CN117024381A - Cabazitaxel derivative and liposome preparation thereof - Google Patents

Abstract

Cabazitaxel derivatives and liposome preparations thereof belong to the field of medical technology. The present invention relates to cabazitaxel derivatives and liposome preparations thereof as represented by the general formula (I) or (II), specifically cabazitaxel. Synthesis of derivatives and liposome formulations containing the derivatives. The cabazitaxel derivative has stronger tumor cell toxicity. After being prepared into liposomes, it can effectively reduce the amount of impurities produced during the preparation process, thereby avoiding a series of safety studies required for preparation development and reducing development costs. The liposome preparation involved in the invention has better medicinal efficacy.

Description

Cabazitaxel derivatives and liposome preparations thereof

Technical field

The invention belongs to the field of medical technology and relates to cabazitaxel derivatives and preparations thereof. Specifically, it relates to the synthesis of cabazitaxel derivatives and liposome preparations containing the derivatives and their application in drug delivery systems.

Background technique

Cabazitaxel (CTX) is a second-generation taxane drug with broad-spectrum anti-tumor activity. Its mechanism of action is similar to that of paclitaxel and docetaxel. It binds to tubulin and acts in the M phase of cells to inhibit cell proliferation. Due to the methylation of the 7- and 10-position hydroxyl groups in the structure, cabazitaxel has a lower affinity for P-glycoprotein, which can overcome the problem of multidrug resistance to other taxanes and treat docetaxel. drug-resistant tumors. Sanofi-Aventis develops cabazitaxel injection It was approved by the U.S. Food and Drug Administration (FDA) in June 2010 for use in combination with prednisone to treat advanced metastatic castration-resistant prostate cancer after treatment with docetaxel.

Cabazitaxel has poor water solubility and commercially available preparations Using Tween 80 and 13% (w/w) ethanol as co-solvents, studies have shown that the use of Tween 80 can cause severe hemolytic reactions, allergic reactions, and peripheral neuropathy. In addition, the injection has serious side effects, such as reduced white blood cell levels, severe gastrointestinal problems (gastric or intestinal leakage, intestinal obstruction, infection, and gastric or intestinal bleeding), and kidney failure. Clinical trial results show that the maximum tolerated dose of cabazitaxel is 25 mg/m ² , which is much lower than the other two types of taxane anti-tumor drugs. In addition,/> Because it is necessary to use 13% (w/w) ethanol to dissolve and dilute before administration, and then use sterile saline or 5% glucose solution for secondary dilution, the final infusion solution is easy to precipitate, has poor stability, and cannot be stored for a long time. use.

In order to solve the shortcomings of commercially available preparations of cabazitaxel, it is necessary to develop new preparations that can improve the anti-tumor effect of cabazitaxel and have low side effects. Liposomes are bilayer vesicles composed of lipids. Liposomes are an ideal drug carrier system with many advantages: they are similar in shape to cell membranes and have good biocompatibility and biodegradability; they can carry water-soluble drugs, poorly soluble drugs and biological macromolecules; they are easy to chemically Modifications to improve drug delivery; protect drugs from effects such as enzymatic degradation, immunity, and chemical inactivation in the body. The researchers also found that surface-modified polyethylene glycol liposomes can significantly improve the stability and blood circulation time in the body after intravenous administration, and reduce the recognition and adsorption of liposomes by macrophages, thereby improving the efficiency of liposome drugs. therapeutic effect. Liposomes can be loaded with drugs through passive drug loading and active drug loading. Current research on cabazitaxel liposomes is mostly passive drug-loading liposomes. However, liposomes prepared through passive drug loading have low drug loading, are prone to leakage, have poor stability, and may also experience rapid drug release. The active drug loading method uses the principle that the neutral form of weakly acidic and weakly base drugs can cross the lipid bilayer, enter the internal aqueous phase, and then protonate and form a stable complex with counterions, without the ability to cross the membrane. .

Cabazitaxel has poor water solubility and is a hydrophobic uncharged compound, so it cannot be encapsulated in liposomes by active drug loading. Therefore, a nitrogen-containing group can be connected to the 2’-hydroxyl group of cabazitaxel through an esterification reaction to make the derivative weakly alkaline, and the active drug loading method can be used to achieve high drug loading and high encapsulation efficiency.

During the preparation process of liposome preparations, factors such as the pH of the internal and external water phases in the liposome preparation formula and process, and the drug loading temperature may lead to the degradation of derivatives, thus introducing new impurities. The limit of degradation products in new drug preparations stipulates that when the maximum daily dose is 10 to 100 mg, if the degradation products exceed 0.5%, a series of safety experimental studies need to be carried out, which will bring about a substantial increase in research and development costs, and may cause degradation The increase in products leads to an increase in the toxic and side effects of the preparation, so controlling the amount of impurities is of great significance to the development of cabazitaxel preparations.

Contents of the invention

For cabazitaxel injection currently used clinically There are problems such as high toxic and side effects. The present invention synthesizes two weakly alkaline cabazitaxel derivatives and uses an active drug loading method to prepare liposome preparations with high drug loading capacity, high encapsulation rate and good stability.

Through comparative studies, it was found that compared with the cabazitaxel derivative CN1 (CN111004195A) disclosed by the inventor, the cabazitaxel derivative designed and synthesized by the present invention has significantly reduced unknown impurities after being prepared into liposomes, thus improving the safety of the preparation. , and can effectively reduce development costs. The structural formula of CN1 is:

The purpose of the present invention is to weakly alkalize cabazitaxel and prepare it into a liposome nanodrug delivery system, so as to give it long circulation properties in the blood for anti-tumor research.

The present invention achieves the above objects through the following technical solutions:

The cabazitaxel derivative or its pharmaceutically acceptable salt according to the present invention has a structure represented by general formula (I) or (II):

Among them, n=1～5;

Further, the cabazitaxel derivative or a pharmaceutically acceptable salt thereof is selected from the following compounds:

The pharmaceutically acceptable salt is a salt formed by the cabazitaxel derivative and a pharmaceutically acceptable inorganic acid or organic acid.

The synthesis method of cabazitaxel derivatives provided by the invention includes the following steps:

Under the catalysis of DMAP and EDCI, 4-diethylaminobutyric acid or 4-(4-methyl-1-piperazinyl)butyric acid and cabazitaxel undergo an esterification reaction and are separated and purified. The entire reaction was carried out under _N2 protection.

Further, the present invention provides a liposome containing a cabazitaxel derivative, wherein the liposome contains a weakly basic derivative of cabazitaxel, phospholipids, cholesterol, and PEGylated phospholipids. The weight ratio of the cabazitaxel derivative to the total lipid is 0.10 to 0.50, preferably the weight ratio is 0.15 to 0.45, and the total lipid is the sum of phospholipids, cholesterol and/or PEGylated phospholipids. The dosages of phospholipids, cholesterol, and PEGylated phospholipids are conventional dosages in this field.

The invention also provides a method for preparing the liposomes containing cabazitaxel derivatives, which includes the following steps:

(1) Weigh the membrane materials required to prepare liposomes, prepare liposomes using the film dispersion method, ethanol injection method or cross-flow mixing method, and squeeze them through polycarbonate membranes of different pore sizes in sequence to form nanoparticles. size of small unilamellar liposomes;

(2) Replace the external water phase of the small single-chamber liposome obtained in step (1) to obtain a blank liposome with a gradient between the internal and external water phases of the liposome;

(3) Add the organic solution of the cabazitaxel derivative to the gradient blank liposome obtained in step (2), and incubate to obtain the cabazitaxel derivative liposome preparation.

Preferably, in step (2), the internal aqueous phase solution is citric acid solution, ammonium sulfate solution, sulfobutyl ether-β-cyclodextrin triethylammonium salt solution or sucrose octasulfate triethylammonium salt solution .

Further preferably, the internal aqueous phase solution is sucrose octasulfate triethylammonium salt solution.

Preferably, in step (2), the external aqueous phase solution is sucrose solution and histidine solution, HEPES buffer, phosphate buffer or acetate buffer.

Further preferably, the external aqueous phase solution is sucrose solution and histidine solution.

Preferably, in step (3), the solvent of the organic solution is methanol, ethanol, acetone, tetrahydrofuran, acetonitrile or DMSO; the organic solvent is removed by tangential ultrafiltration, dialysis and other methods.

Further preferably, the solvent of the organic solution is DMSO.

By preparing cabazitaxel into a weakly alkaline derivative and then using it to prepare liposomes, the present invention solves the problem of side effects caused by Tween 80 in cabazitaxel injection, and can also increase its anti-tumor effect and has a relatively high Great potential for clinical application.

The present invention also provides the use of the cabazitaxel derivative or its pharmaceutically acceptable salt or the liposome containing the cabazitaxel derivative in the preparation of a drug delivery system.

The present invention also provides the use of the cabazitaxel derivative or its pharmaceutically acceptable salt or the liposome containing the cabazitaxel derivative in the preparation of anti-tumor drugs.

The advantages of the liposome nanodrug delivery system of the present invention are: (1) small and uniform particle size (~100nm), which is beneficial to enrichment into tumor sites through the EPR effect; (2) high drug loading capacity and high encapsulation It has good efficiency and stability, is conducive to reducing adverse reactions caused by excipients and biological materials, and is easy to industrialize; (3) effectively avoids uptake by the reticuloendothelial system, achieves long circulation in the blood, and increases the reach of tumor sites probability; (4) compared with commercially available preparations Compared with liposomes, it can improve the anti-tumor effect and reduce toxic and side effects; (5) The content of new impurities after preparing liposomes is small, which can effectively ensure the safety of the preparation and reduce development costs.

Description of the drawings

Figure 1 is a structural diagram of the cabazitaxel derivative (CTX-DA) whose base moiety is 2'-O-(4-diethylaminobutyryl) in Example 1 of the present invention.

Figure 2 is ^{a 1} H-NMR spectrum of the cabazitaxel derivative (CTX-DA) whose base moiety is 2'-O-(4-diethylaminobutyryl) in Example 1 of the present invention.

Figure 3 is a structural diagram of the cabazitaxel derivative (CTX-PA) whose base moiety is 2'-O-(N-methyl-piperazinylbutyryl) in Example 2 of the present invention.

Figure 4 is ^{a 1} H-NMR spectrum of the cabazitaxel derivative (CTX-PA) whose base moiety is 2'-O-(N-methyl-piperazinylbutyryl) in Example 2 of the present invention.

Detailed ways

The following examples are intended to further illustrate the invention without limiting it in any way.

Example 1

Synthesis of Cabazitaxel Derivative (CTX-DA) whose base part is 2’-O-(4-diethylaminobutyryl)

Dissolve diethylamine (12.5mL, 6.1g, 84mmol) and ethyl 4-bromobutyrate (3.16mL, 4.1g, 21mmol) in ethyl acetate, stir at room temperature overnight, and monitor the reaction progress with thin layer chromatography until bromine The chemical is completely consumed. After the reaction, the organic phase was washed with water, saturated sodium bicarbonate aqueous solution and sodium chloride aqueous solution, then dried over sodium sulfate and concentrated to obtain a slightly yellow oily substance, which was separated and purified by column chromatography to obtain ethyl 4-diethylaminobutyric acid. ester. Water (10 mL) and hydrochloric acid (HCl, 12 mL) were added to the ethyl 4-diethylaminobutyrate obtained above, and the mixture was heated to reflux at 110°C for 8 hours. The reaction mixture was then cooled to room temperature and concentrated until an oily liquid remained, then dissolved in distilled water and the concentration process was repeated twice to remove excess HCl to obtain a white solid. Dissolve the white solid in 4 mL of hot glacial acetic acid, let it stand at room temperature for 3 hours, and then transfer it to a 4°C refrigerator for 16 hours. The solid obtained was ground and washed three times with 20 mL of diethyl ether, and the supernatant diethyl ether was discarded. The precipitate was placed in a vacuum drying box and dried at 37°C for 2 h. The white solid 4-diethylaminobutyric acid (yield 44.9%) was obtained and used for further reaction.

Weigh 4-diethylaminobutyric acid (47.7mg, 0.3mmol), EDCI (57.5mg, 0.3mmol), and DMAP (3.7mg, 0.03mmol) and dissolve them in dichloromethane, stir for 30 minutes in an ice bath, and then Cabazitaxel (125.4 mg, 0.15 mmol) was added, the reaction system was raised to room temperature, and stirred overnight. The reaction progress was monitored by thin layer chromatography. After the reaction was completed, it was separated and purified by column chromatography to obtain the white powdery cabazitaxel derivative CTX. -DA (yield 68.3%, purity 99.3%), the entire reaction was carried out under N ₂ protection. Proton nuclear magnetic resonance spectroscopy was used to determine the structure of the compound in Example 1. The results are shown in Figure 1-2. The spectral analysis results are as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.02–7.95 (m, 2H), 7.88 (d, J = 8.1Hz, 1H), 7.74 (t, J = 7.3Hz, 1H), 7.66 (t, J＝7.5Hz,2H),7.49–7.32(m,4H),7.19(t,J＝7.3Hz,1H),5.83(t,J＝9.2Hz,1H),5.37(d,J＝7.1Hz, 1H),5.09(d,J＝8.0Hz,2H),4.99–4.92(m,1H),4.69(s,1H),3.75(dd,J＝10.6,6.6Hz,1H),3.59(d,J ＝7.1Hz,1H),3.28(s,3H),3.21(s,3H),3.09(s,4H),2.67–2.51(m,5H),2.25(s,3H),1.81(s,6H) ,1.58–1.12(m,21H),0.98(d,J=6.1Hz,6H).

Example 2

Synthesis of cabazitaxel derivative (CTX-PA) whose base part is 2'-O-(N-methyl-piperazinylbutyryl). Weigh: 4-(4-methyl-1-piperazinyl) ) Butyric acid (56 mg, 0.3 mmol), EDCI (57.5 mg, 0.3 mmol), and DMAP (3.7 mg, 0.03 mmol) were dissolved in dichloromethane, stirred in an ice bath for 30 min, and then cabazitaxel (125.4 mg, 0.15 mmol), the reaction system was raised to room temperature, and stirred overnight. The reaction progress was monitored by thin layer chromatography. After the reaction was completed, it was separated and purified by column chromatography to obtain the white powder cabazitaxel derivative CTX-PA (yield 64.44%, Purity 98.9%), the entire reaction was carried out under N ₂ protection, and hydrogen nuclear magnetic resonance spectroscopy was used to determine the structure of the compound in Example 1. The results are shown in Figure 3-4, and the spectrum analysis results are as follows:

¹ H NMR (400MHz, DMSO-d6) δ8.01–7.94(m,2H),7.90–7.80(m,1H),7.78–7.70(m,1H),7.70–7.59(m,2H),7.48– 7.27(m,4H),7.18(t,J＝7.3Hz,1H),5.81(t,J＝9.0Hz,1H),5.37(d,J＝7.1Hz,1H),5.06(q,J＝3.0 ,2.0Hz,2H),4.95(dd,J＝9.6,2.1Hz,1H),4.69(s,1H),3.75(dd,J＝10.6,6.5Hz,1H),3.61–3.55(m,1H) ,3.28(s,3H),3.21(s,3H),2.72–2.59(m,1H),2.49–2.02(m,18H),1.93–1.21(m,21H),0.97(d,J＝7.7Hz ,6H).

Example 3

Preparation of cabazitaxel derivative liposomes

The preparation method 1 of cabazitaxel derivative liposomes in this example includes the following steps:

(1) Preparation of blank liposomes: Weigh HSPC (hydrogenated soybean lecithin), Chol (cholesterol) and DSPE-mPEG ₂₀₀₀ (distearoylphosphatidylethanolamine- Polyethylene glycol 2000) was dissolved in an eggplant-shaped bottle with a small amount of chloroform, and the chloroform was evaporated under reduced pressure at 37°C to form a uniform film on the bottle wall. Add ammonium ion concentration of 650mM sucrose octasulfate triethylammonium salt solution (internal water phase), and hydrate at 65°C for 30 minutes;

Or weigh HSPC, Chol and DSPE-mPEG ₂₀₀₀ and dissolve them in absolute ethanol at a ratio of 3:1:0.05 (w/w). Use a syringe to absorb and inject the ammonium ion concentration of 650mM sucrose octasulfate trisulfate at 65°C. In the ethylammonium salt solution (internal water phase), stir for about 30 minutes to evaporate the ethanol. If the alcohol content is high, the alcohol can be further removed by rotary evaporation. And pass through polycarbonate membranes with pore diameters of 400nm, 200nm and 100nm ten times each at 65°C under nitrogen flow protection to obtain blank liposomes.

(2) Preparation of gradient blank liposomes: Pass the liposomes through an agarose gel column that has been pre-balanced with 300mM sucrose + 25mM histidine solution (external aqueous phase) at pH 6.5, and collect the light blue opalescence. A portion of the eluate was used to obtain blank liposomes with a gradient of sucrose octasulfate triethylammonium.

(3) Drug loading process: Slowly add CTX-DA or CTX-PA DMSO drug stock solution (20 mg/mL) into the blank liposome preparation, incubate in a 60°C water bath for 20 minutes to load the drug, and then take an ice bath after the incubation. After the drug loading was terminated, CTX-DA-LPs and CTX-PA-LPs were obtained. The encapsulation efficiencies were determined by high-performance liquid chromatography and were 99.66±1.07% and 99.86±2.35% respectively.

The preparation method 2 of cabazitaxel derivative liposomes in this example includes the following steps:

(1) Preparation of blank liposomes: Weigh HSPC, Chol and DSPE-mPEG ₂₀₀₀ in an eggplant-shaped bottle according to the ratio of 3:1:0.05 (w/w), dissolve with a small amount of chloroform, and evaporate under reduced pressure at 37°C Chloroform makes the film material form a uniform film on the bottle wall. Add 350mM ammonium sulfate solution (internal aqueous phase) and hydrate at 65°C for 30 minutes;

Or weigh HSPC, Chol and DSPE-mPEG ₂₀₀₀ and dissolve them in absolute ethanol at a ratio of 3:1:0.05 (w/w), suck it up with a syringe and inject it into a 350mM ammonium sulfate solution (internal aqueous phase) stirred at 65°C. , stir for about 30 minutes to evaporate the ethanol. If the alcohol content is high, the alcohol can be further removed by rotary evaporation. And pass through polycarbonate membranes with pore diameters of 400nm, 200nm and 100nm ten times each at 65°C under nitrogen flow protection to obtain blank liposomes.

(2) Preparation of gradient blank liposomes: Pass the liposomes through an agarose gel column that has been pre-equilibrated with 300mM sucrose solution (external aqueous phase), and collect the eluate containing the light blue opalescent part to obtain Blank liposomes from ammonium sulfate gradient.

(3) Drug loading process: Slowly add CTX-DA or CTX-PA DMSO drug stock solution (20 mg/mL) into the blank liposome preparation, incubate in a 60°C water bath for 20 minutes to load the drug, and then take an ice bath after the incubation. After the drug loading was terminated, CTX-DA and CTX-PA liposomes were obtained. The encapsulation efficiencies were measured by high-performance liquid chromatography, which were 93.82±1.74% and 87.36±4.77% respectively, and there were many impurities.

Example 4

Examination of related substances of cabazitaxel derivative liposomes CTX-DA-LPs, CTX-PA-LPs and CN1-LPs (principal component self-control method)

Take appropriate amounts of CTX-DA-LPs, CTX-PA-LPs and CN1-LPs respectively, add methanol to break the emulsification, blow nitrogen until the methanol evaporates, and add solvents with respective initial mobile phase proportions to a test concentration of 0.5 mg/mL. product solution. Precisely measure an appropriate amount of the test solution and add the solvent in the respective initial mobile phase proportions to prepare a reference solution with a concentration of approximately 5.0 μg/mL. Pass the test solution and reference solution through a 0.22 μm filter membrane, and accurately measure 20 μL of each subsequent filtrate for injection analysis. The results showed that CTX-DA-LPs did not contain unknown impurities, CTX-PA-LPs had unknown impurities of 0.48±0.05%, and CN1-LPs had unknown impurities of 0.88±0.09%. The unknown impurities of CTX-DA-LPs and CTX-PA-LPs are less than 0.5%, which both meet the requirements, while the unknown impurities of CN1-LPs are more than 0.5%, which exceeds the limit.

Table 1. Results of related substances of cabazitaxel derivative liposomes (CTX-DA-LPs, CTX-PA-LPs and CN1-LPs).

Example 5

Study on the cytotoxicity of liposomes derived from cabazitaxel in vitro

The cells were seeded into a 96-well plate at 2000 cells/well and placed in an incubator for 24 hours. After observing the cell adhesion under a microscope, the old culture medium was discarded. Seven preparations (CTX solution, CTX-DA solution, CN1 solution, CN1-LPs, CTX-DA-LPs and CTX-PA-LPs) with different molar concentrations were gradiently diluted with fresh culture medium, and 200 μL of drug-containing culture was added to each well. solution, 3 parallel wells for each concentration, blank culture solution was added to the zero adjustment well, and blank culture solution containing cells was added to the control well. Place the 96-well plate with the above drug-containing culture medium into a 37°C incubator and incubate for 48 hours, then take it out. Add 20 μL MTT to each well and incubate for 4 hours. Discard the culture medium. Add 200 μL DMSO to each well and shake for 10 minutes to fully absorb the formazan. Dissolve. Use a microplate reader to measure the absorbance of each well at 490 or 570 nm, and calculate the cell survival rate.

The results are shown in Table 2. Compared with CTX, the anti-tumor activities of CTX-DA and CTX-PA both showed a slight decrease, and there was not much difference between the two. However, compared with CN1, CTX-DA and CTX-PA had enhanced cytotoxicity. Compared with free cabazitaxel derivatives, the cytotoxicity of liposomes was reduced, and the cytotoxicity of CTX-DA-LPs and CTX-PA-LPs was stronger than that of CN1-LPs.

Table 2 Half-inhibition concentration (IC ₅₀ ) of cabazitaxel derivative liposomes (CTX-DA-LPs, CTX-PA-LPs and CN1-LPs).

Example 6

Animal efficacy experiments of cabazitaxel derivative liposomes

Take 100 μL of mouse prostate cancer cell (RM-1, 1×10 ⁸ cells/mL, PBS) suspension and inoculate it subcutaneously into the right back of male C57BL/6 mice to establish an RM-1 tumor-bearing mouse animal model. ^When the tumor volume of the tumor-bearing mice increased to 60-80 mm, the mice were randomly divided into 5 groups (5 mice in each group): (1) normal saline (control) group, (2) CTX-Sol group (6 mg/ kg), (3) CN1-LPs group (6 mg CTX/kg), (4) CTX-DA-LPs group (6 mg CTX/kg), (5) CTX-PA-LPs group (6 mg CTX/kg). Dosing was given every two days for a total of four doses. After administration, the mice were observed, weighed, and tumor volume measured. The mice were sacrificed on the tenth day after administration, and the tumors and major organs were removed for analysis and evaluation.

The results are shown in Table 3. The normal saline group was unable to inhibit tumor growth and the tumors grew rapidly during the administration period. CTX-Sol and CN1-LPs had weak anti-tumor effects. CTX-DA-LPs and CTX-PA-LPs showed ideal anti-tumor effects, among which CTX-PA-LPs had the most significant anti-tumor effect in vivo.

Table 3 Tumor volume of cabazitaxel derivative liposomes (CTX-DA-LPs, CTX-PA-LPs and CN1-LPs) after administration on the tenth day in in vivo anti-tumor experiments.

The above are only preferred embodiments of the present invention. It should be noted that those of ordinary skill in the art can also make several improvements and modifications without departing from the principles of the present invention. These improvements and modifications can also be made should be regarded as the protection scope of the present invention.

Claims (10)

1. A cabazitaxel derivative or a pharmaceutically acceptable salt thereof, having a structure represented by general formula (I) or (II): Among them, n=1~5. 2. The cabazitaxel derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the following compounds: 3. The cabazitaxel derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the pharmaceutically acceptable salt is a combination of the cabazitaxel derivative and a pharmaceutically acceptable salt. Salts formed from inorganic or organic acids. 4. The synthesis method of cabazitaxel derivatives according to any one of claims 1 to 3, characterized in that it includes the following steps: Under the catalysis of DMAP and EDCI, 4-diethylaminobutyric acid or 4-(4-methyl-1-piperazinyl)butyric acid and cabazitaxel are esterified and separated and purified. The whole reaction process is carried out in N ₂ under protection. 5. A liposome containing a cabazitaxel derivative, characterized in that the liposome contains the cabazitaxel derivative according to any one of claims 1 to 3, phospholipids, cholesterol, and PEGylated phospholipids. ; The weight ratio of the cabazitaxel derivative and total lipid is 0.10 to 0.50, and the total lipid is the sum of phospholipids, cholesterol and/or PEGylated phospholipids. 6. The preparation method of liposomes containing cabazitaxel derivatives according to claim 5, characterized in that it includes the following steps: (1) Weigh the membrane materials required to prepare liposomes, prepare liposomes using the film dispersion method, ethanol injection method or cross-flow mixing method, and squeeze them through polycarbonate membranes of different pore sizes in sequence to form nanoparticles. size of small unilamellar liposomes; (2) Replace the external water phase of the small single-chamber liposome obtained in step (1) to obtain a blank liposome with a gradient between the internal and external water phases of the liposome; (3) Add the organic solution of the cabazitaxel derivative to the gradient blank liposome obtained in step (2), and incubate to obtain the cabazitaxel derivative liposome preparation. 7. The preparation method according to claim 6, characterized in that, in the step (2), the internal aqueous phase solution is citric acid solution, ammonium sulfate solution, sulfobutyl ether-β-cyclodextrin Triethylammonium salt solution or sucrose octasulfate triethylammonium salt solution; the external aqueous phase solution is sucrose solution and histidine solution, HEPES buffer, phosphate buffer or acetate buffer. 8. The preparation method according to claim 6, wherein in step (3), the solvent of the organic solution is methanol, ethanol, acetone, tetrahydrofuran, acetonitrile or DMSO. 9. Use of the cabazitaxel derivative or a pharmaceutically acceptable salt thereof according to claim 1 or the liposome containing the cabazitaxel derivative according to claim 5 in the preparation of a drug delivery system. 10. Use of the cabazitaxel derivative or a pharmaceutically acceptable salt thereof according to claim 1 or the liposome containing the cabazitaxel derivative according to claim 5 in the preparation of anti-tumor drugs.