CN111991375A

CN111991375A - Reed-ciclovir liposome for aerosol inhalation and preparation method thereof

Info

Publication number: CN111991375A
Application number: CN202011028771.3A
Authority: CN
Inventors: 尹莉芳; 李菁菁; 任连杰
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2020-09-25
Filing date: 2020-09-25
Publication date: 2020-11-27

Abstract

The invention discloses a Reidesvir liposome for aerosol inhalation and a preparation method thereof. The liposome comprises: the injection comprises the components of Reidesciclovir or salt thereof, liposome material, stabilizer, aqueous medium and organic solvent. The preparation method comprises the following steps: taking the Reidesciclovir or the salt thereof and liposome materials, and adding an organic solvent for dissolving; removing the organic solvent by evaporation under reduced pressure to form a thin film; adding an aqueous medium or an aqueous medium dissolved with a stabilizer, and hydrating the film; dispersing the hydrated solution by ultrasonic; centrifuging to remove the precipitate to obtain a Reidesvir liposome suspension for aerosol inhalation; adding a freeze-drying protective agent and freeze-drying; redissolving with water phase medium, and performing ultrasonic atomization administration. The liposome can be redissolved by adding aqueous medium before use to form liposome suspension for administration by aerosol inhalation. The liposome improves the solubility in aqueous solution, improves the in-vivo metabolism and tissue distribution conditions of the Reidesciclovir by aerosol inhalation administration, and obviously improves the drug concentration in lung.

Description

Reed-ciclovir liposome for aerosol inhalation and preparation method thereof

Technical Field

The invention relates to a medicinal preparation and a preparation method thereof, in particular to a Reidesvir liposome for aerosol inhalation and a preparation method thereof.

Background

The novel coronavirus pneumonia (new coronavirus pneumonia, CODV-19) is a newly-discovered acute respiratory infectious disease, which is taken as an acute respiratory infectious disease and is incorporated into a second infectious disease specified in infectious disease prevention and treatment Law of the people's republic of China, and is managed according to the first infectious disease. Currently, no antiviral drugs have been found that demonstrate efficacy in a strict "randomized, double-blind, placebo-controlled study", and trials of interferon-alpha, ribavirin (either combined with interferon-alpha or lopinavir/ritonavir), chloroquine phosphate, and arbidol are recommended. Aiming at the pneumonia epidemic situation caused by COVID-19 infection, the search for a medicament with exact curative effect is important.

Reidesciclovir (GS-5734) is a novel adenosine analog monophosphate amide prodrug developed by Gilidard scientific, USA, and its triphosphate active metabolite (GS-443902) can interfere with the activity of viral RNA-dependent RNA polymerase (RdRp) and exert antiviral action by inhibiting viral nucleic acid synthesis. The application of the Redcixvir in the early research is anti-Ebola virus (filovirus), and related researches show that the anti-filovirus effect is good. In vitro cell experiments and animal model experiments prove that the Reidesciclovir has antiviral effect on SARS coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV). According to the literature report, the novel coronavirus COVID-19 is a variant of Severe Acute Respiratory Syndrome (SARS) coronavirus (SARS-CoV) which causes 2002 and 2003 outbreak, and the homology of the two is more than 85 percent. Accordingly, Reidesciclovir was first attempted in the United states for the treatment of new coronavirus infections and received FDA's Emergency Use Authority (EUA) for the treatment of new coronary pneumonia at 1/5/2020 for the treatment of critically ill patients suspected of or diagnosed with new coronary pneumonia. On day 10/8 of 2020, the Jilide science announced that Reidcisvir has been filed by the U.S. Food and Drug Administration (FDA)

The new drug application for the treatment of new coronavirus pneumonia (COVID)-19) treatment of the patient.

The recommended administration scheme of the Rudexilvir in adults and adolescents (the weight is more than or equal to 40kg) is as follows: the Darcy's disease is treated by intravenous infusion of 200mg of Darcy's disease for the first time on the 1 st day (intravenous infusion is more than 30 min), and then intravenous infusion of Darcy's disease is maintained for 9-13 days at 100mg multiplied by 1 times per day (each time is more than 30 min). The administered dose of Reidesvir is relatively large, but its solubility in water is low, about 0.03mg/mL, its solubility in aqueous media is poor and it is chemically unstable. Therefore, currently approved Reidesvir injection on the market adopts cyclodextrin inclusion technology to increase the solubility and stability of Reidesvir. However, in the method, the dosage of the cyclodextrin is very large, the mass ratio of the cyclodextrin to the Rudexiluwei is up to 30: 1, the complete inclusion of the medicament can be ensured, and the potential safety hazard exists when a large amount of auxiliary materials directly enter the systemic circulation. According to the literature, ridciclovir is distributed to the testis, epididymis, eye and brain tissue within 4 hours after intravenous administration. The drug concentration levels in the brain were lower at hour 4 relative to other tissues, but higher than plasma levels of the ridciclovir concentration were still detectable 168 hours after administration. Thus, the marketed injection of Reidesciclovir presents a potential risk of inducing systemic toxic side effects.

The medicine is delivered into the body in the mode of intravenous injection and the like, and only a part of the medicine can reach the focus and play a therapeutic role, so that the administration dosage of the medicine is increased, and the toxic and side effects of the medicine on non-focus tissues are easily caused. The medicine can be directly delivered to the lesion part of the lung by adopting an inhalation administration mode, and has the advantages of large absorption surface area, quick response, high lung medicine concentration, low dose, small dosage entering systemic circulation, less adverse reaction, strong compliance, avoidance of gastrointestinal damage and liver first pass effect and the like. The liposome is a novel inhalation drug delivery carrier, is composed of phospholipid bilayers, has good physiological compatibility with an alveolar surfactant (the main component of which is dipalmitoyl phosphatidylcholine and DPPC) composed of phospholipids, and is not easy to cause toxicity and immune response.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to provide a Reidesvir liposome for aerosol inhalation, which has the characteristics of high solubility, good stability, uniform particle size and the like.

The invention also aims to provide a preparation method of the Reidesvir liposome for aerosol inhalation.

The technical scheme is as follows: the invention provides a Reidesvir liposome for aerosol inhalation, which comprises the following raw materials in percentage by mass: 0.2-50% of Reidesciclovir or salt thereof, 20-99% of liposome material, 0-50% of stabilizing agent and the balance of aqueous phase medium and organic solvent. Preferably, the mass ratio of the Rudexilvir or the salt thereof to the liposome material is 1: 50-1: 1; the mass ratio of the stabilizing agent to the liposome material is 0: 1-10: 1; the volume ratio of the aqueous phase medium to the organic solvent is 0: 100 and 100: 0.

Further, the liposome material is selected from the group consisting of Egg Phosphatidylcholine (EPC), Egg Phosphatidylglycerol (EPG), Egg Phosphatidylinositol (EPI), Egg Phosphatidylserine (EPS), phosphatidylethanolamine (EPE), phosphatidic acid (EPA), Soybean Phosphatidylcholine (SPC), Soybean Phosphatidylglycerol (SPG), Soybean Phosphatidylserine (SPS), Soybean Phosphatidylinositol (SPI), Soybean Phosphatidylethanolamine (SPE), Soybean Phosphatidic Acid (SPA), Hydrogenated Egg Phosphatidylcholine (HEPC), Hydrogenated Egg Phosphatidylglycerol (HEPG), Hydrogenated Egg Phosphatidylinositol (HEPI), Hydrogenated Egg Phosphatidylserine (HEPS), hydrogenated phosphatidylethanolamine (HEPE), hydrogenated phosphatidic acid (HEPA), Hydrogenated Soybean Phosphatidylcholine (HSPC), Hydrogenated Soybean Phosphatidylglycerol (HSPG), Hydrogenated Soybean Phosphatidylserine (HSPS), Hydrogenated Soybean Phosphatidylinositol (HSPI), Hydrogenated Soybean Phosphatidylethanolamine (HSPE), Hydrogenated Soybean Phosphatidic Acid (HSPA), Dipalmitoylphosphatidylcholine (DPPC), Dimyristoylphosphatidylcholine (DMPC), Dimyristoylphosphatidylglycerol (DMPG), Dipalmitoylphosphatidylglycerol (DPPG), Distearoylphosphatidylcholine (DSPC), Distearoylphosphatidylglycerol (DSPG), Dioleylphosphatidylethanolamine (DOPE), palmitoylstearylphosphatidylcholine (PSPC), palmitoylstearoylphosphatidylglycerol (PSPG), Monooleoylphosphatidylethanolamine (MOPE), tocopherol, ammonium salts of fatty acids, ammonium salts of phospholipids, ammonium salts of glycerides, tetradecylamine, hexadecylamine, dodecylamine, octadecylamine, dilauroylethylphosphonic acid choline (DLEP), diacylethylphosphonic acid choline (DMEP), dipalmitoylethylphosphonic acid choline (DPEP) and distearoylethylphosphonic acid choline (DSEP), N- (2, 3-bis- (9- (Z) -octadecenyloxy) -prop-1-yl-N, N, N-trimethylammonium chloride (DOTMA), 1, 2-bis (oleoyloxy) -3- (trimethylammonium) propane (DOTAP), Distearoylphosphatidylglycerol (DSPG), dimyristoylphosphatidic acid (DMPA), dipalmitoylphosphatidic acid (DPPA), distearoylphosphatidic acid (DSPA), Dimyristoylphosphatidylglycerol (DMPI), Dipalmitoylphosphatidylglycerol (DPPI), Distearoylphosphatidylinositol (DSPI), Dimyristoylphosphatidylphosphatidylserine (DMPS), Dipalmitoylphosphatidylserine (DPPS), Distearoylphosphatidylserine (DSPS), palmitolysolecithin (P-lysoPC), myristoyl lysolecithin (M-lysoPC), Stearoyl lysolecithin (S-lysoPC), phosphatidylcholine-polyethylene glycol (PC-PEG), phosphatidylethanolamine-polyethylene glycol (PE-PEG), distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG), distearoylphosphatidylcholine-polyethylene glycol (DSPC-PEG), cholesterol, lanosterol, sitosterol, stigmasterol, ergosterol and one or more mixtures of other functionalized phospholipids and water-soluble derivatives of sterols.

Further, the stabilizer is selected from the group consisting of glycerin, syrup, sorbitol, gum arabic, agar, carrageenan, guar gum, carrageenan, locust bean gum, pectin, propylene glycol alginate, sodium alginate, tragacanth, xanthan gum, peach gum, starch slurry, carboxymethyl cellulose and its sodium salt, microcrystalline cellulose and its sodium salt, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, colloidal aluminosilicate, one or more of colloidal magnesium aluminate, carbomer, gelatin, polyethylene glycol, polyvidone, hyaluronic acid, chitosan, modified chitosan, amphotericin B, polyamine, stearylamine, arginine, vitamin C, vitamin E, ascorbic acid, butyl hydroxy anisole, dibutyl hydroxy toluene, L-cysteine, sodium sulfite, sodium bisulfite, sodium metabisulfite, tea polyphenols and thimerosal; the organic solvent is selected from one or more of ethanol, methanol, diethyl ether, chloroform, dichloromethane, acetonitrile, acetone, chain, cyclic or aromatic hydrocarbon containing 3-20 carbon atoms, alcohol, amine, ether, ester, ketone, aldehyde and acid.

Further, the aqueous medium is selected from one or more of water for injection, pure water, an aqueous glucose solution, an aqueous glucose sodium chloride solution, an aqueous phosphate solution, an aqueous acetate solution, an organic acid, or a mixture of buffer pairs having a buffer capacity.

Furthermore, a freeze-drying protective agent is added into the liposome, a freeze-dried preparation is obtained after freeze-drying, and an aqueous phase medium is added into the freeze-dried preparation for redissolving before use to form liposome suspension for atomization inhalation administration.

Further, the lyoprotectant is selected from trehalose, lactose, sucrose, maltose, glucose, raffinose, fructose, xylitol, sorbitol, mannitol, ethanol, glycerol, propylene glycol, inositol, sodium sulfate, calcium lactate, sodium glutamate, sodium chloride, potassium chloride, sodium thiosulfate, ammonium acetate, ammonium chloride, citric acid, boric acid, phosphoric acid, tartaric acid, proline, 4-hydroxyproline, serine, alanine, lysine, sarcosine, gamma-aminobutyric acid, glutamic acid, arginine, histidine, threonine, aspartic acid, malic acid, lactic acid, ethylenediamine tetraacetic acid, sodium hydroxide, sodium bicarbonate, polyethylene glycol, dextran, povidone, polyvinylpyrrolidone, methylcellulose, gelatin, pectin, acacia, starch, dextrin, albumin, peptone, polypeptide, dimethyl sulfoxide, sodium chloride, sodium sulfate, sodium acetate, ammonium chloride, citric acid, boric acid, phosphoric acid, tartaric acid, proline, 4-hydroxyproline, serine, alanine, lysine, sarcosine, gamma-aminobutyric acid, glutamic acid, histidine, One or more of vitamin C, vitamin E, ascorbic acid, butyl hydroxy anisol, dibutyl hydroxy toluene, L-cysteine, sodium sulfite, sodium bisulfite, sodium pyrosulfite, tea polyphenols, and thimerosal.

Further, the lyophilized preparation keeps a suspension state after being redissolved, does not settle within at least 12 hours, and the content of the remidcvir or the salt thereof after being redissolved is 0.01-20mg/mL calculated by the amount of the free state.

Furthermore, the particle size of the liposome is 20-1000 nm; the encapsulation rate of the Rudexilvir or the salt thereof is 30-100%; the drug loading rate of the Rudexilvir or the salt thereof is 1-50%.

Further, the liposomes have a Mass Median Aerodynamic Diameter (MMAD) of between 1 and 8 μm, an effective deposition rate (FPF) of fine particles of between 30 and 80%, and a particle geometric standard deviation of less than 3% after nebulization.

The preparation method of the Rudexilvir liposome for atomization and inhalation comprises the following steps:

(1) taking the Reidesciclovir or the salt thereof and the liposome material, adding an organic solvent, and carrying out ultrasonic treatment to completely dissolve the Reidesciclovir or the salt thereof and the liposome material;

(2) removing the organic solvent by evaporation under reduced pressure to form a thin film;

(3) adding an aqueous medium or an aqueous medium dissolved with a stabilizer to hydrate the film;

(4) dispersing the hydrated solution by using a probe to prepare a liposome;

(5) centrifuging to remove the precipitate to obtain a Reidesvir liposome suspension for aerosol inhalation;

(6) adding a freeze-drying protective agent and freeze-drying;

(7) redissolving with water phase medium, and performing ultrasonic atomization administration.

The invention uses liposome to carry the Reidesciclovir or the salt thereof for pulmonary administration, so that the Reidesciclovir has the advantages of both liposome and pulmonary administration: the liposome can integrate the insoluble drug of the Reidcvir or the salt thereof into a phospholipid bilayer, greatly increase the solubility of the Reidcvir or the salt thereof in water to achieve the administration dosage, and improve the in-vivo and in-vitro stability; through the mode of inhalation administration, the Reidesciclovir or the salt thereof is directly concentrated at the focus part, so that the local concentration and the residence time of the Reidesciclovir or the salt thereof in the lung are increased, and the treatment effect is enhanced; the liposome can reduce the irritation and toxicity of the Reidcciclovir or the salt thereof to the respiratory tract and the lung; the Rudexilvir or the salt thereof is slowly released through liposome phospholipid bilayer, so that the elimination rate of the Rudexilvir or the salt thereof in vivo is reduced, and the action time is prolonged.

Has the advantages that: the invention has the following characteristics and advantages:

1. the obtained Reidesvir liposome for aerosol inhalation has a proper and uniform particle size of 100-300 nm. The Mass Median Aerodynamic Diameter (MMAD) of the preparation is 4.12 mu m, the optimal range of the particle size value of the inhaled fogdrop in the lung is achieved, the effective deposition rate (FPF) of fine particles is 56.89%, and the geometric standard deviation of the particles is less than 3.0, so that the preparation has good lung absorbability, can be deposited in the lung in a large amount and plays a role in pharmacodynamic treatment.

2. The invention prepares the Reidesvir liposome for aerosol inhalation for the first time, and the medicament can be directly used in the lung. Compared with the Reidesciclovir cyclodextrin injection, the concentration Cmax of the lung tissue drug active metabolite of the Reidesciclovir liposome for atomization and inhalation is more than 90 times of that of intravenous administration (20mg/kg), so that the administration effect and efficiency are greatly improved, the administration dosage can be reduced, and the systemic side effect of the Reidesciclovir is reduced.

3. The invention solves the problem of extremely poor solubility of the Reidesciclovir (the water solubility is less than 0.03mg/mL), prepares the Reidesciclovir liposome suspension by adopting a liposome entrapment technology, has the final preparation entrapment rate of more than 80 percent, has the drug concentration of more than 5mg/mL after redissolution, has small administration volume and short administration time, and is beneficial to improving the compliance of patients. After re-dissolution, the preparation keeps a suspension state within 12 hours without obvious sedimentation, and the administration requirement of aerosol inhalation is well met.

4. The auxiliary materials adopted by the liposome technology are lipid materials with good biocompatibility, and the surface active substances of the alveoli are mainly lipid, so that the liposome is not easy to generate stimulation to cause inflammation after being administrated by the lung, and has good safety.

5. By adopting liposome technology, the medicine can effectively permeate into lung cells, the medicine intake rate is improved, the drug effect taking time is shortened, the curative effect is enhanced, the toxic and side effects are reduced, higher lung tissue concentration can be achieved, and the medicine has good safety.

Drawings

FIG. 1 is a graph showing the results of different solvents on the reconstitution stability of liposomes at 25 ℃ in example 27;

FIG. 2 is a graph showing the results of different solvents on the reconstitution stability of liposomes at 4 ℃ in example 27;

FIG. 3 is a TEM representation of the Reidesvir liposomes in example 28;

FIG. 4 is a graph showing the release of Reidesciclovir in artificial lung fluid at 37 ℃ in example 29;

FIG. 5 is a graph of the particle size distribution of the nebulized aerosol of the liposomal suspension of Reidesvir in example 30;

FIG. 6 is a graph of the concentration of active metabolites in lung tissue versus time in example 32;

FIG. 7 is a diagram showing the measurement of serum inflammatory factors in example 33, in which the left diagram shows the measurement of proinflammatory factor interleukin-6 (IL-6) and the right diagram shows the measurement of inhibin factor interleukin-10 (IL-10);

FIG. 8 is a photograph showing the measurement of lung tissue homogenate inflammatory factor in example 33, wherein the left photograph shows the measurement of proinflammatory factor interleukin-6 (IL-6), and the right photograph shows the measurement of the inhibin factor interleukin-10 (IL-10).

Detailed Description

Example 1

The Ruidexilvir liposome for atomizing inhalation comprises the following components in percentage by mass:

example 1 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH6.5 for hydration, and then forming the liposome by ultrasonic dispersion through a probe. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 2

example 2 preparation process: the prescribed amounts of Reidesciclovir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol were weighed, dissolved completely in 5mL of ethanol, and slowly injected into 5mL of pH6.5 phosphate buffer preheated to 45 ℃ with rapid stirring. Keeping the temperature and continuously stirring for 1h until the ethanol is completely volatilized, keeping the temperature and standing for 30 min. Dispersing with probe to form liposome. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 3

example 3 preparation process: the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol were dissolved in 5mL of chloroform in a solanaceous flask, 1mL of phosphate buffer pH6.5 was added, and the mixture was sonicated with a probe to form an emulsion. Evaporating chloroform at 45 deg.C under reduced pressure, adding 4mL phosphate buffer solution with pH of 6.5, hydrating to obtain liposome, and ultrasonic dispersing with probe. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 4

The results of examining the particle size and PDI of the liposomes obtained from the 3 liposome preparation methods (i.e., examples 1 to 3) by the encapsulation efficiency measuring method and calculating the encapsulation efficiency are shown in Table 1.

TABLE 1 characterization of liposomes by different preparation methods

From the above data, it can be seen that three preparation methods all can obtain liposomes with suitable (100-200nm) and uniformity. The liposome prepared by different processes has relatively close entrapment rate, but the liposome prepared by an ethanol injection method and a thin film dispersion method has better stability. Because the ethanol injection method takes a long time and the organic solvent ethanol is difficult to remove, the thin film dispersion method is preferred for preparing the Reidesvir liposome.

Example 5

example 5 preparation process: weighing the formulated amounts of Reidesvir, egg yolk lecithin (PC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH6.5 for hydration, and then forming the liposome by ultrasonic dispersion through a probe. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 6

example 6 preparation process: weighing the formulated amounts of Reidesciclovir, Dioleoylphosphatidylcholine (DOPC) and cholesterol in an eggplant-shaped bottle, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH6.5 for hydration, and then forming the liposome by ultrasonic dispersion through a probe. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 7

example 7 preparation process: weighing the prescription dose of Reidesvir, 1, 2-palmitoyl phosphatidyl glycerol (DPPG) and cholesterol in a solanaceous bottle, adding 10mL of chloroform and 5mL of methanol, performing ultrasonic treatment to completely dissolve lipid materials and drugs, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH6.5 for hydration, and then forming the liposome by ultrasonic dispersion through a probe. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 8

example 8 preparation process: weighing the formulated amounts of Reidesciclovir, Distearoylphosphatidylcholine (DSPC) and cholesterol in a solanaceous bottle, adding 15mL of chloroform, ultrasonically dissolving lipid and drug completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH6.5 for hydration, and then forming the liposome by ultrasonic dispersion through a probe. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 9

example 9 preparation process: weighing the formulated amounts of Reidesciclovir, distearoyl phosphatidyl glycerol DSPG and cholesterol in an eggplant-shaped bottle, adding 15mL of chloroform, performing ultrasonic treatment to completely dissolve lipid materials and drugs, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH6.5 for hydration, and then forming the liposome by ultrasonic dispersion through a probe. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 10

example 10 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH6.5 for hydration, and then forming the liposome by ultrasonic dispersion through a probe. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 11

example 11 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH6.5 for hydration, and then forming the liposome by ultrasonic dispersion through a probe. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 12

example 12 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH6.5 for hydration, and then forming the liposome by ultrasonic dispersion through a probe. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 13

example 13 preparative process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH6.5 for hydration, and then forming the liposome by ultrasonic dispersion through a probe. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 14

example 14 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH6.5 for hydration, and then forming the liposome by ultrasonic dispersion through a probe. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 15

example 15 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH6.5 for hydration, and then forming the liposome by ultrasonic dispersion through a probe. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 16

example 16 preparation process: weighing the formulated amounts of Reidesciclovir, Dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylethanolamine-polyethylene glycol 2000(DSPE-PEG2000) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH6.5 for hydration, and then forming the liposome by ultrasonic dispersion through a probe. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 17

example 17 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. 5mL of a phosphate buffer solution of pH6.5 in which a prescribed amount of hydroxypropylmethylcellulose was dissolved was added to hydrate, and then dispersed by ultrasonic dispersion with a probe to form liposomes. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 18

example 18 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. 5mL of pH6.5 phosphate buffer solution in which a prescribed amount of povidone was dissolved was added for hydration, followed by ultrasonic dispersion by a probe to form liposomes. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 19

example 19 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH6.5 dissolved with prescription amount of hyaluronic acid for hydration, and then dispersing by ultrasonic through a probe to form liposome. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 20

example 20 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. 5mL of a phosphate buffer solution of pH6.5 in which a prescribed amount of vitamin C was dissolved was added for hydration, followed by ultrasonic dispersion by a probe to form liposomes. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 21

example 21 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. 5mL of pH6.5 phosphate buffer containing a prescribed amount of vitamin E dissolved therein was added to hydrate, followed by ultrasonic dispersion by a probe to form liposomes. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 22

example 22 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of water for injection to hydrate, and then forming liposome by ultrasonic dispersion through a probe. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 23

example 23 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of 0.9% physiological saline for hydration, and then carrying out ultrasonic dispersion by a probe to form the liposome. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 24

example 24 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of acetate buffer solution with pH4.0 for hydration, and then performing ultrasonic dispersion by a probe to form the liposome. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 25

example 25 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH7.4 for hydration, and then forming the liposome by ultrasonic dispersion through a probe. Centrifuging to remove the unencapsulated drug to obtain the Reed-Sivir liposome for aerosol inhalation.

Example 26

example 26 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH6.5 for hydration, and then forming the liposome by ultrasonic dispersion through a probe. Centrifuging to remove the drug which is not carried, adding 5mL of 10% trehalose solution as a freeze-drying protective agent, and freeze-drying to obtain the lyophilized Reidesvir liposome for aerosol inhalation.

Example 27 screening of Reidesvir liposome reconstitution solvent and stability Studies

The selection of an appropriate redissolving solvent is beneficial to maintaining the particle size, uniformity and suspension state of the liposome. Pure water, 0.9% physiological saline and pH6.5PBS solution are selected as the re-dissolving solvent of the freeze-dried liposome, and the influence of the re-dissolving solvent on the particle size and PDI of the liposome and the stability of the liposome at different temperatures are examined. The results of the experiment are shown in FIGS. 1 and 2.

As can be seen from the figure, under different solvent redissolving conditions, the liposome has good particle size and uniformity, the particle size and PDI are not obviously changed within 10 days, and the preparation stability at 25 ℃ is not obviously different from that at 4 ℃. Therefore, all three solvents can be used for re-dissolving the lyophilized preparation of the Reidesvir liposome.

Example 28 TEM characterization of Reidesvir liposomes

example 28 preparation process: weighing the formulated amounts of Reidesvir, Dipalmitoylphosphatidylcholine (DPPC) and cholesterol in a bottle shaped like a eggplant, adding 15mL of chloroform, ultrasonically dissolving lipid materials and drugs completely, and removing chloroform by evaporation under reduced pressure. Adding 5mL of phosphate buffer solution with pH6.5 for hydration, and then forming the liposome by ultrasonic dispersion through a probe. Centrifuging to remove the drug which is not carried, carefully dropping the preparation solution on a copper net, drying, dropping a drop of 2% phosphotungstic acid staining solution on the copper net for staining for 30s, absorbing the staining solution, drying and taking TEM photography. The results of the experiment are shown in FIG. 3.

According to the figure 3, under TEM, the particle size of the Reidesvir liposome is about 50nm, the shape is round and regular, and the particle size is uniform.

Example 29 in vitro Release Studies of Reidesvir liposomes for Aerosol inhalation

Precisely weighing 3 parts of liposome freeze-dried preparation which is equivalent to 0.5mg of Reidesvir, redissolving the preparation by 2mL of physiological saline, transferring the redissolved preparation into a dialysis bag with Mw of 3500Da, putting the dialysis bag into a dissolution cup, adding 200mL of newly prepared artificial lung fluid, and performing drug release investigation at 37 ℃. Taking 1mL of solution at 5min, 10min, 15min, 30min, 60min, 120min, 240min and 360min, and supplementing 1mL of artificial lung solution into release medium. The content of Reidesciclovir was determined by HPLC. The results of the experiment are shown in FIG. 4.

According to the figure 4, in the artificial lung fluid, the Reidesciclovir can be gradually released from the liposome, and the release degree reaches over 90% within 6h, so that the release is sufficient.

Example 30 in vitro particle size distribution determination of Reidesvir liposomes for aerosol inhalation

The aerosol particle size of the inhaled formulation directly affects the deposition of the drug in the lung, and also has a significant impact on the clinical efficacy. Deposition of particles in the lung is determined primarily by inertial impaction, gravity deposition and diffusion movements, particles typically larger than 10 μm in size are often deposited in the oropharynx due to impaction with the larynx; 5-10 μm particles are mainly deposited in the main airway and oropharynx by inertial collision; the particles with the diameter of 0.3-5 mu m are easy to generate gravity sedimentation and are distributed in peripheral bronchus and alveolus; particles of 0.3 μm are deposited in the alveoli or exhaled out of the lungs mainly by diffusion. Therefore, the determination of the in vitro particle size distribution of pulmonary inhalation formulations is a very important aspect of the development of inhalation products and product quality control.

According to the requirement of 0951 of the fourth general rule of Chinese pharmacopoeia (2020 edition), the Ruidecy Wevir liposome is atomized by an atomizer, and the NGI is used for detecting the particle size distribution. The results of the experiment are shown in FIG. 5.

Table 2 NGI assay results for rdixivir liposomal suspensions

According to the determination result, the average median particle diameter (MMAD) of the Reidesciclovir liposome suspension is about 4 μm, the percentage of Fine Particles (FPF) is more than 50%, and the Geometric Standard Deviation (GSD) is less than 3%, so that the lung administration requirement can be well met.

Example 31 determination of delivery Rate and Total delivery of Reidesvir liposomes for Aerosol inhalation

According to the requirements of the fourth general rule of 0111 of Chinese pharmacopoeia (2020 edition), the Rudexilvir liposome suspension is atomized by an atomizer, the concentration of the Rudevir is 5mg/mL, the volume of the atomized solution is 2mL, and the delivery rate and the total delivery amount are measured by a breathing simulator and a filtering system.

Table 3 delivery rate and total delivery measurements of rdciclovir liposomal suspension

Example 32 Lung tissue active metabolite concentration Studies with Reidesvir liposomes for Aerosol inhalation

Since Reidcciclovir belongs to a prodrug, the half-life in ordinary mice is extremely short (t)_1/2< 5min), difficult to measure, therefore the active metabolite, reed-seivir triphosphate (GS-443902), was selected for the measurement. The triphosphate metabolite has higher concentration in tissue cells and longer half-life (t)_1/222h), which is beneficial to more accurate analysis and determination, and the determination of active metabolites is more significant for the research of drug effect than the prototype drug.

Babl/c mice were selected as experimental animals, and divided into a Reidesvir cyclodextrin intravenous injection group and a Reidesvir liposome inhalation group (n ═ 6), and administered with Reidesvir at a dose of 20mg/kg, and subjected to intravenous injection or tracheal injection. Mice were sacrificed after 1h, 2h, 4h, 8h, 12h, 24h of administration, lung tissue weighed and recorded, 1mL of extract was added for homogenization, 0.1mL of tissue homogenate was added, an internal standard (sofosbuvir triphosphate) was added, vortexed and mixed, and precipitated with methanol. Centrifuging the homogenate for 20000g for 20min, collecting supernatant, volatilizing, redissolving mobile phase, and determining contents of the Rudexiluwei triphosphate by HPLC or LC-MS/MS. The results of the experiment are shown in FIG. 6.

The experimental results show that compared with a Redecevir cyclodextrin intravenous injection group, a tissue drug concentration-time curve of a Redecevir liposome inhalation group is obviously changed, and an active metabolite, namely, Redecevir triphosphate, is in lung tissuesThe accumulation amount of (C) is obviously increased_maxThe lung-specific delivery rate is improved by more than 90 times, and the lung administration mode is mainly adopted in the Reidesvir liposome inhalation group, so that the drug is directly delivered to the lung, and the accumulation of the drug in the lung is facilitated. In addition, the Reidesciclovir liposome inhalation group is compared with the Reidesciclovir cyclodextrin intravenous injection group, C_maxThe appearance time is obviously advanced, which probably is because the liposome has good cell compatibility, can increase the medicine intake of cells, accelerate the Reidesvir to enter the cells, further metabolize into Reidesvir triphosphate, and is beneficial to more quickly exerting the medicine effect.

Example 33 Rysciclovir Liposome safety Studies for Aerosol inhalation

Babl/c mice were selected as experimental animals, and divided into a blank control group, a blank liposome inhalation group, a Reidesciclovir cyclodextrin intravenous injection group, and a Reidesciclovir liposome inhalation group (n ═ 6), and administered with a dosage of 20 mg/kg/day of Reidesciclovir, continuously administered for 10 days, and administered by intravenous injection or nasal drip respectively. At day 11 post-dose, sacrifice, remove blood from the eye, centrifuge (3500rpm, 10min) and remove serum. In each group, lung tissue is homogenized, the homogenate is centrifuged (15000rpm, 10min), supernatant is taken, expression conditions of proinflammatory factor interleukin-6 (IL-6) and inflammation suppressor interleukin-10 (IL-10) in the sample are measured by using an ELISA kit, and inflammation conditions are judged. The results of the experiment are shown in FIGS. 7 and 8.

Because the solubility of the Redexiluwei in water is extremely poor, proper auxiliary materials must be added to increase the solubility so as to achieve the administration concentration. The solubility of the Reidesvir is increased by adopting a cyclodextrin inclusion mode in the currently marketed Reidesvir injection, and the cyclodextrin dosage is large, so that potential safety risks exist. From the data analysis, compared with a blank control group, the proinflammatory factor IL-6 in the serum of the Reidsievir cyclodextrin injection group is increased to a certain degree, and the inflammation-inhibiting factor IL-10 is reduced to a certain degree, which indicates that the Reidsievir cyclodextrin solution is administrated in an intravenous mode, and the risk of causing systemic inflammation possibly exists. Compared with a blank control group, the blank liposome inhalation group and the Reidesvir liposome inhalation group have no obvious change in the expression quantity of each inflammatory factor, which indicates that the injection has good safety.

Claims

1. A Rudexilvir liposome for aerosol inhalation, which is characterized in that: the material comprises the following raw materials in percentage by mass: 0.2-50% of Reidesciclovir or salt thereof, 20-99% of liposome material, 0-50% of stabilizing agent and the balance of aqueous phase medium and organic solvent.

2. A reideciclovir liposome for nebulisation according to claim 1, characterized in that: the liposome material is selected from the group consisting of Egg Phosphatidyl Choline (EPC), Egg Phosphatidyl Glycerol (EPG), Egg Phosphatidyl Inositol (EPI), Egg Phosphatidyl Serine (EPS), phosphatidyl ethanolamine (EPE), phosphatidic acid (EPA), Soybean Phosphatidyl Choline (SPC), Soybean Phosphatidyl Glycerol (SPG), Soybean Phosphatidyl Serine (SPS), Soybean Phosphatidyl Inositol (SPI), Soybean Phosphatidyl Ethanolamine (SPE), Soybean Phosphatidic Acid (SPA), Hydrogenated Egg Phosphatidyl Choline (HEPC), Hydrogenated Egg Phosphatidyl Glycerol (HEPG), Hydrogenated Egg Phosphatidyl Inositol (HEPI), Hydrogenated Egg Phosphatidyl Serine (HEPS), hydrogenated phosphatidyl ethanolamine (HEPE), hydrogenated phosphatidic acid (HEPA), Hydrogenated Soybean Phosphatidyl Choline (HSPC), Hydrogenated Soybean Phosphatidyl Glycerol (HSPG), Hydrogenated Soybean Phosphatidyl Serine (HSPS), Hydrogenated Soybean Phosphatidyl Inositol (HSPI), Hydrogenated Soybean Phosphatidylethanolamine (HSPE), Hydrogenated Soybean Phosphatidic Acid (HSPA), Dipalmitoylphosphatidylcholine (DPPC), Dimyristoylphosphatidylcholine (DMPC), Dimyristoylphosphatidylglycerol (DMPG), Dipalmitoylphosphatidylglycerol (DPPG), Distearoylphosphatidylcholine (DSPC), Distearoylphosphatidylglycerol (DSPG), Dioleylphosphatidylethanolamine (DOPE), palmitoylstearoylphosphatidylglycerol (PSPG), Monooleoylphosphatidylethanolamine (MOPE), tocopherol, the ammonium salts of fatty acids, the ammonium salts of phospholipids, the ammonium salts of glycerides, tetradecylamine, hexadecylamine, dodecylamine, octadecylamine, dilauroylethylphosphonic acid choline (DLEP), Dimyristoylethylphosphocholine (DMEP), Dipalmitoylethylphosphocholine (DPEP) and Distearoylethylphosphonocholine (DSEP), N- (2, 3-di- (9- (Z) -octadecenyloxy) -propanoic acid 1-yl-N, N, N-trimethylammonium chloride (DOTMA), 1, 2-bis (oleoyloxy) -3- (trimethylammonium) propane (DOTAP), Distearoylphosphatidylglycerol (DSPG), dimyristoylphosphatidic acid (DMPA), dipalmitoylphosphatidic acid (DPPA), distearoylphosphatidic acid (DSPA), Dimyristoylphosphatidylglycerol (DMPI), Dipalmitoylphosphatidylglycerol (DPPI), Distearoylphosphatidylinositol (DSPI), Dimyristoylphosphatidylserine (DMPS), Dipalmitoylphosphatidylserine (DPPS), Distearoylphosphatidylserine (DSPS), palmitoyl lysolecithin (P-LysopC), myristoyl lysolecithin (M-LysopC), stearoyl lysolecithin (S-lysoPC), phosphatidylcholine-polyethylene glycol (PC-PEG), phosphatidylethanolamine-polyethylene glycol (PE-PEG), Distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG), distearoylphosphatidylcholine-polyethylene glycol (DSPC-PEG), cholesterol, lanosterol, sitosterol, stigmasterol, ergosterol and one or more of other functionalized phospholipids and water-soluble derivatives of sterols.

3. A reideciclovir liposome for nebulisation according to claim 1, characterized in that: the stabilizer is selected from glycerol, syrup, sorbitol, acacia, agar, carrageenan, guar gum, carrageenan, locust bean gum, pectin, propylene glycol alginate, sodium alginate, tragacanth, xanthan gum, peach gum, starch slurry, carboxymethyl cellulose and its sodium salt, microcrystalline cellulose and its sodium salt, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, colloidal aluminosilicate, one or more of colloidal magnesium aluminate, carbomer, gelatin, polyethylene glycol, polyvidone, hyaluronic acid, chitosan, modified chitosan, amphotericin B, polyamine, stearylamine, arginine, vitamin C, vitamin E, ascorbic acid, butyl hydroxy anisole, dibutyl hydroxy toluene, L-cysteine, sodium sulfite, sodium bisulfite, sodium metabisulfite, tea polyphenols and thimerosal; the organic solvent is selected from one or more of ethanol, methanol, diethyl ether, chloroform, dichloromethane, acetonitrile, acetone, chain, cyclic or aromatic hydrocarbon containing 3-20 carbon atoms, alcohol, amine, ether, ester, ketone, aldehyde and acid.

4. A reideciclovir liposome for nebulisation according to claim 1, characterized in that: the aqueous medium is selected from one or more of water for injection, pure water, aqueous glucose solution, aqueous glucose sodium chloride solution, aqueous phosphate solution, aqueous acetate solution, organic acid or buffer pair with buffer capacity.

5. A reideciclovir liposome for nebulisation according to claim 1, characterized in that: adding a freeze-drying protective agent into the liposome, and freeze-drying to obtain a freeze-dried preparation, wherein an aqueous phase medium is added into the freeze-dried preparation for redissolution before use to form liposome suspension for aerosol inhalation administration.

6. A Reidesciclovir liposome for aerosol inhalation according to claim 5, wherein: the freeze-drying protective agent is selected from trehalose, lactose, sucrose, maltose, glucose, raffinose, fructose, xylitol, sorbitol, mannitol, ethanol, glycerol, propylene glycol, inositol, sodium sulfate, calcium lactate, sodium glutamate, sodium chloride, potassium chloride, sodium thiosulfate, ammonium acetate, ammonium chloride, citric acid, boric acid, phosphoric acid, tartaric acid, proline, 4-hydroxyproline, serine, alanine, lysine, sarcosine, gamma-aminobutyric acid, glutamic acid, arginine, histidine, threonine, aspartic acid, malic acid, lactic acid, ethylene diamine tetraacetic acid, sodium hydroxide, sodium bicarbonate, polyethylene glycol, dextran, povidone, polyvinylpyrrolidone, methyl cellulose, gelatin, pectin, acacia, starch, dextrin, albumin, peptone, polypeptide, dimethyl sulfoxide, vitamin C, sodium chloride, sodium bicarbonate, sodium hydroxide, sodium hydrogen carbonate, polyethylene glycol, dextran, povidone, polyvinylpyrrolidone, methyl cellulose, gelatin, pectin, acacia, dextrin, albumin, peptone, polypeptide, dimethyl sulfoxide, vitamin C, One or more of vitamin E, ascorbic acid, butyl hydroxy anisol, dibutyl hydroxy toluene, L-cysteine, sodium sulfite, sodium bisulfite, sodium pyrosulfite, tea polyphenol and thimerosal.

7. A Reidesciclovir liposome for aerosol inhalation according to claim 5, wherein: the lyophilized preparation keeps a suspension state after being redissolved, does not settle within at least 12 hours, and the content of the remidcvir or the salt thereof after being redissolved is 0.01-20mg/mL calculated by the amount of the free state.

8. A reideciclovir liposome for nebulisation according to claim 1, characterized in that: the particle size of the liposome is 20-1000 nm; the encapsulation rate of the Rudexilvir or the salt thereof is 30-100%; the drug loading rate of the Rudexilvir or the salt thereof is 1-50%.

9. A reideciclovir liposome for nebulisation according to claim 1, characterized in that: after the liposome is atomized, the Mass Median Aerodynamic Diameter (MMAD) of the liposome is between 1 and 8 mu m, the effective deposition rate (FPF) of fine particles is between 30 and 80 percent, and the geometric standard deviation of the particles is less than 3 percent.

10. The process for preparing the rdixivir liposome for aerosol inhalation according to claim 1, wherein: the method comprises the following steps:

(4) dispersing the hydrated solution by using a probe to prepare a liposome;

(6) adding a freeze-drying protective agent and freeze-drying;