numerous pulmonary vascular branches, the drug can be rapidly absorbed into the blood and has a faster onset of action.

[0038] 2. The GLP-1 class drug dry powder inhalation formulation prepared by this invention reduces the distribution of the drug in the systemic circulation because the drug enters the respiratory tract directly, requiring a relatively lower dose and thus resulting in fewer systemic adverse reactions. This local administration method reduces the toxic effects of the drug on the liver and other organs.

[0039] 3. The GLP-1 class drug dry powder inhalation formulation prepared by this invention belongs to inhalation therapy, a non-invasive treatment method that does not require swallowing or injection, reducing patient pain and discomfort. Inhalation therapy is simple to operate, and the inhalation device is compact, convenient, and portable, making it suitable for patients taking medication long-term.

[0040] 4. In preparing dry powder inhalers of GLP-1 receptor agonists, the present invention uses the combined application of two or more carriers, which is more conducive to increasing the performance of powder particles. When using air jet milling, it is necessary to control appropriate process parameters to obtain the desired particle size of active ingredients. Attached Figure Description

[0041] The invention will now be further described with reference to the accompanying drawings.

[0042] Figure 1 This is a graph showing the particle mass ratio of the dry powder inhalation formulations prepared in Examples 1, 2, 3, 11, and 12 of the present invention. Figure 2 The graph shows the particle mass ratio of the dry powder inhalation formulations prepared in Examples 4, 5, 6, 13, and 14 of this invention. Figure 3 The diagram shows the particle mass ratio of the dry powder inhalation formulations prepared in Examples 7, 8, 15, 16, and 17 of this invention. Figure 4 The graph shows the particle mass ratio of the dry powder inhalation formulations prepared in Examples 9, 10, 18, 19, and 20 of this invention. Figure 5 The results of the glucose tolerance test in the db / db mouse group prepared by the dry powder inhalation formulations in Examples 2, 7, 9, 14, 15, and 18 of this invention are as follows; Figure 6 The results of the glucose tolerance test in HFD mice prepared according to Examples 2, 7, 9, 14, 15, and 18 of this invention are as follows: Figure 7 The results of insulin sensitivity experiments in the db / db mouse group prepared in Examples 2, 7, 9, 14, 15, and 18 of this invention are as follows: Figure 8 The results of insulin sensitivity experiments in HFD mice prepared according to Examples 2, 7, 9, 14, 15, and 18 of this invention are as follows. Detailed Implementation

[0043] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0044] In view of the lack of GLP-1 receptor agonists in the pulmonary inhalation administration method in the prior art, the first aspect of the present invention provides a dry powder inhaler of GLP-1 receptor agonists, comprising the following raw materials in weight percentage: 0.01% to 10% GLP-1 drug, 10% to 99% carrier, and 0% to 80% excipients.

[0045] In some specific embodiments, the dry powder inhaler of the GLP-1 receptor agonist comprises the following raw materials by weight percentage: 0.05% to 10% GLP-1 drug, 10% to 99% carrier, and 0% to 80% excipients.

[0046] The GLP-1 class drugs are at least one of the following: GLP-1R single-target drugs, GLP-1R / GIPR dual-target drugs, and GLP-1R / GIPR / GCGR triple-target drugs.

[0047] In some specific embodiments, the GLP-1 class drug is at least one of semaglutide, liraglutide, oxaliplatin, telpoglycinide, texipatide, retaglutide, loxenatide, mastodextrin, abiglutide, sevitodextrin, loxenatide, esupragglutide α, glutastatin monoclonal antibody, vepenaenate, liximab, ibennatide, exenatide, and dulaglutide.

[0048] The carrier is at least two of the following: lactose, dactose, mannitol, xylitol, cyclodextrin, cyclodextrin derivatives, trehalose, trehalose hydrate, dipalmitoyl lecithin (DPPC), distearate phosphatidylcholine (DSPC), glucose, amino acids, and amino acid derivatives.

[0049] Furthermore, the carrier is composed of a combination of first lactose and second lactose.

[0050] In some specific embodiments, the D90 value of the first lactose is 65-250 μm.

[0051] In some specific embodiments, the D90 value of the second lactose is less than 30 μm.

[0052] In some specific embodiments, the amino acid is at least one selected from leucine, alanine, and glycine.

[0053] In some specific embodiments, the cyclodextrin derivative is at least one selected from hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, methyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, glucosyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and 2,6-dimethoxy-β-cyclodextrin.

[0054] In some specific embodiments, the trehalose hydrate is trehalose dihydrate.

[0055] In some specific embodiments, the amino acid derivative is at least one selected from dileucine, trileucine, N-acetyl-L-leucine, alanine methyl ester, guanidinoacetic acid, and N-acetylglycine.

[0056] The excipients are at least one of dispersants, flavoring agents, and gliding agents.

[0057] In some specific embodiments, the dispersant is at least one selected from lactose trisaccharide, poloxamer, polyethylene glycol, calcium chloride, and chitosan.

[0058] Furthermore, the third lactose is lactose that has passed through a 60-120 mesh sieve.

[0059] Furthermore, the molecular weight of the polyethylene glycol is between 1000 and 40000.

[0060] In some specific embodiments, the flavoring agent is at least one of aspartame, sucrose, and peppermint extract.

[0061] In some specific embodiments, the flow aid is at least one of magnesium stearate, micronized silica gel, and talc.

[0062] The second aspect of this invention provides a method for preparing a dry powder inhaler of a GLP-1 receptor agonist, including an air jet milling method and a spray drying method.

[0063] The preparation of a dry powder inhaler of a GLP-1 receptor agonist using an air jet milling method includes the following steps: The GLP-1 drug, after being pulverized by airflow, is first mixed with a carrier to obtain a mixture; the mixture is then second mixed with excipients to obtain a dry powder inhaler of the GLP-1 receptor agonist.

[0064] In some specific implementations, the inlet pressure for GLP-1 class drug air jet milling is 9.0-15.5 bar, the milling pressure is 8.5-15 bar, and the feed rate is 2-5 rpm.

[0065] In some specific embodiments, the first mixing speed is 24 rpm and the mixing time is 30-45 min.

[0066] In some specific implementations, the first mixing speed is 24 rpm and the mixing time is 25-30 min.

[0067] The preparation of a dry powder inhaler of a GLP-1 receptor agonist using a spray drying method includes the following steps: GLP-1 drugs, carriers, and excipients are added to a solvent and stirred until homogeneous to prepare a stock solution with a solid content of 5% to 50%. The stock solution is then spray-dried to obtain a dry powder inhaler of GLP-1 receptor agonists.

[0068] In some specific embodiments, the solvent is at least one selected from deionized water, anhydrous ethanol, dimethyl sulfoxide, and methanol.

[0069] In some specific embodiments, the spray drying conditions are: inlet air temperature 100℃~150℃, feed rate 4mL / min~7mL / min, outlet air temperature 40℃~70℃, and atomization pressure 1.20bar~1.70bar.

[0070] The third aspect of this invention provides the application of a dry powder inhaler of a GLP-1 receptor agonist in lowering blood sugar, reducing weight, and comprehensive metabolic management.

[0071] The following is a detailed description with reference to specific examples.

[0072] Example 1

[0073] The dry powder inhaler of a GLP-1 receptor agonist was prepared by spray drying, and the steps are as follows: 0.05 g of smegglutinin, 98.95 g of alanine and 1 g of β-cyclodextrin were dispersed in deionized water to obtain a stock solution with a solid content of 5% before spray drying. The solution was then spray dried using a spray dryer with the following conditions: inlet air temperature of 120°C, feed rate of 5.5 mL / min, outlet air temperature of 58°C, and nebulization pressure of 1.45 bar, to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0074] Example 2

[0075] The dry powder inhaler of a GLP-1 receptor agonist was prepared by spray drying, and the steps are as follows: 1g of smegglutide, 98g of dileucine and 1g of trileucine were dispersed in deionized water to obtain a stock solution with a solid content of 18% before spray drying. The solution was then spray dried using a spray dryer with the following conditions: inlet air temperature of 110℃, feed rate of 5.0mL / min, outlet air temperature of 55℃, and atomization pressure of 1.55bar, to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0076] Example 3

[0077] The dry powder inhaler of a GLP-1 receptor agonist was prepared by spray drying, and the steps are as follows: 8g of smegglutide, 35g of dipalmitoyl lecithin (DPPC), 52g of trehalose and 5g of calcium chloride were dispersed in anhydrous ethanol to obtain a stock solution with a solid content of 25% before spray drying. The solution was then spray dried using a spray dryer with the following conditions: inlet air temperature of 130℃, feed rate of 6.0mL / min, outlet air temperature of 65℃, and nebulization pressure of 1.60bar, to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0078] Comparative Example 1

[0079] A dry powder inhaler of GLP-1 receptor agonist was prepared by spray drying. The only difference from Example 1 was that alanine was replaced with an equal mass of β-cyclodextrin in Example 1.

[0080] Comparative Example 2

[0081] A dry powder inhaler of GLP-1 receptor agonist was prepared by spray drying. The only difference from Example 1 was that the cyclodextrin in Example 1 was replaced with an equal mass of alanine.

[0082] Example 4

[0083] The dry powder inhaler of a GLP-1 receptor agonist was prepared by spray drying, and the steps are as follows: 0.1 g of liraglutide, 98.9 g of glycine and 1 g of calcium chloride were dispersed in deionized water to obtain a stock solution with a solid content of 30% before spray drying. The solution was then spray dried using a spray dryer with the following conditions: inlet air temperature of 135°C, feed rate of 6.0 mL / min, outlet air temperature of 60°C, and atomization pressure of 1.58 bar, to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0084] Example 5

[0085] The dry powder inhaler of a GLP-1 receptor agonist was prepared by spray drying, and the steps are as follows: 3g of liraglutide, 95g of L-leucine, and 2g of xylitol were dispersed in deionized water to obtain a stock solution with a solid content of 11% before spray drying. The solution was then spray dried using a spray dryer with the following conditions: inlet air temperature of 121℃, feed rate of 5.1mL / min, outlet air temperature of 55℃, and nebulization pressure of 1.38bar, to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0086] Example 6

[0087] The dry powder inhaler of a GLP-1 receptor agonist was prepared by spray drying, and the steps are as follows: 5g liraglutide, 90g dipalmitoyl lecithin (DPPC) and 5g glucose were dispersed in deionized water to obtain a stock solution with a solid content of 20% before spray drying. The solution was then spray dried using a spray dryer with the following conditions: inlet air temperature of 130℃, feed rate of 4.5mL / min, outlet air temperature of 65℃, and nebulization pressure of 1.52bar, to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0088] Comparative Example 3

[0089] A dry powder inhaler of GLP-1 receptor agonist was prepared by spray drying. The only difference from Example 5 was that L-leucine in Example 5 was replaced with an equal mass of xylitol.

[0090] Comparative Example 4

[0091] A dry powder inhaler of GLP-1 receptor agonist was prepared by spray drying. The only difference from Example 5 was that xylitol in Example 5 was replaced with an equal mass of L-leucine.

[0092] Example 7

[0093] The dry powder inhaler of a GLP-1 receptor agonist was prepared by spray drying, and the steps are as follows: 0.05 g of telpoide, 35 g of distearate phosphatidylcholine (DSPC), 50 g of trehalose, and 14.95 g of hydroxypropyl-β-cyclodextrin were dispersed in a DMSO-water mixture (volume ratio 4:1) to obtain a stock solution with a solid content of 6% before spray drying. The solution was then spray dried using a spray dryer with the following conditions: inlet air temperature of 140°C, feed rate of 6.5 mL / min, outlet air temperature of 60°C, and nebulization pressure of 1.67 bar, to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0094] Example 8

[0095] The dry powder inhaler of a GLP-1 receptor agonist was prepared by spray drying, and the steps are as follows: 7g of telpolide, 90g of distearate phosphatidylcholine (DSPC), and 3g of poloxamer 188 were suspended in a methanol-water mixture (volume ratio 3:2) to obtain a stock solution with a solid content of 24% before spray drying. The solution was then spray dried using a spray dryer with the following conditions: inlet air temperature of 125℃, feed rate of 5.8mL / min, outlet air temperature of 60℃, and nebulization pressure of 1.45bar, to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0096] Comparative Example 5

[0097] A dry powder inhaler of GLP-1 receptor agonist was prepared by spray drying. The only difference from Example 7 was that "distearylphosphatidylcholine" in Example 7 was replaced with an equal mass of "a mixture of trehalose and hydroxypropyl-β-cyclodextrin in a mass ratio of 1:1".

[0098] Comparative Example 6

[0099] A dry powder inhaler of GLP-1 receptor agonist was prepared by spray drying. The only difference from Example 7 was that "trehalose" in Example 7 was replaced with an equal mass of "a mixture of distearylphosphatidylcholine and hydroxypropyl-β-cyclodextrin in a mass ratio of 1:1".

[0100] Comparative Example 7

[0101] A dry powder inhaler of GLP-1 receptor agonist was prepared by spray drying. The only difference from Example 7 was that "hydroxypropyl-β-cyclodextrin" in Example 7 was replaced with an equal mass of "a mixture of trehalose and distearate phosphatidylcholine in a mass ratio of 1:1".

[0102] Example 9

[0103] The dry powder inhaler of a GLP-1 receptor agonist was prepared by spray drying, and the steps are as follows: 1g of retaliglutide, 98g of L-leucine and 1g of glycine were dispersed in deionized water to obtain a stock solution with a solid content of 32% before spray drying. The solution was then spray dried using a spray dryer with the following conditions: inlet air temperature of 122℃, feed rate of 5.3mL / min, outlet air temperature of 53℃ and nebulization pressure of 1.67bar, to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0104] Example 10

[0105] The dry powder inhaler of a GLP-1 receptor agonist was prepared by spray drying, and the steps are as follows: 3g of retaliglutide, 95g of alanine and 2g of hydroxypropyl-β-cyclodextrin were dispersed in deionized water to obtain a stock solution with a solid content of 17% before spray drying. The solution was then spray dried using a spray dryer with the following conditions: inlet air temperature of 140℃, feed rate of 6.0mL / min, outlet air temperature of 45℃ and nebulization pressure of 1.59bar, to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0106] Comparative Example 8

[0107] A dry powder inhaler of GLP-1 receptor agonist was prepared by spray drying. The only difference from Example 9 was that glycine in Example 9 was replaced with an equal mass of L-leucine.

[0108] Comparative Example 9

[0109] A dry powder inhaler of GLP-1 receptor agonist was prepared by spray drying. The only difference from Example 9 was that L-leucine in Example 9 was replaced with an equal mass of glycine.

[0110] Example 11

[0111] The dry powder inhaler of a GLP-1 receptor agonist was prepared using an air jet milling method, and the steps are as follows: Smegglutide was added to an air jet mill for pulverization. Nitrogen gas was used for pressurization, with the inlet pressure set at 12.5 bar, the pulverization pressure at 12.0 bar, and the feed speed at 2 rpm to obtain fine powder particles of smegglutide. Mix 35g of primary lactose (D90 value 65-140μm) and 5g of secondary lactose (D90 value <10μm) evenly, and mix using a V-type mixer for 30 minutes at a speed of 24 rpm to obtain a premix. 2g of Smeglucopyranoside fine powder granules and the premix were repeatedly passed through a 100-mesh screen of a vibrating granulator to obtain a mixture. The mixing time was 30min to ensure uniform mixing. The mixture was mixed with 56.9g of lactose (passed through an 80-mesh sieve) and 0.1g of peppermint extract using a V-type mixer at 24 rpm for 25 minutes. Then, 1g of magnesium stearate was added and mixed for 5 minutes to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0112] Example 12

[0113] The dry powder inhaler of a GLP-1 receptor agonist was prepared using an air jet milling method, and the steps are as follows: Smegglutide was added to an air jet mill for pulverization. Nitrogen gas was used for pressurization, with the inlet pressure set to 9 bar, the pulverization pressure to 8.5 bar, and the feed speed to 2 rpm, to obtain fine powder particles of smegglutide. Mix 45g of primary lactose (D90 value 120-160μm) and 10g of secondary lactose (D90 value <30μm) evenly, and mix using a V-type mixer for 45 minutes at a speed of 24 rpm to obtain a premix. 5g of Smeglucopyranoside fine powder granules and the premix were repeatedly passed through a 120-mesh screen of a vibrating granulator to obtain a mixture. The mixing time was 30 minutes to ensure uniform mixing. The mixture was mixed with 36.9g of lactose (passed through an 80-mesh sieve), 3g of magnesium stearate, and 0.1g of aspartame using a V-type mixer at 24 rpm for 25 minutes. Then, 1g of magnesium stearate was added and mixed for 5 minutes to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0114] Comparative Example 10

[0115] The active ingredient particles of a dry powder inhaler for GLP-1 receptor agonists were prepared using air jet milling. The only difference from Example 12 was the air jet milling parameter settings. The settings of "inlet pressure 9 bar, milling pressure 8.5 bar, feed speed 2 rpm" in Example 12 were adjusted to "pressure 8.0 bar, milling pressure 7.5 bar, feed speed 1 rpm".

[0116] Example 13

[0117] The dry powder inhaler of a GLP-1 receptor agonist was prepared using an air jet milling method, and the steps are as follows: Liraglutide was added to an air jet mill for pulverization. Nitrogen gas was used for pressurization, with the inlet pressure set at 15.5 bar, the pulverization pressure at 15 bar, and the feed speed at 5 rpm to obtain fine liraglutide powder particles. Mix 25g of primary lactose (D90 value 120-160μm) and 15g of secondary lactose (D90 value <30μm) evenly, and mix with a V-type mixer for 15 minutes at a speed of 24 rpm to obtain a premix. 8g of liraglutide fine powder granules and the premix were repeatedly passed through a 120-mesh screen of a vibrating granulator to obtain a mixture. The mixing time was 30 minutes to ensure uniform mixing. The mixture was mixed with 50.5g of lactose (passed through an 80-mesh sieve), 0.5g of micronized silica gel, and 1g of sucrose using a V-type mixer at 24 rpm for 25 minutes. Then, 1g of magnesium stearate was added and mixed for 5 minutes to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0118] Comparative Example 11

[0119] The dry powder inhaler of GLP-1 receptor agonist was prepared by air jet milling. The only difference from Example 13 is that the "inlet pressure 15.5 bar, milling pressure 15 bar, feed rate 5 rpm" in Example 13 was adjusted to "pressure 16.5 bar, milling pressure 15.5 bar, feed rate 6 rpm".

[0120] Comparative Example 12

[0121] A dry powder inhaler of GLP-1 receptor agonist was prepared using air jet milling. The only difference from Example 11 was that the premix in Example 11 was replaced with an equal mass of first lactose (D90 value 65-140 μm).

[0122] Comparative Example 13

[0123] A dry powder inhaler of GLP-1 receptor agonist was prepared using air jet milling. The only difference from Example 11 was that the premix in Example 11 was replaced with an equal mass of second lactose (D90 value < 10 μm).

[0124] Comparative Example 14

[0125] A dry powder inhaler of GLP-1 receptor agonist was prepared using air jet milling. The only difference from Example 11 was that the premix in Example 11 was replaced with an equal mass of trehalose dihydrate.

[0126] Comparative Example 15

[0127] A dry powder inhaler of GLP-1 receptor agonist was prepared using air jet milling. The only difference from Example 11 was that the premix in Example 11 was replaced with an equal mass of sucrose.

[0128] Example 14

[0129] The dry powder inhaler of a GLP-1 receptor agonist was prepared using an air jet milling method, and the steps are as follows: Liraglutide was added to an air jet mill for pulverization. Nitrogen gas was used for pressurization, with the inlet pressure set at 12.5 bar, the pulverization pressure at 12.0 bar, and the feed speed at 2 rpm to obtain fine liraglutide powder particles. 30g of L-leucine (D90 value 200-260μm) and 8g of lactose (D90 value <30μm) were mixed evenly and then mixed for 5 minutes using a V-type mixer at 24 rpm to obtain a premix. 10g of liraglutide fine powder granules and the premix were repeatedly passed through a 100-mesh sieve of a vibrating granulator to obtain a mixture. The mixing time was 30 minutes to ensure uniform mixing. The mixture was combined with 46.5g of lactose (passed through an 80-mesh sieve), 5g of magnesium stearate, and 0.5g of sucrose using a V-type mixer at 24 rpm for 5 minutes to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0130] Example 15

[0131] The dry powder inhaler of a GLP-1 receptor agonist was prepared using an air jet milling method, and the steps are as follows: The telpoeptide was added to an air jet mill for pulverization. Nitrogen gas was used for pressurization, with the inlet pressure set at 12.5 bar, the pulverization pressure at 12.0 bar, and the feed speed at 2 rpm to obtain fine telpoeptide powder particles. 30g of hydroxypropyl-β-cyclodextrin (D90 value 85-116μm) was mixed with 8% mannitol (D90 value <30μm) until homogeneous. The mixture was then mixed for 5 minutes using a V-type mixer at 24 rpm to obtain a premix. 1g of telpoeptide fine powder granules and the premix were repeatedly passed through an 80-mesh sieve of a vibrating granulator to obtain a mixture. The mixing time was 30 minutes to ensure uniform mixing. The mixture was combined with 55.5g of lactose (passed through an 80-mesh sieve), 5g of poloxamer 188, and 0.5g of peppermint extract using a V-type mixer at 24 rpm for 5 minutes to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0132] Example 16

[0133] The dry powder inhaler of a GLP-1 receptor agonist was prepared using an air jet milling method, and the steps are as follows: The telpoeptide was added to an air jet mill for pulverization. Nitrogen gas was used for pressurization, with the inlet pressure set at 12.5 bar, the pulverization pressure at 12.0 bar, and the feed speed at 2 rpm to obtain fine telpoeptide powder particles. Mix 35g of cyclodextrin (D90 value 134-196μm) and 5g of mannitol (D90 value <10μm) evenly using a V-type mixer at 24rpm for 5min to obtain a premix. 3g of telpoeptide fine powder granules and the premix were repeatedly passed through a 120-mesh sieve of a vibrating granulator to obtain a mixture. The mixing time was 30 minutes to ensure uniform mixing. The mixture was combined with 55.8g of lactose (80 mesh), 1g of PEG4000, and 0.2g of peppermint extract using a V-type mixer at 24 rpm for 5 minutes to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0134] Example 17

[0135] The dry powder inhaler of a GLP-1 receptor agonist was prepared using an air jet milling method, and the steps are as follows: The telpoeptide was added to an air jet mill for pulverization. Nitrogen gas was used for pressurization, with the inlet pressure set at 12.5 bar, the pulverization pressure at 12.0 bar, and the feed speed at 2 rpm to obtain fine telpoeptide powder particles. Mix 45g of lactose (D90 value 76-120μm) and 5g of mannitol (D90 value <30μm) evenly using a V-type mixer at 24 rpm for 5 minutes to obtain a premix. 10g of telpoeptide fine powder granules and the premix were repeatedly passed through the screen of a vibrating granulator to obtain a mixture. The mixing time was 30 minutes to ensure uniform mixing. The mixture was mixed with 36.9g of lactose (100 mesh), 3g of magnesium stearate, and 0.1g of aspartame using a V-type mixer at 24 rpm for 5 minutes to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0136] Example 18

[0137] The dry powder inhaler of a GLP-1 receptor agonist was prepared using an air jet milling method, and the steps are as follows: Retaglutide was added to an air jet mill for pulverization. Nitrogen gas was used for pressurization, with the inlet pressure set at 12.5 bar, the pulverization pressure at 12.0 bar, and the feed speed at 2 rpm to obtain fine powder particles of retaglutide. Mix 25g of mannitol (D90 value 180-220μm) and 10g of lactose (D90 value <10μm) evenly using a V-type mixer at 24rpm for 5min to obtain a premix. 0.5g of Retaglutide fine powder granules and the premix were repeatedly passed through an 80-mesh sieve of a vibrating granulator to obtain a mixture. The mixing time was 30 minutes to ensure uniform mixing. The mixture was combined with 63g of lactose (passed through a 100-mesh sieve), 0.5g of micronized silica gel, and 1g of peppermint extract using a V-type mixer at 24 rpm for 5 minutes to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0138] Example 19

[0139] The dry powder inhaler of a GLP-1 receptor agonist was prepared using an air jet milling method, and the steps are as follows: Retaglutide was added to an air jet mill for pulverization. Nitrogen gas was used for pressurization, with the inlet pressure set at 12.5 bar, the pulverization pressure at 12.0 bar, and the feed speed at 2 rpm to obtain fine powder particles of retaglutide. 30g of hydroxypropyl-β-cyclodextrin (D90 value 72-118μm) and 9g of lactose (D90 value <10μm) were mixed evenly using a V-type mixer at 24rpm for 5min to obtain a premix. 5g of Retaglutide fine powder granules and the premix were repeatedly passed through a 120-mesh sieve of a vibrating granulator to obtain a mixture. The mixing time was 30 minutes to ensure uniform mixing. The mixture was mixed with 50.5g of lactose (passed through a 100-mesh sieve), 5g of stearic acid, and 0.5g of glucose using a V-type mixer at 24 rpm for 5 minutes to obtain the final product, which is a dry powder inhaler of GLP-1 receptor agonist.

[0140] Example 20

[0141] The dry powder inhaler of a GLP-1 receptor agonist was prepared using an air jet milling method, and the steps are as follows: Retaglutide was added to an air jet mill for pulverization. Nitrogen gas was used for pressurization, with the inlet pressure set at 12.5 bar, the pulverization pressure at 12.0 bar, and the feed speed at 2 rpm to obtain fine powder particles of retaglutide. Mix 30g of hydroxypropyl-β-cyclodextrin (D90 value 130-170μm) with 20g of lactose (D90 value <30μm) until homogeneous. Use a V-type mixer at 24rpm for 5min to obtain a premix. 10g of Retaglutide fine powder granules and the premix were repeatedly passed through the screen of a vibrating granulator to obtain a mixture. The mixing time was 30 minutes to ensure uniform mixing. The mixture was mixed with 32g of lactose (passed through a 100-mesh sieve), 5g of stearic acid, and 3g of sucrose using a V-type mixer at 24 rpm for 5 minutes to obtain a dry powder inhaler of GLP-1 receptor agonist.

[0142] (a) Particle size determination

[0143] The dry powder inhalers of GLP-1 receptor agonists prepared in Examples 1-10 and Comparative Examples 1-9 were respectively filled into #3 capsules. The active ingredient particles obtained in Examples 11-20 and Comparative Examples 10-15 were subjected to particle size testing. According to Method III of General Chapter 0982 in Part IV of the 2025 edition of the Chinese Pharmacopoeia, a laser particle size analyzer was used for dry particle size determination. An R4 lens was selected, the dispersion pressure was set to 3.0 bar, and the injection rate to 50%. 10g of the contents of 10 capsules or 10g of the active ingredient particles were taken for measurement. The samples were tested in triplicate, and the average value was taken. The test results are shown in Table 1. Table 1. Particle size results for different samples

[0144] As can be seen from the data recorded in Table 1, the dry powder inhalers prepared in Examples 1-20 have a particle size D90 value of 4.04-5.27 μm, which is consistent with the particle size range for effective deposition in the lungs.

[0145] Specific analysis of the experimental results of Examples 1, 1, and 2 shows that using β-cyclodextrin and alanine as a carrier results in a lower D90 value for the dry powder inhaler, which is around 5 μm, compared to using either as a carrier. This is more conducive to obtaining a highly efficient dry powder inhaler. Similarly, the experimental results of Examples 5, 3, and 4 show that using L-leucine and xylitol as a carrier results in a lower D90 value for the dry powder inhaler compared to using either as a carrier. This is more conducive to obtaining a highly efficient dry powder inhaler. The experimental results of Examples 7, 5, 6, and 7 show that using a combination of hydroxypropyl-β-cyclodextrin, trehalose, and distearate phosphatidylcholine as a carrier results in better product performance. The test results of Examples 9, 8, and 9 show that using L-leucine and glycine as a carrier results in a dry powder inhaler that better meets the inhalation requirements compared to using L-leucine alone.

[0146] Specifically, the experimental results of Examples 11, 10, and 11 show that the airflow pulverization process described in this application is more conducive to obtaining dry powder inhalers with suitable particle size. The experimental results of Examples 11, 12, 13, 14, and 15 show that using a combination of first lactose and second lactose as a carrier is more conducive to obtaining dry powder inhalers with appropriate particle size. In summary, when preparing dry powder inhalers containing GLP-1 receptor agonists, the combined use of two or more carriers is more beneficial to increasing the performance of powder particles. When using air jet milling, it is necessary to control appropriate process parameters to obtain the desired particle size of the active ingredient.

[0147] (II) Measurement of Aerodynamic Characteristics

[0148] Using a new generation pharmaceutical disc impactor (NGI), 10 capsules prepared in Examples 1-20 and Comparative Examples 1-9 and 12-15 were separated. The active ingredient particle size obtained in Comparative Examples 10 and 11 was not up to standard, and therefore no formulation was prepared; i.e., no aerodynamic property testing was performed. The above component separation was repeated three times, with an airflow rate of 60 L / min. The number of particles deposited at each stage was determined by gravimetric analysis. The aerodynamic parameters of each group of dry powder inhalation formulations and the mass ratio of dry powder particles deposited in each stage collector of the NGI were calculated. The test results are as follows: Figures 1-4 As shown in Table 2: Table 2. Results of aerodynamic property determination for different samples

[0149] In Table 2, FPM represents the fine particle mass, i.e., the mass of drug particles with an aerodynamic diameter of less than 5 μm; FPF represents the fine particle fraction or in vitro deposition rate, i.e., the ratio of the mass of drug particles with an aerodynamic diameter of less than 5 μm to the total released mass; TEM represents the total released mass, i.e., the dose of drug released from the inhalation device, which is equal to the sum of the drug masses in the adapter, artificial larynx, pre-separator, and impactor collection cups; MMAD represents the mass median aerodynamic diameter, i.e., the aerodynamic diameter of particles when the cumulative mass is 50%; and GSD represents the geometric standard deviation, the closer this value is to 1, the narrower the particle size distribution. Depend on Figures 1-4 It can be seen that the particles of the dry powder inhalation formulations in Examples 1-20 are mostly deposited in the second and third layers, which is consistent with the inhalation size. As shown in Table 2, the aerodynamic parameters of the dry powder inhalation formulations prepared in Examples 1-20 are within the acceptable range and meet the requirements for pulmonary medication. In contrast, the dry powder inhalation formulations prepared in Comparative Examples 1-15 have lower mass and in vitro deposition rate of drug particles with a diameter less than 5 μm, and the median aerodynamic particle size is much larger than 5 μm, indicating a wider particle size distribution, making them unsuitable for pulmonary medication.

[0150] (III) In vivo pharmacokinetic evaluation

[0151] 3.1 Experimental animals: SPF-grade male rats, weighing 180–220g.

[0152] 3.2 Control group drugs: Liraglutide injection (trade name: Saxenda®) 18mg: 3mL Smegglutide injection (trade name: NovoRapid®) 1.34 mg / mL, 1.5 mL 3.3 Control group (intravenous injection, IV): Group 1: Three SPF-grade male rats were randomly selected. One of the veins on the left and right sides of the tail was selected and wiped with 75% alcohol. The drug was administered from the lower 1 / 4 of the tail at a dose of 0.05 mg / kg, slowly.

[0153] Group 2: Same treatment as above, administer liraglutide injection (trade name: Saxenda®) slowly at 0.1 mg / kg.

[0154] 3.4 Control group (subcutaneous injection, SC) experiment: Group 1: Three rats were randomly selected. The skin of the lower lateral abdomen was selected, the skin was gently pinched up, the needle was inserted 2-3 cm under the skin at a 45-degree angle to the skin, the skin was released, the piston was pulled, and when no blood return was seen, the piston was pushed to inject the drug. The drug was administered at 0.05 mg / kg, and smegglutide injection (trade name: Novogene®) was slowly administered.

[0155] Group 2: Same treatment as above, administer liraglutide injection (trade name: Saxenda®) slowly at 0.1 mg / kg.

[0156] 3.5 Test Sample Group Experiment: Three rats were randomly selected. A cotton ball soaked in ether was placed in a small beaker and placed over the rat's mouth and nose to induce anesthesia through inhalation. A nebulizer was inserted into the airway through the epiglottis to administer 0.05 mg / kg of the drug from Example 1.

[0157] The same treatment method was used, administering 0.05 mg / kg of the drug from Example 12.

[0158] The same treatment method was used, administering 0.1 mg / kg of the drug from Example 4.

[0159] The same treatment method was used, administering 0.1 mg / kg of the drug from Example 13.

[0160] 3.6 Sample Collection: In the above experiments, blood was collected from the tail vein of rats at 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after drug administration, with approximately 0.25 mL collected at each time point. Pharmacokinetic treatments were performed on the collected blood samples, and the results are shown in Table 3 below. Table 3. Pharmacokinetic evaluation results of different samples in vivo

[0161] In Table 3, Cmax represents the maximum plasma concentration, or peak concentration, which is the highest plasma concentration reached after drug administration. It reflects the rate and extent of drug absorption in the body. Tmax represents the time to peak concentration, which is the time required for the blood drug concentration to reach its peak after administration. It is closely related to the drug absorption rate and is one of the simple indicators reflecting the bioavailability of a drug formulation. AUC represents the area under the blood concentration-time curve, which is a direct indicator of the amount of drug exposed in the blood and reflects the extent of drug absorption in the body. In bioequivalence evaluation, AUC is used as one of the main parameters to compare the bioavailability of different formulations in the same subject. The larger the AUC, the faster the drug is absorbed and distributed, and the stronger the efficacy may be. F represents bioavailability, reflecting the relative amount and rate of drug absorption into the bloodstream. It is calculated by comparing the amount of drug absorbed into the systemic circulation (A) with the administered dose (D), using the formula F = A / D × 100%. Bioavailability is very important for predicting the rate of drug absorption and metabolism in the body.

[0162] As can be seen from the test results in Table 3, the dry powder inhalation formulation prepared in this embodiment reaches the peak drug concentration significantly faster than subcutaneous injection. The AUC values ​​of the different dosage groups in this embodiment are approximately 2-3 times higher than those of the subcutaneous injection group, indicating that inhaled administration is absorbed and distributed more quickly in the body. Compared to subcutaneous injection, the inhaled formulation has better absolute bioavailability.

[0163] (iv) Evaluation of its application in lowering blood sugar and reducing weight

[0164] 4.1 Laboratory animals: db / db mice, male, weighing 20–30g.

[0165] C57BL / 6J mice, male, weighing 15–20g.

[0166] 4.2 Establishment of animal pathological models

[0167] db / db mouse model: The db / db mouse model was established by feeding 5-week-old male db / db mice with normal diet and unlimited food and water. The light and dark periods were 12h and the constant temperature was 22℃.

[0168] HFD mouse model: In this experiment, male C57BL / 6J mice aged 5 weeks were fed a high-fat diet until they were 13 weeks old. Food and water were unlimited. The light and dark periods were 12 hours and the constant temperature was 22°C, respectively, to establish an HFD mouse model.

[0169] 4.3 Group Dosing

[0170] The db / db mice and HFD mice described above were randomly divided into: blank group, model group, control group, and example group.

[0171] 4.3.1 The administration method and dosage for the control group were as follows: For db / db mice, smegglutide was administered subcutaneously at a dose of 0.1 mg / kg, calculated based on body surface area, every 3 days for 6 weeks.

[0172] For HFD mice, semaglutide was administered subcutaneously. The dosage was calculated based on body surface area, with a dose of 0.1 mg / kg for the first 4 weeks and 0.2 mg / kg for the next 4 weeks, once every 3 days for 8 consecutive weeks.

[0173] 4.3.2 The administration method and dosage for the Example Group were as follows: For db / db mice and HFD mice, after inhalation anesthesia, a nebulizer needle was inserted into the airway through the epiglottis, and 0.05 mg / kg of the drug in Examples 2, 7, 9, 14, 15 and 18 were administered, respectively. Each example group was given once a day for 8 consecutive weeks.

[0174] 4.4 Experimental Methods

[0175] 4.4.1 Body weight and feeding efficiency experiment

[0176] Mice were weighed twice a week, and the average weight was recorded as the weekly weight. Food intake for each cage of mice was recorded twice a week, and the average daily food intake was calculated. The feeding efficiency of the mice was calculated using the formula: Feeding efficiency = Total food intake / Total body weight.

[0177] 4.4.2 Fasting blood glucose, glucose tolerance test and insulin sensitivity test

[0178] a. Fasting blood glucose test

[0179] After the last drug intervention, mice in each group were fasted for 10 hours, and blood glucose levels in the tail vein were measured using blood glucose test strips.

[0180] b. Glucose tolerance test

[0181] After the last drug intervention, mice in each group were fasted for 10 hours and then injected intraperitoneally with 50% high glucose solution at a dose of 2 mg / g. Blood glucose levels in the tail vein of the mice were measured using blood glucose test strips at 0 min, 30 min, 60 min, 90 min and 120 min after injection.

[0182] c. Intraperitoneal insulin sensitivity test

[0183] After the last drug intervention, 4-5 hours after feeding, mice in each group were given an intraperitoneal injection of insulin solution at the calculated dose. Blood glucose levels in the tail vein of the mice were measured using blood glucose test strips at 0 min, 30 min, 60 min, 90 min and 120 min after injection.

[0184] 4.4.3 Liver and peritesticular white fat / brown fat weight experiment

[0185] After the last drug intervention, mice in each group were fasted for 10 hours. They were then anesthetized with 0.3% sodium pentobarbital at a dose of 0.1 mL / 10 g. Blood was collected via the retroorbital vein, and the mice were euthanized by cervical dislocation. The mice were dissected, and the hypothalamus, abdominal skin, liver, and peritesticular white and brown adipose tissues were harvested. The liver, peritesticular white and brown adipose tissues were weighed and analyzed separately.

[0186] 4.5 Experimental Results and Discussion

[0187] 4.5.1 Results and Discussion of Experiments on Body Weight and Feeding Efficiency

[0188] Table 4. Results of experiments on body weight and feeding efficiency of db / db mice

[0189] As can be seen from the data recorded in Table 4, the GLP-1 class drug dry powder inhalation formulation provided in the embodiment group of the present invention, after intervening in db / db mice for 6 weeks, can significantly reduce the weight of the mice (P<0.01), and there is no significant difference in weight compared with the control group (P>0.05); it can reduce their feeding efficiency, and the feeding efficiency of the embodiment group is close to or better than that of the control group.

[0190] Table 5 Results of HFD mouse body weight and feeding efficiency experiments

[0191] As recorded in Table 5 above, the GLP-1 class drug dry powder inhalation formulation provided in the embodiment group of the present invention, when used to intervene in obese HFD mice for 8 weeks, can also significantly reduce the weight of the mice (P<0.01), which is better than the weight of the control group; it can also reduce their feeding efficiency, and the feeding efficiency of the embodiment group is close to that of the control group.

[0192] After intervention with the GLP-1 class drug dry powder inhalation formulation provided in this embodiment of the invention, the above db / db mice and HFD mice showed a decrease in feeding efficiency and a weight loss of approximately 33%. The control group received semaglutide injection. Semaglutide injection has been widely recognized globally for its significant effects in lowering blood sugar and reducing weight. The GLP-1 class drug dry powder inhalation formulation provided in this embodiment of the invention showed no significant difference or even better intervention effect on obesity compared to the control group. Furthermore, this invention does not require invasive drug delivery, making it more economical and naturally safe.

[0193] 4.5.2 Results and Discussion of Fasting Blood Glucose, Glucose Tolerance Test, and Insulin Sensitivity Test

[0194] Table 6 Results of fasting blood glucose tests in db / db mice and HFD mice

[0195] In Table 6, FBG is an abbreviation for Fasting Blood Glucose, which refers to the blood glucose level measured the morning after an overnight fast.

[0196] As shown in Table 6, Figure 5-8 As shown, the GLP-1 class drug dry powder inhalation formulation provided in this embodiment of the invention can significantly reduce the fasting blood glucose level of db / db mice and HFD mice (P>0.05), wherein the fasting blood glucose level of HFD mice is not significantly different from that of the control group (P>0.05); the GLP-1 class drug dry powder inhalation formulation provided in this embodiment of the invention can significantly improve the glucose tolerance of db / db mice and HFD mice (P<0.05) and significantly improve their insulin sensitivity (P<0.05), both of which are close to those of the control group.

[0197] After intervention with the GLP-1 class drug dry powder inhalation formulation provided in this embodiment of the invention, the fasting blood glucose levels of the above db / db mice and HFD mice decreased by an average of about 20%-30%, while the control group was treated with semaglutide injection. Semaglutide's significant effects in lowering blood sugar and reducing weight are widely recognized globally. The GLP-1 class drug dry powder inhalation formulation provided in this embodiment of the invention has no significant difference or is even better than the control group in terms of intervention effect on obesity. Moreover, this invention does not require invasive drug delivery, is more economical, and is natural and safe. The beneficial effects of this invention are obvious.

[0198] 4.5.3 Results and Discussion of Liver and Peritoneal White Fat / Brown Fat Weight Experiment

[0199] Table 7 Results of experiments on liver and peritesticular white / brown adipose tissue weight in db / db mice

[0200] Table 8 Results of experiments on the weight of white / brown adipose tissue in the liver and peritestes of HFD mice.

[0201] As shown in Tables 7-8, the GLP-1 class drug dry powder inhalation formulation provided in the embodiments of the present invention significantly reduced the weight of liver and peritesticular white adipose tissue (eWAT) in db / db mice (P < 0.01), significantly reduced the weight of liver and peritesticular white adipose tissue in HFD mice (P < 0.01), and significantly increased the weight of brown adipose tissue (BAT) in db / db mice and HFD mice (P < 0.01). Among them, the weight of liver and peritesticular white adipose tissue and brown adipose tissue in the GLP-1 class drug dry powder inhalation formulation provided in Example 3 of the present invention was close to that of the control group, or even better.

[0202] After intervention with the GLP-1 class drug dry powder inhalation formulation provided in this embodiment of the invention, the average weight of white adipose tissue in the liver and peritoneal region of the above db / db mice and HFD mice decreased by about 30-50%, and the average weight of brown adipose tissue increased by about 50%. The control group received semaglutide injection. Semaglutide's significant effects in lowering blood sugar and reducing weight are widely recognized globally. The intervention effect of the GLP-1 class drug dry powder inhalation formulation provided in this embodiment of the invention on obesity is not significantly different from or even better than that of the control group. Moreover, this invention does not require invasive drug delivery, is more economical, and is natural and safe. The beneficial effects of this invention are obvious.

[0203] In summary, based on the experimental results and discussion in sections 4.5.1 to 4.5.3, intervention with the GLP-1 class drug dry powder inhalation formulation provided in this invention for 6 or 8 weeks in obese patients can significantly reduce body weight, feeding efficiency, and fasting blood glucose in db / db mice or HFD mice, and significantly increase glucose tolerance and insulin sensitivity in HFD mice. Using this invention, the weight of white adipose tissue in the liver and peritoneum of db / db mice and HFD mice is significantly reduced, while the weight of brown adipose tissue is significantly increased. These experimental results are similar to or better than those of existing formulations.

[0204] The experimental results of the GLP-1 class drug dry powder inhalation formulation provided in the embodiments of the present invention, compared with those of the control group, show no significant difference or are even better than those of the control group. The control group used semaglutide injection. Semaglutide's significant effects in lowering blood sugar and weight loss are widely recognized worldwide. Moreover, the present invention, with its advantages of not requiring invasive drug delivery, being more cost-effective, and naturally safe, still shows similar or better efficacy than semaglutide. The beneficial effects of the present invention are obvious.

[0205] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0206] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A dry powder inhaler of a GLP-1 receptor agonist, characterized in that, The raw materials include the following percentages by weight: GLP-1 drugs 0.01%–10%, carriers 10%–99%, and excipients 0%–80%; The carrier is at least two of the following: lactose, thalassyl lactose, mannitol, xylitol, cyclodextrin, cyclodextrin derivatives, trehalose, trehalose hydrate, dipalmitoyl lecithin, distearate phosphatidylcholine, glucose, amino acids, and amino acid derivatives.

2. The dry powder inhaler of the GLP-1 receptor agonist according to claim 1, characterized in that, The dry powder inhaler of the GLP-1 receptor agonist comprises the following raw materials in weight percentages: 0.05% to 10% GLP-1 drug, 10% to 99% carrier, and 0% to 80% excipients.

3. The dry powder inhaler of the GLP-1 receptor agonist according to claim 1, characterized in that, The carrier is composed of hydroxypropyl-β-cyclodextrin, trehalose, and distearate phosphatidylcholine.

4. The dry powder inhaler of the GLP-1 receptor agonist according to claim 1, characterized in that, The first lactose has a D90 value of 65-250 μm, and the second lactose has a D90 value of less than 30 μm.

5. The dry powder inhaler of the GLP-1 receptor agonist according to claim 1, characterized in that, The GLP-1 class drugs are at least one of the following: semaglutide, liraglutide, oxaliplatin, telpoglycinide, texipatide, retaglutide, loxenatide, mastodextrin, abiglutide, sevidotide, loxenatide, esupagglutide α, glutastatin monoclonal antibody, vepenaenate, liximab, ibennatide, exenatide, and dulaglutide.

6. A method for preparing a dry powder inhaler of a GLP-1 receptor agonist, characterized in that, The dry powder inhaler for preparing the GLP-1 receptor agonist according to any one of claims 1-5 includes air jet milling and spray drying.

7. The method for preparing a dry powder inhaler of a GLP-1 receptor agonist according to claim 6, characterized in that, The preparation of a dry powder inhaler of a GLP-1 receptor agonist using an air jet milling method includes the following steps: The GLP-1 drug, after being pulverized by airflow, is first mixed with a carrier to obtain a mixture; the mixture is then second mixed with excipients to obtain a dry powder inhaler of the GLP-1 receptor agonist.

8. The method for preparing a dry powder inhaler of a GLP-1 receptor agonist according to claim 7, characterized in that, The inlet pressure for GLP-1 class drugs in air jet milling is 9.0-15.5 bar, the milling pressure is 8.5-15 bar, and the feed rate is 2-5 rpm.

9. The method for preparing a dry powder inhaler of a GLP-1 receptor agonist according to claim 6, characterized in that, The preparation of a dry powder inhaler of a GLP-1 receptor agonist using a spray drying method includes the following steps: GLP-1 drugs, carriers, and excipients are added to a solvent and stirred until homogeneous to prepare a stock solution with a solid content of 5% to 50%. The stock solution is then spray-dried to obtain a dry powder inhaler of GLP-1 receptor agonists.

10. The use of the dry powder inhaler of the GLP-1 receptor agonist according to any one of claims 1-5 in lowering blood sugar, reducing weight and comprehensive metabolic management.

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