Polymyxin inhalation liquid preparation and preparation method thereof

Abstract

The invention relates to a polymyxin inhalation liquid preparation and a preparation method thereof. The polymyxin inhalation liquid preparation comprises 0.1-5% (W / V) of polymyxin B sulfate, 0.05-1% (W / V) of a stabilizer, 0.1-0.9% (W / V) of an osmotic pressure regulator, a pH value regulator and a solvent, the pH (Potential of Hydrogen) of the liquid preparation is 3.0 to 6.0; the solvent is selected from purified water and water for injection; the polymyxin inhalation solution provided by the invention is simple in composition, the pH value of the polymyxin inhalation solution is 3.0-6.0, osmotic pressure and isotonic pressure are simultaneously realized, bronchus spasm and cough caused by the polymyxin inhalation solution can be reduced, safety evaluation verifies that the polymyxin inhalation solution has better safety, and a new choice is provided for clinical application.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a polymyxin inhalation liquid preparation and a preparation method thereof. Background Art

[0002] Pneumonia is the leading cause of death from infectious diseases worldwide. Lower respiratory tract infections, including hospital-acquired pneumonia and ventilator-associated pneumonia, are the most common hospital-acquired infections. In particular, the rapid spread of multidrug-resistant bacteria around the world in recent years and the lag in the development of new therapeutic drugs have made the treatment of pneumonia more difficult. The results of my country's CHINET bacterial resistance test in 2018 showed that the top three bacterial species with the highest rates of severe infection in respiratory specimens were Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Among them, pan-resistant Acinetobacter baumannii is the main conditional pathogen that causes outbreaks and epidemics of hospital infections in intensive care units. With the increasing incidence of lower respiratory tract infections caused by multidrug-resistant bacteria and the resulting high mortality rate and limited treatment options, people have begun to pay attention to the application of auxiliary treatment strategies, such as nebulized antibiotic therapy.

[0003] Polymyxin B and polymyxin E (also known as colistin) are polypeptide antibiotics that were approved in the late 1950s for the treatment of infections caused by Gram-negative bacteria. In the 1970s, polymyxins were abandoned due to nephrotoxicity and neurotoxicity, mainly due to the lack of research on their pharmacokinetics / pharmacodynamics / toxicokinetics (PK / PD / TD). However, since the late 1990s, the increasing incidence of antibiotic resistance and the lack of new antibiotics in clinical practice have forced clinicians to use polymyxins as a last resort for the treatment of infections caused by multidrug-resistant Gram-negative bacteria (including Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae). Polymyxin B and polymyxin E have the same antibacterial mechanism of action, which can expand the bacterial cell membrane area by replacing calcium and magnesium ions in the anionic lipopolysaccharide molecules of the cell membrane, increase the permeability of the cell membrane, and cause leakage of cell contents, thereby leading to cell death.

[0004] Compared with the injection method, pulmonary inhalation can directly deliver drugs to the absorption site or site of action, avoiding the first-pass effect of the liver and gastrointestinal degradation, increasing the concentration of drugs in the respiratory tract, greatly reducing the concentration of drugs entering the systemic circulation, improving the therapeutic effect and patient compliance, and the inhalation dose is much lower than the injection dose, greatly reducing the injection risk, and is suitable for patients who need long-term treatment. In addition, the direct use of marketed antibacterial drug injections for aerosol inhalation administration has a major safety hazard. The additives contained in the injection may irritate the bronchi after inhalation, affecting the aerosol effect, making it difficult to reach the target site to exert its therapeutic effect. At the same time, the aerosol deposited in the lungs is cleared slowly, which may cause adverse reactions. Inhalation liquid preparations have the characteristics of rapid effect, small dosage, few adverse reactions, and simple prescriptions. Compared with aerosols and powder sprays, the single administration dose of inhaled liquid is small, and the suspension or solution containing the drug can be aerosolized into a large dose of small droplets, and it is not affected by the patient's breathing behavior. It has a wide range of applications and can be used by children and the elderly.

[0005] At present, there are special inhalation preparations of polymyxin E mesylate abroad. The instructions recommend a dose of 125 mg (166,250 U) for patients with cystic fibrosis caused by Pseudomonas aeruginosa aged ≥ 6 years, every 12 hours. The International Consensus Guidelines for the Optimal Use of Polymyxins (2019 Edition) point out that the benefits of polymyxin inhalation for the treatment of pneumonia outweigh the risks. For patients with suspected or confirmed HAP / VAP caused by extensively drug-resistant Gram-negative bacteria who need intravenous polymyxin treatment, they should receive additional polymyxin inhalation treatment (weak recommendation, very low-quality evidence). Polymyxin E or polymyxin B can be used for inhalation treatment (weak recommendation, very low-quality evidence). The Chinese Expert Consensus on the Clinical Application of Polymyxins (2019 Edition) points out that polymyxin E or polymyxin B can be used for nebulized inhalation. However, many reports have mentioned that polymyxins will have some safety issues after inhalation, and there are currently no reports on polymyxin B and polymyxin E inhalation preparations. Summary of the invention

[0006] The purpose of the present invention is to overcome the defects in the prior art, provide a polymyxin inhalation liquid preparation, and also provide a preparation method thereof.

[0007] To achieve the above object, the technical solution adopted by the present invention is: On the one hand, the present invention provides a polymyxin inhalation liquid preparation, which includes 0.1-5% (W / V) of polymyxin B sulfate, 0.05-1% (W / V) of a stabilizer, 0.1-0.9% (W / V) of an osmotic pressure regulator, a pH regulator and a solvent; the pH of the liquid preparation is 3.0-6.0; and the solvent is selected from purified water and water for injection.

[0008] As some preferred embodiments of the present invention, the concentration of polymyxin B sulfate is 0.1-5% (W / V), preferably 1.25-2.5% (W / V), and more preferably 1.25% (W / V).

[0009] As some preferred embodiments of the present invention, the stabilizer is selected from sodium metabisulfite or disodium ethylenediaminetetraacetate.

[0010] As some preferred embodiments of the present invention, the stabilizer is selected from sodium metabisulfite 0.3% (W / V).

[0011] As some preferred embodiments of the present invention, the osmotic pressure regulator is sodium chloride with a concentration of 0.9% (W / V).

[0012] As some preferred embodiments of the present invention, the pH adjuster is selected from one or more of hydrochloric acid, sodium hydroxide, citric acid-sodium citrate, citric acid-disodium hydrogen phosphate, and disodium hydrogen phosphate-sodium dihydrogen phosphate buffer systems.

[0013] As some preferred embodiments of the present invention, the pH adjuster is a disodium hydrogen phosphate-sodium dihydrogen phosphate buffer system and hydrochloric acid, and the pH of the solution is 3.0-6.0, and most preferably pH 5.0.

[0014] On the other hand, the present invention provides a method for preparing the above-mentioned polymyxin inhalation liquid preparation, which specifically comprises the following steps: S1: Add a pH adjuster to the solvent, stir evenly, and adjust the pH to 3.0-6.0; S2: Add polymyxin and stir to dissolve; S3: Add the prescribed amount of osmotic pressure regulator and stir evenly; S4: Add stabilizer and disperse evenly by ultrasonication; S5: Sterilize by filtering through a 0.22 μm filter membrane.

[0015] In the present application, the polymyxin B sulfate 0.1-5%, stabilizer 0.05-1%, and osmotic pressure regulator 0.1-0.9% are all mass volume concentrations, with the unit of g / 100mL.

[0016] The beneficial effects of adopting the above technical solution are: 1. The polymyxin inhalation liquid preparation provided by the present invention has simple components and isotonic osmotic pressure, and can reduce bronchospasm and cough caused by polymyxin inhalation solution.

[0017] 2. The polymyxin inhalation solution preparation provided by the invention does not contain any preservatives, and safety evaluation has shown that it has good safety.

[0018] 3. Compared with intravenous administration, the polymyxin inhalation solution provided by the present invention can significantly increase the drug concentration in the pulmonary infection lesions, improve the bioavailability of the drug, improve the efficacy, and reduce nephrotoxicity and neurotoxicity.

[0019] 4. The preparation process of the present invention is simple, the equipment cost is low, it is easy to industrialize, and the production efficiency is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the specific implementation of the present invention or the technical solution in the prior art, the drawings required for use in the specific implementation or the description of the prior art are briefly introduced below.

[0021] Figure 1 This is a comparison chart of rat lung function test in Experimental Example 3 of the present invention; Figure 2 This is a tissue section of a rat in Test Example 3 of the present invention (H&E×200). DETAILED DESCRIPTION

[0022] In order to make the purpose, technical scheme and advantages of the present invention clearer, the invention is described clearly and completely in conjunction with specific embodiments below, which is only for the convenience of describing the present invention and cannot be understood as limiting the present invention. The test methods and operations in this embodiment are conventional methods and conventional operations unless otherwise specified; the raw materials, reagents, etc. used are commercially available products unless otherwise specified.

[0023] Example 1 Preparation method: S1: Prepare citrate buffer (pH 5.0) as follows: weigh 30.02 mg citric acid and 60.00 mg sodium citrate, dissolve in appropriate amount of purified water, adjust pH to 5.0 with 0.1 mol / L sodium hydroxide, transfer to a volumetric flask and dilute to 100 mL, so that the concentration of citric acid is 0.03% and the concentration of sodium citrate is 0.06%; S2: Take 2 mL of the above citrate buffer, add the prescribed amount of polymyxin B sulfate, and stir evenly; S3: Add the prescribed amount of sodium chloride and stir evenly; S4: Add the prescribed amount of disodium ethylenediaminetetraacetate, disperse evenly by ultrasonication, and sterilize through a 0.22 μm filter membrane to obtain the polymyxin B sulfate inhalation solution preparation.

[0024] Example 2 Preparation method: S1: Prepare citric acid-sodium hydrogen phosphate buffer (pH 5.0) as follows: weigh 0.1002 g citric acid and 0.3754 g sodium hydrogen phosphate, dissolve in appropriate amount of pure water, adjust pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, transfer to a volumetric flask and dilute to 100 mL, so that the concentration of citric acid is about 0.10% and the concentration of sodium hydrogen phosphate is about 0.375%. S2: Take 2 mL of the above citrate-disodium hydrogen phosphate buffer, add polymyxin B sulfate, and stir evenly; S3: Add the prescribed amount of sodium chloride and stir evenly; S4: Add the prescribed amount of disodium ethylenediaminetetraacetate, disperse evenly by ultrasonication, and sterilize through a 0.22 μm filter membrane to obtain the polymyxin B sulfate inhalation solution preparation.

[0025] Example 3 Preparation method: S1: Prepare phosphate buffer (pH 5.0); the preparation method is as follows: weigh 1.560 g sodium dihydrogen phosphate and 3.581 g disodium hydrogen phosphate, dissolve in appropriate amount of purified water, adjust pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, transfer to a volumetric flask and make up to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156%, and the concentration of sodium dihydrogen phosphate is 0.358%; S2: Take 2 mL of the above phosphate buffer, add polymyxin B sulfate, and stir evenly; S3: Add the prescribed amount of sodium chloride and stir evenly; S4: Add the prescribed amount of disodium ethylenediaminetetraacetate, disperse evenly by ultrasonication, and sterilize through a 0.22 μm filter membrane to obtain the polymyxin B sulfate inhalation solution preparation.

[0026] Example 4 Preparation method: S1: Prepare phosphate buffer (pH 5.0); the preparation method is as follows: weigh 1.560 g sodium dihydrogen phosphate and 3.581 g disodium hydrogen phosphate, dissolve in appropriate amount of purified water, adjust pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, transfer to a volumetric flask and make up to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156%, and the concentration of sodium dihydrogen phosphate is 0.358%; S2: Take 2 mL of the above phosphate buffer, add polymyxin B sulfate, and stir evenly; S3: Add the prescribed amount of sodium chloride and stir evenly; S4: Add the prescribed amount of disodium ethylenediaminetetraacetate, disperse evenly by ultrasonication, and sterilize through a 0.22 μm filter membrane to obtain the polymyxin B sulfate inhalation solution preparation.

[0027] Example 5 Preparation method: S1: Prepare phosphate buffer (pH 5.0) as follows: weigh 1.560 g sodium dihydrogen phosphate and 3.581 g sodium dihydrogen phosphate, dissolve in appropriate amount of purified water, adjust pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, transfer to a volumetric flask and make up to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of sodium dihydrogen phosphate is 0.358%.

[0028] S2: Take 2 mL of the above phosphate buffer, add polymyxin B sulfate, and stir evenly; S3: Add the prescribed amount of sodium chloride and stir evenly; S4: Add the prescribed amount of sodium metabisulfite, disperse evenly by ultrasonication, and sterilize by filtering through a 0.22 μm filter membrane to obtain the polymyxin B sulfate inhalation solution preparation.

[0029] Example 6 Preparation method: S1: Prepare phosphate buffer (pH 5.0) as follows: weigh 1.560 g sodium dihydrogen phosphate and 3.581 g sodium dihydrogen phosphate, dissolve in appropriate amount of purified water, adjust pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, transfer to a volumetric flask and make up to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of sodium dihydrogen phosphate is 0.358%.

[0030] S2: Take 2 mL of the above phosphate buffer, add polymyxin B sulfate, and stir evenly; S3: Add the prescribed amount of sodium chloride and stir evenly; S4: Add the prescribed amount of sodium metabisulfite, disperse evenly by ultrasonication, and sterilize by filtering through a 0.22 μm filter membrane to obtain the polymyxin B sulfate inhalation solution preparation.

[0031] Example 7 Components Addition amount Polymyxin B sulfate 100 mg Sodium dihydrogen phosphate 3.1 mg Disodium hydrogen phosphate 7.2 mg Sodium metabisulfite 6 mg Sodium chloride 18 mg Preparation method: S1: Prepare phosphate buffer (pH 5.0) as follows: weigh 1.560 g sodium dihydrogen phosphate and 3.581 g sodium dihydrogen phosphate, dissolve in appropriate amount of purified water, adjust pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, transfer to a volumetric flask and make up to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of sodium dihydrogen phosphate is 0.358%.

[0032] S2: Take 2 mL of the above phosphate buffer, add polymyxin B sulfate, and stir evenly; S3: Add the prescribed amount of sodium chloride and stir evenly; S4: Add the prescribed amount of sodium metabisulfite, disperse evenly by ultrasonication, and sterilize by filtering through a 0.22 μm filter membrane to obtain the polymyxin B sulfate inhalation solution preparation.

[0033] Example 8 Components Addition amount Polymyxin B sulfate 25 mg Sodium dihydrogen phosphate 3.1 mg Disodium hydrogen phosphate 7.2 mg Sodium metabisulfite 1 mg Sodium chloride 18 mg Preparation method: S1: Prepare phosphate buffer (pH 5.0) as follows: weigh 1.560 g sodium dihydrogen phosphate and 3.581 g sodium dihydrogen phosphate, dissolve in appropriate amount of purified water, adjust pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, transfer to a volumetric flask and make up to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of sodium dihydrogen phosphate is 0.358%.

[0034] S2: Take 2 mL of the above phosphate buffer, add polymyxin B sulfate, and stir evenly; S3: Add the prescribed amount of sodium chloride and stir evenly; S4: Add the prescribed amount of sodium metabisulfite, disperse evenly by ultrasonication, and sterilize by filtering through a 0.22 μm filter membrane to obtain the polymyxin B sulfate inhalation solution preparation.

[0035] Example 9 Components Addition amount Polymyxin B sulfate 25 mg Sodium dihydrogen phosphate 3.1 mg Disodium hydrogen phosphate 7.2 mg Sodium metabisulfite 3 mg Sodium chloride 18 mg Preparation method: S1: Prepare phosphate buffer (pH 5.0) as follows: weigh 1.560 g sodium dihydrogen phosphate and 3.581 g sodium dihydrogen phosphate, dissolve in appropriate amount of purified water, adjust pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, transfer to a volumetric flask and make up to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of sodium dihydrogen phosphate is 0.358%.

[0036] S2: Take 2 mL of the above phosphate buffer, add polymyxin B sulfate, and stir evenly; S3: Add the prescribed amount of sodium chloride and stir evenly; S4: Add the prescribed amount of sodium metabisulfite, disperse evenly by ultrasonication, and sterilize by filtering through a 0.22 μm filter membrane to obtain the polymyxin B sulfate inhalation solution preparation.

[0037] Example 10 Components Addition amount Polymyxin B sulfate 25 mg Sodium dihydrogen phosphate 3.1 mg Disodium hydrogen phosphate 7.2 mg Sodium metabisulfite 20 mg Sodium chloride 18 mg Preparation method: S1: Prepare phosphate buffer (pH 5.0) as follows: weigh 1.560 g sodium dihydrogen phosphate and 3.581 g sodium dihydrogen phosphate, dissolve in appropriate amount of purified water, adjust pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, transfer to a volumetric flask and make up to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of sodium dihydrogen phosphate is 0.358%.

[0038] S2: Take 2 mL of the above phosphate buffer, add polymyxin B sulfate, and stir evenly; S3: Add the prescribed amount of sodium chloride and stir evenly; S4: Add the prescribed amount of sodium metabisulfite, disperse evenly by ultrasonication, and sterilize by filtering through a 0.22 μm filter membrane to obtain the polymyxin B sulfate inhalation solution preparation.

[0039] Embodiment 11 Components Addition amount Polymyxin B sulfate 25 mg Sodium dihydrogen phosphate 3.1 mg Disodium hydrogen phosphate 7.2 mg Sodium metabisulfite 6 mg Sodium chloride 2 mg Preparation method: S1: Prepare phosphate buffer (pH 5.0) as follows: weigh 1.560 g sodium dihydrogen phosphate and 3.581 g sodium dihydrogen phosphate, dissolve in appropriate amount of purified water, adjust pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, transfer to a volumetric flask and make up to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of sodium dihydrogen phosphate is 0.358%.

[0040] S2: Take 2 mL of the above phosphate buffer, add polymyxin B sulfate, and stir evenly; S3: Add the prescribed amount of sodium chloride and stir evenly; S4: Add the prescribed amount of sodium metabisulfite, disperse evenly by ultrasonication, and sterilize by filtering through a 0.22 μm filter membrane to obtain the polymyxin B sulfate inhalation solution preparation.

[0041] Example 12 Components Addition amount Polymyxin B sulfate 25 mg Sodium dihydrogen phosphate 3.1 mg Disodium hydrogen phosphate 7.2 mg Sodium metabisulfite 6 mg Sodium chloride 16 mg S1: Prepare phosphate buffer (pH 5.0) as follows: weigh 1.560 g sodium dihydrogen phosphate and 3.581 g sodium dihydrogen phosphate, dissolve in appropriate amount of purified water, adjust pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, transfer to a volumetric flask and make up to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of sodium dihydrogen phosphate is 0.358%.

[0042] S2: Take 2 mL of the above phosphate buffer, add polymyxin B sulfate, and stir evenly; S3: Add the prescribed amount of sodium chloride and stir evenly; S4: Add the prescribed amount of sodium metabisulfite, disperse evenly by ultrasonication, and sterilize by filtering through a 0.22 μm filter membrane to obtain the polymyxin B sulfate inhalation solution preparation.

[0043] Test Example 1 Stability Study Accurately weigh 25 mg of polymyxin B sulfate in 3 portions, place in a vial, add PBS solution with a pH value of 5.0 to dissolve to make a 12.5 mg / mL solution, add 0.9% (W / V) osmotic pressure regulator, add 0.3% sodium metabisulfite, 0.05% EDTA-2Na, and no stabilizer to each sample, to obtain stabilizer type screening samples.

[0044] Place the above samples at room temperature and take them out at 0 d, 5 d, and 10 d. Pipette 0.08 mL of the above prepared sample solution into a 10 mL volumetric flask, dilute with mobile phase, and measure the content of polymyxin B sulfate, see Table 1: Table 1 Effect of stabilizer types on the stability of PMBS (measured in PMB1) (n=3) Test Example 2 Physical and Chemical Property Testing The preparation prepared in Example 5 was tested for osmotic pressure using a YASN Osmo310 osmometer, and the results showed that the osmotic pressure was isotonic.

[0045] Test Example 3 Safety Evaluation 1. Experimental Animals Healthy female SD rats, weighing 200-250 g, were provided by the Experimental Animal Center of Hebei Medical University. The experimental rats were kept in clean cages with free access to water and food. The room temperature was controlled at (25±2)℃, the relative humidity was adjusted to 50-75%, and the light cycle was 12 h.

[0046] 2. Methods 2.1 Experimental Grouping Six female SD rats were randomly divided into a homemade preparation group (Example 5), i.e., Polymyxin B Sulfate inhalation PMBS inh., and a negative control group, i.e., normal saline (Normal Saline NS). There were three rats in each group. The rats were fasted for 12 h before the start of the experiment and were free to drink water. The oral and nasal exposure system of mice and rats was used to inhale the aerosolized drug. The homemade preparation group was given aerosolized polymyxin B inhalation (12.5 mg / mL) at 4.5 mg / kg; the negative control group was given sodium chloride injection. Each group was given once a day. The drug was given for 7 consecutive days.

[0047] 2.2 Administration The oral and nasal exposure system for mice and rats was used to inhale the nebulized drugs. Before the experiment, the air inlet and the nebulizer outlet of the device were connected to ensure that the nebulized gas could effectively enter the device. Then 2 mL of polymyxin B sulfate inhalation solution, polymyxin B sulfate injection and normal saline were added to the nebulizer cup, and the nebulizer was turned on for nebulization. The animal inhalation dose was calculated based on the clinical human nebulization inhalation dosage. The homemade preparation group was given nebulized polymyxin B inhalation (12.5 mg / mL) at 4.5 mg / kg; the negative control group was given sodium chloride injection. Each group was given once a day for 7 consecutive days. At the 7th day of administration, the rat lung function test was performed. After the measurement, the heart, liver, lung, spleen and kidney were dissected and separated, and the sections were stained and observed.

[0048] 2.3 Pulmonary function test in rats A small animal whole body plethysmography system was used to detect some physiological indices related to lung function, including general indices, lung volume indices, conductivity indices, airway obstruction indices and ventilation indices.

[0049] 2.4 Histopathological analysis After the administration, the heart, liver, spleen, lungs, and kidneys were removed and the blood stains were immediately washed with normal saline, dried with filter paper, and fixed in 4% formaldehyde solution. After fixation, they were dehydrated and embedded. Finally, they were sectioned and stained with H&E, and then observed under a microscope for adverse reactions in the above-mentioned different organs. The main observation was whether there were pathological phenomena such as alveolar swelling, congestion, infiltration and hyperplasia in the lung tissue, so as to examine the irritation of polymyxin B sulfate inhalation preparations to lung tissue.

[0050] 3. Results 3.1 Pulmonary function test of mice The rat lung function test was performed using a small animal whole body scanning system. The results included multiple parameters. This section used respiratory rate, tidal volume, inspiratory time, expiratory time, airway stenosis index, apnea, maximum inspiratory flow rate, maximum expiratory flow rate, and minute ventilation as evaluation indicators. The results showed that there was no significant difference between the negative control group and the homemade preparation group. In general, the polymyxin B sulfate inhalation preparation has good safety and less damage to the lungs. For details, see Figure 1 .

[0051] 3.2 Histopathological analysis like Figure 2 As shown, according to the results of pathological analysis, there was no significant difference in the histopathological examination of the homemade preparation group compared with the normal saline group, indicating that aerosol inhalation of polymyxin B sulfate inhalation preparation had no significant changes in lung histopathology.

[0052] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A polymyxin inhalation liquid preparation, characterized in that: The invention comprises polymyxin B sulfate 0.1-5% (W / V), stabilizer 0.05-1% (W / V), osmotic pressure regulator 0.1-0.9% (W / V), pH regulator and solvent; the pH of the liquid preparation is 3.0-6.0; and the solvent is selected from purified water or water for injection.

2. A polymyxin inhalation liquid preparation according to claim 1, characterized in that: The concentration of polymyxin B sulfate is 1.25-2.5% (W / V).

3. A polymyxin inhalation liquid preparation according to claim 1, characterized in that: The stabilizer is selected from sodium pyrosulfite or disodium ethylenediaminetetraacetate.

4. A polymyxin inhalation liquid preparation according to claim 1, characterized in that: The stabilizer is selected from sodium metabisulfite 0.3% (W / V).

5. A polymyxin inhalation liquid preparation according to claim 1, characterized in that: The osmotic pressure regulator is selected from sodium chloride with a concentration of 0.9% (W / V).

6. A polymyxin inhalation liquid preparation according to claim 1, characterized in that: The pH adjuster is selected from one or more of hydrochloric acid, sodium hydroxide, citric acid-sodium citrate, citric acid-disodium hydrogen phosphate, and disodium hydrogen phosphate-sodium dihydrogen phosphate buffer systems.

7. A polymyxin inhalation liquid preparation according to claim 1, characterized in that: The pH of the liquid preparation is 5.

0.

8. A method for preparing the polymyxin inhalation liquid preparation according to any one of claims 1 to 7, characterized in that: The specific steps include: S1: Add a pH adjuster to the solvent, stir evenly, and adjust the pH to 3.0-6.0; S2: Add polymyxin sulfate and stir to dissolve; S3: Add the prescribed amount of osmotic pressure regulator and stir evenly; S4: Add stabilizer and disperse evenly by ultrasonication; S5: Sterilize by filtering through a 0.22 μm filter membrane.

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