Polymyxin B sulfate dry powder, inhalation dry powder inhalation and preparation method of polymyxin B sulfate dry powder and inhalation dry powder inhalation

Abstract

The invention relates to polymyxin B sulfate dry powder, a dry powder inhalation and a preparation method of the polymyxin B sulfate dry powder and the dry powder inhalation. The polymyxin B sulfate dry powder is prepared from polymyxin B sulfate and an aqueous solution of a carrier through spray drying, the carrier is composed of guar gum and L-leucine in a mass ratio of (1-2.5): 1; the mass percentage ratio of the polymyxin B sulfate to the carrier is (45%-65%): (35%-55%), and the total amount of the polymyxin B sulfate and the carrier is 100%; in the aqueous solution, the total concentration of the polymyxin B sulfate and the carrier is 3 mg / mL to 18 mg / mL. The polymyxin B sulfate inhalation powder inhalation prepared from the polymyxin B sulfate dry powder can directly deliver the medicine to a lung focus through local administration, the effective deposition rate of the lung is high, the administration dosage is greatly reduced, and the formation of a bacterial biofilm can be effectively inhibited.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and relates to pharmaceutical preparations, in particular to polymyxin B sulfate dry powder, inhalation powder spray and a preparation method thereof. Background Art

[0002] Pulmonary infection is a large class of diseases caused by pathogenic microorganisms or other factors invading the lung parenchyma and causing inflammation. It has become a major challenge to global public health. Among the top ten causes of death in the world in 2021 released by the World Health Organization (WHO), lung infection ranked fifth, causing the death of approximately 2.5 million people, making it the world's most deadly infectious disease. Among the pathogens that cause lung infections, Gram-negative bacteria account for a very high proportion, about 70% to 80%, of which Pseudomonas aeruginosa (PA) is one of the most important pathogens. Clinical manifestations often include acute fever, cough, and coughing up yellow-green purulent sputum. In severe cases, it can progress to respiratory failure, which is particularly threatening to people with weakened immune systems. Because it is insensitive to or seriously resistant to many commonly used antimicrobial drugs in clinical practice, the treatment of related infections is extremely difficult, and the mortality rate is high, which has imposed a heavy economic burden on my country's medical care.

[0003] Currently, oral or injectable antibiotics are the primary treatments for pulmonary Pseudomonas aeruginosa infections. Since both routes of administration involve systemic administration, they can cause numerous systemic adverse reactions, primarily manifesting as: 1) headache and poor sleep; 2) palpitations, shortness of breath, and irregular heartbeat; 3) itching, rashes, or urticaria; and 4) abdominal distension, abdominal pain, nausea, and vomiting. Furthermore, patients with pulmonary Pseudomonas aeruginosa infections require long-term use of broad-spectrum antibiotics such as imipenem, meropenem, and levofloxacin. According to the latest 2024 bacterial resistance monitoring results released by CHINET, resistance rates to imipenem and meropenem in Pseudomonas aeruginosa reached 21.3% and 17.3%, respectively, while resistance to levofloxacin reached 19.6%. The data for carbapenem-resistant Pseudomonas aeruginosa is even more alarming, with resistance to imipenem reaching 95.4%.

[0004] In addition to multidrug resistance, difficult-to-treat pulmonary Pseudomonas aeruginosa infections are also difficult to treat because the bacteria easily form bacterial biofilms (BFs) in lung lesions. Bacterial biofilms are membrane-like structures formed by bacteria adhering to contact surfaces and surrounding themselves with polysaccharide matrices, fibrin, and lipid proteins. Pseudomonas aeruginosa is highly susceptible to biofilm formation, a pathological barrier that provides shelter for the bacteria, preventing drugs from reaching the bacteria and exerting their efficacy, leading to recurring infections.

[0005] Polymyxin B sulfate (PMBS) is the sulfate form of polymyxin B and is commonly used clinically for treatment. PMBS is a cyclic cationic polypeptide antibiotic that binds to the lipopolysaccharide (LPS) of the outer cell membrane of Gram-negative bacteria, causing cell membrane rupture and leakage of intracellular contents, ultimately leading to bacterial death. It is a last-ditch treatment for infections caused by multidrug-resistant Gram-negative bacteria, particularly Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. According to CHINET's 2024 bacterial resistance monitoring results, the resistance rate of Pseudomonas aeruginosa to polymyxin B is extremely low, at only 0.5%.

[0006] PMBS is one of the mainstays of treatment for carbapenem-resistant Gram-negative infections. To increase drug concentrations in the lungs, international and domestic guidelines and consensus recommend combining intravenous administration with nebulized inhalation to enhance efficacy. While specialized formulations for nebulized inhalation of polymyxins are available internationally, none are currently available in China. Therefore, developing a PMBS-specific inhaled formulation that can effectively disrupt bacterial biofilms for the treatment of PA pulmonary infections is essential.

[0007] Inhalation preparations refer to liquid or solid preparations in which the drug substance is dissolved or dispersed in a suitable medium and delivered to the lungs in the form of an aerosol or vapor to exert a local or systemic effect. Compared with traditional drug delivery methods, inhalation drug delivery systems have significant advantages, such as direct action on lung lesions, reduced systemic exposure, and avoidance of gastrointestinal absorption and first-pass effects. They can not only effectively increase drug concentrations at the lesion site, but also reduce peripheral drug side effects. Therefore, inhalation preparations provide a precise localized treatment strategy for the treatment of bacterial lung infections. Inhalation preparations mainly include inhalation liquid preparations, inhalation aerosols, and inhalation powder inhalers (DPIs). Among them, DPIs are a new inhalation dosage form that integrates powder science and particle engineering. The micronized drug is stored alone or mixed with a carrier in capsules, blisters, or reservoirs. The patient actively inhales the drug, which is atomized and dispersed through a dedicated inhalation device and then enters the lungs with the airflow. Compared to inhaled liquid preparations and inhaled aerosols, DPIs offer the following advantages: 1) ease of use and good patient compliance; 2) lack of propellants, thus avoiding environmental contamination; 3) accurate dosing; 4) absence of preservatives and solvents such as ethanol, making them non-irritating to the mucous membranes and lungs; and 5) solid-state stability. However, the polypeptide structure of polymyxin B sulfate makes it unstable in liquid environments and susceptible to degradation. Therefore, DPIs are the most preferred dosage form for polymyxin B sulfate inhalation preparations.

[0008] However, the preparation of PMBS inhalation powder has the following key bottlenecks: if PMBS is directly prepared into inhalation powder, the powder has a large surface free energy and aggregation tendency, and its fluidity is poor; at the same time, PMBS has high hygroscopicity, which affects the aerosol performance and stability of drug particles. Since it easily absorbs water, the particle size will increase and the aerosolization efficiency will be reduced; these factors will lead to poor aerodynamic properties of PMBS inhalation powder. Coupled with the complex physiological structure of the lungs, drug particles will be deposited in the oropharynx prematurely, resulting in low lung drug delivery efficiency and low drug deposition rate in the lungs. Summary of the Invention

[0009] Based on this, the purpose of the present invention is to provide a polymyxin B sulfate dry powder. The polymyxin B sulfate inhalation powder prepared from the dry powder can deliver the drug directly to the lung lesions through local administration, has a high effective deposition rate in the lungs, greatly reduces the dosage, and can effectively inhibit the formation of bacterial biofilms.

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

[0011] In a first aspect, the present invention provides a polymyxin B sulfate dry powder, which is prepared by spray drying an aqueous 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 aqueous solution, the total concentration of polymyxin B sulfate and the carrier is 3 mg / mL to 18 mg / mL.

[0015] In a second aspect, the present invention provides a method for preparing the polymyxin B sulfate dry powder, 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.

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

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

[0018] The present invention innovatively introduces guar gum and L-leucine as a composite carrier of polymyxin B sulfate. The three components are dissolved in water at specific ratios and concentrations, and the resulting aqueous solution is spray-dried to prepare polymyxin B sulfate dry powder and its inhalation powder. The dry powder has the combined advantages of high antibacterial efficiency, low hygroscopicity, high fluidity, and good aerosol performance, ensuring the stability of the drug in a high-humidity environment and the dispersibility during inhalation. This effectively improves the effective lung deposition rate of the obtained polymyxin B sulfate dry powder and its inhalation powder, and reduces the deposition of the drug in the throat. Furthermore, the dry powder and its inhalation powder can effectively inhibit the formation of bacterial biofilms and break up existing biofilms, thereby significantly improving the therapeutic effect of polymyxin B sulfate and reducing its systemic toxicity.

[0019] Furthermore, in the polymyxin B sulfate dry powder and the inhalation powder thereof of the present invention, the ratio of guar gum to L-leucine is low, the drug content of polymyxin B sulfate is high, and the drug loading capacity is high, which can reduce the dosage of the dry powder and improve patient compliance.

[0020] The spray drying process of the present invention adopts an aqueous solvent system, which ensures efficient simplification of process steps while fully complying with the sustainable production concept of low toxicity and low energy consumption, and is conducive to achieving industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Schematic diagram of the next generation impactor (NGI). DETAILED DESCRIPTION

[0022] To facilitate understanding of the present invention, the present invention will be described more fully below. The present invention can be implemented 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 present disclosure more thorough and comprehensive.

[0023] In the following examples, the experimental methods without specific conditions are generally carried out under conventional conditions or conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which this invention pertains. The terms used in this specification are for the purpose of describing specific embodiments only and are not intended to limit the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0025] Furthermore, as used herein, the term "or" is inclusive and equivalent to the term "and / or," unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for being based on other factors not described, unless the context clearly dictates otherwise. Furthermore, throughout this specification, the meanings of "a," "an," and "the" include plural referents. The meaning of "in" includes "in" and "on."

[0026] In order to improve the ability of polymyxin B sulfate inhalation powder to inhibit bacterial biofilm formation and the effective lung deposition rate, the research team of the present invention previously developed a polymyxin B sulfate dry powder and inhalation powder prepared using raffinose as a carrier. Although this can effectively improve the ability of polymyxin B sulfate inhalation powder to inhibit bacterial biofilm formation and the effective lung deposition rate, the polymyxin B sulfate content in the dry powder formula 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 dry powder dosage is large when used. Based on this, the inventors further discovered that the polymyxin B sulfate dry powder and inhalation powder prepared by using guar gum and L-leucine instead of the original raffinose as a carrier excipient can greatly increase the polymyxin B sulfate content while further improving its ability to inhibit bacterial biofilm formation and the effective lung deposition rate.

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

[0028] The carrier is composed of guar gum and L-leucine in 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 polymyxin B sulfate and the carrier is 3 mg / mL to 18 mg / mL.

[0031] The polymyxin B sulfate dry powder prepared by the present invention has a polymyxin B sulfate content of 45%-65%, which is much higher than the drug content in the polymyxin B sulfate / raffinose dry powder (only 5%-10%). The dry powder dosage can be greatly reduced during medication, thereby improving patient compliance.

[0032] The inventors found that the concentrations of polymyxin B sulfate, guar gum, and L-leucine in the drug solution during spray drying have a significant impact on the performance of the resulting dry powder. When the total concentration is within the range of 3 mg / mL to 18 mg / mL, the prepared polymyxin B sulfate dry powder can have a higher effective lung deposition rate.

[0033] In some preferred embodiments, the mass percentage of polymyxin B sulfate and the 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 the carrier is 53%-57%: 43%-47%.

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

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

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

[0039] In some more preferred embodiments, the mass ratio of guar gum to 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] Some embodiments of the present invention relate to a method for preparing the polymyxin B sulfate dry powder described herein, comprising the steps of 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. This method is simple to operate and can prepare polymyxin B sulfate dry powder with a high effective lung deposition rate in one step.

[0046] In some preferred embodiments, the spray drying conditions include: an air inlet temperature of 100° C. to 160° C., an air outlet temperature of 60° C. to 90° C., and an atomization pressure of 100 kPa to 210 kPa.

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

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

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

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

[0051] In some embodiments, the spray drying conditions also include: a feed rate of 2.5 mL / min to 3.5 mL / min, a nozzle diameter of 0.65 mm to 0.75 mm, and an air flow rate of 0.55 m 3 / h~0.65m 3 / h.

[0052] In some embodiments of the present invention, there is also provided a polymyxin B sulfate inhalation powder, which is obtained by encapsulating 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 the capsule is 25±0.5 mg / capsule.

[0055] The present invention is 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] The polymyxin B sulfate powder was prepared by spray drying using a spray dryer. The specific conditions for spray drying are as follows: the inlet air temperature is set at 130 ° C, the outlet air temperature is 75 ° C, the pumping rate is 3 mL / min, the nozzle diameter is 0.71 mm, the atomization pressure is 200 kPa, and the air flow rate is 0.60 m 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 powder was determined by laser particle size analyzer dry method, the dispersion pressure was 3.5 bar, and each portion was measured three times in parallel. The results are shown in Table 1. The results show that with the increase of the ratio of guar gum and L-leucine, the particle size of polymyxin B sulfate powder increased. 0.5 First decreasing and then increasing, S4 and S5 have smaller particle sizes and can reach deep into the lungs, which is more conducive to pulmonary drug delivery.

[0060] (2) Density determination: Weigh an appropriate amount of polymyxin B sulfate powder and place it in a 1 mL precision syringe. Record the initial volume V0 of the powder. The bulk density of the carrier is ρ0 = m / V0. Tap the syringe until the volume of the carrier remains unchanged. Record the tapped volume V0 of the powder. t , then the tap density of the carrier is ρt=m / V t As shown in Table 1, S1-S6 all have low bulk and tap densities, which facilitates pulmonary drug delivery. This is because low-density carriers are easier to disperse, require a lower inhalation velocity, and are more likely to enter the lower respiratory tract, thereby increasing drug deposition rate (Fine Particle Fraction, FPF). However, too low a bulk density can result in poor powder flowability, causing the powder to settle prematurely in the throat, which in turn affects FPF.

[0061] Table 1 Effects of different mass ratios of raw materials and excipients on the properties of polymyxin B sulfate powder

[0062]

[0063]

[0064] (3) In vitro drug deposition rate (Fine Particle Fraction, FPF): The spray-dried polymyxin B sulfate powder was loaded into No. 3 HPMC capsules (25±0.5 mg / capsule) to obtain polymyxin B sulfate inhalation powder. The new generation pharmaceutical impactor (Next Generation Impactor, NGI, Figure 1 ) measures the in vitro drug deposition rate of inhaled powders. FPF is the most intuitive parameter for evaluating the efficiency of pulmonary drug delivery of inhaled powders. It refers to the percentage of drug deposited in the lungs to the total drug released from the device. A larger FPF indicates better pulmonary drug delivery.

[0065] Assay method: Place one capsule of the polymyxin B sulfate inhalation powder test sample into the inhalation device. Press the button at the bottom of the device with your finger to puncture the capsule. Start the vacuum pump and set the airflow rate to 60 L / min (determined by the inherent internal resistance of the inhalation device). Connect the inhalation device to the adapter and insert the artificial throat. After evacuating for 4 seconds, remove the inhalation device and replace the capsule. A total of 10 capsules were aspirated in this manner, with each sample measured in triplicate. Ultrapure water was used to collect the dry powder formulation from the adapter, throat, pre-separator, S1, S2, S3, S4, S5, S6, S7, and MOC (S1-S7 and MOC correspond to collection trays 1-8, respectively) and the polymyxin B sulfate content was determined. The in vitro drug deposition fraction (FPF) reflects the drug's ability to reach the lungs. Specifically, FPF is calculated by dividing the amount of drug received by the four collection trays S3-S6 by the total amount of drug in the device. The results are shown in Table 2.

[0066] The results showed that polymyxin B sulfate inhalation powders with different formulations all exhibited good inhalation performance. With increasing guar gum and L-leucine ratios, the FPF values initially increased and then decreased. Among them, polymyxin B sulfate inhalation powder (S4) had the highest FPF value, at 72.31±1.34%. This suggests that the addition of guar gum and L-leucine, and their respective ratios, affect the aerodynamic behavior of polymyxin B sulfate. Adding a certain ratio of guar gum and L-leucine can effectively improve the FPF value of polymyxin B sulfate inhalation powders, facilitating drug delivery to the lungs.

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

[0068]

[0069] (4) Minimum inhibitory concentration (MIC): Take frozen Pseudomonas aeruginosa in a 15 mL centrifuge tube, add 5 mL MHB culture medium, and incubate at 37°C, 150 rpm on a shaker for 8 h. Then dilute the bacterial solution to 5 × 10 5 CFU / mL is for standby use. The polymyxin B sulfate powder prepared in Example 1 and the physical mixture of polymyxin B sulfate, guar gum and L-leucine in different proportions are dissolved in phosphate buffered saline (PBS) to prepare a solution with a concentration of 400 μg / mL for standby use. 50 μL of bacterial solution is added to a 96-well plate, followed by addition of 50 μL of polymyxin B sulfate / guar gum / L-leucine solution, and by half dilution, the final concentration of polymyxin B sulfate is 16, 8, 4, 2, 1, 0.5 μg / mL. Subsequently, the 96-well plate is placed in a 37°C constant temperature incubator and cultured for 12 hours, and the absorbance at 600 nm is measured using a microplate reader. The results are shown in Table 3. The minimum inhibitory concentrations of polymyxin B sulfate / guar gum dry powder / L-leucine dry powder with different formulations against Pseudomonas aeruginosa were the same, and all had good antibacterial activity, indicating that the addition of guar gum and L-leucine and the spray drying process did not affect the antibacterial activity of polymyxin B sulfate.

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

[0071]

[0072]

[0073] (5) Ability to inhibit bacterial biofilm formation: Quantitative analysis was performed by crystal violet staining. In a 96-well plate, 100 μL of Pseudomonas aeruginosa bacterial suspension with a concentration of 10×10^7 CFU / mL and 100 μL of polymyxin B sulfate powder solution prepared with PBS were added to each well. The final concentrations of polymyxin B sulfate were 4, 2, and 1 μg / mL, respectively. Three parallel wells were set up, and PBS was used as a control group. The cells were cultured at 37°C for 48 hours to form a biofilm, and then the upper bacterial suspension was removed by aspiration, and the cells were gently rinsed three times with PBS and air-dried. Next, 200 μL of 1% (w / w) crystal violet solution was added to each well for staining. After 10 minutes, the cells were gently rinsed three times with sterile water to remove unbound crystal violet. After that, 200 μL of anhydrous ethanol was added to each well to dissolve the crystal violet in the biofilm. After standing for 20 minutes, the absorbance was measured at a wavelength of 595 nm.

[0074] The results are shown in Table 4. Different mass ratios of polymyxin B sulfate, guar gum, and L-leucine have different efficiencies in removing bacterial biofilms from polymyxin B sulfate dry powder. As the proportion of guar gum increases, the bacterial biofilm inhibition efficiency increases.

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

[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), and then the above solutions were spray dried using a spray dryer to prepare polymyxin B sulfate powder. The spray drying conditions were as follows: inlet air temperature of 130°C, outlet air temperature of 75°C, pumping rate of 3 mL / min, nozzle diameter of 0.71 mm, atomization pressure of 200 kPa, and air flow rate of 0.60 m 3 / h.

[0080] The median particle size d0.5 and FPF value of the spray-dried polymyxin B sulfate 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 increases, d0.5 increases. 0.5 The FPF showed a trend of increasing first and then decreasing. When the total concentration was 15 mg / mL, the FPF of the prepared polymyxin B sulfate powder was the highest.

[0081] Table 5 Effect of solid content on particle size and FPF of polymyxin B sulfate 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 (the total concentration of polymyxin B sulfate, carrier and L-leucine). The above solution was then spray-dried using a spray dryer to prepare different polymyxin B sulfate dry powders. The spray drying conditions were as follows: inlet air temperature of 130°C, outlet air temperature of 75°C, pumping rate of 3 mL / min, nozzle diameter of 0.71 mm, atomization pressure of 200 kPa, and air flow rate of 0.60 m 3 / h.

[0086] The FPF and biofilm inhibition abilities of polymyxin B sulfate powders prepared using different carriers were tested according to the method described in Example 1. The results are shown in Table 6: Polymyxin B sulfate powder prepared using 30% guar gum as a sugar carrier exhibited significantly higher FPF and biofilm inhibition abilities than polymyxin B sulfate powders prepared using other carriers.

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

[0088]

[0089]

[0090] Comparative Example 2

[0091] Polymyxin B sulfate, 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 (the total concentration of polymyxin B sulfate, guar gum and excipients). The above solution was then spray-dried using a spray dryer to prepare different polymyxin B sulfate dry powders. The spray drying conditions were as follows: inlet air temperature of 130°C, outlet air temperature of 75°C, pumping rate of 3 mL / min, nozzle diameter of 0.71 mm, atomization pressure of 200 kPa, and air flow rate of 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 has a significantly higher FPF than the polymyxin B sulfate dry powder containing other excipients.

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

[0094]

[0095] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. A polymyxin B sulfate dry powder, characterized in that, It is prepared by spray drying 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%; In the aqueous solution, the total concentration of polymyxin B sulfate and the carrier is 3 mg / mL to 18 mg / mL.

2. The polymyxin B sulfate dry powder according to claim 1, characterized in that The mass percentage of the polymyxin B sulfate and the carrier is 50%-60%:40%-50%, preferably 53%-60%:40%-57%, more preferably 53%-57%:43%-47%, and more preferably 55%:45%.

3. The polymyxin B sulfate dry powder according to claim 2, characterized in that The mass ratio of the guar gum to L-leucine is 1.5-2.2:1, preferably 25-30:15, and more preferably 30:

15.

4. The polymyxin B sulfate dry powder according to any one of claims 1 to 3, characterized in that In the aqueous solution, the total concentration of polymyxin B sulfate, guar gum and L-leucine is 4 mg / mL to 17 mg / mL, more preferably 5 mg / mL to 16 mg / mL.

5. The polymyxin B sulfate dry powder according to claim 4, characterized in that In the aqueous solution, the total concentration of polymyxin B sulfate, guar gum and L-leucine is 10 mg / mL to 16 mg / mL, preferably 14 mg / mL to 16 mg / mL, and more preferably 15 mg / mL.

6. A method for preparing the polymyxin B sulfate dry powder according to any one of claims 1 to 5, characterized in that: The method comprises 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.

7. The method for preparing polymyxin B sulfate dry powder according to claim 6, wherein: The spray drying conditions include: air inlet temperature of 100°C to 160°C, air outlet temperature of 60°C to 90°C, and atomization pressure of 100kPa to 210kPa; Preferably, the air inlet temperature is 110°C to 150°C, the air outlet temperature is 70°C to 80°C, and the atomization pressure is 120kPa to 210kPa; Preferably, the air inlet temperature is 120°C to 140°C, the air outlet temperature is 70°C to 80°C, and the atomization pressure is 190kPa to 210kPa; Preferably, the air inlet temperature is 125°C to 135°C, the air outlet temperature is 73°C to 78°C, and the atomization pressure is 195kPa to 205kPa; Preferably, the air inlet temperature is 130° C., the air outlet temperature is 75° C., and the atomization pressure is 200 kPa.

8. The method for preparing polymyxin B sulfate dry powder according to claim 6 or 7, characterized in that: The spray drying conditions also include: feed rate of 2.5 mL / min to 3.5 mL / min, nozzle diameter of 0.65 mm to 0.75 mm, air flow of 0.55 m 3 / h~0.65m 3 / h.

9. A polymyxin B sulfate inhalation powder, characterized in that: The polymyxin B sulfate dry powder according to any one of claims 1 to 5 is filled into capsules to obtain the product.

10. The polymyxin B sulfate inhalation powder according to claim 9, characterized in that: The capsule is a No. 3 HPMC capsule; and / or, The loading amount of polymyxin B sulfate dry powder into capsules is 25±0.5 mg / capsule.

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