Inhalation powder compositions

Abstract

An inhaled powder composition, its preparation method, and its use are disclosed. The inhaled powder composition comprises: (a) a glucagon-like peptide-1 receptor agonist (GLP-1RA); (b) a stabilizer; and (c) a carrier; wherein, based on the total weight of the inhaled powder composition, the content of the glucagon-like peptide-1 receptor agonist (GLP-1RA) is about 5% to 50% by weight, the content of the stabilizer is about 5% to 40% by weight, and the content of the carrier is about 15% to 75% by weight.

Description

[0001] Citation of relevant applications

[0002] This disclosure claims the full benefits of Chinese Patent Application No. 202510389530.8, entitled "Inhalation Powder Composition," filed on March 28, 2025, with the State Intellectual Property Office of the People's Republic of China, the entire contents of which are incorporated herein by reference.

[0003] field

[0004] This disclosure generally relates to the biomedical field, and more specifically to inhaled powder compositions. background

[0005] Glucagon-like peptide-1 (GLP-1) is an intestinal hormone secreted by L cells, endocrine cells in the intestinal mucosa, during the course of food intake. GLP-1 receptor agonists (GLP-1RAs) bind to their receptors and have multiple mechanisms for lowering blood sugar, including delaying gastric emptying, inhibiting hepatic glucose output, increasing cardiac output, and providing cardiovascular protection. Therefore, the GLP-1 receptor is an important target for the treatment of diabetes and obesity. Currently, commercially available GLP-1RA products are mainly subcutaneous injections. Subcutaneous injections include Novo Nordisk's liraglutide (Victoza) and Eli Lilly's dulaglutide (Trulicity). However, long-term subcutaneous injections can easily lead to induration at the injection site or subcutaneous fat atrophy, resulting in poor patient compliance.

[0006] In 2019, Novo Nordisk launched Semaglutide, the world's first oral GLP-1 inhibitor. This product allows for once-daily oral administration, reducing the difficulty of administration and increasing user compliance. Even so, Semaglutide has a low oral bioavailability, approximately 1% of the administered dose, resulting in a weekly oral dose that is about 100 times higher than that of subcutaneous injection. Furthermore, Semaglutide has strict administration requirements: it must be taken on an empty stomach in the morning with less than 100 mL of water, and no food or other medications can be consumed within half an hour of administration, making it inconvenient.

[0007] When peptide drugs are administered orally or by injection, they are easily inactivated by digestive juices such as gastric acid and trypsin.

[0008] Overview

[0009] On the one hand, this disclosure relates to an inhaled powder composition comprising:

[0010] (a) Glucagon-like peptide-1 receptor agonist (GLP-1 RA);

[0011] (b) stabilizers; and

[0012] (c) Carrier;

[0013] Based on the total weight of the inhaled powder composition, the content of the glucagon-like peptide-1 receptor agonist (GLP-1RA) is about 5% to 50% by weight, the content of the stabilizer is about 5% to 40% by weight, and the content of the carrier is about 15% to 75% by weight.

[0014] On the other hand, this disclosure relates to a method for preparing the inhaled powder composition described herein, comprising:

[0015] A solution is prepared by mixing and dissolving a glucagon-like peptide-1 receptor agonist (GLP-1 RA), a stabilizer, a carrier, and optional sustained-release material in water; and

[0016] The inhalation powder composition was prepared by spray drying of the solution.

[0017] In another aspect, this disclosure relates to a method for treating inflammatory lung diseases and pulmonary fibrosis caused by inflammatory damage, comprising administering a therapeutically effective amount of the inhaled powder composition of this disclosure to an individual in need of the method. Brief description of the attached figures

[0018] Figure 1 (A) MMAD and (B) FPF of GLP-1 RA inhalation powder with different drug contents are shown.

[0019] Figure 2 The in vitro release curves of GLP-1 RA inhalation powder with different contents of sustained-release material are shown.

[0020] Figure 3 The aerodynamic results of GLP-1 RA inhaled powder aerosols with different contents of sustained-release material are shown.

[0021] Figure 4 The results show the percentage increase in moisture content of GLP-1 RA inhalation powder with different stabilizer contents.

[0022] Figure 5 The aerodynamic results of GLP-1 RA inhaled powder with different stabilizer contents are shown.

[0023] Figure 6 The pharmacokinetic results of different dosage forms of GLP-1 RA are shown.

[0024] Figure 7 The pharmacokinetic results of GLP-1 RA inhalation powder under different types of equal-volume sustained-release / sustained-release compositions are shown.

[0025] Figure 8 The survival rate of Beas 2B cells after inhalation of GLP-1 RA powder is shown in the figure.

[0026] Figure 9 The statistical analysis of Fibronectin mRNA levels is shown.

[0027] Figure 10 Statistical analysis of α-SMA mRNA levels is shown.

[0028] Figure 11 The diagram shows protein level bands for Fibronectin and Collagen I.

[0029] Figure 12 A statistical graph of TNF-α levels in rat bronchoalveolar lavage fluid is shown.

[0030] Figure 13 A statistical graph of IL-6 levels in rat bronchoalveolar lavage fluid is shown.

[0031] Figure 14 A statistical graph of TNF-α levels in rat serum is shown.

[0032] Figure 15 A statistical graph of IL-6 levels in rat serum is shown.

[0033] Figure 16 The image shows H&E and Masson staining of rat lung tissue.

[0034] Figure 17 Western blotting images of Fibronectin and Collagen I in rat lung tissue are shown.

[0035] Figure 18 Immunohistochemical images of Fibronectin and Collagen I in rat lung tissue are shown.

[0036] Figure 19 The graph shows the statistical changes in rat body weight during treatment with different doses of GLP-1RA powder.

[0037] Figure 20 The H&E staining images of the heart, liver, spleen, kidney, and brain of rats after administration of different doses of GLP-1RA powder are shown.

[0038] Figure 21 The graph shows the statistical content of glycated hemoglobin in rat plasma at different time points after inhalation of GLP-1RA powder.

[0039] Detailed Explanation

[0040] The following description includes certain specific details to provide a comprehensive understanding of the various disclosed embodiments. However, those skilled in the art will recognize that the embodiments can still be achieved without employing one or more of these specific details, but by using other methods, components, materials, etc.

[0041] Unless otherwise required in this application, throughout the specification and the appended claims, the words “comprising,” “including,” “containing,” and “having” shall be interpreted in an open-ended, inclusive sense, meaning “including but not limited to.”

[0042] When used in this disclosure and the appended claims, a singular designation without a quantity indication includes a plural designation unless the context clearly specifies otherwise.

[0043] Throughout this specification, the terms "an embodiment," "an embodiment," "in another embodiment," or "in some embodiments" refer to including, in at least one embodiment, a specific reference element, structure, or feature related to that embodiment. Therefore, the phrases "in an embodiment," "in another embodiment," or "in some embodiments" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. Furthermore, specific elements, structures, or features may be combined in one or more embodiments in any suitable manner.

[0044] It should be understood that the singular article “a” (corresponding to the English words “a,” “an,” and “the”) used in this disclosure and the appended claims includes plural objects unless otherwise expressly stated herein. Therefore, for example, a pharmaceutical composition comprising a “carrier” includes a pharmaceutical composition comprising one carrier, or a pharmaceutical composition comprising two or more carriers.

[0045] definition

[0046] Therefore, unless otherwise stated, the following terms used in the specification and appended claims shall have the following meanings:

[0047] In this disclosure, the term "glucagon-like peptide-1 (GLP-1)" refers to a peptide hormone composed of 30 or 31 amino acids, derived from tissue-specific post-translational modifications of proglucagon. It is primarily produced and secreted by certain neurons in the enteroendocrine L cells and the nucleus of the solitary tract in the brainstem after eating.

[0048] In this disclosure, the term "glucagon-like peptide-1 receptor agonist (GLP-1 RA)" refers to a class of drugs that activate the GLP-1 receptor by mimicking the action of the glucagon-like peptide-1 (GLP-1) hormone.

[0049] In this disclosure, the term "pharmaceutical composition" refers to a formulation formed from the glucagon-like peptide-1 receptor agonist (GLP-1 RA) described herein and a medium generally accepted in the art for delivering a bioactive substance to a mammal such as a human. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients.

[0050] In this disclosure, the term "stabilizer" refers to a class of excipients used to improve the physical and chemical stability of drug powders. Their main function is to prevent drug particles from agglomerating, absorbing moisture, degrading, or undergoing other physicochemical changes during storage or transportation.

[0051] In this disclosure, the term "carrier" refers to an excipient that helps drug powder form appropriate particle size, ensuring that the drug is evenly dispersed and reaches the lungs smoothly during inhalation.

[0052] In this disclosure, the term "sustained-release material" refers to a class of excipients capable of controlling the rate of drug release in the lungs or respiratory tract. Its primary function is to prolong the drug's residence time at the target site, thereby improving the drug's efficacy and duration of action.

[0053] In this disclosure, the term "fine particle fraction (FPF)" refers to the percentage of particles with a diameter between 0.5 and 5 μm in the total number of particles.

[0054] In this disclosure, the term "mass median aerodynamic diameter (MMAD)" refers to a particle size that represents the aerodynamic particle size distribution of particulate matter based on mass statistics, where, when particulate matter is sorted by aerodynamic particle size, particles larger than its diameter and particles smaller than its diameter each account for 50% of the total mass of particulate matter.

[0055] In this disclosure, the term "bioavailability" refers to the relative amount of a drug that reaches the bloodstream from the site of administration.

[0056] In this disclosure, the term "AUC" refers to the area under the plasma concentration-time curve.

[0057] In this disclosure, the term "C" max "This refers to the highest blood drug concentration that occurs after administration."

[0058] In this disclosure, the term "T" max"This refers to a blood drug concentration reaching C..." max Time required.

[0059] In this disclosure, the term "mammal" refers to animals including, for example, dogs, cats, cattle, sheep, horses, and humans. In some embodiments, mammals include humans.

[0060] In this disclosure, the term "patient" refers to animals (e.g., humans), companion animals (e.g., dogs, cats, or horses), and livestock (e.g., cattle, pigs, and sheep). In some embodiments, the patient is a mammal that includes both males and females. In some embodiments, the patient is a human.

[0061] In this disclosure, the term "therapeutic effective amount" refers to the amount of an active substance or combination of active substances that improves, reduces, or eliminates a particular disease or condition and its symptoms, or avoids or delays the onset of a particular disease or condition or its symptoms. The amount of active substance constituting a "therapeutic effective amount" as described in this disclosure will vary depending on the active substance, the disease state and its severity, and the age and weight of the mammal to be treated, etc. However, those skilled in the art can determine the amount of active substance described in this disclosure conventionally based on their own knowledge and this disclosure.

[0062] As used in this disclosure, "to treat" or "to treat" encompasses the treatment of a related disease or condition in mammals, such as humans, suffering from a related disease or ailment, and includes:

[0063] (i) To prevent the occurrence of disease or disease state in mammals, especially when the mammal is susceptible to the disease state but has not yet been diagnosed with the disease state;

[0064] (ii) Suppress the disease or disease state, that is, prevent it from occurring; or

[0065] (iii) Alleviate the disease or disease state, even if the disease or disease state subsides or does not progress.

[0066] As used in this disclosure, the terms “disease” and “disease state” may be used interchangeably or may be different, because a particular disease or disease state may not have a known causative agent (and therefore cannot be explained by etiology), and thus is not recognized as a disease, but rather as an undesirable disease state or symptom in which a clinician has identified a more or less specific set of symptoms.

[0067] The term "about" as used herein includes (and describes) embodiments relating to that value or parameter itself. In some embodiments, the term "about" includes an indication of ±10%. In other embodiments, the term "about" includes an indication of ±5%. In some still embodiments, the term "about" includes an indication of ±1%. Furthermore, the term "about X" includes a description of "X". Detailed Implementation

[0068] On the one hand, this disclosure relates to an inhaled powder composition comprising:

[0069] (a) Glucagon-like peptide-1 receptor agonist (GLP-1 RA);

[0070] (b) stabilizers; and

[0071] (c) Carrier;

[0072] Based on the total weight of the inhaled powder composition, the content of the glucagon-like peptide-1 receptor agonist (GLP-1RA) is about 5% to 50% by weight, the content of the stabilizer is about 5% to 40% by weight, and the content of the carrier is about 15% to 75% by weight.

[0073] In some embodiments, the content of glucagon-like peptide-1 receptor agonist (GLP-1 RA) is 5% to 50% by weight.

[0074] In some embodiments, the glucagon-like peptide-1 receptor agonist (GLP-1 RA) is present in a weight ratio of 5% to 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%.

[0075] In some embodiments, the content of glucagon-like peptide-1 receptor agonist (GLP-1 RA) is about 5 to 20% by weight, based on the total weight of the inhaled powder composition.

[0076] In some embodiments, the content of glucagon-like peptide-1 receptor agonist (GLP-1 RA) is about 5 to 20% by weight, based on the total weight of the inhaled powder composition.

[0077] In some embodiments, the content of glucagon-like peptide-1 receptor agonist (GLP-1 RA) is about 5 to 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight, based on the total weight of the inhaled powder composition.

[0078] In some embodiments, the stabilizer content is 5% to 40% by weight, based on the total weight of the inhaled powder composition.

[0079] In some embodiments, the stabilizer content is 5% to 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40% by weight, based on the total weight of the inhaled powder composition.

[0080] In some embodiments, the stabilizer content is about 20% to 30% by weight, based on the total weight of the inhaled powder composition.

[0081] In some embodiments, the stabilizer content is 20% to 30% by weight, based on the total weight of the inhaled powder composition.

[0082] In some embodiments, the stabilizer content is 20% to 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% by weight, based on the total weight of the inhaled powder composition.

[0083] In some embodiments, the carrier content is approximately 15% to 75% by weight, based on the total weight of the inhaled powder composition.

[0084] In some embodiments, the carrier content is approximately 15% to 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, or 41% based on the total weight of the inhaled powder composition. 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75% by weight.

[0085] In some embodiments, the carrier content is about 30% to 45% by weight, based on the total weight of the inhaled powder composition.

[0086] In some embodiments, the carrier content is 30% to 45% by weight, based on the total weight of the inhaled powder composition.

[0087] In some embodiments, the carrier content is 30% to 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, or 45% by weight, based on the total weight of the inhaled powder composition.

[0088] In some embodiments, exemplary examples of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) that can be used in this disclosure include, but are not limited to, smegglutide, liraglutide, telposide, exenatide, dulaglutide, benaglutide, lixisenatide, and loxenatide.

[0089] In some embodiments, exemplary examples of stabilizers that can be used in this disclosure include, but are not limited to, leucine, isoleucine, phenylalanine, tryptophan, methionine, proline, valine, alanine, and glycine.

[0090] In some embodiments, exemplary examples of carriers that can be used in this disclosure include, but are not limited to, mannitol, raffinose, and trehalose.

[0091] In some embodiments, the inhaled powder composition of this disclosure further comprises (d) a sustained-release material.

[0092] In some embodiments, the content of the sustained-release material is about 0 to 45% by weight, based on the total weight of the inhaled powder composition.

[0093] In some embodiments, the content of the sustained-release material is 0% to 45% based on the total weight of the inhaled powder composition.

[0094] In some embodiments, the content of the sustained-release material is 0 to 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, or 45% by weight, based on the total weight of the inhaled powder composition.

[0095] In some embodiments, the content of the sustained-release material is about 15 to 30% by weight, based on the total weight of the inhaled powder composition.

[0096] In some embodiments, the content of the sustained-release material is 15 to 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% by weight, based on the total weight of the inhaled powder composition.

[0097] In some embodiments, exemplary examples of sustained-release materials that can be used in this disclosure include, but are not limited to, polysaccharides containing ionizable groups or ionicly cross-linked hydroxy / carboxylic acid groups, polysaccharide-lipid compositions containing ionizable groups or ionicly cross-linked hydroxy / carboxylic acid groups, and polysaccharide-polymer compositions containing ionizable groups or ionicly cross-linked hydroxy / carboxylic acid groups.

[0098] In some embodiments, exemplary examples of polysaccharides containing ionizable groups or hydroxy / carboxylic acid groups that can be used in this disclosure include, but are not limited to, chitosan, sodium alginate, sodium hyaluronate, and sodium carboxymethyl cellulose.

[0099] In some embodiments, exemplary examples of polysaccharide-lipid compositions containing ionizable groups or hydroxy / carboxylic acid groups that can be used in the present disclosure include, but are not limited to, hyaluronic acid-DPPC.

[0100] In some embodiments, exemplary examples of polysaccharide-polymer compositions containing ionizable groups or hydroxy / carboxylic acid groups that can be used in the present disclosure include, but are not limited to, chitosan-PLGA.

[0101] In some embodiments, the D50 of the inhaled powder composition of this disclosure is about 0.5 to 5 μm.

[0102] In some embodiments, the D50 of the inhaled powder composition of this disclosure is 0.5 to 5 μm.

[0103] In some embodiments, the D50 of the inhaled powder composition of this disclosure is about 0.5 to 4 μm.

[0104] In some embodiments, the D50 of the inhaled powder composition of this disclosure is 0.5 to 4 μm.

[0105] In some embodiments, the D50 of the inhaled powder composition of this disclosure is from 0.5 μm to 0.6 μm, 0.7 μm, 0.8 μm, 0.9 μm, 1.0 μm, 1.1 μm, 1.2 μm, 1.3 μm, 1.4 μm, 1.5 μm, 1.6 μm, 1.7 μm, 1.8 μm, 1.9 μm, 2.0 μm, 2.1 μm, 2.2 μm, 2.3 μm, 2.4 μm, 2.5 μm, 2.6 μm, 2.7 μm, 2.8 μm, 2.9 μm, 3.0 μm, 3.1 μm, 3.2 μm, 3.3 μm, 3.4 μm, 3.5 μm, 3.6 μm, 3.7 μm, 3.8 μm, 3.9 μm, and 4.0 μm.

[0106] In some embodiments, the inhaled powder composition of this disclosure can achieve different local / systemic delivery ratios to achieve both local and systemic therapeutic effects.

[0107] In some embodiments, the inhaled powder composition of this disclosure can achieve additional local lung benefits, while simultaneously achieving both local and systemic therapeutic effects.

[0108] In some embodiments, the inhaled powder composition of this disclosure is able to maintain the inhaled delivery amount while increasing the amount of pulmonary deposition.

[0109] In some embodiments, the inhaled powder composition of this disclosure can achieve the highest systemic distribution ratio (bioavailability).

[0110] In some embodiments, the inhaled powder composition of this disclosure is capable of increasing the inhaled delivery volume and increasing the amount of pulmonary deposition.

[0111] In some embodiments, the inhaled powder composition of this disclosure can achieve optimal lung deposition and the best local therapeutic effect on the lungs.

[0112] In some embodiments, the inhaled powder composition of this disclosure has a sustained-release effect.

[0113] In some embodiments, the inhaled powder composition of this disclosure not only reduces the frequency of medication use and improves patient compliance, but also reduces potential side effects caused by frequent administration.

[0114] On the other hand, this disclosure relates to a method for preparing the inhaled powder composition described herein, comprising:

[0115] A solution is prepared by mixing and dissolving a glucagon-like peptide-1 receptor agonist (GLP-1 RA), a stabilizer, a carrier, and optional sustained-release material in water; and

[0116] The inhalation powder composition was prepared by spray drying of the solution.

[0117] In some implementations, the inlet air temperature in spray drying is approximately 90 to 110°C.

[0118] In some implementations, the outlet air temperature in spray drying is approximately 60 to 80°C.

[0119] In some implementations, the atomizing pressure in spray drying is approximately 40 to 60 kPa.

[0120] In some implementations, the feed rate in the spray drying process is approximately 1 to 4 mL / min.

[0121] In some embodiments, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), a stabilizer, a carrier, and optional sustained-release materials are mixed and dissolved in ultrapure water.

[0122] In some embodiments, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), a stabilizer, a carrier, and optional sustained-release materials are mixed and dissolved in ultrapure water to prepare a solution with a total concentration of approximately 25 mg / mL.

[0123] In some embodiments, the inhalation powder composition of this disclosure is prepared by a one-step spray drying method.

[0124] On the other hand, this disclosure relates to a method for treating inflammatory lung diseases and pulmonary fibrosis caused by inflammatory damage, comprising administering a therapeutically effective amount of the inhaled powder composition of this disclosure to an individual in need of the method.

[0125] In some embodiments, exemplary examples of inflammatory lung diseases that can be used in this disclosure include, but are not limited to, obstructive pulmonary disease / COPD, asthma, pulmonary sarcoidosis, diabetic pneumonia, interstitial lung disease (ILDs), progressive fibrotic interstitial lung disease (PF-ILD), connective tissue disease-associated interstitial lung disease (CTD-ILD), and acute interstitial pneumonia (AIP).

[0126] In some embodiments, exemplary examples of pulmonary fibrosis caused by inflammatory damage that can be used in this disclosure include, but are not limited to, cystic fibrosis, lung fibrosis, pulmonary fibrosis, and idiopathic pulmonary fibrosis (IPF).

[0127] In some embodiments, it can be used for pulmonary fibrosis secondary to systemic inflammatory diseases as disclosed in this disclosure.

[0128] In some embodiments, exemplary examples of systemic inflammatory diseases that can be used in this disclosure include, but are not limited to, rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrotic alveolitis, radiation fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, chronic asthma, silicosis, asbestos-induced pulmonary fibrosis or pleural fibrosis, acute lung injury, and acute respiratory distress.

[0129] In some implementations, exemplary examples of individuals that can be used for the purposes of this disclosure include, but are not limited to, mammals.

[0130] In some implementations, exemplary examples of mammals that can be used in this disclosure include, but are not limited to, humans.

[0131] In the following sections, this disclosure will be explained in detail through the following embodiments to provide a better understanding of the various aspects of this disclosure and its advantages. However, it should be understood that the following embodiments are non-limiting and are only used to illustrate certain implementations of this disclosure.

[0132] Example

[0133] The reagents and equipment used in the embodiments of this disclosure are all conventional and commercially available.

[0134] Reagents and Consumables

[0135] name source batch number Smegglutide Shenzhen Jianyuan DC005B-E231203-Y Mannitol Sigma-Aldrich 102614225 Leucine Solarborg 2230211002 Chitosan Maokang Biotechnology 4012S200409 DPPC Aladdin I2101250 Beas2B cells Beina Bio BNCC359274 Bleomycin MCE HY-17565 Pirfenidone Adooq A16209

[0136] instrument

[0137] name source model spray dryer Swiss BUCHI B-290 New generation particle impactor Copley, UK 5201A Laser particle size analyzer SYMPATEC Germany HELOS&RODOS

[0138] Example 1

[0139] Screening of drug content range in GLP-1 RA inhalation powder based on simulated lung deposition.

[0140] GLP-1 RA peptide, carrier material, and stabilizer were mixed in different mass ratios (Table 1-1), dissolved in ultrapure water, and prepared into a solution with a total concentration of 25 mg / mL. This solution was then used to prepare an inhalation powder using a spray drying process. The specific spray drying parameters were set as follows: inlet air temperature 100℃, outlet air temperature 70℃, atomizing pressure 50 kPa, and feed rate 2 mL / min. The resulting powder was collected.

[0141] The particle size, drug content, and aerodynamic parameters of different formulations of inhaled powder were evaluated. The particle size distribution of different formulations was determined using a laser particle size analyzer. The particle size distribution of the samples was typically represented by the characteristic value of the particle size distribution, namely the median particle size (D50), which indicates that 50% of the particles in the particle volume distribution map have a particle size smaller than this value. A precise amount of GLP-1 RA inhaled powder was weighed, dissolved in ultrapure water, and the drug content was determined using high-performance liquid chromatography (HPLC). The drug content was compared with the theoretical drug content to calculate the percentage of drug content. Each formulation was repeated three times. The aerodynamic properties of different formulations were evaluated using a new generation particle impactor. The inhalation flow rate and inhalation time were 60 L / min and 4 s, respectively. The power was turned off and the device was disassembled. Using ultrapure water as the collection liquid, powder was collected from the adapter, pre-separator, artificial throat, S1–S7, and MOC, respectively. Quantitative analysis was performed using HPLC to calculate the fine particle fraction (FPF) and the mass median aerodynamic diameter (MMAD).

[0142] Table 1-1 Screening of drug content in GLP-1 RA inhalation powder

[0143] Prescription (w / w) Smegglutide Mannitol Leucine G1 5 75 20 G2 20 60 20 G3 30 50 20 G4 50 30 20

[0144] Table 1-2 shows the D50 and drug content results for GLP-1 RA inhalation powder with different drug concentrations. As the drug concentration increases, the D50 of the GLP-1 RA inhalation powder gradually increases. When the drug concentration is 50%, the D50 reaches a maximum of 3.04 ± 0.16 μm, still within the 0.5 to 5 μm range, suitable for pulmonary drug delivery. The drug concentrations of different prescriptions are all within the range of 100 ± 10%, indicating that the spray drying preparation process does not affect the drug concentration.

[0145] Aerodynamic results for GLP-1 RA inhalation powders with different drug concentrations are shown in the figure. Figure 1 As the drug concentration increases, the MMAD of inhaled powder increases, while the FPF decreases.

[0146] Table 1-2 D50 and drug content of GLP-1 RA inhalation powder

[0147] prescription D50(μm) Drug content (%) G1 2.27±0.05 103.24±1.24 G2 2.35±0.08 106.60±2.08 G3 2.71±0.06 100.44±1.82 G4 3.04±0.16 95.93±1.75

[0148] Example 2

[0149] Evaluation of the efficacy and content range of sustained-release components in GLP-1 RA inhalation powder based on droplet characteristics and sustained-release effect.

[0150] GLP-1 RA peptide, carrier material, sustained-release material, and stabilizer were mixed in different mass ratios (Table 2-1), dissolved in ultrapure water, and prepared into a solution with a total concentration of 25 mg / mL. This solution was then used to prepare an inhalation powder using a spray-drying process. The specific spray-drying parameters were set as follows: inlet air temperature 100℃, outlet air temperature 70℃, atomizing pressure 50 kPa, and feed rate 2 mL / min. The resulting powder was collected.

[0151] The particle size, aerodynamic parameters, and in vitro release performance of different formulations of inhaled powder were evaluated. The methods for testing particle size and aerodynamic parameters are described in Example 1. The in vitro release performance of different formulations was determined using the dialysis bag method. A certain amount of sample was placed in a dialysis bag, then in a centrifuge tube containing 40 mL of PBS, and placed on a shaker at 37°C. At 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, and 48 h, 1 mL of PBS was removed, and 1 mL of fresh PBS was added. The sample concentration was detected using high-performance liquid chromatography (HPLC), and in vitro release curves were plotted.

[0152] Table 2-1 Screening of sustained-release material content in GLP-1 RA inhalation powder

[0153] Prescription (w / w) Smegglutide Mannitol Leucine Chitosan G5 20 60 20 0 G6 20 53 20 7 G7 20 45 20 15 G8 20 30 20 30 G9 20 15 20 45

[0154] Table 2-2 shows the D50 results of GLP-1 RA inhalation powder with different sustained-release material contents. As the sustained-release material content increases, the D50 of the GLP-1 RA inhalation powder gradually increases. The sustained-release material is a high-molecular-weight polymer, which increases the viscosity of the precursor liquid, resulting in larger spray droplets and larger dried powder particles. When the sustained-release material content is between 0% and 45%, the D50 of each formulation is in the range of 0.5 to 5 μm.

[0155] The in vitro release curves of GLP-1 RA inhalation powder with different sustained-release material contents are shown in the figure. Figure 2 When the formulation does not contain sustained-release materials, G5 inhaled powder releases rapidly, achieving a release rate of 65.1% within 30 minutes and over 90% within 2 hours. However, as the content of sustained-release materials in the formulation increases, the release of GLP-1 RA inhaled powder gradually slows down. The release rates of G7-G9 at 2 hours are 32.2%, 26.3%, and 9.1%, respectively. G7 and G8 reach release equilibrium (release rate >90%) at 24 hours, with G8 and G9 achieving release rates of 68.4% and 59.1%, respectively.

[0156] Aerodynamic results for GLP-1 RA inhalation powder with different sustained-release material contents are shown in the figure. Figure 3As the content of sustained-release material increases, the MMAD (Multi-Level Adsorption) of inhaled powder aerosols increases, while the FPF (Frequency Delivery Frequency) decreases. In formulations containing sustained-release material, G6-G7 have an FPF greater than 50%, exhibiting good pulmonary delivery performance. When the sustained-release material content is 30%, the FPF of G8 decreases slightly to 38.6±3.7%, but still maintains good delivery efficiency. This may be due to increased interparticle adhesion, leading to agglomeration, which in turn increases MMAD and decreases pulmonary delivery efficiency.

[0157] Table 2-2 D50 of GLP-1 RA inhalation powder

[0158] prescription D50(μm) G5 2.35±0.08 G6 2.52±0.04 G7 2.69±0.02 G8 3.13±0.14 G9 3.79±0.23

[0159] Example 3

[0160] Verification of the stabilizer content range in GLP-1 RA inhalation powder based on powder stability and droplet characteristics.

[0161] GLP-1 RA peptide, carrier material, sustained-release material, and stabilizer were mixed in different mass ratios (Table 3-1), dissolved in ultrapure water, and prepared into a solution with a total concentration of 25 mg / mL. This solution was then used to prepare an inhalation powder using a spray-drying process. The specific spray-drying parameters were set as follows: inlet air temperature 100℃, outlet air temperature 70℃, atomizing pressure 50 kPa, and feed rate 2 mL / min. The resulting powder was collected.

[0162] The particle size, hygroscopicity, and aerodynamic parameters of different formulation inhaled powders were evaluated. The test methods for particle size and aerodynamic parameters are described in Example 1. The specific evaluation method for the drug hygroscopicity test is as follows: First, a dry beaker was placed in a desiccator containing a saturated potassium chloride solution (80±5% RH, 25±1℃). After equilibration, the beaker was accurately weighed (m1). An appropriate amount of the test sample was taken and spread evenly in the beaker, with a thickness of approximately 1 mm, and accurately weighed (m2). The beaker containing the test sample was placed in the desiccator and removed at 1h, 2h, 3h, 4h, 5h, 6h, and 24h, and accurately weighed (m3). The percentage increase in weight was calculated as follows:

[0163] Weight gain percentage = (m3-m2) / (m2-m1)×100%

[0164] Table 3-1 Screening of stabilizer content in GLP-1 RA inhalation powder

[0165] Prescription (w / w) Smegglutide Mannitol Leucine Chitosan G10 20 60 5 15 G11 20 55 10 15 G12* 20 45 20 15 G13 20 35 30 15 G14 20 25 40 15

[0166] *The G12 formulation has the same components as the aforementioned G7.

[0167] Results of moisture gain percentage of GLP-1 RA inhalation powder with different stabilizer contents are as follows: Figure 4 When the stabilizer content is 5-10% (G10 and G11), the percentage of moisture-induced weight gain is less than 15% but not less than 2%, according to Appendix XIXJ of the Chinese Pharmacopoeia—Guidelines for Hygroscopicity Testing of Drugs, it is considered hygroscopic. When the stabilizer content increases to 20% or more, the percentage of moisture-induced weight gain for G12-G14 is less than 2%, which is considered low hygroscopicity, and the powder in the spray atomizer has good powder stability. The stabilizer is a hydrophobic amino acid. During spray drying, hydrophobic molecules in the droplets tend to migrate towards the gas-liquid interface, forming a core-shell structure with a hydrophobic shell and a hydrophilic core. The hydrophobic shell can prevent the particles from absorbing moisture. Therefore, as the stabilizer content increases, the hygroscopicity of the powder in the spray atomizer decreases and its stability increases.

[0168] Aerodynamic results for GLP-1 RA inhalation powders with different stabilizer contents are shown in the figure. Figure 5 As the stabilizer content increases, MMAD (Medium-to-Density Acid) tends to decrease, while FPF (Fan Filter Frequency) shows a trend of first increasing and then decreasing. During spray drying, due to the hydrophobicity of the stabilizer, particles with wrinkled surfaces are formed, resulting in smaller particle size, lower powder density, and improved aerodynamic performance. When the stabilizer content is 20%, G12 has the highest FPF of 51.1±2.7%. When the stabilizer content increases to 30%, it may lead to greater particle shrinkage during drying, increasing inter-particle adhesion and reducing powder flowability. The FPF of G13 decreases slightly to 47.8±3.6%, but it still maintains good delivery efficiency.

[0169] Example 4

[0170] Evaluation of the advantages of sustained-release GLP-1 RA inhalation powder based on animal hemodynamics

[0171] The pharmacokinetics of GLP-1 RA inhalation powder in rats were investigated. The inhalation powder formulation used was G5 and G7 from Example 2 above.

[0172] Before the experiment, SD rats were anesthetized by intraperitoneal injection.

[0173] Inhalation powder group (G5 and G7): The spray needle containing the inhalation powder was inserted into the trachea of ​​the SD rats, and the inhalation powder was sprayed in by pressing the device.

[0174] Intravenous injection group: Gently insert the syringe needle into the selected and sterilized vein. Once it is confirmed that the needle is correctly positioned inside the vein, slowly inject the medication.

[0175] Subcutaneous group: Disinfect the skin on the back of the rat's neck with an alcohol swab. Slightly lift the skin with your thumb and forefinger to create a subcutaneous space, and slowly inject the subcutaneous injection. Remove the syringe and gently press the injection site with a cotton ball for 5 seconds to stop bleeding.

[0176] Oral administration group: A certain amount of GLP-1 RA was dissolved in PBS to prepare a clear solution. The GLP-1 RA solution was administered into the stomach of SD rats using a gavage syringe.

[0177] Plasma sampling and processing: At 1 min, 3 min, 5 min, 10 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, 48 h, and 72 h after drug administration, 400 μL of blood was collected from the orbital sinus into anticoagulated centrifuge tubes. The plasma samples were centrifuged at 4°C for 10 min (5000 rpm), and 100 μL of serum was transferred to another centrifuge tube. A certain amount of methanol was added to the plasma, vortexed for 30 s, and centrifuged at 4°C for 10 min (14000 rpm). The supernatant was collected into a sample vial. GLP-1 RA in the samples was quantified using LC / MS.

[0178] Pharmacokinetic results of different dosage forms of GLP-1 RA are shown in the figure. Figure 6 The peak time T for the G5 group without sustained-release material max The time was 2 hours, and the absolute bioavailability was 24.8%; the T of the group containing the sustained-release material G7 was... max The bioavailability was approximately 43.9% for 10 hours, significantly higher than the 0.8% in the oral group. The introduction of sustained-release materials maintained the release for 48 hours, significantly increasing bioavailability by nearly two times.

[0179] Example 5

[0180] Based on the selection of sustained-release components, the local / systemic distribution ratio of GLP-1 RA inhaled powder can be regulated.

[0181] Pharmacokinetic results of GLP-1 RA inhalation powder under different types of equal-volume sustained-release formulations / sustained-release compositions are shown in [reference needed]. Figure 7 In a powder inhalation formulation of equal volumes of GLP-1 RA / carrier / stabilizer / sustained-release agent (20:45:20:15), the chitosan group showed the highest T... max As in the aforementioned embodiments, it is basically maintained at around 10 hours; the T of the DPPC group alone max The sustained-release effect weakened slightly after about 4 hours; while the chitosan-DPPC composition showed a T... max Extended to 24 hours.

[0182] Furthermore, comparing the relative bioavailability of the three formulations using the curve AUC of the above results, the AUC of G15 was 2.88 times that of G12, while the AUC of G16 was 40.58% of that of G12.

[0183] Table 4-1 Comparison of different sustained-release components in GLP-1 RA inhalation powder

[0184]

[0185] Furthermore, the delivery ratio of the above prescriptions to the lungs / systemic system was compared. G12 showed high blood concentration but low concentration in lung tissue. G15 showed relatively low blood concentration but significantly increased concentration in lung tissue. Group G16 achieved a near-perfect ratio of local lung concentration to systemic blood concentration.

[0186] Therefore, the peptide inhalation powder sustained-release formulation can meet different requirements for local / systemic delivery ratios to the lungs.

[0187] Example 6

[0188] Based on a cell model mediated by the TGF-β signaling pathway, this study validates the mechanism by which GLP-1 RA inhaled powder is used to treat lung inflammation and the fibrosis induced by inflammation.

[0189] TGF-β1 is released during inflammation, regulates immune cells through the Smad signaling pathway, and induces changes in cell morphology, transforming from an epithelial-like structure to a spindle-shaped structure, i.e., epithelial-mesenchymal transition (EMT), which promotes fibrosis.

[0190] Taking the optimal GLP-1RA powder formulation selected in the above implementation case as an example, different concentrations of GLP-1 (7.81, 15.63, 31.25, 62.5, 125, 250, 500 μg / mL, calculated based on the content of semaglutide) were added to Beas2B cells and cultured for 48 h. CCK-8 assays revealed that Beas2B cells at nearly 70-fold dosage gradients showed no cytotoxicity. Experimental results are shown below. Figure 8 The GLP-1RA inhaled powder composition has no significant toxicity to pulmonary airway epithelial cells.

[0191] Furthermore, TGF-β1 (15 ng / mL) was added to Beas 2B cells and incubated for 24 h to induce fibrosis. Subsequently, different concentrations of GLP-1 (10, 50, 100, 200 μg / mL) were added to the cells and cultured for another 24 h. RNA and protein were extracted for RT-PCR and Western blotting experiments. RT-PCR detected the mRNA levels of fibrosis markers Fibronectin and α-SMA; Western blotting detected the protein levels of fibrosis markers Fibronectin and Collagen I. The experimental results are shown below. Figures 9 to 11 GLP-1 can reduce the mRNA levels of Fibronectin and α-SMA induced by TGF-β1, as well as the protein levels of Fibronectin and Collagen I.

[0192] The above-mentioned cellular experiments demonstrate that the GLP-1 inhaled powder composition can act on the target sites and signaling pathways of inflammation at the molecular mechanism level, thereby inhibiting pulmonary epithelial cell fibrosis.

[0193] Example 7

[0194] Animal in vivo studies based on local pulmonary administration to evaluate sustained-release GLP-1 RA inhaled powder.

[0195] Novel applications of this agent in the treatment of inflammatory lung diseases and inflammatory loss-mediated fibrosis.

[0196] A pulmonary fibrosis model was established in rats by intratracheal instillation of bleomycin (5 mg / kg). Seven days later, different doses of GLP-1 powder aerosol granules prepared in Case 2 (100, 200, and 400 μg / rat) were administered via pulmonary administration for 20 days, every other day for a total of 10 administrations. The positive control drug pirfenidone (150 mg / kg) was administered orally for 20 days, once daily. After treatment, the rats were processed, and serum and bronchoalveolar lavage fluid were collected to detect TNF-α and IL-6 levels, respectively. Lung tissue sections were subjected to H&E and Masson staining to observe inflammatory cell infiltration and collagen changes. Lung tissue proteins were extracted, and Western blotting was used to detect changes in the protein levels of fibrosis markers fibronectin and Collagen I. Immunohistochemistry of lung tissue sections was used to detect fibronectin and Collagen I levels. Results are shown below. Figures 12 to 18 .

[0197] In rats with pulmonary fibrosis, the levels of TNF-α and IL-6 in serum and bronchoalveolar lavage fluid were significantly elevated. Treatment with different doses of GLP-1 reduced the levels of TNF-α and IL-6 in both serum and bronchoalveolar lavage fluid. Figures 12 to 15 H&E and Masson staining results showed that the model group rats had significant inflammatory cell infiltration in the lungs accompanied by a large amount of collagen deposition. The inflammatory cell infiltration and collagen deposition were significantly reduced in the GLP-1 treatment group; among them, the 1.2 mg / kg GLP-1 lung administration treatment group had comparable effects to the 150 mg / kg pirfenidone oral treatment group. Figure 16 Western blotting and immunohistochemical results showed that the protein levels of Fibronectin and Collagen I were significantly increased in the lung tissue of rats with pulmonary fibrosis, and that different doses of GLP-1 treatment could reduce the protein levels of Fibronectin and Collagen I. Figure 17 and Figure 18 ).

[0198] The above results indicate that the GLP-1 inhaled powder composition, delivered to pulmonary fibrosis lesions via the lungs, can exhibit therapeutic effects comparable to those of pirfenidone at nearly 400 times the dosage.

[0199] Example 8

[0200] Tolerance and toxicology studies of GLP-1RA inhaled powder composition delivered via the lungs were conducted in animals via airway administration to evaluate its tolerability and safety.

[0201] The body weight of the pulmonary fibrosis rats in the above in vivo experiments was recorded during the treatment period, and the statistical results are shown in [see figure]. Figure 19 Rats showed a tendency to lose weight in the early stages of airway administration, but as the treatment duration increased, the weight of rats in different GLP-1RA dosage groups tended to stabilize and showed a slow tendency to increase, with no significant weight loss. Furthermore, after the treatment period, H&E staining analysis of heart, liver, spleen, kidney, and brain sections of rats was performed. Figure 20 No significant toxic effects on organs were found after administration of GLP-1RA powder inhaler.

[0202] Example 9

[0203] In the above animal experiments, after inhalation of GLP-1RA powder, blood was collected from the orbital cavity at 15 min, 1 h, 6 h, and 8 h after administration and placed in anticoagulant tubes. The supernatant was collected at 5000 rpm, and the glycosylated hemoglobin content in plasma at different time points was detected by ELISA. Figure 21 The results showed that, after inhalation of GLP-1RA powder, the level of glycated hemoglobin in plasma decreased significantly with increasing administration time compared to 15 minutes after administration.

[0204] On the other hand, the TNF-α levels in both serum and bronchoalveolar lavage fluid of the rats with pulmonary fibrosis in Example 7 were significantly elevated, and GLP-1 treatment reduced TNF-α levels in both serum and bronchoalveolar lavage fluid. The protein levels of Fibronectin and Collegan I were also reduced after GLP-1 treatment. These results indicate that GLP-1 lung delivery can treat Bleomycin-induced pulmonary fibrosis in rats to some extent.

[0205] In summary, the GLP-1RA inhalation powder composition, administered via inhalation, provides local anti-inflammatory and anti-fibrotic benefits to the lungs, as well as systemic anti-inflammatory, hypoglycemic, and weight-loss effects. The sustained-release GLP-1RA inhalation powder is suitable for medical use in the treatment of local / systemic inflammatory and fibrotic diseases of the lungs.

[0206] In this disclosure, relational terms such as first and second are used merely to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations.

[0207] As will be understood from the foregoing, although specific embodiments of this disclosure have been described for illustrative purposes, various modifications or alterations can be made by those skilled in the art without departing from the spirit and scope of this disclosure. All such modifications or alterations should fall within the scope of the appended claims.

Claims

1. An inhaled powder composition comprising: (a) Glucagon-like peptide-1 receptor agonist (GLP-1RA); (b) stabilizers; and (c) Carrier; Based on the total weight of the inhaled powder composition, the content of the glucagon-like peptide-1 receptor agonist (GLP-1RA) is about 5% to 50% by weight, the content of the stabilizer is about 5% to 40% by weight, and the content of the carrier is about 15% to 75% by weight.

2. The inhaled powder composition of claim 1, wherein the content of the glucagon-like peptide-1 receptor agonist (GLP-1RA) is about 5 to 20% by weight, based on the total weight of the inhaled powder composition.

3. The inhaled powder composition of claim 1 or 2, wherein the stabilizer content is about 20% to 30% by weight based on the total weight of the inhaled powder composition.

4. The inhaled powder composition according to any one of claims 1 to 3, wherein the carrier content is about 30% to 45% by weight based on the total weight of the inhaled powder composition.

5. The inhaled powder composition according to any one of claims 1 to 4, wherein the glucagon-like peptide-1 receptor agonist (GLP-1RA) is selected from smegglutide, liraglutide, telposide, exenatide, dulaglutide, beraglutide, lixisenatide, and loxenatide.

6. The inhaled powder composition according to any one of claims 1 to 5, wherein the stabilizer is selected from leucine, isoleucine, phenylalanine, tryptophan, methionine, proline, valine, alanine, glycine, and any mixture thereof.

7. The inhaled powder composition according to any one of claims 1 to 6, wherein the carrier is selected from mannitol, raffinose, trehalose, and any mixture thereof.

8. The inhaled powder composition according to any one of claims 1 to 7, further comprising (d) a sustained-release material.

9. The inhaled powder composition of claim 8, wherein the content of the sustained-release material is about 0 to 45% by weight, based on the total weight of the inhaled powder composition.

10. The inhaled powder composition of claim 8 or 9, wherein the content of the sustained-release material is about 15 to 30% by weight, based on the total weight of the inhaled powder composition.

11. The inhaled powder composition according to any one of claims 8 to 10, wherein the sustained-release material is selected from polysaccharides containing ionizable groups or ionically cross-linked hydroxy / carboxylic acid groups, polysaccharide-lipid compositions containing ionizable groups or ionically cross-linked hydroxy / carboxylic acid groups, polysaccharide-polymer compositions containing ionizable groups or ionically cross-linked hydroxy / carboxylic acid groups, or any mixture thereof.

12. The inhaled powder composition of claim 11, wherein the polysaccharide containing ionizable groups or hydroxy / carboxylic acid groups that undergo ionic crosslinking is selected from chitosan, sodium alginate, sodium hyaluronate, sodium carboxymethyl cellulose, or any mixture thereof.

13. The inhaled powder composition of claim 11, wherein the polysaccharide-lipid composition containing ionizable groups or hydroxy / carboxylic acid groups that undergo ionic crosslinking is selected from hyaluronic acid-DPPC or any mixture thereof.

14. The inhaled powder composition of claim 11, wherein the polysaccharide-polymer composition containing ionizable groups or hydroxyl / carboxylic acid groups that undergo ionic crosslinking is selected from chitosan-PLGA or any mixture thereof.

15. The inhaled powder composition according to any one of claims 1 to 14, wherein the D50 is about 0.5 to 5 μm.

16. The inhaled powder composition according to any one of claims 1 to 15, wherein the D50 is about 0.5 to 4 μm.

17. A method for preparing the inhaled powder composition according to any one of claims 1 to 16, comprising: A solution is prepared by mixing and dissolving a glucagon-like peptide-1 receptor agonist (GLP-1RA), a stabilizer, a carrier, and an optional sustained-release material in water. as well as The inhalation powder composition was prepared by spray drying of the solution.

18. The method of claim 17, wherein the inlet air temperature in the spray drying process is approximately 90 to 110°C.

19. The method of claim 17 or 18, wherein the outlet air temperature in the spray drying method is about 60 to 80°C.

20. The method according to any one of claims 17 to 19, wherein the atomizing gas pressure in the spray drying method is about 40 to 60 kPa.

21. The method according to any one of claims 17 to 20, wherein the feed rate in the spray drying process is about 1 to 4 mL / min.

22. A method for treating inflammatory lung diseases and pulmonary fibrosis caused by inflammatory damage, comprising administering to an individual requiring the method a therapeutically effective amount of the inhaled powder composition of any one of claims 1 to 16.

23. The method of claim 22, wherein the inflammatory lung disease is selected from chronic obstructive pulmonary disease / COPD, asthma, pulmonary sarcoidosis, diabetic pneumonia, interstitial lung disease (ILDs), progressive fibrotic interstitial lung disease (PF-ILD), connective tissue disease-associated interstitial lung disease (CTD-ILD), and acute interstitial pneumonia (AIP).

24. The method of claim 22, wherein the pulmonary fibrosis resulting from inflammatory damage is selected from cystic fibrosis, lung fibrosis, pulmonary fibrosis, and idiopathic pulmonary fibrosis (IPF).

25. The method of claim 24, wherein the pulmonary fibrosis and pulmonary fibrosis are secondary to a systemic inflammatory disease.

26. The method of claim 25, wherein the systemic inflammatory disease is selected from rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrotic alveolitis, radiation fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, chronic asthma, silicosis, asbestos-induced pulmonary fibrosis or pleural fibrosis, acute lung injury, and acute respiratory distress.

27. The method of any one of claims 22 to 26, wherein the individual is a mammal.

28. The method of any one of claims 22 to 27, wherein the individual is a human being.

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