Naringin dry powder inhalation as well as preparation method and application thereof

Abstract

The invention provides naringin dry powder inhalation as well as a preparation method and application thereof, belongs to the technical field of pharmaceutical preparations, and particularly provides the naringin dry powder inhalation which comprises the following components in parts by mass: 1-30 parts of micronized naringin and 40-100 parts of a diluent, and the particle size distribution D90 of the micronized naringin is 1-30 [mu] m. The naringin dry powder inhalation provided by the invention is an inhalation administration preparation, has the advantages of high drug absorption rate and quick response, and the naringin dry powder inhalation provided by the invention has extremely low bitter taste and good patient compliance, and can be used for preparing an anti-inflammatory drug inhalant and / or a lung disease treatment drug.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a naringin powder aerosol and a preparation method and application thereof. BACKGROUND

[0002] Naringin is a natural dihydroflavonoid compound, and its powder is white to light yellow crystal at room temperature. Studies have shown that naringin has anti-inflammatory and antiviral effects. However, naringin has very poor water solubility, which leads to very low oral bioavailability. Therefore, in order to achieve the best therapeutic effect, the dosage of naringin needs to be increased when it is taken orally. However, naringin tastes extremely bitter, and increasing the dosage of naringin will greatly reduce patient compliance.

[0003] In order to improve the drug absorption efficiency of naringin and reduce the bitterness of naringin, the current common method is to modify naringin or embed naringin in a carrier. For example, a naringin-loaded hydrotalcite inorganic nanoparticle is disclosed in Chinese Patent Publication No. CN119868278A. The hydrotalcite inorganic nanoparticle is first prepared using an aluminum salt, a magnesium salt, and an alkali hydroxide as raw materials, and then naringin is loaded on the hydrotalcite inorganic nanoparticle. This product can effectively improve the bioavailability of naringin preparations, and the preparation is a solid granular preparation. For another example, a flavored naringin oral solution is disclosed in Chinese Patent Publication No. CN103622905A. The oral solution uses cyclodextrin to increase the solubility of naringin and thus increase the dosage of naringin, and also uses a sweetener and an essence to reduce the bitterness of naringin. The preparation is an oral solution.

[0004] However, the above solid preparations or liquid preparations still have some problems. For example, the solid preparations still have the defect of low bioavailability, and the liquid preparations themselves are unstable and can produce crystal precipitation after long storage. Biological or chemical modification can improve the absorption rate of naringin and reduce the bitterness, but biological or chemical modification can change the structure of naringin, causing its performance to decline and making it unable to be used in the medical field.

[0005] Therefore, there is a need to provide a new naringin preparation to improve the absorption rate of naringin while not reducing patient compliance. SUMMARY

[0006] The technical problem to be solved by the present application is how to reduce the bitterness of naringin while improving the absorption rate of naringin.

[0007] To solve the above technical problem, the present application provides a naringin powder aerosol in a first aspect. The naringin powder aerosol comprises 1-30 parts by mass of micronized naringin and 40-100 parts by mass of a diluent. The particle size distribution D90 of the micronized naringin is 1-30 μm.

[0008] Preferably, the diluent is selected from any one or more of mannitol, lactose, microcrystalline cellulose, starch, pregelatinized starch, β-cyclodextrin, γ-cyclodextrin, maltodextrin, chitosan, sodium alginate, and β-glucan.

[0009] Preferably, the naringin powder aerosol also includes a taste indicator and / or a lubricant.

[0010] Preferably, the taste indicator is selected from any one or more of neotame, sucralose, mogroside, steviol glycoside, aspartame, erythritol, and xylitol.

[0011] Preferably, the content of the taste indicator in the naringin powder aerosol is 0.01 to 30 parts by weight.

[0012] Preferably, the lubricant is selected from one or more of magnesium stearate, leucine, and talc.

[0013] Preferably, the lubricant content in the naringin powder atomizer is 0.01 to 2 parts.

[0014] The naringin powder inhaler provided by this invention comprises micronized naringin with extremely low particle size and a diluent. The powder inhaler has a good powder state, stable properties, and is suitable for long-term storage and transportation. Furthermore, this powder inhaler is administered via pulmonary delivery, avoiding the first-pass effect of oral administration and effectively improving the absorption rate of naringin. Additionally, the naringin powder inhaler provided by this invention is nearly odorless. To allow patients to more intuitively understand the progress of medication, a taste indicator is added to the naringin powder inhaler provided by this invention to help patients more intuitively understand whether the drug has been successfully inhaled.

[0015] A second aspect of the present invention provides a method for preparing the naringin powder aerosol described in the first aspect, comprising the following steps: S1: Take naringin raw material and pulverize it; S2: Take the raw materials for diluent, taste indicator, and lubricant, and pulverize them; S3: Mix and pulverize the components to obtain naringin powder atomizer.

[0016] A third aspect of the present invention provides an application of the naringin powder inhaler described in the first aspect, wherein the application is to use the naringin powder inhaler in the preparation of anti-inflammatory drug inhalers and / or drugs for the treatment of lung diseases.

[0017] Compared with the prior art, the present invention has the following beneficial effects: 1. The naringin powder aerosol provided by the present invention micronizes naringin and mixes it with a diluent without changing the molecular structure of naringin or having a negative impact on the drug efficacy of naringin. 2. The naringin powder inhaler provided by the present invention is an inhalation preparation. The absorption site of naringin is the lungs, and it enters the blood directly from the lungs, avoiding the first-pass effect of oral administration. It can effectively improve the blood drug concentration and absorption rate, and has the advantages of high absorption rate and fast onset of action. 3. Because naringin is encapsulated in the diluent, the naringin powder inhaler provided by this invention produces almost no bitter taste, resulting in good patient compliance; 4. The preparation method of the naringin powder atomizer provided by the present invention only requires pulverization and mixing. The preparation method is simple, can be used for large-scale production, and has broad application prospects. Attached Figure Description

[0018] Figure 1 The results of NGI analysis for product M1 in Example 1; Figure 2 The results of NGI analysis for product M2 in Example 2; Figure 3 The results of NGI analysis for product M3 in Example 3; Figure 4 This is a powder electron microscope image of product M4 from Example 4. Detailed Implementation

[0019] To make the above-mentioned objects, features, and advantages of the present invention more apparent and understandable, specific embodiments of the present invention are described in detail below. It should be noted that the following embodiments are only used to illustrate the implementation methods and typical parameters of the present invention, and are not intended to limit the parameter range described in the present invention. Reasonable variations derived therefrom are still within the protection scope of the present invention.

[0020] It should be noted that the endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0021] As described in the background section, existing naringin powder inhalers suffer from low absorption efficiency and poor patient compliance. To address these technical problems, this invention provides a naringin powder inhaler comprising, by weight, 1-30 parts of micronized naringin and 40-100 parts of diluent, wherein the particle size distribution D90 of the micronized naringin is 1-30 μm.

[0022] In the above embodiments, the diluent is selected from any one or more of mannitol, lactose, microcrystalline cellulose, starch, pregelatinized starch, β-cyclodextrin, γ-cyclodextrin, maltodextrin, chitosan, sodium alginate, and β-glucan.

[0023] More specifically, in the above embodiments, the particle size distribution D90 of the diluent is 50~200μm. In the above embodiments, the naringin powder aerosol also includes a taste indicator and / or a lubricant.

[0024] In the above embodiments, the taste indicator is selected from any one or more of neotame, sucralose, mogroside, steviol glycoside, aspartame, erythritol, and xylitol.

[0025] In the above embodiments, the content of the taste indicator in the naringin powder aerosol is 0.01 to 30 parts by weight.

[0026] More specifically, in the above embodiments, the particle size distribution D90 of the taste indicator is 50~200μm.

[0027] In the above embodiments, the lubricant is selected from any one or more of magnesium stearate, leucine, and talc.

[0028] In the above embodiments, the lubricant content in the naringin powder aerosol is 0.01 to 2 parts by weight.

[0029] More specifically, in the above embodiments, the particle size distribution D90 of the lubricant is 50~200μm.

[0030] More specifically, in the above embodiments, the preparation method of naringin powder aerosol includes the following steps: S1: Take naringin raw material and pulverize it; S2: Take the raw materials for diluent, taste indicator, and lubricant, and pulverize them; S3: Mix and pulverize the components to obtain naringin powder atomizer.

[0031] More specifically, in the above embodiments, the pulverizing process is preferably any one of air jet milling, freeze drying, supercritical fluid technology, spray drying granulation, and grinding.

[0032] More specifically, in the above embodiments, the mixing process is preferably carried out using any one of a high-shear mixer, a planetary mixer, a trough mixer, or a resonant mixer.

[0033] More specifically, the naringin powder aerosol prepared according to the above embodiments can be released using capsules, preferably hydroxypropyl methylcellulose capsules or gelatin capsules.

[0034] The technical solutions of the present invention are further described below through specific embodiments. Unless otherwise defined, all terms, symbols, and other scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. In some cases, terms with a conventional understanding are limited herein for clarification or ease of reference, and such limitations should not be construed as indicating a significant difference from the conventional understanding in the art. The technical methods described or referenced herein are generally well understood by those skilled in the art and have been adopted by conventional methods. Unless otherwise stated, the use of commercially available kits, reagents, and instruments shall be performed according to the manufacturer's instructions and parameters.

[0035] Example 1 Preparation of 2% naringin-mannitol naringin powder atomizer S1: Take naringin raw material and process it with an air jet mill at a feed pressure of 7 bar and a grinding pressure of 7 bar until the particle size D90 is 4~7 μm to obtain micronized naringin. S2: Mannitol and neotame were pulverized using an air jet mill, and the particle size D90 after pulverization was 55~60μm. S3: By weight, take 2 parts of micronized naringin, 97.9 parts of pulverized mannitol, and 0.01 parts of pulverized neotame and put them into a high-shear mixer. Mix at 500 rpm for 20 min. After mixing, fill into 3# HPMC capsules. Each capsule contains 10 mg of drug to obtain the product naringin powder aerosol, denoted as M1. Each capsule in product M1 contains 200 μg of naringin.

[0036] Product M1 was analyzed using a pharmaceutical impactor; the NGI analysis results are as follows: Figure 1 As shown in Table 1, simulated inhalation of M1 was performed using a capsule inhaler to detect the delivery dose of naringin, the proportion of fine particles (particles with an aerodynamic diameter of less than 5 μm), the fine particle dose, and the median mass size of the inhaled mist.

[0037] Table 1 Example 2 Preparation of 5% naringin-lactose naringin powder aerosol S1: Take naringin raw material and process it with a fluidized bed pulverizer at a feed pressure of 6 bar, a pulverizing pressure of 6 bar, and a classifier speed of 8000 rpm to reduce the particle size of naringin to 3~5 μm with a particle size D90, thereby obtaining micronized naringin. S2: Take L251 type lactose and mogroside, and pulverize them separately using an air jet mill. The particle size D90 after pulverization is 55~60μm. S3: By weight, take 5 parts of micronized naringin, 94.5 parts of pulverized L251 lactose, and 0.5 parts of pulverized mogroside and put them into a high-shear mixer. Mix at 1000 rpm for 5 minutes. After mixing, fill the mixture into No. 3 gelatin capsules. Each capsule contains 10 mg of drug to obtain the product naringin powder aerosol, denoted as M2. Each capsule in product M2 contains 500 μg of naringin.

[0038] Product M2 was analyzed using a pharmaceutical impactor; the NGI analysis results are as follows: Figure 2 As shown in Table 2, simulated inhalation of M2 was performed using a capsule inhaler to detect the delivery dose of naringin, the proportion of fine particles (particles with an aerodynamic diameter of less than 5 μm), the fine particle dose, and the median mass size in the inhaled mist.

[0039] Table 2 Example 3 Preparation of 2% naringin-lactose naringin powder aerosol S1: Take naringin raw material and process it with an air jet mill at a feed pressure of 7 bar and a grinding pressure of 7 bar until the particle size D90 is 4~7 μm to obtain micronized naringin. S2: Take L251 type lactose, magnesium stearate and mogroside, and pulverize them separately using an air jet mill. The particle size D90 after pulverization is 55~60μm. S3: By weight, take 97.4 parts of pulverized L251 lactose, 0.5 parts of pulverized magnesium stearate, and 0.01 parts of pulverized neotame and put them into a high-shear mixer. Mix at 500 rpm for 10 min. Then add 2 parts of micronized naringin and continue mixing at 500 rpm for 10 min. After mixing, fill the mixture into 3# HPMC capsules. Each capsule contains 10 mg of drug. The product naringin powder aerosol is obtained and is denoted as M3. Each capsule of product M3 contains 200 μg of naringin.

[0040] Product M3 was analyzed using a pharmaceutical impactor; the NGI analysis results are as follows: Figure 1 As shown in Table 3, simulated inhalation of M3 was performed using a capsule inhaler to detect the delivery dose of naringin, the proportion of fine particles (particles with an aerodynamic diameter of less than 5 μm), the fine particle dose, and the median mass size of the inhaled mist.

[0041] Table 3 Example 4 Preparation of 15% naringin-aspartame naringin powder aerosol By weight, 15 parts of naringin raw material and 0.1 parts of magnesium stearate were dissolved in 500 mL of ethanol solution, and 84 parts of lactose and 0.9 parts of aspartame were dissolved in 500 mL of ddH2O. After mixing the ethanol solution and aqueous solution until clear and transparent, the mixture was spray-dried at an inlet temperature of 140℃ and an outlet temperature of 70~75℃ to prepare powder. The powder was then filled into 3# HPMC capsules, with each capsule containing 10 mg of drug, to obtain the product naringin powder aerosol, denoted as M4. Each capsule of product M4 contains 1.5 mg of naringin.

[0042] The above electron micrographs of the powder at different resolutions are as follows: Figure 4 As shown.

[0043] Example 5 Pharmacokinetics of Naringin Powder Inhalation The micronized naringin and pulverized mannitol from Example 1 were mixed in a mass ratio of 2:98 and then filled into 3# HPMC capsules, which were designated as product M5.

[0044] Several rats with similar body weight, growth status, and health status were divided into three groups and labeled. Product M5 was used for administration. Group 1 was administered a single oral gavage at a dose of 10 mg / kg; Group 2 was administered intravenously at a dose of 10 mg / kg; and Group 3 was administered via tracheal nebulization at a dose of 5 mg / kg. Blood samples were collected at different time points after administration, and the concentration of naringin in the samples was determined using LC-MS / MS. The main pharmacokinetic parameters were calculated, and the results are shown in Table 4.

[0045] Table 4 As shown in Table 4, the T value of naringin in the tracheal nebulization inhalation group was... max The bioavailability (F) was significantly reduced compared to the gavage group, and significantly increased. This demonstrates the effectiveness of the product provided by this invention.

[0046] Example 6 Effects of naringin powder inhaler on inflammatory factors Logarithmic growth phase mouse Lewis lung cancer cell line was used to prepare 1×10⁻⁶ cells under sterile conditions. 7 Cell suspension was administered at a dose of 0.1 mL / mouse via the tail vein of C57 mice. The mice were euthanized 14 days after inoculation, and lung tissue was harvested for observation. The levels of inflammatory factors IL-6 and TNF-α in the lung tissue were measured. The types and dosages of drugs administered and the inflammatory factor indicators are shown in Table 5.

[0047] Table 5 As shown in Table 5, compared with the control group mice, oral and inhaled administration of naringin powder significantly reduced the levels of TNF-α and IL-6 in lung tissue and serum. The high-dose oral and inhaled naringin groups were comparable to the oxaliplatin group.

[0048] As can be seen from the above results, the naringin powder aerosol provided by the present invention has excellent anti-inflammatory and anti-tumor effects, which are comparable to those of traditional oxaliplatin, and it has broad application prospects.

[0049] While the disclosure is as stated above, its scope of protection is not limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of this disclosure, and all such changes and modifications will fall within the protection scope of this invention.

Claims

1. A naringin powder mist, characterized by, by mass, comprising 1-30 parts of micronized naringin and 40-100 parts of diluent, wherein the particle size distribution D90 of the micronized naringin is 1-30 μm.

2. The naringin powder mist of claim 1, wherein the naringin powder mist is prepared by mixing 0.1 to 1% of the naringin powder and 99 to 99% of the water. The diluent is selected from any one or more of mannitol, lactose, microcrystalline cellulose, starch, pregelatinized starch, β-cyclodextrin, γ-cyclodextrin, maltodextrin, chitosan, sodium alginate, and β-glucan.

3. The naringin powder mist of claim 1, wherein the naringin powder mist is prepared by mixing 0.1 to 1% of the naringin powder and 99 to 99% of the water. The naringin powder inhalation also comprises a taste indicator and / or a lubricant.

4. The naringin powder atomizing agent as described in claim 3, characterized in that, The taste indicator is selected from any one or more of neotame, sucralose, mogroside, steviol glycoside, aspartame, erythritol, and xylitol.

5. The naringin powder mist of claim 3, wherein the naringin powder mist is prepared by mixing 0.1 to 1% of the naringin powder and 99 to 99% of the water. The content of the taste indicator in the naringin powder inhalation is 0.01-30 parts by mass.

6. The naringin powder mist of claim 3, wherein the naringin powder mist is prepared by mixing 0.1 to 1% of the naringin powder and 99 to 99% of the water. The lubricant is selected from any one or more of magnesium stearate, leucine, and talc.

7. The naringin powder mist of claim 3, wherein the naringin powder mist is prepared by mixing 0.1 to 1% of the naringin powder and 99 to 99% of the water. The content of the lubricant in the naringin powder inhalation is 0.01-2 parts by mass.

8. A method for preparing naringin powder aerosol according to any one of claims 1 to 7, characterized in that, The application comprises the following steps: S1: taking naringin raw material and crushing; S2: taking diluent raw material, taste indicator raw material, and lubricant raw material and crushing; S3: mixing the crushed components to obtain naringin powder inhalation.

9. The use of naringin powder aerosol according to any one of claims 1 to 7, characterized in that, The application is the use of the naringin powder inhalation in the preparation of anti-inflammatory drug inhalants and / or lung disease treatment drugs.

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