Compound polymyxin inhalation preparation and application thereof in preparation of medicine for treating pulmonary infection

Abstract

The invention discloses a compound polymyxin inhalation preparation which is composed of polymyxin polypeptides, aminoglycoside antibiotics and pharmaceutically acceptable auxiliary materials, the molar ratio of the polymyxin polypeptides to the aminoglycoside antibiotics in the inhalation preparation is (1: 20)-(1: 80), and the molar ratio of the polymyxin polypeptides to the aminoglycoside antibiotics in the compound proportion is 1t compared with the molar ratio of a single component or the molar ratio of the aminoglycoside antibiotics in the single component; a compound proportion condition of 1: 20 can significantly reduce lung toxicity and also can achieve a drug effect of significantly eliminating lung infection multi-drug-resistant bacteria, the compound drug is delivered by adopting an inhalation liquid preparation form, the total drug delivery efficiency of aerosol inhalation is greatly improved, the median particle size of the drug is smaller, the proportion of particles smaller than 5 [mu] m exceeds 55%, and the drug delivery efficiency of aerosol inhalation is greatly improved. The medicine is more easily inhaled into the lung to achieve an anti-infection treatment effect.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and specifically relates to an inhalation preparation of a compound polymyxin and an application thereof in preparing a medicine for treating lung infection. Background Art

[0002] Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae and Pseudomonas aeruginosa are the main bacterial pathogens that cause death from bacterial infections. Among them, the mortality rate of infections caused by Gram-negative bacteria is higher than that of other bacteria. As the situation of bacterial resistance becomes increasingly severe, polymyxin has become the last line of defense for the treatment of lung infections, especially for the treatment of lung infections caused by multidrug-resistant Gram-negative bacteria.

[0003] At present, the clinical use of polymyxins still faces the challenges of nephrotoxicity and pulmonary toxicity (for inhaled administration). The routes of administration of polymyxins include intravenous injection, nebulized inhalation, and intraventricular injection / intracerebrovascular injection. The "Multidisciplinary Expert Consensus on the Rational Clinical Use of Polymyxin Antibiotics in China" provides relevant instructions for the use of polymyxins in clinical use. Existing polymyxins are mainly administered by injection, but after intravenous administration, polymyxin drug molecules are difficult to distribute to lung tissue. It is difficult for patients with pneumonia to achieve the required lung tissue drug concentration when taking the drug intravenously, and it is impossible to effectively inhibit bacterial infection in the lungs. Increasing the dose or long-term administration brings challenges such as large drug toxicity and side effects. Therefore, it is recommended to simultaneously assist in the inhalation treatment of pneumonia (especially severe pneumonia) with polymyxin drugs. The results of a recent study published in The Lancet Infectious Diseases support the clinical efficacy and safety of inhaled colistin (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 and side effects, and low risk of drug resistance.

[0004] At present, there is an urgent need to develop polymyxin inhalation preparations for clinical use in China to improve the therapeutic effect, reduce the nephrotoxicity and pulmonary toxicity of polymyxin, and broaden its drug treatment window and safe dosage. Summary of the invention

[0005] The purpose of this section is to summarize some aspects of embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the specification abstract and the invention title of this application to avoid blurring the purpose of this section, the specification abstract and the invention title, and such simplifications or omissions cannot be used to limit the scope of the present invention.

[0006] In view of the above problems and / or the problems existing in the 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 inhalation preparation of compound polymyxin.

[0008] In order to solve the above technical problems, the present invention provides the following technical solutions: satisfying the following conditions:

[0009] (i) Containing polymyxin polypeptides, aminoglycoside antibiotics, and other pharmaceutically acceptable excipients;

[0010] (ii) an aminoglycoside antibiotic selected from one or more of tobramycin, amikacin, gentamicin, streptomycin, kanamycin, neomycin, prazomicin or any aminoglycoside novel molecule;

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

[0012] As a preferred embodiment of the inhalation preparation of the compound polymyxin of the present invention, the polymyxin includes polymyxin B, polymyxin E (also known as colistin) or any one or more of any discovered or new polymyxin polypeptides.

[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 its medicinal effect.

[0014] As a preferred embodiment of the inhalation preparation of the compound polymyxin of the present invention, the pharmaceutically acceptable excipients include one or more of a propellant, a solubilizer, a salt, a pH regulator, an antibacterial agent, a stabilizer, and an excipient.

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

[0016] It should be noted that the aerosol is a preparation in which a compound polymyxin drug (polymyxin polypeptide and aminoglycoside antibiotic) is sealed together with a suitable propellant in a pressure-resistant container with a quantitative valve system and a certain pressure to form a solution, suspension or emulsion. When used, the content is sprayed out in the form of mist with the help of the pressure of the propellant for pulmonary inhalation. Co-solvents, solubilizers and stabilizers can be added at the same time.

[0017] The powder inhaler is a preparation in which the compound polymyxin drug (polymyxin polypeptide and aminoglycoside antibiotic) is micronized, and then, alone or mixed with a suitable carrier, it is in the form of capsules, blister or multi-dose reservoir, and a special dry powder inhalation device is used for the patient to inhale the aerosolized drug into the lungs.

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

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

[0020] The preparation that can be converted into steam is a solution, suspension or solid preparation that converts a compound polymyxin drug (polymyxin polypeptide and aminoglycoside antibiotic) into steam, 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 invention, the liquid preparation comprises an inhalation solution dissolved in an aqueous medium that can be directly atomized and inhaled or a concentrated solution that needs to be diluted before use, and the pH value is 3-10.

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

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

[0024] As a preferred embodiment of the inhalation preparation of the compound polymyxin of the present invention, the inhalation preparation has reduced pulmonary toxicity compared with polymyxin alone.

[0025] As a preferred embodiment of the inhalation preparation of the compound polymyxin of the present invention, the laser median particle size of the inhalation preparation is 3 to 5 μm, which is smaller than that of the single polymyxin preparation of the same concentration.

[0026] As a preferred embodiment of the inhalation preparation of the compound polymyxin of the present invention, the proportion of particles with a laser particle size of less than 5 μm in the inhalation preparation is greater than 50%, which is greater than that of the single polymyxin preparation with the same concentration.

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

[0028] Specifically, the compound polymyxin aminoglycoside drug prepared from the inhalation preparation of the compound polymyxin of the present invention is atomized by a nebulizer and inhaled orally to treat lung infection.

[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] Beneficial effects of the present invention:

[0031] The present invention uses polymyxin and aminoglycoside drugs as a compound inhalation preparation. When the molar ratio of the two is within the range of 1:20 to 1:80, the pulmonary toxicity can be significantly reduced compared with single polymyxin and preparation formulas with other ratios, and the compound inhalation preparation has a good effect of inhibiting bacterial growth. At the same time, as an inhalation preparation, the drug's pulmonary delivery efficiency and the pharmaceutical delivery performance and safety index of the proportion of particles below 5 μm are significantly improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative labor. The following polymyxin E and amikacin are respectively used as representatives of polymyxin antibiotics and aminoglycoside antibiotics. Among them:

[0033] Figure 1 This is a graph showing the in vivo efficacy results of the drug prescription of Example 1 of the present invention.

[0034] Figure 2 This is a graph showing the pulmonary toxicity results of the drug prescription according to Example 3 of the present invention.

[0035] Figure 3 This is a graph showing the drug delivery rate results for the drug prescription according to Example 4 of the present invention.

[0036] Figure 4 This is a laser particle size map of the drug prescription of Example 5 of the present invention.

[0037] Figure 5 This is a laser particle size map of the drug prescription of Example 6 of the present invention. DETAILED DESCRIPTION

[0038] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0039] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0040] 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 term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0041] Unless otherwise specified, the raw materials used in the present invention are all commercially available in the art.

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

[0043] Instruments and equipment: pulmonary liquid quantitative nebulizer, electronic balance, three-dimensional grinder, biological safety cabinet, biochemical incubator, high-pressure steam sterilizer.

[0044] Culture medium and reagents: nutrient agar, CAB medium, nutrient broth, cyclophosphamide for injection, and Shutai-50.

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

[0046] Experimental animals: 27 ICR mice (SPF grade), male, weight: 18-22 g. Animal experiments were commissioned by a CRO (contract research and development outsourcing service organization) company.

[0047] Establishment of lung infection model in immunocompromised mice: Healthy ICR male mice were randomly divided into groups, with 3 mice in each group. The mice were first given 150 mg / kg of cyclophosphamide on the 4th day before infection, and 100 mg / kg of cyclophosphamide on the 1st day before infection to suppress the immunity.

[0048] Take each strain and inoculate the nutrient agar medium slant. After culturing at 35-37℃ for 18-24h, inoculate 100mL of nutrient broth liquid medium. After culturing at 35-37℃ for 16h, aspirate 10mL of bacterial liquid, centrifuge at 1250g for 5min, discard the supernatant, resuspend with an equal volume of saline, centrifuge again, discard the supernatant and add 10mL of sterile saline to mix as the initial bacterial suspension.

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

[0050] Mice in each experimental group were given an intraperitoneal injection of 50 mg / kg of Shutai-50. After the mice were fully anesthetized, they were intubated with a small animal endotracheal intubation tool and 25 μL of modeling bacterial solution was injected. The mice were kept in a head-high and foot-low position and rotated left and right to ensure that the bacterial solution was evenly distributed in the left and right lungs of the mice.

[0051] Antibiotic inhalation efficacy test method: After each group of mice was infected with bacterial liquid, the mouse lung nebulizer needle was inserted into the trachea, and each group of mice was given the corresponding drug and dose using the mouse lung nebulizer needle. The drug was administered twice, at 2 and 12 hours after infection, and the volume of each administration was 25μL.

[0052] Sample collection and testing: Samples were collected 24 hours after infection.

[0053] Isolation of lung tissue: After euthanasia of each group of mice, the whole lung tissue of each group of mice was collected and placed in a tissue grinding tube for lung tissue homogenate colony counting. The whole lung tissue was weighed and placed in 5 mL of sterile pre-cooled saline for low temperature grinding. The homogenate was diluted 10 times with sterile saline to obtain the original homogenate, 10 -1 , 10 -2 , 10 -3 , 10 -4Prepare a series of homogenates, take 1 mL of each concentration of homogenate on a sterile plate, pour into the culture medium, and mix well. Prepare 2 plates for each dilution concentration. Incubate the plates at 37°C for 36-48 hours and then take them out for reading. Select the plates with colony readings between 30 and 300 CFU for statistics.

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

[0055] The drug-resistant strains of indications isolated clinically in at least 3 regions in the past 3 years are used. Specifically, the strain information used in the present invention is: 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), carbapenem-resistant Escherichia coli (KFN-2023-D2-005). All are isolated from clinical multi-drug resistant bacteria in the past three years.

[0056] According to the implementation standard of CLSIM100 antimicrobial susceptibility test, the agar double dilution method was used, and the multi-point inoculation instrument was inoculated on a series of plate culture media containing the test drugs. 4 CFU / point. The final concentrations of each drug-containing plate are 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, and 0.0625 mg / L. The results are observed after culturing at 37°C for 18 hours, and the results are graded according to the bacterial growth. Grading standards refer to:

[0057] Level 1 Bacteria do not grow

[0058] Level 2 0 < Bacterial growth rate ≤ 25%

[0059] Level 3 25 < Bacterial growth rate ≤ 50%

[0060] Level 4 50 < Bacterial growth rate ≤ 75%

[0061] Level 5 75 < Bacterial growth rate

[0062] The method for determining pulmonary toxicity is as follows:

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

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

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

[0066] Sample collection and testing: Samples were collected 72 hours after the first administration. After euthanasia, the whole lung tissues of the rats in each group were taken from the small animal sampling table for lung tissue pathology examination and semi-quantitative scoring. The semi-quantitative scoring criteria for histopathology are as follows:

[0067] Grade 0 = No changes or minor changes in lung tissue

[0068] Grade 1 = minimal change 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 is as follows:

[0072] Equipment: A measuring device consisting of a breathing simulator and a filtration system is used. The breathing simulator can simulate different breathing characteristics, and the filtration system uses low-resistance PP filter paper. The measuring device collects the amount of drugs deposited in the filtration system, and then uses high-performance liquid chromatography to measure the collected drugs.

[0073] Test conditions and parameters: According to the instructions for use of the drug, take a fixed volume of the drug into the nebulizer, connect the nebulizer nozzle to the filter system, and ensure air tightness. Breathing simulator, the nebulizer working time is 10 minutes, the nebulizer is turned off after the nebulization is completed, and a new filter paper is placed in the filter device until all the nebulization is completed. Collect the drugs in the filter system, the amount of drug collected by the first filter paper compared with the nebulization 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] The measurement is carried out in accordance with the provisions of the delivery rate and total delivery amount determination method in the Appendix "0111 Inhalation Preparations" of the General Rules of Part IV of the 2020 Edition of the Chinese Pharmacopoeia.

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

[0076] The drug delivery rate was determined using a breathing simulator and a filter system measurement device, nebulized using a Gentec nebulizer device.

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

[0078] Atomizer laser particle size test method: The data was measured using a laser particle size analyzer (Sympatec Inhaler), which is based on the light scattering method. The atomizer was connected to the helos module, with a constant flow rate of 15 mL / min, and the measurement was performed according to the equipment test method.

[0079] The laser particle size test method was used, and the Gentec atomization device was used for atomization to determine the median particle size of the drug and the proportion of particles less than 5μm.

[0080] Example 1

[0081] The drug prescription of compound polymyxin E and amikacin is composed of a molar ratio of 1:40, which is recorded as prescription 1.

[0082] The in vivo efficacy test of prescription 1 was carried out with reference to the above-mentioned in vivo efficacy experimental method, wherein the inhaled antibiotic 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.

[0083] The results are as follows Figure 1 As shown, it can be seen that the drug prescription of the compound polymyxin of this embodiment can achieve significant efficacy in treating multidrug-resistant bacteria in lung infection within the high and low dose ranges, and the bacterial clearance rate in the high dose group is higher than that in the low dose group.

[0084] Example 2

[0085] Referring to the above-mentioned in vitro efficacy test method, this example compares the in vitro antibacterial properties of different compound polymyxin drug prescriptions. The composition of each prescription and its corresponding antibacterial activity are shown in Table 1 (the concentration of polymyxin E in the solutions of all prescriptions remains unchanged).

[0086] Table 1

[0087]

[0088] It can be seen from Table 1 that within the prescription range of the present invention, that is, the molar ratio of polymyxin E to aminoglycoside is between 1:20 and 1:80, the minimum antibacterial efficacy is better than that of the formulation with a ratio below 1:20, and good bacterial inhibition and clearance effects can be achieved.

[0089] Example 3

[0090] Referring to the above-mentioned method for determining lung toxicity, this example compares the lung toxicity of different compound polymyxin drug prescriptions, and the composition of each prescription and its corresponding lung toxicity are as follows: Figure 2 shown.

[0091] from Figure 2 The results showed that compared with polymyxin alone, the combination of polymyxin E and aminoglycosides can reduce the pulmonary toxicity of polymyxin, and in the molar ratio range of 1:20 to 1:80, the compound polymyxin aminoglycoside preparation has a better overall effect in reducing toxicity than single polymyxin E and other preparations with a ratio below 1:20.

[0092] Example 4

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

[0094] The drug and sterile water for injection were prepared into the target prescription liquid solution. Unless otherwise specified, the prescription units were all mmol, the formula ratios were all molar ratios, the concentration of polymyxin E alone was 4.33mmol / mL, and the other prescription concentrations were 4.33mmol / mL polymyxin E and aminoglycoside compound prescriptions with different molar ratios. The composition of each prescription and its corresponding delivery pharmaceutical performance-delivery rate are as follows Figure 3 shown.

[0095] Figure 3 The results of drug delivery rate showed that the total atomization rate of compound polymyxin drugs was higher than that of single-ingredient preparations, and the addition of aminoglycosides could improve the total atomization efficiency of compound preparations. Among them, the total atomization rate of compound preparations at 1:20 to 1:80 was more than 7 times that of single-ingredient polymyxin drugs. In general, the total atomization rate of drugs in the range of 1:20 to 1:80 of compound polymyxin preparations was better than that of compound preparations and single-ingredient polymyxins at a ratio below 1:20.

[0096] Example 5

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

[0098] Unless otherwise specified, the units of all prescriptions are mmol, and the formula ratios are all molar ratios. The concentration of polymyxin E alone is 8.65mmol / mL, and the concentrations of the other prescriptions are 8.65mmol / mL polymyxin E and aminoglycoside compound prescriptions with different molar ratios. The composition of each prescription and its corresponding laser particle size are as follows: Figure 4 shown.

[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 concentration of the other prescriptions is 4.33 mmol / mL polymyxin E and aminoglycoside compound prescriptions of different molar ratios. The composition of each prescription and its corresponding delivery pharmaceutical performance - laser particle size is as follows Figure 5 shown.

[0101] Figure 4 , Figure 5 The laser particle size results showed that the median particle size of compound polymyxin amikacin preparations was smaller than that of single preparations, the proportion of amikacin drugs increased, and the median particle size of drugs decreased overall. In the range of 1:20 to 1:40, the median particle size of compound polymyxin amikacin preparations was smaller than that of preparations below 1:20. The proportion of particles below 5μm in compound polymyxin amikacin drugs was greater than that in single preparations. The proportion of amikacin drugs increased, and the proportion of drug particles below 5μm increased overall. In the range of 1:20 to 1:40, the proportion of particles below 5μm in compound polymyxin preparations exceeded 55%, and they were all higher than those in preparations below 1:20. In general, the preparations were delivered by atomized inhalation liquid preparations, and the median particle size and proportion of particles below 5μm of compound polymyxin amikacin preparations in drug prescriptions within the range of 1:20 to 1:40 were much better than those of compound preparations and single polymyxins with a ratio below 1:20.

[0102] By comparing Example 5 and Example 6, the drug concentration of polymyxin E was adjusted, and the conclusions on the median particle size and the proportion of particles below 5 μm of the two formulations were still consistent.

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

[0104] The delivery efficiency represents the amount of drug aerosol that can be produced for inhalation per unit time, and the proportion of particles below 5 μm represents the proportion of drugs that can enter the deep lungs to take effect after inhalation. The delivery efficiency and the proportion of particles below 5 μm comprehensively determine the drug concentration at the lungs where the drug takes effect. At the same time, the drug is a concentration-dependent antibacterial drug, and a high lung drug concentration is beneficial to improving the efficacy. The formulation of this scheme can significantly improve the delivery efficiency and the proportion of particles below 5 μm of the compound preparation. 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 invention can improve the antibacterial effect by improving the delivery efficiency.

[0105] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. An inhalation preparation of compound polymyxin, characterized in that The following conditions are met, (i) Containing polymyxin polypeptides, aminoglycoside antibiotics, and other pharmaceutically acceptable excipients; (ii) the polymyxin polypeptide is selected from one or more of polymyxin B, E or any discovered or new polymyxin polypeptide; (iii) aminoglycoside antibiotics selected from one or more of tobramycin, amikacin, gentamicin, streptomycin, kanamycin, neomycin, prazomicin or any aminoglycoside novel molecule; (iv) The molar ratio of the polymyxin polypeptide to the aminoglycoside antibiotic is 1:20 to 1:

80.

2. The inhalation preparation of compound polymyxin according to claim 1, characterized in that: The polymyxin polypeptide includes one or more of polymyxin B sulfate, polymyxin E sulfate, polymyxin E methanesulfonate sodium or any polymyxin polypeptide.

3. The inhalation preparation of compound polymyxin according to claim 1, characterized in that: The pharmaceutically acceptable excipients include one or more of propellants, solubilizers, salts, pH regulators, antibacterial agents, stabilizers, and excipients.

4. The inhalation preparation of compound polymyxin according to any one of claims 1, 2 or 3, characterized in that: The dosage form of the inhalation preparation includes aerosol, powder spray, spray, liquid preparation, and other preparations that can be converted into vapor.

5. The inhalation preparation of compound polymyxin according to claim 4, characterized in that: The liquid preparation includes an inhalation solution dissolved in an aqueous medium that can be directly atomized and inhaled or a concentrated solution that needs to be diluted before use, and the pH value is 3-10.

6. The inhalation preparation of compound polymyxin according to claim 5, characterized in that: The concentration of the compound polymyxin drug in the liquid preparation is 0.2-400 mmol / mL.

7. The inhalation preparation of compound polymyxin according to claim 4, characterized in that: The inhalation preparation has reduced toxicity in the lungs compared to polymyxin alone.

8. The inhalation preparation of compound polymyxin according to claim 5, characterized in that: The laser median particle size of the inhalation preparation is 3 to 5 μm, which is smaller than that of a single-ingredient polymyxin preparation of the same concentration.

9. The inhalation preparation of compound polymyxin according to claim 6, characterized in that: The particles with a laser particle size of less than 5 μm in the inhalation preparation account for more than 50%, which is greater than that of a single-ingredient polymyxin preparation with the same concentration.

10. Use of the inhalation preparation of compound polymyxin according to any one of claims 1 to 9 in the preparation of a medicament for treating lung infection.

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