An inhalable drug-loaded nanoparticle and a preparation method and application thereof

Abstract

The present application relates to the technical field of pharmaceutical preparation, in particular to a kind of inhalable drug-loaded nanoparticles and its preparation method and application.The drug-loaded nanoparticles include polymer nanocarriers, and nintedanib loaded on the polymer nanocarriers by hydrogen bond;The polymer nanocarriers are obtained by self-assembly of cationic polysaccharide and anionic polymer through electrostatic interaction.Cationic polysaccharide and anionic polymer form polymer nanocarriers with stable internal structure through electrostatic interaction, which can significantly improve the encapsulation efficiency of nintedanib.The drug-loaded nanoparticles prepared by ion crosslinking method have uniform particle size, good bioavailability and sustained-release therapeutic effect, and can be used as a powerful choice for treating idiopathic pulmonary fibrosis by pulmonary inhalation preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to inhalable drug-loaded nanoparticles and a preparation method and application thereof. Background Art

[0002] Pulmonary fibrosis is a chronic, progressive lung disease characterized by the gradual replacement of lung tissue with fibrosis, leading to a continuous decline in respiratory function, shortness of breath, and a sharp decrease in quality of life. Idiopathic pulmonary fibrosis (IPF) is the most common subtype, with a median survival of only 3-5 years. Currently, there is no cure for IPF, and treatment options are available to control symptoms and slow disease progression, including but not limited to oxygen therapy, lung transplantation, and various medications. While significant progress has been made in the medical treatment of IPF in recent years, numerous challenges remain to be overcome, including earlier diagnosis, improved patient compliance, and improved prognosis. Therefore, developing novel drug formulations to address these challenges is crucial.

[0003] Nintedanib (NDNB) is a tyrosine kinase inhibitor regulated by the U.S. Food and Drug Administration.

[0004] The US Food and Drug Administration (FDA) has approved the drug for the treatment of idiopathic pulmonary fibrosis (IPF). Conventional oral administration of nintedanib can easily lead to liver damage in patients and may also cause adverse gastrointestinal reactions such as diarrhea and nausea. Therefore, it is necessary to target nintedanib to the lungs as much as possible. In addition, the current oral dosage form has the problem of low bioavailability, while inhaled preparations can directly enter the lungs, thereby more effectively treating lung diseases such as idiopathic pulmonary fibrosis. For example, the modified ethanol injection method described in the article "Preparation and Characterization Study of Nintedanib Nanoliposomes" in the Journal of Army Medical University, Issue 46(14) in 2024 can prepare targeted nintedanib liposomes with an encapsulation rate of about 32%. Another example is patent CN202310267601.8, which discloses an inhalable lipid nanoparticle, its preparation method, and application. This technical solution encapsulates the anti-fibrotic drug nintedanib and the first-line anti-diabetic drug metformin in inhalable liposomes for the treatment of bleomycin-induced pulmonary fibrosis. This technical solution uses dipalmitoylphosphatidylcholine, cholesterol, and distearoylphosphatidylacetamide-polyethylene glycol to prepare nintedanib liposomes with a hydrated particle size of about 100 nm.

[0005] In the prior art, in order to achieve targeted transport of nintedanib, emulsion evaporation method is often used to prepare lipid carriers, and in the preparation process, more organic solvents are introduced, and the biological safety is poor; and the existing nintedanib drug-loaded particles have low encapsulation efficiency, so that the drug is rapidly released into the body, resulting in a short half-life of the drug in the body, and more frequent administration is required. SUMMARY

[0006] The present application is to overcome the defects of low bioavailability of oral nintedanib and low encapsulation efficiency and poor sustained-release effect of existing inhalable nintedanib in the prior art, and attempts to use ion cross-linking method to prepare nanoparticles to prolong the residence time of nintedanib in the lung, improve the local drug concentration in the lung, improve the bioavailability of the drug, and proposes an inhalable drug-loaded nanoparticle and a preparation method and application thereof to overcome the above-mentioned defects.

[0007] To achieve the above-mentioned application purposes, the present application adopts the following technical solutions:

[0008] In a first aspect, the present application discloses an inhalable drug-loaded nanoparticle:

[0009] The inhalable drug-loaded nanoparticle comprises a polymeric nanocarrier and nintedanib loaded on the polymeric nanocarrier through hydrogen bonds.

[0010] The polymeric nanocarrier is obtained by self-assembly of a cationic polysaccharide and an anionic polymer through electrostatic interaction.

[0011] Nintedanib has good effect in treating pulmonary fibrosis, but nintedanib has low solubility, and the current oral dosage forms all have the problem of low bioavailability, while inhalation preparations can directly enter the lung, thereby more effectively treating lung diseases. Therefore, the present application prepares nintedanib into nanoparticles, and the particle size meets the inhalation standard, thereby achieving the effects of improving bioavailability and improving drug efficacy.

[0012] Nintedanib has multiple polar groups such as hydroxyl and amino groups in its molecular structure. Cationic polysaccharide is a high molecular substance containing amino or amino functional groups in its structure. The cationic polysaccharide and the anionic polymer form a polymeric nanocarrier with stable internal structure through electrostatic interaction, and the polymeric nanocarrier contains multiple hydrogen bond acceptors. Free nintedanib can form multiple hydrogen bonds between the polar groups on the nintedanib and the polymeric nanocarrier, thereby achieving stable combination, and improving the drug loading capacity and encapsulation efficiency of the drug. In this way, more nintedanib can be targeted to the lung, and the nintedanib coated therein can be slowly released, thereby achieving the effect of sustained release.

[0013] Furthermore, the cationic polysaccharide is chitosan. Chitosan is the only naturally positively charged polysaccharide. It possesses excellent biocompatibility, blood compatibility, self-degradation, and safety. More importantly, chitosan exhibits excellent mucosal adhesion. The design and preparation of chitosan-based pulmonary inhalation nanoformulations can prolong the retention time of nintedanib in the lungs, enhance its distribution within the lungs, and increase local drug concentrations in the lungs.

[0014] Furthermore, the anionic polymer contains carboxyl groups. The hydroxyl groups in nintedanib and the amino groups on the cationic polysaccharide can form hydrogen bonds with the carboxyl groups in the anionic polymer. The synergistic effect of multiple hydrogen bonds can significantly enhance the binding force between molecules.

[0015] Furthermore, the anionic polymer is one or more of polyaspartic acid, polyacrylic acid, and polyglutamic acid. The above-mentioned anionic polymers all contain carboxyl groups, which, together with the amino groups in the cationic polysaccharide, form multiple hydrogen bonds with multiple polar groups in nintedanib, significantly enhancing the binding force between molecules, greatly improving the drug loading efficiency and achieving a sustained-release effect. Polyaspartic acid is an amino acid polymer that naturally occurs in snail and mollusk shells and has good biocompatibility and biodegradability. Polyglutamic acid is an anionic natural polymer with an active carboxyl group, which is easily soluble in water, non-toxic, biocompatible, and degradable. It can be biodegraded into endogenous substance glutamate in nature or in the human body, and is not prone to accumulation and toxic side effects.

[0016] Furthermore, the inhalable drug-loaded nanoparticles have a particle size between 220 and 235 nm. Ideally, inhaled nanoparticles should be able to effectively deposit in the alveolar region, allowing the drug to be absorbed by the capillaries in the alveoli and enter the blood circulation. When the nanoparticle size is too large, the drug is more likely to be deposited in the upper respiratory tract and unable to effectively reach the alveoli. When the nanoparticle size is too small, the drug is more likely to be discharged from the lungs with the respiratory airflow, failing to achieve a good therapeutic effect. Therefore, the present invention controls the particle size of the inhalable nintedanib to between 220 and 235 nm, ensuring that the drug can reach the alveoli while being difficult to be discharged from the lungs with breathing.

[0017] Furthermore, the encapsulation efficiency of the inhalable drug-loaded nanoparticles is ≥45%. To ensure drug efficacy, a higher encapsulation efficiency means that more drugs are delivered to the target location and the encapsulated drugs can be slowly released.

[0018] Furthermore, the mass ratio of the cationic polysaccharide to the anionic polymer is 1:0.2-0.6.

[0019] Furthermore, the mass ratio of nintedanib to cationic polysaccharide is 0.4-0.7:1.

[0020] In a second aspect, the present application discloses a preparation method of inhalable drug-loaded nanoparticles, comprising the following steps:

[0021] S1, dissolving the cationic polysaccharide in an acetic acid solution, and then dissolving nintedanib in the cationic polysaccharide acetic acid solution;

[0022] S2, slowly dropping the anionic polymer solution into the cationic polysaccharide acetic acid solution under stirring;

[0023] S3, centrifuging and concentrating to obtain the inhalable drug-loaded nanoparticles.

[0024] In a third aspect, the present application discloses an application of the inhalable drug-loaded nanoparticles in the preparation of a drug for treating idiopathic pulmonary fibrosis.

[0025] Therefore, the present application has the following beneficial effects:

[0026] (1) The present application can achieve a high encapsulation rate by constructing a nano drug delivery system with cationic polysaccharide and anionic polymer, has a longer lung retention time, increases the local blood drug concentration in the lung, and achieves better therapeutic effect.

[0027] (2) The present application prepares nanoparticles by ion crosslinking method, reduces the introduction of organic solvents, and selects cationic polysaccharide and anionic polymer by optimization scheme, so that the drug-loaded nanoparticles have good biocompatibility, biodegradability, etc.

[0028] (3) The inhalable drug-loaded nanoparticles prepared by the present application have smooth surface and spherical shape, good dispersibility, can significantly improve the drug loading efficiency and achieve sustained release effect. BRIEF DESCRIPTION OF DRAWINGS

[0029] Figure 1 SEM image of NDNB / CS-PGA NPs prepared in Example 1 of the present application.

[0030] Figure 2 Particle size distribution graph of NDNB / CS-PGA NPs prepared in Example 1 of the present application.

[0031] Figure 3 Potential distribution graph of NDNB / CS-PGA NPs prepared in Example 1 of the present application.

[0032] Figure 4 Release curve and cumulative release rate comparison graph of NDNB / CS-PGA NPs and NDNB raw material in PBS.

[0033] Figure 5The half inhibitory rate of NDNB / CS-PGA NPs and NDNB of different concentrations on Calu-3 cells is compared.

[0034] Figure 6 The half inhibitory rate of NDNB / CS-PGA NPs and NDNB of different concentrations on HFL1 cells is compared. DETAILED DESCRIPTION

[0035] The technical solutions of the present application are further described below in detail with specific examples and in conjunction with the drawings. It should be understood that the examples described in the present application are implemented on the premise of the technical solutions of the present application, and detailed implementation manners and specific operation processes are given, but only a part of the examples of the present application, not all the examples. Based on the examples in the present application, all other examples obtained by those skilled in the art without creative labor belong to the scope of protection of the present application. Unless otherwise specified, the experimental methods used in the following examples are conventional methods, and the materials, reagents, etc. used in the examples can be obtained from commercial channels if not otherwise specified.

[0036] The drug-loaded nanoparticles prepared in the following examples and comparative examples are subjected to particle size and polydispersity index (PDI) determination by a laser particle size analyzer, and the concentration of nintedanib in the nintedanib nanoparticles is calculated by a UV spectrophotometer through a nintedanib-methanol standard curve. The entrapment efficiency (EE) and drug loading (DL) of the nanoparticles are obtained according to the formula.

[0037]

[0038]

[0039] Example 1

[0040] Dissolve 1 part of chitosan in an aqueous solution containing 0.1% acetic acid, and then weigh 0.5 parts of nintedanib and dissolve it in the above solution;

[0041] Dissolve 0.4 parts of polyglutamic acid in pure water, set the stirring rate to 800 rpm, and stir for 5 min. During the stirring process, slowly drop the polyglutamic acid solution into the acetic acid solution of chitosan and nintedanib to obtain a nanoparticle suspension;

[0042] After stirring, transfer the nanoparticle suspension to an ultrafiltration centrifuge tube (4000 D), centrifuge at 2000 rpm for 20 min, and then concentrate and remove the free nintedanib that is not wrapped. Store the product in a 4°C refrigerator in the dark for later use.

[0043] Example 2

[0044] Dissolve 1 part of chitosan in an aqueous solution containing 0.1% acetic acid, and then dissolve 0.5 parts of nintedanib in the above solution;

[0045] Dissolve 0.2 parts of polyglutamic acid in pure water, set the stirring rate to 800 rpm, and stir for 5 min. During the stirring process, slowly drop the polyglutamic acid solution into the acetic acid solution of chitosan and nintedanib to obtain a nanoparticle suspension;

[0046] After the stirring is completed, transfer the nanoparticle suspension into an ultrafiltration centrifuge tube (4000 D), centrifuge at 2000 rpm for 20 min, remove the uncoated free nintedanib by concentration, and store in a 4°C refrigerator in the dark for standby use.

[0047] Example 3

[0048] Dissolve 1 part of chitosan in an aqueous solution containing 0.1% acetic acid, and then dissolve 0.5 parts of nintedanib in the above solution;

[0049] Dissolve 0.6 parts of polyglutamic acid in pure water, set the stirring rate to 800 rpm, and stir for 5 min. During the stirring process, slowly drop the polyglutamic acid solution into the acetic acid solution of chitosan and nintedanib to obtain a nanoparticle suspension;

[0050] After the stirring is completed, transfer the nanoparticle suspension into an ultrafiltration centrifuge tube (4000 D), centrifuge at 2000 rpm for 20 min, remove the uncoated free nintedanib by concentration, and store in a 4°C refrigerator in the dark for standby use.

[0051] Example 4

[0052] Dissolve 1 part of chitosan in an aqueous solution containing 0.1% acetic acid, and then dissolve 0.4 parts of nintedanib in the above solution;

[0053] Dissolve 0.4 parts of polyglutamic acid in pure water, set the stirring rate to 800 rpm, and stir for 5 min. During the stirring process, slowly drop the polyglutamic acid solution into the acetic acid solution of chitosan and nintedanib to obtain a nanoparticle suspension;

[0054] After the stirring is completed, transfer the nanoparticle suspension into an ultrafiltration centrifuge tube (4000 D), centrifuge at 2000 rpm for 20 min, remove the uncoated free nintedanib by concentration, and store in a 4°C refrigerator in the dark for standby use.

[0055] Example 5

[0056] Dissolve 1 part of chitosan in an aqueous solution containing 0.1% acetic acid, and then dissolve 0.7 parts of nintedanib in the above solution;

[0057] Dissolve 0.4 parts of polyglutamic acid in pure water, set the stirring rate to 800 rpm, and stir for 5 min. During the stirring process, slowly drop the polyglutamic acid solution into the acetic acid solution of chitosan and nintedanib to obtain a nanoparticle suspension;

[0058] After the stirring is completed, transfer the nanoparticle suspension to an ultrafiltration centrifuge tube (4000 D), centrifuge at 2000 rpm for 20 min, and concentrate to remove the uncoated free nintedanib. Then, store the nanoparticle suspension in a 4°C refrigerator in the dark for later use.

[0059] Comparative Example 1

[0060] Dissolve 1 part of chitosan in an aqueous solution containing 0.1% acetic acid, and then dissolve 0.5 parts of nintedanib in the above solution;

[0061] Dissolve 0.1 parts of polyglutamic acid in pure water, set the stirring rate to 800 rpm, and stir for 5 min. During the stirring process, slowly drop the polyglutamic acid solution into the acetic acid solution of chitosan and nintedanib to obtain a nanoparticle suspension;

[0062] After the stirring is completed, transfer the nanoparticle suspension to an ultrafiltration centrifuge tube (4000 D), centrifuge at 2000 rpm for 20 min, and concentrate to remove the uncoated free nintedanib. Then, store the nanoparticle suspension in a 4°C refrigerator in the dark for later use.

[0063] Comparative Example 2

[0064] Dissolve 1 part of chitosan in an aqueous solution containing 0.1% acetic acid, and then dissolve 0.5 parts of nintedanib in the above solution;

[0065] Dissolve 0.8 parts of polyglutamic acid in pure water, set the stirring rate to 800 rpm, and stir for 5 min. During the stirring process, slowly drop the polyglutamic acid solution into the acetic acid solution of chitosan and nintedanib to obtain a nanoparticle suspension;

[0066] After the stirring is completed, transfer the nanoparticle suspension to an ultrafiltration centrifuge tube (4000 D), centrifuge at 2000 rpm for 20 min, and concentrate to remove the uncoated free nintedanib. Then, store the nanoparticle suspension in a 4°C refrigerator in the dark for later use.

[0067] Comparative Example 3

[0068] Dissolve 1 part of chitosan in an aqueous solution containing 0.1% acetic acid, and then dissolve 0.3 parts of nintedanib in the above solution;

[0069] Dissolve 0.4 parts of polyglutamic acid in pure water, set the stirring rate to 800 rpm, and stir for 5 min. During the stirring process, slowly drop the polyglutamic acid solution into the acetic acid solution of chitosan and nintedanib to obtain a nanoparticle suspension;

[0070] After the stirring is completed, transfer the nanoparticle suspension into an ultrafiltration centrifuge tube (4000 D), centrifuge at 2000 rpm for 20 min, and then store in a 4°C refrigerator in the dark after removing the uncoated free nintedanib by concentration.

[0071] Comparative Example 4

[0072] Dissolve 1 part of chitosan in an aqueous solution containing 0.1% acetic acid, and then weigh 0.8 parts of nintedanib and dissolve it in the above solution.

[0073] Dissolve 0.4 parts of polyglutamic acid in pure water, set the stirring rate to 800 rpm, and stir for 5 min. During the stirring process, slowly drop the polyglutamic acid solution into the acetic acid solution of chitosan and nintedanib to obtain a nanoparticle suspension;

[0074] After the stirring is completed, transfer the nanoparticle suspension into an ultrafiltration centrifuge tube (4000 D), centrifuge at 2000 rpm for 20 min, and then store in a 4°C refrigerator in the dark after removing the uncoated free nintedanib by concentration.

[0075] Comparative Example 5

[0076] Using the reverse evaporation method, take DPPC 10 mg, DPPG 1 mg, DPPE-PEG2000 1 mg, and cholesterol 1.5 mg in a 50 mL eggplant-shaped flask, add 2 mL of anhydrous ethanol for dissolution, and then add 0.7 mL of a 0.6 mg / mL nintedanib solution. Place the eggplant-shaped flask in an ultrasonic cleaner (200W) water bath for ultrasonic treatment for 30 min to form a W / O oil-water mixture. After removing the anhydrous ethanol by rotary evaporation under reduced pressure (60 min), add pure water for hydration for 30 min. Filter the hydrated solution through a 200 nm filter three times, and then use a relative molecular mass cutoff of 10 x 10 3 Dialysis bag dialysis to remove free drugs, i.e., nintedanib liposomes.

[0077] Comparative Example 6

[0078] DPPC 10 mg, DPPG 1 mg, DPPE-PEG2000 1 mg and cholesterol 1.5 mg were taken in a 20 mL sample bottle, 1 mL of anhydrous ethanol was added to dissolve the sample, and then the sample bottle was placed in an ultrasonic cleaner (200 W) water bath constant temperature (20 ℃) ultrasonic 20 min, 3 mL of 0.6 mg / mL nintedanib solution was quickly injected into the sample bottle, and the injection was ultrasonic, after ultrasonic for 20 min, 10×10 3 The dialysis bag was dialyzed to remove free drugs and anhydrous ethanol, and nintedanib liposomes were obtained.

[0079] Table 1 Performance table of drug-loaded nanoparticles in different groups

[0080]

[0081] The particle size, PDI, encapsulation efficiency and drug loading of the nanoparticles prepared in different groups are shown in Table 1. The particle size of the nanoparticles prepared in Examples 1-5 is uniform, the dispersibility is good, the encapsulation efficiency can reach 70%, and there is a high drug loading under the premise of high encapsulation efficiency. Compared with Comparative Example 1, when too little anionic polymer is added, the formation of the polymer carrier is hindered, resulting in a substantial reduction in the encapsulated nintedanib, and both the encapsulation efficiency and the drug loading are very low. Compared with Comparative Example 2, when too much anionic polymer is added, the particle size of the drug-loaded nanoparticles decreases, and both the encapsulation efficiency and the drug loading decrease. Compared with Comparative Example 3, the amount of nintedanib added is too small, although there is a high encapsulation efficiency, but the drug loading does not meet the requirements. Compared with Comparative Example 4, when too much nintedanib is added, the drug loading increases, but the low encapsulation efficiency cannot guarantee the sustained-release effect of the drug, and the drug particle size of the comparative example is small, which is easy to be exhaled from the lungs. Compared with Comparative Examples 5 and 6, the nintedanib liposomes prepared by reverse evaporation method and ethanol injection method have a large gap in both encapsulation efficiency and drug loading compared with the examples.

[0082] To verify the stability of the drug-loaded nanoparticles of the application, the inhalable drug-loaded nanoparticles (NDNB / CS-PGA NPs) of chitosan and polyglutamic acid were taken as an example to carry out the stability experiment:

[0083] The NDNB / CS-PGA NPs were stored in a 4 ℃ refrigerator, and the particle size was detected on the 1st day, the 5th day, the 10th day and the 15th day. It was observed that there was no obvious change in the appearance, the particle size of the nanoparticles slowly increased with time, and the outer layer of the nanoparticles may contact with water molecules to form a hydration layer. The particle size of the drug-loaded nanoparticles did not change much within 15 days. As can be seen from Table 5, the NDNB / CS-PGA NPs have good stability.

[0084] Table 2 Particle size change table of NDNB / CS-PGA NPs with time

[0085]

[0086] To verify the sustained-release effect of the drug-loaded nanoparticles of the present invention, a sustained-release experiment was conducted:

[0087] At pH 7.4, the cumulative release of NDNB / methanol and NDNB / CS-PGA NPs in buffer was recorded. Figure 4 As can be seen, when the drug is encapsulated in nanocarriers, the release profile is significantly different from that of the API. The figure shows the release from a solution of NDNB-NPs loaded with the drug. Within 0-8 hours, NDNB-NPs rapidly release, with a cumulative release of 66.03%. From 8-48 hours, the release curve gradually levels off, reaching a maximum cumulative release of 79.67% after 48 hours. Compared to the NDNB / methanol solution, the overall release time of NDNB-NPs is longer and the cumulative release is higher, indicating that the drug encapsulated in chitosan nanoparticles can be slowly released, achieving a sustained-release effect and allowing nintedanib to be more fully dispersed in water.

[0088] To verify the biocompatibility of the drug-loaded nanoparticles of the present invention, a cytotoxicity experiment was performed:

[0089] The cytotoxicity of NDNB / CS-PGA NPs and NDNB was evaluated by calculating the half inhibition rate on Calu-3 cells. Figure 5 As can be seen in the figure, at the same drug concentration, nanoparticle-encapsulated NDNB / CS-PGA NPs showed less inhibition on Calu-3 cells, with a half-maximal inhibition rate of 48.75 μg / mL, while the half-maximal inhibition rate of NDNB / CS-PGA NPs on Calu-3 cells was 35.00 μg / mL. As the drug concentration increased, the difference in cell viability between NDNB / CS-PGA NPs and NDNB became greater. Therefore, at the same concentration, NDNB / CS-PGA NPs showed lower cytotoxicity than NDNB.

[0090] To verify the efficacy of the drug-loaded nanoparticles of the present invention in preparing drugs for treating idiopathic pulmonary fibrosis, an anti-fibrotic activity experiment was conducted:

[0091] The antifibrotic activity of NDNB / CS-PGA NPs and NDNB was evaluated by calculating the half inhibition rate on HFL1 cells (human embryonic lung fibroblasts). Figure 6It is observed that the same drug concentration, the nano-particle wrapped NDNB / CS-PGA NPs have stronger inhibitory effect on HFL1 cells, and the half inhibitory rate is 12.53 μg / mL, higher than the half inhibitory rate of NDNB on HFL1 cells, 17.84 μg / mL, which may be due to the fact that after being wrapped by chitosan, nintedanib can be released better, showing better anti-fibrous activity.

[0092] The above is only the preferred embodiment of the present application, not any form of limitation on the present application, any skilled person in the art, without departing from the technical solution range of the present application, according to the technical essence of the present application, any simple modification, equivalent replacement and improvement of the above embodiment, etc., still belongs to the protection scope of the technical solution of the present application.

Claims

1. An inhalable drug-loaded nanoparticle, characterized in that: The invention comprises a polymer nanocarrier, and nintedanib loaded on the polymer nanocarrier through hydrogen bonds; The polymer nanocarrier is self-assembled by cationic polysaccharide and anionic polymer through electrostatic interaction; The cationic polysaccharide is chitosan, and the anionic polymer is polyglutamic acid; The mass ratio of the cationic polysaccharide to the anionic polymer is 1:0.2-0.6, and the mass ratio of nintedanib to the cationic polysaccharide is 0.4-0.7:1; The method for preparing inhalable drug-loaded nanoparticles comprises the following steps: S1. dissolving the cationic polysaccharide in an acetic acid solution, and then dissolving nintedanib in the cationic polysaccharide acetic acid solution; S2. Under stirring, slowly dripping the anionic polymer solution into the cationic polysaccharide acetic acid solution; S3, performing centrifugation and concentration to obtain the inhalable drug-loaded nanoparticles.

2. The inhalable drug-loaded nanoparticles according to claim 1, characterized in that: The anionic polymer contains a carboxyl group.

3. The inhalable drug-loaded nanoparticles according to any one of claims 1-2, characterized in that: The particle size of the inhalable drug-loaded nanoparticles is between 220 and 235 nm.

4. The inhalable drug-loaded nanoparticles according to any one of claims 1-2, characterized in that: The encapsulation rate of the inhalable drug-loaded nanoparticles is ≥45%.

5. Use of the inhalable drug-loaded nanoparticles according to any one of claims 1 to 4 in the preparation of a drug for treating idiopathic pulmonary fibrosis.

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