Inhalation formulation of complex polymyxin and use thereof in preparation of a medicament for treating lung infection

Abstract

The application discloses a compound polymyxin inhalation preparation, which is composed of a polymyxin polypeptide, an aminoglycoside antibiotic and a pharmaceutically acceptable auxiliary material. The molar ratio of the polymyxin polypeptide to the aminoglycoside antibiotic in the inhalation preparation is 1:20-1:80. Compared with single preparation or a compound preparation with a molar ratio of less than 1:20, the compound preparation with the molar ratio can significantly reduce lung toxicity and achieve a significant effect of clearing multiple drug-resistant bacteria in lung infection. The compound drug is delivered by using an inhalation liquid preparation dosage form, so that the total drug delivery efficiency of atomization inhalation is greatly improved, the median particle size of the drug is smaller, and the proportion of particles with a size of less than 5 microns is more than 55%, so that the drug is more easily inhaled into the lung to achieve an anti-infection treatment effect.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to inhaled formulations of compound polymyxins and their application in the preparation of drugs for treating lung infections. Background Technology

[0002] Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa are the main bacterial pathogens causing death from bacterial infections. Among them, Gram-negative bacteria have a higher mortality rate than other bacteria. With the increasingly severe situation of bacterial drug resistance, polymyxins have become the last line of defense in the treatment of lung infections, especially lung infections caused by multidrug-resistant Gram-negative bacteria.

[0003] Currently, the clinical use of polymyxins still faces challenges related to nephrotoxicity and pulmonary toxicity (especially with inhalation). Polymyxin administration routes include intravenous injection, nebulized inhalation, and intraventricular / intrathecal injection. The "Multidisciplinary Expert Consensus on the Rational Clinical Use of Polymyxin Antibiotics in China" provides relevant guidance on the clinical use of polymyxins. Currently, polymyxins are mainly administered via injection; however, after intravenous administration, the drug molecules are difficult to distribute into lung tissue. In pneumonia patients, intravenous administration often fails to achieve the required drug concentration in lung tissue, thus failing to effectively inhibit pulmonary bacterial infection. Increasing the dosage or long-term administration presents challenges such as significant drug toxicity. Therefore, it is recommended to use polymyxin inhalation therapy concurrently with treatment for pneumonia (especially severe pneumonia). A recent study published in *The Lancet Infectious Diseases* supports the clinical efficacy and safety of inhaled polymyxin administration (Inhaled colistimethate sodium in patients with bronchiectasis and *Pseudomonas aeruginosa* infection: results of PROMIS-I and PROMIS-II, two randomized, double-blind, placebo-controlled phase 3 trials assessing safety and efficacy over 12 months). Inhalation administration offers advantages over intravenous injection, including precise local targeting, lower systemic toxicity, and a lower risk of drug resistance.

[0004] Currently, there is an urgent need in China to develop inhaled polymyxin formulations for clinical use, in order to improve therapeutic efficacy, reduce the nephrotoxicity and pulmonary toxicity of polymyxin, and broaden its therapeutic window and safe dosage. Summary of the Invention

[0005] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0006] In view of the problems existing in the above and / or prior art, the present invention is proposed.

[0007] Therefore, the object of the present invention is to overcome the serious deficiencies in the prior art and provide an inhaled formulation of polymyxin compound.

[0008] To solve the above-mentioned technical problems, the present invention provides the following technical solution: satisfying the following conditions, (i) Contains polymyxin peptides, aminoglycoside antibiotics, and other pharmaceutically acceptable excipients; (ii) Aminoglycoside antibiotics are selected from one or more of tobramycin, amikacin, gentamicin, streptomycin, kanamycin, neomycin, prazomicin, or any new aminoglycoside molecule; (iii) The molar ratio of polymyxin peptides to aminoglycoside antibiotics is 1:20 to 1:80.

[0009] As a preferred embodiment of the compound polymyxin inhalation formulation of the present invention, wherein the polymyxin includes polymyxin B, polymyxin E (also known as colistin) or any discovered or new polymyxin polypeptide or one or more.

[0010] It should be noted that the polymyxin mesylate sodium is a prodrug that is converted into an active ingredient after entering the human body to exert its therapeutic effect.

[0011] As a preferred embodiment of the inhaled compound polymyxin formulation of the present invention, the pharmaceutically acceptable excipients include one or more of the following: propellants, solubilizers, salts, pH adjusters, antibacterial agents, stabilizers, and excipients.

[0012] As a preferred embodiment of the compound polymyxin inhalation formulation of the present invention, the dosage form of the inhalation formulation includes one of aerosol, powder, spray, liquid formulation, and other formulations that can be converted into vapor.

[0013] It should be noted that the aerosol is a formulation in which a compound polymyxin drug (polymyxin polypeptide and aminoglycoside antibiotic) and a suitable propellant are packaged together in a pressure-resistant container with a metering valve system and a certain pressure to form a solution, suspension or emulsion. When used, the contents are sprayed out as a mist by the pressure of the propellant for inhalation into the lungs. Cosolvents, solubilizers and stabilizers may be added.

[0014] The powder inhaler is a preparation in which compound polymyxin drugs (polymyxin polypeptides and aminoglycoside antibiotics) are micronized, and then, alone or mixed with a suitable carrier, in the form of capsules, vesicles or multi-dose reservoirs, and are inhaled by the patient into the lungs using a specially designed dry powder inhalation device.

[0015] The spray is a solution, suspension, or emulsion in which a compound polymyxin drug (polymyxin polypeptide and aminoglycoside antibiotic) is generated into an aerosol for inhalation through a predetermined or metered nebulizer. During use, the contents are released as a mist using pressure from a manual pump, high-pressure gas, ultrasonic vibration, or other methods, allowing a certain amount of atomized liquid to be inhaled as an aerosol in a single breath.

[0016] The liquid formulation is a solution, suspension or emulsion in which a compound polymyxin drug (polymyxin polypeptide and aminoglycoside antibiotic) is continuously supplied for inhalation as an aerosol through a nebulizer, including inhalation solution, inhalation suspension, inhalation solution (concentrated solution to be used after dilution) and inhalation powder (sterile drug powder to be used after dissolution).

[0017] The vapor-convertible formulation is a solution, suspension, or solid formulation that converts a compound polymyxin drug (polymyxin polypeptide and aminoglycoside antibiotic) into vapor, typically added to hot water to generate vapor for inhalation.

[0018] As a preferred embodiment of the compound polymyxin inhalation formulation of the present invention, the liquid formulation includes an inhalation solution that can be directly nebulized and inhaled in an aqueous medium or a concentrated solution that needs to be diluted before use, with a pH of 3 to 10.

[0019] As a preferred embodiment of the inhaled compound polymyxin formulation of the present invention, the concentration of the compound polymyxin drug in the liquid formulation is 0.2~400 mmol / mL.

[0020] It should be noted that this concentration represents the concentration range of compound polymyxin drugs (polymyxin peptides and aminoglycoside antibiotics) dissolved in a solvent for nebulization administration.

[0021] As a preferred embodiment of the inhaled formulation of the compound polymyxin described in this invention, the inhaled formulation has reduced pulmonary toxicity compared to polymyxin monotherapy.

[0022] As a preferred embodiment of the compound polymyxin inhalation formulation of the present invention, the median particle size of the laser inhalation formulation is 3~5 μm.

[0023] As a preferred embodiment of the compound polymyxin inhalation formulation of the present invention, the proportion of particles with a laser particle size of less than 5 μm in the inhalation formulation is >50%.

[0024] Another object of the present invention is to provide the use of an inhaled formulation of polymyxin compound in the preparation of a medicament for treating pulmonary infections.

[0025] Specifically, the compound polymyxin inhalation formulation of the present invention provides a compound polymyxin aminoglycoside drug that is nebulized via a nebulizer and inhaled orally to treat lung infections.

[0026] The nebulizers include, but are not limited to, dry powder inhalers, metered inhalation devices, jet nebulizers, soft mist nebulizers, ultrasonic nebulizers, and mesh nebulizers.

[0027] Beneficial effects of this invention: This invention uses polymyxin and aminoglycoside drugs as a compound inhaled formulation. In the range of 1:20 to 1:80, compared with formulations containing polymyxin alone or in other proportions, it can significantly reduce pulmonary toxicity and has a good effect on inhibiting bacterial growth. At the same time, as an inhaled formulation, it significantly improves the pulmonary delivery efficiency of the drug and the pharmaceutical delivery performance and safety indicators of the proportion of particles smaller than 5 μm. Attached Figure Description

[0028] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Polymyxin E and amikacin are hereinafter referred to as representatives of polymyxin antibiotics and aminoglycoside antibiotics, respectively. Figure 1 This is a diagram showing the in vivo efficacy of the drug prescription in Example 1 of the present invention.

[0029] Figure 2 This is a graph showing the pulmonary toxicity results of the drug prescription in Example 3 of the present invention.

[0030] Figure 3 This is a graph showing the drug delivery rate results of the drug prescription in Example 4 of the present invention.

[0031] Figure 4 is a laser particle size diagram of the drug prescription of Example 5 of the present invention.

[0032] Figure 5 This is a laser particle size distribution of the drug prescription in Example 6 of the present invention. Detailed Implementation

[0033] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0034] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0035] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0036] Unless otherwise specified, all raw materials used in this invention are commercially available in the field.

[0037] The in vivo efficacy test methods are as follows: Instruments and equipment: quantitative nebulizer for lung fluid, electronic balance, three-dimensional grinder, biosafety cabinet, biochemical incubator, autoclave.

[0038] Culture media and reagents: Nutrient agar, CAB medium, nutrient broth, cyclophosphamide for injection, and Sutacetin-50. Bacterial species information: Pseudomonas aeruginosa (KFN-2023-D2-031), Klebsiella pneumoniae (KFN-2023-D2-031), and Acinetobacter baumannii (KFN-2023-D2-064). All were isolated from multidrug-resistant bacteria found in clinical practice within the past three years.

[0039] Laboratory animals: 27 male ICR mice (SPF grade), weighing 18-22 g. Animal experiments were outsourced to a CRO (Contract Research Organization).

[0040] Establishment of a lung infection model in immunocompromised mice: Healthy male ICR mice were randomly divided into groups of 3. Cyclophosphamide 150 mg / kg was administered 4 days before infection, and cyclophosphamide 100 mg / kg was administered 1 day before infection to induce immunosuppression in the mice.

[0041] Inoculate each strain onto nutrient agar slants and incubate at 35-37 ℃ for 18-24 h. Then, inoculate with 100 mL of nutrient broth and incubate at 35-37 ℃ for 16 h. Finally, take 10 mL of the bacterial suspension and inoculate at 1250 °C. gCentrifuge for 5 min, discard the supernatant, resuspend in an equal volume of physiological saline, centrifuge again, discard the supernatant, add 10 mL of sterile physiological saline and mix well to obtain the initial bacterial suspension.

[0042] Based on the model construction results, the selected bacterial concentration of Pseudomonas aeruginosa KFN-2023-D2-031 was ~10. 6 CFU / mL, Klebsiella pneumoniae KFN-2023-D2-031 selectable bacterial concentration ~10 7 CFU / mL, Acinetobacter baumannii KFN-2023-D2-064 selectable bacterial concentration ~10 7 CFU / mL, prepare bacterial suspensions separately for later use.

[0043] Mice from each experimental group were injected intraperitoneally with Shutai-50 at a dose of 50 mg / kg. After the mice were completely anesthetized, they were intubated with a small animal tracheal intubation tool and 25 μL of model bacterial solution was injected. The mice were kept in a head-up, feet-down position and rotated left and right to promote the even distribution of bacterial solution in the left and right lungs of the mice.

[0044] Antibiotic inhalation efficacy test method: After mice in each group were infected with bacterial solution, a nebulizer needle was inserted into the trachea of ​​the mice. Each group of mice was given the corresponding drug and dosage through the nebulizer needle. The drugs were administered twice, at 2 and 12 h after infection, with each administration volume being 25 μL.

[0045] Sample collection and testing: Samples were collected 24 hours after infection.

[0046] Lung tissue isolation: After euthanasia, whole lung tissue from each group of mice was collected in tissue homogenate tubes for colony counting. The whole lung tissue was weighed and then homogenized at low temperature in 5 mL of sterile pre-cooled physiological saline. The homogenate was diluted 10-fold with sterile physiological saline to obtain the original homogenate and 10-fold diluted homogenate. -1 10 -2 10 -3 10 -4 For each concentration of homogenate, take 1 mL of homogenate from each concentration and place it in a sterile Petri dish. Pour in culture medium and mix well. Prepare two plates for each dilution. Incubate the plates at 37°C for 36–48 h and then read the values. Select plates with colony counts between 30 and 300 CFU for statistical analysis.

[0047] The in vitro efficacy test methods are as follows: The strains used in this invention were clinically isolated from at least three regions within the past three years and were identified as resistant to the indicated diseases. Specifically, the strains used in this invention are: multidrug-resistant Pseudomonas aeruginosa (KFN-2023-D2-072), carbapenem-resistant Klebsiella pneumoniae (KFN-2023-D2-097), multidrug-resistant Acinetobacter baumannii (KFN-2023-D2-109), and carbapenem-resistant Escherichia coli (KFN-2023-D2-005). All strains were isolated from clinically resistant multidrug-resistant bacteria within the past three years.

[0048] Following the CLSI M100 antimicrobial susceptibility testing standards, the agar two-fold dilution method was used, and multiple inoculation was performed on a series of agar plates containing the test drug using a multi-point inoculator. 4 CFU / point. The final concentrations of each drug-containing plate were 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, and 0.0625 mg / L. After incubation at 37℃ for 18 h, the results were observed and graded according to bacterial growth. The grading criteria are as follows: Grade 1 bacteria do not grow Level 2 (0 < Bacterial growth rate ≤ 25%) Grade 3, 25°C: Bacterial growth rate ≤50% Level 4 (50°C) < Bacterial growth rate ≤75% Level 5, 75% bacterial growth rate The methods for determining lung toxicity are as follows: Instruments and equipment: quantitative nebulizer for lung fluid, electronic balance, cryostat staining machine, inverted microscope, pathological slide scanner.

[0049] Laboratory animals: 170 male Sprague-Dawley (SD) rats (SPF grade), weighing 240–360 g. Animal experiments were approved by the company's ethics committee.

[0050] Grouping and administration: SD rats were randomly divided into a solvent control group and an experimental group (administering different inhaled formulations of compound polymyxin). After tracheal intubation, each group of rats was administered 0.1 mL of the sample solution via nebulizer to the lungs once daily for 3 consecutive days.

[0051] Sample collection and testing: Samples were collected 72 hours after the first administration. After euthanasia, whole lung tissue was harvested from each group of rats and placed on a small animal sampling platform for histopathological examination and semi-quantitative scoring. The semi-quantitative histopathological scoring criteria are as follows: Grade 0 = No changes or minimal changes in lung tissue Grade 1 = Minimal lesions affecting 1-25% of lung tissue Grade 2 = Multiple lesions affecting 25-50% of lung tissue Grade 3 = Severe lesions affecting >50% of lung tissue The inhalation delivery pharmaceutical performance - delivery rate test method is as follows: Equipment and apparatus: The measuring device consists of a breathing simulator and a filtration system. The breathing simulator can simulate different breathing characteristics, and the filtration system uses low-resistivity PP filter paper. The measuring device collects the amount of drug deposited in the filtration system, and then uses high-performance liquid chromatography (HPLC) to determine the amount of drug collected.

[0052] Test conditions and parameters: Following the drug instructions, a fixed volume of drug was placed in the nebulizer. The nebulizer nozzle was connected to the filtration system, ensuring an airtight seal. A breathing simulator was used, and the nebulizer operated for 10 minutes. After nebulization, the nebulizer was turned off, and new filter paper was placed in the filtration device until all nebulization was completed. The drug in the filtration system was collected. The amount of drug collected by the first filter paper compared to the nebulization time was the delivery rate. The amount of drug collected by all filter papers and filter paper devices was the total delivery.

[0053] The determination was performed in accordance with the delivery rate and total delivery amount determination method specified in Appendix 0111 of the General Rules of the 2020 Chinese Pharmacopoeia.

[0054] Unless otherwise specified, the atomizing device used in the following examples is a Gentec piezoelectric atomizer, model GUN-300-A adult type.

[0055] The drug delivery rate was determined using a breathing simulator and filtration system, nebulized using a Gentec nebulizer.

[0056] The inhalation delivery pharmaceutical properties - laser particle size testing method is as follows: Atomizer laser particle size testing method: Data is measured using a laser particle size analyzer (Sympatec Inhaler), based on the principle of light scattering. The atomizing device is connected to the helos module, with a constant flow rate of 15 mL / min, and measurements are performed according to the equipment testing method.

[0057] The median particle size and the percentage of particles smaller than 5 μm were determined by using a laser particle size analyzer and a Gentec nebulizer.

[0058] Example 1 Polymyxin E and amikacin are combined in a molar ratio of 1:40 to form a compound polymyxin drug prescription, denoted as prescription 1.

[0059] In vivo efficacy tests were conducted on prescription 1 according to the above-mentioned in vivo efficacy test methods. The antibiotic inhalation administration was divided into a low-dose group and a high-dose group (polymyxin E: amikacin), with a low dose of 0.1 mg / kg : 2 mg / kg and a high dose of 2 mg / kg : 40 mg / kg.

[0060] The results are as follows Figure 1 As shown, the compound polymyxin formulation of this embodiment can achieve significant therapeutic effects on multidrug-resistant bacteria in lung infections in both high and low dose ranges, and the bacterial clearance rate of the high-dose group is higher than that of the low-dose group.

[0061] Example 2 Referring to the above-mentioned in vitro pharmacodynamic experimental methods, this embodiment compares the in vitro antibacterial properties of different compound polymyxin drug formulations. The composition of each formulation and its corresponding antibacterial properties are shown in Table 1 (the concentration of polymyxin E remains unchanged in the solution of all formulations).

[0062] Table 1 As can be seen from Table 1, within the formulation range of this invention, that is, under the formulation conditions where the molar ratio of polymyxin E and aminoglycosides is 1:20 to 1:80, the minimum antibacterial efficacy is better than that of formulations with a ratio below 1:20, and can achieve good antibacterial inhibition and elimination effects.

[0063] Example 3 Referring to the above-described method for determining pulmonary toxicity, this embodiment compares the pulmonary toxicity of different compound polymyxin formulations. The composition of each formulation and its corresponding pulmonary toxicity are as follows: Figure 2 As shown.

[0064] from Figure 2 The results showed that, compared with polymyxin alone, the combination of polymyxin E and aminoglycosides could reduce the pulmonary toxicity of polymyxin. Moreover, in the molar ratio range of 1:20 to 1:80, the combination of polymyxin and aminoglycosides had a better overall effect in reducing toxicity than polymyxin alone and other preparations with a ratio below 1:20.

[0065] Example 4 Referring to the above-described test method for inhalation delivery pharmaceutical performance-delivery rate, this embodiment compares the inhalation delivery pharmaceutical performance-delivery rate of different compound polymyxin formulations. Specifically: The drugs were prepared into target formulation liquid solutions with sterile water for injection. Unless otherwise specified, all formulation units are in mmol, and all formulation ratios are molar ratios. The concentration of polymyxin E monotherapy is 4.33 mmol / mL. The other formulations are polymyxin E with different molar ratios of aminoglycosides. The composition of each formulation and its corresponding delivery pharmaceutical properties—delivery rate—are as follows: Figure 3 As shown.

[0066] Figure 3 The drug delivery rate results showed that the total nebulization rate of compound polymyxin drugs was higher than that of single-agent formulations, and the addition of aminoglycosides improved the total nebulization efficiency of the compound formulations. Specifically, the total nebulization rate of compound formulations with a dilution ratio of 1:20 to 1:80 was more than 7 times that of single-agent polymyxin drugs. Overall, the total nebulization rate of compound polymyxin formulations in the 1:20–1:80 dilution range was superior to that of compound formulations with a dilution ratio below 1:20 and single-agent polymyxins.

[0067] Example 5 Referring to the above-described test method for inhalation delivery pharmaceutical performance - laser particle size, this embodiment compares the inhalation delivery pharmaceutical performance - laser particle size of different compound polymyxin formulations. Specifically: Unless otherwise specified, all prescription units are in mmol, and all formulation ratios are molar ratios. The concentration of polymyxin E alone is 8.65 mmol / mL. The other prescriptions are polymyxin E with different molar ratios of aminoglycosides. The composition of each prescription and its corresponding laser particle size are shown in Figure 4.

[0068] Example 6 The difference between this embodiment and Example 5 is that the concentration of polymyxin E monotherapy was adjusted to 4.33 mmol / mL, while the other formulations consisted of polymyxin E at a concentration of 4.33 mmol / mL and aminoglycoside compound formulations with different molar ratios. The composition of each formulation and its corresponding delivery pharmaceutical properties—laser particle size—are as follows: Figure 5 As shown.

[0069] Figure 4 Figure 5Laser particle size analysis results showed that the median particle size of the compound polymyxin amikacin formulation was smaller than that of the single-component formulation. With an increased proportion of amikacin, the overall median particle size decreased. Within the 1:20–1:40 ratio, the median particle size of the compound polymyxin amikacin formulation was smaller than that of formulations with a ratio below 1:20. The proportion of particles smaller than 5 μm in the compound polymyxin amikacin formulation was greater than that in the single-component formulation. An increased proportion of amikacin generally increased the proportion of particles smaller than 5 μm. Within the 1:20–1:40 ratio, the proportion of particles smaller than 5 μm in the compound polymyxin formulation exceeded 55%, and was higher than that of formulations with a ratio below 1:20. Overall, when delivering this formulation via nebulized inhalation, the median particle size and proportion of particles smaller than 5 μm in the 1:20–1:40 ratio of the compound polymyxin amikacin formulation were significantly better than those of compound formulations with a ratio below 1:20 and single polymyxin formulations.

[0070] Comparing Examples 5 and 6, with adjustments to the concentration of polymyxin E, the median particle size and the proportion of particles smaller than 5 μm in the two formulations remained consistent.

[0071] Furthermore, oral and nasal inhalation is a unique and highly challenging drug delivery route, as polymyxin combination drugs need to be delivered deep into the lungs for anti-infective treatment. To achieve stable drug delivery, the formulation and composition must meet aerodynamic requirements. Only when the particle size is 1–5 μm can aerosol particles achieve widespread distribution within the lungs. Within the 1–5 μm range, the smaller the atomized particle size, the easier it is for the drug to enter the bronchi and alveoli.

[0072] Delivery efficiency represents the amount of drug aerosol generated per unit time for inhalation, while the proportion of particles smaller than 5 μm represents the percentage of inhaled drug that can reach the deep lung sites of action. Delivery efficiency and the proportion of particles smaller than 5 μm together determine the drug concentration at the lung sites of action. Furthermore, this drug is a concentration-dependent antibacterial agent; a higher drug concentration in the lungs is beneficial for improving efficacy. The formulation of this solution can significantly improve the delivery efficiency and the proportion of particles smaller than 5 μm in the compound preparation. Based on the efficacy results and the antibacterial principle of the drug, it can be inferred that the concentration of the compound drug within the scope of this invention can improve antibacterial efficacy by increasing delivery efficiency.

[0073] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. An inhaled formulation of a compound polymyxin, characterized in that, It contains polymyxin peptides, aminoglycoside antibiotics, and other pharmaceutically acceptable excipients; The polymyxin polypeptide is selected from polymyxin E, polymyxin E sulfate, or polymyxin E methanesulfonate sodium. Wherein, the molar ratio of the polymyxin peptide to the aminoglycoside antibiotic is any of the following: (a) The molar ratio of the polymyxin polypeptide to the tobramycin is 1:20 to 1:40; (b) The molar ratio of the polymyxin polypeptide to the gentamicin is 1:40 to 1:80; (c) The molar ratio of the polymyxin peptide to the prazomicin is 1:20 to 1:80; (d) The molar ratio of the polymyxin-like polypeptide to the amikacin is 1:40 to 1:80; The inhaled formulation is a liquid formulation, the median laser particle size of the inhaled formulation is 3~5μm, and the proportion of laser particles smaller than 5μm in the inhaled formulation is >50%.

2. The inhaled formulation of polymyxin compound as described in claim 1, characterized in that: Pharmaceutically acceptable excipients include one or more of the following: solubilizers, salts, pH adjusters, and stabilizers.

3. The inhaled formulation of compound polymyxin as described in claim 1, characterized in that: The liquid formulation includes an inhalation solution dissolved in an aqueous medium that can be directly atomized and inhaled, with a pH of 3 to 10.

4. The inhaled formulation of compound polymyxin as described in claim 3, characterized in that: The concentration of the compound polymyxin drug in the liquid preparation is 0.2~400 mmol / mL.

5. The use of the inhaled formulation of the compound polymyxin according to any one of claims 1 to 4 in the preparation of a medicament for treating pulmonary infections.

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