Anti-influenza virus pharmaceutical preparation

Abstract

The present disclosure provides a pharmaceutical preparation, which comprises the following preparation raw materials: an active ingredient selected from one of peramivir, zanamivir, lanimivir and a hydrate or solvate thereof; the carboxylic acid anion donor is selected from at least one of pamoic acid and hydroxynaphthoic acid; and a first pH adjusting agent, which is an alkaline pH adjusting agent.

Description

Technical Field

[0001] The present application relates to the field of drugs, and more specifically, to an anti-influenza virus pharmaceutical preparation, a preparation method thereof, and the use of the anti-influenza virus pharmaceutical preparation in the preparation of a drug for preventing or treating diseases caused by influenza virus. Background Art

[0002] Peramivir ((1S,2S,3R,4R)-3-[(1S)-1-(acetylamino)-2-ethylbutyl]-4-formamidinium-2-hydroxycyclopentanecarboxylic acid) is a neuraminidase inhibitor. Like oseltamivir and zanamivir, peramivir can bind to the active site of influenza virus neuraminidase to prevent virus transmission. Compared with oseltamivir and zanamivir, peramivir exhibits unique in vitro anti-drug resistance, and some virus variants resistant to oseltamivir and zanamivir are also sensitive to peramivir.

[0004] Peramivir is used for the prevention and treatment of influenza A or B virus infection; the specifications of the peramivir injection approved by the US FDA for marketing are 200 mg / 20 ml (10 mg / ml), and the specifications approved by Japan for marketing are 300 mg / 60 ml (5 mg / ml) and 150 mg / 15 ml (10 mg / ml). The specifications approved by China for marketing are 300 mg / 100 ml (3 mg / ml) and 150 mg / 100 ml (1.5 mg / ml).

[0005] Due to the large polarity of peramivir and its low oral bioavailability, the currently marketed peramivir only has intravenous administration preparations, and the administration route is relatively single, which is difficult to meet the increasingly severe clinical needs. Moreover, peramivir has extremely low solubility, and the highest concentration of the currently clinically used peramivir injection is only 10 mg / ml; at a clinical use dose of 600 mg, the liquid volume of at least 60 ml limits the development, administration method and clinical use of peramivir preparations. Summary of the Invention

[0006] In a first aspect, the present application provides a pharmaceutical preparation, and its formulation raw materials include:

[0007] An active ingredient selected from one of peramivir, zanamivir, laninamivir and their hydrates or solvates;

[0008] A carboxylic acid anion donor selected from at least one of pamoic acid and naphthoic acid; and

[0009] A first pH regulator, which is a basic pH regulator.

[0010] In some embodiments, the hydroxynaphthoic acid is selected from one or more of 2-hydroxy-1-naphthoic acid, 3-hydroxy-1-naphthoic acid, 4-hydroxy-1-naphthoic acid, 5-hydroxy-1-naphthoic acid, 6-hydroxy-1-naphthoic acid, 1-hydroxy-2-naphthoic acid, 2-hydroxy-3-naphthoic acid, and 8-hydroxy-2-naphthoic acid; optionally, the hydroxynaphthoic acid is 2-hydroxy-3-naphthoic acid.

[0011] In some embodiments, the first pH regulator is selected from one or more of sodium hydroxide, potassium hydroxide, diethylamine, triethylamine, ethylenediamine, sodium bicarbonate, sodium carbonate, tromethamine, and meglumine.

[0012] In some embodiments, the molar ratio of the active ingredient to the carboxyl group in the carboxylic acid anion donor is 1:0.5 - 3, or 1:0.7 - 2.

[0013] In some embodiments, the formulation raw materials further comprise a cation donor;

[0014] Optionally, the cation donor is selected from one or more of inorganic salts of magnesium ions, calcium ions, zinc ions, potassium ions, and sodium ions, tromethamine, meglumine, and ethylenediamine; or, the cation donor is selected from one or more of magnesium chloride, magnesium sulfate, calcium chloride, and zinc chloride, and the cation donor is the same as or different from the first pH regulator.

[0015] In some embodiments, the molar ratio of the active ingredient: the carboxyl group in the carboxylate anion donor: the cation in the cation donor is 1:0.5 - 3:0 - 5, or 1:0.7 - 2:0.2 - 2.

[0016] In some embodiments, the formulation raw materials comprise:

[0017] An active ingredient selected from one of peramivir, zanamivir, laninamivir, and their hydrates or solvates;

[0018] A carboxylate anion donor selected from one or more of 2-hydroxy-3-naphthoic acid, 1-hydroxy-2-naphthoic acid, and ditanate;

[0019] A first pH regulator selected from one or more of sodium hydroxide, potassium hydroxide, diethylamine, ethylenediamine, triethylamine, sodium bicarbonate, sodium carbonate, tromethamine, and meglumine; and

[0020] An optional cation donor selected from one or more of magnesium chloride, magnesium sulfate, calcium chloride, and zinc chloride.

[0021] In some embodiments, the formulated raw materials further contain a second pH regulator, and the second pH regulator is selected from one or more of sodium hydroxide, potassium hydroxide, diethylamine, triethylamine, ethylenediamine, sodium bicarbonate, sodium carbonate, tromethamine, meglumine, hydrochloric acid, sodium citrate, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, and phosphoric acid.

[0022] In some embodiments, the pharmaceutical preparation is an aqueous pharmaceutical preparation or a freeze-dried pharmaceutical preparation. Optionally, the aqueous pharmaceutical preparation is an inhalation liquid preparation, an injection aqueous solution, a spray, or an aerosol; optionally, the aqueous pharmaceutical preparation is an oral atomization inhalation preparation.

[0023] In some embodiments, the pharmaceutical preparation is an aqueous pharmaceutical preparation, wherein the concentration of the active ingredient reaches 100 mg / ml, and optionally the concentration of the active ingredient is 20 mg / ml to 100 mg / ml; or the pharmaceutical preparation is a freeze-dried pharmaceutical preparation, and in the aqueous solution formed by reconstituting the freeze-dried pharmaceutical preparation with water, the concentration of the active ingredient reaches 100 mg / ml, and optionally the concentration of the active ingredient is 20 mg / ml to 100 mg / ml.

[0024] In some embodiments, the pH value of the aqueous pharmaceutical preparation or the aqueous solution formed by reconstituting the freeze-dried pharmaceutical preparation with water is 5.5 - 8.5 or 6.5 - 8.0.

[0025] In some embodiments, the pharmaceutical preparation is a freeze-dried pharmaceutical preparation, and the freeze-dried pharmaceutical preparation contains a freeze-dried excipient; optionally, the freeze-dried excipient is selected from one or more of sodium chloride, glucose, glycine, cysteine, and lysine; or the freeze-dried excipient is selected from one of sodium chloride, glucose, and glycine; optionally, the freeze-dried pharmaceutical preparation contains 0 wt% to 5 wt% of the freeze-dried excipient.

[0026] In some embodiments, the administration route of the pharmaceutical preparation is selected from intravenous administration, oral atomization inhalation, nasal administration, subcutaneous administration, intradermal administration, and intramuscular administration, or is oral atomization inhalation.

[0027] In a second aspect, the present application provides a preparation method of the pharmaceutical preparation described in the first aspect, comprising the following steps:

[0028] (1) Dissolve the carboxyl anion donor and the basic pH regulator in water; and

[0029] (2) Add the active ingredient to the aqueous solution obtained in step (1).

[0030] In some embodiments, the preparation method further includes: (3) After adding the active ingredient, add the cation donor.

[0031] In some embodiments, the preparation method further comprises: using a second pH regulator to adjust the pH value of the aqueous solution obtained in step (1) to above 7 or 7-9, and / or adjusting the pH value of the aqueous solution obtained in step (2) to 5.5-8.5 or 6.5-8.0, wherein the second pH regulator is selected from one or more of sodium hydroxide, potassium hydroxide, diethylamine, triethylamine, ethylenediamine, sodium bicarbonate, sodium carbonate, tromethamine and meglumine, hydrochloric acid, sodium citrate, citric acid, sodium dihydrogen phosphate and phosphoric acid.

[0032] In some embodiments, the preparation method further comprises: subjecting the aqueous solution obtained in step (2) to aseptic filling and / or freeze-drying to obtain a freeze-dried pharmaceutical preparation.

[0033] In a third aspect, the present application provides the use of the pharmaceutical preparation described in the first aspect in the preparation of a drug for preventing or treating diseases caused by influenza virus, for example, the disease is an acute respiratory infectious disease caused by influenza A or B virus. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The embodiments illustrated herein are further described below with reference to the accompanying drawings, but the accompanying drawings are only for enabling those skilled in the art to better understand the present application and are not intended to limit the scope of the present application.

[0035] Figure 1 Shows the drug plasma concentration-time curves of peramivir inhalation solution prepared according to Prescription 5 of Example 1 and peramivir injection in the plasma of SD rats.

[0036] Figure 2 Shows the drug concentration-time curves of peramivir inhalation solution prepared according to Prescription 5 of Example 1 and peramivir injection in the lung tissue of SD rats.

[0037] Figure 3 Shows the drug concentration-time curves of peramivir inhalation solution prepared according to Prescription 5 of Example 1 in the plasma and lung tissue of SD rats.

[0038] Figure 4 Shows the drug concentration-time curves of peramivir injection prepared according to Prescription 5 of Example 1 in the plasma and lung tissue of SD rats. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0039] In the following, the inventive concept of the present application will be further elaborated based on specific embodiments. However, the specific embodiments listed are for illustrative purposes only and are not intended to limit the scope of the present application. Those skilled in the art will recognize that the specific features in any of the following embodiments can be used in any other embodiment as long as they do not deviate from the inventive concept described herein.

[0040] Unless otherwise specified, all numbers representing feature sizes, quantities, and physical and chemical properties used in this specification and claims should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise stated, the numerical parameters listed in the above specification and the appended claims are approximate values, and those skilled in the art can appropriately change these approximate values in seeking to obtain the required characteristics using the teachings disclosed herein. The use of numerical ranges expressed with endpoints includes all numbers within that range and any range within that range. For example, 1 to 5 includes 1, 1.1, 1.3, 1.5, 2, 2.75, 3, 3.80, 4, and 5, etc.

[0041] Peramivir, zanamivir, and laninamivir are zwitterions, and salt bridges are formed between the carboxyl groups and guanidine groups between molecules, making it easy to aggregate into unit cells and not easily soluble.

[0042]

[0043]

[0044] The injection dose of peramivir used clinically is 600 mg. According to the above-mentioned human tissue migration data, 3-9% of the AUC migrates into the upper respiratory tract fluid. If an inhalation preparation is developed, the dose may only need to be 10% of the injection dose, that is, the inhalation dose is 60 mg. The atomization delivery rate is generally about 25%, and the volume of the inhalation preparation is generally about 2 ml. It is known that the solubility of peramivir is relatively low (the solubility at pH 1.0 is about 59 mg / ml, and the solubility at pH ≥ 5 is ≤ 20 mg / ml). The existing solubility of peramivir cannot meet the requirements for preparing an inhalation preparation. The dosing volume limits the development, dosing method, and clinical use of peramivir preparations; conventional solubilization techniques (such as adding organic solvents, surfactants, etc.) cannot solubilize peramivir.

[0045] Without being bound by theory, the pharmaceutical preparation in the present application contains a carboxyl anion donor (for example, pamoic acid or naphthoic acid), and its carboxyl group preferentially acts on the guanidine group on the peramivir molecule, thereby preventing the polymerization between peramivir molecules and greatly improving the solubility of peramivir. The pharmaceutical preparation in the present application may also contain a cation donor, which acts on the carboxyl group on the peramivir molecule, can further improve the solubility of peramivir, and improve the stability of the composition.

[0046] On the one hand, the present application provides a pharmaceutical preparation, the formulation raw materials of which include: an active ingredient selected from one of peramivir, zanamivir, laninamivir and their hydrates or solvates; a carboxyl anion donor selected from one or more of pamoic acid and naphthol carboxylic acid; and a first pH regulator, which is a basic pH regulator.

[0047] In some embodiments, the naphthol carboxylic acid is selected from one or more of 2-hydroxy-1-naphthoic acid, 3-hydroxy-1-naphthoic acid, 4-hydroxy-1-naphthoic acid, 5-hydroxy-1-naphthoic acid, 6-hydroxy-1-naphthoic acid, 1-hydroxy-2-naphthoic acid, 2-hydroxy-3-naphthoic acid and 8-hydroxy-2-naphthoic acid. In some embodiments, 2-hydroxy-3-naphthoic acid is used to provide a carboxyl anion. In some embodiments, pamoic acid is used to provide a carboxyl anion.

[0048] In some embodiments, the first pH regulator is selected from one or more of sodium hydroxide, potassium hydroxide, diethylamine, triethylamine, ethylenediamine, sodium bicarbonate, sodium carbonate, tromethamine and meglumine. For example, the first pH regulator is selected from one or more of sodium hydroxide, tromethamine and meglumine.

[0049] In some embodiments, pamoic acid and naphthol carboxylic acid are insoluble in water. Adding the first pH regulator makes them into pamoate and naphthol carboxylate, and the pH is adjusted to visually clear, and the measured pH value is 7-9.

[0050] In some embodiments, the pharmaceutical preparation of the present application is prepared from the formulation raw materials of the present application, namely the active ingredient, the carboxyl anion donor and the first pH regulator in water. In some embodiments, the molar ratio of the active ingredient to the carboxyl group in the carboxyl anion donor is 1:0.5-3, optionally 1:0.7-2. The proportion of the hydroxy naphthoic acid anion will affect the solubility and stability of the product. When the content of the hydroxy naphthoic acid anion is too low, the reconstituted pharmaceutical preparation cannot be clarified or the clarification time maintained is short. When the added content of the hydroxy naphthoic acid anion is too high, a large amount of base will be added to dissolve the hydroxy naphthoic acid, and the final product will be adjusted back to the physiological pH value with acid. At this time, the osmotic pressure of the final product is relatively high, and it is necessary to ensure that it is within the physiological range.

[0051] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application further include a cation donor. In some embodiments, the cation donor is selected from one or more of inorganic salts containing magnesium ions, calcium ions, zinc ions, potassium ions or sodium ions, tromethamine, meglumine and ethylenediamine. In some embodiments, the cation donor is selected from one or more of magnesium chloride, magnesium sulfate, calcium chloride, tromethamine and meglumine. In some embodiments, the cation donor is tromethamine. Since tromethamine can form hydrogen bonds with peramivir and may have a certain chelating effect, tromethamine has a better effect on increasing the stability of the sample.

[0052] In some embodiments, the first pH regulator, such as tromethamine and meglumine, also has the function of a cation ligand. Therefore, the raw material of the cation donor used can be the same as or different from the raw material of the first pH regulator.

[0053] By measuring the submicrostructure of the embodiments of the present application by dynamic light scattering, it can be observed that the aqueous solution sample of the embodiments of the present application or the sample after freeze-drying and reconstitution is a nanoaggregate structure. By adding the selected cation, the particle size can be controlled within a few nanometers (0.5 - 10 nm), while without adding a cation, the particle size is dozens to hundreds of nanometers (20 - 200 nm). The larger the particle size after freeze-drying and reconstitution, the greater the possibility of aggregation and the less stable the sample. The addition of a cation can further enhance the solubility stability of the active ingredient in the prepared aqueous solution or in the aqueous solution after freeze-drying and reconstitution.

[0054] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application include: an active ingredient selected from one of peramivir, zanamivir, laninamivir and their hydrates or solvates; a carboxyl anion donor selected from one or more of pamoic acid and naphthol carboxylic acid; a first pH regulator; and a cation donor, wherein the molar ratio of the active ingredient: the carboxyl group in the carboxyl anion donor: the cation in the cation donor is 1:0.5 - 3:0 - 5. In some embodiments, the molar ratio of the active ingredient: the carboxyl group in the carboxyl anion donor: the cation in the cation donor is 1:0.7 - 2:0.2 - 2.

[0055] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application include: an active ingredient selected from one of peramivir, zanamivir, laninamivir and their hydrates or solvates; a carboxyl anion donor selected from one or more of 2-hydroxy-3-naphthoic acid, 1-hydroxy-2-naphthoic acid and pamoic acid; a first pH regulator selected from one or more of sodium hydroxide, potassium hydroxide, diethylamine, ethylenediamine, triethylamine, sodium bicarbonate, sodium carbonate, tromethamine and meglumine; and an optional cation donor selected from one or more of magnesium chloride, magnesium sulfate, calcium chloride and zinc chloride.

[0056] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application include: an active ingredient selected from one of peramivir, zanamivir, laninamivir, and their hydrates or solvates; a carboxyl anion donor selected from one or more of 2-hydroxy-3-naphthoic acid, 1-hydroxy-2-naphthoic acid, and pamoic acid; a first pH regulator selected from one or more of tromethamine, meglumine, and sodium hydroxide; and an optional cation donor selected from one or more of magnesium chloride, magnesium sulfate, calcium chloride, and zinc chloride.

[0057] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application include: peramivir trihydrate; 2-hydroxy-3-naphthoic acid, 1-hydroxy-2-naphthoic acid, or pamoic acid; tromethamine; and magnesium sulfate.

[0058] As an embodiment, the formulation raw materials of the pharmaceutical preparation of the present application include: peramivir trihydrate; 2-hydroxy-3-naphthoic acid; tromethamine; and magnesium sulfate; optionally, the dosage ratio of peramivir trihydrate: 2-hydroxy-3-naphthoic acid: tromethamine: magnesium sulfate is 69.9 mg: 34.4 - 86 mg: 38.1 mg: 4.8 mg; optionally, the pharmaceutical preparation is an aqueous solution, wherein the concentration of peramivir is 60 mg / ml.

[0059] As an embodiment, the formulation raw materials of the pharmaceutical preparation of the present application include: peramivir trihydrate; 1-hydroxy-2-naphthoic acid; tromethamine; and magnesium sulfate; optionally, the dosage ratio of peramivir trihydrate: 1-hydroxy-2-naphthoic acid: tromethamine: magnesium sulfate is 69.9 mg: 68.8 mg: 38.1 mg: 4.8 mg; optionally, the pharmaceutical preparation is an aqueous solution, wherein the concentration of peramivir is 60 mg / ml.

[0060] As an embodiment, the formulation raw materials of the pharmaceutical preparation of the present application include: peramivir trihydrate; pamoic acid; tromethamine; and magnesium sulfate; optionally, the dosage ratio of peramivir trihydrate: pamoic acid: tromethamine: magnesium sulfate is 69.9 mg: 56.8 - 142 mg: 38.1 mg: 4.8 mg; optionally, the pharmaceutical preparation is an aqueous solution, wherein the concentration of peramivir is 60 mg / ml.

[0061] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application include: peramivir trihydrate; pamoic acid; and meglumine; optionally, the dosage ratio of peramivir trihydrate: pamoic acid: meglumine is 69.9 mg: 63.9 mg: 17.9 mg; optionally, the pharmaceutical preparation is an aqueous solution, wherein the concentration of peramivir is 60 mg / ml.

[0062] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application include: peramivir trihydrate; pamoic acid; meglumine; and magnesium sulfate, magnesium chloride, zinc chloride or anhydrous calcium chloride.

[0063] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application include: peramivir trihydrate; pamoic acid; meglumine; and magnesium sulfate; optionally, the dosage ratio of peramivir trihydrate:pamoic acid:meglumine:magnesium sulfate is 69.9 mg:63.9 mg:17.9 mg:4.8 - 9.6 mg; optionally, the pharmaceutical preparation is an aqueous solution, wherein the concentration of peramivir is 60 mg / ml.

[0064] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application include: peramivir trihydrate; pamoic acid; meglumine; and magnesium chloride; optionally, the dosage ratio of peramivir trihydrate:pamoic acid:meglumine:magnesium chloride is 69.9 mg:63.9 mg:17.9 mg:5 - 10 mg; optionally, the pharmaceutical preparation is an aqueous solution, wherein the concentration of peramivir is 60 mg / ml.

[0065] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application include: peramivir trihydrate; pamoic acid; meglumine; and zinc chloride; optionally, the dosage ratio of peramivir trihydrate:pamoic acid:meglumine:zinc chloride is 69.9 mg:63.9 mg:17.9 mg:5.8 mg; optionally, the pharmaceutical preparation is an aqueous solution, wherein the concentration of peramivir is 60 mg / ml.

[0066] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application include: peramivir trihydrate; pamoic acid; meglumine; and anhydrous calcium chloride; optionally, the dosage ratio of peramivir trihydrate:pamoic acid:meglumine:anhydrous calcium chloride is 69.9 mg:63.9 mg:17.9 mg:1.1 mg; optionally, the pharmaceutical preparation is an aqueous solution, wherein the concentration of peramivir is 60 mg / ml.

[0067] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application include: peramivir trihydrate, zanamivir or laninamivir; pamoic acid; sodium hydroxide; and magnesium sulfate.

[0068] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application include: peramivir trihydrate; pamoic acid; sodium hydroxide; and magnesium sulfate; optionally, the dosage ratio of peramivir trihydrate:pamoic acid:sodium hydroxide:magnesium sulfate is 46.6 - 116.5 mg:63.9 - 95.9 mg:14.6 mg:4 mg; optionally, the pharmaceutical preparation is an aqueous solution, wherein the concentration of peramivir is 40 - 100 mg / ml.

[0069] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application include: zanamivir; pamoic acid; sodium hydroxide; and magnesium sulfate; optionally, the dosage ratio of zanamivir:pamoic acid:sodium hydroxide:magnesium sulfate is 24.3 mg:63.9 mg:14.6 mg:4 mg; optionally, the pharmaceutical preparation is an aqueous solution, wherein the concentration of zanamivir is 24.3 mg / ml.

[0070] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application include: laninamivir; pamoic acid; sodium hydroxide; and magnesium sulfate; optionally, the dosage ratio of laninamivir:pamoic acid:sodium hydroxide:magnesium sulfate is 25.3 mg:63.9 mg:14.6 mg:4 mg; optionally, the pharmaceutical preparation is an aqueous solution, wherein the concentration of laninamivir is 25.3 mg / ml.

[0071] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application include: peramivir trihydrate; pamoic acid; sodium hydroxide; and magnesium chloride; optionally, the dosage ratio of peramivir trihydrate:pamoic acid:sodium hydroxide:magnesium chloride is 58.2 mg:29.5 mg:14.6 mg:5 mg; optionally, the pharmaceutical preparation is an aqueous solution, and the concentration of peramivir is 50 mg / ml.

[0072] In some embodiments, the formulation raw materials of the pharmaceutical preparation of the present application further include: a second pH regulator, and the second pH regulator is selected from one or more of the first pH regulators (sodium hydroxide, potassium hydroxide, diethylamine, triethylamine, ethylenediamine, sodium bicarbonate, sodium carbonate, tromethamine, and meglumine), hydrochloric acid, sodium citrate, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, and phosphoric acid. The second pH regulator can be used to adjust the pH during the preparation process of the pharmaceutical preparation.

[0073] In some embodiments, the pharmaceutical preparation of the present application is a (sterile) aqueous pharmaceutical preparation or a (sterile) freeze-dried pharmaceutical preparation. In some embodiments, the aqueous pharmaceutical preparation of the present application is an inhalation liquid preparation, an injection aqueous solution, a spray, or an aerosol. The various dosage forms of the pharmaceutical preparation of the present application can be prepared by conventional methods in the art. For example, conventional mixing methods, dissolution methods, grinding methods, freeze-drying methods, etc.

[0074] In some embodiments, the aqueous pharmaceutical preparation of the present application is an oral aerosol inhalation preparation. Compared with intravenous preparations and oral preparations, the inhalation preparation has a high lesion concentration and low systemic exposure. It can reduce the dosage, enhance the efficacy, and reduce the systemic toxic and side effects.

[0075] In some embodiments, the pharmaceutical preparation of the present application is an aqueous pharmaceutical preparation, wherein the concentration of the active ingredient reaches 100 mg / ml, and the relatively high drug loading can inhibit the occurrence of viral drug resistance. In some other embodiments, the concentration of the active ingredient in the aqueous pharmaceutical preparation of the present application is 20 mg / ml to 100 mg / ml. The concentration or loading amount of the active ingredient mentioned in the present disclosure is calculated based on peramivir (C 15 H 28 N 4 O 4 ), zanamivir (C 12 H 20 N 4 O 7 ), or laninamivir (C 13 H 22 N 4 O 7 ).

[0076] In some embodiments, the pharmaceutical preparation of the present application is a freeze-dried pharmaceutical preparation. In the aqueous solution formed by reconstituting the freeze-dried pharmaceutical preparation with water, the concentration of the active ingredient reaches 100 mg / ml. In some other embodiments, in the aqueous solution formed by reconstituting the freeze-dried pharmaceutical preparation of the present application with water, the concentration of the active ingredient is 20 mg / ml to 100 mg / ml.

[0077] In some embodiments, the pH value of the aqueous pharmaceutical preparation or the aqueous solution formed by reconstituting the freeze-dried pharmaceutical preparation of the present application with water is 5.5 - 8.5, and further preferably 6.5 - 8.0.

[0078] In some embodiments, the freeze-dried pharmaceutical preparation of the present application contains a freeze-dried excipient. In some embodiments, the freeze-dried excipient is selected from one or more of sodium chloride, glucose, glycine, cysteine, and lysine. In some embodiments, the pharmaceutical preparation of the present application contains 0 wt% - 5 wt% of the freeze-dried excipient.

[0079] In some embodiments, the solvent for formulating or clinically compatibly formulating the pharmaceutical preparation of the present application is selected from water for injection, physiological saline, glucose solution, or a physiologically acceptable buffer.

[0080] In some embodiments, the administration routes of the pharmaceutical preparation of the present application include intravenous administration, oral aerosol inhalation, nasal administration, subcutaneous administration, intradermal administration, and intramuscular administration. For example, it is administered by oral aerosol inhalation.

[0081] In some embodiments, the pharmaceutical preparation of the present application is an orally inhaled aerosol preparation, wherein the dose of the active ingredient is 20 - 800 mg, and the administration volume is not more than 8 ml; or, the dose of the active ingredient is 40 - 320 mg, and the administration volume is not more than 4 ml; or, the dose of the active ingredient is 60 - 240 mg, and the administration volume is not more than 4 ml.

[0082] The pharmaceutical preparation of the present application can improve the antiviral efficacy of the active ingredient. For example, an orally inhaled aerosol preparation can be made into an aqueous preparation with a high drug loading, and the single inhalation amount can reach 20 - 800 mg (calculated according to the inhalation volume of 1 - 8 ml), thereby effectively inhibiting the virus and avoiding the drug failure caused by virus resistance, while improving the compliance of patients.

[0083] In some embodiments, due to the high drug loading of the inhalation liquid preparation prepared by the present application, the volume of the liquid medicine can be reduced to 1 ml (100 mg / ml). After reducing the volume, the aseptic assurance level in the production process can be improved, while reducing the scale and production cost; it also facilitates the production, transportation and storage processes, and is more beneficial to ensuring its quality; during clinical use, the infusion volume and time can also be reduced, improving the compliance of patients.

[0084] In some embodiments, the pharmaceutical preparation of the present application has a long-acting effect of absorbing and distributing in the body for at least 48 - 72 hours. The oil-water partition coefficient LogP [n-octanol / water] of peramivir is -1.16, indicating that peramivir has strong hydrophilicity, but the distribution amount in n-octanol is extremely small, that is, the lipophilicity is weak; peramivir itself is a strongly polar compound with poor membrane permeability and can stay in the lungs for a long time. Therefore, the compound properties of peramivir itself make it have a certain long-acting effect. In addition, peramivir forms a salt with cations, increasing the ionization of peramivir. This complex is positively charged at physiological pH values, which can reduce the apparent permeability in the lung epithelial model and increase the retention time of peramivir in the lungs, thereby achieving a long-acting effect. Moreover, the submicron structure of the aqueous preparation provided by the present application has a nanoaggregate structure, and its large steric hindrance itself has the effect of prolonging the action time of peramivir. The aqueous preparation provided by the present invention can achieve antiviral efficacy by administering once within one week through the orally inhaled route, reducing the dosing frequency and greatly improving the compliance of patients.

[0085] The present application provides an aqueous preparation with a high drug loading (up to 800 mg). During clinical use, the drug can be completely dissolved by the water for injection system, avoiding the use of excipients such as surfactants, solubilizers, and cosolvents to improve solubility, and at the same time avoiding the toxic reactions such as hemolysis and irritation caused by surfactants and organic solvents.

[0086] On the other hand, the present application also provides a method for preparing the above-mentioned pharmaceutical preparation, which includes the following steps: (1) dissolving the carboxyl anion donor and the basic pH regulator in water; and (2) adding the active ingredient to the aqueous solution obtained in step (1).

[0087] In some embodiments, the preparation method of the present application further includes: (3) adding a cation donor after adding the active ingredient.

[0088] In some embodiments, the preparation method of the present application further includes: using a second pH regulator to adjust the pH value of the aqueous solution obtained in step (1) to above 7, such as 7-9, and / or adjusting the pH value of the aqueous solution obtained in step (2) to 5.5-8.5, such as 6.5-8.0.

[0089] In some embodiments, the preparation method of the pharmaceutical preparation of the present application further includes: subjecting the aqueous solution obtained in step (2) to aseptic filling and / or freeze-drying to obtain a freeze-dried pharmaceutical preparation.

[0090] In some embodiments, the present application provides a method for preparing the above-mentioned pharmaceutical preparation, including:

[0091] Step 1: Weigh the carboxyl anion donor and the first pH regulator, add water, stir and shake until dissolved, add the active ingredient, and stir at 50°C to 95°C until clear and keep warm.

[0092] Step 2 (optional): Continue to stir and cool down to below 40°C, add a cation donor (preferably a metal cation donor), stir to dissolve, and make up the volume.

[0093] Step 3: Optionally add a freeze-drying excipient, and perform aseptic filling and / or freeze-drying.

[0094] In some embodiments, before aseptic filling and / or freeze-drying, it further includes sterilizing filtration.

[0095] In some embodiments, the water used in step 1 is water for injection.

[0096] In some embodiments, the pH value of the solution obtained in step 1 is not less than 7, for example, 7-9, and the pH value of the solution obtained in step 2 is 5.5-8.5, for example, 6.5-8.0.

[0097] In some embodiments, in step 1, in addition to using the first pH regulator to dissolve the carboxyl anion donor in water, a second pH regulator can also be used to adjust the pH to the range of 7-9; and / or in step 2, a second pH regulator can also be used to adjust the pH to a suitable pH value of 5.5-8.5, such as 6.5-8.0. The second pH regulator can be the same as or different from the first pH.

[0098] On the other hand, the present application provides the use of the pharmaceutical preparation of the present application in the preparation of a medicament for preventing or treating diseases caused by influenza virus.

[0099] On the other hand, the present application provides a method for preventing or treating diseases caused by influenza virus, which method comprises administering the pharmaceutical preparation of the present application to an individual in need (preferably, a mammal, such as a human).

[0100] According to the results of the pharmacokinetic experiments in rats, it is shown that after administration of the peramivir pharmaceutical preparation provided by the present application, peramivir can be enriched in the lungs, has the effect of preventing or treating diseases caused by influenza virus, and the enrichment of the active drug in the lungs can be achieved by the administration method of aerosol inhalation.

[0101] In some embodiments, the diseases caused by influenza (abbreviation for influenza) virus that the pharmaceutical preparation of the present application aims to prevent or treat are acute respiratory infectious diseases caused by influenza A or B virus. Influenza viruses include H1N1 and H3N2 subtypes in influenza A virus, as well as Victoria and Yamagata lineages in influenza B virus, etc.

[0102] Examples

[0103] Unless otherwise specified, the drugs or reagents used in the following examples are all conventional commercially available products. The peramivir raw material used is peramivir trihydrate, manufacturer: Hunan Jiudian Hongyang Pharmaceutical Co., Ltd.

[0104] Comparative Example 1 (investigating sodium benzoate as a carboxyl anion donor)

[0105]

[0106] Preparation process: Weigh the prescribed amount of sodium benzoate and ultrapure water, ultrasonically shake until dissolved, adjust the pH to 7.4 ± 0.2 with 0.1 M HCl or 5 M NaOH solution, add the prescribed amount of peramivir trihydrate, stir in a water bath at 80 °C until dissolved and clear, then keep warm and shake for 5 min. Stir and cool in a water bath at room temperature, add the prescribed amount of magnesium chloride hexahydrate, stir to dissolve, and make up the volume to the prescribed amount with ultrapure water. Filter with a 0.22 μm filter membrane and then fill; further semi-cork and freeze-dry to obtain a freeze-dried preparation, and reconstitute it with water for injection to the concentration before freeze-drying before use.

[0107] Test results: The solution before freeze-drying was placed in the dark at room temperature, and a large amount of precipitation was visible in all the formulated preparations within 1 h, and the solution became significantly turbid.

[0108] Example 1

[0109] Prepare formulations using different types and different molar ratios of anion donors:

[0110]

[0111] Preparation process: Weigh the prescribed amount of anionic donor, tromethamine, and ultrapure water, and ultrasonically shake until dissolved. Adjust the pH to 7.4 ± 0.2 with 0.1 M HCl or 5 M NaOH solution. Add the prescribed amount of peramivir trihydrate, and stir in a water bath at 75 °C until dissolved and clear, then keep warm and shake for 5 min. Stir and cool in a water bath at room temperature, add the prescribed amount of magnesium sulfate, stir until dissolved, and make up to the prescribed volume with ultrapure water. Filter through a 0.22 μm filter membrane and then fill; further half-cork and freeze-dry to obtain the freeze-dried preparation, and reconstitute to the concentration before freeze-drying with water for injection before use.

[0112] Example 2

[0113] Prepare using different types and different molar ratios of cationic donors:

[0114]

[0115] Preparation process: Weigh the prescribed amount of pamoic acid, meglumine, and ultrapure water, and ultrasonically shake until dissolved. Adjust the pH to 7.4 ± 0.2 with 0.1 M HCl or 5 M NaOH solution. Add the prescribed amount of peramivir trihydrate, and stir in a water bath at 75 °C until dissolved and clear, then keep warm and shake for 5 min. Stir and cool in a water bath at room temperature, add the prescribed amount of cationic donor, stir until dissolved, and make up to the prescribed volume with ultrapure water. Filter through a 0.22 μm filter membrane and then fill; further half-cork and freeze-dry to obtain the freeze-dried preparation, and reconstitute to the concentration before freeze-drying with water for injection before use.

[0116] Test results

[0117] Prescription number 1 2 3 4 5 6 7 Osmotic pressure mM 448 502 462 525 360 371 365 pH of the liquid medicine 7.49 7.44 7.53 7.51 7.27 7.37 7.45 Z-average particle size nm 4.74 3.15 2.92 3.05 4.18 3.90 106.55

[0118] Example 3

[0119] Prepare using different active ingredients (with different concentrations):

[0120]

[0121] Preparation process: Weigh the prescribed amount of pamoic acid, sodium hydroxide, and ultrapure water, and ultrasonically shake until dissolved. Adjust the pH to 7.4 ± 0.2 with 0.1 M HCl or 5 M NaOH solution. Add the prescribed amount of active ingredient, and stir in a water bath at 90 °C until dissolved and clear, then keep warm and shake for 5 min. Stir and cool in a water bath at room temperature, add the prescribed amount of cationic donor, stir until dissolved, and make up to the prescribed volume with ultrapure water. Filter through a 0.22 μm filter membrane and then fill; further half-cork and freeze-dry to obtain the freeze-dried preparation, and reconstitute to the concentration before freeze-drying with water for injection before use.

[0122] Example 4

[0123] Investigation on Stability at Different pH Values

[0124]

[0125] Preparation process: Weigh the prescribed amounts of ditanate, sodium hydroxide, and ultrapure water, and ultrasonically shake until dissolved. Add the prescribed amount of the active ingredient, stir in a water bath at 75°C until clear, and then keep shaking for 5 minutes while maintaining the temperature. Stir and cool in a room-temperature water bath, add the prescribed amount of the cation donor, stir until dissolved, and adjust the pH to 6.0, 7.8, 8.3, 8.8, and 9.6 respectively with 0.1M HCl or 5M NaOH solution. Make up to the prescribed volume with ultrapure water. Filter through a 0.22μm filter membrane and then fill; further half-cork and freeze-dry to obtain the freeze-dried preparation, which is reconstituted to the concentration before freeze-drying with water for injection before use.

[0126] Test results: After reconstitution with water for injection, Prescription 1, Prescription 2, and Prescription 3 were clear and transparent, Prescription 4 was slightly turbid, and Prescription 5 was significantly turbid. After standing for 6 hours, Prescription 1, Prescription 2, and Prescription 3 were clear and transparent. After standing for 20 hours, Prescription 2 and Prescription 3 were clear and transparent, and Prescription 1 was slightly turbid.

[0127] Performance Testing

[0128] Unless otherwise specified, the following high-performance liquid chromatography conditions were used to detect the amount of peramivir:

[0129] Analysis Conditions for Test Samples

[0130] Detection system: HPLC-UV (Shimadzu SPD-10AVP, LC-20AD)

[0131] Liquid chromatography column: Ultimate XB-C18 4.6×150mm 5μm

[0132] Column temperature: 35°C

[0133] Mobile phase A: 10mM potassium dihydrogen phosphate (pH = 3.0)

[0134] Mobile phase B: Acetonitrile

[0135] Initial phase: 30% B phase

[0136] Needle washing solution: 50% acetonitrile aqueous solution

[0137] Flow rate: 1.000 mL / min

[0138] Detection wavelength: 280nm

[0139] Liquid phase ratio:

[0140]

[0141] Analysis and Detection Conditions for Biological Samples

[0142] Detection system: LCMS-8045

[0143] Liquid chromatography column: Luna Omega C18 50×2.1mm, 1.6μm (SN: H20-064432)

[0144] Mobile phase A: 0.1% formic acid aqueous solution (pH = 5.3)

[0145] Mobile phase B: Methanol

[0146] Needle washing solution: Methanol: Isopropanol: Water (1:1:1)

[0147] Flow rate: 0.5 mL / min

[0148] Column temperature: 40 °C

[0149] Autosampler temperature: 4 °C

[0150] Liquid phase ratio:

[0151]

[0152] Mass spectrometry system: YQ-09-067

[0153] Ionization mode: ESI+

[0154] Scanning mode: MRM

[0155] Test Example 1 Prescription 5: Pharmacokinetic study of plasma and lung tissue after aerosol inhalation in SD rats

[0156] Test method: 45 male rats (SPF-grade SD rats, with a body weight range of 180 - 220 g at the time of purchase, Zhejiang Vital River Laboratory Animal Technology Co., Ltd.) were randomly divided into 2 groups. They were respectively given 4.50 mg / kg peramivir inhalation solution (solution inhalation, 24 rats in group 1) and 25 mg / kg peramivir injection (intravenous injection, 21 rats in group 2). Blood samples and lung tissues were collected at 0.5, 1, 4, 8, 24, 48, 72, 96 h after administration and at 0.25, 0.5, 1, 2, 4, 6, 8 h after administration. The concentration of peramivir in plasma and lung tissue was determined by LC-MS / MS method, and the pharmacokinetic parameters were calculated using WinNonlin 8.2. The drug plasma concentration-time curves of the two groups of experiments are as Figure 1 - Figure 4 shown.

[0157] Test results: The plasma drug exposure of Group 1 (inhalation group) was lower than that of Group 2 (intravenous injection group), but the drug exposure in lung tissue was higher than that of Group 2. After nebulized inhalation of peramivir inhalation solution, it showed the advantages of high local exposure, low systemic circulation exposure, and relatively long half-life. The main pharmacokinetic parameters are shown in the following table:

[0158]

[0159]

[0160] Test Example 1 Prescription 5: Histopathology and Toxicokinetics Study of SD Rats after Nebulized Inhalation

[0161] Test method: A small animal single-concentration nose and mouth exposure system was used, and the generator was an impinging liquid aerosol generator. The parameter settings for the low-dose group were aerosol flow rate of 10 L / min, dilution flow rate of 0 L / min, and extraction flow rate of 6 L / min. The parameter settings for the high-dose group were aerosol flow rate of 16 L / min, dilution flow rate of 0 L / min, and extraction flow rate of 12 L / min. Sampling was carried out after the aerosol concentration was stable. After the sampling ended, the animals were placed for 4 hours of exposure to the drug. The concentration at the sampling port was detected every 1 hour. After the animals' exposure to the drug ended, the animals were taken down in sequence, and the particle size distribution was detected using an aerodynamic particle size analyzer.

[0162] Forty healthy animals (SPF-grade SD rats, with the body weight range of female being 186.4 - 229.1 g and male being 217.2 - 248.9 g at the time of grouping, Zhejiang Vital River Laboratory Animal Technology Co., Ltd.) were selected. Male and female animals were randomly block-designed and grouped according to body weight by gender into 2 groups, with 20 animals in each group. Among them, there were 6 animals in the main experimental group and 14 animals in the TK satellite group, with an equal number of males and females. The animals were administered by inhalation through the nose and mouth once for 4 hours and observed for 7 days. The animals in the main experimental group were observed for their clinical symptoms every day during the observation period. The body weights of the animals were measured on D1, D2, D4, and D7, and on D8, the animals were dissected, specimens were taken, fixed, and subjected to histopathological examination. The animals in the TK satellite group were bled at 0.5, 1, 2, 4, 6, 8, 24, 36, 48, and 72 hours after drug administration, and lung tissue and perfusion fluid were collected at 0.5, 4, 8, 24, 36, 48, and 72 hours after drug administration for detection and analysis.

[0163] The actual administered doses in the low-dose group were 67.30 mg / kg, and in the high-dose group were 125.16 mg / kg. During the observation period, no abnormal clinical symptoms were observed in the animals of the main experimental group. In the high-dose group, the animals showed a transient decrease in body weight on the day of administration, which recovered and increased steadily the next day. The results of histopathological examinations showed that in the low- and high-dose groups, the lungs of the animals had very mild to mild neutrophil infiltration and focal lesions, and the laryngopharynx had very mild inflammatory cell infiltration in the lamina propria of the epiglottis mucosa, focal lesions, and very mild edema. The number of cases and frequency of lesions in the low- and high-dose groups were comparable, and there was no dose-response relationship.

[0164] Table 1 Summary Table of Histopathological Examination Results - Abnormal Lesions

[0165]

[0166] Note: For the grading of lesion severity, "+" indicates very mild, "2+" indicates mild, "3+" indicates moderate, and "4+" indicates severe.

[0167] After rats were respectively inhaled with peramivir inhalation solution at 67.30 mg / kg and 125.16 mg / kg, the plasma AUC0-72h of female rats were 6040 ng / mL*h and 41000 ng / mL*h respectively; Cmax were 1060 ng / mL and 5100 ng / mL respectively; Tmax were 0.500 h and 2.00 h respectively; T1 / 2 were 7.77 h and 12.3 h respectively. The AUC0-72h of male rats were 4360 ng / mL*h and 25100 ng / mL*h respectively, Cmax were 715 ng / mL and 1520 ng / mL respectively; Tmax were 0.500 h and 8.00 h respectively; T1 / 2 were 11.0 h and 8.84 h respectively.

[0168] The AUC0-72h of the lung tissue of female rats were 202000 ng / mL*h and 222000 ng / mL*h respectively; Cmax were 6290 ng / mL and 8330 ng / mL respectively; Tmax were 0.500 h and 4.00 h respectively; T1 / 2 were 29.7 h and 21.0 h respectively. The AUC0-72h of male rats were 210000 ng / mL*h and 271000 ng / mL*h respectively, Cmax were 7879 ng / mL and 10400 ng / mL respectively; Tmax were 0.500 h and 4.00 h respectively; T1 / 2 were 24.4 h and 28.0 h respectively.

[0169] The AUC0-72h values of the lavage fluid in female rats were 4780 ng / mL*h and 7940 ng / mL*h respectively; the Cmax values were 598 ng / mL and 423 ng / mL respectively; the Tmax was 0.500 h for both; the T1 / 2 values were 38.3 h and 22.7 h respectively. For male rats, the AUC0-72h values were 4350 ng / mL*h and 7310 ng / mL*h respectively, the Cmax values were 574 ng / mL and 393 ng / mL respectively; the Tmax was 0.500 h for both; the T1 / 2 values were 27.3 h and 25.9 h respectively.

[0170] The toxicokinetic results showed that the plasma exposure levels in the low- and high-dose groups were much lower than the lung tissue exposure levels, and the exposure level in female rats was slightly higher than that in male rats; the plasma exposure level ratios in the low- and high-dose groups of male and female rats were 6.79 and 5.76 respectively, both higher than the dose ratio of 1.86; there was no obvious dose relationship in the lung tissue drug exposure levels in the low- and high-dose groups of male and female rats, and there was no gender difference.

[0171] Although the embodiments described herein are described with reference to specific examples, it should be understood that those skilled in the art can make various adjustments and changes to them as long as they do not violate the scope and gist of the present disclosure.

Claims

1. A pharmaceutical preparation, the raw materials of which include: An active ingredient selected from the group consisting of peramivir, zanamivir, laninamivir and hydrates or solvates thereof; a carboxylate anion donor selected from at least one of pamoic acid and hydroxynaphthoic acid; and The first pH adjuster is an alkaline pH adjuster.

2. The pharmaceutical preparation according to claim 1, wherein the hydroxynaphthoic acid is selected from one or more of 2-hydroxy-1-naphthoic acid, 3-hydroxy-1-naphthoic acid, 4-hydroxy-1-naphthoic acid, 5-hydroxy-1-naphthoic acid, 6-hydroxy-1-naphthoic acid, 1-hydroxy-2-naphthoic acid, 2-hydroxy-3-naphthoic acid and 8-hydroxy-2-naphthoic acid; optionally, the hydroxynaphthoic acid is 2-hydroxy-3-naphthoic acid.

3. The pharmaceutical preparation according to claim 1 or 2, wherein the first pH adjuster is selected from one or more of sodium hydroxide, potassium hydroxide, diethylamine, triethylamine, ethylenediamine, sodium bicarbonate, sodium carbonate, tromethamine and meglumine.

4. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the molar ratio of the active ingredient to the carboxyl group in the carboxyl anion donor is 1:0.5-3, or 1:0.7-2.

5. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the formulation raw material further comprises a cation donor; Optionally, the cation donor is selected from one or more of inorganic salts of magnesium ion, calcium ion, zinc ion, potassium ion and sodium ion, tromethamine, meglumine and ethylenediamine; or, the cation donor is selected from one or more of magnesium chloride, magnesium sulfate, calcium chloride and zinc chloride, and the cation donor is the same as or different from the first pH adjuster.

6. The pharmaceutical preparation according to claim 5, wherein the molar ratio of the active ingredient: the carboxyl group in the carboxyl anion donor: the cation in the cation donor is 1:0.5-3:0-5, or 1:0.7-2:0.2-2.

7. The pharmaceutical preparation according to claim 6, wherein the formulation raw materials comprise: An active ingredient selected from the group consisting of peramivir, zanamivir, laninamivir and hydrates or solvates thereof; A carboxyl anion donor selected from one or more of 2-hydroxy-3-naphthoic acid, 1-hydroxy-2-naphthoic acid and pamoic acid; A first pH adjusting agent is selected from one or more of sodium hydroxide, potassium hydroxide, diethylamine, ethylenediamine, triethylamine, sodium bicarbonate, sodium carbonate, tromethamine and meglumine; and The optional cation donor is selected from one or more of magnesium chloride, magnesium sulfate, calcium chloride and zinc chloride.

8. The pharmaceutical preparation according to any one of claims 1 to 7, wherein the formulation raw materials further comprise a second pH adjuster, and the second pH adjuster is selected from one or more of sodium hydroxide, potassium hydroxide, diethylamine, triethylamine, ethylenediamine, sodium bicarbonate, sodium carbonate, tromethamine and meglumine, hydrochloric acid, sodium citrate, citric acid, sodium dihydrogen phosphate and phosphoric acid.

9. The pharmaceutical preparation according to any one of claims 1 to 8, wherein the pharmaceutical preparation is an aqueous pharmaceutical preparation or a lyophilized pharmaceutical preparation, optionally, the aqueous pharmaceutical preparation is an inhalation liquid preparation, an injection aqueous solution, a spray or an aerosol; optionally, the aqueous pharmaceutical preparation is an oral atomization inhalation preparation.

10. The pharmaceutical preparation according to claim 9, which is an aqueous pharmaceutical preparation. in, The concentration of the active ingredient reaches 100 mg / ml, optionally the concentration of the active ingredient is 20 mg / ml to 100 mg / ml; or the pharmaceutical preparation is a lyophilized pharmaceutical preparation, and in the aqueous solution formed by compounding the lyophilized pharmaceutical preparation with water, the concentration of the active ingredient reaches 100 mg / ml, optionally the concentration of the active ingredient is 20 mg / ml to 100 mg / ml.

11. The pharmaceutical preparation according to claim 9 or 10, wherein the pH value of the aqueous solution formed by compounding the aqueous pharmaceutical preparation or the lyophilized pharmaceutical preparation with water is 5.5-8.5 or 6.5-8.

0.

12. The pharmaceutical preparation according to claim 9, wherein the pharmaceutical preparation is a lyophilized pharmaceutical preparation, and the lyophilized pharmaceutical preparation contains a lyophilized excipient; optionally, the lyophilized excipient is selected from one or more of sodium chloride, glucose, glycine, cysteine, and lysine; or, the lyophilized excipient is selected from one of sodium chloride, glucose, and glycine; optionally, the lyophilized pharmaceutical preparation contains 0% to 5% by weight of the lyophilized excipient.

13. The pharmaceutical preparation according to any one of claims 1 to 8, wherein the administration route of the pharmaceutical preparation is selected from intravenous administration, oral aerosol inhalation, nasal administration, subcutaneous administration, intradermal administration and intramuscular administration, or is oral aerosol inhalation.

14. A method for preparing the pharmaceutical preparation according to any one of claims 1 to 13, The following steps are involved: (1) dissolving the carboxyl anion donor and the alkaline pH adjuster in water; and (2) Adding the active ingredient to the aqueous solution obtained in step (1).

15. The preparation method according to claim 14, further comprising include: (3) After adding the active ingredient, add the cation donor.

16. The preparation method according to claim 14 or 15, further comprising include: Using a second pH adjuster, the pH value of the aqueous solution obtained in step (1) is adjusted to above 7 or 7-9, and / or the pH value of the aqueous solution obtained in step (2) is adjusted to 5.5-8.5 or 6.5-8.0; The second pH regulator is selected from one or more of sodium hydroxide, potassium hydroxide, diethylamine, triethylamine, ethylenediamine, sodium bicarbonate, sodium carbonate, tromethamine and meglumine, hydrochloric acid, sodium citrate, citric acid, sodium dihydrogen phosphate and phosphoric acid.

17. The preparation method according to any one of claims 14 to 16, further comprising: include: The step of aseptically filling and / or freeze-drying the aqueous solution obtained in step (2) to obtain a freeze-dried pharmaceutical preparation.

18. Use of the pharmaceutical preparation according to any one of claims 1 to 13 in the preparation of a medicament for preventing or treating a disease caused by influenza virus, for example, the disease is an acute respiratory infectious disease caused by influenza A or B virus.

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