A polymyxin inhalation liquid formulation and its preparation method

Abstract

This invention relates to a polymyxin inhalation liquid formulation and its preparation method, comprising 0.1-5% (w / v) polymyxin B sulfate, 0.05-1% (w / v) stabilizer, 0.1-0.9% (w / v) osmolarity regulator, pH adjuster, and solvent; the pH of the liquid formulation is 3.0-6.0; the solvent is selected from purified water and water for injection; the polymyxin inhalation solution provided by this invention has a simple composition, a pH of 3.0-6.0, and is osmotonic, which can reduce bronchospasm and cough caused by polymyxin inhalation solution. Safety evaluation has verified that it has good safety, providing a new option for clinical application.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and particularly relates to a polymyxin inhalation liquid formulation and its preparation method. Background Technology

[0002] Pneumonia is a 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 recent years, the rapid global spread of multidrug-resistant bacteria and the lag in the development of new therapeutic drugs have made pneumonia treatment even more challenging. In 2018, the CHINET bacterial resistance test results in my country showed that the top three bacteria with the highest rate of severe infection in respiratory specimens were Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Among them, pan-drug-resistant Acinetobacter baumannii is a major opportunistic pathogen causing hospital-acquired infection outbreaks and epidemics in intensive care units. With the increasing incidence of lower respiratory tract infections caused by multidrug-resistant bacteria, the resulting high mortality rate, and limited treatment options, there is renewed focus on the application of adjunctive therapy strategies, such as nebulized antibiotic therapy.

[0003] Polymyxin B and polymyxin E (also known as colistin) are polypeptide antibiotics approved in the late 1950s for treating infections caused by Gram-negative bacteria. In the 1970s, polymyxins were discontinued due to nephrotoxicity and neurotoxicity, primarily due to a lack of pharmacokinetic / pharmacodynamic / toxicokinetic (PK / PD / TD) studies. However, since the late 1990s, the increasing antibiotic resistance and the lack of new antibiotics in clinical practice have forced clinicians to use polymyxins as a last resort for treating infections caused by multidrug-resistant Gram-negative bacteria, including *Pseudomonas aeruginosa*, *Acinetobacter baumannii*, and *Klebsiella pneumoniae*. Polymyxin B and polymyxin E share the same antibacterial mechanism of action: they increase bacterial cell membrane surface area by displacing calcium and magnesium ions in the cell membrane anionic lipopolysaccharide molecule, increasing cell membrane permeability, leading to leakage of cell contents, and ultimately cell death.

[0004] Compared to injection, pulmonary inhalation delivers drugs directly to the absorption or site of action, avoiding the first-pass effect in the liver and gastrointestinal degradation. This increases drug concentration in the respiratory tract and significantly reduces the concentration entering systemic circulation, improving therapeutic efficacy and patient compliance. Furthermore, the inhaled dose is much lower than the injection dose, greatly reducing injection risks and making it suitable for patients requiring long-term treatment. Directly using marketed injectable antibiotics for nebulized inhalation poses significant safety risks. Additives in injectables may irritate the bronchi after inhalation, affecting nebulization and hindering the drug's ability to reach the target site. Additionally, the slow clearance of aerosols deposited in the lungs may lead to adverse reactions. Inhaled liquid formulations, on the other hand, offer rapid onset of action, small dosage, fewer adverse reactions, and simple formulation. Compared to aerosols and powder inhalers, inhaled liquids deliver smaller single doses, atomizing drug suspensions or solutions into large doses of small droplets. They are unaffected by patient breathing behavior, making them suitable for a wide range of users, including children and the elderly.

[0005] Currently, there are inhaled polymyxin E mesylate formulations available internationally. The recommended dose for patients ≥ 6 years old with cystic fibrosis caused by *Pseudomonas aeruginosa* is 125 mg (166,250 U), every 12 hours. The international consensus guidelines for optimal polymyxin use (2019 edition) state that the benefits of polymyxin inhalation therapy for pneumonia outweigh the risks. For patients with suspected or confirmed extensively resistant Gram-negative pneumonia (HAP / VAP) caused by these bacteria, if intravenous polymyxin therapy is required, additional polymyxin inhalation therapy should be administered (weak recommendation, very low-quality evidence). Inhalation therapy can use either polymyxin E or polymyxin B (weak recommendation, very low-quality evidence). The Chinese expert consensus on the clinical application of polymyxin (2019 edition) indicates that nebulized inhalation can use either polymyxin E or polymyxin B. However, several reports have mentioned safety issues associated with polymyxin inhalation, and there are currently no reports of inhaled polymyxin B or polymyxin E formulations. Summary of the Invention

[0006] The purpose of this invention is to overcome the defects in the prior art and provide a polymyxin inhalation liquid formulation, and at the same time provide its preparation method.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0008] The present invention provides a polymyxin inhalation liquid formulation comprising polymyxin B sulfate 0.1-5% (W / V), a stabilizer 0.05-1% (W / V), an osmotic pressure regulator 0.1-0.9% (W / V), a pH adjuster, and a solvent; the pH of the liquid formulation is 3.0-6.0; the solvent is selected from purified water and water for injection.

[0009] 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).

[0010] As some preferred embodiments of the present invention, the stabilizer is selected from sodium metabisulfite or disodium ethylenediaminetetraacetate.

[0011] As some preferred embodiments of the present invention, the stabilizer is selected from sodium metabisulfite 0.3% (w / v).

[0012] As some preferred embodiments of the present invention, the osmotic pressure regulator is sodium chloride, with a concentration of [missing information].

[0013] 0.9% (W / V).

[0014] 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.

[0015] 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 to 6.0, most preferably pH 5.0.

[0016] On the other hand, the present invention provides a method for preparing the above-mentioned polymyxin inhalation liquid formulation, specifically including the following steps:

[0017] S1: Add pH adjuster to solvent, stir well, and adjust pH to 3.0-6.0;

[0018] S2: Add polymyxin and stir to dissolve;

[0019] S3: Add the prescribed amount of osmotic pressure regulator and stir well;

[0020] S4: Add stabilizer and ultrasonically disperse evenly;

[0021] S5: Sterilize by passing through a 0.22 μm filter membrane.

[0022] In this 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 units of g / 100mL.

[0023] The beneficial effects of adopting the above technical solution are as follows:

[0024] 1. The polymyxin inhalation liquid formulation provided by the present invention has a simple composition and isotonic osmotic pressure, which can reduce bronchospasm and cough caused by polymyxin inhalation solution.

[0025] 2. The polymyxin inhalation solution formulation provided by the invention does not contain any preservatives, and its safety has been verified through safety evaluation.

[0026] 3. Compared with intravenous administration, the polymyxin inhalation solution provided by this invention can significantly increase the drug concentration at the site of lung infection, improve drug bioavailability, enhance efficacy, and reduce nephrotoxicity and neurotoxicity.

[0027] 4. The preparation process of this invention is simple, the equipment cost is low, it is easy to industrialize, and the production efficiency is high. Attached Figure Description

[0028] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the accompanying drawings used in the description of the specific embodiments or the prior art will be briefly introduced below.

[0029] Figure 1 This is a comparison chart of lung function tests in rats in Experiment Example 3 of this invention;

[0030] Figure 2 It is a tissue section (H&E×200) of the rat in Experiment Example 3 of this invention. Detailed Implementation

[0031] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be described clearly and completely below with reference to specific embodiments. This description is only for the purpose of facilitating the description of this invention and should not be construed as a limitation thereof. Unless otherwise specified, the experimental methods and operations in this embodiment are conventional methods and operations; the raw materials, reagents, and other materials used are commercially available products unless otherwise specified.

[0032] Example 1

[0033]

[0034] Preparation method:

[0035] S1: Prepare citrate buffer (pH 5.0) as follows: Weigh 30.02 mg citric acid and 60.00 mg sodium citrate, dissolve in an appropriate amount of purified water, adjust the pH to 5.0 with 0.1 mol / L sodium hydroxide, transfer to a volumetric flask and bring the volume to 100 mL, so that the concentration of citric acid is 0.03% and the concentration of sodium citrate is 0.06%.

[0036] S2: Take 2 mL of the above citrate buffer, add the prescribed amount of polymyxin B sulfate, and stir well;

[0037] S3: Add the prescribed amount of sodium chloride and stir well;

[0038] S4: Add the prescribed amount of disodium EDTA, disperse evenly by ultrasonication, and then sterilize by passing through a 0.22 μm filter membrane to obtain the polymyxin B sulfate inhalation solution preparation.

[0039] Example 2

[0040]

[0041] Preparation method:

[0042] S1: Prepare a citrate-disodium hydrogen phosphate buffer solution (pH 5.0) as follows: Weigh 0.1002 g of citric acid and 0.3754 g of disodium hydrogen phosphate, dissolve in an appropriate amount of purified water, adjust the pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, then transfer to a volumetric flask and bring the volume to 100 mL, so that the concentration of citric acid is approximately 0.10% and the concentration of disodium hydrogen phosphate is approximately 0.375%.

[0043] S2: Take 2 mL of the above citrate-disodium hydrogen phosphate buffer, add polymyxin B sulfate, and stir well;

[0044] S3: Add the prescribed amount of sodium chloride and stir well;

[0045] S4: Add the prescribed amount of disodium EDTA, disperse evenly by ultrasonication, and then sterilize by passing through a 0.22 μm filter membrane to obtain the polymyxin B sulfate inhalation solution preparation.

[0046] Example 3

[0047] Preparation method:

[0048] S1: Prepare phosphate buffer solution (pH 5.0); the preparation method is as follows: Weigh 1.560 g sodium dihydrogen phosphate and 3.581 g disodium hydrogen phosphate, dissolve them in an appropriate amount of purified water, adjust the pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, then transfer to a volumetric flask and bring the volume to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of disodium hydrogen phosphate is 0.358%.

[0049] S2: Take 2 mL of the above phosphate buffer solution, add polymyxin B sulfate, and stir well;

[0050] S3: Add the prescribed amount of sodium chloride and stir well;

[0051] S4: Add the prescribed amount of disodium EDTA, disperse evenly by ultrasonication, and then sterilize by passing through a 0.22 μm filter membrane to obtain the polymyxin B sulfate inhalation solution preparation.

[0052] Example 4

[0053]

[0054] Preparation method:

[0055] S1: Prepare phosphate buffer solution (pH 5.0); the preparation method is as follows: Weigh 1.560 g sodium dihydrogen phosphate and 3.581 g disodium hydrogen phosphate, dissolve them in an appropriate amount of purified water, adjust the pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, then transfer to a volumetric flask and bring the volume to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of disodium hydrogen phosphate is 0.358%.

[0056] S2: Take 2 mL of the above phosphate buffer solution, add polymyxin B sulfate, and stir well;

[0057] S3: Add the prescribed amount of sodium chloride and stir well;

[0058] S4: Add the prescribed amount of disodium EDTA, disperse evenly by ultrasonication, and then sterilize by passing through a 0.22 μm filter membrane to obtain the polymyxin B sulfate inhalation solution preparation.

[0059] Example 5

[0060]

[0061] Preparation method:

[0062] S1: Prepare phosphate buffer (pH 5.0) as follows: Weigh 1.560 g sodium dihydrogen phosphate and 3.581 g disodium hydrogen phosphate, dissolve them in an appropriate amount of purified water, adjust the pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, then transfer to a volumetric flask and bring the volume to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of disodium hydrogen phosphate is 0.358%.

[0063] S2: Take 2 mL of the above phosphate buffer solution, add polymyxin B sulfate, and stir well;

[0064] S3: Add the prescribed amount of sodium chloride and stir well;

[0065] S4: Add the prescribed amount of sodium metabisulfite, disperse evenly by ultrasonication, and then sterilize by passing through a 0.22 μm filter membrane to obtain the polymyxin B inhalation solution preparation.

[0066] Example 6

[0067]

[0068] Preparation method:

[0069] S1: Prepare phosphate buffer (pH 5.0) as follows: Weigh 1.560 g sodium dihydrogen phosphate and 3.581 g disodium hydrogen phosphate, dissolve them in an appropriate amount of purified water, adjust the pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, then transfer to a volumetric flask and bring the volume to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of disodium hydrogen phosphate is 0.358%.

[0070] S2: Take 2 mL of the above phosphate buffer solution, add polymyxin B sulfate, and stir well;

[0071] S3: Add the prescribed amount of sodium chloride and stir well;

[0072] S4: Add the prescribed amount of sodium metabisulfite, disperse evenly by ultrasonication, and then sterilize by passing through a 0.22 μm filter membrane to obtain the polymyxin B inhalation solution preparation.

[0073] Example 7

[0074] Components Added 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

[0075] Preparation method:

[0076] S1: Prepare phosphate buffer (pH 5.0) as follows: Weigh 1.560 g sodium dihydrogen phosphate and 3.581 g disodium hydrogen phosphate, dissolve them in an appropriate amount of purified water, adjust the pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, then transfer to a volumetric flask and bring the volume to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of disodium hydrogen phosphate is 0.358%.

[0077] S2: Take 2 mL of the above phosphate buffer solution, add polymyxin B sulfate, and stir well;

[0078] S3: Add the prescribed amount of sodium chloride and stir well;

[0079] S4: Add the prescribed amount of sodium metabisulfite, disperse evenly by ultrasonication, and then sterilize by passing through a 0.22 μm filter membrane to obtain the polymyxin B inhalation solution preparation.

[0080] Example 8

[0081] Components Added 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

[0082] Preparation method:

[0083] S1: Prepare phosphate buffer (pH 5.0) as follows: Weigh 1.560 g sodium dihydrogen phosphate and 3.581 g disodium hydrogen phosphate, dissolve them in an appropriate amount of purified water, adjust the pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, then transfer to a volumetric flask and bring the volume to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of disodium hydrogen phosphate is 0.358%.

[0084] S2: Take 2 mL of the above phosphate buffer solution, add polymyxin B sulfate, and stir well;

[0085] S3: Add the prescribed amount of sodium chloride and stir well;

[0086] S4: Add the prescribed amount of sodium metabisulfite, disperse evenly by ultrasonication, and then sterilize by passing through a 0.22 μm filter membrane to obtain the polymyxin B inhalation solution preparation.

[0087] Example 9

[0088] Components Added 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

[0089] Preparation method:

[0090] S1: Prepare phosphate buffer (pH 5.0) as follows: Weigh 1.560 g sodium dihydrogen phosphate and 3.581 g disodium hydrogen phosphate, dissolve them in an appropriate amount of purified water, adjust the pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, then transfer to a volumetric flask and bring the volume to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of disodium hydrogen phosphate is 0.358%.

[0091] S2: Take 2 mL of the above phosphate buffer solution, add polymyxin B sulfate, and stir well;

[0092] S3: Add the prescribed amount of sodium chloride and stir well;

[0093] S4: Add the prescribed amount of sodium metabisulfite, disperse evenly by ultrasonication, and then sterilize by passing through a 0.22 μm filter membrane to obtain the polymyxin B inhalation solution preparation.

[0094] Example 10

[0095] Components Added 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

[0096] Preparation method:

[0097] S1: Prepare phosphate buffer (pH 5.0) as follows: Weigh 1.560 g sodium dihydrogen phosphate and 3.581 g disodium hydrogen phosphate, dissolve them in an appropriate amount of purified water, adjust the pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, then transfer to a volumetric flask and bring the volume to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of disodium hydrogen phosphate is 0.358%.

[0098] S2: Take 2 mL of the above phosphate buffer solution, add polymyxin B sulfate, and stir well;

[0099] S3: Add the prescribed amount of sodium chloride and stir well;

[0100] S4: Add the prescribed amount of sodium metabisulfite, disperse evenly by ultrasonication, and then sterilize by passing through a 0.22 μm filter membrane to obtain the polymyxin B inhalation solution preparation.

[0101] Example 11

[0102] Components Added 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

[0103] Preparation method:

[0104] S1: Prepare phosphate buffer (pH 5.0) as follows: Weigh 1.560 g sodium dihydrogen phosphate and 3.581 g disodium hydrogen phosphate, dissolve them in an appropriate amount of purified water, adjust the pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, then transfer to a volumetric flask and bring the volume to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of disodium hydrogen phosphate is 0.358%.

[0105] S2: Take 2 mL of the above phosphate buffer solution, add polymyxin B sulfate, and stir well;

[0106] S3: Add the prescribed amount of sodium chloride and stir well;

[0107] S4: Add the prescribed amount of sodium metabisulfite, disperse evenly by ultrasonication, and then sterilize by passing through a 0.22 μm filter membrane to obtain the polymyxin B inhalation solution preparation.

[0108] Example 12

[0109] Components Added 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

[0110] S1: Prepare phosphate buffer (pH 5.0) as follows: Weigh 1.560 g sodium dihydrogen phosphate and 3.581 g disodium hydrogen phosphate, dissolve them in an appropriate amount of purified water, adjust the pH to 5.0 with 0.1 mol / L sodium hydroxide and 0.1 mol / L hydrochloric acid, then transfer to a volumetric flask and bring the volume to 1000 mL, so that the concentration of sodium dihydrogen phosphate is 0.156% and the concentration of disodium hydrogen phosphate is 0.358%.

[0111] S2: Take 2 mL of the above phosphate buffer solution, add polymyxin B sulfate, and stir well;

[0112] S3: Add the prescribed amount of sodium chloride and stir well;

[0113] S4: Add the prescribed amount of sodium metabisulfite, disperse evenly by ultrasonication, and then sterilize by passing through a 0.22 μm filter membrane to obtain the polymyxin B inhalation solution preparation.

[0114] Stability Study of Experiment Example 1

[0115] Accurately weigh 25 mg of polymyxin B sulfate into three portions, place them in vials, and dissolve them in PBS solution with a pH of 5.0 to prepare a 12.5 mg / mL solution. Add 0.9% (w / v) of osmotic pressure regulator. Add 0.3% sodium metabisulfite, 0.05% EDTA-2Na, and no stabilizer to each sample to obtain the stabilizer selection samples.

[0116] The samples were placed at room temperature and collected at 0, 5, and 10 days. 0.08 mL of the prepared sample solution was transferred to a 10 mL volumetric flask and diluted to volume with the mobile phase. The polymyxin B sulfate content was measured, as shown in Table 1.

[0117] Table 1. Effect of stabilizer type on the stability of PMBS (based on PMB1) (n=3)

[0118]

[0119] Test Example 2: Physicochemical Property Testing

[0120] The osmotic pressure of the formulation prepared in Example 5 was measured using a YASN Osmo310 osmometer, and the results showed that the osmotic pressure was isotonic.

[0121] Safety evaluation of test example 3

[0122] 1. Laboratory animals

[0123] Healthy female SD rats, weighing 200–250 g, were provided by the Experimental Animal Center of Hebei Medical University. The rats were housed in clean cages with free access to water and food. The room temperature was controlled at (25±2)℃, and the relative humidity was adjusted to 50–75%, with a 12-hour light cycle.

[0124] 2. Methods

[0125] 2.1 Experimental Grouping

[0126] Six female SD rats were randomly divided into a self-prepared formulation group (Example 5), receiving polymyxin B sulfate inhalation solution (PMBS inh.), and a negative control group, receiving normal saline (Normal Saline NS). Each group consisted of three rats. The rats were fasted for 12 hours prior to the experiment but allowed free access to water. The rats were administered the nebulized drug via a rat-mouse-nasal exposure system. The self-prepared formulation group received 4.5 mg / kg of nebulized polymyxin B inhalation solution (12.5 mg / mL); the negative control group received sodium chloride injection. Both groups received the medication once daily for 7 consecutive days.

[0127] 2.2 Administration method

[0128] The rats and mice used a nasal-oral exposure system to administer nebulized drugs. Before the experiment, the air inlet and 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 physiological saline were added to the nebulizer cup, and the nebulizer was turned on for nebulized drug administration. The animal inhalation dose was calculated based on the clinical human nebulized inhalation dose. The self-prepared formulation group was given 4.5 mg / kg of nebulized polymyxin B inhalation agent (12.5 mg / mL), and the negative control group was given sodium chloride injection. All groups were administered the drug once daily for 7 consecutive days. On the 7th day of administration, pulmonary function tests were performed on the rats. After the tests, the heart, liver, lungs, spleen, and kidneys were dissected and separated for section staining and observation.

[0129] 2.3 Lung function test in rats

[0130] The small animal whole-body volume plethysmography system, as shown in the figure, was used to detect several physiological indicators related to lung function, including general indicators, lung volume indicators, conductivity indicators, airway obstruction indicators, and ventilation indicators.

[0131] 2.4 Histopathological analysis

[0132] After administration, the heart, liver, spleen, lungs, and kidneys were dissected and immediately rinsed with physiological saline to remove blood stains. The blood was then blotted dry with filter paper and fixed in 4% formaldehyde solution. After fixation, the organs were dehydrated and embedded. Finally, sections were prepared and H&E stained. The organs were then placed under a microscope to observe the adverse reactions of the different organs. The main observation was whether there were lesions such as alveolar swelling, congestion, infiltration, and hyperplasia in the lung tissue, so as to investigate the irritant effect of polymyxin B sulfate inhalation on lung tissue.

[0133] 3. Results

[0134] 3.1 Lung function test in mice

[0135] Rats underwent pulmonary function testing 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. Results showed no significant difference between the negative control group and the self-prepared formulation group. Overall, polymyxin B sulfate inhalation formulation showed good safety and minimal lung damage. (See details below.) Figure 1 .

[0136] 3.2 Histopathological analysis

[0137] like Figure 2 As shown in the pathological analysis, there was no significant difference in histopathological examination between the self-made preparation group and the saline group, indicating that nebulized inhalation of polymyxin B sulfate preparation did not significantly alter lung histopathology.

[0138] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A polymyxin inhalation liquid formulation, characterized in that, The liquid preparation comprises 0.1-5% (W / V) of polymyxin B sulfate, 0.05-1% (W / V) of stabilizer, 0.1-0.9% (W / V) of osmotic pressure regulator, pH regulator and solvent; the pH of the liquid preparation is 3.0-6.0; the solvent is selected from purified water or water for injection, the stabilizer is selected from sodium metabisulfite or disodium ethylenediaminetetraacetate, and the pH regulator is a sodium phosphate dibasic-sodium phosphate monobasic buffer system.

2. The polymyxin inhalation liquid formulation of claim 1, wherein, The concentration of the polymyxin B sulfate is 1.25-2.5% (W / V).

3. The polymyxin inhalation liquid formulation of claim 1, wherein The stabilizer is selected from 0.3% (W / V) of sodium metabisulfite.

4. The polymyxin inhalation liquid formulation of claim 1, wherein The osmotic pressure regulator is selected from sodium chloride with a concentration of 0.9% (W / V).

5. The polymyxin inhalation liquid formulation of claim 1, wherein The pH of the liquid preparation is 5.

0.

6. A process for the preparation of a polymyxin inhalation liquid formulation according to any one of claims 1 to 5, characterized in that, Specifically comprising the following steps: S1: adding the pH regulator to the solvent, stirring uniformly, and adjusting the pH to 3.0-6.0; S2: adding the polymyxin B sulfate, and stirring to dissolve; S3: adding the prescribed amount of osmotic pressure regulator, and stirring uniformly; S4: adding the stabilizer, and ultrasonic dispersion uniformly; S5: sterilizing through a 0.22 μm filter membrane, and obtaining the product.

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