Stilbene glucoside and tanshinone IIA combined liposome and preparation method thereof

Abstract

The invention relates to a brain-targeted stilbene glucoside and tanshinone IIA loaded combined liposome for treating Alzheimer's disease and improving learning and memory ability disorders and a preparation method thereof. The composition comprises a modification factor Angiopep-2, a liposome carrier, stilbene glucoside and tanshinone IIA. Angiopep-2 is used as a target head, and a film dispersion and ammonium sulfate gradient method is adopted to prepare the liposome. According to the present invention, the problems of poor solubility and low bioavailability of stilbene glucoside and tanshinone IIA are solved, and the Angiopep-2 and the blood brain barrier (BBB) surface LRP-1 are subjected to specific recognition and are combined to enter the brain, such that the blood brain barrier transmittance of the drug is increased, and the targeting ability of the drug is improved. The traditional Chinese medicine composition has a good application prospect in the aspects of treating the Alzheimer's disease and improving learning and memory dysfunction.

Description

Technical Field

[0001] The present invention relates to a drug for treating Alzheimer's disease, and particularly to stilbene glucoside modified by Angiopep-2, tanshinone IIA liposome and a preparation method thereof. Background Art

[0002] Alzheimer's disease (AD), also known as senile dementia, is the most common type of dementia. As an irreversible neurodegenerative disease, the cause of AD is still unclear. Currently, the mainstream medical view is that some pathological features caused by Aβ precipitation, such as neuroinflammation, oxidative stress, and neuron damage, can promote the development of AD. At present, there is no effective cure method and drug for AD.

[0003] Stilbene glucoside mainly exists in Polygonum multiflorum Thunb. and is one of its main active ingredients. It is a polyhydroxy phenolic compound with good water solubility. Modern medical research has found that stilbene glucoside can inhibit Aβ plaque deposition and Tau protein aggregation, etc., and has a powerful anti-inflammatory effect. Tanshinone IIA generally comes from the dried roots and rhizomes of the plant Salvia miltiorrhiza Bunge, and has the effects of antioxidant and free radical scavenging, can protect hippocampal neurons and reduce apoptosis. Therefore, the two are combined to relieve the symptoms of AD from multiple aspects.

[0004] Although tanshinone IIA can effectively protect neurons, its poor water solubility, low absorption rate, fast metabolism, and short half-life lead to low bioavailability, which limits the efficacy of tanshinone IIA. Moreover, due to the existence of the blood-brain barrier, it hinders the drug from exerting its effect, and there are problems such as the drug cannot pass through the blood-brain barrier, poor bioavailability, and fast clearance rate.

[0005] As a new type of nano-drug delivery carrier, liposomes can encapsulate both hydrophilic and hydrophobic drugs at the same time to solve problems such as poor drug solubility, but the passive targeting efficiency of liposomes is relatively low.

[0006] Chinese Patent (CN116421647A) discloses a new application of a compound Danshen preparation, which has the effect of improving post-stroke cognitive impairment without dementia, but there are problems such as poor ability of the drug to penetrate the blood-brain barrier, difficulty in achieving the effect of targeted treatment, and low bioavailability. Summary of the Invention

[0007] The purpose of the present invention is to provide a combination liposome of stilbene glucoside and tanshinone IIA and a preparation method thereof to improve the solubility and bioavailability of the drug and increase the ability to target and penetrate the blood-brain barrier.

[0008] To achieve the above object, the present invention provides a combination liposome of stilbene glucoside and tanshinone IIA, which comprises stilbene glucoside, tanshinone IIA and a liposome carrier. Among them, the liposome carrier includes lecithin, cholesterol, DSPE-PEG2000, DSPE-PEG2000-NH2, DSPE-PEG2000-Ang, and also includes a modifying factor Angiopep-2. The mass ratio of lecithin to cholesterol is 5:1 to 10:1, preferably 8:1; the mass ratio of lecithin to stilbene glucoside is 30:1 to 100:1, preferably 80:1.

[0009] There are two technical solutions for the preparation method:

[0010] I. Angiopep-2 modified stilbene glucoside / tanshinone IIA liposome

[0011] (1) Dissolve lecithin, cholesterol, DSPE-PEG 2000 , DSPE-PEG 2000 -NH2 and tanshinone IIA in an appropriate amount of methanol;

[0012] (2) Under the condition of a 40 °C water bath, evaporate the above mixture under reduced pressure with a rotary evaporator until a film is formed;

[0013] (3) Absorb ammonium sulfate solution (250 mmol / L) and ultrasonically dissolve the film in an ultrasonic cleaner to obtain a liposome suspension;

[0014] (4) Transfer the above suspension to a cell crusher and ultrasonically crush it for 10 min, then pass it through a 0.22 μm microporous filter membrane twice to obtain tanshinone IIA liposome; the ultrasonic power of the cell crusher is 500 W to 700 W, preferably 600 W.

[0015] (5) Put the tanshinone IIA liposome into a dialysis bag with a cut-off relative molecular mass of 14,000 Da and place it in a beaker containing PBS solution for dialysis for 24 h (replace PBS every 8 h);

[0016] (6) Mix the solution with stilbene glucoside and shake it at 40 °C in a water bath for 20 min to obtain stilbene glucoside / tanshinone IIA liposome.

[0017] (7) Weigh Angiopep-2, dissolve it in the stilbene glucoside / tanshinone IIA liposome, and stir it at room temperature for 4 h to obtain Angiopep-2 modified stilbene glucoside / tanshinone IIA liposome.

[0018] II. DSPE-PEG 2000 -Ang modified stilbene glucoside / tanshinone IIA liposome

[0019] (1) Under stirring conditions, add the Angiopep-2 solution to the DSPE PEG 2000 NH2 solution. After the addition, continue the reaction for 4 h. After the reaction is completed, place the reaction solution in a dialysis bag for dialysis to obtain DSPE-PEG 2000 -Ang.

[0020] (2) Dissolve lecithin, cholesterol, DSPE-PEG 2000 , DSPE-PEG 2000 -Ang, and tanshinone IIA in an appropriate amount of methanol.

[0021] (3) Under the condition of a 40 °C water bath, use a rotary evaporator to evaporate the above mixture under reduced pressure until a film is formed.

[0022] (4) Pipette ammonium sulfate solution (250 mmol / L) and ultrasonically dissolve the film in an ultrasonic cleaner to obtain a liposome suspension.

[0023] (5) Transfer the above suspension to a cell disruptor and ultrasonically crush it for 10 min, then pass it through a 0.22 μm microporous filter membrane twice to obtain Ang-tanshinone IIA liposomes; the ultrasonic power of the cell disruptor is 500 W to 700 W, preferably 600 W.

[0024] (6) Place the Ang-tanshinone IIA liposomes in a dialysis bag with a cut-off relative molecular mass of 14,000 Da, and place it in a beaker containing PBS solution for dialysis for 24 h (replace PBS every 8 h);

[0025] (7) Mix the solution with the stilbene glucoside film and shake it at 40 °C in a water bath for 20 min to obtain Angiopep-2-modified stilbene glucoside / tanshinone IIA liposomes.

[0026] On the other hand, an Angiopep-2-modified stilbene glucoside / tanshinone IIA liposome prepared by the preparation method described in Scheme 1 or Scheme 2.

[0027] Furthermore, the use of the Angiopep-2-modified stilbene glucoside / tanshinone IIA liposome of the present invention in the preparation of various drugs, such as drugs for improving nerve function, drugs for improving learning and memory ability disorders, drugs for reducing the content and / or protein expression of IL-6 in the brain tissue, and drugs for reducing the content of the oxide MDA in the brain tissue, increasing the content of the antioxidant enzyme SOD, and antioxidative stress.

[0028] The present invention has the following characteristics compared with the prior art:

[0029] (1) The combination of stilbene glycoside and tanshinone IIA in the present invention can protect hippocampal neurons and reduce apoptosis, thereby alleviating AD symptoms from multiple targets.

[0030] (2) In view of the poor solubility of tanshinone IIA in the present invention, by loading stilbene glycoside and tanshinone IIA into the hydrophilic core and hydrophobic lipid bilayer of liposomes respectively, the solubility and bioavailability of the drug are increased, and the drug loading capacity is improved.

[0031] (3) Construct Angiopep-2 modified stilbene glycoside / tanshinone IIA liposomes to increase the ability of the drug to target and penetrate the blood-brain barrier, and enhance the uptake of the drug by brain cells.

[0032] The beneficial effects of the present invention: Since the brain-targeting short peptide Angiopep-2 is modified on the surface of liposomes to enhance the uptake of the drug by brain cells, Angiopep-2 modified stilbene glycoside / tanshinone IIA liposomes are constructed. Stilbene glycoside and tanshinone IIA are loaded into the hydrophilic core and hydrophobic lipid bilayer of liposomes respectively by the thin film dispersion method and ammonium sulfate gradient method, so as to increase the circulation time of the drug in vivo and solve the problems such as poor bioavailability. At the same time, Angiopep-2 on the surface of liposomes can be specifically recognized by the transport carrier on the blood-brain barrier, which can effectively mediate the drug to penetrate the blood-brain barrier and exert its efficacy, and improve the targeting ability of liposomes.

[0033] The following further describes the present invention with reference to specific examples. It should be understood that the specific examples described herein are only used to explain the present invention and are not used to limit the scope of the present invention. Description of the Drawings

[0034] Figure 1 To record the fluorescence intensity map of N2a cells in each well. It shows the drug targeting property.

[0035] Figure 2 It is a group of graphs of the results of behavioral experiments after drug administration to mice. It evaluates the drug efficacy.

[0036] Figure 3 It is a graph of biochemical indexes of mice. It evaluates the drug efficacy. Detailed Embodiments

[0037] All reagents are commercially available reagents, of analytical grade, and all excipients used are commercially available excipients, meeting the pharmaceutical, injectable standards or pharmacopoeia standards. The experimental methods in the following examples are all conventional methods unless otherwise specified.

[0038] Example 1 Components of Angiopep-2 Modified Stilbene Glycoside / Tanshinone IIA Combined Liposomes I

[0039] Table 1

[0040]

[0041] II Preparation Method

[0042] Preparation of Angiopep-2 modified stilbene glucoside / tanshinone IIA liposomes by thin film dispersion and ammonium sulfate gradient method, which includes the following steps: Dissolve lecithin (80 mg), cholesterol (10 mg), DSPE-PEG 2000 (2 mg), DSPE-PEG 2000 -NH2 (2 mg), and tanshinone IIA (1 mg) in an appropriate amount of methanol. Under the condition of a 40°C water bath, evaporate the above mixture under reduced pressure with a rotary evaporator until a thin film is formed. Absorb 5 ml of ammonium sulfate solution (250 mmol / L) and ultrasonically dissolve the thin film in an ultrasonic cleaner to obtain a liposome suspension. Transfer the above suspension to a cell crusher and ultrasonically crush it for 10 min with an ultrasonic power of 600 W. Filter through a 0.22 μm microporous membrane twice to obtain tanshinone IIA liposomes. Put the tanshinone IIA liposomes into a dialysis bag with a molecular weight cut-off of 14,000 Da and dialyze in a beaker containing PBS solution for 24 h (replace PBS every 8 h). Dissolve stilbene glucoside (1 mg) in methanol and evaporate it into a thin film at 40°C under reduced pressure and mix it with the dialyzed liposomes. Shake at 40°C in a water bath for 20 min to obtain stilbene glucoside / tanshinone IIA liposomes. Weigh Angiopep-2 (2 mg) and dissolve it in 5 ml of stilbene glucoside / tanshinone IIA liposomes and stir at room temperature for 4 h to obtain Angiopep-2 modified stilbene glucoside / tanshinone IIA liposomes.

[0043] Example 2 Components of Angiopep-2 modified stilbene glucoside and tanshinone IIA combined liposomes I

[0044] Table 2

[0045]

[0046] II Preparation Method

[0047] Preparation of Angiopep-2 modified stilbene glucoside / tanshinone IIA liposomes by thin film dispersion and ammonium sulfate gradient method, which includes the following steps: Dissolve lecithin (60 mg), cholesterol (6 mg), DSPE-PEG 2000 (2 mg), DSPE-PEG 2000-NH2 (2 mg) and tanshinone IIA (1 mg) were dissolved in an appropriate amount of methanol. The above mixture was evaporated under reduced pressure using a rotary evaporator in a 40 °C water bath until a thin film was formed. 5 ml of ammonium sulfate solution (250 mmol / L) was aspirated and the thin film was ultrasonically dissolved in an ultrasonic cleaner to obtain a liposome suspension. The above suspension was transferred to a cell disruptor and ultrasonically crushed for 10 min with an ultrasonic power of 500 W, and then passed through a 0.22 μm microporous filter membrane twice to obtain tanshinone IIA liposomes. The tanshinone IIA liposomes were placed in a dialysis bag with a molecular weight cut-off of 14,000 Da and dialyzed in a beaker containing PBS solution for 24 h (the PBS was changed every 8 h). Stilbene glucoside (1 mg) was dissolved in methanol and evaporated to form a thin film under reduced pressure at 40 °C and then mixed with the dialyzed liposomes. The mixture was shaken at 40 °C in a water bath for 20 min to obtain stilbene glucoside / tanshinone IIA liposomes. Angiopep-2 (2 mg) was weighed and dissolved in 5 ml of stilbene glucoside / tanshinone IIA liposomes and stirred at room temperature for 4 h to obtain Angiopep-2-modified stilbene glucoside / tanshinone IIA liposomes.

[0048] Example 3 Use the prepared DSPE-PEG 2000 -Ang to modify the first component of stilbene glucoside and tanshinone IIA liposomes

[0049] Table 3

[0050]

[0051] II Preparation method

[0052] Under stirring conditions, the Angiopep-2 solution was added to the DSPE PEG NH2 solution. After the addition, the reaction continued for 4 h. After the reaction was completed, the reaction solution was placed in a dialysis bag for dialysis to obtain DSPE-PEG 2000 -Ang. Lecithin (80 mg), cholesterol (10 mg), DSPE-PEG 2000 (2 mg), DSPE-PEG 2000- Ang (2 mg) and tanshinone IIA (1 mg) were dissolved in an appropriate amount of methanol. The above mixture was evaporated under reduced pressure using a rotary evaporator in a 40 °C water bath until a thin film was formed. 5 ml of ammonium sulfate solution (250 mmol / L) was aspirated and the thin film was ultrasonically dissolved in an ultrasonic cleaner to obtain a liposome suspension. The above suspension was transferred to a cell crusher and ultrasonically crushed for 10 min with an ultrasonic power of 600 W, and then passed through a 0.22 μm microporous filter membrane twice to obtain Ang - tanshinone IIA liposomes. The Ang - tanshinone IIA liposomes were placed in a dialysis bag with a molecular weight cut-off of 14,000 Da and dialyzed in a beaker containing PBS solution for 24 h (PBS was replaced every 8 h). Stilbene glucoside (1 mg) was dissolved in methanol and evaporated under reduced pressure at 40 °C to form a thin film, which was then mixed with the dialyzed liposomes. The mixture was shaken at 40 °C in a water bath for 20 min to obtain Angiopep - 2 - modified stilbene glucoside / tanshinone IIA liposomes.

[0053] Example 4 Preparation of DSPE - PEG 2000 - Ang - modified stilbene glucoside and tanshinone IIA combined liposomes

[0054] Component I

[0055] Table 4

[0056]

[0057] II Preparation method

[0058] Under stirring conditions, the Angiopep - 2 solution was added to the DSPE - PEG - NH2 solution. After addition, the reaction continued for 4 h. After the reaction was completed, the reaction solution was placed in a dialysis bag for dialysis to obtain DSPE - PEG 2000 - Ang. Lecithin (60 mg), cholesterol (6 mg), DSPE - PEG 2000 (2 mg), DSPE - PEG 2000- Ang (2 mg) and tanshinone IIA (1 mg) were dissolved in an appropriate amount of methanol. The above mixture was evaporated under reduced pressure using a rotary evaporator in a 40 °C water bath until a thin film was formed. 5 ml of ammonium sulfate solution (250 mmol / L) was aspirated and the thin film was ultrasonically dissolved in an ultrasonic cleaner to obtain a liposome suspension. The above suspension was transferred to a cell disruptor and ultrasonically pulverized for 10 min with an ultrasonic power of 500 W, and then passed through a 0.22 μm microporous filter membrane twice to obtain Ang - tanshinone IIA liposomes. The Ang - tanshinone IIA liposomes were placed in a dialysis bag with a cut - off relative molecular mass of 14,000 Da and dialyzed in a beaker containing PBS solution for 24 h (PBS was changed every 8 h). Stilbene glucoside (1 mg) was dissolved in methanol and evaporated under reduced pressure at 40 °C to form a thin film, which was then mixed with the dialyzed liposomes. The mixture was shaken at 40 °C in a water bath for 20 min to obtain Angiopep - 2 - modified stilbene glucoside / tanshinone IIA liposomes.

[0059] Example 5 Experimental design for the physicochemical properties of Angiopep - 2 - modified stilbene glucoside and tanshinone IIA combined liposomes:

[0060] Prepare Angiopep - 2 - modified stilbene glucoside and tanshinone IIA combined liposomes according to the preparation method in Example 1 above; in addition, prepare blank liposomes according to the preparation method in Example 1 above, except that stilbene glucoside and tanshinone IIA are not added, and other operations are the same as those in the preparation method of Example 1. The particle size and Zeta potential of the liposomes were measured using a laser particle size analyzer, and the average value of three measurement results was taken each time; and the encapsulation efficiency of Angiopep - 2 - modified stilbene glucoside / tanshinone IIA liposomes within 30 days was tested, as shown in Table 5 and Table 6.

[0061] Table 5

[0062]

[0063] Table 6

[0064]

[0065] The particle size of the blank liposomes prepared in this study was about 100 nm. After being modified with Angiopep - 2, the particle size increased slightly. The PDI of the liposomes was about 0.2, indicating that the microparticles of each liposome were monodisperse and the stability of the liposomes was strong. The Zeta potential was about - 2.7 mV; and within 30 days, the encapsulation efficiency of the prepared liposomes was above 80%, indicating that the prepared liposomes had good stability.

[0066] Example 6 Investigation on the targeting of Angiopep - 2 - modified liposomes to N2a cells

[0067] Experimental design:

[0068] According to the preparation method of Example 1 above, after the liposomes were dialyzed for 24 h, the fluorescent probe daunorubicin for film formation was added, and the mixture was shaken in a water bath at 400 °C for 20 min to obtain daunorubicin liposomes (DNR-Lip). An amount of Angiopep-2 was weighed and dissolved in the daunorubicin liposomes, and the mixture was stirred at room temperature for 4 h to obtain Angiopep-2-modified daunorubicin liposomes (Ang-DNR-Lip). According to the preparation method of Example 1 above, except that daunorubicin was not added, blank liposomes (Blank-Lip) were obtained. An appropriate amount of daunorubicin was weighed and dissolved in water to obtain a free daunorubicin solution (Free DNR). The administration times were 1, 2, and 4 h. The above solutions were added respectively, and the fluorescence intensities of N2a cells in each well were recorded, as Figure 1 shown.

[0069] In the investigation of the targeting ability to N2a cells, the uptake ability of the liposomes modified with Angiopep-2 to N2a cells was significantly improved, indicating that the targeting ability of the liposomes was enhanced after modification, suggesting that the drug delivery system provided by the present invention can significantly improve the targeting of drugs, thereby enhancing the effect of treating Alzheimer's disease across the blood-brain barrier.

[0070] Example 7 Experimental design for the pharmacodynamic evaluation of Angiopep-2-modified stilbene glucoside / tanshinone IIA combined liposomes:

[0071] A transgenic mouse model of learning and memory impairment was established. The mice were randomly divided into a model group, a high-dose group of Ang-stilbene glucoside / tanshinone IIA-Lips (20 mg / kg), a medium-dose group of Ang-stilbene glucoside / tanshinone

[0072] IIA-Lips (10 mg / kg), a low-dose group of Ang-stilbene glucoside / tanshinone IIA-Lips (5 mg / kg), and ordinary mice were used as a blank control group, with 10 mice in each group. After the mice in each group were administered, the results of the step-down test and the Morris water maze test in the behavioral experiments were studied and analyzed, as Figure 2 shown. After the experiment, the mice were sacrificed and the biochemical indexes were analyzed for pharmacodynamic evaluation, as shown in Figure 3 .

[0073] After administration of Angiopep-2 modified stilbene glucoside / tanshinone IIA liposomes, it was found that: the number of errors of mice in the step-down test was significantly reduced, and the step-down latency was significantly increased; in the Morris water maze test, the escape latency of mice was significantly shortened, and the number of times of crossing the platform was significantly increased. Analysis of the levels of SOD, MDA, and IL-6 in the brains of mice showed that the levels of oxidative stress and inflammation in the brains of mice were significantly reduced after administration. It shows that the Angiopep-2 modified stilbene glucoside / tanshinone IIA liposomes provided by the present invention can significantly improve the learning and memory ability of model mice, and its mechanism may be related to antioxidant stress and reducing the levels of inflammatory factors. Among them, the medium-dose group (10 mg / kg) of Ang-stilbene glucoside / tanshinone IIA-Lips had the most significant effect.

[0074] In summary, the drug combination, dosage form, formulation, and preparation method provided by the present invention have successfully improved the solubility of stilbene glucoside and tanshinone IIA, solved the problem of their low bioavailability, improved their ability to target and cross the blood-brain barrier, and can effectively improve the learning and memory ability disorder of AD patients.

Claims

1. A combination liposome of stilbene glycoside and tanshinone IIA, comprising stilbene glycoside, tanshinone IIA and a liposome carrier, wherein the liposome carrier comprises lecithin, cholesterol and DSPE-PEG 2000 , DSPE-PEG 2000 -NH2, DSPE-PEG 2000 -Ang; characterized in that The combined liposome also includes a modification factor, Angiopep-2, and the mass ratio of lecithin to cholesterol is 5:1 to 10:1; the mass ratio of lecithin to stilbene glucoside is 30:1 to 100:

1.

2. The combination liposome of stilbene glycoside and tanshinone IIA according to claim 1, characterized in that The mass ratio of lecithin to cholesterol is 8:1; the mass ratio of lecithin to stilbene glucoside is 80:

1.

3. The preparation method of the combination liposome of stilbene glycoside and tanshinone IIA according to claim 1 or 2, comprising the following steps: 1) Dissolve lecithin, cholesterol, DSPE-PEG 2000 , DSPE-PEG 2000 -NH2 and tanshinone IIA in a solvent and mix evenly; 2) Under the condition of a 40°C water bath, evaporate the solvent in the mixture obtained in step 1) under reduced pressure to form a film; 3) Hydrate the film mixture in step 2) in an ammonium sulfate solution to obtain a liposome suspension; 4) Ultrasonically crush the liposome suspension in step 3) and filter it through a microporous membrane to obtain tanshinone IIA liposomes; 5) Put the tanshinone IIA liposomes in step 4) into a dialysis bag and dialyze for 24 h; 6) Mix the dialysate in step 5) with a stilbene glycoside film, and shake it at 40°C in a water bath to obtain stilbene glycoside / tanshinone IIA liposomes; 7) Weigh Angiopep-2, dissolve it in the stilbene glycoside / tanshinone IIA liposomes in step 6), and stir at room temperature to obtain Angiopep-2-modified stilbene glycoside / tanshinone IIA liposomes.

4. The preparation method of the combination liposome of stilbene glycoside and tanshinone IIA according to claim 1 or 2, comprising the following steps: 1) Add an Angiopep-2 solution to a DSPE PEG NH2 solution under stirring conditions, continue the reaction after adding, and place the reaction solution in a dialysis bag for dialysis after the reaction is completed to obtain DSPE-PEG 2000 -Ang; 2) Dissolve lecithin, cholesterol, DSPE-PEG 2000 , the DSPE-PEG obtained in step 1 2000 -Ang and tanshinone IIA in a solvent and mix evenly; 3) Under the condition of a 40°C water bath, evaporate the solvent in the mixture obtained in step 3.2) under reduced pressure to form a film; 4) Hydrate the thin film mixture from step 3) in an ammonium sulfate solution to obtain a liposome suspension; 5) Ultrasonically crush the liposome suspension from step 4) and filter it through a microporous membrane to obtain Ang-Tanshinone IIA liposomes; 6) Place the Ang-Tanshinone IIA liposomes from step 5) into a dialysis bag and dialyze for 24 h; 7) Mix the dialysate from step 5) with a thin film of stilbene glycoside, and shake it under a water bath condition at 40 °C to obtain Angiopep-2 modified stilbene glycoside / Tanshinone IIA liposomes.

5. The method for preparing the stilbene glycoside and Tanshinone IIA combined liposomes as claimed in claim 3, wherein In step 4), the ultrasonic power of the ultrasonic cell disruptor is 500W to 700W.

6. The method for preparing the stilbene glycoside and Tanshinone IIA combined liposomes as claimed in claim 5, wherein In step 4), the ultrasonic power of the ultrasonic cell disruptor is 600W.

7. The method for preparing the stilbene glycoside and Tanshinone IIA combined liposomes as claimed in claim 4, wherein In step 5), the ultrasonic power of the ultrasonic cell disruptor is 500W to 700W.

8. The method for preparing the stilbene glycoside and Tanshinone IIA combined liposomes as claimed in claim 7, wherein In step 5), the ultrasonic power of the ultrasonic cell disruptor is 600W.

9. The application of the stilbene glycoside and Tanshinone IIA combined liposomes as claimed in claim 1 or 2 in the preparation of a drug, wherein It is at least one of a1) to a5): a1) Preparing a drug for treating Alzheimer's disease; a2) Preparing a drug for improving nerve function; a3) Preparing a drug for improving learning and memory ability disorders; a4) Preparing a drug for reducing the content and / or protein expression of IL-6 in the brain tissue; a5) Preparing a drug for reducing the content of oxide MDA in the brain tissue, increasing the content of antioxidant enzyme SOD, and antioxidating stress.

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