WO2021196659A1 - 糖基聚醚类化合物脂质体及其制备方法和药物 - Google Patents

糖基聚醚类化合物脂质体及其制备方法和药物 Download PDF

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WO2021196659A1
WO2021196659A1 PCT/CN2020/130320 CN2020130320W WO2021196659A1 WO 2021196659 A1 WO2021196659 A1 WO 2021196659A1 CN 2020130320 W CN2020130320 W CN 2020130320W WO 2021196659 A1 WO2021196659 A1 WO 2021196659A1
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liposome
drug
liposomes
compound
glycosyl
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刘天罡
黄敏坚
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武汉大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the field of pharmaceutical preparations, in particular to a glycosyl polyether compound liposome and a preparation method and medicine thereof.
  • Glycopolyether compounds are a class of fat-soluble substances and have good application prospects. Both in the field of cancer therapy or in the field of anti-virus, especially in the field of anti-RNA virus, they have shown good therapeutic effects. However, oral administration or intraperitoneal administration makes most of it easy to be metabolized, resulting in low bioavailability, resulting in short administration time and small area of action, which affects the effect of administration.
  • glycopolyether compounds it is very necessary to develop a new dosage form that has good water solubility, fast absorption, and has a certain targeting effect, long-term effect, and controlled release.
  • the present invention solves at least one of the technical problems in the prior art to a certain extent.
  • the present invention provides a glycosyl polyether compound liposome and a preparation method thereof.
  • the provided glycosyl polyether compound liposome is used to treat diseases, and its bioavailability and stability are high.
  • Encapsulate drugs in liposomes to form drug liposomes which can utilize the characteristics of liposomes to make the formed drug liposomes have a targeted dislocation effect, which can reduce drug toxicity, reduce drug consumption, and improve drug efficacy .
  • the drug liposome enters the body, it is preferentially taken up by tissues rich in reticuloendothelial cells such as liver, spleen, lung, bone marrow, etc. Therefore, the glycosyl polyether compound is wrapped in liposomes to prepare drug liposomes, which can increase the dissolution rate and bioavailability of the glycopolyether compound in water, so that the drug is slowly released in various tissues and organs, and the local area is improved. Administration effect.
  • the present invention provides a pharmaceutical liposome, including glycosyl polyether compounds and liposomes, the liposomes encapsulating the Glycopolyether compounds form a double-layer film.
  • the toxicity of the drug can be reduced, and the dosage of the drug can be reduced.
  • the targeting effect and bioavailability of the drug can be improved, thereby increasing The therapeutic effect of glycosyl polyether compounds on diseases.
  • the pharmaceutical liposomes described above may further include the following technical features:
  • the glycosyl polyether compound includes at least one compound selected from the group consisting of a compound having a structural formula represented by formula I or a compound having a structural formula represented by formula II:
  • R 5 is a sugar group or -CH 2 -R 1 ,
  • Each R 1 is independently selected from -H, alkyl, alkylamino, alkoxy, or hydroxy;
  • Each R 2 is independently selected from -H, methyl, alkoxy, or glycosyl.
  • glycosyl polyether compounds show good anti-cancer effects and anti-viral effects, and can improve the bioavailability and disease treatment effects by preparing drug liposomes.
  • the alkylamino group, the alkyl group or the alkoxy group has at most 3 carbon atoms.
  • each R 1 is independently -CH 3 , -CH 2 CH 3 , -OCH 3 , -CH 2 CH 2 CH 3 or -OH.
  • the sugar groups are each independently
  • R 6 is each independently -H, -CH 3 , a saturated chain hydrocarbon with no more than 8 carbons, or a sulfonic acid derivative with no more than 8 carbons.
  • the glycosyl polyether compound includes at least one selected from the group consisting of compounds having the following structural formulas:
  • the mass ratio of the liposome to the glycosyl polyether compound is 5:1-20:1.
  • the obtained drug liposome can realize the encapsulation of the glycopolyether compound by the liposome, and the encapsulation rate can reach more than 80%.
  • the liposome includes cholesterol and at least one of the following substances: ganglioside, phosphatidylcholine, soybean soft phospholipid, hydrogenated soybean phospholipid, polyethylene glycol PEG.
  • the average particle size of the drug liposome is 100-130 nanometers, preferably 100-120 nanometers.
  • the drug liposome has a uniform particle size and can exert a good drug treatment effect in the body.
  • the present invention provides a medicament comprising the pharmaceutical liposome described in the first aspect of the present invention and pharmaceutically acceptable excipients.
  • the drug liposome can be directly used as a drug, and can also be prepared into different drug dosage forms together with pharmaceutically usable auxiliary materials and the like.
  • the medicine may be in at least one of a powder and a liquid preparation.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergies or similar inappropriate reactions, such as gastrointestinal discomfort, dizziness, and the like.
  • the term "pharmaceutically acceptable” as used herein refers to those approved by a federal regulatory agency or a national government or listed in the US Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • the present invention provides a method for preparing pharmaceutical liposomes, which are the pharmaceutical liposomes described in the first aspect of the present invention.
  • the method includes: using an organic solvent to dissolve liposomes and glycosyl polyether compounds; suspended evaporation to remove the organic solvent, mixing with an aqueous medium, and performing ultrasonic treatment to obtain the drug liposomes.
  • the organic solvent can dissolve the liposome and the glycopolyether compound, and after suspension steaming and subsequent ultrasonic treatment, it can promote the liposome to encapsulate the glycopolyether compound, and the obtained drug liposome has a high encapsulation rate.
  • a rotary evaporator can be used at room temperature to perform vacuum distillation to remove most of the organic solvents, and then a nitrogen blower can be used to remove the remaining organic solvents.
  • the method may further include the following technical features:
  • the method further includes: performing pressure treatment after ultrasonic treatment, and filtering with a 100-400 nanometer microporous filter membrane, so as to obtain the drug liposome.
  • performing pressure treatment after ultrasonic treatment and filtering with a 100-400 nanometer microporous filter membrane, so as to obtain the drug liposome.
  • the organic solvent includes trimeric methane and a lower alcohol
  • the lower alcohol has 1 to 5 carbon atoms.
  • the lower alcohol includes at least one selected from methanol and ethanol.
  • the aqueous medium includes at least one selected from sucrose buffer and phosphate buffer
  • the sucrose buffer includes sucrose, glycine and calcium chloride dihydrate
  • the phosphate buffer The pH of the solution is 7.2-7.4.
  • the mass ratio of sucrose, glycine and calcium chloride dihydrate in the sucrose buffer is between 10:1 and 20:1.
  • 2125mg sucrose, 94mg glycine and 7mg calcium chloride dihydrate can be mixed and dissolved in 25ml of aqueous solution. , Preparation of sucrose buffer.
  • the liposomes include cholesterol and other liposomes, and the molar ratio of the other liposomes to the cholesterol is 2:1 to 4:1.
  • a drug liposome with a good membrane structure can be obtained, and the drug encapsulation rate is high.
  • the provided drug liposomes or drugs can be used to prevent or treat diseases related to RNA virus infection. Therefore, the present invention also provides a method for preventing or treating RNA virus infection, comprising: administering a therapeutically effective amount of drug liposomes or drugs to a subject in need, and the drug liposomes are any of the first aspect of the present invention.
  • the drug is the drug according to the second aspect of the present invention.
  • the RNA virus includes at least one including but not limited to Japanese encephalitis virus, Zika virus, dengue virus, new coronavirus, West Nile virus, or Chikungunya virus.
  • the beneficial effects obtained by the present invention are: the drug liposomes provided by the present invention have small particle size, narrow and uniform particle size distribution, and fully ensure the physiological effects of glycosyl polyether compounds. Moreover, the preparation method is simple, and a new approach can be developed for clinical application.
  • Fig. 1 is the blood drug concentration of mice in different treatment groups provided according to an embodiment of the present invention.
  • Fig. 2 is a diagram of the survival situation of breast cancer nude mice in different treatment groups according to an embodiment of the present invention.
  • Fig. 3 is a graph showing changes in body weight of C57 mice in different treatment groups after being infected with Japanese encephalitis virus according to an embodiment of the present invention.
  • Fig. 4 is a graph showing the amount of virus in the blood of C57 mice in different treatment groups one day after being infected with Japanese encephalitis virus according to an embodiment of the present invention.
  • Fig. 5 is a diagram showing the survival of C57 mice in different treatment groups 12 days after being infected with Japanese encephalitis virus according to the present invention.
  • glycosyl polyether compound and “glycosyl polyether compound” refer to polyether compounds with sugar group modification.
  • glycosyl polyether compounds mentioned can exist in the form of isomers, as long as they have anti-viral or anti-cancer therapeutic effects.
  • “Isomers” are different compounds that have the same molecular formula.
  • “Stereoisomers” are isomers that differ only in the arrangement of their atoms in space. The term “isomer” as used herein includes any and all geometric isomers and stereoisomers.
  • isomers include cis and trans isomers, E- and Z-isomers, R- and S-enantiomers, diastereomers, (d) isomers , (1)-isomers, racemic mixtures thereof, and other mixtures thereof falling within the scope of this specification.
  • liposome-encapsulated drugs refer to liposome-encapsulated drugs.
  • liposome-encapsulated glycopolyether compounds can be called glycopolyether compound liposomes.
  • liposome-encapsulated maduramycin can be called maduramycin liposome.
  • the mentioned liposomes are generally understood in the art and refer to lipid molecules capable of forming a lipid bilayer, including but not limited to cholesterol, gangliosides, phosphatidylcholines, soybean soft phospholipids, hydrogenated soybean phospholipids, Polyethylene glycol PEG.
  • glycosyl polyether compound used can be obtained by self-preparation or directly purchased.
  • Example 1 Maduramycin was used as a representative compound of the compound represented by formula I, and liposome encapsulation was performed.
  • the specific structural formula of Maduramycin is as follows:
  • sucrose buffer (2125mg of sucrose, 94mg of glycine and 7mg of calcium chloride dihydrate can be mixed and dissolved in 25ml of aqueous solution to prepare sucrose buffer), in a water bath at 50°C
  • a high-pressure homogenizer adjust the pressure to uniformly increase from 500 psi to 1500 psi, maintain for 5 minutes, and then squeeze through the 400nm, 200nm, 100nm microporous membranes for 2 times to make the average particle size It reaches about 100nm, and measures the average particle size with a particle size detector to obtain a suspension containing liposome-encapsulated glycopolyether compounds with a uniform particle size.
  • J1-001-1 was used as the representative compound of the compound represented by formula II to carry out liposome encapsulation.
  • the specific structural formula of J1-001-1 is as follows:
  • sucrose buffer After the organic solvent is removed, add a certain amount of sucrose buffer, sonicate it in a water bath at 50°C for 20 minutes, place it in a high-pressure homogenizer, adjust the pressure to uniformly increase from 500psi to 1500psi, maintain it for 5 minutes, and then sequentially Extrude twice through the 400nm, 200nm, 100nm microporous filter membrane to make the average particle size reach about 100nm, and measure the average particle size with a particle size detector to obtain the liposome-encapsulated sugar with uniform particle size.
  • Suspensions of base polyether compounds Suspensions of base polyether compounds.
  • Example 3 J1-001-2 was used as the representative compound of the compound represented by formula II, and liposome encapsulation was performed.
  • the specific structure of the compound is as follows:
  • Example 4 J1-001-3 was used as the representative compound of the compound represented by formula II to carry out liposome encapsulation.
  • the specific structural formula of the compound is as follows:
  • Example 5 J1-001-4 was used as the representative compound of the compound represented by formula II to carry out liposome encapsulation.
  • the structural formula of the compound is as follows:
  • the method for determining the entrapment efficiency of maduramycin liposomes is as follows: First, use blank liposomes to pre-saturate Sephadex G50 (2 ⁇ 80cm) column (eliminate the adsorption of gel liposomes), and take 1 mL The maduramycin liposome suspension prepared in Example 1 above was applied to the column, and the aqueous medium (sucrose buffer and phosphate buffer) was used as the eluent, and the flow rate was controlled at 0.5-0.8 mL/min.
  • the mass of maduramycin in the liposomes it is calculated that the encapsulation rate of maduramycin in liposomes is 85.93%.
  • the determination method of liposome-encapsulated J1-001-1, J1-001-2, J1-001-3 or J1-001-4 Analytical HPLC determination.
  • the encapsulation efficiency of liposome-encapsulated J1-001-1, J1-001-2, J1-001-3 or J1-001-4 is 83.65%, 88.48%, 84.64%, 89.36%, respectively.
  • aqueous medium sucrose buffer and phosphate buffer
  • the average particle size of maduramycin liposomes, J1-001-1 liposomes, J1-001-2 liposomes, J1-001-3 liposomes, and J1-001-4 liposomes The diameters are 110nm, 105nm, 121nm, 115nm, 108nm, 102nm, respectively.
  • nude mice (Balb/c) with half male and female, each weighing 28-30g, divided into two groups, labeled as maduramycin free group and maduramycin liposome group.
  • the cultured and collected A549 lung cancer cells were inoculated into the abdominal cavity of nude mice to establish a nude mouse model of lung cancer transplantation tumor.
  • the volume of the subcutaneous tumor is about 100 mm 3
  • the intraperitoneal administration is started, and the dosage is 2 mg/kg/day.
  • the administration period was 10 days, and the blood of the mice was collected 3 hours after the administration to measure the blood drug concentration. The result is shown in Figure 1.
  • the distribution of the maduramycin liposome group and the maduramycin free group in the heart, kidney, spleen, and liver of the mice were compared. Except for the content of the two groups in the heart tissue, there was almost no change.
  • the maduramycin free group and the maduramycin liposome group decreased the maduramycin content in kidney tissue by 83.15%, the maduramycin content in liver tissue decreased by 78.96%, and the maduramycin content in spleen tissue was decreased by 78.96%.
  • the content of maduramycin decreased by 35.19%, and the content of maduramycin in tumor tissues increased by 65.78%.
  • the experimental results fully show that the drug liposomes described in the present invention have a targeted regulation effect on drug distribution, and that liposome-encapsulated drug liposomes will improve the therapeutic effect of breast cancer and reduce liver cancer Toxic side effects in kidney and other tissues.
  • Figure 2 is a graph of the survival of breast cancer nude mice in different treatment groups. It is not difficult to see from Figure 2 that the nude mice in the maduramycin liposome group have been alive, while the nude mice in the free maduramycin group died after 7 days. This result shows that compared with free maduramycin, maduramycin encapsulated in liposomes has a better therapeutic effect on cancer.
  • mice Select female C57 mice about 4 weeks old, and use JEV virus for drug in vivo inhibition verification experiment, set up mock group (non-challenged and non-medicated mice are normal mice) and WT group (only challenged mice) , Maduramycin liposome high-dose group (1.0mg/kg/day), Maduramycin liposome low-dose group (0.2mg/kg/day), each group contains 5 mice.
  • the administration method is intraperitoneal administration every day, and the administration period is 7 days.
  • mice The blood of the mice was drawn to detect the amount of virus after the administration, and the survival status of the mice and the changes in the body weight of the mice were observed at the same time. After the experiment, the mice were euthanized.
  • Figure 3 shows the results of changes in body weight of C57 mice in different treatment groups after being infected with Japanese encephalitis virus
  • Figure 4 shows the results of blood levels of C57 mice in different treatment groups after being infected with Japanese encephalitis virus for 1 day
  • Number A is the WT group
  • number B is the low-dose maduramycin liposome group
  • number C is the high-dose maduramycin liposome group
  • Figure 5 shows the results of the survival of mice in different treatment groups 12 days after virus infection.
  • the experimental results showed that after 1 day of administration of the high-dose maduramycin liposome group (1.0mg/kg/day), the amount of virus in the blood of mice decreased by 2 orders of magnitude; the low-dose maduramycin liposome group (0.2mg/kg/day) One day after the administration, the amount of virus in the blood of the mice dropped by an order of magnitude.
  • the drugs were administered for 7 days, and the mice in the high-dose group (1.0 mg/kg/day) did not die after 12 days after the administration.
  • the low-dose maduramycin liposome group (0.2 mg/kg/day) ) After the tenth day, some mice died. Therefore, the experimental results show that maduramycin liposomes can inhibit the Japanese encephalitis virus in mice and achieve the therapeutic effect.
  • J1-001-1 liposomes, J1-001-2 liposomes, J1-001-3 liposomes, J1-001-4 liposomes, etc. were used to treat the infection according to the same method as in Example 9 above.
  • Mice treated with Japanese encephalitis virus can also inhibit the virus in the mice, showing a good therapeutic effect. And compared with the free glycopolyether compound, it shows a better and lasting therapeutic effect.
  • RNA viruses such as Zika virus, dengue virus, new coronavirus, West Nile virus, or Chikungunya virus
  • Maduramycin liposomes J1-001- 1 Liposomes, J1-001-2 liposomes, J1-001-3 liposomes, J1-001-4 liposomes, etc. are treated in the same way as in Example 9 above, and can also inhibit the in vivo Virus, showing a good therapeutic effect.

Abstract

提供了一种糖基聚醚类化合物脂质体及其制备方法和药物。糖基聚醚类化合物脂质体包括糖基聚醚化合物和脂质体，通过脂质体包裹糖基聚醚类化合物形成双层膜。提供的糖基聚醚类化合物脂质体粒径小，粒度分布窄而均匀，充分保证了发挥糖基聚醚类化合物的生理功效，而且制备方法简单。

Description

糖基聚醚类化合物脂质体及其制备方法和药物 技术领域
本发明涉及药物制剂领域，具体涉及一种糖基聚醚类化合物脂质体及其制备方法和药物。
背景技术
糖基聚醚类化合物是一类脂溶性物质，具有良好的应用前景，无论是在癌症治疗领域还是在抗病毒领域，尤其是抗RNA病毒领域，均表现出良好的治疗效果。但是口服或腹腔等方式给药，使其大部分容易被代谢，导致其生物利用度低，造成给药时间短、作用面积小，影响了给药效果。
因此，针对糖基聚醚类化合物，开发一种水溶性好、吸收快，并且具有一定靶向作用、长效、控制释放的新剂型是非常必要的。
发明内容
本发明至少在一定程度上解决现有技术中的技术问题至少之一。为此，本发明提供了一种糖基聚醚类化合物脂质体及其制备方法。应用所提供的糖基聚醚类化合物脂质体治疗疾病，其生物利用度好、稳定性高。
将药物包封于脂质体中，形成药物脂质体，能够利用脂质体的特性，使得形成的药物脂质体具有靶向走位作用，可降低药物毒性，减少药物用量，提高药物疗效。而且当药物脂质体进入体内，优先被富含网状内皮细胞的组织如肝、脾、肺、骨髓等所摄取。因此，将糖基聚醚类化合物利用脂质体包裹制备为药物脂质体，可增加糖基聚醚类化合物在水中溶出度与生物利用度，使药物在各组织器官中缓慢释放，提高局部给药效果。
具体而言，本发明提供了如下技术方案：在本发明的第一方面，本发明提供了一种药物脂质体，包括糖基聚醚化合物和脂质体，所述脂质体包裹所述糖基聚醚类化合物形成双层膜。通过将糖即聚醚化合物包裹于脂质体中，形成药物脂质体，一方面可以降低药物的毒性，减少药物用量，重要的是，能够提高药物的靶向作用以及生物利用度，从而提高糖基聚醚化合物对于疾病的治疗效果。
根据本发明的实施例，以上所述的药物脂质体可以进一步包括如下技术特征：
根据本发明的实施例，所述糖基聚醚类化合物包括选自具有式I所示结构式的化合物或者具有式II所示结构式的化合物中的至少一种：
Figure PCTCN2020130320-appb-000001
其中，
R 3为
Figure PCTCN2020130320-appb-000002
或者
Figure PCTCN2020130320-appb-000003
R 4为
Figure PCTCN2020130320-appb-000004
或者
Figure PCTCN2020130320-appb-000005
R 5为糖基或-CH 2-R 1，
各R 1各自独立地选自-H、烷基、烷氨基、烷氧基或者羟基；
各R 2各自独立地选自-H、甲基、烷氧基或糖基。
这些糖基聚醚类化合物表现为良好的抗癌效果和抗病毒效果，可以通过制备药物脂质体，提高生物利用度和疾病治疗效果。
根据本发明的实施例，所述烷氨基、烷基或所述烷氧基最多具有3个碳原子。
根据本发明的实施例，各R 1各自独立地为-CH 3、-CH 2CH 3、-OCH 3、-CH 2CH 2CH 3或-OH。
根据本发明的实施例，所述糖基各自独立地为
Figure PCTCN2020130320-appb-000006
或者
Figure PCTCN2020130320-appb-000007
其中R 6各自独立地为-H、-CH 3、不超过8个碳的饱和链烃、或不超过8个碳的磺酸基衍生物。
根据本发明的实施例，所述糖基聚醚化合物包括选自具有下列结构式的化合物中的至少一种：
Figure PCTCN2020130320-appb-000008
根据本发明的实施例，所述脂质体与所述糖基聚醚化合物的质量比为5：1～20：1。在该条件下，所获得的药物脂质体，能够实现脂质体对于糖基聚醚化合物的包裹，包封率达到80％以上。
根据本发明的实施例，所述脂质体包括胆固醇和下列中至少一种物质：神经节苷脂、磷脂酰胆碱、大豆软磷脂、氢化大豆磷脂、聚乙二醇PEG。利用胆固醇和其他的脂质体来制备药物脂质体，药物脂质体的双层膜结构更加完整，而且包封率高。
根据本发明的实施例，所述药物脂质体的平均粒径为100～130纳米，优选为100～120纳米。药物脂质体粒径均一，能够在体内发挥良好的药物治疗效果。
在本发明的第二方面，本发明提供了一种药物，包括本发明第一方面所述的药物脂质体和药学上可接受的辅料。该药物脂质体可以直接作为药物使用，也可以和药学上可用的辅料等一起制备成不同的药物剂型。根据本发明的实施例，所述药物可以呈粉末剂、液体制剂中的至少一种。所提到的“药学上可接受的”是指当给人施用时生理上可耐受的并且一般不产生过敏或相似不适当的反应，例如肠胃不适、眩晕等的分子实体和组合物。优选地，本文所用的术语“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可的药典上列举的在动物中、更特别在人体中使用的。
在本发明的第三方面，本发明提供了一种制备药物脂质体的方法，所述药物脂质体为本发明第一方面所述的药物脂质体。所述方法包括：利用有机溶剂溶解脂质体和糖基聚醚化合物；悬蒸去除所述有机溶剂，与水相介质混合，进行超声处理，以便获得所述药物脂质体。通过有机溶剂能够溶解脂质体和糖基聚醚化合物，经过悬蒸和后续的超声处理，能够促进脂质体包裹糖基聚醚化合物，所获得的药物脂质体的包封率高。可以在常温下采用旋转蒸发仪进行减压蒸馏除去大部分有机溶剂，后用氮吹仪除去残留有机溶剂。
根据本发明的实施例，所述方法可以进一步包括如下技术特征：
根据本发明的实施例，所述方法进一步包括：在超声处理后进行施压处理，并采用100～400纳米的微孔滤膜进行过滤，以便获得所述药物脂质体。由此可以获得粒径均一的药物脂质体。
根据本发明的实施例，所述有机溶剂包括三聚甲烷和低级醇，所述低级醇的碳原子数为1～5个。优选地，所述低级醇包括选自甲醇、乙醇中的至少一种。由此可以溶解脂质体和糖基聚醚类化合物，获得高包封率的药物脂质体。
根据本发明的实施例，所述水相介质包括选自蔗糖缓冲液、磷酸盐缓冲液中的至少一种，所述蔗糖缓冲液包括蔗糖、甘氨酸和二水合氯化钙，所述磷酸盐缓冲液的pH值为7.2-7.4。蔗糖缓冲液中蔗糖、甘氨酸和二水合氯化钙的质量比为10:1至20:1之间，例如可以将2125mg蔗糖，94mg甘氨酸和7mg二水合氯化钙混合，溶于25毫升水溶液中，制 备蔗糖缓冲液。
所述脂质体包括胆固醇和其他脂质体，所述其他脂质体与所述胆固醇的摩尔比为2：1～4：1。由此可以获得膜结构好的药物脂质体，而且药物的包封率高。
所提供的药物脂质体或者药物能够用于预防或治疗RNA病毒感染相关的疾病。因此，本发明还提供了一种预防或治疗RNA病毒感染的方法，包括：向所需要的对象施用治疗有效量的药物脂质体或者药物，所述药物脂质体为本发明第一方面任一实施例所述的药物脂质体，所述药物为本发明第二方面所述的药物。
根据本发明的实施例，所述RNA病毒包括包括但不限于日本脑炎病毒、寨卡病毒、登革热病毒、新型冠状病毒、西尼罗河病毒或基孔肯雅病毒的至少一种等。
本发明所取得的有益效果为：本发明所提供的药物脂质体粒径小，粒度分布窄而均匀，充分保证了发挥糖基聚醚类化合物的生理功效。而且制备方法简单，能够为临床应用开发一条新的途径。
附图说明
图1是根据本发明的实施例提供的不同处理组小鼠的血药浓度。
图2是根据本发明的实施例提供的不同处理组的乳腺癌裸鼠的存活情况图。
图3是根据本发明的实施例提供的不同处理组的C57小鼠感染日本脑炎病毒后体重的变化图。
图4是根据本发明的实施例提供的不同处理组的C57小鼠感染日本脑炎病毒后1天后血液的病毒量图。
图5是根据本发明的是实施例提供的不同处理组的C57小鼠感染日本脑炎病毒后12天后小鼠的存活情况图。
具体实施方式
下面详细描述本发明的实施例，需要说明的是，所描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。同时对本文中的一些术语进行解释和说明，以方便本领域技术人员的理解，需要说明的是，这些解释和说明仅用于方便理解，而不应看做是对本发明保护范围的限制。
本文中，无论是“糖基聚醚化合物”、“糖基聚醚类化合物”均是指带有糖基修饰的聚醚类化合物。本文中，所提到的糖基聚醚化合物可以以异构体的方式存在，只要具有抗病毒或者抗癌等治疗效果即可。“异构体”为具有相同分子式的不同化合物。“立体异构体”为仅 仅原子的空间排列方式不同的异构体。如本文使用的术语“异构体”包括任何和所有的几何异构体和立体异构体。例如，“异构体”包括顺式和反式异构体、E-和Z-异构体、R-和S-对映异构体、非对映异构体、(d)异构体、(l)-异构体、其外消旋混合物、及落入本说明书范围的其它其混合物。
本文中所提到的药物脂质体，是指脂质体包裹的药物，例如脂质体包裹的糖基聚醚化合物可以称为糖基聚醚化合物脂质体。具体地，脂质体包裹的马杜拉霉素可以称为马杜拉霉素脂质体。
所提到的脂质体作本领域通常理解，指能够形成类脂质双分子层的脂分子，包括但不限于胆固醇，神经节苷脂、磷脂酰胆碱、大豆软磷脂、氢化大豆磷脂、聚乙二醇PEG。
本文中，所用到的糖基聚醚化合物可以通过自己制备获得，也可以直接购买获得。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1脂质体包裹马杜拉霉素(也称为马杜拉霉素脂质体)
实施例1以马度拉霉素作为式I所示化合物的代表化合物，进行脂质体包裹。其中马度拉霉素的具体结构式如下：
Figure PCTCN2020130320-appb-000009
具体制备步骤如下：
(1)称取20g大豆软磷脂、10g胆固醇与5g马杜拉霉素，置于圆底瓶中；
(2)取15mL的三氯甲烷和2mL甲醇的混合溶剂溶解；
(3)溶解后的溶液置于常温下的旋转蒸发仪中，减压蒸馏除去大部分有机溶剂，后用氮吹仪除去残留有机溶剂；
(4)去除有机溶剂后，加入一定量的蔗糖缓冲液(可以将2125mg蔗糖，94mg甘氨酸和7mg二水合氯化钙混合，溶于25毫升水溶液中，制备蔗糖缓冲液)，在50℃水浴下超声20分钟后，置于高压匀浆机内，调节压力从500psi均匀增加到1500psi，维持时间5分钟，后依次通过400nm，200nm，100nm的微孔滤膜进行挤压2次，使平均粒径达到100nm 左右，并用粒径检测仪测量粒径均大小，以便获得粒径大小均一的含有脂质体包裹的糖基聚醚类化合物的混悬液。
实施例2脂质体包裹J1-001-1(也称为J1-001-1脂质体)
实施例2以J1-001-1作为式II所示化合物的代表化合物，进行脂质体包裹。其中J1-001-1的具体结构式如下：
Figure PCTCN2020130320-appb-000010
具体制备步骤如下：
(1)称取25g神经节苷脂、10g胆固醇与5g J1-001-1，置于圆底瓶中；
(2)取15mL的三氯甲烷和2mL甲醇的混合溶剂溶解；
(3)使溶液溶解后，置于常温下的旋转蒸发仪中，减压蒸馏除去大部分有机溶剂，后用氮吹仪除去残留有机溶剂；
(4)有机溶剂去除后，加入一定量的蔗糖缓冲液，在50℃水浴下超声20分钟后，置于高压匀浆机内，调节压力从500psi均匀增加到1500psi，维持时间5分钟，后依次通过400nm，200nm，100nm的微孔滤膜进行挤压2次，使平均粒径达到100nm左右，并用粒径检测仪测量粒径均大小，以便获得粒径大小均一的含有脂质体包裹的糖基聚醚类化合物的混悬液。
实施例3脂质体包裹J1-001-2(也称为J1-001-2脂质体)
实施例3以J1-001-2作为式II所示化合物的代表化合物，进行脂质体包裹。其中该化合物的具体结构如下：
Figure PCTCN2020130320-appb-000011
具体制备步骤如下：
(1)称取25g神经节苷脂、10g胆固醇与5g J1-001-2，置于圆底瓶中；
(2)取15mL的三氯甲烷和2mL甲醇的混合溶剂溶解；
(3)使溶液溶解后，置于常温下的旋转蒸发仪中，减压蒸馏除去大部分有机溶剂，后用氮吹仪除去残留有机溶剂；
(4)有机溶剂去除后，加入一定量的磷酸盐缓冲液，在50℃水浴下超声20分钟后，置于高压匀浆机内，调节压力从500psi均匀增加到1500psi，维持时间5分钟，后依次通过400nm，200nm，100nm的微孔滤膜进行挤压2次，使平均粒径达到100nm左右，并用粒径检测仪测量粒径均大小，以便获得粒径大小均一的含有脂质体包裹糖基聚醚类化合物的混悬液。
实施例4脂质体包裹J1-001-3(也称为J1-001-3脂质体)
实施例4以J1-001-3作为式II所示化合物的代表化合物，进行脂质体包裹。该化合物的具体结构式如下：
Figure PCTCN2020130320-appb-000012
具体制备步骤如下：
(1)称取25g神经节苷脂、10g胆固醇与5g J1-001-3，置于圆底瓶中；
(2)取15mL的三氯甲烷和2mL甲醇的混合溶剂溶解；
(3)使溶液溶解后，置于常温下的旋转蒸发仪中，减压蒸馏除去大部分有机溶剂，后用氮吹仪除去残留有机溶剂；
(4)有机溶剂去除后，加入一定量的磷酸盐缓冲液，在50℃水浴下超声20分钟后，置于高压匀浆机内，调节压力从500psi均匀增加到1500psi，维持时间5分钟，后依次通过400nm，200nm，100nm的微孔滤膜进行挤压2次，使平均粒径达到100nm左右，并用粒径检测仪测量粒径均大小，以便获得粒径大小均一的含有脂质体包裹的糖基聚醚类化合物的混悬液。
实施例5脂质体包裹J1-001-4(也称为J1-001-4脂质体)
实施例5以J1-001-4作为式II所示化合物的代表化合物，进行脂质体包裹。该化合物的结构式如下：
Figure PCTCN2020130320-appb-000013
(1)称取25g神经节苷脂、10g胆固醇与5g J1-001-4，置于圆底瓶中；
(2)取15mL的三氯甲烷和2mL甲醇的混合溶剂溶解；
(3)使溶液溶解后，置于常温下的旋转蒸发仪中，减压蒸馏除去大部分有机溶剂，后用氮吹仪除去残留有机溶剂；
(4)有机溶剂去除后，加入一定量的水相介质，在50℃水浴下超声20分钟后，置于高压匀浆机内，调节压力从500psi均匀增加到1500psi，维持时间5分钟，后依次通过400nm，200nm，100nm的微孔滤膜进行挤压2次，使平均粒径达到100nm左右，并用粒径检测仪测量粒径均大小，以便获得粒径大小均一的含有脂质体包裹的糖基聚醚类化合物的混悬液。
实施例6各脂质体包裹糖基聚醚化合物的包封率测定
马杜拉霉素脂质体包封率的测定方法如下：首先用空白脂质体预先饱和葡聚糖凝胶G50(2×80cm)柱(消除凝胶脂质体的吸附作用)，取lmL上述实施例1制备的马杜拉霉素脂质体混悬液上柱，以水相介质(蔗糖缓冲液和磷酸盐缓冲液)为洗脱液，流速控制在0.5-0.8mL/min，弃去含有空白脂质体的流出液约12mL，收集含有游离马杜拉霉素的滤液，用正己烷萃取，浓缩除去正己烷，测得游离马杜拉霉素的质量。
根据脂质体中马杜拉霉素的质量，计算得到利用脂质体包裹马杜拉霉素，其包封率为85.93％。
脂质体包裹的J1-001-1、J1-001-2、J1-001-3或J1-001-4的测定方法：采用分析性的HPLC测定。首先用游离的药物在HPLC上建立标准曲线(HPLC条件为：C18反相柱；流动相：水-甲醇-四氢呋喃梯度洗脱；柱温度为室温；检测波长为239nm，流速为1mL/min，进样量为10μL)，然后采用相同的条件对脂质体包裹的各糖基聚醚化合物进行HPLC检测。
通过计算得到脂质体包裹J1-001-1、J1-001-2、J1-001-3或J1-001-4的包封率分别为83.65％、88.48％、84.64％、89.36％。
实施例7脂质体包裹糖基聚醚化合物的粒径测定
取脂质体包裹的各糖基聚醚化合物适量，用水相介质(蔗糖缓冲液和磷酸盐缓冲液) 为稀释液，将脂质体混悬液稀释至适当倍数，利用粒径测量仪进行测量。
经测定，马杜拉霉素脂质体、J1-001-1脂质体、J1-001-2脂质体、J1-001-3脂质体、J1-001-4脂质体的平均粒径分别为110nm、105nm、121nm、115nm、108nm、102nm。
实施例8马杜拉霉素脂质体对乳腺癌小鼠模型的疗效
选用裸鼠(Balb/c)20只雌雄各半，每只鼠的重量在28-30g，分为两组，分别标记为马杜拉霉素游离组和马杜拉霉素脂质体组，将培养收集的A549肺癌细胞接种于裸鼠腹腔体内，建立肺癌移植瘤裸鼠模型。当皮下瘤体积为100mm 3左右时，开始腹腔给药，给药量均为2mg/kg/天。给药周期为10天，每天给药后3小时收集小鼠血液测量血药浓度。其结果如图1所示。从图1可以看出，马杜拉霉素脂质体组的血药浓度远高于马杜拉霉素游离组(马杜拉霉素游离组裸鼠在7天后死亡，所以后续未采集该组裸鼠的血药浓度)。
将马杜拉霉素脂质体组与马杜拉霉素游离组小鼠在心、肾、脾、肝中的分布情况进行比较，除心组织中两组的含量几乎无变化外，相较于马杜拉霉素游离组，马杜拉霉素脂质体组在肾组织中马杜拉霉素含量下降83.15％，肝组织中马杜拉霉素含量下降78.96％，脾组织中马杜拉霉素含量下降35.19％，肿瘤组织中马杜拉霉素含量增加65.78％。
因此，实验结果充分显示了本发明中所述的药物脂质体对药物分布具有靶向调节作用，显示经过脂质体包裹的药物脂质体将会提高乳腺癌的治疗效果，并降低在肝肾等组织中的毒副作用。
图2为不同处理组乳腺癌裸鼠的存活情况图，从图2中不难看出马杜拉霉素脂质体组裸鼠一直存活，而马杜拉霉素游离组裸鼠在7天后死亡。该结果说明，相较于游离马杜拉霉素，经过脂质体包裹的马杜拉霉素对于癌症的治疗效果更好。
实施例9马杜拉霉素脂质体在C57小鼠体内对日本脑炎病毒(JEV)的抑制活性
选取4周左右的雌性C57小鼠，用JEV病毒进行药物体内抑制验证实验，设置mock组(不攻毒和不加药物的小鼠即正常小鼠)、WT组(只攻毒的小鼠)、马杜拉霉素脂质体高剂量组(1.0mg/kg/天)、马杜拉霉素脂质体低剂量组(0.2mg/kg/天)，每组为5只小鼠。给药方式为每天腹腔给药，给药周期为7天。
抽取小鼠血液，检测给药后的病毒量，同时观察小鼠的存活状态与小鼠体重变化。实验结束后为小鼠安乐死。
实验结果图3、图4、图5所示。其中图3为不同处理组的C57小鼠感染日本脑炎病毒后体重的变化结果图，图4为不同处理组的C57小鼠感染日本脑炎病毒1天后血液的病毒 量结果图，图4中编号A为WT组，编号B为马杜拉霉素脂质体低剂量组，编号C为马杜拉霉素脂质体高剂量组。图5为不同处理组感染病毒后12天后小鼠的存活情况结果图。
实验结果显示，马杜拉霉素脂质体高剂量组(1.0mg/kg/天)给药1天后，小鼠血液的病毒量下降了2个数量级；马杜拉霉素脂质体低剂量组(0.2mg/kg/天)给药1天后，小鼠血液的病毒量下降了1个数量级。药物均给药7天，且在给毒后12天后高剂量组小鼠(1.0mg/kg/天)没有出现死亡情况，马杜拉霉素脂质体低剂量组(0.2mg/kg/天)在第十天后部分小鼠出现死亡。因此，实验结果表明马杜拉霉素脂质体能够抑制小鼠体内的日本脑炎病毒，达到治疗的效果。
同样地，采用J1-001-1脂质体、J1-001-2脂质体、J1-001-3脂质体、J1-001-4脂质体等按照上述实施例9相同的方法对感染了日本脑炎病毒的小鼠进行治疗，也能够抑制小鼠体内的病毒，表现出良好的治疗效果。且相较于游离的糖基聚醚化合物表现出更加良好和持久的治疗效果。
同样地，采用其他的RNA病毒，例如寨卡病毒、登革热病毒、新型冠状病毒、西尼罗河病毒或基孔肯雅病毒等感染小鼠，同时采用马杜拉霉素脂质体、J1-001-1脂质体、J1-001-2脂质体、J1-001-3脂质体、J1-001-4脂质体等按照上述实施例9相同的方法进行治疗，也能够抑制小鼠体内的病毒，表现出良好的治疗效果。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (20)

  1. 一种药物脂质体，其特征在于，包括糖基聚醚化合物和脂质体，所述脂质体包裹所述糖基聚醚类化合物形成双层膜。
  2. 根据权利要求1所述的药物脂质体，其特征在于，所述糖基聚醚类化合物包括选自具有式I所示结构式的化合物或者式II所示结构式的化合物中至少一种：
    Figure PCTCN2020130320-appb-100001
    其中，R 3为
    Figure PCTCN2020130320-appb-100002
    或者
    Figure PCTCN2020130320-appb-100003
    R 4为
    Figure PCTCN2020130320-appb-100004
    或者
    Figure PCTCN2020130320-appb-100005
    R 5选自糖基或-CH 2-R 1；
    各R 1各自独立地选自-H、烷基、烷氨基、烷氧基或者羟基；
    各R 2各自独立地选自-H、甲基、烷氧基或糖基；
  3. 根据权利要求2所述的药物脂质体，其特征在于，所述烷基、烷氨基或所述烷氧基至多具有3个碳原子。
  4. 根据权利要求2所述的药物脂质体，其特征在于，各R 1各自独立地为-CH 3、-CH 2CH 3、-OCH 3、-CH 2CH 2CH 3或-OH。
  5. 根据权利要求2所述的药物脂质体，其特征在于，所述糖基各自独立地为
    Figure PCTCN2020130320-appb-100006
    或者
    Figure PCTCN2020130320-appb-100007
    R 6各自独立地为-H、-CH 3、不超过8个碳的饱和链烃、或不超过8个碳的磺酸基衍生物。
  6. 根据权利要求1所述的药物脂质体，其特征在于，所述糖基聚醚化合物包括选自具有下列结构式的化合物中的至少一种：
    Figure PCTCN2020130320-appb-100008
    Figure PCTCN2020130320-appb-100009
  7. 根据权利要求1所述的药物脂质体，其特征在于，所述脂质体与所述糖基聚醚化合物的质量比为5：1～20：1。
  8. 根据权利要求1所述的药物脂质体，其特征在于，所述脂质体包括胆固醇和下列中至少一种物质：神经节苷脂、磷脂酰胆碱、大豆软磷脂、氢化大豆磷脂、聚乙二醇PEG。
  9. 根据权利要求1所述的药物脂质体，其特征在于，所述药物脂质体的平均粒径为100～130纳米。
  10. 根据权利要求1所述的药物脂质体，其特征在于，所述药物脂质体的平均粒径为100～120纳米。
  11. 一种药物，其特征在于，包括权利要求1～10中任一项所述的药物脂质体和药学上可接受的辅料。
  12. 根据权利要求11所述的药物，其特征在于，所述药物呈粉末剂、液体制剂中的至少一种。
  13. 一种制备权利要求1～10中任一项所述的药物脂质体的方法，其特征在于，包括：
    利用有机溶剂溶解脂质体和糖基聚醚化合物；
    悬蒸去除所述有机溶剂，与水相介质混合，进行超声处理，以便获得所述药物脂质体。
  14. 根据权利要求13所述的方法，其特征在于，进一步包括：
    在超声处理后，进行施压处理，并采用100～400纳米的微孔滤膜进行过滤，以便获得所述药物脂质体。
  15. 根据权利要求13所述的方法，其特征在于，所述有机溶剂包括三聚甲烷和低级醇，所述低级醇的碳原子数为1～5个。
  16. 根据权利要求15所述的方法，其特征在于，所述低级醇包括选自甲醇、乙醇中的至少一种。
  17. 根据权利要求13所述的方法，其特征在于，所述水相介质包括选自蔗糖缓冲液、磷酸盐缓冲液中的至少一种，所述蔗糖缓冲液包括蔗糖、甘氨酸和二水合氯化钙，所述磷酸盐缓冲液的pH值为7.2-7.4。
  18. 根据权利要求13所述的方法，其特征在于，所述脂质体包括胆固醇和其他脂质体，所述其他脂质体与所述胆固醇的摩尔比为2：1～4：1。
  19. 一种预防或治疗RNA病毒感染的方法，其特征在于，包括：向所需要的对象施用治疗有效量的药物脂质体或者药物，所述药物脂质体为权利要求1～10任一项所述的药物脂质体，所述药物为权利要求11或12所述的药物。
  20. 根据权利要求19所述的方法，其特征在于，所述RNA病毒包括日本脑炎病毒、寨卡病毒、登革热病毒、新型冠状病毒、西尼罗河病毒或基孔肯雅病毒的至少一种。
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