CN113456591B - Glycosyl polyether compound liposome and preparation method and medicament thereof - Google Patents

Glycosyl polyether compound liposome and preparation method and medicament thereof Download PDF

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CN113456591B
CN113456591B CN202010244757.0A CN202010244757A CN113456591B CN 113456591 B CN113456591 B CN 113456591B CN 202010244757 A CN202010244757 A CN 202010244757A CN 113456591 B CN113456591 B CN 113456591B
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liposome
polyether compound
glycosyl
organic solvent
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CN113456591A (en
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刘天罡
黄敏坚
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Wuhan Hesheng Technology Co ltd
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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
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
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    • 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
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Abstract

The invention provides a glycosyl polyether compound liposome, a preparation method thereof and a medicament. The glycosyl polyether compound liposome comprises a glycosyl polyether compound and a liposome, wherein the glycosyl polyether compound is wrapped by the liposome to form a bilayer membrane. Which is prepared by dissolving a liposome and a sugar-based polyether compound with an organic solvent; removing the organic solvent by suspension evaporation, mixing with a water phase medium, and performing ultrasonic treatment to obtain the product. The provided medicine comprises the glycosyl polyether compound liposome. The glycosyl polyether compound liposome provided by the invention has small particle size and narrow and uniform particle size distribution, fully ensures the physiological effect of the glycosyl polyether compound, and has simple preparation method.

Description

Glycosyl polyether compound liposome and preparation method and medicament thereof
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a glycosyl polyether compound liposome, a preparation method thereof and a medicament.
Background
The glycosyl polyether compound is a fat-soluble substance, has good application prospect, and shows good treatment effect in the field of cancer treatment or anti-virus, especially anti-RNA virus. However, most of the medicine is easy to metabolize by oral or abdominal administration, so that the bioavailability is low, the administration time is short, the action area is small, and the administration effect is influenced.
Therefore, it is very necessary to develop a new dosage form which has good water solubility, fast absorption, certain targeting effect, long-acting effect and controlled release for glycosyl polyether compounds.
Disclosure of Invention
The present invention solves at least one of the technical problems of the prior art to at least a certain extent. Therefore, the invention provides a glycosyl polyether compound liposome and a preparation method thereof. The glycosyl polyether compound liposome is used for treating diseases, and has good bioavailability and high stability.
The medicine is encapsulated in the liposome to form the medicine liposome, and the characteristics of the liposome can be utilized to ensure that the formed medicine liposome has the function of targeted dislocation, thereby reducing the toxicity of the medicine, reducing the dosage of the medicine and improving the curative effect of the medicine. Moreover, when the liposome is introduced into 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 prepared into the drug liposome by liposome encapsulation, so that the dissolution rate and bioavailability of the glycosyl polyether compound in water can be increased, the drug can be slowly released in various tissues and organs, and the local administration effect is improved.
Specifically, the invention provides the following technical scheme: in a first aspect of the invention, the invention provides a drug liposome, which comprises a glycosyl polyether compound and a liposome, wherein the liposome wraps the glycosyl polyether compound to form a bilayer membrane. The sugar, namely the polyether compound, is wrapped in the liposome to form the drug liposome, so that on one hand, the toxicity of the drug can be reduced, the dosage of the drug is reduced, and importantly, the targeting effect and bioavailability of the drug can be improved, thereby improving the treatment effect of the glycosyl polyether compound on diseases.
According to an embodiment of the present invention, the pharmaceutical liposome described above may further include the following technical features:
according to an embodiment of the present invention, the sugar-based polyether compound includes at least one selected from a compound having a structural formula shown in formula I or a compound having a structural formula shown in formula II:
Figure GDA0003626818940000021
wherein the content of the first and second substances,
R3is composed of
Figure GDA0003626818940000022
Or
Figure GDA0003626818940000023
R4Is composed of
Figure GDA0003626818940000024
Or
Figure GDA0003626818940000025
R5Is glycosyl or-CH2-R1，
Each R1Each independently selected from-H, alkyl, alkylamino, alkoxy or hydroxy;
each R2Each independently selected from-H, methyl, alkoxy or glycosyl.
The glycosyl polyether compounds have good anticancer effect and antiviral effect, and can improve bioavailability and disease treatment effect by preparing medicinal liposome.
According to an embodiment of the invention, said alkylamino, alkyl or said alkoxy group has at most 3 carbon atoms.
According to an embodiment of the invention, each R1Each independently is-CH3、-CH2CH3、-OCH3、-CH2CH2CH3or-OH.
According to an embodiment of the invention, each of said glycosyl groups is independently
Figure GDA0003626818940000031
Or
Figure GDA0003626818940000032
Wherein R is6Each independently is-H, -CH3Saturated chain hydrocarbons of no more than 8 carbons, or sulfonic acid derivatives of no more than 8 carbons.
According to an embodiment of the present invention, the sugar-based polyether compound includes at least one selected from the group consisting of compounds having the following structural formula:
Figure GDA0003626818940000033
Figure GDA0003626818940000041
according to an embodiment of the present invention, the mass ratio of the liposome to the sugar-based polyether compound is 5: 1-20: 1. under the condition, the obtained medicinal liposome can wrap the glycosyl polyether compound, and the entrapment rate reaches more than 80%.
According to an embodiment of the invention, the liposome comprises cholesterol and at least one of the following: ganglioside, phosphatidyl choline, soybean lecithin, hydrogenated soybean lecithin, and polyethylene glycol (PEG). The liposome is prepared from cholesterol and other liposomes, and the bilayer membrane structure of the liposome is more complete and has high entrapment rate.
According to the embodiment of the invention, the average particle size of the drug liposome is 100-130 nm, preferably 100-120 nm. The medicinal liposome has uniform particle size, and can exert good medicinal treatment effect in vivo.
In a second aspect of the invention, there is provided a medicament comprising a pharmaceutical liposome according to the first aspect of the invention and a pharmaceutically acceptable excipient. The medicinal liposome can be directly used as a medicament, and can also be prepared into different medicament forms together with pharmaceutically available auxiliary materials and the like. According to an embodiment of the present invention, the drug may be in at least one of a powder formulation, a liquid formulation. Reference to "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and do not typically produce allergic or similar untoward reactions, such as gastrointestinal upset, dizziness and the like. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by a federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
In a third aspect of the invention, there is provided a method of preparing a pharmaceutical liposome according to the first aspect of the invention. The method comprises the following steps: dissolving the liposome and the glycosyl polyether compound by using an organic solvent; removing the organic solvent by rotary evaporation, mixing with an aqueous medium, and performing ultrasonic treatment to obtain the drug liposome. The liposome and the glycosyl polyether compound can be dissolved by an organic solvent, and the glycosyl polyether compound can be promoted to be wrapped by the liposome through rotary evaporation and subsequent ultrasonic treatment, so that the obtained medicinal liposome has high encapsulation rate. Most of the organic solvent can be removed by reduced pressure distillation at normal temperature by using a rotary evaporator, and then the residual organic solvent can be removed by using a nitrogen blowing instrument.
According to an embodiment of the present invention, the method may further include the following technical features:
according to an embodiment of the invention, the method further comprises: and (3) after ultrasonic treatment, performing pressure treatment, and filtering by adopting a microporous filter membrane of 100-400 nanometers so as to obtain the medicinal liposome. Thus, a liposome of a drug having a uniform particle size can be obtained.
According to the embodiment of the invention, the organic solvent comprises trimeric methane and lower alcohol, and the number of carbon atoms of the lower alcohol is 1-5. Preferably, the lower alcohol includes at least one selected from methanol and ethanol. Therefore, the liposome and the glycosyl polyether compound can be dissolved, and the medicinal liposome with high encapsulation efficiency is obtained.
According to an embodiment of the present invention, the aqueous medium comprises at least one selected from the group consisting of sucrose buffer comprising sucrose, glycine and calcium chloride dihydrate, and phosphate buffer having a pH value of 7.2 to 7.4. The mass ratio of sucrose, glycine and calcium chloride dihydrate in the sucrose buffer is 10:1 to 20:1, and for example, 2125mg of sucrose, 94mg of glycine and 7mg of calcium chloride dihydrate are mixed and dissolved in 25 ml of an aqueous solution to prepare the sucrose buffer.
The liposome comprises cholesterol and other liposome, and the molar ratio of the other liposome to the cholesterol is 2: 1-4: 1. therefore, the medicine liposome with good membrane structure can be obtained, and the entrapment rate of the medicine is high.
The beneficial effects obtained by the invention are as follows: the medicinal liposome provided by the invention has small particle size and narrow and uniform particle size distribution, and fully ensures the physiological effect of the glycosyl polyether compound to be exerted. And the preparation method is simple, and a new way can be developed for clinical application.
Drawings
Fig. 1 is a graph of blood drug levels in mice of different treatment groups provided in accordance with an embodiment of the present invention.
Figure 2 is a graph of the survival of breast cancer nude mice of different treatment groups provided according to an embodiment of the present invention.
Figure 3 is according to the embodiment of the invention provides different treatment groups of C57 mice infected with Japanese encephalitis virus after the change in body weight graph.
Figure 4 is according to the embodiment of the invention provides different treatment groups of C57 mice infected with Japanese encephalitis virus 1 days after the viral load graph of blood.
Figure 5 is an example of different treatment groups of C57 mice infected with Japanese encephalitis virus 12 days after the mice survival diagram.
Detailed Description
The following detailed description of embodiments of the invention is intended to be illustrative, and is not to be construed as limiting the invention. While certain terms have been explained and illustrated herein to facilitate understanding by those skilled in the art, it is to be understood that such explanations and illustrations are provided for convenience and should not be construed as limiting the scope of the invention.
Herein, both "glycosyl polyether compound" and "glycosyl polyether compound" refer to polyether compounds with glycosyl modification. Herein, the sugar-based polyether compound may be present in an isomeric form as long as it has a therapeutic effect against viruses or cancers, etc. "isomers" are different compounds having the same molecular formula. "stereoisomers" are isomers that differ only in the spatial arrangement of the atoms. The term "isomer" as used herein includes any and all geometric isomers and stereoisomers. For example, "isomers" include cis and trans isomers, E-and Z-isomers, R-and S-enantiomers, diastereomers, (d) isomers, (l) -isomers, racemic mixtures thereof, and other mixtures thereof falling within the scope of the present specification.
As used herein, a drug liposome refers to a liposome-encapsulated drug, for example, a liposome-encapsulated glycosyl polyether compound can be referred to as a glycosyl polyether compound liposome. In particular, liposome-encapsulated maduramicin may be referred to as maduramicin liposomes.
Reference to liposomes is generally understood in the art to refer to lipid molecules capable of forming lipid-like bilayers, including but not limited to cholesterol, gangliosides, phosphatidylcholine, soy lecithin, hydrogenated soy phospholipids, polyethylene glycol PEG.
Herein, the sugar-based polyether compound to be used may be obtained by self-preparation or may be directly purchased.
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples do not specify particular techniques or conditions, and are performed according to techniques or conditions described in literature in the art or according to the product specification. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1 Liposome encapsulation of Maduramycin (also known as Maduramycin liposomes)
Example 1 encapsulation in liposomes was performed with maduramicin as a representative compound of the compound of formula I. The specific structural formula of the maduramicin is as follows:
Figure GDA0003626818940000061
the preparation method comprises the following specific steps:
(1) weighing 20g of soybean lecithin, 10g of cholesterol and 5g of maduramicin, and placing the mixture in a round-bottomed bottle;
(2) dissolving 15mL of a mixed solvent of trichloromethane and 2mL of methanol;
(3) putting the dissolved solution into a rotary evaporator at normal temperature, distilling under reduced pressure to remove most of the organic solvent, and removing residual organic solvent by using a nitrogen blowing instrument;
(4) removing organic solvent, adding a certain amount of sucrose buffer solution (prepared by mixing 2125mg sucrose, 94mg glycine and 7mg calcium chloride dihydrate, dissolving in 25 ml water solution), performing ultrasonic treatment in 50 deg.C water bath for 20 min, placing in a high-pressure homogenizer, adjusting pressure to be uniformly increased from 500psi to 1500psi, maintaining for 5 min, sequentially extruding with 400nm, 200nm and 100nm microporous filter membranes for 2 times to make average particle diameter reach about 100nm, and measuring the average particle diameter with a particle diameter detector to obtain suspension containing liposome-coated glycosyl polyether compound with uniform particle diameter.
EXAMPLE 2 Liposomal encapsulation J1-001-1 (also known as J1-001-1 liposomes)
Example 2 Liposomal encapsulation was performed using J1-001-1 as a representative compound of the compound represented by formula II. Wherein the specific structural formula of J1-001-1 is as follows:
Figure GDA0003626818940000071
the preparation method comprises the following specific steps:
(1) weighing 25g of ganglioside, 10g of cholesterol and 5g J1-001-1, and placing in a round-bottomed bottle;
(2) dissolving 15mL of a mixed solvent of trichloromethane and 2mL of methanol;
(3) dissolving the solution, placing the solution in a rotary evaporator at normal temperature, distilling under reduced pressure to remove most of the organic solvent, and removing residual organic solvent with a nitrogen blowing instrument;
(4) after removing the organic solvent, adding a certain amount of sucrose buffer solution, carrying out ultrasonic treatment in a water bath at 50 ℃ for 20 minutes, placing the mixture in a high-pressure homogenizer, adjusting the pressure to be uniformly increased from 500psi to 1500psi, maintaining the pressure for 5 minutes, then sequentially extruding the mixture for 2 times through 400nm, 200nm and 100nm microporous filter membranes to enable the average particle size to reach about 100nm, and measuring the average particle size by using a particle size detector so as to obtain the suspension containing the liposome-coated glycosyl polyether compound with uniform particle size.
EXAMPLE 3 Liposomal encapsulation J1-001-2 (also known as J1-001-2 liposomes)
Example 3 Liposomal encapsulation was performed using J1-001-2 as a representative compound of the compound represented by formula II. Wherein the specific structure of the compound is as follows:
Figure GDA0003626818940000072
the preparation method comprises the following specific steps:
(1) weighing 25g of ganglioside, 10g of cholesterol and 5g J1-001-2, and placing in a round-bottomed bottle;
(2) dissolving 15mL of a mixed solvent of trichloromethane and 2mL of methanol;
(3) dissolving the solution, placing the solution in a rotary evaporator at normal temperature, distilling under reduced pressure to remove most of the organic solvent, and removing residual organic solvent with a nitrogen blowing instrument;
(4) removing the organic solvent, adding a certain amount of phosphate buffer solution, carrying out ultrasonic treatment in a water bath at 50 ℃ for 20 minutes, placing the mixture in a high-pressure homogenizer, adjusting the pressure to be uniformly increased from 500psi to 1500psi, maintaining the pressure for 5 minutes, extruding the mixture for 2 times through 400nm, 200nm and 100nm microporous filter membranes in sequence to enable the average particle size to reach about 100nm, and measuring the average particle size by using a particle size detector so as to obtain the suspension containing the liposome-coated glycosyl polyether compound with uniform particle size.
Example 4 Liposomal encapsulation J1-001-3 (also known as J1-001-3 liposomes)
Example 4 Liposomal encapsulation was performed using J1-001-3 as a representative compound of the compound represented by formula II. The specific structural formula of the compound is as follows:
Figure GDA0003626818940000081
the preparation method comprises the following specific steps:
(1) weighing 25g of ganglioside, 10g of cholesterol and 5g J1-001-3, and placing in a round-bottomed bottle;
(2) dissolving 15mL of a mixed solvent of trichloromethane and 2mL of methanol;
(3) dissolving the solution, placing the solution in a rotary evaporator at normal temperature, distilling under reduced pressure to remove most of the organic solvent, and removing residual organic solvent with a nitrogen blowing instrument;
(4) removing the organic solvent, adding a certain amount of phosphate buffer solution, carrying out ultrasonic treatment in a water bath at 50 ℃ for 20 minutes, placing the mixture in a high-pressure homogenizer, adjusting the pressure to be uniformly increased from 500psi to 1500psi, maintaining the pressure for 5 minutes, extruding the mixture for 2 times through 400nm, 200nm and 100nm microporous filter membranes in sequence to enable the average particle size to reach about 100nm, and measuring the average particle size by using a particle size detector so as to obtain the liposome-coated glycosyl polyether compound-containing suspension with uniform particle size.
EXAMPLE 5 Liposome encapsulation J1-001-4 (also known as J1-001-4 liposome)
Example 5 Liposomal encapsulation was performed using J1-001-4 as a representative compound of the compound represented by formula II. The structural formula of the compound is as follows:
Figure GDA0003626818940000091
(1) weighing 25g of ganglioside, 10g of cholesterol and 5g J1-001-4, and placing in a round-bottomed bottle;
(2) dissolving 15mL of a mixed solvent of trichloromethane and 2mL of methanol;
(3) dissolving the solution, placing the solution in a rotary evaporator at normal temperature, distilling under reduced pressure to remove most of the organic solvent, and removing residual organic solvent with a nitrogen blowing instrument;
(4) removing the organic solvent, adding a certain amount of aqueous medium, carrying out ultrasonic treatment in a water bath at 50 ℃ for 20 minutes, placing the mixture in a high-pressure homogenizer, adjusting the pressure to be uniformly increased from 500psi to 1500psi, maintaining the pressure for 5 minutes, extruding the mixture for 2 times through 400nm, 200nm and 100nm microporous filter membranes in sequence to enable the average particle size to reach about 100nm, and measuring the average particle size by using a particle size detector so as to obtain the liposome-coated glycosyl polyether compound-containing suspension with uniform particle size.
EXAMPLE 6 encapsulation efficiency measurement of Each liposome-entrapped glycosyl polyether Compound
The method for measuring the encapsulation efficiency of the maduramicin liposome comprises the following steps: first, a column of Sephadex G50 (2X 80cm) was preliminarily saturated with blank liposomes (adsorption of geliposomes was eliminated), lmL of the maduramicin liposome suspension prepared in example 1 was loaded onto the column, an aqueous medium (sucrose buffer and phosphate buffer) was used as an eluent, the flow rate was controlled to 0.5-0.8mL/min, about 12mL of the effluent containing blank liposomes was discarded, the filtrate containing free maduramicin was collected, extracted with n-hexane, and concentrated to remove n-hexane, and the quality of free maduramicin was determined.
According to the mass of maduramicin in the liposome, the encapsulation rate of the maduramicin encapsulated by the liposome is 85.93 percent.
Methods for assaying liposome-encapsulated J1-001-1, J1-001-2, J1-001-3, or J1-001-4: analytical HPLC determination was used. Firstly, a standard curve is established on HPLC by using free drugs (HPLC condition is that a C18 reversed phase column is adopted, mobile phase is that water-methanol-tetrahydrofuran gradient elution is adopted, column temperature is room temperature, detection wavelength is 239nm, flow rate is 1mL/min, and sample injection amount is 10 mu L), and then HPLC detection is carried out on each glycosyl polyether compound wrapped by liposome by adopting the same condition.
The encapsulation efficiency of the liposome-encapsulated J1-001-1, J1-001-2, J1-001-3 or J1-001-4 is 83.65%, 88.48%, 84.64% and 89.36% respectively by calculation.
Example 7 particle size measurement of Liposome-Encapsulated glycosyl polyether Compound
Taking a proper amount of each glycosyl polyether compound wrapped by the liposome, taking aqueous phase media (sucrose buffer solution and phosphate buffer solution) as diluent, diluting the liposome suspension to a proper multiple, and measuring by using a particle size measuring instrument.
The average particle diameters of maduramicin liposome, J1-001-1 liposome, J1-001-2 liposome, J1-001-3 liposome and J1-001-4 liposome are respectively 110nm, 105nm, 121nm, 115nm, 108nm and 102 nm.
Example 8 therapeutic efficacy of maduramicin liposomes on mouse models of breast cancer
20 nude mice (Balb/c) are selected to be male and female, each mouse has the weight of 28-30g and is divided into two groups, the two groups are respectively marked as a maduramicin free group and a maduramicin liposome group, A549 lung cancer cells cultured and collected are inoculated in the abdominal cavity of the nude mice, and a lung cancer transplantation tumor nude mouse model is established. When the volume of subcutaneous tumor is 100mm3At the left and right, the administration of the drug into the abdominal cavity is started, and the dosage is 2 mg/kg/day. The administration period was 10 days, and blood concentration in the blood was measured by collecting blood of the mice 3 hours after the administration each day. The results are shown in FIG. 1. As can be seen from fig. 1, the plasma concentration of maduramicin liposome group was much higher than that of maduramicin free group (nude mice in maduramicin free group died after 7 days, so the plasma concentration of nude mice in this group was not collected subsequently).
Compared with the maduramicin free group, the maduramicin liposome group has 83.15% lower maduramicin content in kidney tissue, 78.96% lower maduramicin content in liver tissue, 35.19% lower maduramicin content in spleen tissue and 65.78% higher maduramicin content in tumor tissue compared with the maduramicin free group except that the contents of the two groups in heart tissue are almost unchanged.
Therefore, the experimental results fully show that the drug liposome has a targeted regulation effect on drug distribution, and show that the drug liposome coated by the liposome can improve the treatment effect of breast cancer and reduce the toxic and side effects in tissues such as liver and kidney.
FIG. 2 is a graph showing the survival of nude mice with breast cancer in different treatment groups, and it can be easily seen from FIG. 2 that nude mice in maduramicin liposome group survived all the time, while nude mice in maduramicin free group died after 7 days. The results indicate that liposome-encapsulated maduramicin is more effective in the treatment of cancer than free maduramicin.
Example 9 inhibitory Activity of Maduramycin liposomes against Japanese Encephalitis Virus (JEV) in C57 mice
Female C57 mice of about 4 weeks are selected, JEV is used for carrying out drug in vivo inhibition verification experiments, and a mock group (mice without toxicity attack and without drugs, namely normal mice), a WT group (mice only with toxicity attack), a maduramicin liposome high dose group (1.0 mg/kg/day) and a maduramicin liposome low dose group (0.2 mg/kg/day) are set, wherein each group comprises 5 mice. The administration mode is intraperitoneal administration every day, and the administration period is 7 days.
Blood was drawn from the mice, and the amount of virus after administration was measured, while observing the survival state of the mice and the change in body weight of the mice. Mice were euthanized at the end of the experiment.
The experimental results are shown in fig. 3, 4 and 5. Wherein FIG. 3 is a graph showing the results of the change in body weight of C57 mice in different treatment groups after being infected with Japanese encephalitis virus, FIG. 4 is a graph showing the results of the amount of virus in blood of C57 mice in different treatment groups after being infected with Japanese encephalitis virus for 1 day, in FIG. 4, reference number A is a WT group, reference number B is a maduramicin liposome low dose group, and reference number C is a maduramicin liposome high dose group. FIG. 5 is a graph showing the results of mice survival after 12 days of virus infection in different treatment groups.
The experimental results show that the virus amount of the blood of the mice is reduced by 2 orders of magnitude after the maduramicin liposome high-dose group (1.0 mg/kg/day) is administrated for 1 day; after administration of the maduramicin liposome low dose group (0.2 mg/kg/day) for 1 day, the viral load in the blood of mice decreased by 1 order of magnitude. The drugs were all administered for 7 days, and no mortality occurred in the high dose group (1.0 mg/kg/day) and in the low dose group (0.2 mg/kg/day) of maduramicin liposomes after 12 days post-administration, some of the mice died after the tenth day. Therefore, the experimental result shows that the maduramicin liposome can inhibit Japanese encephalitis virus in mice to achieve the treatment effect.
Similarly, the use of J1-001-1 liposome, J1-001-2 liposome, J1-001-3 liposome, J1-001-4 liposome and the like in accordance with the above example 9 in mice infected with Japanese encephalitis virus treatment, can also inhibit the virus in mice, showing good therapeutic effect. And shows a more excellent and lasting therapeutic effect compared to the free glycosyl polyether compound.
Similarly, when mice were infected with other RNA viruses, such as Zika virus, dengue virus, novel coronavirus, West Nile virus, and chikungunya virus, and treated with maduramicin liposome, J1-001-1 liposome, J1-001-2 liposome, J1-001-3 liposome, and J1-001-4 liposome in the same manner as in example 9, the viruses in the mice could be inhibited, and a good therapeutic effect could be exhibited.
In the description of the specification, reference to the description of "one embodiment," "some embodiments," "an example," "a specific example," or "some examples" or the like means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (12)

1. The drug liposome is characterized by comprising a glycosyl polyether compound and a liposome, wherein the glycosyl polyether compound is wrapped by the liposome to form a double-layer membrane;
the sugar-based polyether compound includes at least one selected from the group consisting of compounds having the following structural formula:
Figure FDA0003626818930000011
the liposome comprises cholesterol and at least one of the following substances: ganglioside, phosphatidyl choline, soybean lecithin, hydrogenated soybean lecithin, and polyethylene glycol (PEG).
2. The pharmaceutical liposome of claim 1, wherein the mass ratio of the liposome to the sugar-based polyether compound is 5: 1-20: 1.
3. the pharmacosome of claim 1, wherein the average particle size of the pharmacosome is 100 to 130 nm.
4. The drug liposome of claim 1, wherein the average particle size of the drug liposome is 100-120 nm.
5. A medicament comprising a pharmaceutical liposome according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient.
6. The medicament of claim 5, wherein the medicament is in at least one of a powder formulation and a liquid formulation.
7. A method of preparing a pharmacosome according to any one of claims 1 to 4, comprising:
dissolving the liposome and the glycosyl polyether compound by using an organic solvent;
removing the organic solvent by rotary evaporation, mixing with an aqueous medium, and performing ultrasonic treatment to obtain the drug liposome.
8. The method of claim 7, further comprising:
and after ultrasonic treatment, performing pressure application treatment, and filtering by adopting a microporous filter membrane of 100-400 nanometers so as to obtain the medicinal liposome.
9. The method according to claim 7, wherein the organic solvent comprises trimeric methane and a lower alcohol, and the number of carbon atoms of the lower alcohol is 1-5.
10. The method of claim 9, wherein the lower alcohol comprises at least one selected from the group consisting of methanol and ethanol.
11. The method according to claim 7, wherein the aqueous medium comprises at least one selected from the group consisting of a sucrose buffer comprising sucrose, glycine and calcium chloride dihydrate, and a phosphate buffer having a pH of 7.2 to 7.4.
12. The method of claim 7, wherein the liposomes comprise cholesterol and other liposomes in a molar ratio of 2: 1-4: 1.
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