Inhalation type quercetin dry powder inhalation and preparation method thereof

Abstract

The invention discloses inhalation type quercetin dry powder inhalation and a preparation method thereof, and belongs to the technical field of inhalation administration. Aiming at the problems of low oral bioavailability, poor targeting property and the like of quercetin, the dry powder inhalation is prepared from the following components in percentage by weight: 10 to 100 percent of quercetin, 0 to 85 percent of diluent and 0 to 5 percent of taste indicator, and the particle size of quercetin particles is D90lt; 20 [mu] m. The preparation method comprises the following steps: crushing the quercetin and the diluent, mixing with the taste indicator, sieving, spheroidizing in a spheroidizing disc to prepare spherical particles, and finally filling into an inhaler. The dry powder aerosol realizes lung targeted delivery through inhalation administration, has good fluidity and lung deposition effect, is mainly used for treating lung nodules, and provides an efficient and safe treatment scheme for lung diseases.

Description

Technical Field

[0001] The invention relates to the technical field of inhalation drug administration, and in particular to an inhalable quercetin powder aerosol and a preparation method thereof. Background Art

[0002] Pulmonary nodules are a common lung lesion, usually discovered through imaging examinations (such as chest X-rays or CT scans), and refer to round or quasi-round lung lesions with a diameter of ≤3 cm. According to size, pulmonary nodules can be divided into micronodules (diameter <5 mm), small nodules (diameter 5-10 mm) and larger nodules (diameter 10-30 mm). Although many pulmonary nodules are benign, some may develop into lung cancer, so early intervention and treatment are crucial. Quercetin is a natural flavonoid compound that is widely found in many plants, such as onions, apples, and tea. Quercetin has multiple biological activities, including antioxidant, anti-inflammatory, anti-tumor, and immunomodulatory effects. In recent years, studies have shown that quercetin has potential application value in the treatment of lung diseases, especially in the prevention and treatment of pulmonary nodules. Quercetin can reduce lung inflammation by inhibiting the release of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Quercetin can also reduce the levels of oxidative stress markers, such as malondialdehyde (MDA), and improve the lung microenvironment. Furthermore, quercetin can activate macrophages, enhancing their ability to phagocytose pathogens and necrotic tissue, and promote the migration of immune cells to lesions by upregulating the expression of adhesion molecules. These mechanisms make quercetin a promising adjuvant therapy for the treatment of inflammatory and infectious pulmonary nodules, such as tuberculosis or fungal infections.

[0003] However, the application of quercetin is limited by its physicochemical properties. Quercetin is almost insoluble in water and has extremely poor water solubility, resulting in low oral bioavailability. Studies have shown that the absorption rate of oral quercetin is only about 20%, and it is rapidly metabolized in the body with a short half-life, making it difficult to maintain effective blood concentrations. In order to achieve therapeutic effects, large doses of quercetin are often required, but high doses may cause gastrointestinal discomfort, such as nausea, diarrhea and other side effects. In addition, oral administration requires gastrointestinal absorption and first-pass metabolism in the liver, which further reduces the bioavailability of quercetin. For lung diseases, oral quercetin is difficult to target and deliver to the lungs, and the blood concentration in the lungs is low, resulting in poor efficacy.

[0004] To overcome the limitations of oral administration of quercetin, researchers have explored alternative routes of administration, with inhalation being a promising approach. Inhalation delivery involves delivering the drug directly into the lungs through the respiratory tract. The drug is inhaled in aerosol, nebulized, or dry powder form and absorbed through the alveolar epithelium into the bloodstream. Inhalation delivery offers the following advantages: Improved bioavailability: Inhalation bypasses first-pass metabolism in the gastrointestinal tract and liver, allowing for direct absorption through the lungs, significantly increasing drug bioavailability. For compounds like quercetin, which are poorly water-soluble and highly lipid-soluble, pulmonary absorption may be more efficient. Rapid onset of action: Inhalation delivery rapidly delivers the drug to the site of action, with a short onset of action, making it suitable for relieving acute symptoms. Local treatment: For lung diseases, inhalation delivery can directly target the lesion, increasing local drug concentrations while minimizing systemic side effects. Reduced dose: Due to improved bioavailability, the required dose can be reduced, lowering treatment costs and the risk of side effects. Therefore, formulating quercetin into an inhalable powder aerosol for the treatment of lung diseases such as pulmonary nodules offers significant advantages and promising applications.

[0005] However, to achieve inhaled administration of quercetin, challenges in formulation technology need to be addressed. Quercetin is a solid powder, and direct inhalation may cause respiratory irritation or discomfort, and it is difficult to control the dosage. Therefore, it needs to be made into a powder inhalation form suitable for inhalation to ensure that the particle size, morphology, fluidity and stability of the powder inhalation meet the requirements of inhaled administration. Generally, the particle size of the inhaled powder inhalation needs to be controlled within the range of 1-5μm to ensure that the drug can be deposited in the alveolar area deep in the lungs. In addition, the fluidity of the powder inhalation is crucial for the normal operation of the quantitative filling and inhalation device.

[0006] The present invention utilizes a specific preparation method to produce quercetin into highly spherical particles, improving their fluidity and facilitating quantitative filling and use with an inhalation device. Specifically, the present invention utilizes spheroidization technology to mix quercetin with other excipients to form spherical particles measuring hundreds of micrometers in size. Upon inhalation, these particles disperse into micrometer-sized fine particles suitable for pulmonary absorption. In this way, the present invention addresses the technical challenges of quercetin inhalation administration and provides a new and effective method for the treatment of pulmonary nodules.

[0007] In summary, the development of inhaled quercetin powder spray can not only improve the bioavailability of quercetin and reduce the dosage, but also directly act on the lungs to enhance the therapeutic effect, and has important clinical application value. Summary of the Invention

[0008] In order to solve the problems of low bioavailability of quercetin after oral administration, difficulty in targeting the lungs, large required dosage and poor fluidity of the preparation, the present invention provides an inhaled quercetin powder inhaler and a preparation method thereof. The inhaled quercetin powder inhaler is made into μm-level dry powder particles of quercetin through a specific preparation process, with a particle size D90 of less than 20 μm, preferably less than 10 μm, and more preferably less than 5 μm, suitable for inhalation administration. The preparation method includes the steps of crushing the quercetin raw material, mixing it with excipients, and spheroidizing it to obtain particles with high sphericity, thereby improving the fluidity and dispersibility of the powder. The powder inhaler can be directly absorbed through the lungs, significantly improving the bioavailability of quercetin, reducing the dosage of the drug, and can target the lungs, making it particularly suitable for treating lung diseases such as pulmonary nodules. The preparation method of the present invention successfully solves the technical difficulties of quercetin inhalation administration, providing a new treatment method for clinical application.

[0009] In order to achieve the above object, the present invention adopts the following technical solutions:

[0010] An inhalable quercetin powder inhaler, the powder inhaler consisting of quercetin, a diluent and a taste indicator;

[0011] The dosage form of the powder inhaler is dry powder;

[0012] In the powder inhaler, the weight percentage of the quercetin is 10-100%, the weight percentage of the diluent is 0-85%, and the weight percentage of the taste indicator is 0-5%.

[0013] Preferably, in the powder inhaler, the weight percentage of the quercetin is 40-80%, the weight percentage of the diluent is 19-59%, and the weight percentage of the taste indicator is 0-1%.

[0014] Preferably, the particle size of the quercetin is D90 < 20 μm;

[0015] The particle size of the taste indicator is 5 μm <D90<500μm;

[0016] The particle size of the diluent is 5 μm <D90<20μm。

[0017] Preferably, the particle size of the quercetin is D90 < 10 μm;

[0018] The particle size of the taste indicator is 10 μm <D90<300μm;

[0019] The particle size of the diluent is 5 μm <D90<10μm。

[0020] Preferably, the particle size of the quercetin is D90 < 5 μm;

[0021] The particle size of the taste indicator is 30 μm <D90<100μm;

[0022] The particle size of the diluent is 5 μm <D90<10μm。

[0023] Preferably, the quercetin is selected from anhydrous quercetin, dihydrate quercetin or hemihydrate quercetin;

[0024] The taste indicator is selected from neotame, sucralose, aspartame, stevia, licorice, disodium glycyrrhizate, tripotassium glycyrrhizate, erythritol, xylitol, sorbitol, mannitol, maltitol, isomalt, hydrogenated starch hydrolysate or neomethyl hesperidin dihydrochalcone.

[0025] The diluent is selected from lactose monohydrate, anhydrous lactose, mannitol, sucrose or trehalose.

[0026] Preferably, the diluent is lactose monohydrate or mannitol.

[0027] The preparation method of the inhalable quercetin powder spray comprises the following steps:

[0028] (1) crushing quercetin and a diluent;

[0029] (2) mixing the crushed quercetin, a diluent, and a taste indicator in proportion to obtain a mixture;

[0030] (3) sieving the mixture obtained in step (2) to obtain agglomerates;

[0031] (4) spheroidizing the agglomerates obtained in step (3) in a spheroidizing pan to prepare spherical particles;

[0032] (5) The spherical particles prepared in step (4) are quantitatively loaded into an inhaler.

[0033] In the preparation method of the inhalable quercetin powder aerosol, the aperture of the sieve used in step (3) is 200-500 μm;

[0034] The rotation speed of the spheroidization in step (4) is 5-50 rpm, wherein the angle between the bottom surface of the spheroidization disk and the horizontal plane is between 15-45°.

[0035] The preparation method of the inhalable quercetin powder aerosol, wherein the crushing equipment in step (1) is selected from a ball mill, a disc-type airflow mill, a hammer mill, a nail-disc mill or a fluidized bed airflow mill;

[0036] The mixing equipment in step (2) is selected from a high shear mixer, a planetary mixer, a tank mixer or a resonance mixer.

[0037] Beneficial effects of the present invention:

[0038] Significantly improve bioavailability: Through the inhalation route of administration, the quercetin powder spray of the present invention can be directly absorbed through the lungs, avoiding first-pass metabolism through the gastrointestinal tract and liver during oral administration. Traditional oral quercetin has poor water solubility, an absorption rate of only about 20%, and rapid metabolism, making it difficult to maintain effective blood drug concentrations. The present invention, through efficient absorption in the lungs, can achieve higher blood drug concentrations at lower doses, thereby significantly improving the bioavailability of quercetin and enhancing the therapeutic effect. Achieve targeted lung delivery: The present invention accurately delivers quercetin to the lungs, allowing the drug to be locally enriched in lesions such as lung nodules. This targeted delivery method not only increases the local drug concentration in the lungs and enhances the effect of treating lung diseases (such as lung nodules and pulmonary fibrosis), but also reduces the distribution of the drug throughout the body, thereby reducing the risk of systemic side effects. This feature is particularly suitable for lung diseases that require local treatment. Excellent fluidity: The present invention uses a spheroidization process to prepare quercetin particles, giving them high sphericity, and significantly improving fluidity compared to untreated quercetin powder. Good fluidity makes the particles easier to quantitatively fill and operate, ensuring the accuracy and consistency of dosage. This not only improves production efficiency, but also ensures product quality, providing convenience for subsequent industrial production. Suitable particle size distribution: By precisely controlling the preparation process, the present invention ensures that the particle size D90 of the quercetin particles is less than 20μm, preferably less than 10μm, and more preferably less than 5μm. This particle size range enables the drug particles to be effectively deposited in the alveolar area deep in the lungs, achieving optimal absorption and local therapeutic effects. Compared with traditional preparations, the particle size design of the present invention significantly improves the accuracy and efficiency of drug delivery. Good dispersibility and stability: The present invention adds surfactants to the preparation, which effectively improves the dispersibility of quercetin powder, prevents particle agglomeration, and ensures the stability of the preparation. Excellent dispersibility enables the powder aerosol to be evenly atomized during inhalation, avoiding the decrease in delivery efficiency due to particle aggregation, thereby ensuring the effective deposition and absorption of the drug in the lungs. Reduce side effects: Since inhalation administration can achieve higher local drug concentrations at lower doses, the present invention can significantly reduce systemic side effects, such as gastrointestinal discomfort, compared to traditional oral administration. This improves the safety and tolerance of patients, which is especially important for patients who take long-term medication. Easy to operate and improve compliance: The inhaled quercetin powder spray of the present invention is in the form of a dry powder inhaler, and patients can self-administer the drug through a portable inhalation device without the assistance of professional medical staff. Compared with injection or other complex administration methods, this non-invasive operation is simpler and helps to improve patients' treatment compliance, thereby improving the treatment effect.

[0039] In summary, the inhalable quercetin powder spray of the present invention, through its innovative preparation process and inhalation administration route, successfully overcomes the limitations of traditional oral quercetin, such as low bioavailability, poor targeting, and insufficient formulation fluidity. This invention achieves efficient quercetin delivery, targeted therapy, and improved safety, providing a novel solution for the treatment of lung diseases such as pulmonary nodules, with significant clinical application value and broad market prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 The present invention is a flow chart for preparing the inhalable quercetin powder aerosol.

[0041] Figure 2 This is a diagram of the quercetin mist distribution (60 L / min) of Example 1 of the present invention.

[0042] Figure 3 This is a diagram of quercetin mist distribution (60 L / min) in Example 2 of the present invention.

[0043] Figure 4 This is a diagram of animal tissue sections according to Example 3 of the present invention. DETAILED DESCRIPTION

[0044] The present invention is described in more detail below in an exemplary manner.

[0045] Inhaled quercetin powder inhaler, which consists of quercetin, a diluent, and a taste indicator;

[0046] The dosage form of the powder inhaler is dry powder;

[0047] The powder inhaler comprises, by weight, 10-100% of quercetin, 0-85% of diluent, and 0-5% of taste indicator. The powder inhaler comprises, by weight, 40-80% of quercetin, 19-59% of diluent, and 0-1% of taste indicator.

[0048] The particle size of the quercetin is D90 < 20 μm;

[0049] The particle size of the taste indicator is 5 μm <D90<500μm;

[0050] The particle size of the diluent is 5 μm <D90<20μm。

[0051] The particle size of the quercetin is D90 < 10 μm;

[0052] The particle size of the taste indicator is 10 μm <D90<300μm;

[0053] The particle size of the diluent is 5 μm <D90<10μm。

[0054] The particle size of the quercetin is D90 < 5 μm;

[0055] The particle size of the taste indicator is 30 μm <D90<100μm;

[0056] The particle size of the diluent is 5 μm <D90<10μm。

[0057] The quercetin is selected from anhydrous quercetin, dihydrate quercetin or hemihydrate quercetin;

[0058] The taste indicator is selected from neotame, sucralose, aspartame, stevia, licorice, disodium glycyrrhizate, tripotassium glycyrrhizate, erythritol, xylitol, sorbitol, mannitol, maltitol, isomalt, hydrogenated starch hydrolysate or neomethyl hesperidin dihydrochalcone.

[0059] The diluent is selected from lactose monohydrate, anhydrous lactose, mannitol, sucrose or trehalose.

[0060] The diluent is lactose monohydrate or mannitol.

[0061] like Figure 1 As shown, the preparation method of the inhalable quercetin powder spray comprises the following steps:

[0062] (1) crushing quercetin and a diluent;

[0063] (2) mixing the crushed quercetin, a diluent, and a taste indicator in proportion to obtain a mixture;

[0064] (3) sieving the mixture obtained in step (2) to obtain agglomerates;

[0065] (4) spheroidizing the agglomerates obtained in step (3) in a spheroidizing pan to prepare spherical particles;

[0066] (5) The spherical particles prepared in step (4) are quantitatively loaded into an inhaler.

[0067] In the preparation method of the inhalable quercetin powder aerosol, the aperture of the sieve used in step (3) is 200-500 μm;

[0068] The rotation speed of the spheroidization in step (4) is 5-50 rpm, wherein the angle between the bottom surface of the spheroidization disk and the horizontal plane is between 15-45°.

[0069] The preparation method of the inhalable quercetin powder aerosol, wherein the crushing equipment in step (1) is selected from a ball mill, a disc-type airflow mill, a hammer mill, a nail-disc mill or a fluidized bed airflow mill;

[0070] The mixing equipment in step (2) is selected from a high shear mixer, a planetary mixer, a tank mixer or a resonance mixer.

[0071] In addition, combined Figure 1 The picture shows a process flow chart for the preparation of an inhaled quercetin powder spray. The specific steps are as follows:

[0072] Micronization:

[0073] The quercetin and diluent are micronized separately to reduce the particle size of the raw materials to a target range (eg, D90 < 20 μm) to meet the requirements of inhalation administration.

[0074] mix:

[0075] The micronized quercetin is mixed with a diluent and a taste indicator is added, and the mixture is uniformly mixed to obtain a mixture. This step ensures uniform distribution of the components.

[0076] Spheroidization:

[0077] The mixture is fed into a spheroidizing device for spheroidization to form highly spherical particles. This step improves the fluidity and dispersibility of the particles.

[0078] Filling:

[0079] The spheroparticles are quantitatively loaded into the inhalation device to ensure the accuracy and consistency of each dose.

[0080] Finished product:

[0081] The final product is an inhaled quercetin powder spray that can be used to treat lung diseases (such as lung nodules).

[0082] The entire flow chart clearly shows the key steps from raw material processing to finished product preparation, reflecting the systematic and standardized nature of the formulation process.

[0083] Example 1

[0084] Take 500g of anhydrous quercetin, 499g of lactose monohydrate, and 1g of neotame.

[0085] Step 1: Use a disc jet mill to grind anhydrous quercetin and lactose monohydrate into particle sizes D90 of 3 μm and 8 μm, respectively.

[0086] Step 2: Add the crushed anhydrous quercetin, lactose monohydrate and neotame into a high shear mixer and mix for 10 minutes to obtain a uniform mixture.

[0087] Step 3: The mixture was sieved through a sieve with a pore size of 300 μm to obtain agglomerates.

[0088] Step 4: Place the agglomerates in a spheroidizing dish at a rotation speed of 30 rpm and an angle of 30° between the bottom and the horizontal plane, and spheroidize for 20 minutes to prepare spherical particles.

[0089] Step 5: The spherical particles are quantitatively loaded into the dry powder inhaler. Each dose contains 10 mg of quercetin. The distribution of the tested aerosol particles is shown in Table 1. Figure 2 shown.

[0090] Table 1 Mist particle distribution data

[0091] FPF (%) MMAD (μm) GSD <![CDATA[R 2 <!-- 5 -->]]> 57.38±2.05 2.23±0.1 1.78±0 1±0

[0092] Example 2

[0093] Take 600g of quercetin dihydrate, 395g of mannitol, and 5g of sucralose.

[0094] Step 1: Use a fluidized bed jet mill to grind quercetin dihydrate and mannitol to a particle size D90 of 4 μm and 7 μm, respectively.

[0095] Step 2: Add the crushed quercetin dihydrate, mannitol and sucralose into a planetary mixer and mix for 15 minutes to obtain a uniform mixture.

[0096] Step 3: The mixture was sieved through a sieve with a pore size of 400 μm to obtain agglomerates.

[0097] Step 4: Place the agglomerates in a spheroidizing dish at a rotation speed of 40 rpm and an angle of 25° between the bottom and the horizontal plane, and spheroidize for 15 minutes to prepare spherical particles.

[0098] Step 5: The spherical particles are quantitatively loaded into the dry powder inhaler. Each dose contains 15 mg of quercetin. The distribution of the tested aerosol particles is shown in Table 2. Figure 3 shown.

[0099] Table 2 Mist particle distribution data

[0100] FPF (%) MMAD (μm) GSD <![CDATA[R 2 ]]> 60.46±1.95 2.19±0.02 1.77±0.01 1±0

[0101] Example 3

[0102] Twenty-four healthy, SPF-grade Sprague-Dawley (SD) rats were selected, half male and half female. Males weighed between 235.2 and 266.1 g, and females weighed between 205.0 and 231.5 g. The rats were randomly divided into four groups based on sex and weight, with three rats of each sex in each group.

[0103] All animals were exposed to quercetin dry powder by inhalation through the mouth and nose on Day 1. The administration time for Groups 1-2 was 10 minutes, and the administration time for Groups 3-4 was 20 minutes.

[0104] Acclimation period: All animals were observed once daily at the cage side. A detailed clinical observation was conducted on all animals on Day 1. Animals in Groups 1-3 and Group 4 were weighed on Day 1 and Day 5, respectively.

[0105] During the experiment, all animals in Groups 1-4 were observed at their cages twice daily (morning and afternoon) and once on the day of dissection. All surviving animals in Groups 1-4 underwent detailed clinical observations daily during the dosing period. All surviving animals in Groups 1-4 were weighed on Day 1 (before dosing), Day 4, Day 8, Day 11, and Day 14. Animals scheduled for dissection were weighed once on the day of dissection (Day 15) after fasting. Food consumption (24 ± 1 h) was measured per cage for all surviving animals in Groups 1-4 on Day 4 (Day 4-Day 5) and Day 11 (Day 11-Day 12). All surviving animals in Groups 1-4 were euthanized on Day 15 with an intramuscular injection of Zoltrate 50. Death was confirmed by exsanguination of the abdominal aorta and vein, and a complete gross autopsy was performed.

[0106] The animals were grouped as shown in Table 3 below:

[0107] Table 3

[0108]

[0109] The results of drug administration inspection are shown in Table 4 below:

[0110] Table 4

[0111]

[0112] The test results are as follows Figure 4As shown, Figure A is "Quercetin 5.21 mg / kg, #101 (M), at the end of the dosing period, lungs: no obvious abnormalities, HE, 10x", Figure B is "Quercetin 5.21 mg / kg, #104 (F), at the end of the dosing period, lungs: no obvious abnormalities, HE, 10x", Figure C is "Quercetin 6.86 mg / kg, #201 (M), at the end of the dosing period, lungs: no obvious abnormalities, HE, 10x", and Figure D is "Quercetin 6.86 mg / kg, #204 (F), at the end of the dosing period, lungs: no obvious abnormalities, HE, 10x". In general, Example 3 systematically evaluated the safety of inhaled quercetin powder spray at dosing times of 10 minutes and 20 minutes by administering it to rats. The experimental results showed that within the given dose and time, inhalation of quercetin dry powder did not produce obvious toxic reactions in rats, showing good safety. This result provides important experimental basis and support for further preclinical research and potential clinical applications of inhaled quercetin powder (such as the treatment of lung diseases).

[0113] In general, the bioavailability is significantly improved. Technical effect: The inhaled quercetin powder spray of the present invention is administered by inhalation in the lungs, bypassing the gastrointestinal tract and first-pass metabolism of the liver, and is directly absorbed into the blood circulation through the alveoli. Compared with oral administration (bioavailability is only about 20%), pulmonary absorption significantly improves the effective utilization rate of quercetin. Expansion: Due to its poor water solubility and rapid metabolism, quercetin is difficult to maintain an effective blood concentration when taken orally. The present invention utilizes the large surface area of ​​the lungs to enhance the absorption efficiency, which may increase the blood concentration by several times, laying the foundation for low-dose and high-efficiency treatment. This mode of administration is particularly suitable for rapidly metabolized drugs, can shorten the onset time, and is suitable for the relief of acute lung symptoms. Targeted lung delivery is achieved. Technical effect: The powder spray delivers quercetin directly to the lungs, achieving local high-concentration distribution, and is particularly suitable for the treatment of lung diseases such as lung nodules. Expansion: For lung nodules, local high concentration of quercetin can fully exert its anti-inflammatory, antioxidant and anti-tumor effects, directly act on the lesions, inhibit the release of inflammatory factors (such as TNF-α, IL-6), and improve the lung microenvironment. Compared with oral administration, targeted delivery reduces the distribution of drugs throughout the body, reduces side effects such as gastrointestinal discomfort, and improves the safety and specificity of treatment. Reduce the dosage of medication, technical effect: Due to the improved bioavailability and targeted delivery, the required quercetin dosage is significantly reduced, and it can still reach or exceed the efficacy of oral administration. Expansion: The dose reduction not only reduces the cost of treatment, but also reduces the toxic side effects that may be caused by high-dose oral administration, such as liver and kidney burden, which is particularly suitable for long-term treatment of patients. For example, each dose in the embodiment contains only 10-15 mg of quercetin, which reflects high efficiency compared to the commonly used oral dose of hundreds of milligrams. The fluidity is significantly improved, technical effect: The spherical particles prepared by the spheroidization process have high sphericity and excellent fluidity, which are convenient for quantitative filling and inhalation devices. Extension: Spherical particles reduce the friction and agglomeration tendency between particles. Compared with irregular particles, they have a smaller flow angle and a shorter flow time, ensuring dosage consistency and production efficiency. This characteristic is particularly critical in industrial production, which can reduce equipment blockage, improve filling accuracy, and provide technical support for large-scale production. Optimize particle size distribution, technical effect: The particle size D90 of quercetin particles is controlled to be less than 20μm (preferably less than 5μm) to ensure that the drug is effectively deposited in the alveolar area. Extension: The particle size of 1-5μm is the optimal range for deep lung deposition. The present invention accurately controls the particle size distribution through micronization and spheroidization processes, avoiding the deposition of large particles in the upper respiratory tract or the loss of small particles with exhalation. The particle size design of the diluent and taste indicator (5-20μm and 5-500μm) further optimizes the overall performance of the preparation and balances dispersibility and stability. Enhance dispersibility and stability, technical effect: Diluents and taste indicators are added to the preparation, and the spheroidization process is used to improve the dispersibility and stability of the powder and prevent particle agglomeration. Extension: Good dispersibility ensures that the powder inhaler is evenly atomized during inhalation, avoiding the decrease in delivery efficiency due to agglomeration, thereby increasing the lung deposition rate.Improved stability extends the shelf life of the preparation, reduces performance degradation caused by environmental factors (such as humidity), and lays the foundation for product commercialization. Improve patient compliance, technical effects: Inhalation drug delivery is easy to operate, and with a portable dry powder inhaler, patients can administer the drug themselves, and the non-invasive design improves treatment compliance. Expansion: Compared with oral tablets or injections, inhalation drug delivery does not require swallowing or professional operation, and is particularly suitable for elderly patients with dysphagia or patients who are unwilling to receive injections. Portability allows patients to take medication at any time at home or on the go, which enhances the flexibility and continuity of treatment and is particularly beneficial for the management of chronic lung disease.

[0114] Clinical application prospects: The inhaled quercetin powder spray of the present invention is not only suitable for lung nodules, but can also be extended to other lung diseases, such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis and even adjuvant treatment of early lung cancer. Its anti-inflammatory and antioxidant properties provide the possibility for multi-target treatment. Technological innovation: The application of spheroidization technology is a highlight of the present invention. It not only solves the problem of poor fluidity of quercetin powder, but also provides a reference for the development of inhalation preparations for other poorly soluble drugs. Market potential: With the increasing incidence of lung diseases and the increasing demand of patients for high-efficiency and low-side effect treatments, the present invention has broad market prospects, especially in the context of the popularization of portable inhalation devices.

[0115] The applicant declares that the present invention is illustrated by the above-described embodiments, but the present invention is not limited to the above-described embodiments. This does not mean that the present invention must rely on the above-described embodiments in order to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions for the raw materials used in the present invention, additions of auxiliary components, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present invention.

Claims

1. An inhalable quercetin powder spray, characterized in that: The powder inhaler consists of quercetin, a diluent, and a taste indicator; The dosage form of the powder inhaler is dry powder; In the powder inhaler, the weight percentage of the quercetin is 10-100%, the weight percentage of the diluent is 0-85%, and the weight percentage of the taste indicator is 0-5%.

2. The inhalable quercetin powder spray according to claim 1, characterized in that: In the powder inhaler, the weight percentage of the quercetin is 40-80%, the weight percentage of the diluent is 19-59%, and the weight percentage of the taste indicator is 0-1%.

3. The inhalable quercetin powder inhaler according to claim 2, characterized in that: The particle size of the quercetin is D90 < 20 μm; The particle size of the taste indicator is 5 μm <D90<500μm; The particle size of the diluent is 5 μm <D90<20μm。 4. The inhalable quercetin powder inhaler according to claim 3, characterized in that: The particle size of the quercetin is D90 < 10 μm; The particle size of the taste indicator is 10 μm <D90<300μm; The particle size of the diluent is 5 μm <D90<10μm。 5. The inhalable quercetin powder spray according to claim 4, characterized in that: The particle size of the quercetin is D90 < 5 μm; The particle size of the taste indicator is 30 μm <D90<100μm; The particle size of the diluent is 5 μm <D90<10μm。 6. The inhalable quercetin powder inhaler according to claim 5, characterized in that: The quercetin is selected from anhydrous quercetin, dihydrate quercetin or hemihydrate quercetin; The taste indicator is selected from neotame, sucralose, aspartame, stevia, licorice, disodium glycyrrhizate, tripotassium glycyrrhizate, erythritol, xylitol, sorbitol, mannitol, maltitol, isomalt, hydrogenated starch hydrolysate or neomethyl hesperidin dihydrochalcone. The diluent is selected from lactose monohydrate, anhydrous lactose, mannitol, sucrose or trehalose.

7. The inhalable quercetin powder inhaler according to claim 6, characterized in that: The diluent is lactose monohydrate or mannitol.

8. A method for preparing the inhalable quercetin powder aerosol according to claim 1, comprising the following steps: (1) crushing quercetin and a diluent; (2) mixing the crushed quercetin, a diluent, and a taste indicator in proportion to obtain a mixture; (3) sieving the mixture obtained in step (2) to obtain agglomerates; (4) spheroidizing the agglomerates obtained in step (3) in a spheroidizing pan to prepare spherical particles; (5) The spherical particles prepared in step (4) are quantitatively loaded into an inhaler.

9. The method for preparing the inhalable quercetin powder aerosol according to claim 8, wherein: The pore size of the sieve used in step (3) is 200-500 μm; The rotation speed of the spheroidization in step (4) is 5-50 rpm, wherein the angle between the bottom surface of the spheroidization disk and the horizontal plane is between 15-45°.

10. The method for preparing the inhalable quercetin powder aerosol according to claim 8, wherein: The equipment for pulverizing in step (1) is selected from a ball mill, a disc-type airflow mill, a hammer mill, a spike-disc mill or a fluidized bed airflow mill; The mixing equipment in step (2) is selected from a high shear mixer, a planetary mixer, a tank mixer or a resonance mixer.

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