Polymyxin b sulfate dry powder, inhalation powder aerosol and method of making same

Abstract

The present application relates to a kind of polymyxin B sulfate dry powder, inhalation powder aerosol and preparation method thereof.The polymyxin B sulfate dry powder is prepared by spray drying from the aqueous solution of polymyxin B sulfate and carrier;The carrier is composed of guar gum and L-leucine with a mass ratio of 1-2.5:1;The mass percentage of polymyxin B sulfate and carrier is 45%-65%:35%-55%, and the total amount of polymyxin B sulfate and carrier is 100%;The total concentration of polymyxin B sulfate and carrier in the aqueous solution is 3mg / mL-18mg / mL.The polymyxin B sulfate inhalation powder aerosol prepared from the polymyxin B sulfate dry powder can directly deliver the drug to the lung lesions by local administration, with high lung effective deposition rate, greatly reducing the dosage, and can effectively inhibit the formation of bacterial biofilm.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicines, and relates to a pharmaceutical preparation, in particular to a polymyxin B sulfate dry powder, an inhalation powder aerosol and a preparation method thereof. BACKGROUND

[0002] Pulmonary infection is a large category of diseases caused by pathogenic microorganisms or other factors invading the lung parenchyma to trigger inflammation, which has become a major challenge to global public health. In the top ten causes of death in the world published by the World Health Organization (WHO) in 2021, pulmonary infection ranked fifth, causing about 2.5 million deaths, which is the most deadly infectious disease in the world. Among the pathogenic bacteria causing pulmonary infection, gram-negative bacteria account for a high proportion, about 70% to 80%, among which Pseudomonas aeruginosa (PA) is one of the most important pathogenic bacteria, which often presents as acute fever, cough, and yellow-green purulent sputum, and can progress to respiratory failure in severe cases, especially posing a great threat to people with low immunity. Because it is not sensitive or seriously resistant to many commonly used clinical antibiotics, the treatment of its related infections is extremely difficult, and the mortality rate is high, which has caused a heavy economic burden to China's medical care.

[0003] For the treatment of pulmonary Pseudomonas aeruginosa infection, the current clinical treatment mainly adopts oral or injection of antibiotics. Since both of the two administration methods belong to systemic administration, they will produce many systemic adverse reactions, mainly including: 1) head discomfort and poor sleep; 2) palpitation, shortness of breath, and irregular heart rhythm; 3) itching, red rash or urticaria; 4) abdominal distension, abdominal pain, nausea and vomiting, etc. At the same time, patients with pulmonary Pseudomonas aeruginosa infection need to use broad-spectrum antibiotics such as imipenem, meropenem, and levofloxacin for a long time. According to the latest CHINET bacterial drug resistance monitoring results in 2024, the drug resistance rates of Pseudomonas aeruginosa to imipenem and meropenem are 21.3% and 17.3% respectively, and the drug resistance rate to levofloxacin is 19.6%, and the data of carbapenem-resistant Pseudomonas aeruginosa is even more alarming, with a drug resistance rate of 95.4% to imipenem.

[0004] In addition to the factor of multi-drug resistance, refractory pulmonary Pseudomonas aeruginosa infection is also difficult to treat because bacteria can easily form bacterial biofilm (BF) in lung lesions. Bacterial biofilm refers to a large number of bacterial aggregation film-like substances formed by bacteria adhering to the contact surface and wrapping themselves in polysaccharide matrix, fibrin, and lipid protein secreted by bacteria. Pseudomonas aeruginosa is prone to form biofilm, which can provide shelter for bacteria and hinder the contact of drugs with bacteria to exert drug efficacy, resulting in continuous recurrence of infection.

[0005] Polymyxin B sulfate (PMBS) is the sulfate form of polymyxin B, which is commonly used in clinical treatment. PMBS is a cyclic cationic polypeptide antibiotic that binds to the lipopolysaccharide of the outer cell membrane of gram-negative bacteria, causing the cell membrane to rupture and the intracellular contents to leak, ultimately leading to bacterial death. It is the last line of defense for treating infections caused by multi-drug resistant gram-negative bacteria, especially Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. According to the CHINET 2024 Bacterial Drug Resistance Monitoring Results, the drug resistance rate of Pseudomonas aeruginosa to polymyxin B is extremely low, only 0.5%.

[0006] PMBS is one of the main drugs for treating carbapenem-resistant gram-negative bacterial infections. To increase lung drug concentration, domestic and foreign guidelines and consensus recommend combined nebulization in addition to intravenous administration to improve efficacy. Currently, there are special preparations for polymyxin nebulization abroad, but there are no special polymyxin inhalation preparations in China. Therefore, it is necessary to develop a PMBS special inhalation preparation that can efficiently break bacterial biofilm for the treatment of pulmonary PA infection.

[0007] Inhalation preparations refer to liquid or solid preparations in which the raw drug is dissolved or dispersed in a suitable medium, delivered to the lungs in the form of aerosol or vapor, and exert local or systemic effects. Compared with traditional administration methods, inhalation preparations have the advantages of direct action on lung lesions, reduced systemic exposure, avoidance of gastrointestinal absorption and first-pass effect, etc. They not only effectively increase drug concentration at the lesion site, but also reduce peripheral side effects. Therefore, inhalation preparations provide a precise local treatment approach for pulmonary bacterial infections. Inhalation preparations mainly include inhalation liquid preparations, inhalation aerosols, and inhalation powder aerosols (Dry Powder Inhalers, DPIs). DPIs are a new type of inhalation preparation that combines powder science and particle engineering. Micronized drugs are stored in capsules, blisters, or reservoirs, and are inhaled by patients, dispersed by a special inhalation device, and then enter the lungs with the airflow. Compared with inhalation liquid preparations and inhalation aerosols, DPIs have the following characteristics: 1) easy to use, good patient compliance; 2) no propellant, avoiding environmental pollution; 3) accurate dosing; 4) no preservatives or solvents such as ethanol, no irritation to the mucosa and lungs; 5) drugs are in solid form, with good stability. The polypeptide structure of polymyxin B sulfate makes it unstable in a liquid environment and prone to degradation. Therefore, DPIs are the most preferred dosage form for polymyxin B sulfate-related inhalation preparations.

[0008] However, there are the following key bottlenecks in the preparation of the PMBS inhalation powder aerosol: if the PMBS is directly prepared into the inhalation powder aerosol, the powder has a large surface free energy and a tendency to aggregate, and the powder has poor fluidity; meanwhile, the PMBS has high hygroscopicity, which will affect the aerosol performance and stability of the drug particles, and due to easy water absorption, the particle size will be increased and the aerosolization efficiency will be reduced; these factors will result in poor aerodynamic properties of the PMBS inhalation powder aerosol, and in addition, there is a complex physiological structure in the lung, which will cause the drug particles to be prematurely deposited in the oropharynx, and the drug delivery efficiency in the lung is low, and the deposition rate of the drug in the lung is low. SUMMARY

[0009] Therefore, the purpose of the present application is to provide a polymyxin B sulfate dry powder, and a polymyxin B sulfate inhalation powder aerosol prepared from the dry powder, which can deliver the drug directly to the lung lesion by local administration, has a high lung effective deposition rate, greatly reduces the administration dose, and can effectively inhibit the formation of bacterial biofilm.

[0010] The technical solutions for achieving the above-mentioned purposes include the following.

[0011] In a first aspect, the present application provides a polymyxin B sulfate dry powder, which is prepared by spray drying a water solution of polymyxin B sulfate and a carrier.

[0012] The carrier is composed of guar gum and L-leucine in a mass ratio of 1-2.5:1.

[0013] The mass percentage of the polymyxin B sulfate and the carrier is 45%-65%:35%-55%, and the total amount of the polymyxin B sulfate and the carrier is 100%.

[0014] In the water solution, the total concentration of the polymyxin B sulfate and the carrier is 3mg / mL-18mg / mL.

[0015] In a second aspect, the present application provides a preparation method of the polymyxin B sulfate dry powder, which comprises the following steps: dissolving the polymyxin B sulfate, the guar gum and the L-leucine in water to obtain the water solution, and then spray drying the water solution to obtain the polymyxin B sulfate dry powder.

[0016] In a third aspect, the present application provides a polymyxin B sulfate inhalation powder aerosol, which is obtained by loading the polymyxin B sulfate dry powder of the present application into a capsule.

[0017] The present application has the following beneficial effects:

[0018] The present application innovatively introduces guar gum and L-leucine as a complex carrier of polymyxin B sulfate, and the three components are dissolved in water in a specific ratio and concentration, and the obtained aqueous solution is prepared into polymyxin B sulfate dry powder and inhalation powder mist by a spray drying method, so that the comprehensive advantages of high efficiency antibacterial, low hygroscopicity, high fluidity and good aerosol performance are realized, the stability of the drug in a high humidity environment and the dispersibility in the inhalation process can be ensured, so that the lung effective deposition rate of the obtained polymyxin B sulfate dry powder and inhalation powder mist can be effectively improved, and the deposition of the drug in the throat is reduced; and the polymyxin B sulfate dry powder and inhalation powder mist can effectively inhibit the formation of bacterial biofilm and break the formed biofilm, so that the therapeutic effect of polymyxin B sulfate can be more significantly improved and the systemic toxicity can be reduced.

[0019] In addition, in the polymyxin B sulfate dry powder and inhalation powder mist of the present application, the ratio of guar gum and L-leucine is low, the drug content of polymyxin B sulfate is high, the drug loading capacity is high, the dosage of the dry powder can be reduced, and the compliance of the patient can be improved.

[0020] The spray drying process of the present application adopts an aqueous solvent system, which not only ensures efficient simplification of the process steps, but also fully follows the sustainable production concept of low toxicity and low energy consumption, and is conducive to realizing industrialized mass production. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 It is a schematic diagram of a new generation of drug impactor (NGI). DETAILED DESCRIPTION

[0022] In order to facilitate the understanding of the present application, the present application will be described more fully below. The present application can be realized in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present application more thorough and comprehensive.

[0023] The experimental methods in the following examples not specified in the specific conditions are usually carried out according to the conventional conditions or according to the conditions recommended by the manufacturer. Various common chemical reagents used in the examples are commercially available products.

[0024] Unless otherwise defined, all technical and scientific terms used in the present application have the same meaning as understood by those skilled in the art to which the present application belongs. The terms used in the specification of the present application are only for the purpose of describing the specific embodiments and are not used to limit the present application. The term "and / or" used in the present application includes any and all combinations of one or more related listed items.

[0025] Furthermore, as used herein, the term "or" is the inclusive, not the exclusive, "or", and is equivalent to the term "and / or", unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for other factors based on which something is done, unless the context clearly dictates otherwise. Furthermore, throughout the specification, "one", "a", and "the" are meant to include plural references. The meaning of "in" includes "in" and "on".

[0026] In order to improve the ability of the inhaled powder mist of polymyxin B sulfate to inhibit the formation of bacterial biofilm and the effective deposition rate in the lung, the research team of the present application previously developed a polymyxin B sulfate dry powder and its inhaled powder mist prepared by using raffinose as a carrier. Although the inhaled powder mist of polymyxin B sulfate can effectively improve the ability of the inhaled powder mist of polymyxin B sulfate to inhibit the formation of bacterial biofilm and the effective deposition rate in the lung, in the dry powder formula, the content of polymyxin B sulfate is low (only 5%-10%), and most of the components are raffinose, that is, the drug loading of the dry powder is low, and the dose of the dry powder is large when the drug is used. On this basis, the inventors further found that the polymyxin B sulfate dry powder and its inhaled powder mist prepared by using guar gum in combination with L-leucine to replace the original raffinose as a carrier material in combination with polymyxin B sulfate can greatly improve the content of polymyxin B sulfate while further improving the ability of the inhaled powder mist of polymyxin B sulfate to inhibit the formation of bacterial biofilm and the effective deposition rate in the lung.

[0027] Based on this, in some embodiments of the present application, a polymyxin B sulfate dry powder is involved, which is prepared by spray drying of an aqueous solution of polymyxin B sulfate and a carrier;

[0028] The carrier is composed of guar gum and L-leucine with a mass ratio of 1-2.5:1;

[0029] The mass percentage of the polymyxin B sulfate and the carrier is 45%-65%:35%-55%, and the total amount of the polymyxin B sulfate and the carrier is 100%;

[0030] In the aqueous solution, the total concentration of the polymyxin B sulfate and the carrier is 3mg / mL-18mg / mL.

[0031] In the polymyxin B sulfate dry powder prepared by the present application, the content of polymyxin B sulfate is 45%-65%, which is much higher than the drug content (only 5%-10%) in the polymyxin B sulfate / raffinose dry powder, and the dose of the dry powder can be greatly reduced when the drug is used, and the patient compliance is improved.

[0032] The inventors have found that the concentrations of polymyxin B sulfate, guar gum and L-leucine in the liquid for spray drying have a significant effect on the properties of the dry powder obtained, and that within a range of total concentrations of 3 mg / mL to 18 mg / mL, the polymyxin B sulfate dry powder produced has a higher rate of effective lung deposition.

[0033] In some preferred embodiments, the mass percentage of polymyxin B sulfate and carrier is 50-60%: 40-50%.

[0034] In some preferred embodiments, the mass percentage of polymyxin B sulfate and carrier is 53-60%: 40-57%.

[0035] In some more preferred embodiments, the mass percentage of polymyxin B sulfate and carrier is 53-57%: 43-47%.

[0036] In some more preferred embodiments, the mass percentage of polymyxin B sulfate and carrier is 55%: 45%.

[0037] In some preferred embodiments, the mass ratio of guar gum and L-leucine is 1.5-2.2: 1.

[0038] In some more preferred embodiments, the mass ratio of guar gum and L-leucine is 25-30: 15.

[0039] In some more preferred embodiments, the mass ratio of guar gum and L-leucine is 30: 15.

[0040] In some preferred embodiments, the total concentration of polymyxin B sulfate, guar gum and L-leucine in the aqueous solution is 4 mg / mL to 17 mg / mL.

[0041] In some more preferred embodiments, the total concentration of polymyxin B sulfate, guar gum and L-leucine in the aqueous solution is 5 mg / mL to 16 mg / mL.

[0042] In some more preferred embodiments, the total concentration of polymyxin B sulfate, guar gum and L-leucine in the aqueous solution is 10 mg / mL to 16 mg / mL.

[0043] In some more preferred embodiments, the total concentration of polymyxin B sulfate, guar gum and L-leucine in the aqueous solution is 14 mg / mL to 16 mg / mL.

[0044] In some more preferred embodiments, the total concentration of polymyxin B sulfate, guar gum and L-leucine in the aqueous solution is 15 mg / mL.

[0045] In some embodiments of the present application, a method for preparing the polymyxin B sulfate dry powder of the present application is provided, comprising the following steps: dissolving the polymyxin B sulfate, guar gum and L-leucine in water to obtain the aqueous solution, and then spray drying the aqueous solution to obtain the polymyxin B sulfate dry powder. The method is simple and can prepare the polymyxin B sulfate dry powder with high lung effective deposition rate in one step.

[0046] In some preferred embodiments, the spray drying conditions include: the inlet air temperature is 100-160℃, the outlet air temperature is 60-90℃, and the atomization pressure is 100-210 kPa.

[0047] In some more preferred embodiments, the inlet air temperature is 110-150℃, the outlet air temperature is 70-80℃, and the atomization pressure is 120-210 kPa.

[0048] In some more preferred embodiments, the inlet air temperature is 120-140℃, the outlet air temperature is 70-80℃, and the atomization pressure is 190-210 kPa.

[0049] In some more preferred embodiments, the inlet air temperature is 125-135℃, the outlet air temperature is 73-78℃, and the atomization pressure is 195-205 kPa.

[0050] In some more preferred embodiments, the inlet air temperature is 130℃, the outlet air temperature is 75℃, and the atomization pressure is 200 kPa.

[0051] In some embodiments, the spray drying conditions further include: the feeding speed is 2.5-3.5 mL / min, the nozzle diameter is 0.65-0.75 mm, and the gas flow rate is 0.55-0.65 m 3 3 / h.

[0052] In some embodiments of the present application, a polymyxin B sulfate inhalation powder is also provided, which is obtained by loading the polymyxin B sulfate dry powder into a capsule.

[0053] In some embodiments, the capsule is a size 3 HPMC capsule.

[0054] ​In some embodiments, the loading amount of polymyxin B sulfate dry powder into capsules is 25 ± 0.5 mg / capsule.

[0055] The present invention will be further described in detail below with reference to specific embodiments.

[0056] Example 1

[0057] Polymyxin B sulfate, guar gum, and L-leucine were mixed in different mass ratios (20:60:20).

[0058] Polymyxin B sulfate (30:50:20, 40:45:15, 55:30:15, 60:25:15, 70:10:20, 100:0:0, 55:45:0, 55:0:45) was dissolved in water to prepare solutions with a concentration of 15 mg / mL (total concentration of polymyxin B sulfate, guar gum, and L-leucine). These solutions were then spray-dried to prepare polymyxin B sulfate powder. The specific spray-drying conditions were as follows: inlet air temperature set at 130℃, outlet air temperature at 75℃, pump rate at 3 mL / min, nozzle diameter at 0.71 mm, atomization pressure at 200 kPa, and air flow rate at 0.60 m³ / min. 3 / h. Subsequently, the polymyxin B sulfate dry powder prepared under these conditions was evaluated and characterized as follows.

[0059] (1) Particle size determination: The particle size of polymyxin B sulfate dry powder was determined using a laser particle size analyzer with a dry method. The dispersion pressure was 3.5 bar. Each sample was measured in triplicate, and the results are shown in Table 1. The results show that with the increase of the ratio of guar gum and L-leucine, d 0.5 The particles first decrease in size and then increase in size. S4 and S5 have smaller particle sizes, which can reach deep into the lungs and are more conducive to drug delivery to the lungs.

[0060] (2) Density determination: Weigh an appropriate amount of polymyxin B sulfate dry powder and place it in a 1mL precision syringe. Record the initial volume of the powder, V0. The loose density of the carrier is ρ0 = m / V0. Tap the syringe gently until the volume of the carrier remains unchanged, and record the tapped volume of the powder, V. t Then the tap density of the carrier is ρt=m / V t The results are shown in Table 1. S1 to S6 all have relatively low bulk density and tapped density, which is beneficial for drug delivery to the lungs. This is because low-density carriers are easier to disperse, require a lower inhalation rate, and are more likely to enter the lower respiratory tract, thereby increasing the fine particle fraction (FPF). However, excessively low bulk density can result in poor powder flowability, causing the powder to deposit prematurely in the throat, which in turn affects the FPF.

[0061] Table 1 Effect of different quality ratios of raw and auxiliary materials on the properties of polymyxin B sulfate dry powder

[0062]

[0063]

[0064] (3) In vitro drug deposition rate (Fine Particle Fraction, FPF): The spray-dried polymyxin B sulfate dry powder was loaded into a size 3 HPMC capsule (25 ± 0.5 mg / capsule) to obtain a polymyxin B sulfate inhalation powder, and a Next Generation Impactor (NGI, Copley Scientific, UK) was used to determine the in vitro drug deposition rate of the inhalation powder. FPF is the most intuitive parameter for evaluating the lung drug delivery efficiency of the inhalation powder, and refers to the percentage of the amount of drug deposited in the lungs to the total amount of drug released from the device. The larger the FPF, the more conducive to lung drug delivery. Figure 1

[0065] Determination method: One test capsule of the above-mentioned polymyxin B sulfate inhalation powder was loaded into the inhalation device, the bottom end of the device was pressed with the fingers to pierce the bottom end of the capsule, the vacuum pump was turned on, and the gas flow was set to 60 L / min (determined by the inherent internal resistance of the inhalation device); the inhalation device was connected to the adapter and inserted into the artificial larynx, and after 4 seconds of suction, the inhalation device was removed and a new capsule was placed. A total of 10 capsules were suctioned, and each sample was determined in triplicate. The dry powder in the adapter, larynx, pre-separator, S1, S2, S3, S4, S5, S6, S7, MOC (S1-S7, MOC correspond to the first to eighth collection pans, respectively) was collected with ultrapure water and the content of polymyxin B sulfate was determined. The in vitro drug deposition rate FPF reflects the ability of the drug to be delivered to the lungs. Specifically, FPF is equal to the amount of drug received by S3 to S6 four collection pans divided by the total amount of drug in the device. The results are shown in Table 2.

[0066] The results show that the polymyxin B sulfate inhalation powders of different formulations all have good inhalation performance, and as the ratio of guar gum and L-leucine increases, the FPF value shows a trend of first increasing and then decreasing. Among them, the polymyxin B sulfate inhalation powder shown in S4 has the highest FPF value, which is 72.31 ± 1.34%. This shows that the addition of guar gum and L-leucine and their ratio will affect the aerodynamic behavior of polymyxin B sulfate, and the addition of a certain ratio of guar gum and L-leucine can effectively improve the FPF value of the polymyxin B sulfate inhalation powder, and is more conducive to the delivery of the drug to the lungs.

[0067] Table 2 FPF of polymyxin B sulfate inhalation powder

[0068] ​

[0069] (4) Minimal Inhibit Concentration (MIC): Frozen P. aeruginosa was taken in 15 mL centrifuge tube, 5 mL MHB broth was added, and incubated at 37 °C, 150 rpm for 8 h. Subsequently, the bacterial solution was diluted to 5 x 10 5 CFU / mL for standby. The dry powder of polymyxin B sulfate prepared in Example 1 and the physical mixtures of polymyxin B sulfate and guar gum and L-leucine in different proportions were respectively prepared into solutions with a concentration of 400 pg / mL using Phosphate Buffered Saline (PBS) for standby. 50 pL of bacterial solution was added to a 96-well plate, followed by the addition of 50 pL of polymyxin B sulfate / guar gum / L-leucine solution, and the final concentration of polymyxin B sulfate was 16, 8, 4, 2, 1, 0.5 pg / mL by half dilution. Subsequently, the 96-well plate was placed in a 37 °C incubator for 12 h, and the absorbance at 600 nm was measured using a microplate reader. The results are shown in Table 3, and the minimal inhibitory concentrations of different formulations of polymyxin B sulfate / guar gum / L-leucine dry powder for P. aeruginosa are the same, all having good antibacterial activity, indicating that the addition of guar gum and L-leucine and the spray drying process do not affect the antibacterial activity of polymyxin B sulfate.

[0070] Table 3 Antibacterial activity (minimal inhibitory concentration MIC) of different formulations of polymyxin B sulfate dry powder and its physical mixtures

[0071]

[0072]

[0073] (5) Ability to inhibit bacterial biofilm formation: Quantitative analysis was performed by crystal violet staining method. In a 96-well plate, 100 pL of P. aeruginosa solution with a concentration of 10 x 10^7 CFU / mL and 100 pL of polymyxin B sulfate dry powder solution prepared with PBS were added to each well, and the final concentration of polymyxin B sulfate was 4, 2 and 1 pg / mL, respectively. Three parallel holes were set, and PBS was used as the control group. Incubated at 37 °C for 48 hours to form a biofilm, then the upper bacterial suspension was removed and washed with PBS three times, and dried. Then, 200 pL of 1% (w / w) crystal violet solution was added to each well for staining, and after 10 min, the unbound crystal violet was washed with sterile water three times. Subsequently, 200 pL of absolute ethanol was added to each well to dissolve the crystal violet in the biofilm, and after 20 min, the absorbance was measured at a wavelength of 595 nm.

[0074] The results are shown in Table 4. The different mass ratios of polymyxin B sulfate and guar gum and L-leucine had different effects on the removal of bacterial biofilm by polymyxin B sulfate dry powder. As the proportion of guar gum increased, the efficiency of bacterial biofilm inhibition increased.

[0075] Table 4 Bacterial biofilm inhibition rate of polymyxin B sulfate dry powder with different formulations

[0076]

[0077]

[0078] Example 2

[0079] Polymyxin B sulfate, guar gum and L-leucine were dissolved in water at a mass ratio of 55:30:15 to prepare solutions with concentrations of 5, 10, 15, 20 and 30 mg / mL (total concentration of polymyxin B sulfate, guar gum and L-leucine). The solutions were then spray dried using a spray dryer to prepare polymyxin B sulfate dry powder. The spray drying conditions were as follows: inlet temperature 130°C, outlet temperature 75°C, pump liquid rate 3 mL / min, nozzle diameter 0.71 mm, atomization pressure 200 kPa, and air flow rate 0.60 m 3 / h.

[0080] The median particle size d0.5 and FPF of the spray-dried polymyxin B sulfate dry powder were tested according to the method in Example 1. The results are shown in Table 5. As the total concentration of polymyxin B sulfate / guar gum / L-leucine increased, the d 0.5 tended to increase, and the FPF tended to increase first and then decrease. When the total concentration was 15 mg / mL, the FPF of the prepared polymyxin B sulfate dry powder was the highest.

[0081] Table 5 Effect of solid content on the particle size and FPF of polymyxin B sulfate dry powder

[0082]

[0083]

[0084] Comparative Example 1

[0085] Polymyxin B sulfate and different carriers (guar gum, lactose, trehalose, galactose, raffinose, erythritol) and L-leucine were dissolved in water at a mass ratio of 55:30:15 to prepare a solution with a concentration of 15 mg / mL (total concentration of polymyxin B sulfate, carrier and L-leucine), and then spray drying was performed on the above solution using a spray dryer to prepare different polymyxin B sulfate dry powder powders. The spray drying conditions were as follows: inlet air temperature 130°C, outlet air temperature 75°C, pump liquid rate 3 mL / min, nozzle diameter 0.71 mm, atomization pressure 200 kPa, and air flow rate 0.60 m 3 / h.

[0086] The FPF and the ability to inhibit bacterial biofilm formation of the polymyxin B sulfate dry powder prepared with different carriers were tested according to the method in Example 1. The results are shown in Table 6: the polymyxin B sulfate dry powder prepared with 30% guar gum as a sugar carrier had a significantly higher FPF and the ability to inhibit biofilm formation than the polymyxin B sulfate dry powder prepared with other carriers.

[0087] Table 6 Biofilm inhibition rate and FPF of polymyxin B sulfate dry powder with different carriers

[0088]

[0089]

[0090] Comparative Example 2

[0091] Polymyxin B sulfate and guar gum and different excipients (L-leucine, mannitol, lactose) were dissolved in water at a mass ratio of 55:30:15 to prepare a solution with a concentration of 15 mg / mL (total concentration of polymyxin B sulfate, guar gum and excipient), and then spray drying was performed on the above solution using a spray dryer to prepare different polymyxin B sulfate dry powder powders. The spray drying conditions were as follows: inlet air temperature 130°C, outlet air temperature 75°C, pump liquid rate 3 mL / min, nozzle diameter 0.71 mm, atomization pressure 200 kPa, and air flow rate 0.60 m 3 / h.

[0092] The FPF of the polymyxin B sulfate dry powder prepared in this example was tested according to the method in Example 1. The results are shown in Table 7: the polymyxin B sulfate dry powder containing 15% L-leucine had a significantly higher FPF than the polymyxin B sulfate dry powder containing other excipients.

[0093] Table 7 FPF of polymyxin B sulfate dry powder with different excipients

[0094]

[0095] The above embodiments only express several implementation manners of the present application, and the description is more specific and detailed, but it should not be understood as a limitation on the scope of the patent. It should be noted that for ordinary skilled persons in the art, without departing from the concept of the present application, several modifications and improvements can be made, which are within the scope of protection of the present application. Therefore, the protection scope of the patent of the present application should be subject to the appended claims.

Claims

1. A dry powder of polymyxin B sulfate, characterized in that, The dry powder of polymyxin B sulfate is prepared by spray drying from an aqueous solution of polymyxin B sulfate and a carrier; The carrier is composed of guar gum and L-leucine in a mass ratio of 1-2.5:1; The mass percentage of the polymyxin B sulfate and the carrier is 45%-65%:35%-55%, and the total amount of the polymyxin B sulfate and the carrier is 100%. The total concentration of the polymyxin B sulfate, the guar gum and the L-leucine in the aqueous solution is 3 mg / mL~18mg / mL.

2. The polymyxin B sulfate dry powder of claim 1, wherein, The mass percentage of the polymyxin B sulfate and the carrier is 50%-60%:40%-50%.

3. The polymyxin B sulfate dry powder of claim 2, wherein, The mass percentage of the polymyxin B sulfate and the carrier is 53%-60%:40%-57%.

4. The polymyxin B sulfate dry powder of claim 3, wherein, The mass percentage of the polymyxin B sulfate and the carrier is 53%-57%:43%-47%.

5. The polymyxin B sulfate dry powder of claim 4, wherein, The mass percentage of the polymyxin B sulfate and the carrier is 55%:45%.

6. The polymyxin B sulfate dry powder of claim 2, wherein, The mass ratio of the guar gum and the L-leucine is 1.5-2.2:

1.

7. The polymyxin B sulfate dry powder of claim 6, wherein, The mass ratio of the guar gum and the L-leucine is 25-30:

15.

8. The polymyxin B sulfate dry powder of claim 7, wherein, The mass ratio of the guar gum and the L-leucine is 30:

15.

9. The polymyxin B sulfate dry powder of any one of claims 1-8, wherein, The total concentration of the polymyxin B sulfate, the guar gum and the L-leucine in the aqueous solution is 4mg / mL~17mg / mL.

10. The polymyxin B sulfate dry powder of claim 9, wherein, The total concentration of the polymyxin B sulfate, the guar gum and the L-leucine in the aqueous solution is 5mg / mL~16mg / mL.

11. The polymyxin B sulfate dry powder of claim 10, wherein, The total concentration of the polymyxin B sulfate, the guar gum and the L-leucine in the aqueous solution is 10mg / mL~16mg / mL.

12. The polymyxin B sulfate dry powder of claim 11, wherein, The total concentration of the polymyxin B sulfate, the guar gum and the L-leucine in the aqueous solution is 14mg / mL~16mg / mL.

13. The polymyxin B sulfate dry powder of claim 12, wherein, The total concentration of the polymyxin B sulfate, the guar gum and the L-leucine in the aqueous solution is 15mg / mL.

14. A process for the preparation of a dry powder of polymyxin B sulfate as claimed in any one of claims 1 to 13, characterized in that, The total concentration of the polymyxin B sulfate, the guar gum and the L-leucine in the aqueous solution is 15mg / mL.

15. The method of claim 14, wherein the dry powder of colistimethate is prepared by, The method comprises the following steps: dissolving the polymyxin B sulfate, the guar gum and the L-leucine in water to obtain the aqueous solution, and then spray drying the aqueous solution to obtain the dry powder of polymyxin B sulfate.

16. The method of claim 15, wherein the dry powder of colistimethate is prepared by, The spray drying conditions comprise: an inlet air temperature of 100 ℃~160 ℃, an outlet air temperature of 60 ℃~90 ℃, and an atomization pressure of 100 kPa~210 kPa.

17. The method of claim 16, wherein the dry powder of colistimethate is prepared by, The spray drying conditions comprise: an inlet air temperature of 110 ℃ ~ 150 ℃, an outlet air temperature of 70 ℃ ~ 80 ℃, and an atomization pressure of 120 kPa ~ 210 kPa.

18. The method of claim 17, wherein the dry powder of colistimethate is prepared by, The inlet air temperature is 120 ℃ ~140 ℃, the outlet air temperature is 70 ℃~80 ℃, and the atomization pressure is 190 kPa~210 kPa.

19. The method of claim 18, wherein the dry powder of colistimethate is prepared by, The inlet air temperature is 125 ℃ ~ 135 ℃, the outlet air temperature is 73 ℃ ~ 78 ℃, and the atomization pressure is 195 kPa ~ 205 kPa.

20. The method of claim any one of claims 14-19, wherein the dry powder of polymyxin B sulfate is prepared by, The conditions of the spray drying further include: the feeding speed is 2.5 mL / min ~ 3.5 mL / min, the nozzle diameter is 0.65 mm ~ 0.75 mm, the gas flow is 0.55 m 3 / h ~ 0.65 m 3 / h.

21. A sulfact polymyxin B inhalation powder characterized in that, The inlet air temperature is 130 ℃, the outlet air temperature is 75 ℃, and the atomization pressure is 200 kPa.

22. The polymyxin B sulfate inhalation powder of claim 21, wherein, The dry powder of polymyxin B sulfate as claimed in any one of claims 1-13 is filled into a capsule to obtain. The capsule is a No. 3 HPMC capsule; and / or, The loading of polymyxin B sulfate dry powder into the capsule was 25 ± 0.5 mg / capsule. The loading of polymyxin B sulfate dry powder into the capsule was 25 ± 0.5 mg / capsule.

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