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] The application belongs to the technical field of biological medicine, and particularly relates to a compound polymyxin inhalation preparation and application thereof in the preparation of a drug for treating lung infection. BACKGROUND

[0002] Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae and Pseudomonas aeruginosa are the main bacterial pathogens causing bacterial infection death, among which gram-negative bacteria have a higher mortality rate than other bacteria, and with the increasingly severe situation of bacterial drug resistance, polymyxin has become the last line of defense for treating lung infection, especially for treating lung infection caused by multi-drug resistant gram-negative bacteria.

[0003] At present, the clinical use of polymyxin still faces the challenges of nephrotoxicity and pulmonary toxicity (for inhalation administration). The administration routes of polymyxin include intravenous injection, aerosol inhalation, intracerebral injection / intrathecal injection. The use of polymyxin in clinical use is described in the "Chinese Multidisciplinary Expert Consensus on Clinical Rational Use of Polymyxin Antibacterial Drugs". The existing polymyxin is mainly administered by injection, but after intravenous administration, it is difficult for the polymyxin drug molecules to distribute to the lung tissue. It is difficult for patients with pneumonia to achieve the required lung tissue drug concentration when administered intravenously, and the lung bacterial infection cannot be effectively inhibited. Increasing the dose or long-term administration brings challenges such as large drug toxicity and side effects. Therefore, it is recommended to assist the inhalation treatment of polymyxin drugs for pneumonia (especially severe pneumonia). The research results published in "Lancet Infectious Diseases" recently support the clinical effectiveness and safety of polymyxin inhalation administration (Inhaled colistimethate sodium in patients with bronchiectasis and Pseudomonas aeruginosa infection: results of PROMIS-I and PROMIS-II, two randomised, double-blind, placebo-controlled phase 3 trials assessing safety and efficacy over 12 months). Compared with intravenous injection, aerosol inhalation has the advantages of local targeted precise administration, low systemic toxicity, low drug resistance risk, etc.

[0004] At present, there is an urgent need to develop a polymyxin inhalation preparation product for clinical use in China, to improve the treatment effect, reduce the nephrotoxicity and pulmonary toxicity of polymyxin, and broaden the drug treatment window and safe use dose. SUMMARY

[0005] This section is intended to introduce some aspects of one or more embodiments of the present application, which are described below. This section is not intended to limit the scope or the patentability of the embodiments.

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

[0007] Therefore, the purpose of the present application is to overcome the serious shortcomings in the prior art, and to provide a compound polymyxin inhalation preparation.

[0008] To solve the above technical problems, the present application provides the following technical solutions: meeting the following conditions,

[0009] (i) containing polymyxin polypeptide, aminoglycoside antibiotic, other pharmaceutically acceptable excipients;

[0010] (ii) the aminoglycoside antibiotic is selected from one or more of tobramycin, amikacin, gentamicin, streptomycin, kanamycin, neomycin, prazmycin or any new molecule of aminoglycoside;

[0011] (iii) the molar ratio of the polymyxin polypeptide to the aminoglycoside antibiotic is 1:20-1:80.

[0012] As a preferred scheme of the compound polymyxin inhalation preparation of the present application, wherein: the polymyxin includes one or more of polymyxin B, polymyxin E (also known as colistin) or any discovered or new polymyxin polypeptide.

[0013] It should be noted that the polymyxin sodium methanesulfonate is a prodrug, which is converted into an active ingredient after entering the human body to exert the drug efficacy.

[0014] As a preferred scheme of the compound polymyxin inhalation preparation of the present application, wherein: the pharmaceutically acceptable excipients include one or more of propellants, solubilizers, salts, pH regulators, bacteriostatic agents, stabilizers, excipients.

[0015] As a preferred scheme of the compound polymyxin inhalation preparation of the present application, wherein: the dosage form of the inhalation preparation includes one of aerosol, powder aerosol, spray, liquid preparation, and other preparations that can be converted into vapor.

[0016] It is to be noted that the aerosol is a preparation in which a compound polymyxin drug (polymyxin polypeptide and aminoglycoside antibiotic) and a suitable propellant are sealed in a pressure-resistant container with a quantitative valve system and a certain pressure, forming a solution, suspension or emulsion, and when used, the content is sprayed in the form of mist by the pressure of the propellant, and is used for pulmonary inhalation, and a cosolvent, solubilizer and stabilizer can be added.

[0017] The powder aerosol is a preparation in which a compound polymyxin drug (polymyxin polypeptide and aminoglycoside antibiotic) is micronized and then used alone or mixed with a suitable carrier in the form of a capsule, a bubble capsule or a multi-dose reservoir, and the patient inhales the aerosolized drug into the lungs by using a special dry powder inhalation device.

[0018] The spray is a solution, suspension or emulsion of a compound polymyxin drug (polymyxin polypeptide and aminoglycoside antibiotic) that generates an aerosol for inhalation by a pre-measured or quantitative nebulizer. When used, the content is released in the form of mist by the pressure of a manual pump, high-pressure gas, ultrasonic vibration or other methods, and a certain amount of nebulized liquid can be inhaled in the form of an aerosol in one breath.

[0019] The liquid preparation is a solution, suspension or emulsion of a compound polymyxin drug (polymyxin polypeptide and aminoglycoside antibiotic) that generates a continuous aerosol for inhalation by a nebulizer, including inhalation solution, inhalation suspension, inhalation solution (concentrated solution that needs to be diluted before use) and inhalation powder (sterile drug powder that needs to be dissolved before use).

[0020] The vaporizable preparation is a solution, suspension or solid preparation of a compound polymyxin drug (polymyxin polypeptide and aminoglycoside antibiotic) that is converted into vapor, which is usually added to hot water to generate steam for inhalation.

[0021] As a preferred embodiment of the inhalation preparation of the compound polymyxin of the present application, the liquid preparation includes inhalation solution that can be directly nebulized and inhaled by dissolving in an aqueous medium, or concentrated solution that needs to be diluted before use, and the pH is 3-10.

[0022] As a preferred embodiment of the inhalation preparation of the compound polymyxin of the present application, the concentration of the compound polymyxin drug in the liquid preparation is 0.2-400 mmol / mL.

[0023] It is to be noted that the concentration represents the concentration range of the compound polymyxin drug (polymyxin polypeptide and aminoglycoside antibiotic) dissolved in the solvent for nebulization administration.

[0024] As a preferred scheme of the inhalation preparation of the compound polymyxin according to the application, the inhalation preparation has reduced lung toxicity compared with polymyxin alone.

[0025] As a preferred scheme of the inhalation preparation of the compound polymyxin according to the application, the laser median particle size of the inhalation preparation is 3-5 μm, which is smaller than that of the polymyxin preparation alone at the same concentration.

[0026] As a preferred scheme of the inhalation preparation of the compound polymyxin according to the application, the proportion of particles with a particle size of 5 μm or less in the inhalation preparation is greater than 50%, which is greater than that of the polymyxin preparation alone at the same concentration.

[0027] Another object of the application is to provide the use of the inhalation preparation of the compound polymyxin in the preparation of a medicament for treating lung infection.

[0028] Specifically, the inhalation preparation of the compound polymyxin according to the application is used to treat lung infection by aerosolizing the compound polymyxin aminoglycoside through a nebulizer.

[0029] The nebulizer includes, but is not limited to, a dry powder inhaler, a metered dose inhaler, a jet nebulizer, a soft mist nebulizer, an ultrasonic nebulizer, and a mesh nebulizer.

[0030] The application has the following beneficial effects:

[0031] The application uses polymyxin and aminoglycoside as a compound inhalation preparation, and the molar ratio of the two is 1:20-1:80. Compared with the polymyxin alone and other formulations with different ratios, the lung toxicity is significantly reduced, the effect of inhibiting bacterial growth is good, and as an inhalation preparation, the lung delivery efficiency, the proportion of particles with a particle size of 5 μm or less, the pharmaceutical delivery performance, and the safety index are significantly improved. BRIEF DESCRIPTION OF DRAWINGS

[0032] In order to more clearly illustrate the technical solutions of the embodiments of the application, the following will briefly introduce the drawings needed in the embodiment description. Obviously, the drawings in the following description are only some embodiments of the application, and other drawings can be obtained by those skilled in the art without creative labor. The following polymyxin E and amikacin are respectively taken as representatives of polymyxin antibiotics and aminoglycoside antibiotics.

[0033] Figure 1 The in vivo pharmacodynamic results of the drug prescription of Example 1 of the application.

[0034] Figure 2 The lung toxicity results of the drug prescription of Example 3 of the application.

[0035] Figure 3 Drug delivery rate results plot for the drug prescription of Example 4 of the present invention.

[0036] Figure 4 Laser particle size plot for the drug prescription of Example 5 of the present invention.

[0037] Figure 5 Laser particle size plot for the drug prescription of Example 6 of the present invention. DETAILED DESCRIPTION

[0038] In order to make the above objectives, features and advantages of the present invention more apparent, the specific embodiments of the present invention will be described in detail below with reference made to the embodiments of the present invention.

[0039] In the following description, a large number of specific details are set forth in order to provide a thorough understanding of the present invention. However, the present invention can be practiced in other manners different from those described herein, and it is understood that persons skilled in the art can make similar generalizations without departing from the scope of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.

[0040] Secondly, the "one embodiment" or "embodiment" referred to herein means that the specific features, structures or characteristics can be included in at least one implementation of the present invention. The "in one embodiment" appearing in different places in the specification does not mean the same embodiment, nor is it an embodiment that is separate or alternative to other embodiments.

[0041] The raw materials used in the present invention are commercially available in the art without special instructions.

[0042] The in vivo drug efficacy experiment method is as follows:

[0043] Instrument and equipment: lung liquid quantitative atomizer, electronic balance, three-dimensional grinding instrument, biological safety cabinet, biochemical incubator, high-pressure steam sterilizer.

[0044] Culture medium and reagent: nutrient agar, CAB culture medium, nutrient broth, cyclophosphamide for injection, Cetrotide-50.

[0045] Strain information: Pseudomonas aeruginosa (KFN-2023-D2-031), Klebsiella pneumoniae (KFN-2023-D2-031), Acinetobacter baumannii (KFN-2023-D2-064). All were isolated from clinically multidrug-resistant bacteria in the past three years.

[0046] Experimental animals: 27 ICR mice (SPF level), male, body weight: 18-22g. Animal experiments were conducted by CRO (medical research and development contract outsourcing service agency) company.

[0047] Establishment of immunocompromised mice lung infection model: healthy ICR male mice were randomly divided into groups, 3 mice per group. Cyclophosphamide 150 mg / kg was administered 4 days before infection, and cyclophosphamide 100 mg / kg was administered 1 day before infection to immunosuppress the mice.

[0048] Each strain was inoculated into nutrient agar slant and cultured at 35-37°C for 18-24h, then inoculated into 100mL nutrient broth liquid medium and cultured at 35-37°C for 16h, 10mL of bacterial solution was taken and centrifuged at 1250g for 5min, the supernatant was discarded, and the same volume of normal saline was used to resuspend the bacteria, which was then centrifuged again, the supernatant was discarded, and 10mL of sterile normal saline was added and mixed to prepare the initial bacterial suspension.

[0049] According to the model construction results, the concentration of Pseudomonas aeruginosa KFN-2023-D2-031 selected strain was ~10 6 CFU / mL, Klebsiella pneumoniae KFN-2023-D2-031 selected strain concentration ~10 7 CFU / mL, Acinetobacter baumannii KFN-2023-D2-064 selected strain concentration ~10 7 CFU / mL, and bacterial suspensions were prepared for use.

[0050] Each experimental group of mice was given Cetepine-50 intraperitoneally at a dose of 50mg / kg, and after the mice were completely anesthetized, they were intubated with small animal tracheal intubation tools, 25μL of modeling bacterial solution was injected, the mice were kept in a head-high and foot-low position, and rotated left and right to promote uniform distribution of the bacterial solution in the left and right lungs of the mice.

[0051] Antibiotic inhalation administration efficacy test method: after the bacterial solution was injected into each group of mice, the mouse lung nebulization needle was inserted into the trachea, and each group of mice was given the corresponding drug and dose using the mouse lung nebulization needle, a total of two times, the administration time was 2h and 12h after infection, and the administration volume was 25μL each time.

[0052] Sample collection and detection: sample collection was performed at 24h after infection.

[0053] Isolation of lung tissue: after euthanizing each group of mice, the whole lung tissue of each group of mice was taken into a tissue grinding tube for lung homogenate colony counting. The whole lung tissue was weighed and placed into 5mL of sterile pre-cooled normal saline for low-temperature grinding, and the homogenate was diluted 10 times with sterile normal saline to obtain the original homogenate, 10 -1 , 10 -2 , 10 -3 , 10 -4The homogenate liquid of the same series was taken, 1 mL of the homogenate liquid of each concentration was placed in a sterile flat dish, poured into the culture medium, and mixed. Two plates were prepared for each dilution concentration. The plates were placed in a 37℃ incubator for 36-48h, and then taken out for reading. Plates with colony readings of 30-300 CFU were selected for statistics.

[0054] The in vitro drug efficacy experiment method is as follows:

[0055] The drug-resistant strains of indications isolated from at least three regions in the past three years were used, and specifically, the strain information used in the application: multi-drug resistant Pseudomonas aeruginosa (KFN-2023-D2-072), carbapenem-resistant Klebsiella pneumoniae (KFN-2023-D2-097), multi-drug resistant Acinetobacter baumannii (KFN-2023-D2-109), and carbapenem-resistant Escherichia coli (KFN-2023-D2-005). All were isolated from multi-drug resistant bacteria in the past three years.

[0056] Referring to the CLSIM100 antimicrobial drug sensitivity test execution standard, the agar double dilution method was used, and the multi-point inoculator was inoculated into the plate culture medium containing a series of drug-containing plates, 10 4 CFU / point. The final concentration of each drug-containing plate was 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625 mg / L, and the results were observed after 18h of culture at 37℃. The results were classified according to the bacterial growth. The classification standard is as follows:

[0057] 1st grade: no bacterial growth

[0058] 2nd grade: 0< bacterial growth rate ≤25%

[0059] 3rd grade: 25< bacterial growth rate ≤50%

[0060] 4th grade: 50< bacterial growth rate ≤75%

[0061] 5th grade: 75< bacterial growth rate

[0062] The lung toxicity determination method is as follows:

[0063] Instrument and equipment: lung liquid quantitative atomizer, electronic balance, frozen section staining machine, inverted microscope, pathological section scanner.

[0064] Experimental animals: 170 Sprague-Dawley (SD) rats (SPF level), male, body weight: 240-360g. The animal experiment was approved by the company's ethics committee.

[0065] Grouping and administration method: SD rats were randomly divided into solvent control group and test group (administered with different compound polymyxin inhalation preparations). After tracheal intubation of rats in each group, 0.1 mL of sample solution in each group was atomized for administration by using a lung liquid quantitative atomizer, once a day for 3 consecutive days.

[0066] Sample collection and detection: sample collection was performed at 72 h after the first administration. After euthanasia of rats in each group, whole lung tissue of rats in each group was taken on a small animal sampling table for lung histopathological examination and semi-quantitative scoring. The semi-quantitative histopathological scoring criteria are as follows:

[0067] Grade 0 = no change or insignificant slight change in lung tissue

[0068] Grade 1 = minimal lesions affecting 1-25% of lung tissue

[0069] Grade 2 = multiple lesions affecting 25-50% of lung tissue

[0070] Grade 3 = severe lesions affecting > 50% of lung tissue

[0071] Inhalation delivery pharmaceutical performance - delivery rate test method as follows:

[0072] Device device: a measuring device composed of a breathing simulator and a filtering system is used, the breathing simulator can simulate different breathing characteristics, and the filtering system uses low resistance PP filter paper. The amount of drug deposited in the filtering system is collected, and the collected drug is determined by high performance liquid chromatography.

[0073] Test conditions and parameters: according to the instructions for use of the drug, a certain volume of drug is taken in the atomizer, the atomizer nozzle is connected with the filtering system, and the air tightness is ensured. The breathing simulator, the working time of the atomizer is 10 minutes, the atomizer is turned off after atomization, and a new filter paper is placed in the filtering device until the atomization is completed. Collect the drug in the filtering system, the amount of drug collected by the first filter paper compared with the atomization time is the delivery rate, and the amount of drug collected by all filter papers and filter paper devices is the total delivery amount.

[0074] Reference is made to the determination method of delivery rate and total delivery amount in appendix "0111 inhalation preparations" of Chinese Pharmacopoeia 2020 edition four general rules.

[0075] Unless otherwise specified, the following examples use the following atomization device: Gentec piezoelectric atomization generator, model GUN-300-A adult type.

[0076] The delivery rate of the drug is determined by using the Gentec atomization device for atomization by using the breathing simulator and filtering system measuring device.

[0077] Inhalation delivery pharmaceutical performance - laser particle size test method as follows:

[0078] Laser particle size test method of nebulizer: data was determined using a laser particle size instrument (Sympatec Inhaler), which is based on the principle of light scattering method. The nebulization device was connected to the helos module, constant flow 15 mL / min, and determined according to the device test method.

[0079] Using the laser particle size test method, using the Gentec nebulization device, the median particle size and the proportion of particles less than 5 μm of the drug were determined.

[0080] Example 1

[0081] Polymyxin E and amikacin were formulated into a compound polymyxin with a molar ratio of 1:40, which was referred to as prescription 1.

[0082] The in vivo efficacy of prescription 1 was tested according to the above in vivo efficacy test method, wherein the inhalation administration of antibiotics was divided into low-dose and high-dose groups (polymyxin E: amikacin), low-dose 0.1 mg / kg:2 mg / kg, high-dose 2 mg / kg:40 mg / kg.

[0083] The results are shown in Figure 1 It can be seen that the pharmaceutical prescription of the compound polymyxin of the present embodiment can achieve significant therapeutic effect on pulmonary infection of multi-drug resistant bacteria in the high and low dose range, and the bacterial clearance rate of the high dose group is higher than that of the low dose group.

[0084] Example 2

[0085] According to the above in vitro efficacy test method, the in vitro antibacterial performance of different compound polymyxin pharmaceutical prescriptions was compared in this embodiment, and the composition of each prescription and its corresponding antibacterial property are shown in Table 1 (the concentration of polymyxin E in all prescriptions is constant).

[0086] Table 1

[0087]

[0088] As can be seen from Table 1, within the prescription range of the present application, i.e. under the preparation prescription condition that the molar ratio of polymyxin E and aminoglycoside is 1:20-1:80, the minimum antibacterial efficacy is better than that of the preparation prescription with a ratio of less than 1:20, and good bacterial inhibition and clearance efficacy can be achieved.

[0089] Example 3

[0090] According to the above lung toxicity determination method, the lung toxicity of different compound polymyxin pharmaceutical prescriptions was compared in this embodiment, and the composition of each prescription and its corresponding lung toxicity are shown in Figure 2 .

[0091] From Figure 2 The results show that, compared with polymyxin alone, polymyxin E and aminoglycoside compound can reduce the lung toxicity of polymyxin, and the compound polymyxin aminoglycoside preparation in the molar ratio of 1:20-1:80 has a better toxicity reduction effect than the single polymyxin E and other preparations below the ratio of 1:20.

[0092] Example 4

[0093] Referring to the above test method of inhalation delivery pharmaceutical performance-delivery rate, this embodiment compares the inhalation delivery pharmaceutical performance-delivery rate of different compound polymyxin drug prescriptions, specifically:

[0094] The drug is configured with sterile water for injection as a target prescription liquid solution, and no special instructions, each prescription unit is mmol, and the prescription ratio is molar ratio. The concentration of polymyxin E alone is 4.33 mmol / mL, and the concentration of the rest of the prescriptions is 4.33 mmol / mL polymyxin E and different molar ratios of aminoglycoside compound prescriptions. The composition of each prescription and the corresponding delivery pharmaceutical performance-delivery rate are shown in Figure 3 .

[0095] Figure 3 The drug delivery rate results show that the total atomization rate of compound polymyxin drugs is higher than that of single preparation, and the addition of aminoglycoside drugs can improve the total atomization efficiency of compound preparation. Among them, the total atomization rate of 1:20-1:80 compound preparation is more than 7 times that of single polymyxin drug. Overall, the total atomization rate of compound polymyxin preparation in the range of 1:20-1:80 is better than that of 1:20 below the ratio of compound preparation and single polymyxin.

[0096] Example 5

[0097] Referring to the above test method of inhalation delivery pharmaceutical performance-laser particle size, this embodiment compares the inhalation delivery pharmaceutical performance-laser particle size of different compound polymyxin drug prescriptions, specifically:

[0098] No special instructions, each prescription unit is mmol, and the prescription ratio is molar ratio. The concentration of polymyxin E alone is 8.65 mmol / mL, and the concentration of the rest of the prescriptions is 8.65 mmol / mL polymyxin E and different molar ratios of aminoglycoside compound prescriptions. The composition of each prescription and the corresponding laser particle size are shown in Figure 4 .

[0099] Example 6

[0100] The difference between this embodiment and embodiment 5 is that the concentration of polymyxin E alone is adjusted to 4.33 mmol / mL, and the rest of the prescription concentration is 4.33 mmol / mL polymyxin E and different molar ratios of aminoglycoside compound prescription. The composition of each prescription and the corresponding delivery pharmaceutical performance-laser particle size are as shown in Table 5. Figure 5

[0101] Figure 4 Figure 5 The laser particle size results of the compound polymyxin amikacin preparation show that the median particle size of the compound polymyxin amikacin preparation is smaller than that of the single preparation, and the proportion of amikacin drug increases, and the median particle size of the drug decreases as a whole. Within the range of 1:20 to 1:40, the median particle size of the compound polymyxin amikacin preparation is smaller than that of the preparation below 1:20. The proportion of particles below 5 μm in the compound polymyxin amikacin preparation is greater than that of the single preparation. The proportion of particles below 5 μm in the drug increases as a whole with the increase of the proportion of amikacin drug. Within the range of 1:20 to 1:40, the proportion of particles below 5 μm in the compound polymyxin preparation is more than 55%, and it is higher than that of the preparation below 1:20. Overall, the median particle size and the proportion of particles below 5 μm of the compound polymyxin amikacin preparation within the range of 1:20 to 1:40 are far superior to those of the compound preparation below 1:20 and the single polymyxin in the delivery of the preparation by nebulized inhalation of the liquid preparation.

[0102] Comparing embodiment 5 and embodiment 6, the drug concentration of polymyxin E is adjusted, and the conclusions of the median particle size and the proportion of particles below 5 μm of the two preparation formulas are still consistent.

[0103] In addition, oral and nasal inhalation administration is a unique and extremely challenging drug delivery route, and the compound polymyxin drug needs to be delivered to the deep lung position for anti-infective treatment. In order to achieve the effect of stable drug delivery, the prescription composition and preparation should meet the demand of aerodynamics. Only when the particle size is 1-5 μm, the aerosol particles can be widely distributed in the lung. Within the range of 1 to 5 μm, the smaller the particle size of the drug after atomization, the easier it is to enter the bronchi and alveoli of the lung.

[0104] The delivery efficiency represents the amount of drug aerosol that can be inhaled per unit time, and the proportion of particles below 5 μm represents the proportion of drugs that can enter the deep lung drug effective position after inhalation. The delivery efficiency and the proportion of particles below 5 μm comprehensively determine the drug concentration in the lung effective position. At the same time, the drug is a concentration-dependent antibacterial drug, and high lung drug concentration is beneficial to improve the efficacy. The preparation formula of the present scheme can significantly improve the delivery efficiency and the proportion of particles below 5 μm of the compound preparation, and combined with the efficacy results and the antibacterial principle of the drug, it can be inferred that the compound drug concentration within the scope of the present application can improve the antibacterial effect by improving the delivery efficiency.

[0105] ​​It should be noted that the above examples are only used to illustrate the technical solutions of the present application but not limit the present application. Although the present application is described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or equivalently replaced, without departing from the spirit and scope of the technical solutions of the present application, which should be covered in the scope of the claims of the present application.

Claims

1. An inhaled formulation of a compound polymyxin characterized in that Satisfy the following conditions, (i) containing polymyxin polypeptide, aminoglycoside antibiotic, other pharmaceutically acceptable excipients; (ii) the polymyxin polypeptide is selected from polymyxin E, polymyxin E sulfate or sodium polymyxin E methanesulfonate; (iii) the aminoglycoside antibiotic is selected from one of amikacin and prazolmycin; (iv) the molar ratio of the polymyxin polypeptide to the aminoglycoside antibiotic is 1:40~1:60; The dosage form of the inhalation preparation is a liquid preparation, the laser median particle size of the inhalation preparation is 3~5μm, and the proportion of particles with a laser particle size of 5μm or less is >50%.

2. The complexed polymyxin inhalation formulation of claim 1, wherein: The pharmaceutically acceptable excipients include one or more of solubilizers, salts, pH regulators, stabilizers.

3. The complexed polymyxin inhalation formulation of claim 1, wherein: The liquid preparation includes an inhalation solution that can be directly atomized and inhaled by dissolving in an aqueous medium, and the pH is 3~10.

4. The complexed polymyxin inhalation formulation of claim 3, wherein: The concentration of the compound polymyxin drug in the liquid preparation is 0.2~400 mmol / mL.

5. Use of the compound polymyxin inhalation preparation according to any one of claims 1~4 in the preparation of a medicament for treating lung infections.

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