Inhalation preparation containing peramivir, preparation method therefor, pharmaceutical combination, and use thereof

Abstract

Provided are an inhalation preparation containing peramivir, a preparation method therefor, a pharmaceutical combination, and use thereof. The inhalation preparation consists of peramivir or a pharmaceutically acceptable salt thereof, a pH regulator organic acid, a buffer agent, an osmotic pressure regulator, and water. The present invention does not contain inorganic acids, and uses the buffer agent of organic acids such as citric acid and disodium hydrogen phosphate, such that after the inhalation preparation is subjected to illumination and high temperature at a high concentration, related substances do not change significantly. In the process of low-temperature ultrasonic nebulization, there is no drug crystallization phenomenon, such that delivery of a specified dose of the drug is completed without drug precipitation.

Description

Inhaled formulations containing peramivir, their preparation methods, drug components, and uses

[0001] This application claims priority to an earlier application filed on February 27, 2025, with the China National Intellectual Property Administration, patent application number 202510224477.6, entitled "Inhalation formulation containing peramivir and its preparation method, pharmaceutical components and uses thereof". The entire contents of the earlier application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to an inhaled formulation containing peramivir, its preparation method, pharmaceutical components, and uses. Background Technology

[0003] Influenza (flu) is a highly contagious acute respiratory illness caused by the influenza virus. Based on the type of virus, it is mainly divided into influenza A and influenza B. Influenza is a seasonal disease, with peak incidence during the winter and spring seasons each year. The main affected populations are children and the elderly, and other groups with weakened immune systems. Data shows that during the annual influenza season, the influenza incidence rate among children in my country is 20%–30%; the incidence rate among people over 65 years of age is as high as 8.8%. According to the World Health Organization, influenza causes 3 million severe illnesses and 650,000 respiratory disease-related deaths globally each year. The Lancet reports that approximately 88,100 people die from influenza-related illnesses in China in a normal year. Due to frequent mutations of the influenza virus, existing first-line drugs have high resistance rates and insufficient efficacy. For example, in 2017, the WHO no longer recommended the prophylactic use of oseltamivir and restricted its use for the treatment of severe illness caused by hospitalized patients with confirmed or suspected severe influenza. In addition, the routes of administration of existing influenza drugs are limited to oral and injection, which are systemic administration methods and have certain toxic side effects, hindering the patient's medication experience. There is an urgent clinical need for a safe and effective inhaled antiviral preparation.

[0004] Peramivir is a neuraminidase inhibitor (NAI) antiviral drug developed by BioCryst Pharmaceuticals in the United States. It is administered by injection and is a first-line antiviral drug for influenza. Compared to first-generation NAIs oseltamivir and zanamivir, peramivir has a stronger affinity for influenza virus neuraminidase, and its clinical efficacy in treating influenza in children is superior to oseltamivir, while both have comparable safety profiles. Developing peramivir as an inhaled formulation, administered via a suitable inhaler, delivers the drug directly to the lung lesions compared to intravenous infusion (or bolus injection), resulting in a high lung deposition rate. This effectively avoids the first-pass effect in the enterohepatic system and gastrointestinal degradation, improving bioavailability, reducing dosage, and minimizing adverse drug reactions. Nebulized inhalation is simple and painless, making it easier for children, the elderly, and patients with impaired respiratory function to comply with, resulting in good adherence. It is currently an important clinical treatment for respiratory diseases.

[0005] CN109771398B discloses a peramivir solution inhaler and its preparation method. The formulation is made of peramivir, an osmotic pressure regulator, a pH regulator, sodium dihydrogen phosphate, and water. The concentration of peramivir is 15 mg / ml to 25 mg / ml, the pH value is 5.0 to 6.0, and it is administered through a nebulizer. Its mass median aerodynamic diameter (MMAD) is between 3 and 4 μm, and the effective particle deposition rate (FPF) is between 60% and 80%. According to the IF document of the Japanese marketed peramivir injection, the saturated solubility of peramivir in a pH 3-10 buffer solution is approximately 15.3-23.2 mg / ml. This concentration is very close to the saturated solubility of peramivir. When inhaled via nebulizer, the drug solution is atomized into extremely small droplets. The surface area of ​​these droplets increases significantly, causing them to evaporate rapidly and absorb heat from the surrounding air, thereby lowering the ambient temperature. This can easily lead to drug precipitation, especially in winter, when precipitation is more severe. Ultimately, this results in a decrease in the actual amount deposited in the lungs, affecting the accuracy of the dosage and failing to meet clinical treatment needs.

[0006] CN103446051A discloses a method of administration containing a formulation of peramivir and / or its derivatives, specifically a method of administering peramivir dry powder via inhalation. This method uses hydrofluorocarbons (HFCs) as the propellant. While HFCs offer advantages such as minimal ozone depletion and good chemical stability, they are expensive, have low boiling points, and require storage at low temperatures. Furthermore, dry powder inhalation requires active inhalation by the patient, placing specific demands on the inhalation rate and force. Incorrect inhalation may result in drug deposition in the mouth or throat, failing to exert a local therapeutic effect on the lungs and leading to poor treatment efficacy.

[0007] CN114177135B discloses a peramivir pharmaceutical composition and its preparation method, which discloses an emulsified injectable formulation containing peramivir. The preparation of the emulsified injectable formulation requires precise control of the ratio of the oil phase and the water phase, selection of a suitable emulsifier, and strict requirements on conditions such as temperature and stirring speed during the emulsification process. These factors increase the difficulty and cost of preparation.

[0008] In summary, existing drug formulations containing peramivir either present problems such as the inconvenience of intravenous injection requiring hospitalization, the reduction of actual lung deposition due to drug precipitation in inhaled nebulized formulations, or low patient compliance with dry powder inhalation. Therefore, there is an urgent need to find an inhaled formulation containing peramivir that is easy for patients to use, has high patient compliance, and is stable. Summary of the Invention

[0009] To overcome the shortcomings of the prior art, the present invention provides an inhalation formulation composition that does not contain inorganic acid modifiers but contains peramivir, buffer salts, organic acids, and osmotic pressure modifiers. This composition addresses the problems of reduced patient compliance and inconvenience of intravenous injection, enabling the delivery of the prescribed dose without drug precipitation, thereby significantly improving the lung deposition rate and ensuring clinical treatment efficacy.

[0010] To achieve the above objectives, the present invention first provides an inhalation formulation comprising peramivir, which is composed of the active ingredient peramivir or a pharmaceutically acceptable salt thereof, a pH adjuster, a buffer, an osmolarity regulator, and water; wherein the pH adjuster is an organic acid.

[0011] According to embodiments of the present invention, in the above-described inhaled formulation, the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, hydrobromide, acetate, methanesulfonate, nitrate, phosphate, maleate, fumarate, tartrate, citrate, succinate, hydroxyethanesulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate, borate, lactate, benzoate, ascorbate, and salicylate.

[0012] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the pH adjuster is selected from at least one of citric acid, oxalic acid, glycine, or arginine.

[0013] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the pH adjuster is citric acid.

[0014] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the amount of the pH adjuster added is 0.2 to 1.5 mg / ml (the pH of the inhalation formulation corresponding to citric acid in this dosage range is 4.5 to 6.0).

[0015] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the amount of pH adjuster added is 0.8 to 1.2 mg / ml.

[0016] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the amount of pH adjuster added is 0.95 to 1.05 mg / ml.

[0017] According to an embodiment of the present invention, in the above-mentioned inhaled formulation, the concentration of peramivir or a pharmaceutically acceptable salt thereof is 5.0 to 25.0 mg / ml.

[0018] According to an embodiment of the present invention, in the above-described inhaled formulation, the concentration of peramivir or a pharmaceutically acceptable salt thereof is 8.0–25.0 mg / ml.

[0019] According to an embodiment of the present invention, in the above-mentioned inhaled formulation, the concentration of peramivir or a pharmaceutically acceptable salt thereof is 8.0–20.0 mg / ml or 16.0–25.0 mg / ml.

[0020] According to an embodiment of the present invention, in the above-mentioned inhaled formulation, the concentration of peramivir or a pharmaceutically acceptable salt thereof is 8.0 mg / ml or 16.0–20.0 mg / ml.

[0021] According to embodiments of the present invention, in the above-described inhaled formulation, the concentration of peramivir or a pharmaceutically acceptable salt thereof is 8.0 mg / ml, 16.0 mg / ml, or 20.0 mg / ml.

[0022] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the buffer is selected from at least one of disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium bicarbonate, potassium bicarbonate, sodium citrate, or potassium citrate.

[0023] According to an embodiment of the present invention, in the above-described inhalation formulation, the buffer is selected from at least one of disodium hydrogen phosphate or dipotassium hydrogen phosphate.

[0024] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the buffer is disodium hydrogen phosphate.

[0025] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the concentration of the buffer is 0.5 to 2.0 mg / ml.

[0026] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the concentration of the buffer is 0.8 to 1.5 mg / ml.

[0027] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the concentration of the buffer is 0.9 to 1.2 mg / ml.

[0028] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the osmotic pressure regulator is selected from at least one of sodium chloride, potassium chloride, magnesium chloride, calcium chloride, glucose, mannitol, sucrose, lactose, boric acid, borax, sorbitol, or glycerol.

[0029] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the osmotic pressure regulator is selected from at least one of sodium chloride, potassium chloride, glucose or mannitol.

[0030] According to an embodiment of the present invention, in the above-described inhalation formulation, the osmotic pressure regulator is selected from at least one of sodium chloride or potassium chloride.

[0031] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the osmotic pressure regulator is sodium chloride.

[0032] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the concentration of the osmotic pressure regulator is 3 to 10 mg / ml.

[0033] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the concentration of the osmotic pressure regulator is 5-8 mg / ml.

[0034] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the concentration of the osmotic pressure regulator is 6.5 to 7.5 mg / ml.

[0035] According to an embodiment of the present invention, the inhalation formulation containing peramivir comprises the active drug peramivir or a pharmaceutically acceptable salt thereof, at a mass concentration of 5.0–25.0 mg / ml; a buffer, disodium hydrogen phosphate or dipotassium hydrogen phosphate, at a mass concentration of 0.5–2.0 mg / ml; an osmolarity regulator, one of sodium chloride, potassium chloride, glucose or mannitol, at a mass concentration of 3–10 mg / ml; a pH regulator, citric acid, at a mass concentration of 0.2–1.5 mg / ml; and an appropriate amount of water; the inhalation formulation containing peramivir does not contain inorganic acids.

[0036] According to an embodiment of the present invention, the inhalation formulation containing peramivir comprises the active drug peramivir or a pharmaceutically acceptable salt thereof, at a mass concentration of 8.0–25.0 mg / ml; a buffer salt, disodium hydrogen phosphate or dipotassium hydrogen phosphate, at a mass concentration of 0.8–1.5 mg / ml; an osmolarity regulator, one of sodium chloride, potassium chloride, glucose or mannitol, at a mass concentration of 5–8 mg / ml; a pH regulator, citric acid, at a mass concentration of 0.8–1.2 mg / ml; and an appropriate amount of water; the inhalation formulation containing peramivir does not contain inorganic acids.

[0037] According to an embodiment of the present invention, the inhaled formulation containing peramivir comprises the active drug peramivir or a pharmaceutically acceptable salt thereof, at a mass concentration of 16.0–25.0 mg / ml; the buffer salt disodium hydrogen phosphate or dipotassium hydrogen phosphate, at a mass concentration of 0.9–1.2 mg / ml; the osmolarity regulator one of sodium chloride, potassium chloride, glucose or mannitol, at a mass concentration of 6.5–7.5 mg / ml; the pH regulator citric acid, at a mass concentration of 0.8–1.2 mg / ml; and an appropriate amount of water; the inhaled formulation containing peramivir does not contain inorganic acids.

[0038] According to an embodiment of the present invention, the inhaled formulation containing peramivir comprises the active drug peramivir or a pharmaceutically acceptable salt thereof, at a mass concentration of 16.0–20.0 mg / ml; the buffer salt disodium hydrogen phosphate or dipotassium hydrogen phosphate, at a mass concentration of 0.9–1.2 mg / ml; the osmolarity regulator one of sodium chloride, potassium chloride, glucose or mannitol, at a mass concentration of 6.5–7.5 mg / ml; the pH regulator citric acid, at a mass concentration of 0.95–1.05 mg / ml; and an appropriate amount of water; the inhaled formulation containing peramivir does not contain inorganic acids.

[0039] Based on the above, the present invention also provides some more specific formulations of the inhaled preparations, as follows:

[0040] Prescription A: Peramivir 5.0 mg / ml, citrate 0.2 mg / ml, anhydrous disodium hydrogen phosphate 0.5 mg / ml, sodium chloride 3.0 mg / ml, water as needed;

[0041] Or prescription B: Peramivir 8.0 mg / ml, citrate 1.0 mg / ml, anhydrous disodium hydrogen phosphate 1.1 mg / ml, sodium chloride 7.0 mg / ml, water as needed;

[0042] Or prescription C: Peramivir 10mg / ml, citrate 0.8mg / ml, anhydrous disodium hydrogen phosphate 1.2mg / ml, sodium chloride 5.0mg / ml, water as needed;

[0043] Or prescription D: Peramivir 16mg / ml, citrate 1.0mg / ml, anhydrous disodium hydrogen phosphate 1.1mg / ml, sodium chloride 7.0mg / ml, water as needed;

[0044] Or prescription E: Peramivir 12mg / ml, citrate 1.2mg / ml, anhydrous disodium hydrogen phosphate 0.9mg / ml, sodium chloride 8.0mg / ml, water as needed;

[0045] Or prescription F: Peramivir 20mg / ml, citrate 1.0mg / ml, anhydrous disodium hydrogen phosphate 1.1mg / ml, sodium chloride 7.0mg / ml, water as needed;

[0046] Or prescription G: Peramivir 14mg / ml, citrate 0.8mg / ml, anhydrous disodium hydrogen phosphate 2.0mg / ml, sodium chloride 9.0mg / ml, water as needed;

[0047] Or prescription H: Peramivir 20mg / ml, citrate 1.0mg / ml, anhydrous disodium hydrogen phosphate 1.5mg / ml, sodium chloride 7.0mg / ml, water as needed.

[0048] In the above-mentioned inhaled preparations, the unit dose of the inhaled preparation is 1 to 10 ml.

[0049] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the unit dose of the inhalation formulation is 2 to 7.5 ml.

[0050] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the unit dose of the inhalation formulation is 2.0 ml, 2.5 ml, 3 ml, 3.5 ml, 4 ml, 4.5 ml, 5 ml, 5.5 ml, 6 ml, 6.5 ml, 7 ml or 7.5 ml.

[0051] According to an embodiment of the present invention, in the above-mentioned inhalation formulation, the median droplet size of the inhalation formulation is 3.5 to 3.8 μm, and the mass percentage of particles with an aerodynamic diameter of less than 5 μm in the droplets is not less than 70%.

[0052] The present invention also provides a method for preparing the above-mentioned inhaled formulation containing peramivir, which includes the following steps: dissolving a pH adjuster and a buffer in water according to the prescription amount, then adding peramivir or a pharmaceutically acceptable salt thereof, dissolving, then adding an osmotic pressure adjuster, dissolving, making up to volume with water, and then filtering and sterilizing to obtain the product.

[0053] According to an embodiment of the present invention, in the above-mentioned method for preparing an inhaled formulation containing peramivir, after dissolving the pH adjuster and buffer in water, the system is heated to 55-95°C, and then peramivir or a pharmaceutically acceptable salt thereof is added. After dissolving, the system is cooled to room temperature, and then an osmotic pressure adjuster is added.

[0054] According to an embodiment of the present invention, in the above-described method for preparing an inhaled formulation containing peramivir, the temperature is heated to 60–85°C.

[0055] According to an embodiment of the present invention, in the above-described method for preparing an inhaled formulation containing peramivir, the temperature is heated to 70–85°C.

[0056] According to an embodiment of the present invention, in the above-described method for preparing an inhaled formulation containing peramivir, the temperature is heated to 80-85°C.

[0057] Based on the above-mentioned inhaled formulation, the present invention also provides a pharmaceutical component comprising an inhaled formulation containing peramivir, the pharmaceutical component comprising the above-mentioned inhaled formulation containing peramivir, and a nebulizer for use in conjunction with the inhaled formulation; the nebulizer is a vibrating screen nebulizer, an ultrasonic nebulizer, or a compressed air nebulizer.

[0058] According to an embodiment of the present invention, in the above-mentioned drug component, the nebulizer is a vibrating screen nebulizer.

[0059] According to an embodiment of the present invention, in the above-mentioned drug component, the aperture of the vibrating screen in the vibrating screen atomizer is 1 to 5 μm, for example 1.7 μm, 2.0 μm, 2.5 μm, 2.8 μm, 3.0 μm, 3.2 μm, 3.5 μm, 4.0 μm, 5.0 μm.

[0060] According to an embodiment of the present invention, in the above-mentioned drug component, the aperture of the vibrating screen in the vibrating screen atomizer is 2 to 4 μm.

[0061] According to an embodiment of the present invention, in the above-mentioned drug component, the aperture of the vibrating screen in the vibrating screen nebulizer is 2.8-3.2 μm. According to an embodiment of the present invention, in the above-mentioned drug component, the number of holes in the central region of the vibrating screen in the vibrating screen nebulizer is 800-2000.

[0062] According to an embodiment of the present invention, in the above-mentioned drug component, the number of holes in the central region of the vibrating screen in the vibrating screen atomizer is 1000 to 1800.

[0063] According to an embodiment of the present invention, in the above-mentioned drug component, the number of holes in the central region of the vibrating screen in the vibrating screen atomizer is 1000, 1100, 1200 or 1400-1800.

[0064] According to an embodiment of the present invention, in the above-mentioned drug component, the number of holes in the central region of the vibrating screen in the vibrating screen atomizer is 1000, 1100, 1200, 1400, 1600 or 1800.

[0065] According to an embodiment of the present invention, in the above-mentioned drug component, the vibration frequency of the vibrating screen nebulizer is 90-180 kHz.

[0066] According to an embodiment of the present invention, in the above-mentioned drug component, the vibration frequency of the vibrating screen nebulizer is 100-130 kHz.

[0067] According to an embodiment of the present invention, in the above-mentioned drug component, the atomization rate of the vibrating screen nebulizer is 0.10 to 0.50 ml / min.

[0068] According to an embodiment of the present invention, in the above-mentioned drug component, the atomization rate of the vibrating screen nebulizer is 0.25 to 0.45 ml / min, such as 0.3 ml / min.

[0069] The present invention also provides the use of the aforementioned inhaled formulation containing peramivir, the inhaled formulation containing peramivir prepared by the aforementioned preparation method, or the pharmaceutical component of the aforementioned inhaled formulation containing peramivir in the preparation of a drug for the prevention and / or treatment of influenza.

[0070] The present invention also provides the aforementioned inhaled formulation containing peramivir for the prevention and / or treatment of influenza, or an inhaled formulation containing peramivir prepared by the aforementioned preparation method.

[0071] The present invention also provides a method for preventing and / or treating influenza, the method comprising administering the inhaled formulation containing peramivir to a subject in need, or preparing an inhaled formulation containing peramivir using the preparation method described herein.

[0072] According to an embodiment of the present invention, the unit dose of the inhaled formulation containing peramivir is 1 to 10 ml.

[0073] According to an embodiment of the invention, the subject in need may be a mammal, such as a human.

[0074] In this invention, the water used is generally water for injection. Beneficial effects

[0075] (1) The inhaled formulation containing peramivir described in this invention shows no significant changes in related substances after being exposed to light and stored at high temperature for one month; and no drug crystallization occurs within 30 minutes during low-temperature ultrasonic nebulization.

[0076] (2) The drug component described in this invention can avoid the irritation of the throat caused by the inhalation of dry powder, and also overcomes the defect that intravenous drugs cannot be directly targeted to the lungs.

[0077] (3) The drug component described in this invention is convenient for patients to use in the preparation of drugs for treating influenza, without the need to go to the hospital and waste time. The drug component is also easy to carry, does not contain the propellant component in dry powder inhalation preparations, and avoids indirect pollution to the environment.

[0078] (4) The inhalation formulation composition of the present invention improves patient compliance, delivers the drug directly to the lungs through the nebulizer, maintains a lung deposition rate of more than 60%, and a throat deposition rate of less than 20%.

[0079] (5) Animal experiments have shown that the inhaled formulation composition and / or pharmaceutical components of the present invention have superior effects in the preparation of drugs for treating influenza. Attached Figure Description

[0080] Figure 1 shows the delivery rate curve of the compressed air nebulizer. The left axis, corresponding to the box legend curve, represents the trend of the amount of drug delivered per minute over time, in units of mg / min. The right axis, corresponding to the triangular legend curve, represents the cumulative total amount of nebulized drug entering the breathing simulator over time (percentage of the injected drug volume %).

[0081] Figure 2 shows the delivery rate curve of the vibrating screen nebulizer. The left axis, corresponding to the box legend curve, represents the trend of the amount of drug delivered per minute over time, in units of mg / min. The right axis, corresponding to the triangular legend curve, represents the cumulative total amount of nebulized drug entering the breathing simulator over time (percentage of the injected drug volume %). Detailed Implementation

[0082] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below. Obviously, the described embodiments are merely exemplary and do not represent all technical solutions of this application. Based on the embodiments of this invention, other technical solutions obtained by those skilled in the art without creative effort are all within the protection scope of this invention.

[0083] Terminology Explanation

[0084] The specific abbreviations used in this invention are as follows: "FPD" is an abbreviation for fine particle dose; "MMAD" is an abbreviation for mass median aerodynamic diameter; "GSD" is an abbreviation for geometric standard deviation; "NGI" is an abbreviation for Next Generation Impactor; and "FPF" refers to Fine Particle Fraction.

[0085] The term "particle size" can refer to a measurement made on a single particle or a distribution of particles. These parameters can be measured using a variety of techniques, including dynamic light scattering, static light scattering, laser diffraction, deposition, time-of-flight, or other methods known to those skilled in the art. Particle size distribution can also be quantified by the size of a distribution (Dx) corresponding to a certain percentage of the total, where a certain percentage (x) of the population is smaller than a defined size. For example, a distribution with a D90 value of 500 nm means that 90% of the distribution (based on volume) has a size smaller than 500 nm.

[0086] Example 1

[0087] Table 1. Prescription for Example 1

[0088] (The units for active pharmaceutical ingredients and excipients are expressed in concentration mg / ml)

[0089] Preparation method (for 200ml):

[0090] (1) Dissolve the prescribed amount of citric acid and anhydrous disodium hydrogen phosphate in an appropriate amount of water for injection;

[0091] (2) Heat the solution in step (1) to 60-95°C, add the prescribed amount of peramivir or its pharmaceutically acceptable salt to it, stir to dissolve, and then cool to room temperature;

[0092] (3) Add the prescribed amount of sodium chloride to the solution in step (2) and stir to dissolve;

[0093] (4) Add water for injection to bring the volume to 200ml, then filter and sterilize.

[0094] (5) The filtered and sterilized solution is then blown, filled, and sealed to obtain the final product.

[0095] Detection method 1: The above preparation was placed at a high temperature of 60°C for 30 days, and the appearance of the preparation was observed at 0, 10 and 30 days respectively, and the content of related substances was determined. The specific results are shown in Table 2.

[0096] Table 2 Stability test data

[0097] Method 2: The preparations corresponding to the above 9 prescriptions were placed under light conditions of 4500±500lx UV 1W / m2, and their related substances were tested at 0 and 14 days respectively. The specific test results are shown in Table 3.

[0098] Table 3. Test results under illumination conditions

[0099] Test method 3: Place the corresponding preparations of the above 9 prescriptions under low temperature conditions of 2-8℃ for ultrasonic atomization, and observe the appearance of the solution within 30 minutes of atomization. The specific test results are shown in Table 4.

[0100] Table 4. Observation results of low-temperature ultrasonic atomization

[0101] As shown in Tables 1-4, Example 1 used the organic acid citric acid as a pH adjuster and anhydrous disodium hydrogen phosphate as a buffer. The levels of related substances in different concentrations of peramivir were low, not exceeding the formulation standards (impurity A ≤ 0.5%, other individual impurities ≤ 0.2%, total impurities ≤ 1.0%). Even at a peramivir concentration as high as 25 mg / ml, the inhaled formulation did not show precipitation at low temperatures, only turbidity. At low and high concentrations of 5–20 mg / ml, the inhaled formulation remained a colorless and clear liquid at low temperatures, solving the problem of drug precipitation at high concentrations of peramivir.

[0102] Test method 4: Formulas 1-9 in Table 1 and control examples were placed under sealed high temperature (60℃) and light (4500lx±500lx) conditions for 0 days, 5 days, 10 days and 30 days respectively to examine the relevant substances. The specific results are detailed in Table 5.

[0103] Control example: Peramivir 20g, citric acid 0.1g, disodium hydrogen phosphate 0.1g, sodium chloride 7g, appropriate amount of 5% hydrochloric acid, and 1000ml of water for injection (after volume adjustment).

[0104] The method for determining the content of related substances was as follows: HPLC: Agilent 1260 Infinity USA; Column: Eclipse Plus C18 (5μm, 4.6×250mm, Agilent, USA); Mobile phase: gradient elution as follows:

[0105] Flow rate 1 mL / min; injection volume 20 μL; detection wavelength 210 nm; column temperature: room temperature.

[0106] Table 5 Results of related substances (%) under different detection methods

[0107] The data in Table 5 show that the peramivir inhalation formulation described in this invention has a significantly more stable advantage compared to the control example.

[0108] Experimental Example 1: Buffered Salt Screening 1 (Peramivir 5 mg / ml, Sodium Chloride 3 mg / ml)

[0109] Table 6 Prescription for Experimental Example 1

[0110] The above-mentioned formulation was prepared according to the preparation method of Example 1.

[0111] Detection method 1: The above preparation was placed at a high temperature of 60°C for 30 days, and the appearance of the preparation was observed at 0, 10 and 30 days respectively, and the content of related substances was determined. The specific results are detailed in Table 7.

[0112] Table 7. Detection results under high temperature conditions

[0113] Method 2: The preparations corresponding to the above 9 prescriptions were placed under light conditions of 4500±500lx UV 1W / m2, and their related substances were tested at 0 and 14 days respectively. The specific test results are shown in Table 8.

[0114] Table 8. Detection results under illumination conditions

[0115] Test method 3: Place the corresponding preparations of the above 9 prescriptions under low temperature conditions of 2-8℃ for ultrasonic atomization, and observe the appearance of the solution within 30 minutes of atomization. The specific test results are shown in Table 9.

[0116] Table 9. Observation results of low-temperature ultrasonic atomization

[0117] Tables 6-9 show that when the peramivir concentration is low (5 mg / ml), no precipitation of the inhaled formulation occurs at low temperatures when hydrochloric acid is used as the pH adjuster in various buffer salt systems. Therefore, further research is needed to investigate the precipitation results of high-concentration peramivir when using hydrochloric acid.

[0118] Experimental Example 2: Buffer Salt Screening Experiment 2 (Peramivir 8 mg / ml, Sodium Chloride 7 mg / ml)

[0119] Table 10 Prescription for Experimental Case 2

[0120] The prescription formulations in Table 10 were prepared according to the preparation method of Example 1.

[0121] Detection method 1: The above preparation was placed at a high temperature of 60°C for 30 days, and the appearance of the preparation was observed at 0, 10 and 30 days respectively, and the content of related substances was determined. The specific results are shown in Table 11.

[0122] Table 11 Detection results under high temperature conditions

[0123] Method 2: The preparations corresponding to the above 9 prescriptions were placed under light conditions of 4500±500lx UV 1W / m2, and their related substances were tested at 0 and 14 days respectively. The specific test results are shown in Table 12.

[0124] Table 12 Results under illumination conditions

[0125] Test method 3: Place the corresponding preparations of the above 9 prescriptions under low temperature conditions of 2-8℃ for ultrasonic atomization, and observe the appearance of the solution within 30 minutes of atomization. The specific test results are shown in Table 13.

[0126] Table 13 Results of Low-Temperature Ultrasonic Atomization

[0127] Tables 10-13 show that when the peramivir concentration is low (8 mg / ml), the related substance levels are lowest in the unbuffered system. Under various buffered systems, using hydrochloric acid as a pH adjuster, the related substance levels of each formulation showed no significant difference and were all below the formulation quality standards (impurity A ≤ 0.5%, other individual impurities ≤ 0.2%, total impurities ≤ 1.0%). No precipitation was observed in the inhaled formulation at low temperatures. Therefore, further research is needed to investigate the precipitation results of high-concentration peramivir when using hydrochloric acid.

[0128] Experimental Example 3: Buffered Salt Screening 3 (Peramivir 16 mg / ml, Sodium Chloride 7 mg / ml)

[0129] Table 14 Prescription for Experimental Case 3

[0130] The prescription formulations in Table 14 were prepared according to the preparation method of Example 1.

[0131] Detection method 1: The above preparation was placed at a high temperature of 60°C for 30 days, and the appearance of the preparation was observed at 0, 10 and 30 days respectively, and the content of related substances was determined. The specific results are detailed in Table 15.

[0132] Table 15 Detection results under high temperature conditions

[0133] Method 2: The preparations corresponding to the above 9 prescriptions were placed under light conditions of 4500±500lx UV 1W / m2, and their related substances were tested at 0 and 14 days respectively. The specific test results are shown in Table 16.

[0134] Table 16 Results under illumination conditions

[0135] Test method 3: Place the corresponding preparations of the above 9 prescriptions under low temperature conditions of 2-8℃ for ultrasonic atomization, and observe the appearance of the solution within 30 minutes of atomization. The specific test results are shown in Table 17.

[0136] Table 17 Results of Low-Temperature Ultrasonic Atomization

[0137] Tables 14-17 show that when the peramivir concentration is high (16 mg / ml), the related substance levels in the system without buffer salts under high temperature conditions are the lowest, followed by low levels in the systems with dipotassium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate. All related substance levels in each formulation are below the formulation quality standards (impurity A ≤ 0.5%, other individual impurities ≤ 0.2%, total impurities ≤ 1.0%). Under light conditions, the related substance levels are low in the systems without buffer salts, with sodium citrate as the buffer, and with potassium bicarbonate as the buffer. In all buffer salt systems, using hydrochloric acid as a pH adjuster, the inhaled formulations cannot maintain a colorless and clear liquid at low temperatures, exhibiting turbidity or precipitation. This indicates that when hydrochloric acid is used, the concentration of peramivir at 16 mg / ml is close to its saturation solubility, leading to drug precipitation, especially in winter, which is more severe. This ultimately reduces the actual amount deposited in the lungs, affecting the accuracy of the dosage and failing to meet clinical treatment needs. Therefore, further optimization of the peramivir inhalation formulation is needed.

[0138] Experimental Example 4: Buffered Salt Screening 4 (Peramivir 20 mg / ml, Sodium Chloride 7 mg / ml)

[0139] Table 18 Prescription for Experimental Case 4

[0140] The prescription formulations in Table 18 were prepared according to the preparation method of Example 1.

[0141] Detection method 1: The above preparation was placed at a high temperature of 60°C for 30 days, and the appearance of the preparation was observed at 0, 10 and 30 days respectively, and the content of related substances was determined. The specific results are shown in Table 19.

[0142] Table 19 Detection results under high temperature conditions

[0143] Method 2: The preparations corresponding to the above 9 prescriptions were placed under light conditions of 4500±500lx UV 1W / m2, and their related substances were tested at 0 and 14 days respectively. The specific test results are shown in Table 20.

[0144] Table 20 Results under illumination conditions

[0145] Test method 3: Place the corresponding preparations of the above 9 prescriptions under low temperature conditions of 2-8℃ for ultrasonic atomization, and observe the appearance of the solution within 30 minutes of atomization. The specific test results are shown in Table 21.

[0146] Table 21 Results of Low-Temperature Ultrasonic Atomization

[0147] Tables 18-21 show that when the peramivir concentration is high (peramivir 20 mg / ml), the related substances level in the system without buffer salts under high temperature conditions is the lowest. The related substances levels in the other buffer salt systems show no significant differences and are all below the formulation quality standards (impurity A ≤ 0.5%, other individual impurities ≤ 0.2%, total impurities ≤ 1.0%). Under light conditions, the related substances levels are lower in the systems without buffer salts, with sodium citrate as the buffer, and with potassium bicarbonate as the buffer. In all buffer salt systems, using hydrochloric acid as a pH adjuster, the inhaled formulations could not maintain a colorless and clear liquid at low temperatures, and precipitation occurred, with the precipitation further exacerbated.

[0148] Experimental Example 5: Buffered Salt Screening 5 (Peramivir 25 mg / ml, Sodium Chloride 9 mg / ml)

[0149] Table 22 Prescription for Experimental Case 5

[0150] The prescription formulations in Table 22 were prepared according to the preparation method of Example 1.

[0151] Detection method 1: The above preparation was placed at a high temperature of 60°C for 30 days, and the appearance of the preparation was observed at 0, 10 and 30 days respectively, and the content of related substances was determined. The specific results are detailed in Table 23.

[0152] Table 23 Detection results under high temperature conditions

[0153] Method 2: The preparations corresponding to the above 9 prescriptions were placed under light conditions of 4500±500lx UV 1W / m2, and their related substances were tested at 0 and 14 days respectively. The specific test results are shown in Table 24.

[0154] Table 24 Results under illumination conditions

[0155] Test method 3: Place the corresponding preparations of the above 9 prescriptions under low temperature conditions of 2-8℃ for ultrasonic atomization, and observe the appearance of the solution within 30 minutes of atomization. The specific test results are shown in Table 25.

[0156] Table 25 Results of Low-Temperature Ultrasonic Atomization

[0157] Tables 22-25 show that when peramivir is at a high concentration (25 mg / ml), the related substances levels are lowest in the system without buffer salts under high temperature conditions. The levels are slightly lower in the buffer systems containing sodium bicarbonate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate. All related substances in each formulation are below the formulation quality standards (impurity A ≤ 0.5%, other individual impurities ≤ 0.2%, total impurities ≤ 1.0%). Under light conditions, the levels of related substances are lower in the systems without buffer salts, with sodium citrate as the buffer, and with potassium bicarbonate as the buffer. In all buffer systems, using hydrochloric acid as a pH adjuster, the inhaled formulations could not maintain a colorless and clear liquid at low temperatures, and precipitation occurred, with the precipitation situation further aggravated.

[0158] The formulations in Examples 1-5 show that the higher the API concentration, the easier it is for crystallization to occur after ultrasonic atomization; the formulations with added bicarbonate crystallize more easily or faster than other formulations; and the content and levels of related substances in these formulations are not significantly different. Therefore, this invention selected the buffer salts sodium citrate, sodium dihydrogen phosphate, and disodium hydrogen phosphate for the investigation of acid-base regulators, mainly to investigate related substances and ultrasonic atomization phenomena.

[0159] Experiment 6: Investigation of Buffers and pH Adjusters (Peramivir 20 mg / ml, Sodium Chloride 7 mg / ml)

[0160] Table 26 Prescription for Experimental Case 6

[0161] Prescription 10: Peramivir 4.0g, sodium citrate 0.2g, hydrochloric acid adjusted to 5.0, sodium chloride 1.4g, water for injection added to 200ml.

[0162] Prescription 11: Peramivir 4.0g, sodium citrate 0.2g, citrate adjusted to 5.0, sodium chloride 1.4g, water for injection added to 200ml.

[0163] The prescription formulations in Table 26 were prepared according to the preparation method of Example 1.

[0164] Detection method 1: The above preparation was placed at a high temperature of 60°C for 30 days, and the appearance of the preparation was observed at 0, 10 and 30 days respectively, and the content of related substances was determined. The specific results are detailed in Table 27.

[0165] Table 27 Detection results under high temperature conditions

[0166] Method 2: The preparations corresponding to the above 9 prescriptions were placed under light conditions of 4500±500lx UV 1W / m2, and their related substances were tested at 0 and 14 days respectively. The specific test results are shown in Table 28.

[0167] Table 28 Results under illumination conditions

[0168] Test method 3: Place the corresponding preparations of the above 9 prescriptions under low temperature conditions of 2-8℃ for ultrasonic atomization, and observe the appearance of the solution within 30 minutes of atomization. The specific test results are shown in Table 29.

[0169] Table 29 Results of Low-Temperature Ultrasonic Atomization

[0170] As shown in Tables 26-29, when organic acids such as citric acid and oxalic acid are used, the precipitation of inhaled formulations is more effectively suppressed compared to the use of inorganic acids such as sulfuric acid and hydrochloric acid. In particular, when citric acid is used, the inhaled formulation remains a colorless and clear liquid at low temperatures. In addition, when disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium citrate are used as buffers, disodium hydrogen phosphate is more effective in suppressing precipitation than sodium dihydrogen phosphate and sodium citrate.

[0171] Experiment 7: Investigation of Buffers and pH Adjusters (Peramivir 25 mg / ml, Sodium Chloride 9 mg / ml)

[0172] Table 30 Prescription for Experimental Case 7

[0173] Prescription 10: Peramivir 5.0g, sodium citrate 0.2g, hydrochloric acid adjusted to 5.0, sodium chloride 1.8g, water for injection added to 200ml.

[0174] Prescription 11: Peramivir 5.0g, sodium citrate 0.2g, citrate adjusted to 5.0g, sodium chloride 1.8g, water for injection added to 200ml.

[0175] The prescription formulations in Table 30 were prepared according to the preparation method of Example 1.

[0176] Detection method 1: The above preparation was placed at a high temperature of 60°C for 30 days, and the appearance of the preparation was observed at 0, 10 and 30 days respectively, and the content of related substances was determined. The specific results are shown in Table 31.

[0177] Table 31 Detection results under high temperature conditions

[0178] Method 2: The preparations corresponding to the above 9 prescriptions were placed under light conditions of 4500±500lx UV 1W / m2, and their related substances were tested at 0 and 14 days respectively. The specific test results are shown in Table 32.

[0179] Table 32 Results under illumination conditions

[0180] Test method 3: Place the corresponding preparations of the above 9 prescriptions under low temperature conditions of 2-8℃ for ultrasonic atomization, and observe the appearance of the solution within 30 minutes of atomization. The specific test results are shown in Table 33.

[0181] Table 33 Results of Low-Temperature Ultrasonic Atomization

[0182] As shown in Tables 30-33, further increasing the peramivir concentration to 25 mg / ml only resulted in turbidity in the inhaled formulation when using a combination of citrate and disodium hydrogen phosphate; other combinations resulted in precipitation. Therefore, for extremely high concentrations of peramivir, it is more appropriate to use citrate as a pH adjuster and disodium hydrogen phosphate as a buffer.

[0183] The results of experiments 6 and 7 show that citric acid, as a pH adjuster, is the most suitable inhaled formulation containing peramivir as described in this invention.

[0184] Experimental Example 8: Comparison of Atomizers Based on Different Principles

[0185] This experiment compared the differences in fine particle dosage, total delivery volume, and delivery rate between a compressed air nebulizer (brand: PARI LC-SPRINT) and a vibrating screen nebulizer (brand: Bukele VM-101).

[0186] Table 34 shows the results of repeating the experiment twice using the same type of atomizer. For example, compressed air atomizer-1 and compressed air atomizer-2 are the results of repeating the experiment twice using the same type of compressed air atomizer.

[0187] Prescription F contains: Peramivir 20 mg / ml, citrate 1.0 mg / ml, anhydrous disodium hydrogen phosphate 1.1 mg / ml, sodium chloride 7.0 mg / ml, and appropriate amount of water.

[0188] Table 34: Comparison of atomization characteristics between atomizers based on two principles

[0189] Note: Atomization time calculation: The atomization time is calculated from the start of atomization until the observation that no more fog is produced.

[0190] The above detection results are based on the method described in the reference, "Determination of Peramivir Content and Related Substances by HPLC", Journal of Pharmaceutical and Clinical Research, 2013, Apr, 21(2).

[0191] The results in Table 34 show that, in terms of atomization time, the compressed air atomizer stopped producing mist after 3 minutes of atomization, and the vibrating screen atomizer stopped producing mist after 7 minutes of atomization.

[0192] In terms of drug residue levels in the devices, the residual drug level in compressed air nebulizers reached 24.52-24.92 mg, accounting for 61.3-62.3% of the total drug solution dispensed; and in vibrating screen nebulizers, after no longer producing mist as observed by the naked eye, the residual drug level reached 4.95-6.57 mg, accounting for 12.4-16.4% of the total drug solution dispensed.

[0193] Analysis of data on atomization time and drug residue shows that the longer atomization time of the vibrating screen atomizer is mainly due to more thorough atomization and less residue.

[0194] In terms of fine particle dosage, compressed air nebulizers deliver 8.95-9.31 mg of fine particles, while vibrating screen nebulizers deliver 22.98-26.35 mg. This is related to the difference in the atomization principles of the two types of nebulizers; vibrating screen nebulizers more easily convert liquid medication into fine particles.

[0195] Analysis of drug residue data shows that the vibrating screen nebulizer has a higher dose of fine particles, which is also related to the lower amount of residue after atomization.

[0196] In terms of median particle size, the median particle size of compressed air atomizers is larger than that of vibrating screen atomizers.

[0197] The delivery rate and total delivery volume of the two nebulizers were validated using prescription F (2.5 ml, containing 50 mg peramivir) and the rate change trend curves are shown in Figure 1 and Figure 2.

[0198] According to Figures 1 and 2, the nebulization rate of the compressed air nebulizer shows a clear trend of high initial rate followed by a decrease. The rate starts quickly, then drops rapidly after three minutes. From the fifth minute onwards, only a small amount of aerosol is generated, and extending the nebulization time does not significantly increase the total delivery volume. The cumulative nebulized volume shows an initial rapid increase followed by an inflection point and a slow growth rate. Ultimately, only 35% of the administered drug dose enters the breathing simulator. The vibrating screen nebulizer has an initial nebulization rate comparable to the compressed air nebulizer, and its rate remains relatively stable with the nebulization time until complete. The total nebulized volume entering the breathing simulator is uniformly distributed in a nearly linear manner, and ultimately, 72% of the administered drug dose enters the breathing simulator.

[0199] According to Figures 1 and 2, the delivery rate of the vibrating screen atomizer is stable, the total delivery amount accounts for a higher proportion of the administered dose, and the residual amount and the proportion of the dose dispersed into the air are also lower.

[0200] Experimental Example 9: Investigation of Atomizing Plate Parameters in a Vibrating Screen Atomizer

[0201] The purpose of this experiment is to investigate the parameters of the atomizing plate in the vibrating screen atomizer. Formula F (2ml: 40mg) was used for atomization, and the influence of the atomizing plate parameters (number of holes and hole diameter) on the atomization effect was observed. The specific results are shown in Table 35.

[0202] Table 35: Results of the investigation on the pore size and number of pores of the atomizing plate

[0203] Note: Due to limitations in the precision and drilling area of ​​laser drilling equipment, the minimum diameter range for examining holes is 1.7µm, and the maximum is 5.0µm; the maximum number of holes that can be examined is 2000. The aperture diameter mentioned is the average aperture diameter on a single atomizing sheet, calculated statistically using an optical testing instrument.

[0204] As shown in Table 35, both pore size and pore number affect the nebulization time; the larger the pore size and the more pores, the faster the nebulization rate. The pore size of the selected nebulizer also has a significant impact on the particle size, while the number of pores has a smaller impact. Based on the formulation specifications and patient compliance, the nebulization rate was considered to be controlled at around 0.3 ml / min. Therefore, the adjacent parameters of the 3.0 μm 1600-pore nebulizer were further investigated. When the pore size was in the range of 2.8-3.2 μm and the number of pores was in the range of 1100, 1200, 1400, 1600, and 1800, the nebulization rate and nebulized particle size were relatively stable, and there was a certain range of optimal pore size and number of pores to choose from.

[0205] Experimental Example 10: Investigation of the Effect of Different Drug Concentrations on Nebulization Characteristics

[0206] The purpose of this experiment is to investigate the effect of different drug concentrations on nebulization characteristics. The specific formulation is as follows:

[0207] Prescription C: Peramivir 10mg / ml, citrate 0.8mg / ml, anhydrous disodium hydrogen phosphate 1.2mg / ml, sodium chloride 5.0mg / ml, water as needed;

[0208] Prescription D: Peramivir 16mg / ml, citrate 1.0mg / ml, anhydrous disodium hydrogen phosphate 1.1mg / ml, sodium chloride 7.0mg / ml, water as needed;

[0209] Prescription E: Peramivir 12mg / ml, citrate 1.2mg / ml, anhydrous disodium hydrogen phosphate 0.9mg / ml, sodium chloride 8.0mg / ml, water as needed;

[0210] Prescription F: Peramivir 20mg / ml, citrate 1.0mg / ml, anhydrous disodium hydrogen phosphate 1.1mg / ml, sodium chloride 7.0mg / ml, water as needed;

[0211] Prescription G: Peramivir 14mg / ml, citrate 0.8mg / ml, anhydrous disodium hydrogen phosphate 2.0mg / ml, sodium chloride 9.0mg / ml, water as needed.

[0212] The results of the investigation are shown in Table 36.

[0213] Table 36: Effects of Different Drug Concentrations on Nebulization Characteristics

[0214] Note: The above detection results refer to the method in the reference "Determination of Peramivir Content and Related Substances by HPLC", Journal of Pharmaceutical and Clinical Research, 2013, Apr, 21(2).

[0215] Table 36 shows that the drug residue levels are low for formulations with different API concentrations. The FPD increases almost proportionally with increasing concentration, and the FPF data are also comparable, with little difference in median particle size. The aerodynamic characteristics at different drug concentrations are quite similar, indicating that under the current formulation composition, atomization characteristics are not easily affected by API concentration.

[0216] The exemplary embodiments of the present invention have been described above. However, the scope of protection of this application is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. An inhaled formulation containing peramivir, characterized in that: The inhaled formulation comprises the active ingredient peramivir or a pharmaceutically acceptable salt thereof, a pH adjuster, a buffer, an osmolarity regulator, and water; wherein the pH adjuster is an organic acid.

2. The inhaled formulation containing peramivir according to claim 1, characterized in that: At least one of the following must be met: The pH adjuster is selected from at least one of citric acid, oxalic acid, glycine, or arginine; preferably, the pH adjuster is citric acid. The pH adjuster is added at a concentration of 0.2–1.5 mg / ml; preferably 0.8–1.2 mg / ml; more preferably 0.95–1.05 mg / ml. Furthermore, the concentration of the peramivir or its pharmaceutically acceptable salt is 5.0–25.0 mg / ml; preferably 8.0–25.0 mg / ml; more preferably 8.0–20.0 mg / ml or 16.0–25.0 mg / ml; even more preferably 8.0 mg / ml or 16.0–20.0 mg / ml; most preferably 8.0 mg / ml, 16.0 mg / ml or 20.0 mg / ml. Further, the buffer is selected from at least one of disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium bicarbonate, potassium bicarbonate, sodium citrate, or potassium citrate; preferably, the buffer is selected from at least one of disodium hydrogen phosphate or dipotassium hydrogen phosphate; more preferably, the buffer is disodium hydrogen phosphate. Furthermore, the concentration of the buffer is 0.5–2.0 mg / ml; preferably 0.8–1.5 mg / ml; more preferably 0.9–1.2 mg / ml; Further, the osmotic pressure regulator is selected from at least one of sodium chloride, potassium chloride, magnesium chloride, calcium chloride, glucose, mannitol, sucrose, lactose, boric acid, borax, sorbitol, or glycerol; preferably, the osmotic pressure regulator is selected from at least one of sodium chloride, potassium chloride, glucose, or mannitol; more preferably, the osmotic pressure regulator is selected from at least one of sodium chloride or potassium chloride; most preferably, the osmotic pressure regulator is sodium chloride. Furthermore, the concentration of the osmotic pressure regulator is 3–10 mg / ml; preferably 5–8 mg / ml; more preferably 6.5–7.5 mg / ml.

3. The inhaled formulation containing peramivir according to claim 1, characterized in that: The formulation of the inhaled preparation is as follows: Prescription A: Peramivir 5.0 mg / ml, citrate 0.2 mg / ml, anhydrous disodium hydrogen phosphate 0.5 mg / ml, sodium chloride 3.0 mg / ml, water as needed; Or prescription B: Peramivir 8.0 mg / ml, citrate 1.0 mg / ml, anhydrous disodium hydrogen phosphate 1.1 mg / ml, sodium chloride 7.0 mg / ml, water as needed; Or prescription C: Peramivir 10mg / ml, citrate 0.8mg / ml, anhydrous disodium hydrogen phosphate 1.2mg / ml, sodium chloride 5.0mg / ml, water as needed; Or prescription D: Peramivir 16mg / ml, citrate 1.0mg / ml, anhydrous disodium hydrogen phosphate 1.1mg / ml, sodium chloride 7.0mg / ml, water as needed; Or prescription E: Peramivir 12mg / ml, citrate 1.2mg / ml, anhydrous disodium hydrogen phosphate 0.9mg / ml, sodium chloride 8.0mg / ml, water as needed; Or prescription F: Peramivir 20mg / ml, citrate 1.0mg / ml, anhydrous disodium hydrogen phosphate 1.1mg / ml, sodium chloride 7.0mg / ml, water as needed; Or prescription G: Peramivir 14mg / ml, citrate 0.8mg / ml, anhydrous disodium hydrogen phosphate 2.0mg / ml, sodium chloride 9.0mg / ml, water as needed; Or prescription H: Peramivir 20mg / ml, citrate 1.0mg / ml, anhydrous disodium hydrogen phosphate 1.5mg / ml, sodium chloride 7.0mg / ml, water as needed.

4. The inhaled formulation containing peramivir according to claim 1, characterized in that: The unit dose of the inhaled preparation is 1 to 10 ml; preferably 2 to 7.5 ml; more preferably 2.0 ml, 2.5 ml, 3 ml, 3.5 ml, 4 ml, 4.5 ml, 5 ml, 5.5 ml, 6 ml, 6.5 ml, 7 ml or 7.5 ml.

5. The inhaled formulation containing peramivir according to any one of claims 1 to 4, characterized in that: The median droplet size of the inhaled formulation is 3.5–3.8 μm, and the mass percentage of particles with an aerodynamic diameter of less than 5 μm in the droplets is not less than 70%.

6. The method for preparing an inhaled formulation containing peramivir according to any one of claims 1 to 5, characterized in that: Includes the following steps: According to the prescription dosage, first dissolve the pH adjuster and buffer in water, then add peramivir or its pharmaceutically acceptable salt, dissolve, then add the osmotic pressure adjuster, dissolve, bring to volume with water, filter and sterilize to obtain the final product.

7. The method for preparing an inhaled formulation containing peramivir according to claim 6, characterized in that: After dissolving the pH adjuster and buffer in water, the system is heated to 55–95°C, and then peramivir or its pharmaceutically acceptable salt is added. After dissolving, the system is cooled to room temperature, and then the osmotic pressure adjuster is added. Preferably, the system is heated to 60–85°C; more preferably, to 70–85°C; and most preferably, to 80–85°C.

8. A pharmaceutical component comprising an inhaled formulation of peramivir, characterized in that: The drug component comprises an inhaled formulation containing peramivir as described in any one of claims 1 to 5, and a nebulizer for use in conjunction with the inhaled formulation; the nebulizer is a vibrating screen nebulizer, an ultrasonic nebulizer, or a compressed air nebulizer.

9. The pharmaceutical component comprising an inhaled formulation of peramivir according to claim 8, characterized in that: At least one of the following must be met: The atomizer is a vibrating screen atomizer; The aperture of the vibrating screen in the vibrating screen atomizer is 1-5 μm; preferably 2-4 μm, more preferably 2.8-3.2 μm; The number of holes in the central region of the vibrating screen atomizer is 800-2000; preferably 1000-1800; more preferably 1000, 1100, 1200 or 1400-1800; most preferably 1000, 1100, 1200, 1400, 1600 or 1800. The vibration frequency of the vibrating screen atomizer is 90-180KHz, more preferably 100-130KHz; The atomization rate of the vibrating screen atomizer is 0.10 to 0.50 ml / min, preferably 0.25 to 0.45 ml / min.

10. The use of the pharmaceutical component of the inhaled formulation containing peramivir according to any one of claims 1 to 5, the inhaled formulation containing peramivir prepared by the preparation method according to any one of claims 6 to 7, or the inhaled formulation containing peramivir according to any one of claims 8 to 9 in the preparation of a medicine for the prevention and / or treatment of influenza.

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